Pediatric Residency Training Program


Genetic Disorders and Inborn Errors of Metabolism

Sharon L. Young M.D.

  1. Inheritance Patterns
  2. Classic Mendelian patterns (Figure 5-1)
  3. Autosomal dominantdescribes a disorder that is manifested if only one abnormal allele is present. If one parent is affected, the risk of having an affected child is 50%.
  4. Autosomal recessivedescribes a disorder that is manifested if two abnormal alleles are present. If both parents are heterozygotes, neither parent is affected, and the risk of having an affected child is 25%.
  5. X-linked dominantdescribes a disorder in which the allele is on the X chromosome. The disorder is manifested if one abnormal allele is present. X-linked dominant disorders are generally more severe or lethal in males. Affected females have a 50% risk of having an affected daughter.
  6. X-linked recessivedescribes a disorder in which the allele is on the X chromosome and is only manifested if no normal alleles are present. Usually, only males are affectedbecause the abnormal X chromosome is paired with a Y chromosome.
  7. Nonclassic Patterns
  8. Unstable repeat sequencesoccur when the number of specific nucleotide copies within a gene increases, resulting in increased disease severity (e.g., fragile X syndrome).
  9. Uniparental disomyoccurs when, instead of inheriting one gene or chromosome from each parent, both members of a chromosome or gene pair are inherited from the same parent.
  10. Translocationsoccur when there is transfer of chromosomal material from one chromosome to another.



Figure 5-1. Pedigrees of different Mendelian inheritance patterns. (Modified with permission from Sakala EP. BRS Obstetrics and Gynecology. 2nd Ed. Philadelphia: Lippincott Williams & Wilkins, 2000:52.)

  1. Genomic imprintingoccurs when a gene defect is expressed solely based on the sex of the parent passing on the defective gene. For example, if a mother passes on an abnormal 11q region on chromosome 15, the offspring will have Angelman syndrome, but if a father passes on this same abnormal region, the offspring will have Prader-Willi syndrome. The mnemonic “Mom is an angel for Angelman syndrome, and P is for paternal and Prader-Willi syndrome” may be used to differentiate between the causes of the two syndromes.
  2. Abnormalities of Morphogenesis: malformation, deformation, disruption, syndrome
  3. Malformationoccurs when an intrinsically abnormal process forms abnormal tissue (e.g., bladder extrophy results from the failure of infraumbilical mesenchyme to migrate and form the lower abdominal wall).
  4. Deformationoccurs when mechanical forces exerted on normal tissue result in abnormal tissues (e.g., constraint caused by an abnormally shaped uterus results in an abnormally shaped fetal skull).
  5. Disruptionoccurs when normal tissue becomes abnormal after being


subjected to destructive forces (e.g., decreased blood flow to an organ causes tissue ischemia, eventually resulting in an atretic organ).

  1. Syndromeoccurs when a collection of seemingly unrelated abnormal features occur in a familiar pattern (e.g., because many of the clinical features of children with Down syndrome are similar, these children appear to be related to each other).
  2. Fetal Evaluation and Prenatal Diagnosis
  3. Ultrasound

is used to assess gestational age and fetal growth and to evaluate for major fetal anomalies.

  1. Maternal serum markers
  2. α-Fetoprotein (AFP)is elevated with fetal neural tube defects, multiple gestation pregnancies, underestimated gestational age, ventral abdominal wall defects, fetal demise, or fetal conditions that cause edema or skin defects. Low AFP levels are associated with overestimated gestational age, trisomies 21 and 18, and intrauterine growth retardation.
  3. Triple markeris used as a noninvasive method to assess the fetus for the possibility of trisomy syndromes. The three markers are AFP, unconjugated estriol, and βsubunit of human chorionic gonado-tropin (β-HCG).
  4. Low AFP, low unconjugated estriol, and highβ-HCG suggest Down syndrome.
  5. Low values of all three markers suggest trisomy 18.
  6. Genetic evaluation of the fetus
  7. Chorionic villus sampling (CVS)collects villus tissue from the chorion of the trophoblast at 10–13 weeks gestation. Karyotyping, DNA extraction, and enzyme analyses from CVS can be used to assess for genetic and metabolic diseases.
  8. Amniocentesiscollects amniotic fluid containing sloughed fetal cells at 16–18 weeks gestation. This technique assesses for the same diseases as CVS.
  9. Percutaneous umbilical blood samplinginvolves obtaining a sample of fetal blood to assess for hematologic abnormalities, genetic disorders, infections, and fetal acidosis. It can also be used to administer medications or blood transfusions to the fetus.

III. Common Genetic Disorders

  1. Common Syndromes
  2. Marfan syndromeis an autosomal dominant connective tissue disorder that affects primarily the ocular, cardiovascular, and skeletal systems. The gene defect has been mapped to a region on chromosome 15 that codes for fibrillin, a protein that plays a major role in providing structure for connective tissues.



  1. Clinical features
  2. Skeletal findingsinclude tall stature with elongated extremities and long fingers (i.e., arachnodactyly), joint laxity, chest wall deformities (e.g., pectus excavatum), and scoliosis or kyphosis. Marfan syndrome is suggested by a decreased upper-to-lower segment ratio (U/L; the lower segment is the distance from the symphysis pubis to the heel, and the upper segment is the height minus the lower segment).
  3. Ocular findingsinclude upward lens subluxation and retinal detachment.
  4. Cardiovascular findingsinclude aortic root dilatation (with or without aortic dissection), mitral valve prolapse, and aortic regurgitation.
  5. Diagnosisis based on clinical findings; however, homocystinuria has many of the same clinical features. Therefore, screening tests to rule out homocystinuria are also generally performed (see section V.D).
  6. Complicationsinclude endocarditis, retinal detachment, and sudden death as a result of aortic dissection.
  7. Hypertensionand chest trauma increase dissection risk. The overall risk is reduced with β-blocker medications and avoidance of contact sports.
  8. Endocarditis prophylaxisand regular ophthalmologic examinations are warranted.
  9. Prader-Willi syndromeis an example of genomic imprinting (see section I.B.4) and is caused by the absence of a region on the paternally derived chromosome 15.
  10. Clinical features
  11. Craniofacialfindings include almond-shaped eyes and a down-turned, fishlike mouth.
  12. Growthproblems include failure to thrive (FTT) because of feeding difficulties in the first year of life, followed by obesity as a result of hyperphagia later in childhood.Patients also have short stature with small hands and feet.
  13. Neurologic featuresinclude hypotonia (most pronounced during the newborn period), mental retardation, learning disabilities, and behavioral problems.
  14. Hypogonadismmanifests as a small penis, small testes, or cryptorchidism.
  15. Diagnosis, based on fluorescent in situ hybridization (FISH) probes, detects the chromosomal deletion in almost all patients.
  16. Complications
  17. In infancy, hypotonia may lead to poor sucking, feeding problems, and developmental delay.
  18. In childhood, obesity may lead to obstructive sleep apnea.
  19. In adulthood, obesity may lead to cardiac diseaseand type 2 diabetes mellitus. Psychiatric illnesses may also be present.



  1. Angelman syndromeis also known as the “happy puppet” syndrome because of its characteristic jerky, puppetlike gait and the happy demeanor with frequent laughter and smiling of affected individuals. Angelman syndrome is an example of genomic imprinting and is caused by a deletion of a region on the maternally derived chromosome 15 (seesection I.B.4).
  2. Clinical features
  3. Neurologicfindings include jerky arm movements, ataxia, and paroxysms of inappropriate laughter. Mental retardation is severe with significant speech delay.
  4. Craniofacialfindings include a small wide head, large mouth with widely spaced teeth, tongue protrusion, and prognathia. Most affected individuals have blond hair and pale blue deep-set eyes.
  5. Diagnosisis based on FISH probes to detect the chromosomal deletion on chromosome 15.
  6. Noonan syndromeis often described as the male version of Turner syndrome, but females may also be affected. Cases are usually sporadic; however, an autosomal dominant pattern has been reported. A gene for the disorder has been mapped to chromosome 12.
  7. Clinical features(variable)
  8. Skeletalfindings include short stature and a shield chest.
  9. Craniofacialfindings include a short webbed neck and low hairline, hypertelorism (i.e., widely spaced eyes), epicanthal skin folds, downslanting palpebral fissures, and low-set ears.
  10. Cardiac defectsinclude right-sided heart lesions, most commonly pulmonary valve stenosis. (In contrast, patients with Turner syndrome have left-sided heart lesions.)
  11. Mental retardation occurs in 25% of the patients.
  12. Diagnosisis based on clinical features.
  13. DiGeorge syndrome and velocardiofacial syndromeare two distinct syndromes with a deletion at chromosome 22q11. Some experts support changing the name of both syndromes to CATCH-22 (C—cardiac anomaly, A—abnormal facies, T—thymic hypoplasia, C—cleft palate, H—hypocalcemia, and a gene defect on chromosome 22). Inheritance is both sporadic and autosomal dominant.
  14. DiGeorge syndromeis caused by a defect in the structures derived from the third and fourth pharyngeal pouches.
  15. Clinical features
  16. Craniofacialfindings include short palpebral fissures, small chin, and ear anomalies.
  17. Cardiacfindings include aortic arch anomalies, ventricular septal defects, and tetralogy of Fallot.
  18. Thymus and parathyroid hypoplasiacause cell-mediated immunodeficiency and severe hypocalcemia.
  19. Diagnosisis based on FISH probes to detect the deletion on chromosome 22.



  1. Complicationsinclude infections as a result of cell-mediated immunodeficiency and seizures caused by hypocalcemia (see Chapter 15, section X.E).
  2. Velocardiofacial syndrome
  3. Clinical features
  4. Craniofacialfindings include cleft palate, wide prominent nose with a squared nasal root, short chin, and fish-shaped mouth.
  5. Cardiacfindings include ventricular septal defects and a right-sided aortic arch.
  6. Neurologicfindings include neonatal hypotonia, learning disabilities, and perseverative behaviors.
  7. Diagnosisis based on FISH probes to detect the deletion on chromosome 22.
  8. Ehlers-Danlos syndromeis characterized by production of defective type V collagen resulting in hyperextensible joints, fragile vessels, and loose skin. Inheritance is autosomal dominant.
  9. Clinical features
  10. Musculoskeletalfindings include hyperextensible joints with a tendency toward joint dislocation and scoliosis.
  11. Dermatologicfindings include soft, velvety textured, loose, fragile skin. Minor lacerations result in large wounds that heal poorly with broad, atrophic, tissue paper-thin scars.
  12. Cardiovascularfindings include mitral valve prolapse, aortic root dilatation, and fragile blood vessels that result in ease of bruising.
  13. Gastrointestinal (GI) featuresinclude constipation, rectal prolapse, and hernias.
  14. Diagnosisis based on clinical findings.
  15. Complicationsinclude aortic dissection and GI bleeding as a result of blood vessel fragility.
  16. Osteogenesis imperfecta (OI)results from mutations that cause production of abnormal type I collagen. OI is classified into four types based on clinical, radiographic, and genetic criteria. Type I is described below.

 .    Clinical features

  1. Blue sclerae
  2. Skeletalfindings such as fragile bones resulting in frequent fractures, genu valgum (knock-knees), scoliosis or kyphosis, joint laxity, and osteoporosis or osteopenia.
  3. Yellow or gray-blue teeth
  4. Easy bruisability
  5. Diagnosisis based on clinical features and decreased type I collagen synthesis in fibroblasts.
  6. Complicationsinclude early conductive hearing loss and skeletal deformities as a result of fractures.



  1. VACTERL (VATER) associationis a group of malformations that occur sporadically.

 .    Clinical features

  1. V—vertebral defects
  2. A—anal atresia
  3. C—cardiac anomalies, predominantly ventricular septal defects
  4. TE—tracheoesophageal fistula
  5. R—renaland genital defects
  6. L—limb defects, including radial hypoplasia, syndactyly and polydactyly
  7. Diagnosisis based on clinical features.
  8. CHARGE associationis a group of malformations that occur sporadically.

 .    Clinical features

  1. C—colobomas(absence or defect of ocular tissue), usually of the retina. Impaired vision is very common.
  2. H—heart defects, most commonly tetralogy of Fallot
  3. A—atresia of the nasal choanae
  4. R—retardationof growth and cognition
  5. G—genital anomalies, including genital hypoplasia
  6. E—ear anomalies, including cup-shaped ears and hearing loss
  7. Diagnosisis based on clinical features.
  8. Williams syndromeis most notable for the unique loquacious personality often described as a “cocktail party” personality. It is caused by a deletion on chromosome 7 that includes the gene for elastin. Inheritance is autosomal dominant.

 .    Clinical features

  1. “Elfin facies”with short palpebral fissures, flat nasal bridge, and round cheeks
  2. Mental retardationand loquacious personality
  3. Supravalvular aortic stenosis
  4. Idiopathic hypercalcemiain infancy
  5. Connective tissue abnormalities, including a hoarse voice and hernias
  6. Diagnosisis based on detection of the deletion with FISH probes.
  7. Cornelia de Lange (Brachmann-de Lange) syndromeis most notable for a single eyebrow and very short stature without skeletal abnormalities. Inheritance is mostly sporadic, but autosomal dominant inheritance may occur.

 .    Clinical features

  1. Small for gestational ageand FTT
  2. Craniofacialfindings include single eyebrow (synophrys), long, curly eyelashes, microcephaly, thin, down-turned upper lip, and micrognathia.
  3. Infantile hypertonia
  4. Mental retardation



  1. Small hands and feet
  2. Cardiac defects
  3. Behavioralfindings include autistic features, lack of facial expression, and self-destructive tendencies.
  4. Diagnosisis based on clinical features.
  5. Russell-Silver syndromeis known for the features of short stature and skeletal asymmetry with a normal head circumference. Inheritance is sporadic.

 .    Clinical features

  1. Small for gestational age
  2. Craniofacialfindings include a small triangular face, prominent forehead, and down-turned mouth. Because of the small face, the head appears large, but the head circumference is normal.
  3. Skeletalfindings include short stature and limb asymmetry.
  4. Café-au-lait spotson the skin
  5. Excessive sweating
  6. Diagnosisis based on clinical features.
  7. Pierre Robin syndrome

 .    Clinical features include micrognathia, cleft lip and palate, and a large protruding tongue. Feeding is often difficult because of the cleft palate.

  1. Diagnosisis based on clinical features.
  2. Complicationsinclude recurrent otitis media and upper airway obstruction that often requires tracheostomy.
  3. Cri du chat syndromeis caused by a partial deletion of the short arm of chromosome 5. Most cases occur sporadically.

 .    Clinical features include slow growth, microcephaly, mental retardation, hypertelorism, downslanting palpebral fissures, and a characteristic catlike cry.

  1. Diagnosisis based on detection of the chromosomal deletion and the presence of clinical features.
  2. Trisomy syndromes
  3. Down syndrome (trisomy 21) is the most common trisomy syndromeand involves chromosome 21. The risk of Down syndrome increases with maternal age because of the increased occurrence of nondisjunction within the ovum. Incidence is estimated to be 1:660 live births. Table 5-1 describes the clinical features and complications of Down syndrome.
  4. Trisomy 18is the second most common trisomy syndrome and is three times more common in females.
  5. Clinical features
  6. Neurologicfindings include mental retardation and hypertonia with scissoring of the lower extremities.
  7. Delicate, small facial features
  8. Musculoskeletalfindings include clenched hands with overlapping digits, dorsiflexed big toes, and rocker bottom feet.



Table 5-1. Clinical Features and Complications Associated with Down Syndrome

Clinical Features


Craniofacial features
   Epicanthal skin folds
   Upslanting palpebral fissures
   Brushfield spots (speckled irides)
   Protruding tongue
Mental retardation
Musculoskeletal features
   Single palmar creases
   Wide space between first and second toes
Gastrointestinal features
   Duodenal atresia
   Hirschsprung's disease and omphalocele
   Pyloric stenosis
Cardiac features (40%)
   Endocardial cushion defects (most

Atlantoaxial cervical spine instability (20%)
   Flexion-extension cervical spine radiographs
      should be assessed by 3–5 years of age
Leukemia(20 times more common than in
   general population)
Celiac disease
   Total IgA and IgA anti-endomysium antibody
      screen at 2 years of age
Early Alzheimer's disease
Obstructive sleep apnea
Conductive hearing loss
   Hearing screens needed every 1–2 years
   Annual TSH screening
Cataracts, glaucoma, and refractive errors
   Annual ophthalmologic examinations

TSH = thyroid-stimulating hormone.

  1. Diagnosisis based on chromosomal analysis.
  2. Prognosis.Most affected individuals (95%) die within the first year of life.
  3. Trisomy 13is associated with midline defects, particularly of the face and forebrain.
  4. Clinical features
  5. Neurologicfindings include holoprosencephaly, microcephaly, seizures, and severe mental retardation.
  6. Ocularfindings include microphthalmia, retinal dysplasia, colobomas, and, rarely, a single eye.
  7. Cleft lip and palate
  8. Diagnosisis based on chromosomal analysis.
  9. Prognosisis poor, with death usually occurring within the first month of life.
  10. Sex Chromosome Syndromes
  11. Turner syndromeoccurs when only one X chromosome is present. Incidence is 1:2, 000 live births.
  12. Clinical features
  13. Short stature
  14. Webbed neckand low posterior hairline
  15. Shield chestwith broadly spaced nipples and scoliosis or kyphosis
  16. Swelling of the dorsum of hands and feet(congenital lymphedema) may be present at birth.
  17. Ovarian dysgenesiscauses delayed puberty.Turner syndrome should be considered in any female with pubertal delay.Hormonal therapy is typically needed to stimulate puberty.



  1. Cardiac defectsusually include left-sided heart lesions, especially coarctation of the aorta, bicuspid aortic valve, and hypoplastic left heart.
  2. Hypothyroidism may occur.
  3. Diagnosisis based on clinical features and chromosomal analysis.
  4. Fragile X syndromeis an X-linked disorder caused by a site on the X chromosome that contains a variable number of CGG repeats. Fragile X syndrome is an example ofanticipation. As the disorder passes from generation to generation, there is an increase in the number of CGG repeats, corresponding to an increase in syndrome severity. Fragile X syndrome is more severe in males, but females may also have mental retardation. It occurs in 1:1, 250 males and 1:2, 500 females, making fragile X syndrome the most common inherited cause of mental retardation.
  5. Clinical features
  6. Mild to severe mental retardation
  7. Craniofacialfindings include large ears, macrocephaly, thickened nasal bridge, and blue irides.
  8. Large testesdevelop during puberty.
  9. Behavioralfindings include emotional instability, autistic features, and attention deficit/hyperactivity disorder.
  10. Diagnosisis based on chromosomal analysis.
  11. Klinefelter syndromeis the most common cause of male hypogonadism and infertility. Chromosomal analysis generally reveals an XXY genotype. Risk increases with advancing maternal age. Incidence is 1:500 live male births.
  12. Clinical features
  13. Tall stature with long extremities
  14. Hypogonadism, including small penis and testes, delayed pubertyowing to lack of testosterone, and infertility.
  15. Gynecomastia
  16. Variable intelligence
  17. Behavioral findingsinclude antisocial behavior and excessive shyness or aggression. These findings may be noted before the appearance of the physical findings.
  18. Diagnosisis based on chromosomal analysis.
  19. Skeletal dysplasias

are a diverse group of inherited diseases characterized by short stature caused by bone growth abnormalities.

  1. Classificationis based on the location of the bone abnormality or shortening.
  2. Rhizomeliarefers to proximal long bone abnormalities (e.g., short humerus and femur).
  3. Mesomeliarefers to medial long bone abnormalities (e.g., short ulna and tibia).
  4. Acromeliarefers to distal abnormalities (e.g., small hands and feet).
  5. Spondylodysplasiasinvolve abnormalities of the spine, with or without limb abnormalities.



  1. Achondroplasiais the most common skeletal dysplasia and is characterized by rhizomelia. Although inheritance is autosomal dominant, most cases are sporadic. Achondroplasia is caused by a mutation in the fibroblast growth factor receptor 3 gene. Incidence increases with advancing paternal age.
  2. Clinical features
  3. Craniofacial findingsinclude megalencephaly (large brain), foramen magnum stenosis, frontal bossing, midface hypoplasia, and low nasal bridge.
  4. Skeletal findings
  5. Lumbar kyphosis in infancyevolving into lumbar lordosis in later childhood and adulthood
  6. Rhizomelic limb shortening, bowed legs, and joint hyperextensibility
  7. Trident-shaped hands
  8. Recurrent otitis media with conductive hearing loss
  9. Diagnosisis based on clinical features and radiographs of the limbs demonstrating rhizomelic shortening.
  10. Complications
  11. Foramen magnum stenosismay lead to hydrocephalus or cord compression. Head circumference must be monitored closely. Head sweating and dilated facial veins may be subtle signs of cord compression.Sudden infant death may occur as a result of cord compression.
  12. Obstructive sleep apneaandrespiratory compromisemay occur from foramen magnum narrowing and upper airway obstruction.
  13. Orthopedic problemssuch as severe bowed legs (genu varum) and back pain
  14. Environmental defects. Environmental factors

may cause congenital abnormalities and have an impact on the fetus.

  1. Potter syndromeis caused by severe oligohydramnios, which causes lung hypoplasia and fetal compression with limb abnormalities and facial features termed Potter facies. Severe oligohydramnios may occur as the result of a chronic amniotic fluid leak or intrauterine renal failure caused by bilateral renal agenesis, polycystic kidneys, or obstructive uropathy.
  2. Amniotic band syndrome (amnion rupture sequence) occurs as a result of rupture of the amniotic sac. Fluid leak leads to intrauterine constraint, and small strands from the amnion may wrap around the fetus, causing limb scarring and amputation.
  3. Syndromes caused by teratogens (Table 5-2)
  4. Fetal alcohol syndromeis caused by alcohol, the most common teratogen. Fetal alcohol syndrome may occur if a woman chronically drinks alcohol or binges during her pregnancy. Features include small-for-gestational-age (SGA) at birth, FTT, microcephaly, a long smooth philtrum with a thin, smooth upper lip, mental retardation, attention deficit/hyperactivity disorder, and cardiac defects (ventricular septal defect is most common).



Table 5-2. Teratogens and Associated Anomalies


Associated Anomalies


Microcephaly; short palpebral fissures; long, smooth philtrum;variable mental retardation

Cigarette smoking

Small-for-gestational age, polycythemia


Intrauterine growth retardation, microcephaly, genitourinary tract abnormalities

Diethylstilbestrol (DES)

Increased risk of cervical carcinoma, genitourinary anomalies


Central nervous system malformations, microtia, cardiac defects, thymic hypoplasia


Wide anterior fontanelle, thick hair with a low hairline, small nails, cardiac defects


Hypothyroidism, goiter


Phocomelia (malformed extremities resulting in flipperlike appendages)

Valproic acid

Narrow head, high forehead, midface hypoplasia, spina bifida, cardiac defects, convex nails


Hypoplastic nose with a deep groove between the nasal alae and the nasal tip, stippling of the epiphyses, hypoplastic nails

  1. Fetal phenytoin syndromecauses a spectrum of defects with mild to moderate mental retardation, cardiac defects, growth retardation, nail and digit abnormalities, and characteristic facial features. Pregnant women with seizure disorders face the dilemma of either exposing their unborn fetus to anticonvulsants (which may have teratogenic effects) or risk having a seizure (which may cause fetal injury).
  2. Defects of multifactorial inheritance
  3. Cleft lip and palate.A wide variety of syndromic and nonsyndromic diseases have cleft lip and palate as a feature, but the inheritance patterns are widely different.
  4. Neural tube defects (NTDs)are themost common congenital anomalies of the central nervous system. Etiology is multifactorial and includes nutrition, genetic predisposition, drugs, and radiation exposure. Folic acid dosages of 400–800 µg/day may help prevent NTDs (see Chapter 12, section III.C).
  5. Congenital heart disease (CHD)is a congenital defect with many causes, including syndromes, drugs, maternal disease, and genetic inheritance. Risk of CHD in the general population is approximately 1%, andrecurrence risk increases with each child affected.
  6. Inborn Errors of Metabolism (IEM) (Figure 5-2)

General Concepts. IEM are a heterogeneous group of diseases that can present in a variety of ways. Individually, each disease is rare, but collectively the overall incidence is 1:5, 000 live births. Although most IEM are inherited in an autosomal recessive fashion, some are X-linked recessive, and many occur spontaneously.




Figure 5-2. Summary chart of inborn errors of metabolism.MELAS=mitochondrialencephalopathy, lacticacidosis, andstrokelike episodes;MERRF =myoclonusepilepsy andragged-redfibers.

  1. Clinical features (Table 5-3)
  2. IEM should be suspected if a child:
  3. Is acutely ill and fails to respond to usual therapy
  4. Has unexplained seizures, developmental delay, progressive neurologic deterioration, persistent or recurrent vomiting, or FTT
  5. Has laboratory values inconsistent with the clinical presentation
  6. Onset of symptomsof an IEM often conjures an image of a critically ill neonate, but it is important to remember that each IEM may have subtypes that may present at an older age or in adulthood.
  7. Acute severe neonatal illnessis theclassic presentation. An apparently healthy newborn develops an acute severe illness within the first few hours to weeks of life.
  8. Recurrent intermittent episodesmay present attimes of stress, such as surgery, fasting, or illness.
  9. Chronic and progressive symptomsare typical ofmitochondrial


 Because of the slow progressive course, diagnosis is often delayed.

Table 5-3. Typical Clinical Features of Inborn Errors of Metabolism (IEM)

General symptoms:


Lethargy or coma
Poor feeding or failure to thrive
Intractable hiccups
Unusual odor (especially when acutely ill):











Sweet maple syrup

Maple syrup urine disease



Sweaty feet

Isovaleric or glutaric acidemia



Rotten cabbage

Hereditary tyrosinemia



Hypertonia or hypotonia
Unexplained developmental delay
Unexplained and difficult-to-control seizures



Cherry-red macula, cataracts, or corneal clouding



Vomiting with metabolic acidosis should raise suspicion of an IEM because excessive
    vomiting normally causes metabolic alkalosis



Hypoglycemia with ketosis is suggestive of organic acidemias and carbohydrate disease Serum NH3 > 200 mM is suggestive of urea cycle defects
Elevated NH3 and metabolic acidosis are suggestive of organic acidemias
Urinary ketones in a newborn are always abnormal

NH3 = ammonia.

  1. Family historysuspicious for IEM includes:
  2. Neonatal deathsin siblings or affected males on the maternal side
  3. Parental consanguinity
  4. Mental retardationor neurologic disability
  5. Unusual dietary preferencesin relatives
  6. Clinical pearl: Sepsis is much more common than metabolic disease.However, it is important to keep in mind that thepresenting symptoms of IEM may be similar to those of sepsis, and patients with IEM are vulnerable to sepsis.
  7. Initial laboratory evaluation

includes assessment formetabolic acidosis andelevated serum ammonia (Table 5-4). Further evaluation depends on whether metabolic acidosis or hyperammonemia are present.

  1. Management

includes stabilization and prevention of further catabolism.

  1. Provide a source of energy. Intravenous glucoseis the most basic energy source.
  2. Prevent exposure to the offending substance.Initially, enteral feedings should be avoided and protein should be eliminated until a specific diagnosis is known. Lipids may be considered as a source of energy if a fatty acid oxidation defect is not suspected.



Table 5-4. Initial Evaluation for Inborn Errors of Metabolism


Reason for Test

Initial studies


   Serum glucose

Rule out hypoglycemia

   Sreum Ca and Mg

Rule out hypocalcemia or hyper- or hypomagnesemia

   CBC with differential

Assess for anemia, neutropenia, thrombocytopenia


Assess for ketones
   Presence of ketones is especially suspicious in newborns
      because normally they do not produce ketones well
   In older children, absence of ketones with hypoglycemia is
      suspicious for fatty acid oxidation defect

   Arterial blood gas and
      serum electrolytes

Assess for anion gap metabolic acidosis

   Plasma NH3

Rule out urea cycle defects (may also be elevated with
   hypoxia or severe dehydration)


If positive, dipstick for glucose; nonglucose-reducing
   substance is suggestive of galactosemia

If metabolic acidosis is present:

   Serum lactate and

Rule out lactic acidemias or organic acidemias

   Plasma amino acids

Rule out aminoacidemias or organic acidemias

If increased ammonia is present:

   Plasma amino acids

If elevated, then suspect aminoacidemias

   Urine organic acids

If elevated orotic acid, suspect ornithine transcarbamylase

CBC = complete blood count; NH3 = ammonia.

  1. Correct acidosis or hyperammonemia.
  2. Sodium bicarbonatecorrects acidosis.
  3. Sodium benzoate and sodium phenylacetateincrease ammonia excretion.
  4. Oral Neosporin and lactuloseprevent bacterial production of ammonia in the colon.
  5. Dialysismay be necessary if other interventions fail to correct the electrolyte abnormalities.
  6. Defects in Amino Acid Metabolism

In general, individuals with these disorders may present with an unusual odor, vomiting with severe acidosis, lethargy, coma, and neutropenia. For characteristics of phenylketonuria (PKU), hereditary tyrosinemia, and maple syrup urine disease, see Table 5-5. Other examples of defects in amino acid metabolism are described in this section.

  1. Homocystinuria

This condition is caused bycystathionine synthase deficiency. Inheritance isautosomal recessive.

  1. Clinical featuresshare some characteristics with Marfan syndrome (see section III.A.1).
  2. Marfanoid body habitus without arachnodactyly
  3. Downward lens subluxation(in Marfan syndrome, lens subluxation is upward)



Table 5-5. Characteristics of Selected Defects in Amino Acid Metabolism


Phenylketonuria (PKU)

Maple Syrup Urine Disease

Tyrosinemia Type I


Autosomal recessive

Autosomal recessive

Autosomal recessive

Clinical features

Developmental delay
Infantile hypotonia
Mousy or musty odor
Progressive mental retardation
Decreased pigment (light eyes and hair)
Mild PKU may present in early childhood with developmental delay, hyperactivity

Progressive vomiting and poor feeding
Lethargy, hypotonia, and coma
Developmental delay
Maple syrup odor in urine
Hypoglycemia and severe acidosis during episodes

Episodes of peripheral neuropathy
Chronic liver disease
Odor of rotten fish or cabbage odor
Renal tubular dysfunction


Phenylalanine:tyrosine ratio in serum

Serum and urine branched-chain amino acids

Succinylacetone in urine


Phenylalanine-restricted diet

Dietary protein restriction

Dietary restriction of phenylalanine, tyrosine, NTBC
Liver transplant


Near-normal intelligence if diet restriction begun < 1 month of age

Protein restriction within 2 weeks of life may avert neurologic damage

Death by 1 year of age if disease begins in infancy
Increased risk of hepatocellular carcinoma and cirrhosis

NTBC = 2-2 nitro-4-trifluoromethylbenzoyl 1,3-cyclohexanedione.

  1. Hypercoagulable stateincreases the risk of stroke, myocardial infarction, and deep vein thrombosis.
  2. Cardiovascular abnormalitiesinclude mitral or aortic regurgitation. Aortic dilatation is absent (in contrast to Marfan syndrome).
  3. Scoliosisand large, stiff joints
  4. Developmental delay, mild mental retardation, and psychiatric illness
  5. Diagnosisis by findingincreased methionine in urine and plasma, or by a positive urinary cyanide nitroprusside test.
  6. Managementincludes amethionine-restricted diet, aspirin to decrease risk of thromboembolism, and folic acid and vitamin B6 supplementation.
  7. Transient tyrosinemia of the newborn

This condition occurs in premature infants who receive high-protein diets.

  1. Clinical featuresbegin during the first 2 weeks of life and may include poor feeding or lethargy. Patients may be asymptomatic.
  2. Diagnosisis based onelevated serum tyrosine and phenylalanine levels.



  1. Managementincludes decreasing protein intake during the acute episode.Vitamin C may help eliminate tyrosine.
  2. Prognosisis good. Thisself-limited disease should resolve within 1 month.
  3. Membrane transport defects
  4. Cystinuriais an autosomal recessive disorder caused by adefect in renal reabsorption of cystine, lysine, arginine, and ornithine that leads torenal stones. Clinical features may include urinary tract infection, dysuria, abdominal or back pain, urgency, and urinary frequency.
  5. Hartnup diseaseis an autosomal recessive disorder caused by a defect in the transport of neutral amino acids. Most patients are asymptomatic but some may present with intermittent ataxia, photosensitive rash, mental retardation, and emotional lability.
  6. Urea cycle defects

The urea cycle is responsible for the disposal of excess dietary nitrogen in the form of urea. Thus, defects in this cycle are manifested byelevated ammonia (NH3) > 200 µM.Ammonia is toxic to the brain and the liver. Typical symptoms include poor feeding, hyperventilation, behavioral changes, seizures, ataxia, and coma.

  1. Transient hyperammonemia of the newbornis aself-limited disorder that may present in premature infants within the initial 24–48 hours of life. Symptoms are nonspecific and include respiratory distress, alkalosis, vomiting, and lethargy rapidly progressing to coma. Aggressive treatment of hyperammonemia is required to prevent neurologic sequelae (see section IV.D.3).
  2. Ornithine transcarbamylase deficiencyis themost common urea cycle defect. Inheritance isX-linked recessive, and therefore males are more severely affected.
  3. Clinical featuresbegin at the onset of protein ingestion and include vomiting and lethargy leading to coma. Some females with mild disease may present in childhood with cyclic vomiting and intermittent ataxia.
  4. Diagnosisis based on elevated urine orotic acid, decreased serum citrulline, and increased ornithine, as well as by liver biopsy.
  5. Managementincludes a low-protein diet and management of hyperammonemia. Liver transplant may be necessary.
  6. Prognosisdepends on the neurologic sequelae of any hyperammonemic episode. Recurrent episodes with illness are common.
  7. Defects in Carbohydrate Metabolism
  8. Galactosemia

This autosomal recessive disorder is caused by galactose-1-phosphate uridyltransferase deficiency. It should besuspected in any newborn with hepatomegaly and hypoglycemia.

  1. Clinical featuresbegin after the newborn feeds a cow's milk-based formula or breastfeeds for the first time (both cow's milk and breast milk contain galactose).



  1. Vomiting, diarrhea, and FTT
  2. Hepatic dysfunctionwithhepatomegaly
  3. Cataractswith a characteristicoil-droplet appearance
  4. Renal tubular acidosis
  5. Diagnosis
  6. Nonglucose-reducing substance in urinetested by a Clinitest. The usual urine dipstick or Clinistix only tests for glucose and is inadequate for the detection of galactose.
  7. Confirmation of enzyme deficiency in red blood cells
  8. Prenatal and newborn screening are available.
  9. Managementincludes agalactose-free diet, such as soy or elemental formulas.
  10. Prognosisis good withnormal intelligence if the disorder is treated early. Mental retardation can be expected if diagnosis is delayed. Nearlyall females suffer from ovarian failure. Death in early infancy, typically fromEscherichia colisepsis, is common if the diagnosis is not suspected and treated.
  11. Hereditary Fructose Intolerance

This condition is caused by fructose-1-phosphate aldolase B deficiency and begins in infancy after the introduction of fruit or fruit juice to the infant's diet. Symptoms include severe hypoglycemia, vomiting, diarrhea, FTT, and seizures. Management includes avoidance of fructose, sucrose, and sorbitol.

  1. Glycogen storage diseases (GSDs)

are characterized byorganomegaly andmetabolic acidosis.

  1. Von Gierke's disease (GSD type 1) is an autosomal recessive disorder caused byglucose-6-phosphatase deficiency.Presenting features may include persistent hypoglycemia, hepatomegaly, metabolic acidosis, hypertriglyceridemia, and enlarged kidneys. Management includes frequent feeding with a high-complex carbohydrate diet. Patients are at high risk for hepatocellular carcinoma.
  2. Pompe's disease (GSD Type 2), caused by α-glucosidase deficiency, should be suspected in any infant with muscular weakness and cardiomegaly. It presents within the first 2 weeks of life with flaccid weakness, poor feeding, progressive cardiomegaly, hepatomegaly, and acidosis.

VII. Fatty Acid Oxidation Defects

These conditions present during an acute illness or fasting when fatty acids are normally used as an energy source. Patients with fatty acid oxidation defects are unable to utilize fatty acids and, as a result, developnonketotic hypoglycemia, hyperammonemia, myopathy, and cardiomyopathy. Medium-chain acyl-CoA dehydrogenase deficiency is the most common fatty acid oxidation disorder. Diagnosis is based on tandem mass spectrometry detecting elevated plasma medium-chain fatty acids. Management includes frequent feedings with a high-carbohydrate, low-fat diet and carnitine supplementation during acute episodes.



VIII. Mitochondrial Disorders

One of these disorders should be suspected if acommon disease has an atypical presentation or if adisease involves three or more organ systems. Examples includeKearns-Sayre syndrome (ophthalmoplegia, pigmentary degeneration of the retina, hearing loss, heart block, and neurologic degeneration) andMELAS (mitochondrialencephalo-pathy,lacticacidosis, andstrokelike episodes).Diagnosis is based on tissue biopsy revealing abnormal mitochondria. Management is predominantly supportive and may include cofactor supplementation.

  1. Lysosomal Storage Diseases
  2. Gangliosidoses
  3. Tay-Sachs diseaseis an autosomal recessive disorder caused byhexosaminidase A deficiency. Incidence is higher in Ashkenazi Jews.
  4. Clinical features
  5. Infantile-onset Tay-Sachs diseasepresents in early infancy with decreasing eye contact, hypotonia, mild motor weakness, and an increased startle as a result ofhyperacusis(increased sensitivity to sound). Other findings include:
  6. Macrocephaly
  7. Cherry-red macula
  8. Progressive blindness, seizures, andsevere developmental delay
  9. Juvenile or adult-onset Tay-Sachs diseasebegins after 2 years of age or in early adulthood. Clinical features include ataxia, dysarthria, and choreoathetosis. Cherry-red macula is absent.
  10. Diagnosisis based on decreased hexosaminidase A activity in leukocytes or fibroblasts.
  11. Prognosis. Infantile Tay-Sachs disease is untreatable, and death occurs by 4 years of age. Patients with thejuvenile or adult-onsetform have a poor prognosis with degeneration into a chronic debilitated state.
  12. Gaucher's disease, caused byglucocerebrosidase deficiency, is themost common gangliosidosis.Inheritance is autosomal recessive. Typical features include hepatosplenomegaly, thrombocytopenia, a characteristicErlenmeyer flask-shape to the distal femur, and early mortality by 4 years of age, if symptoms begin in infancy. Management includes enzyme replacement therapy.
  13. Niemann-Pick disease, caused bysphingomyelinase deficiency, presents by 6 months of age with progressive neurodegeneration, ataxia, seizures, hepatosplenomegaly, and a cherry-red macula. Death occurs by 4 years of age.
  14. Metachromatic leukodystrophyis aneurodegenerative disorder caused byarylsulfatase A deficiency. Presenting features are ataxia, seizures, and progressive mental retardation. Death occurs by 10–20 years of age.



  1. Mucopolysaccharidoses

arelysosomal storage disorders in which glucosaminoglycans accumulate in multiple organs. Common features include organomegaly, short stature, mental retardation, and specific skeletal abnormalities termeddysostosis multiplex (a constellation of bony abnormalities that include a thickened cranium, J-shaped sella turcica, malformed, ovoid or beaklike vertebrae, short and thickened clavicles, and oar-shaped ribs).

  1. Hurler syndrome, caused by α-L-iduronidase deficiency, is themost severe mucopolysaccharidosis.Inheritance is autosomal recessive.
  2. Clinical featuresbegin after 1 year of age with developmental delay, hepatosplenomegaly, and kyphosis. Other findings includeprogressively coarsened facial features, frontal bossing, prominent sagittal and metopic sutures, wide nasal bridge, thickening of the nasopharyngeal tissues, hydrocephalus, corneal clouding, and progressively stiff and contracted joints.
  3. Diagnosisis by finding dermatan and heparan sulfates in the urine and decreased α-L-iduronidase enzyme activity in leukocytes or fibroblasts.
  4. Managementmay include early bone marrow transplant to prevent neurodegeneration.
  5. Prognosisis poor, with death occurring by 10–15 years of age.
  6. Hunter syndromeis unusual because it is inherited in anX-linked recessive fashion, and corneal clouding is absent.
  7. Clinical features
  8. Hepatosplenomegaly, hearing loss, progressively stiff and contracted joints, small papules over shoulder, scapula, and lower back, and dysostosis multiplex
  9. Clinical pearl: The mnemonic “A hunter needs sharp eyes; therefore, no corneal clouding occurs”may help distinguish between Hunter syndrome and Hurler syndrome.
  10. Diagnosisis the same as for Hurler syndrome (see IX.B.1.b).
  11. Prognosis. There is no treatment, and patients typically die by 20 years of age.
  12. Sanfilippo syndromeis an autosomal recessive disorder that is characterized by rapid and severe mental and motor retardation.
  13. Morquio syndromediffers from the other mucopolysaccharidoses in thatmental retardation is absent. Severe scoliosis leading to cor pulmonale results in death by 40 years of age.
  14. Defects in Heme Pigment Biosynthesis (Porphyrias)

These defects cause an elevation of serum porphyrins that leads to skin photosensitivity and neurologic and abdominal symptoms. Acute intermittent porphyria is a classic example.

  1. Clinical features

are episodic and precipitated by drugs (e.g., alcohol, sulfa drugs, and oral contraceptives), hormonal surges (e.g., pregnancy or menses), or poor nutrition.



  1. Neurologicfindings include personality changes, emotional lability, paresthesias, and weakness (because these neurologic findings may not follow expected neural pathways, patients may be accused of malingering).
  2. GIfindings includecolicky abdominal pain, vomiting, and constipation, often mimicking an acute abdomen.
  3. Autonomic instabilityresults in tachycardia, hypertension, sweating, and fever.
  4. Dark burgundy-colored urine is present occasionally.
  5. Diagnosis

is based onincreased serum and urine porphobilinogen.

  1. Management

includes intravenous glucose, correction of electrolyte abnormalities, and avoidance of fasting and precipitating drugs.

  1. Disorders of Metal Metabolism
  2. Wilson's disease

(hepatolenticular degeneration) is an autosomal recessivedefect in copper excretion that causes copper deposition initially in the liver, followed by the brain, eyes, and heart.

  1. Clinical featuresdevelop between 2 and 50 years of age.
  2. Kayser-Fleischer ringsin the peripheral cornea (copper deposition in Descemet's membrane)
  3. Neurologicfindings such as behavior changes, dystonia, dysarthria, tremors, ataxia, and seizures
  4. Hepatic dysfunction
  5. Diagnosis
  6. Decreased serum ceruloplasminis themost commonly used screening test for Wilson's disease.
  7. Elevated serum and urine copper
  8. Copper deposition in hepatocytes obtained by liver biopsy
  9. Managementincludesavoiding copper-containing food (e.g., nuts, liver, shellfish, and chocolate), chelation therapy with oral penicillamine and zinc salts to prevent absorption, and, in some cases, liver transplant.
  10. Menkes kinky-hair disease

is an X-linked recessive disorder caused byabnormal copper transport. Affected patients havelow serum copper, in contrast to those with Wilson's disease. Clinical features develop in the first few months of life and include myoclonic seizures, pale kinky friable hair, optic nerve atrophy, severe mental retardation, progressive neurologic degeneration, and early death. Diagnosis is based ontypical hair findings andlow serum ceruloplasmin and copper.



Review Questions and Answers

  1. A 1-week-old male infant is brought to the emergency department because of vomiting and diarrhea for 3 days. As his vital signs are being measured, he develops a generalized seizure. A stat serum glucose reveals profound hypoglycemia. On examination, you find that the edge of the liver reaches the pelvis. The infant is admitted to the neonatal intensive care unit, but later he dies ofEscherichia colisepsis. Which of the following is the most likely diagnosis?

(A) Gaucher's disease

(B) Galactosemia

(C) Hurler disease

(D) Transient hyperammonemia of the newborn

(E) Niemann-Pick disease

  1. The parents of a 15-year-old boy consult you because they are concerned that their son has been acting strangely for the past 6 months. The boy has developed ataxia, tremors, and seizures. His father reports that his son seems to have developed a different personality. On examination, you note that the boy has brown rings at the edge of his corneas bilaterally. Which of the following is the best serum laboratory screen for the most likely diagnosis?

(A) Aluminum

(B) Lead

(C) Porphobilinogen

(D) Zinc

(E) Ceruloplasmin

  1. A 6-year-old girl is brought to the clinic for a routine health maintenance visit. Her growth was normal until 2 years of age, when her height started to fall off of the growth curve, steadily decreasing to below the fifth percentile. On examination, she has a webbed neck with a normal range of motion, a shield chest with widely spaced nipples, and scoliosis. Past medical history is significant for repaired coarctation of the aorta at 3 years of age. Which of the following is the most likely diagnosis?

(A) Noonan syndrome

(B) Achondroplasia

(C) Turner syndrome

(D) Russell-Silver syndrome

(E) Marfan syndrome

  1. The mother of a 6-year-old boy brings her son to the office for a second opinion regarding her child's developmental delay. Your nurse takes the initial history and reports that he was born at term by normal spontaneous vaginal delivery and seemed normal at birth but has not been meeting his developmental milestones. After assessing his vital signs, your nurse pulls you aside and states, “That mother has no control over her child! He is hyperactive, still in diapers, and he stinks!” You walk into the examination room and immediately notice a mousy, musty smell. Which of the following is the most likely diagnosis?

(A) Phenylketonuria

(B) Tyrosinemia type I

(C) Maple syrup urine disease

(D) Homocystinuria

(E) Cystinuria

  1. During a health maintenance visit, the parents of a 9-month-old infant note that their infant is unable to sit alone or roll over and startles very easily to sound. On examination, you note a cherry-red macula and poor eye contact. Which of the following is correct regarding the likely diagnosis?

(A) No treatment is available, and death will occur early in childhood.

(B) Radiography of the lower extremity reveals an Erlenmeyer flask-shaped distal femur.

(C) Radiography of the extremities reveals dysostosis multiplex.

(D) Mild developmental delay is expected.

(E) Microcephaly should be apparent.



  1. A 5-day-old male infant is brought to the emergency department in shock. The infant's diaper has a sickly sweet smell. Significant laboratory results include serum bicarbonate of 6 mmol/L, serum pH of 6.9, serum glucose of 19 mg/dL, and an elevated serum ammonia of 1, 000µmol/L. Maple syrup urine disease is in the differential diagnosis. Which of the following statements regarding the acute management of this patient is correct?

(A) Antibiotics are not indicated because the infant likely has an inborn error of metabolism.

(B) Oral glucose should be administered.

(C) Total parenteral nutrition with protein and lipids should be started.

(D) Sodium benzoate should be administered.

(E) Enteral feeds with a soy-based formula should be given to provide nutrition and to prevent intestinal villous atrophy.

  1. A 14-year-old boy with mental retardation has been referred to you. The underlying cause of his mental retardation has never been identified. On physical examination, you note that he has large ears and large testes. Which of the following syndromes is associated with mental retardation and these physical findings?

(A) Klinefelter syndrome

(B) Down syndrome

(C) Prader-Willi syndrome

(D) Williams syndrome

(E) Fragile X syndrome

  1. A 4-month-old male infant has been brought to your office for a routine health maintenance evaluation. You note that his height is below the third percentile, yet his head circumference is at the 75th percentile. Facial findings include a prominent forehead and hypoplasia of the midface region. He also has trident-shaped hands and bilateral short femurs and upper arms. Which of the following is a potential complication of this patient's likely disorder?

(A) Lumbar kyphosis in late childhood

(B) Atlantoaxial instability

(C) Spinal cord compression leading to sudden death during infancy

(D) Aortic dissection

(E) Delayed puberty

  1. The mother of a 5-year-old boy is very concerned and shows you a note from his kindergarten teacher. The boy is very active, easily distracted, and unable to perform skills at the same level as others in his class, and the teacher expresses concern and wonders whether the boy could have a severe learning problem. On examination, you note that the boy's height and weight are at the 50th percentile, but his head appears very small. In addition, he has short palpebral fissures and a long, smooth philtrum with a thin upper lip. The remainder of the examination is normal. Which of the following is the most likely diagnosis?

(A) Angelman syndrome

(B) Down syndrome

(C) Fetal phenytoin syndrome

(D) Fetal alcohol syndrome

(E) Prader-Willi syndrome

  1. A 12-year-old boy is brought to the office for a routine health maintenance visit by his parents. They report that he has struggled in school, requiring some special educational assistance since kindergarten, but has been otherwise healthy. Examination reveals that the boy is very tall (> 95th percentile) with long, thin arms with fingers of normal size. Mild scoliosis is evident. On auscultation, a murmur consistent with mitral regurgitation is audible. Based on the likely diagnosis, which of the following would you also expect to find on further evaluation?

(A) Increased upper-to-lower segment ratio

(B) Downward lens subluxation

(C) Aortic root dilatation

(D) Joint laxity

(E) Hypogonadism

  1. You are called to the newborn nursery to evaluate a 1-day-old female infant with unusual physical findings. On examination, you note that the neonate's hands are clenched with overlapping digits and her lower extremities are extended and crossed. You also note the presence of rocker bottom feet and delicate, small facial features. Which of the following chromosomal abnormalities is the most likely cause of the patient's features?

(A) Trisomy 13

(B) Trisomy 18

(C) Trisomy 21

(D) Deletion on chromosome 7

(E) Absence of a region on paternally derived chromosome 15

The response options for statements 12–14 are the same. You will be required to select one answer for each statement in the set.

For each patient, select the most likely genetic condition.



  1. Six-year-old boy with coarsened facial features, stiff joints, and a cloudy cornea

(A) Ehlers-Danlos syndrome

(B) Cri du chat syndrome

(C) Osteogenesis imperfecta

(D) Williams syndrome

(E) Angelman syndrome

(F) Hurler syndrome

(G) Hunter syndrome

(H) Tay-Sachs disease

(I) Gaucher's disease

(J) Homocystinuria

  1. Four-year-old boy with microcephaly, hypertelorism, mental retardation, and a deletion on the short arm of chromosome 5

(A) Ehlers-Danlos syndrome

(B) Cri du chat syndrome

(C) Osteogenesis imperfecta

(D) Williams syndrome

(E) Angelman syndrome

(F) Hurler syndrome

(G) Hunter syndrome

(H) Tay-Sachs disease

(I) Gaucher's disease

(J) Homocystinuria

  1. Fourteen-year-old girl with joint laxity, easily bruisable skin, and a defect in type V collagen

(A) Ehlers-Danlos syndrome

(B) Cri du chat syndrome

(C) Osteogenesis imperfecta

(D) Williams syndrome

(E) Angelman syndrome

(F) Hurler syndrome

(G) Hunter syndrome

(H) Tay-Sachs disease

(I) Gaucher's disease

(J) Homocystinuria



Answers and Explanations

  1. The answer is B[VI.A]. Galactosemia should always be considered in the differential diagnosis of any newborn who develops hypoglycemia and has hepatomegaly. Infants with galactosemia develop vomiting and diarrhea after feeding with either breast milk or cow's milk-based formulas because both types of feedings contain galactose. Soy milk does not contain galactose, which means that an infant who is fed a soy formula will not be symptomatic; this delays the diagnosis. Infants with galactosemia are vulnerable toEscherichia colisepsis, and if the condition is not diagnosed, they may die in early infancy. Children with Gaucher's disease present with neurodegeneration, splenomegaly, and bony changes (the most characteristic of which is an Erlenmeyer flask-shaped distal femur). After the first year of life, individuals with Hurler disease present with developmental delay, coarse facies, corneal clouding, and dysostosis multiplex. Individuals with transient hyperammonemia of the newborn may present with vomiting, and those with Niemann-Pick disease may present with hepatomegaly and seizures, but hypoglycemia andE. colisepsis are not typical features of these diseases.
  2. The answer is E[XI.A.2]. Wilson's disease should always be considered in a patient with personality changes, ataxia, and seizures. The patient's signs and symptoms are suggestive of Wilson's disease, which is caused by a defect in copper excretion leading to copper deposition in the brain, eyes, and liver. Kayser-Fleischer rings, which represent copper deposition in Descemet's membrane, are pathognomonic for Wilson's disease. The most commonly used screening test for Wilson's disease is a low serum ceruloplasmin, which is very suggestive of the disorder. None of the other answer choices are associated with the signs and symptoms present in this patient. Serum porphobilinogen is elevated in acute intermittent porphyria, which may present with weakness, abdominal pain, and autonomic instability. Neither aluminum, zinc, nor lead causes the signs and symptoms seen in this patient.
  3. The answer is C[III.C.1]. Girls with Turner syndrome are usually diagnosed in childhood after an evaluation for short stature, or during adolescence after an evaluation for delayed puberty. Patients with Turner syndrome classically have a webbed neck with a low posterior hairline, a shield chest with widely spaced nipples, and transient swelling of the hands and feet during the newborn period. Noonan syndrome can occur in females and has similar physical findings, but affected patients usually have right-sided heart lesions (e.g., pulmonary stenosis). Patients with Turner syndrome have left-sided heart lesions (e.g., coarctation of the aorta). Patients with achondroplasia are short from birth with shortening of the proximal long bones (rhizomelic short stature), those with Silver-Russell syndrome have short stature with skeletal asymmetry, and those with Marfan syndrome are tall, not short.
  4. The answer is A[Table 5-5]. Patients with mild phenylketonuria may present in childhood with developmental delay, hyperactivity, and a classic mousy or musty odor. Patients with tyrosinemia type I present with peripheral neuropathy and renal and liver disease, and may produce an odor of rotten fish or cabbage. Children with mild maple syrup urine disease may also present with developmental delay, but their urine has a sweet maple syrup odor. Neither homocystinuria nor cystinuria has a peculiar odor as a feature; however, patients with homocystinuria may have developmental delay as a result of strokes from their hypercoagulable state.
  5. The answer is A[IX.A.1]. The infant has infantile Tay-Sachs disease, a devastating progressively neurodegenerative disease caused by hexosaminidase A deficiency. The onset of disease is in early infancy when the infant presents with a hyperactive startle and loses eye contact. Classic features include a cherry-red macula, enlarging head circumference, neurodegeneration with severe developmental delay, progressive blindness, and seizures. Death usually occurs by 4 years of age. An Erlenmeyer flask-shaped distal femur is a feature of Gaucher's disease and not Tay-Sachs disease. Dysostosis multiplex (bony abnormalities that include a thickened skull, malformed vertebrae, and abnormal ribs and clavicle) is found in patients with mucopolysaccharidoses (e.g., Hunter and Hurler syndromes).



  1. The answer is D[IV.C]. In general, the acute management of an inborn error of metabolism involves supplying a source of energy that can be utilized, removing toxic metabolites, and preventing continued exposure to the offending substance. Because of this patient's hyperammonemia, sodium benzoate would be useful to facilitate ammonia excretion. Although the patient's condition is likely to be an inborn error of metabolism (maple syrup urine disease given the diaper odor consistent with the odor of maple syrup), sepsis is more common and can present in a similar fashion. Therefore, initial management should include intravenous antibiotics. Glucose is a basic energy source that can be used in any patient, regardless of the inborn error of metabolism, and should be administered intravenously, not orally, in a patient who is markedly hypoglycemic and in shock. Patients with maple syrup urine disease cannot metabolize branched-chain amino acids; therefore, offering parenteral nutrition with protein would continue the toxic exposure. In addition, until a diagnosis is made, initial management should include avoidance of any enteral feedings to limit continued exposure to the offending substance.
  2. The answer is E[III.C.2]. The characteristic physical features of fragile X syndrome include large ears, macrocephaly, blue irides, and large testes. Klinefelter syndrome is characterized by tall stature, gynecomastia, and a small penis and testes; Down syndrome by characteristic facial features, endocardial cushion defects, duodenal atresia, mental retardation, single palmar creases, and a wide space between the first and second toes; Prader-Willi syndrome by infantile hypotonia, hypogonadism, short stature, and obesity and hyperphagia later in childhood; and Williams syndrome by a loquacious “cocktail party” personality, supravalvular aortic stenosis, and hypercalcemia. Testes are unaffected in Down syndrome and in Williams syndrome.
  3. The answer is C[III.D.2.c]. This patient's physical features are consistent with achondroplasia, the most common skeletal dysplasia. Potential complications of this disorder include cord compression caused by foramen magnum stenosis that can lead to sudden death during infancy, obstructive sleep apnea, and orthopedic problems such as genu varum and back pain caused by lumbar lordosis during late childhood. Neither atlantoaxial instability (a complication of Down syndrome), aortic dissection (a complication of Marfan syndrome), nor delayed puberty is associated with achondroplasia.
  4. The answer is D[III.F.1]. This patient's physical characteristics, along with learning problems and attention deficit/hyperactivity disorder, are consistent with fetal alcohol syndrome. Angelman syndrome is associated with severe mental retardation and a small head, although a puppetlike gait and inappropriate bouts of laughter are also characteristic. Down syndrome is also associated with mental retardation; however, the facial characteristics include upslanting palpebral fissures, epicanthal skin folds, and a protruding tongue. Fetal phenytoin syndrome is associated with mental retardation, nail and digit abnormalities, and cardiac defects. Prader-Willi syndrome is associated with hypogonadism, almond-shaped eyes, short stature, and hyperphagia with obesity during childhood.
  5. The answer is B[V.A]. The clinical features of homocystinuria and Marfan syndrome overlap considerably; however, this patient most likely has homocystinuria based on the presence of a marfanoid body habitus with fingers of normal length (i.e., no arachnodactyly). In addition, patients with homocystinuria have downward lens subluxation (upward lens subluxation is found in Marfan syndrome); mitral or aortic regurgitation (aortic dilatation is absent but is present in Marfan syndrome); large, stiff joints (joint laxity is found in Marfan syndrome); and developmental delay and mild mental retardation (mental retardation is absent in Marfan syndrome). Patients with both disorders have a decreased upper-to-lower segment ratio. Hypogonadism is absent in both disorders.
  6. The answer is B[III.B.2]. The findings of scissoring of the lower extremities, clenched hands with overlapping digits, rocker bottom feet, and delicate small facial features are consistent with the diagnosis of trisomy 18, the second most common trisomy syndrome after trisomy 21. Trisomy 21 is the cause of Down syndrome and is associated with hypotonia, prominent epicanthal folds, upslanting palpebral fissures, and single palmar creases. Trisomy 13 is associated with midline defects of the brain and forebrain. Features include microphthalmia, holoprosencephaly, and cleft lip and palate. Absence of a region on the paternally derived chromosome 15 is the cause of Prader-Willi syndrome, a disorder associated with neonatal hypotonia, hypogonadism, almond-shaped eyes, and short stature. A deletion on chromosome 7 causes Williams syndrome, characterized by elfin facies and a loquacious “cocktail party” personality.



12, 13, and 14. The answers are F [IX.B.1], B [III.A.14], and A [III.A.6], respectively. Hurler syndrome, a mucopolysaccharidosis in which glucosaminoglycans deposit in various tissues causing a progressive clinical picture, is characterized by corneal clouding, changes to the bone termed dysostosis multiplex, organomegaly, and progressively coarsened facies, including frontal bossing, widened nasal bridge, and thickening of the nasopharyngeal tissues.

Cri du chat syndrome, caused by a partial deletion on the short arm of chromosome 5, is characterized by slow growth, microcephaly, mental retardation, hypertelorism, and a classic catlike cry.

Ehlers-Danlos syndrome is caused by a defect in type V collagen that results in hyperextensible joints, fragile blood vessels that cause easily bruised skin, tissue paper-thin scars, and cardiovascular complications (e.g., mitral valve prolapse and aortic root dilatation that can lead to dissection).

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