CURRENT Diagnosis and Treatment Pediatrics, (Current Pediatric Diagnosis & Treatment) 22nd Edition

37. Genetics & Dysmorphology

Margarita Saenz, MD

Anne Chun-Hui Tsai, MD, MSc

David K. Manchester, MD

Ellen R. Elias, MD

Genetics is an exciting and rapidly evolving field that has significant relevance to the understanding of human embryology, physiology, and disease processes. Tremendous advances in molecular biology and biochemistry are allowing more comprehensive understanding of mechanisms inherent in genetic disorders as well as improved diagnostic tests and management options. Many of the newer technologies and terms may be unfamiliar to the clinician in practice. Thus, the topics in the first part of the chapter serve as an introduction and review of the basic principles of genetics, including basic knowledge of cytogenetics and molecular biology. The second part discusses principles of inherited human disorders, encompassing different genetic mechanisms as well as how to obtain a genetic history and pedigree. Topics in the third part of the chapter focus on applied clinical genetics which include dysmorphology, teratology, and perinatology. Common clinical disorders with descriptions of the diseases and discussion of their pathogenesis, diagnosis, and management are also included.



Cytogenetics is the study of genetics at the chromosome level. Chromosomal anomalies occur in 0.4% of all live births and are a common cause of intellectual disabilities (formerly called mental retardation) and congenital anomalies. The prevalence of chromosomal anomalies is much higher among spontaneous abortions and stillbirths.


Human chromosomes consist of DNA (the blueprint of genetic material), specific proteins forming the backbone of the chromosome (called histones), and other chromatin structural and interactive proteins. Chromosomes contain most of the genetic information necessary for growth and differentiation. The nuclei of all normal human cells, with the exception of gametes, contain 46 chromosomes, consisting of 23 pairs (Figure 37–1). Of these, 22 pairs are called autosomes. They are numbered according to their size; chromosome 1 is the largest and chromosome 22 the smallest. In addition, there are two sex chromosomes: two X chromosomes in females and one X and one Y chromosome in males. The two members of a chromosome pair are called homologous chromosomes. One homolog of each chromosome pair is maternal in origin (from the egg); the second is paternal (from the sperm). The egg and sperm each contain 23 chromosomes (haploid cells). During formation of the zygote, they fuse into a cell with 46 chromosomes (diploid cell).


image Figure 37–1. Normal male and female human karyotype. (Courtesy of the Colorado Genetics Laboratory.)

Cell Division

Cells undergo cycles of growth and division that are controlled according to their needs and functions.

Mitosis is a kind of cell division, occurring in stages, during which DNA replication takes place and two daughter cells, genetically identical to the original parent cells, are formed. This cell division is typical for all somatic cells (cells other than the sperm or egg, which are called germline cells). There are four phases of mitosis: interphase, prophase, metaphase, and anaphase. In interphase, chromosomes are long, thin, and nonvisible. At this time, the genetic material is replicated. In prophase, the chromosomes are more condensed. During metaphase (the phase following DNA replication but preceding cell division), individual chromosomes can be visualized. Each arm consists of two identical parts, called chromatids. Chromatids of the same chromosome are called sister chromatids. In anaphase, the genetic material is separated into two cells.

Meiosis is a kind of cell division during which eggs and sperm are formed; it is a cell division limited to gametes. During meiosis, three unique processes take place:

1. Crossing over of genetic material between two homologous chromosomes (this recombination, or exchange of genetic material increases the viability of human beings).

2. Random assortment of maternally and paternally derived homologous chromosomes into the daughter cells.

3. Two cell divisions, the first of which is a reduction division—that is, separation between the homologous chromosomes. The second meiotic division is like mitosis, separating two sister chromatids into two daughter cells.

Chromosome Preparation & Analysis

Chromosome structure is visible only during mitosis, most often achieved in the laboratory by stimulating a blood lymphocyte culture with a mitogen for 3 days. Other tissues used for this purpose include skin, products of conception, cartilage, and bone marrow. Chorionic villi or amniocytes are used for prenatal diagnosis. Spontaneously dividing cells without a mitogen are present in bone marrow, and historically, bone marrow biopsy was done when immediate identification of a patient’s chromosome constitution was necessary for appropriate management (eg, to rule out trisomy 13 in a newborn with a complex congenital heart disease). However, this invasive test has been replaced by the availability of the FISH technique (see the following discussion).

Cells processed for routine chromosome analysis are stained on glass slides to yield a light-and-dark band pattern across the arms of the chromosomes (see Figure 37–1). This band pattern is characteristic and reproducible for each chromosome, allowing the chromosomes to be identified. Using different staining techniques, different banding patterns result: G, Q, and R banding. The most commonly used is G banding. The layout of chromosomes on a sheet of paper in a predetermined order is called a karyotype. High-resolution chromosome analysis is the study of more elongated chromosomes in prometaphase. Although the bands can be visualized in greater detail, subtle chromosomal rearrangements less than 5 million base pair (5 Mb) can still be missed.

Fluorescence in situ hybridization (FISH) is a powerful technique that labels a known chromosome sequence with DNA probes attached to fluorescent dyes, thus enabling visualization of specific regions of chromosomes by fluorescent microscopy. There are many different kinds of probes, including paint probes (a mixture of sequences throughout one chromosome), sequence-specific probes, centromere probes, and telomere probes. A cocktail of differently colored probes, one color for each chromosome, called multicolor FISH, or M-FISH, can detect complex rearrangements between chromosomes. FISH can detect submicroscopic structural rearrangements undetectable by classic cytogenetic techniques and can identify marker chromosomes. (For pictures of FISH studies, go to

Interphase FISH allows noncultured cells (lymphocytes, amniocytes) to be rapidly screened for numerical abnormalities such as trisomy 13, 18, or 21, and sex chromosome anomalies. However, because of the possible background or contamination of the signal, the abnormality must be confirmed by conventional chromosome analysis in aneuploidy cases. Six hundred–cell FISH can also be used to ascertain mosaicism.

Chromosomal Microarray Analysis

Advances in computer technology and bioinformatics have led to the development of new genetic testing using comparative genomic hybridization with microarray technique. This technique allows detection of very small genetic imbalances anywhere in the genome. Its usefulness has been well documented in cancer research and more recently in assessing small chromosomal rearrangements. In particular, it has been used to detect interstitial and subtelomeric submicroscopic imbalances, to characterize their size at the molecular level, and to define the breakpoints of translocations. Clinically available arrays include (1) 0.5- to 1-Mb bacterial artificial chromosome arrays that can pick up rearrangements greater than 0.5 Mb, (2) oligonucleotide arrays using special probes that can pick up changes as small as 3 Kb, and (3) single nucleotide polymorphism (SNP) arrays, which are used more widely in research settings. Although this powerful new technology can identify extremely subtle DNA rearrangements and changes, many human polymorphisms, including small deletions and duplications, are not totally understood. Therefore, special caution and parental studies are often required in interpreting the results.

Stankiewicz P, Beaudet AL: Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev 2007 Jun;17(3):182–192 [Epub 2007 Apr 30] [Review] [PMID: 17467974].

Van den Veyver IB et al: Clinical use of array comparative genomic hybridization (aCGH) for prenatal diagnosis in 300 cases. Prenat Diagn 2009 Jan;29(1):29–39 [PMID: 19012303].

Chromosome Nomenclature

Visible under the microscope is a constriction site on the chromosome called the centromere, which separates the chromosome into two arms: p, for petite, refers to the short arm, and q, the letter following p, refers to the long arm. Each arm is further subdivided into numbered bands visible using different staining techniques. Centromeres are positioned at different sites on different chromosomes and are used to differentiate the chromosome structures seen during mitosis as metacentric (p arm and q arm of almost equal size), submetacentric (p arm shorter than q arm), and acrocentric (almost no p arm). The use of named chromosome arms and bands provides a universal method of chromosome description. Common symbols include del (deletion), dup (duplication), inv (inversion), ish (in situ hybridization), i (isochromosome), pat (paternal origin), mat (maternal origin), and r (ring chromosome). These terms are further defined in the section Chromosomal Abnormalities.

Chromosomal Abnormalities

There are two types of chromosomal anomalies: numerical and structural.

A. Abnormalities of Chromosomal Number

When a human cell has 23 chromosomes, such as human ova or sperm, it is in the haploid state (n). After conception, in cells other than the reproductive cells, 46 chromosomes are present in the diploid state (2n). Any number that is an exact multiple of the haploid number—for example, 46(2n), 69(3n), or 92(4n)—is referred to as euploid. Polyploid cells are those that contain any number other than the usual diploid number of chromosomes. Polyploid conceptions are usually not viable except in a “mosaic state,” with the presence of more than one cell line in the body (see later text for details).

Cells deviating from the multiple of the haploid number are called aneuploid, meaning not euploid, indicating an abnormal number of chromosomes. Trisomy, an example of aneuploidy, is the presence of three of a particular chromosome rather than two. It results from unequal division, called nondisjunction, of chromosomes into daughter cells. Trisomies are the most common numerical chromosomal anomalies found in humans (eg, trisomy 21 [Down syndrome], trisomy 18, and trisomy 13). Monosomies, the presence of only one member of a chromosome pair, may be complete or partial. Complete monosomies may result from nondisjunction or anaphase lag. All complete autosomal monosomies appear to be lethal early in development and only survive in mosaic forms. Sex chromosome monosomy, however, can be viable.

B. Abnormalities of Chromosomal Structure

Many different types of structural chromosomal anomalies exist. Figure 37–2 displays the formal nomenclature as well as the ideogram demonstrating chromosomal anomalies. In clinical context, the sign (+) or (−) preceding the chromosome number indicates increased or decreased number, respectively, of that particular whole chromosome in a cell. For example, 47, XY+21 designates a male with three copies of chromosome 21. The sign (+) or (−) after the chromosome number signifies extra material or missing material, respectively, on one of the arms of the chromosome. For example, 46, XX, 8q− denotes a deletion on the long arm of chromosome 8. Detailed nomenclature, such as 8q11, is required to further demonstrate a specific missing region so that genetic counseling can be provided.


image Figure 37–2. Examples of structural chromosomal abnormalities: deletion, duplication, inversion, ring chromosome, translocation, and insertion.

1. Deletion (del) (see Figure 37–2A)—This refers to an absence of normal chromosomal material. It may be terminal (at the end of a chromosome) or interstitial (within a chromosome). The missing part is described using the code “del,” followed by the number of the chromosome involved in parentheses, and a description of the missing region of that chromosome, also in parentheses, for example, 46, XX, del(1) (p36.3). This chromosome nomenclature describes the loss of genetic material from band 36.3 of the short arm of chromosome 1, which results in 1p36.3 deletion syndrome. Some more common deletions result in clinically recognizable conditions associated with intellectual disabilities and characteristic facial features. (See descriptions of common genetic disorders caused by chromosomal deletions later in the chapter.)

2. Duplication (dup) (see Figure 37–2B)—An extra copy of a chromosomal segment can be tandem (genetic material present in the original direction) or inverted (genetic material present in the opposite direction). A well-described duplication of chromosome 22q11 causes Cat eye syndrome, resulting in iris coloboma and anal or ear anomalies.

3. Inversion (inv) (see Figure 37–2C)—In this aberration, a rearranged section of a chromosome is inverted. It can be paracentric (not involving the centromere) or pericentric (involving the centromere).

4. Ring chromosome (r) (see Figure 37–2D)—Deletion of the normal telomeres (and possibly other subtelomeric sequences) leads to subsequent fusion of both ends to form a circular chromosome. Ring chromosomal anomalies often cause growth retardation and intellectual disability.

5. Translocation (trans) (see Figure 37–2E)—This interchromosomal rearrangement of genetic material may be balanced (the cell has a normal content of genetic material arranged in a structurally abnormal way) or unbalanced (the cell has gained or lost genetic material as a result of chromosomal interchange). Balanced translocations may further be described as reciprocal, the exchange of genetic material between two nonhomologous chromosomes, or Robertsonian, the fusion of two acrocentric chromosomes.

6. Insertion (ins) (see Figure 37–2F)—Breakage within a chromosome at two points and incorporation of another piece of chromosomal material is called insertion. This requires three breakpoints and may occur between two chromosomes or within the same chromosome. The clinical presentation or phenotype depends on the origin of the inserted materials.

C. Sex Chromosomal Anomalies

Abnormalities involving sex chromosomes, including aneuploidy and mosaicism, are relatively common in the general population. The most common sex chromosome anomalies include 45,X (Turner syndrome), 47,XXX,47,XXY (Klinefelter syndrome), 47,XYY, and different mosaic states. (See later text for clinical discussion.)

D. Mosaicism

Mosaicism is the presence of two or more different chromosome constitutions in different cells of the same individual. For example, a patient may have some cells with 47 chromosomes and others with 46 chromosomes (46,XX/47,XX,+21 indicates mosaicism for trisomy 21; similarly, 45,X/46,XX/47,XXX indicates mosaicism for a monosomy and a trisomy X). Mosaicism should be suspected if clinical symptoms are milder than expected in a nonmosaic patient with the same chromosomal abnormality, or if the patient’s skin shows unusual pigmentation. The prognosis is frequently better for a patient with mosaicism than for one with a corresponding chromosomal abnormality without mosaicism. In general, the smaller the proportion of the abnormal cell line, the better the prognosis. In the same patient, however, the proportion of normal and abnormal cells in various tissues, such as skin, brain, internal organs, and peripheral blood, may be significantly different. Therefore, the prognosis for a patient with chromosomal mosaicism can seldom be assessed reliably based on the karyotype in peripheral blood alone.

E. Uniparental Disomy

Under normal circumstances, one member of each homologous pair of chromosomes is of maternal origin from the egg and the other is of paternal origin from the sperm (Figure 37–3A). In uniparental disomy (UPD), both copies of a particular chromosome pair originate from the same parent. If UPD is caused by an error in the first meiotic division, both homologous chromosomes of that parent will be present in the gamete—a phenomenon called heterodisomy (Figure 37–3B). If the disomy is caused by an error in the second meiotic division, two copies of the same chromosome will be present through the mechanism of rescue, duplication, and complementation (Figure 37–3C through 37–3E)—a phenomenon called isodisomy. Isodisomy may also occur as a postfertilization error (Figure 37–3F).


image Figure 37–3. The assortment of homologous chromosomes during normal gametogenesis and uniparental disomy. A: Fertilization of normal gametes. B: Heterodisomy by trisomy rescue. C: Isodisomy by trisomy rescue. D: Isodisomy by monosomy rescue (mitotic duplication). E: Gamete complementation. F: Postfertilization error.

A chromosomal analysis would not reveal an abnormality, but DNA analysis would reveal that the child inherited two copies of DNA of a particular chromosome from one parent without the contribution from the other parent. Possible mechanisms for the adverse effects of UPD include homozygosity for deleterious recessive genes and the consequences of imprinting (see discussion in the Imprinting section, later). It is suspected that UPD of some chromosomes is lethal.

UPD has been documented for certain human chromosomes, including chromosomes 7, 11, 15, and X, and has been found in patients with Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes (BWS). In addition, cystic fibrosis with only one carrier parent (caused by maternal isodisomy) has been reported. UPD may cause severe prenatal and postnatal growth retardation.

F. Contiguous Gene Syndromes

Contiguous gene syndromes result when a deletion causes the loss of genes adjacent to each other on a chromosome. Although many genes may be missing, the deletion may still be too small to be detected by routine karyotype. Therefore, contiguous gene syndromes are sometimes called “microdeletion syndromes.” The genes involved in these syndromes are related only through their linear placement on the same chromosome segments and may not influence each other’s functions directly. Table 37–1 lists examples of some currently known contiguous gene syndromes and their associated chromosomal abnormalities. These deletions may be familial (passed on by a parent) or may occur de novo. The deletions may be diagnosed by high-resolution chromosome analysis in some affected individuals, or may be submicroscopic and detectable only with FISH or DNA analysis.

Table 37–1. Examples of common contiguous gene syndromes.


G. Chromosome Fragility

Disorders of DNA repair are associated with chromosomal breakage and death of somatic cells. Most are autosomal recessive. Phenotypes vary considerably (Table 37–2). As a group these disorders typically affect growth and CNS development. They show increased toxicity to mutagen exposures in vitro. Photosensitivity, increased cancer risks, and premature aging are prevalent. Treatment is largely supportive and focuses on surveillance for complications but in at least one disorder, Fanconi anemia, bone marrow transplant can be beneficial. See for excellent reviews of these disorders.

Table 37–2. DNA repair disorders.


H. Chromosomal Abnormalities in Cancer

Numerical and structural chromosomal abnormalities are often identified in hematopoietic and solid-tumor neoplasms in individuals with otherwise normal chromosomes. These cytogenetic abnormalities have been categorized as primary and secondary. In primary abnormalities, their presence is necessary for initiation of the cancer; an example is 13q− in retinoblastoma. Secondary abnormalities appear de novo in somatic cells only after the cancer has developed, for example, Philadelphia chromosome, t(9;22)(q34;q11), in acute and chronic myeloid leukemia. Primary and secondary chromosomal abnormalities are specific for particular neoplasms and can be used for diagnosis or prognosis. For example, the presence of the Philadelphia chromosome is a good prognostic sign in chronic myelogenous leukemia and indicates a poor prognosis in acute lymphoblastic leukemia. The sites of chromosome breaks coincide with the known loci of oncogenes and antioncogenes.


Advances in molecular biology have revolutionized human genetics, as they allow for the localization, isolation, and characterization of genes that encode protein sequences. As the Human Genome Project has moved into the postcloning era, the function of gene products and their interaction with one another has become the main theme of molecular genetics. Molecular genetics can help explain the complex underlying biology involved in many human diseases.

Molecular diagnosis can be achieved using the following technology: Southern blot analysis is the molecular genetic technique used to look for changes in genomic DNA. A similar technique, called Northern blot analysis, is used to look for RNA abnormalities. Western blot analysis is used to look for protein changes. The polymerase chain reaction (PCR) replicates fragments of DNA between predetermined primers so that sufficient DNA is obtained for characterization or sequencing in the space of a few hours. Quantitative fluorescent PCR combines PCR amplification with fluorescent DNA probes to provide real-time replication and rapid determination of gene copy number and dosage effects. DNA sequencing is the process of determining the nucleotide order of a given DNA fragment. A new generation of sequencing technologies has provided unprecedented opportunities for high-throughput functional genomic research. To date, these technologies have been applied in a variety of contexts, including whole-genome sequencing which can be performed in 1 week; however, the interpretation of the sequencing requires more bioinformatics information. National Institutes of Health (NIH) predicted the eventual cost for whole genome can be reduced to $1000.

ten Bosch JR, Grody WW: Keeping up with the next generation: massively parallel sequencing in clinical diagnostics. J Mol Diagn 2008 Nov;10(6):484–492 [PMID: 18832462].

Molecular Biology in Clinical Genetics & Genetic Diagnosis

Genetic diagnosis can be performed by direct detection of a mutant gene or by indirect methods. Direct detection is possible only when the gene causing the disease and the nature of the mutation are known. The advantage of a diagnostic study using the direct detection of a mutant gene is that it requires the affected individual only and need not involve the testing of other family members. The methods of direct DNA diagnosis include restriction analysis, direct sequencing with assistance of PCR, heteroduplex assay, and protein truncation assay. The molecular mechanisms causing human diseases include point mutations, deletions, and insertions, and the unstable expansion of trinucleotide repeats, which leads to genetic anticipation. Some disorders that may be diagnosed via direct DNA mutational analysis include Duchenne muscular dystrophy, hemophilia, cystic fibrosis, and Fragile X syndrome.

Indirect detection of abnormal genes is used when the gene is known but there is extensive heterogeneity of the molecular defect between families, or when the gene responsible for a disease is unknown but its chromosome location is known. One form of indirect analysis is the linkage method. Linkage traces the inheritance of the abnormal gene between members in a kindred. This method requires that the affected individual be studied, as well as parents and other relatives, both affected and unaffected. Linkage analysis is performed by using markers such as a restriction fragment length polymorphisms. Microsatellite polymorphisms are being used in sibling research studies to identify the multiple genes that contribute to polygenic traits such as diabetes and obesity. They are also used increasingly to identify gene changes in tumors.

Neurofibromatosis is an example of a disorder in which both the direct and indirect assay may be used. An estimated 90%–95% of patients with neurofibromatosis type 1 have a mutation or deletion that can be identified using a direct assay of the neurofibromin gene (NF1). The other cases must rely on indirect methods such as linkage analysis for prenatal diagnosis.

Molecular Biology in Prevention & Treatment of Human Diseases

Molecular diagnosis can prevent genetic disease by detection of mutation and permitting prenatal diagnosis. As diseases often present in spectrums and clinical features among disorders can overlap, molecular testing is useful to confirm a diagnosis. Family studies can also clarify the mode of inheritance, thus allowing more accurate determination of recurrence risks and appropriate options. For example, differentiation of gonadal mosaicism from decreased penetrance of a dominant gene has important implications for genetic counseling. In the past, the diagnosis of a genetic disease characterized by late onset of symptoms (eg, Huntington disease) could not be made prior to the appearance of clinical symptoms. In some inborn errors of metabolism, diagnostic tests (eg, measurement of enzyme activities) could be conducted only on inaccessible tissues. Gene identification (mutation analysis) techniques can enormously enhance the ability to diagnose both symptomatic and presymptomatic individuals, heterozygous carriers of gene mutations, and affected fetuses. However, presymptomatic DNA testing is associated with psychological, ethical, and legal implications and therefore should be used only with informed consent. Formal genetic counseling is indicated to best interpret the results of molecular testing.

A normal gene introduced into an individual affected with a serious inherited disorder during embryonic life (germline therapy) in principle has the potential to be transmitted to future generations, whereas its introduction into somatic cells (somatic therapy) affects only the recipient. Experimental gene therapy by bone marrow transplantation is being tried for adenosine deaminase deficiency. Recombinant enzyme replacement has been successfully applied in treating the nonneurologic form of Gaucher disease, Fabry disease, Pompe disease, mucopolysaccharidosis types I and II, and some types of lysosomal storage disease.

Proteomics is the large-scale study of proteins, particularly their structures and functions. The term “proteomics” was first coined in 1997 as an analogy to genomics, the study of the genes. “Proteome” means a blend of “protein” and “genome.” Understanding the proteome, the structure and function of each protein and the complexities of protein-protein interactions will be critical for developing effective diagnostic techniques and disease treatments. One of the most promising roles of proteomics has been the identification of potential new drugs for the treatment of disease. This relies on genome and proteome information to identify proteins associated with a disease, which computer software can then use as targets for new drugs. For example, in Alzheimer disease, elevations in beta secretase create amyloid/beta-protein, which causes plaque to build up in the patient’s brain, which is thought to play a role in dementia. Targeting this enzyme decreases the amyloid/beta-protein and so slows the progression of the disease.

Pharmacogenomics is a new field offering enormous promise for predicting drug response in patients. For example, by DNA analysis of two specific genes, CYP2C9 and VKORC1, it is now possible to predict response to warfarin anticoagulation therapy and to individualize the dose, saving the patient multiple blood tests and dosage adjustments. It is also possible to predict which patients would be at risk for hearing loss after receiving aminoglycoside treatment, based on mutations in the mitochondrial 12S rRNA gene.

Personalized medicine is an advancing field of medicine that offers increased precision and effectiveness than traditional medicine. A patient’s genomic information offers insight into the individual aspects of one’s medical management. The goal is to optimize care and overall outcomes, one example being the aforementioned area of pharmacogenomics and potential therapeutic responses.

Genetic testing allows practitioners to test patients for a wide variety of genetic conditions. Advances in this area of medicine have included the advent of parents requesting testing for adult onset disease, carrier status, and disease susceptibility in their children. There are significant ethical and legal issues surrounding this topic. The American College of Medical Genetics and Genomics and American Society of Human Genetics formed a consensus statement on the topic that educates families and healthcare providers on the potential negative impacts of such testing. In the face of whole exome or genome sequencing, single-gene analysis, and microarray analysis, carrier status for conditions may be revealed and this requires detailed genetic counseling. The decision-making capacity of the minor should also be taken into account where applicable.

Friedman Ross L et al: Technical report: ethical and policy issues in genetic testing and screening of children. Genet Med 2013;15(3):234–245 [PMID: 23429433].

Garcia DA et al: Estimation of the warfarin dose with clinical and pharmacogenetic data. NEJM 2009;360:753–764 [PMID: 19228618].

Ma Q et al: Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev 2011 Jun;63(2):437–459 [Epub 2011 Mar 24] [PMID: 21436344].



Traditionally, autosomal single-gene disorders follow the principles explained by Mendel’s observations. To summarize, the inheritance of genetic traits through generations relies on segregation and independent assortment. Segregation is the process through which gene pairs are separated during gamete formation. Each gamete receives only one copy of each gene (allele). Independent assortment refers to the idea that the segregation of different alleles occurs independently.

Victor McKusick’s catalog, Mendelian Inheritance in Man, lists more than 10,000 entries in which the mode of inheritance is presumed to be autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, and Y-linked. Single genes at specific loci on one or a pair of chromosomes cause these disorders. An understanding of inheritance terminology is helpful in approaching mendelian disorders. Analysis of the pedigree and the pattern of transmission in the family, identification of a specific condition, and knowledge of that condition’s mode of inheritance usually allow for explanation of the inheritance pattern.


The following terms are important in understanding heredity patterns.

1. Dominant and recessive—As defined by Mendel, concepts for dominant and recessive refer to the phenotypic expression of alleles and are not intrinsic characteristics of gene loci. Therefore, it is inappropriate to discuss “a dominant locus.”

2. Genotype—Genotype means the genetic status, that is, the alleles an individual carries.

3. Phenotype—Phenotype is the expression of an individual’s genotype including appearance, physical features, organ structure, and biochemical and physiologic nature. It may be modified by environment.

4. Pleiotropy—Pleiotropy refers to the phenomenon whereby a single mutant allele can have widespread effects or expression in different tissues or organ systems. In other words, an allele may produce more than one effect on the phenotype. For example, Marfan syndrome has manifestations in different organ systems (skeletal, cardiac, ophthalmologic, etc) due to a single mutation within the fibrillin gene.

5. Penetrance—Penetrance refers to the proportion of individuals with a particular genotype that express the same phenotype. Penetrance is a proportion that ranges between 0 and 1 (or 0 and 100%). When 100% of mutant individuals express the phenotype, penetrance is complete. If some mutant individuals do not express the phenotype, penetrance is said to be incomplete, or reduced. Dominant conditions with incomplete penetrance, therefore, are characterized by “skipped” generations with unaffected, obligate gene carriers.

6. Expressivity—Expressivity refers to the variability in degree of phenotypic expression (severity) seen in different individuals with the same mutant genotype. Expressivity may be extremely variable or fairly consistent, both within and between families. Intrafamilial variability of expression may be due to factors such as epistasis, environment, genetic anticipation, presence of phenocopies, mosaicism, and chance (stochastic factors). Interfamilial variability of expression may be due to the previously mentioned factors, but may also be due to allelic or locus genetic heterogeneity.

7. Genetic heterogeneity—Several different genetic mutations may produce phenotypes that are identical or similar enough to have been traditionally considered as one diagnosis. “Anemia” or “mental retardation” are examples of this. There are two types of genetic heterogeneity, locus heterogeneity and allelic heterogeneity.

A. LOCUS HETEROGENEITY—Locus heterogeneity describes a phenotype caused by mutations at more than one genetic locus; that is, mutations at different loci cause the same phenotype or a group of phenotypes that appear similar enough to have been previously classified as a single disease, clinical “entity,” or diagnostic spectrum. An example would be Sanfilippo syndrome (mucopolysaccharidosis types IIIA, B, C, and D), in which the same phenotype is produced by four different enzyme deficiencies.

B. ALLELIC HETEROGENEITY—A phenotype causing different mutations at a single-gene locus. As an example, cystic fibrosis may be caused by many different genetic changes, such as homozygosity for the common Δ F508mutation, or ΔF508 and an R117H mutation. The latter example represents compound heterozygosity.

8. Phenotypic heterogeneity or “clinical heterogeneity”—This term describes the situation in which more than one phenotype is caused by different allelic mutations at a single locus. For example, different mutations in the FGFR2 gene can cause different craniosynostosis disorders, including Crouzon syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome, and Apert syndrome. These syndromes are clinically distinguishable and are due to the presence of a variety of genetic mutations within single genes.

9. Homozygous—A cell or organism that has identical alleles at a particular locus is said to be homozygous. For example, a cystic fibrosis patient with a ΔF508 mutation on both alleles would be called homozygous for that mutation.

10. Heterozygous—A cell or organism that has nonidentical alleles at a genetic locus is said to be heterozygous. In autosomal dominant conditions, a mutation of only one copy of the gene pair is all that is necessary to result in a disease state. However, an individual who is heterozygous for a recessive disorder will not manifest symptoms (see the next section).

11. Karyotype—A profile of an organism’s chromosomes that is sorted according to size, shape, and number. It is available for analysis in a number of sample types (white blood cells, fibroblasts, etc). It is able to detect structural rearrangements such as inversions, positional insertions, and translocations. Imbalances below 5 million base pairs are difficult to detect.

12. Chromosomal microarray—Method of cytogenetic analysis via several platforms: BAC, oligonucleotide, and SNP. Patient DNA is hybridized with control DNA and each is labeled with a different fluorescent dye. Data is plotted on a log2 scale, as in the case of oligonucletide arrays, and reviewed for numerical imbalances. Microarray is limited in the detection of balanced rearrangements and the structural nature of an imbalance.

13. Next-generation sequence analysis—Genetic analysis via breakage of the genome into fragments, attaching those segments of DNA to special adapters, or passage through specialized channels where the sequence is determined. Millions of segments are analyzed simultaneously, lending the term “high throughput” to this approach. Regions are repeatedly analyzed and compared with a reference human genome.

14. Whole exome sequencing—Determination of the sequence of an individual’s exome, the coding sequence of the human genome. Exome represents only about 1% of the genome.

15. Whole genome sequencing—Determination of the sequence of the entire human genome

Bick D, Dimmock D: Whole exome and whole genome sequencing. Curr Opin Pediatr 2011 Dec;23(6):594–600 [PMID: 21881504].

Online Mendelian Inheritance in Man:

Hereditary Patterns

A. Autosomal Dominant Inheritance

Autosomal dominant inheritance has the following characteristics:

1. If a parent is affected, the risk for each offspring of inheriting the abnormal dominant gene is 50%, or 1:2. This is true whether the gene is penetrant or not in the parent.

2. Affected individuals in the same family may experience variable expressivity.

3. Nonpenetrance is common, and the penetrance rate varies for each dominantly inherited condition.

4. Both males and females can pass on the abnormal gene to children of either sex, although the manifestations may vary according to sex. For example, pattern baldness is a dominant trait but affects only males. In this case, the trait is said to be sex-limited.

5. Dominant inheritance is typically said to be vertical, that is, the condition passes from one generation to the next in a vertical fashion (Figure 37–4).

6. In some cases, the patient appears to be the first affected individual in the family. This spontaneous appearance is often caused by a new mutation. The mutation rate increases with advancing paternal age (particularly after age 40 years).

7. Explanations for a negative family history include:

A. Nonpaternity.

B. Decreased penetrance or mild manifestations in one of the parents.

C. Germline mosaicism (ie, mosaicism in the germ cell line of either parent). Germline mosaicism may mimic autosomal recessive inheritance, because it leads to situations in which two children of completely normal parents are affected with a genetic disorder. Recurrence risks are in the range of 1%–7%.

D. The abnormality present in the patient may be a phenocopy, or it may be a similar but genetically different abnormality with a different mode of inheritance.

8. As a general rule, dominant traits are more often related to structural abnormalities of a protein.

9. If an abnormality represents a new mutation of a dominant trait, the parents of the affected individual run a low risk during subsequent pregnancies. The risk for an affected sibling is still slightly increased over the general population, because of the possibility of germline mosaicism.

10. Prevention options available for future pregnancies include prenatal diagnosis, artificial insemination, and germ cell donation.


image Figure 37–4. Autosomal dominant inheritance. Variable expressivity in Neurofibromatosis type 1.

B. Autosomal Recessive Inheritance

Autosomal recessive inheritance also has some distinctive characteristics:

1. The recurrence risk for parents of an affected child is 25%, or 1:4 for each pregnancy. The gene carrier frequency in the general population can be used to assess the risk of having an affected child with a new partner, for unaffected siblings, and for the affected individuals themselves.

2. There is less variability among affected persons. Parents are carriers and are clinically normal. (There are, however, exceptions to this rule. For example, carriers of sickle cell trait may become symptomatic if they become hypoxic.)

3. Males and females are affected equally.

4. Inheritance is horizontal; siblings may be affected (Figure 37–5).

5. The family history is usually negative, with the exception of siblings. However, in common conditions such as cystic fibrosis, a second- or third-degree relative may be affected.

6. Recessive conditions are frequently associated with enzyme defects.

7. In rare instances, a child with a recessive disorder and a normal karyotype may have inherited both copies of the abnormal gene from one parent and none from the other. This UPD was first described in a girl with cystic fibrosis and growth retardation.

8. Options available for future pregnancies include prenatal diagnosis, adoption, artificial insemination, and egg or sperm donation.


image Figure 37–5. Autosomal recessive inheritance: cystic fibrosis.

C. X-Linked Inheritance

When a gene for a specific disorder is on the X chromosome, the condition is said to be X-linked, or sex-linked. Females may be either homozygous or heterozygous, because they have two X chromosomes. Males, by contrast, have only one X, and a male is said to be hemizygous for any gene on his X chromosome. The severity of any disorder is greater in males than in females (within a specific family). According to the Lyon hypothesis, because one of the two X chromosomes in each cell is inactivated, and this inactivation is random, the clinical picture in females depends on the percentage of mutant versus normal alleles inactivated. The X chromosome is not inactivated until about 14 days of gestation, and parts of the short arm remain active throughout life.

1. X-linked recessive inheritance—The following features are characteristic of X-linked recessive inheritance:

1. Males are affected, and heterozygous females are either normal or have mild manifestations.

2. Inheritance is diagonal through the maternal side of the family (Figure 37–6A).

3. A female carrier has a 50% chance that each daughter will be a carrier and a 50% chance that each son will be affected.

4. All of the daughters of an affected male are carriers, and none of his sons are affected.

5. The mutation rate is high in some X-linked disorders, particularly when the affected male dies or is so incapacitated by the disorder that reproduction is unlikely. In such instances, the mutation is thought to occur as a new mutation in the affected male, and in the mother, each one-third of the time and to be present in earlier generations one-third of the time. For this reason, genetic counseling may be difficult in families with an isolated case.

6. On rare occasions, a female may be fully affected. Several possible mechanisms may account for a fully affected female: (a) unfavorable lyonization; (b) 45,X karyotype; (c) homozygosity for the abnormal gene; (d) an X-autosome translocation, or other structural abnormality of one X chromosome, in which the X chromosome of normal structure is preferentially inactivated; (e) UPD; and (f) nonrandom inactivation, which may be controlled by an autosomal gene.


image Figure 37–6. A: X-linked recessive inheritance. B: X-linked dominant inheritance.

2. X-linked dominant inheritance—The X-linked dominant inheritance pattern is much less common than the X-linked recessive type. Examples include incontinentia pigmenti and hypophosphatemic or vitamin D–resistant rickets. The following features are characteristic of X-linked dominant inheritance:

1. The heterozygous female is symptomatic, and the disease is twice as common in females because they have two X chromosomes that can have the mutation.

2. Clinical manifestations are more variable in females than in males.

3. The risk for the offspring of heterozygous females to be affected is 50% regardless of sex.

4. All of the daughters but none of the sons of affected males will have the disorder (Figure 37–6B).

5. Although a homozygous female is possible (particularly in an inbred population), she would be severely involved. All of her children would also be affected but more mildly.

6. Some disorders (eg, incontinentia pigmenti) are lethal in males (and in homozygous females). Affected women have twice as many daughters as sons and an increased incidence of miscarriages, because affected males will be spontaneously aborted. A 47,XXY karyotype has allowed affected males to survive.

D. Y-Linked Inheritance

In Y-linked inheritance, also known as “holandric” inheritance, a disorder is caused by genes located on the Y chromosome. These conditions are relatively rare with only about 40 entries listed in McKusick’s catalog. Male-to-male transmission is seen in this category, with all sons of affected males being affected and no daughters or females being affected.


Many common attributes, such as height, are familial, and are the result of the actions of multiple rather than single genes. Inheritance of these traits is described as polygenic or multifactorial. The latter term recognizes that environmental factors such as diet also contribute to these traits. Geneticists are now finding that multiple genes are often expressed in hierarchies, in which the action of a small number of genes, two or three, explains much of the variation observed within affected populations.

Studies of twins have proven useful in determining the relative importance of genetic versus environmental factors in the expression of polygenic traits. If genetic factors are of little or no importance, then the concordance between monozygotic and dizygotic twins should be the same. (Dizygotic twins are no more genetically similar to each other than to other siblings.) If an abnormality is completely genetic, the concordance between identical twins should be 100%. In polygenic conditions, the concordance rate for identical twins is usually higher than that seen in dizygotic twins but is still not 100%, indicating that both genetic and environmental factors are playing a role.

Many disorders and congenital abnormalities that are clearly familial but do not segregate as mendelian traits (eg, autosomal dominant, recessive) show polygenic inheritance. For the most part, these conditions become manifest when thresholds of additive gene actions or contributing environmental factors are exceeded. Many common disorders ranging from hypertension, stroke, and thrombophlebitis to behavioral traits such as alcoholism demonstrate multifactorial (polygenic) inheritance. Some common birth defects, including isolated congenital heart disease, cleft lip and palate, and neural tube defects, also demonstrate polygenic inheritance. Neural tube defects provide a good model illustrating how identification of both environmental and genetic contributions to multifactorial traits can lead to preventive measures.

Polygenic or multifactorial inheritance has several distinctive characteristics:

1. The risk for relatives of affected persons is increased. The risk is higher for first-degree relatives (those who have 50% of their genes in common) and lower for more distant relations, although the risk for the latter is higher than for the general population (Table 37–3).

Table 37–3. Empiric risks for some congenital disorders.


2. The recurrence risk varies with the number of affected family members. For example, after one child is born with a neural tube defect, the recurrence risk is 2%–3%. If a second affected child is born, the risk for any future child increases to 10%–12%. This is in contrast to single-gene disorders, in which the risk is the same no matter how many family members are affected.

3. The risk is higher if the defect is more severe. In Hirschsprung disease, another polygenic condition, the longer the aganglionic segment, the higher is the recurrence risk.

4. Sex ratios may not be equal. If a marked discrepancy exists, the recurrence risk is higher if a child of the less commonly affected sex has the disorder. This assumes that more genetic factors are required to raise the more resistant sex above the threshold. For example, pyloric stenosis is more common in males. If the first affected child is a female, the recurrence risk is higher than if the child is a male.

5. The risk for the offspring of an affected person is approximately the same as the risk for siblings, assuming that the spouse of the affected person has a negative family history. For many conditions, however, assortative mating, “like marrying like,” adds to risks in offspring.


Epigenetic Regulation

Although development is regulated by genes, it is initiated and sustained by nongenetic processes. Epigenetic events are points of interaction between developmental programs and the physicochemical environments in differentiating cells. Genetic imprinting and DNA methylation are examples of epigenetic processes that affect development. Certain genes important in regulation of growth and differentiation are themselves regulated by chemical modification that occurs in specific patterns in gametes. For example, genes that are methylated are “turned off” and not transcribed. The pattern of which genes are methylated may be determined or affected by the sex of the parent of origin (see the next section). Expression of imprinted genes may sometimes be limited to specific organs (eg, the brain), and imprinting may be relaxed and methyl groups lost as development progresses. Disruption of imprinting is now recognized as contributing to birth defect syndromes (described in the next section). Certain techniques developed to assist infertile couples (advanced reproductive technology) may affect epigenetic processes and lead to genetic disorders in the offspring conceived via these methods.

Niemitz EL, Feinberg AP: Epigenetics and assisted reproductive technology: a call for investigation. Am J Hum Genet 2004;74:599 [PMID: 14991528].


Although the homologs of chromosome pairs may appear identical on routine karyotype analysis, it is now known that the parental origin of each homolog can affect which genes are actually transcribed and which are inactivated. The term imprinting refers to the process by which preferential transcription of certain genes takes place, depending on the parental origin, that is, which homolog (maternal or paternal) the gene is located on. Certain chromosomes, particularly chromosome X, and the autosomes 15, 11, and 7, have imprinted regions where some genes are only read from one homolog (ie, either the maternal or paternal allele) under normal circumstances, and the gene on the other homolog is normally inactivated. Errors in imprinting may arise because of uniparental disomy or UPD (in which a copy from one parent is missing), by a chromosomal deletion causing loss of the gene normally transcribed, or by mutations in the imprinting genes that normally code for transcription or inactivation of other genes downstream. A good example of how imprinting may affect human disease is Beckwith-Wiedemann syndrome, the gene for which is located on chromosome 11p15.

Cohen MM et al: Overgrowth Syndromes. New York, NY: Oxford University Press; 2002.

Genetic Anticipation

Geneticists coined the term “anticipation” to describe an unusual pattern of inheritance in which symptoms became manifest at earlier ages and with increasing severity as traits are passed to subsequent generations. Mapping of the genes responsible for these disorders led to the discovery that certain repeat sequences of DNA at disease loci were not stable when passed through meiosis. Repeated DNA sequences, in particular triplets (eg, CGG and CAG), tended to increase their copy number. As these runs of triplets expanded, they eventually affected the expression of genes and produced symptoms. Curiously, all the disorders undergoing triplet repeat expansion detected thus far produce neurologic symptoms. Most are progressive. In general, the size of the triplet expansion is roughly correlated with the timing and severity of symptoms. The reasons for the meiotic instability of these sequences are not yet understood. The mechanisms appear to involve interactions between DNA structure (eg, formation of hairpin loops) and replication enzymes (DNA polymerase complexes) during meiosis.

Triplet repeat instability can modify the inheritance of autosomal dominant, autosomal recessive, and X-linked traits. Autosomal dominant disorders include several spinal cerebellar atrophies, Huntington disease, and myotonic dystrophy. Unstable triplet repeat expansion contributes to at least one autosomal recessive disorder, Friedreich ataxia. The most common X-linked disorder demonstrating triplet repeat instability and expansion is Fragile X syndrome.

Mitochondrial Inheritance

Mitochondrial disorders can be caused by both nuclear and mitochondrial genes. The former would follow Mendelian inheritance, either AR, AD, or X-Linked, while the latter demonstrates mitochondrial inheritance. Mitochondrial DNA is double-stranded, circular, and smaller than nuclear DNA, and is found in the cytoplasm. It codes for enzymes involved in oxidative phosphorylation, which generates adenosine triphosphate. Since the 1990s, enormous advances in technology and improved clinical documentation have led to a better understanding of the interesting disorders caused by mutations in mitochondrial DNA (mtDNA).

Mitochondrial disorders can be associated with point mutations, deletions, or duplications in mtDNA. However, there is a threshold effect depending on the heteroplasmy (see next). Because of the difficulty in predicting mitochondrial DNA disorders and the variability of the clinical course, it is often difficult to calculate specific recurrence risks.

Mitochondrial disorders related to mtDNA have the following characteristics:

1. They show remarkable phenotypic variability.

2. They are maternally inherited, because only the egg has any cytoplasmic material, and during early embryo-genesis any sperm-born mitochondrial material will be eliminated.

3. In most mitochondrial disorders, cells are heteroplasmic (Figure 37–7). That is, all cells contain both normal and mutated or abnormal mtDNA. The proportion of normal to abnormal mtDNA in the mother’s egg seems to determine the severity of the offspring’s disease and the age at onset in most cases.


image Figure 37–7. Mitochondrial inheritance. Mutations are transmitted through the maternal line.

4. Those tissues with the highest adenosine triphosphate requirements—specifically, central nervous system (CNS) and skeletal muscle—seem to be most susceptible to mutations in mtDNA.

5. Somatic cells show an increase in mtDNA mutations and a decline in oxidative phosphorylation function with age. This explains the later onset of some of these disorders and may indeed be a clue to the whole aging process.

Rahman S, Hanna MG: Diagnosis and therapy in neuromuscular disorders: diagnosis and new treatments in mitochondrial diseases. J Neurol Neurosurg Psychiatry 2009 Sep;80(9):943–953 [PMID: 19684231].

Wong LJ et al: Current molecular diagnostic algorithm for mitochondrial disorders. Mol Genet Metab 2010 Jun;100(2): 111–117 [PMID: 20359921].


Critical in the evaluation of a potential genetic condition is the construction of a family tree, also known as a pedigree. Underused by most medical personnel, the pedigree is a valuable record of genetic and medical information, which is much more useful in visual form than in list form. Tips for pedigree preparation include the following:

• Start with the proband—the patient’s siblings and parents, and obtain a three-generational history at minimum, as possible.

• Always ask about consanguinity.

• Obtain data from both sides of the family.

• Ask about spontaneous abortions, stillbirths, infertility, children relinquished for adoption, and deceased individuals.

In the course of taking the family history, one may find information that is not relevant in elucidating the cause of the patients’ problem but may indicate a risk for other important health concerns. Conditions unrelated to the chief complaint should be directed for follow-up care. Examples of the latter scenario include: an overwhelming family history of early-onset breast and ovarian cancer, or multiple pregnancy.

Bennett RL et al: Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of genetic counselors. J Genet Couns 2008;17:424–433 [PMID: 18792771].


Birth defects are the leading cause of death in the first year of life. They are evident in 2%–3% of newborn infants and in up to 7% of adults. Many are now detected by ultrasound prior to birth. Clinical investigation of the causes and consequences of birth defects is called dysmorphology.


Developmental Biology

Cell proliferation and programmed cell death (apoptosis) both contribute to embryonic structural formation. The genes that control these processes continue to be further characterized. Products of other genes establish regulatory pathways in which positive and negative signaling loops initiate and maintain cell differentiation with precise timing. Cell biology provides techniques that allow experimental access to developmental pathways. Embryology has become more experimental than descriptive and practitioners can expect systems biology to soon begin to inform them about the origins of specific birth defects. Further understanding of these mechanisms will open the door to interventions that may well prevent birth defects or treat them prenatally. An example of the evolution of the aforementioned process is the ground breaking fetal surgery for neural tube defects.

Cellular Interactions

The picture emerging from experimental studies of morphogenesis is one of a hierarchy of gene expression during development. Morphogenesis begins with expression of genes encoding transcription factors. These proteins bind to DNA in undifferentiated embryonic cells and recruit them into developmental fields, groups of cells primed to respond to specific signals later in development. The recruitment also establishes spatial relationships and orients cells with respect to their neighbors. As fields differentiate into identifiable tissues (eg, ectoderm, mesoderm, and endoderm), cellular proliferation, migration, and further differentiation are mediated through genes encoding cell signaling proteins.

Signaling proteins include growth factors and their receptors, cellular adhesion molecules, and extracellular matrix proteins that both provide structure and position signals to developing tissues.

Environmental Factors

The effects of exogenous agents during development are also mediated through genetically regulated pathways. At the cellular level, xenobiotics (compounds foreign to nature) cause birth defects either because they disrupt cell signaling and thereby misdirect morphogenesis, or because they are cytotoxic and lead to cell death in excess of the usual developmental program.

In general, drug receptors expressed in embryos and fetuses are the same molecules that mediate pharmacologic effects in adults. However, effector systems may be different, reflecting incomplete morphogenesis and differences between fetal and postnatal physiology. These circumstances allow prediction of dose-response relationships during development on the one hand, but call for caution about predicting effects on the other.

Xenobiotics must traverse the placenta to affect embryonic and fetal tissues. The human placenta is a relatively good barrier against microorganisms, but it is ineffective at excluding drugs and many chemicals. The physicochemical properties (eg, molecular size, solubility, and charge) that allow foreign chemicals to be absorbed into the maternal circulation also allow them to cross the placenta. The placenta can metabolize some xenobiotics but it is most active against steroid hormones and low-level environmental contaminants than drugs.

The timing of xenobiotic exposures is an important determinant of their effects. Morphogenic processes express the so-called critical periods, during which developing organs they produce are particularly susceptible to maldevelopment. Critical periods of susceptibility are not all confined to early gestation. The developing brain is susceptible to toxicity throughout pregnancy.

Over-the-counter, prescribed, and abused drugs that are pharmacologically active in mothers will be active across the placenta. Exposure to agents achieving cytotoxic levels in adults are likely to be teratogenic (ie, cause birth defects). Abused substances such as alcohol that are toxic to adults are predictably toxic to embryos and fetuses. Drugs generally safe in adults will be generally safe for fetuses. An exception is ibuprofen with its prostaglandin blocking properties that can affect fetal circulation, which is prostaglandin dependent. It is important to keep in mind that embryonic and fetal physiology may differ from that of an adult with respect to drug action.

Effects of toxic environmental contaminants on the embryo and fetus are dose-dependent. Thus, the level of exposure to a toxin frequently becomes the primary determinant of its risk. Exposures producing symptoms in mothers can be assumed to be potentially toxic to the fetus.

Transplacental pharmacologic effects can be therapeutic. The potential for embryonic and fetal drug therapies during pregnancy is increasing. Folic acid supplementation can lower risks for birth defects such as spina bifida, and maternally administered corticosteroids can induce fetal synthesis and secretion of pulmonary surfactants prior to delivery.

Mechanical Factors

Much of embryonic development and all of fetal growth occurs normally within the low pressure and space provided by amniotic fluid. Loss or inadequate production of amniotic fluid can have disastrous effects, as can disruption of placental membranes. Disruption of placental membranes in early gestation leads to major structural distortion and most often lethal. Later, deformation or even amputation of fetal extremities (amniotic band sequence) can occur.

Movement is also important for morphogenesis. Fetal movement is necessary for normal development of joints and is the principal determinant of folds and creases present at birth in the face, hands, feet, and other areas of the body. Clubfoot is an etiologically heterogeneous condition in which the foot is malpositioned at birth. It more often results from mechanical constraint secondary to intrauterine crowding, weak fetal muscles, or abnormal neurologic function than from primary skeletal maldevelopment.

Lung and kidney development are particularly sensitive to mechanical forces. Constriction of the chest through maldevelopment of the ribs, lack of surrounding amniotic fluid, or lack of movement (fetal breathing) leads to varying degrees of pulmonary hypoplasia in which lungs are smaller than normal and develop fewer alveoli. The presentation at birth is respiratory distress and may be lethal.

Cystic renal dysplasia is frequently associated with obstruction ureters or bladder outflow. As pressure within obstructed renal collecting systems increases, it distorts cell interactions and alters histogenesis. Developing kidneys exposed to increased internal pressures for long periods eventually become nonfunctional.


An important task for the clinician presented with an infant with a birth defect is to determine whether the problem is isolated or part of a larger embryopathy (syndromic).


Classification of dysmorphic features strives to reflect mechanisms of maldevelopment. However, much of the terminology that describes abnormal development in humans remains historical and documents recognition of patterns prior to understanding of their biology. For example, birth defects are referred to as malformations when they result from altered genetic or developmental processes. When physical forces interrupt or distort morphogenesis, their effects are termed disruptions and deformations, respectively. The term dysplasia is used to denote abnormal histogenesis. Malformations occurring together more frequently than would be expected by chance alone may be classified as belonging to associations. Those in which the order of maldevelopment is understood may be referred to as sequences. For example, Robin sequence (or Pierre Robin anomaly) is used to describe cleft palate that has occurred because poor growth of the jaw (retrognathia) has displaced the tongue and prevented posterior closure of the palate. Syndromes are simply recurrent patterns of maldevelopment, in many with a known genetic cause.

Evaluation of the Dysmorphic Infant

As with any medical problem the history and physical examinations provide most of the clues to diagnosis. Special aspects of these procedures are outlined in the following sections. The extent of an infant’s abnormalities may not be immediately apparent, and parents who feel grief and guilt are often desperate for information.

A. History

Pregnancy histories nearly always contain important clues to the diagnosis. Parental recall after delivery of an abnormal infant is better than recall after a normal birth. An obstetric wheel can help document gestational age and events of the first trimester: the last menstrual period, the onset of symptoms of pregnancy, the date of diagnosis of the pregnancy, the date of the first prenatal visit, and the physician’s impressions of fetal growth at that time. Family histories should always be reviewed. Environmental histories should include descriptions of parental habits and work settings in addition to medications and use of drugs, tobacco, and alcohol.

B. Physical Examination

Meticulous physical examination is crucial for accurate diagnosis in dysmorphic infants and children. In addition to the routine procedures described in Chapter 2, special attention should be paid to the neonate’s physical measurements (Figure 37–8). Photographs are helpful and should include a consistent method of measurement for reference.


image Figure 37–8. Neonatal measurements.

C. Imaging and Laboratory Studies

Radiologic investigation is fundamental in the assessment and management of dysmorphic patients. A series of 9 plain radiographs, called a skeletal survey, is useful in the evaluation of patients with suspected skeletal dysplasia. Magnetic resonance imaging (MRI), with or without angiogram, venogram, or spectroscopy, contributes to diagnostic evaluation. Computed tomography (CT) is useful for bony structure assessment, but less so for deep tissue evaluation in comparison to MRI. Ultrasonography also has case-dependent utility for noninvasive imaging. Consultation with a radiologist is encouraged if there is any question about which imaging modality would serve the patient best.

Traditional cytogenetic analysis provides specific diagnoses in approximately 5% of dysmorphic infants who survive the neonatal period. Chromosomal abnormalities are recognized in 10%–15% of infants who die. With the availability of chromosomal microarray at least 10%–15% additional subtle chromosomal anomalies have been identified. Of note, many copy number variations (CNVs) exist in different individuals; therefore, interpretation is sometimes difficult and may require parental samples for clarification. Common disorders such as trisomies 21, 13, and 18 can be determined rapidly through use of FISH, but this technique should be accompanied by a complete karyotype. As a rule, a normal karyotype does not rule out the presence of significant genetic disease. Any case requiring rapid diagnosis should be discussed with an experienced clinical geneticist.

D. Perinatal Autopsy

When a dysmorphic infant dies, postmortem examination can provide important diagnostic information. The pediatrician should discuss the case thoroughly with the pathologist, and photographs should be obtained. Radiologic imaging should be included whenever limb anomalies or disproportionate growth is present. Tissue, most often skin, can be submitted for cytogenetic analysis. Fibroblasts from cytogenetic analysis can routinely be frozen and preserved for future studies. The pediatrician and the pathologist should also consider whether samples of blood, urine, or other tissue should be obtained for biochemical analyses. Placental as well as fetal tissue can be used for viral culture.

Hudgins L, Cassidy SB: Congenital anomalies: In Martin RJ et al (eds): Fanaroff and Martin’s Neonatal-Perinatal Medicine—Diseases of the Fetus and Infant, 8th ed. Philadelphia, PA: Elsevier Mosby; 2006:561–582.



1. Trisomy 21 (Down Syndrome)


image Characteristic features include upslanting palpebral fissures, epicanthal folds, midface hypoplasia, and small, dysplastic pinnae.

image Generalized hypotonia.

image Cognitive disabilities (usually mild to moderate).

image Associated with congenital heart disease and gastrointestinal anomalies.

Down syndrome occurs in about 1:700 newborns. Cognitive disabilities in the mild/moderate range are characteristic of Down syndrome, as is generalized hypotonia. The affected newborn may have prolonged physiologic jaundice, polycythemia, and a transient leukemoid reaction. Feeding problems are common during infancy. Problems which may be seen during childhood include thyroid dysfunction, visual issues, hearing loss, obstructive sleep apnea, celiac disease, atlanto-occipital instability, and autism. Leukemia is 12–20 times more common in patients with Down syndrome.

image Clinical Findings

The principal physical findings include a flattened occiput, characteristic facies (upslanting palpebral fissures, epicanthal folds, midface hypoplasia, and small, dysplastic pinnae), and minor limb abnormalities. About one-third to one-half of children with Down syndrome have congenital heart disease, most often endocardial cushion defects or other septal defects. Anomalies of the gastrointestinal tract, including esophageal and duodenal atresias, are seen in about 15% of cases.

Information regarding healthcare guidelines for patients with Down syndrome.

2. Trisomy 18 Syndrome

The incidence of trisomy 18 syndrome is about 1:4000 live births, and the ratio of affected males to females is approximately 1:3. Trisomy 18 is characterized by prenatal and postnatal growth retardation, which is often severe, and hypertonicity. Complications are related to associated birth defects. Death is often caused by heart failure or pneumonia and usually occurs in infancy or early childhood, although a small percentage of patients reach adulthood. Surviving children show significant cognitive disabilities.

image Clinical Findings

Infants with trisomy 18 are often small for gestational age and have dysmorphic features including a characteristic facies and extremities (overlapping fingers and rocker-bottom feet) and congenital heart disease (often ventricular septal defect or patent ductus arteriosus). To see clinical pictures of patients with trisomy 18, visit the following website:

3. Trisomy 13 Syndrome

The incidence of trisomy 13 is about 1 per 12,000 live births, and 60% of affected individuals are female. Most infants with trisomy 13 have congenital anomalies that are incompatible with survival. Surviving children demonstrate failure to thrive, cognitive disabilities, apneic spells, seizures, and deafness. Death usually occurs in early infancy or by the second year of life, commonly as a result of heart failure or infection.

image Clinical Findings

The symptoms and signs include characteristic features, often a normal birth weight, CNS malformations, eye malformations, cleft lip and palate, polydactyly or syndactyly, and congenital heart disease. The facies of an infant with trisomy 13 can be viewed at the following website:

image Treatment of Trisomies

A. Medical Therapy

Interventions for specific issues such as surgery or medications for heart problems, antibiotics for infections, serial thyroid function tests, infant stimulation programs, special education, and physical, occupational, and speech therapies are all indicated. The goal of treatment is to help affected children develop to their full potential. Parents’ participation in support groups such as the local chapter of the National Down Syndrome Congress should be encouraged. See the following website:

There is no treatment other than general supportive care for trisomy 13 or 18. Rapid confirmation of suspected Trisomy 13 or 18 can be made by FISH. A support group for families of children with trisomies 13 and 18 who survive beyond infancy is called SOFT. See the following website:

B. Genetic Counseling

Most parents of trisomic infants have normal karyotypes. The risk of having a child affected with a trisomy increases with maternal age. For example, age-specific risks are approximately 1 per 1500 for mothers aged 25 years; and 1 per 100 for mothers at age 40. The recurrence risk for trisomy in future pregnancies is equal to 1 per 100 plus the age-specific maternal risk.

If the child has a trisomy resulting from a translocation, and the parent has an abnormal karyotype, the risks are increased. When the mother is the carrier of a balanced Robertsonian translocation, there is a 10%–15% chance that the child will be affected and a 33% chance that the child will be a balanced translocation carrier. When the father is the carrier, there is a smaller than 0.5% chance of having another affected child. If the child has a 21/21 translocation and one parent has the translocation, the recurrence risk is 100%.

The mother’s age at the time of conception and the nature of the chromosomal abnormality are important in genetic counseling, which is indicated for parents of all children with chromosomal abnormalities. Prenatal diagnosis is available.


1. Turner Syndrome (Monosomy X, Gonadal Dysgenesis)


image Webbed neck, triangular facies, short stature, wide-set nipples, amenorrhea, and absence of secondary sex characteristics.

image Associated with coarctation of the aorta and genitourinary malformations.

image IQ is usually normal but learning disabilities are common.

image Mosaic individuals may manifest only short stature and amenorrhea.

The incidence of Turner syndrome is 1 per 10,000 females. However, it is estimated that 95% of conceptuses with monosomy X are miscarried and only 5% are liveborn.

image Clinical Findings

Newborns with Turner syndrome may have webbed neck, edema of the hands and feet, coarctation of the aorta, and a characteristic triangular facies. Later symptoms include short stature, a shield chest with wide-set nipples, streak ovaries, amenorrhea, absence of secondary sex characteristics, and infertility. Some affected girls, particularly those with mosaicism, have only short stature and amenorrhea, without dysmorphic features.

Complications relate primarily to coarctation of the aorta, when present. Malformations of the urinary tract may be seen. Learning disabilities are common, secondary to difficulties in perceptual motor integration.

image Treatment

In Turner syndrome the identification and treatment of perceptual difficulties before they become problematic is very important. Estrogen replacement therapy permits development of secondary sex characteristics and normal menstruation and prevents osteoporosis. Growth hormone therapy has been used to increase the height of affected girls. Females with 45,X or 45,X mosaicism have a low fertility rate, and those who become pregnant have a high risk of fetal wastage (spontaneous miscarriage, ~30%; stillbirth, 6%–10%). Furthermore, their liveborn offspring have an increased frequency of chromosomal abnormalities involving either sex chromosomes or autosomes and congenital malformations. Thus, prenatal ultrasonography and chromosome analysis are indicated for the offspring of females with sex chromosome abnormalities.

2. Klinefelter Syndrome (XXY)


image Diagnosis is rarely made before puberty.

image Key findings include microorchidism; lack of libido; minimal facial hair; and tall, eunuchoid build.

image IQ can vary (normal to borderline with a small percentage showing cognitive disabilities).

The incidence of Klinefelter syndrome in the newborn population is roughly 1 per 1000, but it is about 1% among intellectual disabilities males and about 3% among males seen at infertility clinics. The maternal age at birth is often advanced. Unlike Turner syndrome, Klinefelter syndrome is rarely the cause of spontaneous abortions. The diagnosis is seldom made before puberty except as a result of prenatal diagnosis, because prepubertal boys have a normal phenotype.

image Clinical Findings

The characteristic findings after puberty include microorchidism associated with otherwise normal external genitalia, azoospermia, sterility, gynecomastia, normal to borderline IQ, diminished facial hair, lack of libido and potency, and a tall, eunuchoid build. In chromosome variants with three or four X chromosomes (XXXY and XXXXY), intellectual disabilities may be severe, and radioulnar synostosis may be present as well as anomalies of the external genitalia and cryptorchidism. In general, the physical and mental abnormalities associated with Klinefelter syndrome increase as the number of sex chromosomes increases.

image Treatment

Males with Klinefelter syndrome require testosterone replacement therapy. The presence of the extra X chromosome may allow expression of what might normally be a lethal X-linked disorder to occur.

3. XYY Syndrome

Newborns with XYY syndrome in general are normal. Affected individuals may on occasion exhibit an abnormal behavior pattern from early childhood and may have mild intellectual disabilities. Fertility may be normal. Many males with an XYY karyotype are normal. There is no treatment.

4. XXX Syndrome

The incidence of females with an XXX karyotype is approximately 1 per 1000. Females with XXX are phenotypically normal. However, they tend to be taller than usual and to have lower IQs than their normal siblings. Learning and behavioral issues are relatively common. This is in contrast to individuals with XXXX, a much rarer condition causing more severe developmental issues, and a dysmorphic phenotype reminiscent of Down syndrome.

Jones KL: Smith’s Recognizable Patterns of Human Malformation, 6th ed. Philadelphia, PA: Elsevier; 2006.


Chromosomal abnormalities most often present in newborns as multiple congenital anomalies in association with intrauterine growth retardation. In addition to trisomies as just described, other more subtle chromosomal abnormalities are also common. In some cases, a chromosomal rearrangement is too subtle to be detected by karyotype. The current technology, comparative genomic hybridization array (microarray), enables screening for multiple submicroscopic chromosomal abnormalities simultaneously, and is a very helpful tool in evaluating the child with a suspected chromosomal abnormality.

Although most cases of severe chromosomal abnormality such as trisomy are lethal, some individuals may survive if the abnormality exists in mosaic form. Two examples of this include trisomy 8 and Cat eye syndrome, caused by extra genetic material, which is derived from a portion of chromosome 22.

Miller DT et al: Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010;86:749–764 [PMID: 20466091].


Three common chromosomal deletion disorders that were previously detected on routine karyotype analysis, and confirmed via FISH assay, but are now detected with microarray, are 1p36− syndrome, Wolf-Hirschhorn syndrome (4p−), and cri du chat syndrome (5p−). Microdeletion or contiguous gene syndrome are referring to those small deletion not readily picked up by karyotype but detected by microarray or FISH.

1. Deletion 1p36 Syndrome

Microcephaly and a large anterior fontanelle are characteristic features of 1p36− syndrome. Cardiac defects are common, and dilated cardiomyopathy may present in infancy. Intellectual disability, hypotonia, hearing loss, and seizures are usually seen.

2. Wolf-Hirschhorn Syndrome

Also known as 4p− (deletion of 4p16), this syndrome is characterized by microcephaly and unusual development of the nose and orbits that produces an appearance suggesting an ancient Greek warrior’s helmet. Other anomalies commonly seen include cleft lip and palate and cardiac and renal defects. Seizure disorders are common, and the majority of patients have severe intellectual disability.

3. Cri du Chat Syndrome

Also known as 5p− (deletion of terminal chromosome 5p), this disorder is characterized by unique facial features, growth retardation, and microcephaly. Patients have an unusual catlike cry. Most patients have major organ anomalies and significant intellectual disability.

Contiguous Gene Disorders

Three common contiguous gene disorders which are usually suspected on the basis of an abnormal phenotype and then confirmed microarray are Williams syndrome, Smith-Magenis syndrome, and Velocardiofacial syndrome. The meiotic mechanisms responsible for interstitial chromosomal deletions causing these disorders also result in duplications. We now understand that interstitial chromosomal duplications in the following regions also produce abnormal phenotypes:

1. Williams Syndrome

Williams syndrome is a contiguous gene disorder that deletes the gene for elastin and other neighboring genes at 7q11.2. It is characterized by short stature; congenital heart disease (supravalvular aortic stenosis); coarse, elfin-like facies with prominent lips; hypercalcemia or hypercalciuria in infancy; developmental delay; and neonatal irritability evolving into an overly friendly personality. Calcium restriction may be necessary in early childhood to prevent nephrocalcinosis. The hypercalcemia often resolves during the first year of life. The natural history includes progression of cardiac disease and predisposition to hypertension and spinal osteoarthritis in adults. Most patients have mild to moderate intellectual deficits.

Duplication of chromosome 7q11.2 results in a syndrome that includes speech delay, and features of autistic spectrum disorders. Physical features are less consistent than in Williams syndrome.

Van der Aa et al: Fourteen new cases contribute to the characterization of the 7q11.23 microdupliction syndrome. Europ J Med Genet 2009;52:94 [PMID: 19249392].

2. Smith-Magenis Syndrome

This syndrome is associated with microdeletion of 17p11 and is characterized by prominent forehead, deep-set eyes, cupid-shaped upper lip, self-mutilating behavior, sleep disturbance, and intellectual disabilities. Some patients also have seizure disorders, hearing loss, thyroid disease, and immunological and lipid abnormalities.

Duplication of 17p11 produces Potocki-Lupski syndrome that is characterized by growth failure, variable levels of cognitive deficiencies, autistic features, and, occasionally, structural abnormalities of the heart.

Potocki L et al: Characterization of Potocki-Lupksi syndrome ([Dup(17)(p11.2p11.2]) and delineation of a dosage sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 2007;80:633 [PMID: 17357070].

3. Velocardiofacial Syndrome (Deletion 22q11 Syndrome)

Also known as DiGeorge syndrome, this condition was originally described in newborns presenting with cyanotic congenital heart disease, usually involving great vessel abnormalities; thymic hypoplasia leading to immunodeficiency; and hypocalcemia due to absent parathyroid glands. This chromosomal abnormality is associated with a highly variable phenotype. Characteristics include mild microcephaly, palatal clefting or incompetence, speech and language delays, and congenital heart disease (Great vessel abnormalities, tetralogy of Fallot, and a variety of other abnormalities). Some affected individuals are predisposed to psychosis.

Duplication of the 22q11 region produces a mild and highly variable phenotype that ranges from developmental delays and learning disabilities to functionally normal.

Ou Z et al: Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes. Genet Med 2008;10:267 [PMID: 18414210].



Neurofibromatosis, Marfan syndrome, achondroplasia, osteogenesis imperfecta, and the craniosynostoses are among the most well-known autosomal dominant disorders. There are many other common autosomal dominant disorders, including Treacher Collins syndrome, associated with a distinct craniofacial phenotype including malar and mandibular hypoplasia, and Noonan syndrome, which has a phenotype similar to Turner syndrome and is characterized by short stature and a webbed neck. Two other common genetic disorders whose causative genes were recently identified and found to be dominant mutations are CHARGE syndrome and Cornelia de Lange syndrome.

1. Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF-1) is one of the most common autosomal dominant disorders, occurring in 1 per 3000 births and seen in all races and ethnic groups. In general, the disorder is progressive, with new manifestations appearing over time. Neurofibromatosis type 2 (NF-2), characterized by bilateral acoustic neuromas, with minimal or no skin manifestations, is a different disease caused by a different gene.

The gene for NF-1 is on the long arm of chromosome 17 and seems to code for a protein similar to a tumor suppresser factor. NF results from many different mutations of this gene. Approximately half of all NF cases are caused by new mutations. Careful evaluation of the parents is necessary to provide accurate genetic counseling. Recent evidence suggests that penetrance is close to 100% in those who carry the gene if individuals are examined carefully.

Café au lait macules may be present at birth, and about 80% of individuals with NF-1 will have more than six by age 1 year. Neurofibromas are benign tumors consisting of Schwann cells, nerve fibers, and fibroblasts; they may be discrete or plexiform. The incidence of Lisch nodules, which can be seen with a slit lamp, also increases with age. Affected individuals commonly have a large head, bony abnormalities on radiographic studies, scoliosis, and a wide spectrum of developmental problems. Although the average IQ is within the normal range, it is lower than in unaffected family members. (For more details of medical evaluation and treatment, see Chapter 25 of this book.) Useful information is provided on the following website:

Hyperpigmented macules can occur in other conditions such as Albright, Noonan, Leopard, and Banayan-Riley-Ruvalcaba (BRR) syndromes. The genes for NF-1, Noonan, and Leopard syndromes are molecules which control cell cycling through the RAS-MAPK signal transduction pathways; therefore, it is not surprising that some features can be shared.

2. Marfan Syndrome


image Skeletal abnormalities (Ghent criteria).

image Lens dislocation.

image Dilation of the aortic root.

image Dural ectasia.

image Positive family history.

image Clinical Findings

Genetic testing is available for mutations causing Marfan syndrome, but the diagnosis remains largely clinical and is based on the Ghent criteria (available at: Children most often present with a positive family history, suspicious skeletal findings, or ophthalmologic complications. Motor milestones are frequently delayed due to joint laxity and mild myopathy. Adolescents are prone to spontaneous pneumothorax. Dysrhythmias may be present. Aortic and valvular complications are not common in children but are more likely in sporadic cases. The characteristic facies is long and thin, with down-slanting palpebral fissures. The palate is high arched, and dentition is often crowded. The uvula may be bifid.

Marfan syndrome is genetically heterogeneous. Mutations in the gene for fibrillin-1 proteins (FBN1) are most common but mutations in (FBN2) and in transforming growth factor β receptors (TGFBR1 and 2) can also produce phenotypes that fit criteria for a clinical diagnosis of Marfan syndrome.

image Differential Diagnosis

Homocystinuria should be excluded through metabolic testing in all individuals with marfanoid skeletal features. An X-linked recessive disorder, Lujan syndrome, combines marfanoid habitus with cognitive disability. Other connective tissue disorders, Ehlers-Danlos syndrome, and Stickler syndrome should also be considered.

Genes mutated in Marfan syndrome can also be mutated in related disorders: Beal syndrome (FBN2), Shprintzen-Goldberg syndrome (FBN1), and the recently described Loeys-Dietz syndrome (TGFBR1 and TGFBR2). The reader is referred to reviews available at for descriptions of these disorders.

image Complications

The skeletal problems including scoliosis are progressive. Astigmatism and myopia are very common and surveillance for lens dislocation is necessary.

The most serious associated medical problems involve the heart. Although many patients with Marfan syndrome have mitral valve prolapse, the most serious concern is progressive aortic root dilation, which may lead to aneurysmal rupture and death, and progressive or acute valvular (aortic more frequently than mitral) incompetency.

Families and practitioners seeking additional information about Marfan syndrome can be referred to the National Marfan Foundation (

image Treatment

A. Medical Therapy

Medical treatment for patients with Marfan syndrome includes surveillance for and appropriate management of the ophthalmologic, orthopedic, and cardiac issues. Serial echocardiograms are indicated to diagnose and follow the degree of aortic root enlargement, which can be managed medically or surgically, in more severe cases. Prophylactic β-adrenergic blockade can slow the rate of aortic dilation and reduce the development of aortic complications.

Interest in the effects of deficient extracellular fibrillin-1 has led to the discovery that the mild myopathy in Marfan syndrome reflects excessive signaling by transforming growth factor β (TGFβ), an inhibitor of myoblast differentiation. Animal studies suggest that aortic aneurysm can be prevented by TGFβ antagonists, including blockers of angiotensin II type 1 receptors. Research studies are currently underway using this approach in human patients.

B. Genetic Counseling

Genetic testing for mutations in FBN1 and FBN2 and in TGFBR1 and TGFBR2 should be considered in all individuals with Marfan syndrome as penetrance is variable and apparently unaffected family members can carry and pass on mutations.

3. Achondroplasia

Achondroplasia, the most common form of skeletal dysplasia, is caused by a mutation in FGFR3.

image Clinical Findings

The classic phenotype includes relative macrocephaly, mid-face hypoplasia, short-limbed dwarfism, and trident-shaped hands. The phenotype is apparent at birth. Individuals with achondroplasia are cognitively normal.

image Treatment

A. Medical Therapy

Orthopedic intervention is necessary for spinal problems including severe lumbar lordosis and gibbus deformity. Long bone lengthening surgery may help to improve upper extremity function.

Head circumference during infancy must be closely monitored and plotted on a diagnosis-specific head circumference chart. Bony overgrowth at the level of the foramen magnum may lead to progressive hydrocephalus and brainstem compression, and may warrant neurosurgical intervention.

Many patients find support through organizations such as the Little People of America, at the following website:

B. Genetic Counseling

The vast majority of cases (approximately 90%) represent a new mutation. Two hemizygous parents with achondroplasia have a 25% risk of having a child homozygous for FGFR3 mutations, which is a lethal disorder.

4. Osteogenesis Imperfecta

Osteogenesis imperfecta (OI), or brittle bone disease, is a relatively common disorder. The more common forms are caused by mutations in type I collagen.

image Clinical Findings

A number of types of OI have now been described, and abnormalities in Type 1 Collagen can now be tested via DNA analysis. The four most common types of OI are

1. Type I, a mild form, with increased incidence of fracturing and blue sclerae.

2. Type II, usually lethal in the newborn period with multiple congenital fractures and severe lung disease.

3. Type III, a severe form causing significant bony deformity secondary to multiple fractures (many of which are congenital), blue sclerae, short stature, and mild restrictive lung disease.

4. Type IV, another mild form with increased incidence of fracturing after birth; dentinogenesis imperfecta is common.

image Treatment

A. Medical Therapy

A major advancement in the treatment of OI patients has been the use of pamidronate, and other bisphosphonate compounds, which have been reported to lead to a reduced incidence of fracture and improve bone density. Patients should be followed by an experienced orthopedist, as rodding of long bones and surgery to correct scoliosis are often required. Hearing assessments are indicated, because of the association between OI and deafness. Close dental follow-up is also necessary.

B. Genetic Counseling

The four main types of OI are associated with mutations in the genes coding for type I collagen. DNA analysis in blood can confirm the diagnosis. The milder forms may be seen as the result of dominant inheritance, while the more severe forms of OI generally result from new mutations.

5. Craniosynostosis Syndromes

The craniosynostosis disorders are common dominant disorders associated with premature fusion of cranial sutures. This class of disorders is usually caused by mutations in FGFR genes.

Crouzon syndrome is the most common of these disorders and is associated with multiple suture fusions, but with normal limbs. Other craniosynostosis disorders have limb as well as craniofacial anomalies, and include Pfeiffer, Apert, Jackson-Weiss, and Saethre-Chotzen syndromes.

Patients with craniosynostosis often have shallow orbits, midface narrowing that may result in upper airway obstruction, and hydrocephalus that may require shunting. Children with craniosynostosis may require multiple-staged craniofacial and neurosurgical procedures to address these issues, but usually have normal intelligence.

6. CHARGE Syndrome

CHARGE syndrome affects structures derived from rostral neural crest cells but also includes abnormal development of the eyes and midbrain. The acronym CHARGE serves as a mnemonic for associated abnormalities that include Colobomas, congenital Heart disease, choanal Atresia, growth Retardation, Genital abnormalities (hypogenitalism), and Ear abnormalities, with deafness. Facial asymmetry is a common finding. CHARGE is now known to be caused by mutations in the CHD7 gene on chromosome 8q. A website with information on CHARGE syndrome is available at

Bergman JE et al: CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype. J Med Genet 2011 May;48(5):334–342 [Epub 2011 Mar 4] [PMID: 21378379].

7. Cornelia de Lange Syndrome

Cornelia de Lange syndrome is characterized by severe growth retardation; limb, especially hand, reduction defects (50%); congenital heart disease (25%); and stereotypical facies with hirsutism, medial fusion of eyebrows (synophrys), and thin, down-turned lips. The course and severity are variable, but the prognosis for survival and normal development is poor.

Heterozygous mutations in the cohesin regulator, NIPBL, or the cohesin structural components SMC1A and SMC3, have been identified in approximately 65% of individuals with CdLS. Cohesin regulates sister chromatid cohesion during mitotis and meiosis. In addition, cohesin has been demonstrated to play a critical role in the regulation of gene expression. Furthermore, multiple proteins in the cohesin pathway are also involved in additional fundamental biological events such as double-stranded DNA break repair, chromatin remodeling, and maintaining genomic stability.

Jones KL: Recognizable Patterns of Human Malformation, 6th ed. Philadelphia, PA: Elsevier; 2006.

Liu J et al: Cornelia de Lange syndrome. Adv Exp Med Biol 2010;685:111–123 [PMID: 20687500].

8. Noonan Syndrome

Noonan syndrome is a common autosomal dominant disorder characterized by short stature, congenital heart disease, abnormalities of cardiac conduction and rhythm, webbed neck, down-slanting palpebral fissures, hearing loss, and low-set ears. The phenotype evolves with age and may be difficult to recognize in older patients. Mild developmental delays are often present. Recent advances in molecular genetic research have led to the definition of the RAS-mitogen-activated protein kinase (MAPK) pathway disorders or “RASopathies.” They comprise Noonan syndrome and related disorders (cardiofaciocutaneous and Costello syndromes), as well as neurofibromatosis type 1. A blood test that screens for the approximately 12 genes in this pathway is called a Noonan chip, and can help diagnose patients with Noonan syndrome and related disorders.

Products of proto-oncogenes help control cell cycling through RAS-MAPK signal transduction pathways. Cell cycling controls are also affected by mutations in other genes that produce more complicated Noonan-like disorders (ie, Costello and cardiofaciocutaneous syndromes) in which cardiomyopathies are prominent. Because mutations causing NF-1 also affect RAS proto-oncogene signaling, it is not surprising that there is an NF-1 subtype with a so-called Noonan phenotype.

Constitutional overactivation at various levels of the RAS-MAPK pathway causes overlapping syndromes, comprising characteristic facial features, cardiac defects, cutaneous abnormalities, growth deficit, neurocognitive delay, and predisposition to malignancies. Each syndrome also exhibits unique features that probably reflect genotype-related specific biological effects.

Zenker M: Clinical manifestations of mutations in RAS and related intracellular signal transduction factors. Curr Opin Pediatr 2011 Aug;23(4):443–451 [PMID: 21750428].


1. Cystic Fibrosis

The gene for cystic fibrosis, CFTR, is found on the long arm of chromosome 7. Approximately 1 in 22 persons are carriers. Many different mutations have been identified; the most common mutation in the Caucasian population is known as Δ F508.

Cloning of the gene for cystic fibrosis and identification of the mutation in the majority of cases have completely changed genetic counseling and prenatal diagnosis for this disorder, although the sweat chloride assay is still important in confirming the diagnosis.

The identification of the mutation in the cystic fibrosis gene has also raised the issue of mass newborn screening, because of the high frequency of this gene in the Caucasian population. Some states, such as Colorado, have offered newborn screening by trypsinogen assay, which can detect 70% of patients with cystic fibrosis. Although early detection can ensure good nutritional status starting at birth, newborn screening is controversial as there is no cure for cystic fibrosis. (For more details of medical management, see Chapters 19 and 22.)

2. Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome is caused by a metabolic error in the final step of cholesterol production, resulting in low cholesterol levels and accumulation of the precursor 7-dehydrocholesterol (7-DHC). Because cholesterol is a necessary precursor for sterol hormones, bile acids and CNS myelin, and cholesterol content is crucial for the integrity of all cell membranes, the medical consequences of both cholesterol deficiency and 7-DHC accumulation are complex and severe. A number of other genetic disorders involving cholesterol biosynthesis more proximally in the pathway have been recently described (ie, Desmosterolosis), but are quite rare with a very severe and often lethal phenotype.

image Clinical Findings

Patients with Smith-Lemli-Opitz syndrome present with a characteristic phenotype, including dysmorphic facial features (Figure 37–9), multiple congenital anomalies, hypotonia, growth failure, and intellectual disability. The diagnosis can be confirmed via a simple blood test looking for the presence of the precursor, 7-DHC. DNA analysis of mutations in the DHR7 gene is also available. Prenatal testing is available.


image Figure 37–9. Child with Smith-Lemli-Opitz syndrome, featuring bitemporal narrowing, upturned nares, ptosis, and small chin.

image Treatment

Treatment with cholesterol can ameliorate the growth failure and lead to improvement in medical issues, although treatment does not cure this complex disorder. Antioxidant treatment is being used to prevent progressive retinal degeneration.

3. Sensorineural Hearing Loss

Although there is marked genetic heterogeneity in causes of sensorineural hearing loss, including dominant, recessive, and X-linked patterns, nonsyndromic, recessively inherited deafness is the predominant form of severe inherited childhood deafness. Several hundred genes are known to cause hereditary hearing loss and deafness. The hearing loss may be conductive, sensorineural, or a combination of both; syndromic or nonsyndromic; and prelingual (before language develops) or postlingual (after language develops). The genetic forms of hearing loss are diagnosed by otologic, audiologic, and physical examination; family history; ancillary testing (such as CT examination of the temporal bone); and molecular genetic testing. Molecular genetic tests are available for many types of syndromic and nonsyndromic deafness, but often only on a research basis. In the clinical setting, molecular genetic testing is available for some recessive conditions including Usher syndrome types 2A (USH2A gene) and 3 (one mutation in USH3A), and at least six other rare forms of genetically caused deafness.

Testing for deafness-causing mutations in two more common genes, GJB2 (which encodes the protein connexin 26) and GJB6 (which encodes the protein connexin 30), plays a prominent role in diagnosis and genetic counseling. Mutations in connexin 26 are present in 49% of cases of prelingual deafness.

Edi Lúcia Sartorato, Karen Friderici, Ignacio Del Castillo: Genetics of deafness. Genet Res Int 2012;2012: (Article ID 562848). doi:10.1155/2012/562848 [PMID: 22567392].

Nance WE: The genetics of deafness. Ment Retard Dev Disabil Res Rev 2003;9:109 [PMID: 12784229].

4. Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder in which anterior horn cells in the spinal cord degenerate. The mechanism for the loss of cells appears to involve apoptosis of neurons in the absence of the product of the SMN1 (survival motor neuron) gene located on chromosome 5q. Loss of anterior horn cells leads to progressive atrophy of skeletal muscle. The disorder has an incidence of approximately 1 in 12,000, with the majority of the cases presenting in infancy. Carrier frequencies approach 1 in 40 in populations with European ancestry.

image Clinical Findings

Three clinical subtypes are recognized based on age of onset and rate of progression. SMA I is the most devastating. Mild weakness may be present at birth but is clearly evident by 3 months and is accompanied by loss of reflexes and fasciculations in affected muscles. Progression of the disorder leads to eventual respiratory failure, usually by age 1 year. Symptoms of SMA II begin later, with weakness and decreased reflexes generally apparent by age 2 years. Children affected with SMA III begin to become weak as they approach adolescence.

Homozygous deletion of exon 7 of SMN1 is detectable in approximately 95%–98% of cases of all types of SMA and confirms the diagnosis. The SMN1 region on chromosome 5q is complex and variability in presentation of the disorder involves expression of up to three copies of the neighboring SMN2 gene. More severe phenotypes have fewer SMN2 copies. Approximately 2%–5% of patients affected with SMA will be compound heterozygotes in whom there is one copy of SMN1 with exon 7 deleted and a second copy with a point mutation.

Prenatal diagnosis is available through genetic testing, but careful molecular analysis of the proband and demonstration of carrier status in parents is advised since, in addition to the problem of potential compound heterozygosity, 2% of cases occur as a result of a de novo mutation in one SMN1 allele. In this case, one of the parents is not a carrier and recurrence risks are low. Carrier testing is further complicated by a duplication of SMN1 in 4% of the population that results in there being two SMN1 genes on one of their chromosomes. Hence, reproductive risk assessment, carrier testing, and prenatal diagnosis of SMA are best undertaken in the context of careful genetic counseling.


1. Duchenne & Becker Muscular Dystrophies

Duchenne muscular dystrophy (DMD) results from failure of synthesis of the muscle cytoskeletal protein dystrophin, the gene for which is located on the X chromosome, Xp12. Approximately 1 in 4000 male children is affected. Mutations in the same gene that result in partial expression of the dystrophin protein produce a less severe phenotype, Becker muscular dystrophy (BMD). In both DMD and BMD, progressive degeneration of skeletal and cardiac muscle occurs. Boys with DMD exhibit proximal muscle weakness and pseudohypertrophy of calf muscles by age 5–6 years. Patients become nonambulatory by age 13. Serum creatine kinase levels are markedly elevated. Boys with DMD frequently die in their twenties of respiratory failure and cardiac dysfunction. The prognosis for BMD is more variable. Although corticosteroids are useful in maintaining strength, they do not slow progression of the disorder. Evolution of the natural history of dystrophinopathies in females is demonstrating an increased incidence of serious cardiovascular disease, including cardiomyopathy and arrhythmias.

The gene for dystrophin is very large and a common target for mutation. Large deletions or duplications can be detected in the gene for dystrophin in 65% of cases. Molecular analysis has largely replaced muscle biopsy for diagnostic purposes.

One-third of DMD cases presenting with a negative family history are likely to be new mutations. Genetic counseling is complicated by the fact that germline mosaicism for mutations in the dystrophin gene occur in approximately 15%–20% of families, which is among the highest rates for this otherwise rare phenomenon. It is also necessary to look for mutations in all sisters of affected boys. Since mutations are now detected in the great majority of DMD cases, there is considerably less need for estimating carrier risks based on creatine kinase levels or using genetic linkage for prenatal diagnosis. Nonetheless, counseling and prenatal diagnosis remain difficult in some families. (Additional information about muscular dystrophies is included in Chapter 25.)

2. Hemophilia

Hemophilia A is an X-linked, recessive, bleeding disorder caused by a deficiency in the activity of coagulation factor VIII. Affected individuals develop a variable phenotype of hemorrhage into joints and muscles, easy bruising, and prolonged bleeding from wounds. The disorder is caused by heterogeneous mutations in the factor VIII gene, which maps to Xq28. Carrier detection and prenatal diagnosis are possible. Replacement of factor VIII is done using a variety of preparations derived from human plasma or recombinant techniques. Although replacement therapy is effective in most cases, 10%–15% of treated individuals develop neutralizing antibodies that decrease its effectiveness. (See Chapter 30 for additional discussion.)

Darras BT, Miller DT, Urion DK: Dystrophinopathies. GeneReviews.



1. Beckwith-Wiedemann Syndrome

The association of macrosomia (enlarged body size), macroglossia (enlarged tongue), and omphalocele constitutes the Beckwith-Wiedemann syndrome (BWS), now known to be related to abnormal expression of genes located on chromosome 11p15. Other associated findings include hypertelorism, unusual ear creases, infantile hypoglycemia due to transient hyperinsulinemia, multiple congenital anomalies (cleft palate and genitourinary anomalies common), and increased risk for certain malignancies, especially Wilms tumor (7%–10%).

A growth factor gene, IGF2, is imprinted such that the maternal allele is ordinarily not expressed during intrauterine development. Chromosomal abnormalities such as duplication of the paternal 11p15 region, or paternal UPD, are associated with BWS. Paternal UPD may also lead to loss of expression of a tumor suppressor gene (H19), normally read from the maternal homolog, contributing to the increased predisposition to cancer seen in this disorder. Children affected with BWS should undergo tumor surveillance protocols, including an abdominal ultrasound every 3 months until they reach age 8 years, as diagnosing malignancy at early stages leads to a significant improvement in outcome.

2. Prader-Willi Syndrome

Prader-Willi syndrome results from lack of expression of several imprinted genes, including SNRPN, located on chromosome 15q11. Clinical characteristics include severe hypotonia in infancy, often necessitating placement of a feeding gastrostomy tube. In older children, characteristic facies evolve over time, including almond-shaped eyes, along with frequent strabismus and obstructive sleep apnea. Short stature, obesity, hypogenitalism, and small hands and feet with tapering fingers are felt to be associated with growth hormone deficiency and GH treatment is now offered to PWS patients. Obsessive hyperphagia (usual onset 3–4 years) is the hallmark of this disorder.

Deletion of the paternally inherited allele of chromosome 15q11 (detected by FISH or microarray) is the most common chromosomal abnormality causing Prader-Willi syndrome, followed by maternal UPD, diagnosed by DNA methylation studies.

3. Angelman Syndrome

Angelman syndrome also involves imprinting and results from a variety of mutations that inactivate a ubiquitin-protein ligase gene, UBE3A, located in the same region of chromosome 15 as SNRPN, the maternally imprinted gene involved in Prader-Willi syndrome (see the preceding section). UBE3A is paternally imprinted, and during normal development the maternal allele is expressed only in the brain. The classic phenotype includes severe intellectual disability with prognathism, seizures, and marked delay in motor milestones, abnormal gait and posturing, poor language development, autism, and paroxysmal laughter and tongue thrusting.

Angelman syndrome is most commonly caused when sequences detectable by microarray or FISH on 15q11 are deleted from the maternal homolog. Uniparental paternal disomy 15 is the least common cause. Mutations in UBE3Acause the disorder in about one-fourth of cases. Imprinting errors, which may be associated with advanced reproductive techniques, may also result in Angelman syndrome.

Iliadou AN, Janson PC, Cnattingius S: Epigenetics and assisted reproductive technology. J Intern Med 2011;270(5):414–420 [PMID: 21848664].

Niemitz EL, Feinberg AP: Epigenetics and assisted reproductive technology: A call for investigation. Am J Hum Genet 2004;74:599–609 [PMID: 14991528].


1. (Autosomal Dominant) Myotonic Dystrophy

Myotonic dystrophy is an autosomal dominant condition characterized by muscle weakness and tonic muscle spasms (myotonia). Additional features include: hypogonadism, frontal balding, cardiac conduction abnormalities, and cataracts. This disorder occurs when a CTG repeat in the DMPK gene on chromosome 19 expands to 50 or more copies. Normal individuals have from 5 to 35 CTG repeat copies. Individuals carrying 35–49 repeats are generally asymptomatic, but repeat copies greater than 35 are meiotically unstable and tend to further expand when passed to subsequent generations. Individuals with 50–100 copies may be only mildly affected (eg, cataracts). Most individuals with repeat copies greater than 100 will have symptoms or electrical myotonia as adults.

As unstable alleles continue to expand and copy numbers approach 400, symptoms become evident in children. Expansion from greater than 1000 copies produces fetal and neonatal disease that can be lethal. This occurs most frequently when the unstable repeats are passed through an affected mother. Therefore, an important component in the workup of the floppy or weak infant is a careful neurologic assessment of both parents for evidence of weakness or myotonia. Molecular testing that measures the number of CTG repeats is diagnostic clinically and prenatally. (See Chapter 25 for additional discussion.)

2. (Autosomal Recessive) Friedreich Ataxia

Symptoms of Friedreich ataxia include loss of coordination (cerebellar dysfunction) with both motor and sensory findings beginning in preadolescence and typically progressing through the teenage years. The gene involved, FDRA,is located on chromosome 9. Normal individuals carry 7–33 GAA repeats at this locus. Close to 96% of affected patients are homozygous for repeat expansions that exceed 66 copies. However, point mutations in the gene also occur. Meiotic instability for GAA repeats is more variable than for others and contractions occur more frequently than do expansions. Relationships between genotype and phenotype are also more complex. Molecular diagnostic testing requires careful interpretation with respect to prognosis and reproductive risks. (See Chapter 25 for additional discussion.)

3. (X-Linked) Fragile X Syndrome

Fragile X syndrome, present in approximately 1 in 1000 males, is the most common cause of cognitive disabilities in males. The responsible gene is FMR1, which has unstable CGG repeats at the 5′ end. Normal individuals have up to 50 CGG repeats. Individuals with 51–200 CGG repeats have a premutation and may manifest symptoms including developmental, behavioral, and physical traits; premature ovarian failure in a subset of females; and a progressive, neurologic deterioration in older males called FXTAS (Fragile X–associated tremor-ataxia syndrome). Affected individuals with Fragile X syndrome (full mutation) have more than 200 CGG repeats and also have hypermethylation of both the CGG expansion and an adjacent CpG island. This methylation turns off the FMR1 gene. DNA analysis, rather than cytogenetic testing, is the method of choice for confirming the diagnosis of Fragile X syndrome.

image Clinical Features

Most males with Fragile X syndrome present with intellectual disabilities, oblong facies with large ears, and large testicles after puberty. Other physical signs include symptoms suggestive of a connective tissue disorder (eg, hyperextensible joints or mitral valve prolapse). Many affected individuals are hyperactive and exhibit behaviors along the autism spectrum.

Unlike other X-linked disorders where female heterozygotes are asymptomatic, females with a full mutation may exhibit a phenotype ranging from normal IQ to intellectual disability, and autism, and may manifest other behavioral problems.

Clinical expression of Fragile X differs in male and female offspring depending on which parent is transmitting the gene. The premutation can change into the full mutation only when passed through a female. Identification of the abnormal DNA amplification by direct DNA analysis can confirm the diagnosis of Fragile X in an affected individual and can detect asymptomatic gene carriers of both sexes. Therefore, DNA analysis is a reliable test for prenatal and postnatal diagnosis of Fragile X syndrome and facilitates genetic counseling. (Management considerations for patients with Fragile X syndrome are described in Chapter 3.)

Hagerman PJ, Hagerman RJ: The fragile-X premutation: a maturing perspective. Am J Hum Genet 2004;74:805–816 [PMID: 15052536].


More than 100 point mutations and rearrangements of mtDNA have been identified, which are associated with a large number of human diseases. Symptoms of mitochondrial disorders are secondary to deficiency in the respiratory chain enzymes of oxidative phosphorylation, which supply energy to all cells. Mitochondrial diseases are usually progressive disorders with neurologic dysfunction including hypotonia, developmental delay, and seizures. Ophthalmologic issues, hearing loss, gastrointestinal tract dysfunction with growth failure, and renal, endocrine, cardiac, and autonomic dysfunction are some of the many issues which can affect patients with mitochondrial diseases. The following disorders are three of the more common ones.


MELAS is an acronym for Mitochondrial Encephalopathy, Lactic Acidosis, and Strokelike episodes. Symptoms occur in the pediatric age group and include recurrent episodes resembling stroke (blindness, paralysis), headache, vomiting, weakness of proximal muscles, and elevated blood lactate. (Note: Lactate may be falsely elevated secondary to technical difficulties in obtaining a free-flowing blood specimen or delay in laboratory measurement.) The most common mutation causing MELAS is in the tRNALeu gene (A3243G).


MERRF is an acronym for Myoclonus Epilepsy with Ragged Red Fibers. Children with MERRF present with a variety of neurologic symptoms, including myoclonus, deafness, weakness of muscles, and seizures. Eighty percent of cases are due to a missense mutation in the mitochondrial tRNALys gene (A8344G).

3. Leigh Subacute Necrotizing Encephalomyelopathy

Multiple different abnormalities in respiratory chain function lead to Leigh disease, a very severe disorder associated with progressive loss of developmental milestones, along with extrapyramidal symptoms and brainstem dysfunction. Episodes of deterioration are frequently associated with an intercurrent febrile illness. Symptoms include hypotonia, unusual choreoathetoid hand movements, feeding dysfunction with failure to thrive, and seizures. Focal necrotic lesions of the brainstem and thalamus are hallmarks on MRI scan. Mitochondrial mutations affecting the respiratory chain, especially complexes I, II, and IV, and nuclear DNA mutations affecting complex II have been identified as causing Leigh disease.

Wong LJ, Scaglia F, Graham BH, Craigen WJ: Current molecular diagnostic algorithm for mitochondrial disorders. Mol Genet Metab 2010 Jun;100(2):111–117 [PMID: 20359921].




image Cleft lip is more common in males, cleft palate in females.

image Cleft lip and palate may be isolated defects (nonsyndromic) or associated with other anomalies as part of a genetic disorder (syndromic).

image Pierre Robin sequence, the association of cleft palate, micrognathia, and glossoptosis may lead to severe airway complications in young infants, necessitating tracheostomy.

image General Considerations

From a genetic standpoint, cleft lip with or without cleft palate is distinct from isolated cleft palate. Although both can occur in a single family, particularly in association with certain syndromes, this pattern is unusual. Racial background is a factor in the incidence of facial clefting. Among Asians, Caucasians, and blacks, the incidence is 1.61, 0.9, and 0.31, respectively, per 1000 live births.

image Findings

A cleft lip may be unilateral or bilateral and complete or incomplete. It may occur with a cleft of the entire palate or just the primary (anterior and gingival ridge) or secondary (posterior) palate. An isolated cleft palate can involve only the soft palate or both the soft and hard palates. It can be a V-shaped or a wide horseshoe, U-shaped cleft. When the cleft palate is associated with micrognathia and glossoptosis (a tongue that falls back and causes respiratory or feeding problems), it is called the Pierre Robin sequence. Among individuals with facial clefts—more commonly those with isolated cleft palate—the incidence of other congenital abnormalities is increased, with up to a 60% association with other anomalies or syndromes. The incidence of congenital heart disease, for example, is 1%–2% in liveborn infants, but among those with Pierre Robin sequence it can be as high as 15%. Associated abnormalities should be looked for in the period immediately after birth and before surgery.

image Differential Diagnosis

A facial cleft may occur in many different circumstances. It may be an isolated abnormality or part of a more generalized syndrome. Prognosis, management, and accurate determination of recurrence risks all depend on accurate diagnosis. In evaluating a child with a facial cleft, the physician must determine if the cleft is nonsyndromic or syndromic.

A. Nonsyndromic

In the past, nonsyndromic cleft lip or cleft palate was considered a classic example of polygenic or multifactorial inheritance. Several recent studies have suggested that one or more major autosomal loci, both recessive and dominant may be involved. Empirically, however, the recurrence risk is still in the range of 2%–3% because of nonpenetrance or the presence of other contributing genes.

B. Syndromic

Cleft lip, with or without cleft palate, and isolated cleft palate may occur in a variety of syndromes that may be environmental, chromosomal, single gene, or of unknown origin (Table 37–4). Prognosis and accurate recurrence risks depend on the correct diagnosis.

Table 37–4. Syndromic isolated cleft palate (CP) and cleft lip with or without cleft palate (CL/CP).


image Complications

Problems associated with facial clefts include early feeding difficulties, which may be severe; airway obstruction necessitating tracheostomy; recurrent serous otitis media associated with fluctuating hearing and language delays; speech problems, including language delay, hypernasality, and articulation errors; and dental and orthodontic complications.

image Treatment

A. Medical Therapy

Long-term management ideally should be provided through a multidisciplinary cleft palate clinic.

B. Genetic Counseling

Accurate counseling depends on accurate diagnosis and the differentiation of syndromic from nonsyndromic clefts. A complete family history must be taken, and the patient and both parents must be examined. The choice of laboratory studies is guided by the presence of other abnormalities and clinical suspicions, and may include microarray analysis and metabolic and DNA studies. Clefts of both the lip and the palate can be detected on detailed prenatal ultrasound.



image Various defects, ranging from anencephaly to open or skin-covered lesions of the spinal cord, may occur in isolation or as part of a syndrome.

image Myelomeningocele is usually associated with hydrocephalus, Arnold-Chiari II malformation, neurogenic bladder and bowel, and congenital paralysis in the lower extremities.

image Anomalies of the CNS, heart, and kidneys may also be seen.

image MRI helps determine the extent of the anatomic defect in skin covered lesions.

image General Considerations

Neural tube defects comprise a variety of malformations, including anencephaly, encephalocele, spina bifida (myelomeningocele), sacral agenesis, and other spinal dysraphisms. Evidence suggests that the neural tube develops via closure at multiple closure sites and that each closure site is mediated by different genes and affected by different teratogens. Hydrocephalus associated with the Arnold-Chiari type II malformation commonly occurs with myelomeningocele. Sacral agenesis, also called the caudal regression syndrome, occurs more frequently in infants of diabetic mothers.

image Clinical Findings

At birth, neural tube defects can present as an obvious rachischisis (open lesion), or as a more subtle skin-covered lesion. In the latter case, MRI should be conducted to better define the anatomic defect. The extent of neurologic deficit depends on the level of the lesion and may include clubfeet, dislocated hips, or total flaccid paralysis below the level of the lesion. Hydrocephalus may be apparent at birth or may develop after the back has been surgically repaired. Neurogenic bladder and bowel are commonly seen. Other anomalies of the CNS may be present, as well as anomalies of the heart or kidneys.

image Differential Diagnosis

Neural tube defects may occur in isolation (nonsyndromic) or as part of a genetic syndrome. They may result from teratogenic exposure to alcohol or the anticonvulsant valproate. Any infant with dysmorphic features or other major anomalies in addition to a neural tube defect should be evaluated by a geneticist, and a microarray analysis should be performed.

image Treatment

A. Neurosurgical Measures

Infants with an open neural tube defect should be placed in prone position, and the lesion kept moist with sterile dressing. Neurosurgical closure should occur within 24–48 hours after birth to reduce risk of infection. The infant should be monitored closely for signs of hydrocephalus. Shunts are required in about 85% of cases of myelomeningocele and are associated with complications including malfunction and infection. Symptoms of the Arnold-Chiari II malformation include feeding dysfunction, abducens nerve palsy, vocal cord paralysis with stridor, and apnea. Shunt malfunction may cause an acute worsening of Arnold-Chiari symptoms that may be life-threatening.

B. Orthopedic Measures

The child’s ability to walk varies according to the level of the lesion. Children with low lumbar and sacral lesions walk with minimal support, while those with high lumbar and thoracic lesions are rarely functional walkers. Orthopedic input is necessary to address foot deformities and scoliosis. Physical therapy services are indicated.

C. Urologic Measures

Neurogenic bladders have variable presentations. Urodynamic studies are recommended early on to define bladder function, and management is guided by the results of these studies. Continence can often be achieved by the use of anticholinergic or sympathomimetic agents, clean intermittent catheterization, and a variety of urologic procedures. Renal function should be monitored regularly, and an ultrasound examination should be periodically repeated. Symptomatic infections should be treated.

Symptoms of neurogenic bowel include incontinence and chronic constipation and are managed with a combination of dietary modifications, laxatives, stool softeners, and rectal stimulation. A surgical procedure called ACE (ante-grade continence enema) may be recommended for patients with severe constipation that is unresponsive to conservative management.

D. Genetic Counseling

Most isolated neural tube defects are polygenic, with a recurrence risk of 2%–3% in future pregnancies. The recurrence risk for siblings of the parents and siblings of the patients is 1%–2%. A patient with spina bifida has a 5% chance of having an affected child. Prenatal diagnosis is possible. In fetuses with open neural tube defects, maternal serum α-fetoprotein levels measured at 16–18 weeks’ gestation are elevated. α-Fetoprotein and acetylcholine esterase levels in amniotic fluid are also elevated. Ultrasound studies alone can detect up to 90% of neural tube defects.

Prophylactic folic acid can significantly lower the incidence and recurrence rate of neural tube defects, if the intake of the folic acid starts at least 3 months prior to conception and continues for the first month of pregnancy, at a dose of 4 mg/d for women at increased risk. For women of childbearing age without a family history of neural tube defects, the dose is 0.4 mg of folic acid daily. Folic acid supplementation prior to conception may also lower the incidence of other congenital malformations such as conotruncal heart defects.

image Special Issues & Prognosis

All children requiring multiple surgical procedures (ie, patients with spina bifida or urinary tract anomalies) have a significant risk for developing hypersensitivity type I (IgE-mediated) allergic reactions to latex. For this reason, nonlatex medical products are now routinely used when caring for patients with neural tube defects.

Most individuals with spina bifida are cognitively normal, but learning disabilities are common. Individuals with encephalocele or other CNS malformations generally have a much poorer intellectual prognosis. Individuals with closed spinal cord abnormalities (eg, sacral lipomas) have more mild issues in general, and intelligence is usually normal. Spinal cord tethering may present later with symptoms of back pain, progressive scoliosis, and changes in bowel or bladder function. This often requires neurosurgical intervention.

Individuals with neural tube defects have lifelong medical issues, requiring the input of a multidisciplinary medical team. A good support for families is the National Spina Bifida Association, at the following website:


The text that follows describes several important and common human malformation syndromes. The best illustrations of these syndromes are found in Smith’s Recognizable Patterns of Human Malformation. An excellent Internet site at the University of Kansas Medical Center can be consulted for further information:

1. Arthrogryposis Multiplex

The term arthrogryposis is often used as shorthand to describe multiple congenital contractures that affect two or more different areas of the body. Arthrogryposis is not a specific diagnosis, but rather a clinical finding, and it is a characteristic of more than 300 different disorders. Causes most often involve constraint, CNS maldevelopment or injury, and neuromuscular disorders. Polyhydramnios is often present as a result of lack of fetal swallowing. Pulmonary hypoplasia may also be present, reflecting lack of fetal breathing. The workup includes brain imaging, careful consideration of metabolic disease, neurologic consultation, and, in some cases, electrophysiologic studies and muscle biopsy. The parents should be examined, and a family history reviewed carefully for findings such as muscle weakness or cramping, cataracts, and early-onset heart disease, suggesting myotonic dystrophy. Mutations in at least five genes (TNNI2TNNT3TPM2MYH3, and MYH8) that encode components of the contractile apparatus of fast-twitch myofibers can cause distal arthrogryposis.

Bamshad M et al: Arthrogryposis: a review and update. J Bone Joint Surg Am 2009 July 1;91(Suppl 4):40–46 [PMID: 19571066].

2. Goldenhar Syndrome

Goldenhar syndrome, also known as vertebro-auriculofacial syndrome, is an association of multiple anomalies involving the head and neck. The classic phenotype includes hemifacial microsomia (one side of the face smaller than the other), and abnormalities of the pinna on the same side with associated deafness. Ear anomalies may be quite severe and include anotia. A characteristic benign fatty tumor in the outer eye, called an epibulbar dermoid, is frequently present, as are preauricular ear tags. Vertebral anomalies, particularly of the cervical vertebrae, are common. The Arnold-Chiari type I malformation (herniation of the cerebellum into the cervical spinal canal) is a common associated anomaly. Cardiac anomalies and hydrocephalus are seen in more severe cases. Most patients with Goldenhar syndrome have normal intelligence. The cause is unknown; however, there is significant overlap with the Townes-Brocks syndrome, caused by mutations in the SALL1 gene. (See Craniofacial Microsomia Overview, GeneReviews, for an excellent discussion and differential diagnosis.)

3. Oligohydramnios Sequence (Potter Sequence)

This condition presents in newborns as severe respiratory distress due to pulmonary hypoplasia in association with positional deformities of the extremities, usually bilateral clubfeet, and typical facies consisting of suborbital creases, depressed nasal tip and low-set ears, and retrognathia. The sequence may be due to prolonged lack of amniotic fluid. Most often it is due to leakage, renal agenesis, or severe obstructive uropathy.

4. Overgrowth Syndromes

Overgrowth syndromes are becoming increasingly recognized as important childhood conditions. They may present at birth and are characterized by macrocephaly, motor delays (cerebral hypotonia), and occasional asymmetry of extremities. Bone age may be advanced. The most common overgrowth syndrome is Sotos syndrome. Patients with Sotos syndrome have a characteristic facies with a prominent forehead and down-slanting palpebral features. Mutations in NSD1 cause Sotos syndrome. Patients have a small but increased risk of cancer.

Other overgrowth syndromes include BWS (described earlier), and two single-gene disorders, Simpson-Golabi-Behmel syndrome and Bannayan-Riley-Ruvalcaba syndrome. Patients with Simpson-Golabi-Behmel syndromeexhibit a BWS-like phenotype, but with additional anomalies, including polydactyly and more severe facial dysmorphism. Unlike patients with BWS, who have normal intelligence, patients with Simpson-Golabi-Behmel syndrome often have developmental delay. It is inherited as an X-linked disorder. Patients with Bannayan-Riley-Ruvalcaba syndrome have macrosomia, macrocephaly, and unusual freckling of the penis. They may present with autism. They may develop hemangiomatous or lymphangiomatous growths and have a predisposition to certain malignancies (thyroid, breast, colon cancer). The cause of Bannayan-Riley-Ruvalcaba syndrome is a mutation of the PTEN gene implicated in Cowden syndrome, the association of intestinal polyposis with malignant potential. Proteus syndrome was recently found to be caused by mosaic AKT-1 mutation.

Lindhurst MJ et al: A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011 Aug 18; 365(7):611–619 [Epub 2011 Jul 27] [PMID: 21793738].

5. Syndromic Short Stature

Short stature is an important component of numerous syndromes, or it may be an isolated finding. In the absence of nutritional deficiencies, endocrine abnormalities, evidence of skeletal dysplasia (disproportionate growth with abnormal skeletal films), or a positive family history, intrinsic short stature can be due to UPD. The phenotype of Russell-Silver syndrome—short stature with normal head growth (pseudohydrocephalus), normal development, and minor dysmorphic features (especially fifth finger clinodactyly)—has been associated in some cases with maternal UPD7.

6. VACTERL Association

The disorder is sporadic, and some of the defects may be life-threatening. The prognosis for normal development is good. The cause is unknown, but a high association with monozygotic twinning suggests a mechanism dating back to events perhaps as early as blastogenesis.

Careful examination and follow-up are important, because numerous other syndromes have overlapping features. Microarray studies and genetic consultation are warranted.


VACTERL association is described by an acronym denoting the association of the following:

image Vertebral defects (segmentation anomalies).

image Imperforate anus.

image Cardiac malformation (most often ventricular septal defect).

image Tracheoesophageal fistula.

image Renal anomalies.

image Limb (most often radial ray) anomalies.

7. Kabuki syndrome

Kabuki syndrome (KS) is characterized by typical facial features (elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild to moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities including isolated premature thelarche in females, feeding problems, and hearing loss. Molecular genetic testing for MLL2, the only gene in which mutations are known to cause KS, is available on a clinical basis. The cause is heterogeneous, as not all individuals with Kabuki syndrome were found to have a MLL2 mutation.

Adam MP et al: Kabuki syndrome. GeneReviews.


Cognitive disabilities or developmental delays affect 8% of the population. Disorders associated with symptoms of delayed development are heterogeneous but frequently include heritable components. Evaluation should be multidisciplinary; Table 37–5 lists the main features of developmental delay, emphasizing the major clinical and genetic considerations. (See Chapter 3 for additional information about developmental delay and intellectual disability.)

Table 37–5. Evaluation of the child with developmental delay.


Obtaining a detailed history, including pertinent prenatal and perinatal events, is critical. Feeding issues and slow growth velocity are seen in many genetic disorders causing developmental delay. Rate of developmental progress and particularly a history of loss of skills are important clues, as the latter might suggest a metabolic disorder with a neurodegenerative component. Family history can provide clues to suggest possible genetic etiologies, particularly if there is a history of consanguinity or a family pattern of other affected individuals.

Physical examination provides helpful clues. Referral to a clinical geneticist is indicated whenever unusual features are encountered. Neurologic, ophthalmologic, and audiologic consultation should be sought when indicated. Brain imaging should be requested in cases involving unexplained deviations from normal head growth. Neuroimaging and skeletal studies may also be indicated when dysmorphic features are present.

Metabolic and genetic testing procedures other than those listed in the Table 37–5 may also be indicated.

Interpretation & Follow-Up

Clinical experience indicates that specific diagnoses can be made in approximately half of patients evaluated according to the protocol presented here. With specific diagnosis comes prognosis, ideas for management, and insight into recurrence risks. Prenatal diagnosis may also become possible.

Follow-up is important both for patients in whom diagnoses have been made and for those patients initially lacking a diagnosis. Genetic information is accumulating rapidly and can be translated into new diagnoses and better understanding with periodic review of clinical cases.


Autism is a developmental disorder comprising abnormal function in three domains: language development, social development, and behavior. Many patients with autism also have cognitive disabilities and might be appropriately evaluated according to the recommendations above. However, given the enormous increase in prevalence of autism in the past decade (1 in 88 children per latest CDC report), it is worth discussing the genetic evaluation of autism separately.

There are multiple known genetic causes of autism. Advances in molecular diagnosis, understanding of metabolic derangements, and technologies such as microarray are allowing more patients with autism to be identified with specific genetic disorders. This allows more accurate genetic counseling for recurrence risk, as well as diagnosis-specific interventions which may improve prognosis.

With this in mind, recommendations for the genetic evaluation of a child with autism include the following:

1. Genetic referral if dysmorphic features or cutaneous abnormalities are present (ie, hypopigmented spots such as those seen in patients with tuberous sclerosis).

2. Laboratory testing to include the following:

A. Microarray.

B. Molecular testing for Fragile X syndrome.

C. Methylation testing for UPD15 if phenotype is suggestive of Angelman syndrome.

D. Measurement of cholesterol and 7-DHC if syndactyly is present between the second and third toes, to rule out a mild form of Smith-Lemli-Opitz syndrome.

E. MECP2 testing if clinical course is suggestive of Rett syndrome (ie, neurodegenerative course, progressive microcephaly, and seizures in a female patient).

F. PTEN molecular testing if the head circumference is greater than 2 standard deviations above the mean, plus evidence of penile freckling, lipomatous lesions, or a strong family history of certain malignancies.

Autism spectrum disorders are discussed in more detail in Chapter 3.



1. Drug Abuse & Fetal Alcohol Syndrome

Fetal alcohol syndrome (FAS) results from excessive exposure to alcohol during gestation and affects 30%–40% of offspring of mothers whose daily intake of alcohol exceeds 3 ounces. Features of the syndrome include: short stature, poor head growth (may be postnatal in onset), developmental delay, and midface hypoplasia characterized by a poorly developed long philtrum, narrow palpebral fissures, and short nose with anteverted nares. Facial findings may be subtle, but careful measurements and comparisons with standards (see Figure 37–8) are helpful. Structural abnormalities occur in half of affected children. Cardiac anomalies and neural tube defects are commonly seen. Genitourinary tract anomalies are frequent. Neurobehavioral effects in FAS include: poor judgment and inappropriate social interactions, and lack of stranger anxiety in toddlers. Cognitive deficiencies and behavioral problems may occur without other classic physical characteristics of fetal alcohol syndrome and constitute an alcohol-related neurological disorder (ARND).

Maternal abuse of psychoactive substances is also associated with increased risks for adverse perinatal outcomes including miscarriage, preterm delivery, growth retardation, and increased risk for injury to the developing CNS. Methamphetamine and crack cocaine are particularly dangerous. Maternal abuse of inhalants, such as glue, appears to be associated with findings similar to those of fetal alcohol syndrome.

Careful evaluation for other syndromes and chromosomal disorders should be included in the workup of exposed infants. Behavioral abnormalities in older children may be the result of maternally abused substances but they may also reflect evolving psychiatric disorders. Psychiatric disorders, many recognized as heritable, affect large numbers of men and women with substance abuse problems. Fetal alcohol spectrum disorders are discussed in more detail in Chapter 3.

2. Maternal Anticonvulsant Effects

Anticonvulsant exposure during pregnancy is associated with adverse outcomes in approximately 10% of children born to women treated with these agents. A syndrome characterized by small head circumference, anteverted nares, cleft lip and palate (occasionally), and distal digital hypoplasia was first described in association with maternal use of phenytoin but also occurs with other anticonvulsants. Risks for spina bifida are increased, especially in pregnancies exposed to valproic acid.

3. Retinoic Acid Embryopathy

Vitamin A and its analogs are potent morphogens that have considerable teratogenic potential. Developmental toxicity occurs in approximately one-third of pregnancies exposed in the first trimester to the synthetic retinoid isotretinoin, commonly prescribed to treat acne. Exposure disrupts migration of rostral neural crest cells and produces CNS maldevelopment, especially of the posterior fossa; ear anomalies (often absence of pinnae); congenital heart disease (great vessel anomalies); and tracheoesophageal fistula. These findings constitute a partial phenocopy of DiGeorge syndrome and demonstrate the continuum of contributing genetic and environmental factors in morphogenesis. It is now recognized that vitamin A itself, when taken as active retinoic acid in doses exceeding 25,000 IU/d during pregnancy, can produce similar fetal anomalies. Vitamin A intake is limited to 10,000 IU/d of retinoic acid. Maternal ingestion of large amounts of vitamin A taken as retinol during pregnancy, however, does not increase risks, because conversion of this precursor to active retinoic acid is internally regulated.


Assisted reproductive technologies including in vitro fertilization are now utilized in a significant number of pregnancies. Although healthy live births are accepted as the usual outcomes resulting from successful application of these procedures, the actual number of viable embryos is limited and questions about the risks of adverse effects continue to be raised. Increased rates of twinning, both monozygotic and dizygotic, are well recognized while the possibility of increased rates of birth defects remains controversial. Abnormal genetic imprinting appears to be associated with in vitro fertilization. Evidence supports increased prevalence of Beckwith-Wiedemann and Angelman syndromes among offspring of in vitro pregnancies.


Prenatal screening for birth defects is now routinely offered to pregnant women of all ages. Prenatal diagnosis introduces options for management.

Prenatal assessment of the fetus includes techniques that screen maternal blood, image the conceptus, fetal DNA analysis via maternal serum samples, and samples of fetal and placental tissues.

image Maternal Blood Analysis

Elevated levels of maternal serum α-fetoprotein correlate with open neural tube defects but low levels are associated with Down syndrome and other chromosomal abnormalities. First trimester measurements of PAPA (pregnancy-associated plasma protein A) and the free β-subunit of human chorionic gonadotropin screen for trisomies 21 and 18. In the second trimester maternal α-fetoprotein, human chorionic gonadotropin, unconjugated estradiol, and inhibin (“quad screen”) combine to estimate risks for trisomies 21 and 18. Low estradiol levels can also predict cases of Smith-Lemli-Opitz syndrome, a devastating autosomal recessive disorder discussed earlier. Noninvasive prenatal testing, via maternal blood sample, can detect specific chromosome imbalances. Massive parallel sequencing technology is applied to the circulating cell free DNA in maternal samples. The detection rate is higher than traditional first trimester screening.

image Analysis of Fetal Samples

A. Amniocentesis

Amniocentesis samples fluid surrounding the fetus; the cells obtained are cultured for cytogenetic, molecular, or metabolic analyses. α-Fetoprotein and other chemical markers can also be measured. This is a safe procedure with a complication rate (primarily for miscarriage) of less than 0.01% in experienced hands.

B. Chorionic Villus Sampling (Placental)

Chorionic villus sampling is generally performed at 10–12 weeks’ gestation. Tissue obtained by chorionic villus sampling provides DNA for molecular analysis and contains dividing cells (cytotrophoblasts) that can be rapidly evaluated by FISH. However, direct cytogenetic preparations may be of poor quality and placental fibroblasts must be routinely grown and analyzed. In addition, chromosomal abnormalities detected by this technique may be confined to the placenta (confined placental mosaicism) and be less informative than amniocentesis.

C. Fetal Blood and Tissue

Fetal blood can be sampled directly in late gestation through ultrasound-guided percutaneous umbilical blood sampling (PUBS). A wide range of diagnostic tests ranging from biochemical to comparative genomic hybridization can be applied. Fetal urine sampled from the bladder or dilated proximal structures can provide important information about fetal renal function.

It is occasionally necessary to obtain biopsy specimens of fetal tissues such as liver or muscle for accurate prenatal diagnosis. These procedures are available in only a few perinatal centers.

D. Preimplantation Genetic Diagnosis

With the advent of single-cell PCR techniques as well as interphase FISH it is now possible to make genetic diagnoses in preimplantation human embryos by removing and analyzing blastocyst cells. Using this procedure parents can now consider selecting pregnancies for positive attributes such as becoming donors for transplantation of tissues to siblings affected by genetic disorders.

image Fetal Imaging

Fetal ultrasonography has become routine and MRI imaging is becoming increasingly common during pregnancy, while fetal x-rays are seldom employed. Ultrasonography has joined maternal blood sampling as a screening technique for common chromosomal aneuploidies, neural tube defects, and other structural anomalies. Pregnancies at increased risk for CNS anomalies, skeletal dysplasias, and structural defects of the heart and kidneys should be monitored by careful ultrasound examinations. Fetal MRI has become routine in the workup of suspected fetal CNS abnormalities as well as in an increasing number of other fetal anomalies.