Atlas of pathophysiology, 2 Edition

Part I - Central concepts


Genetics is the study of heredity—the passing of physical, biochemical, and physiologic traits, both healthy and pathogenic, from biological parents to their children. In this transmission, mistakes or mutations can cause susceptibility to disease, disability, or death.

Genetic information is carried in genes, which are strung together on the deoxyribonucleic acid (DNA) double helix to form chromosomes. Every normal human cell (except reproductive cells) has 46 chromosomes, 22 paired chromosomes called autosomes, and two sex chromosomes (a pair of X's in females and an X and a Y in males). A person's individual set of chromosomes is called his karyotype. The human genome has been under intense study for about 15 years to determine the structure of each gene in the genome and its location within each of the 23 chromosomes comprising the set of human chromosomes. In April 2003, scientists announced the completion of the entire genome sequence. The sequence consists of more than 3.1 billion pairs of DNA bases. Decoding the genome will enable people to know who's likely to get a specific inherited disease and enable researchers to eradicate or improve the treatment of many diseases.

For a wide variety of reasons, not every gene is expressed in every cell. Genetic principles are based on studies of thousands of individuals. Those studies have led to generalities that are usually true, but exceptions occur. Genetics remains an inexact science.

Genetic components

Each of the two strands of DNA in a chromosome consists of thousands of combinations of four nucleotides: adenine (A), thymine (T), cytosine (C), and guanine (G), arranged in complementary triplet pairs (called codons), each of which represents an amino acid; a specific sequence of triplets represents a gene. The strands are held together loosely by chemical bonds between adenine and thymine or between cytosine and guanine. The looseness of the bonds allows the strands to separate easily during DNA replication. The genes carry a code for each trait a person inherits, from blood type to eye color to body shape and a myriad of other traits.

DNA ultimately controls the formation of essential substances throughout the life of every cell in the body. It does this through the genetic code, the precise sequence of AT and CG pairs on the DNA molecule. Genes control not only hereditary traits, transmitted from parents to offspring but also cell reproduction and the daily functions of all cells. Genes control cell function by controlling the structures and chemicals that are synthesized within the cell.

Transmitting traits

Germ cells, or gametes, are one of two classes of cells in the body; each germ cell (ovum or sperm) contains 23 chromosomes (called the haploid number) in its nucleus. All the other cells in the body are somatic cells, which are diploid; that is, they contain 23 pairs of chromosomes.

When human ovum and sperm unite, the corresponding chromosomes pair up, so that the fertilized cell as well as every somatic cell of the new individual has 23 pairs of chromosomes in its nucleus.

Germ cells

The body produces germ cells through a type of cell division called meiosis. Meiosis occurs only when the body is creating haploid germ cells from their diploid precursors. Each of the 23 pairs of chromosomes in the diploid precursor cell replicates and undergoes two cell divisions, so that, on completion, each new germ cell (ovum or sperm) contains one set of 23 chromosomes.

Most of the genes on one chromosome are identical or almost identical to those on its mate. The location (or locus) of a gene on a chromosome is specific and doesn't vary from person to person. This allows each of the thousands of genes on a strand of DNA in an ovum to join the corresponding gene in a sperm when the chromosomes pair up at fertilization.

Sex chromosomes

Only one pair of the 23 pairs of chromosomes in each cell is primarily involved in determining a person's sex. These are the sex chromosomes; the other 22 chromosome pairs are called autosomes. Females have two X chromosomes and males have one X and one Y chromosome.

Each germ cell produced by a male contains either an X or a Y chromosome. When a sperm with an X chromosome fertilizes an ovum, the offspring is female (two X chromosomes); when a sperm with a Y chromosome fertilizes an ovum, the offspring is male (one X and one Y chromosome). Extremely rare errors in cell division can result in a germ cell that has no sex chromosome or has two sex chromosomes. After fertilization, the zygote may have an XXX, XYY, XO, or XXY karyotype and still survive. Most other errors in sex chromosome division are incompatible with life.


The fertilized ovum—now called a zygote—undergoes a kind of cell division called mitosis. Before a cell divides, its chromosomes replicate. During this process, the double helix of DNA separates into two chains; each chain serves as a template for constructing a new chain. Individual DNA nucleotides are linked into new strands with bases complementary to those in the originals. In this way, two identical double helices are formed, each containing one of the original strands and a newly formed complementary strand. These double helices are duplicates of the original DNA chain.

Mitotic cell division occurs in five phases: interphase, prophase, metaphase, anaphase, and telophase. The result of every mitotic cell division is two new daughter cells, each genetically identical to the original and to each other. Then, each of the two resulting cells divides, and so on, eventually forming a many-celled human embryo. Thus, each cell in a person's body (except ovum or sperm) contains an identical set of 46 chromosomes that are unique to that person.


Trait predominance

Each parent contributes one set of chromosomes (and therefore one set of genes) so that every offspring has two genes for every locus on the autosomes. Some characteristics, or traits, such as eye color, are determined by one gene that may have many variants (alleles). Others, called polygenic traits, require the interaction of two or more genes. In addition, environmental factors may affect how genes are expressed, although the environmental factors don't affect the genetic structure.

Variations in a particular gene—such as brown, blue, or green eye color—are called alleles. A person who has identical genes on each member of the chromosome pair is homozygousfor that gene; if the alleles are different, the person is said to be heterozygous.

Autosomal inheritance

On autosomes, one allele may be more influential than another in determining a specific trait. The more powerful, or dominant, gene product is more likely to be exhibited in the offspring than the less influential, or recessive, gene product. Offspring will exhibit a dominant allele when one or both chromosomes in a pair carry it. A recessive allele won't be exhibited unless both chromosomes carry identical copies of the allele. For example, a child may receive a gene for brown eyes from one parent and a gene for blue eyes from the other parent. The gene for brown eyes is dominant, and the gene for blue eyes is recessive. Because the dominant allele is more likely to mask the recessive allele, the child is more likely to have brown eyes.

Sex-linked inheritance

The X and Y chromosomes aren't literally a pair because the X chromosome is much larger than the Y, with more genetic material. The male has only one copy of the genes on the X chromosome. Inheritance of those genes is called X-linked. A man will transmit one copy of each X-linked gene to his daughters and none to his sons. A woman will transmit one copy to each child, whether male or female.

Inheritance of genes on the X chromosome is different in another way. Females have two X chromosomes in each of their cells; however, only one X chromosome is active in each cell because of a process called X inactivation. X inactivation occurs during early embryogenesis in the female, and the X that's inactivated in each cell is random. In some cells, the X the female received from her mother is inactivated, and in other cells the X she received from her father is inactivated. For this reason, at the cellular level a heterozygous female will express the recessive gene in some cells and the dominant gene in others.

Multifactorial inheritance

Multifactorial inheritance is inheritance that's determined by multiple factors, including genetic and possible nongenetic (environmental), each with only a partial effect. The genetic factor may consist of variations for multiple genes: some that provide susceptibility and some that provide protection. Examples of environmental factors that may contribute to such a trait are nutrition, exposure to teratogens or carcinogens, viral infections, exposure to oxidants, and intake of antioxidants.

Pathophysiologic concepts

Autosomal disorders, sex-linked disorders, and multifactorial disorders result from changes to genes or chromosomes. Some defects arise spontaneously, whereas others may be caused by environmental agents, including mutagens, teratogens, and carcinogens.

Environmental teratogens

Teratogens are environmental agents (infectious toxins, maternal systemic diseases, drugs, chemicals, and physical agents) that can harm the developing fetus by causing congenital structural or functional defects. Teratogens may also cause spontaneous abortion, complications during labor and delivery, hidden defects in later development (such as cognitive or behavioral problems), or neoplastic transformations.

Environmental mutagens and carcinogens

A permanent change in genetic material is a mutation, which may occur spontaneously or after exposure of a cell to a mutagen, such as radiation, certain chemicals, or viruses. Mutations can occur at any location in the genome.

Carcinogens are environmental agents, such as cigarette smoke, indoor and outdoor air pollution, and preservatives in certain foods, that may cause cancer.

Every cell has built-in defenses against genetic damage. However, if a mutation isn't identified or repaired, the mutation may produce a trait different from the original trait and may be transmitted to offspring. Mutations may have no effect; some may change expression of a trait, and others may change the way a cell functions. Many mutagens are also carcinogens because they alter cell function. Some mutations cause serious or deadly defects, such as congenital anomalies or cancer.

Autosomal disorders

In single-gene disorders, an error occurs at a single gene site on the DNA strand. A mistake may occur in the copying and transcribing of a single codon through additions, deletions, or excessive repetitions.

Single-gene disorders are inherited in clearly identifiable patterns that are the same as those seen in inheritance of normal traits. Because every person has 22 pairs of autosomes and only 1 pair of sex chromosomes, most hereditary disorders are caused by autosomal defects.

Autosomal dominant transmission usually affects male and female offspring equally. Children of an affected parent have a 50% chance of being affected. Autosomal recessive inheritance also usually affects male and female offspring equally. If both parents are affected, all their offspring will be affected. If both parents are unaffected but are heterozygous for the trait (carriers of the defective gene), there's a 25% chance with each pregnancy that the child will be affected. If only one parent is affected and the other isn't a carrier, none of the offspring will be affected but all will carry the defective gene. If one parent is affected and the other is a carrier, 50% of their children will be affected. Autosomal recessive disorders may occur when no family history of the disease exists.

Sex-linked disorders

Genetic disorders caused by genes located on the sex chromosomes are termed sex-linked disorders. Most sex-linked disorders are controlled by genes located on the X chromosome, usually


as recessive traits. Because males have only one X chromosome, a single X-linked recessive gene can cause disease to be exhibited in a male. Females receive two X chromosomes, so they can be homozygous for a disease allele, homozygous for a normal allele, or heterozygous.

Most people who express X-linked recessive traits are males with unaffected parents. In rare cases, the father is affected and the mother is a carrier. All daughters of an affected male and a noncarrier female will be carriers. Sons of an affected male and a noncarrier female will be unaffected, and the unaffected sons aren't carriers. Unaffected male children of a female carrier don't transmit the disorder.

Characteristics of X-linked dominant inheritance include evidence of the inherited trait in the family history. A person with the abnormal trait must have one affected parent. If the father has an X-linked dominant disorder, all his daughters and none of his sons will be affected. If a mother has an X-linked dominant disorder, each of her children has a 50% chance of being affected.

Multifactorial disorders

Most multifactorial disorders result from the effects of several different genes and an environmental component. In polygenic inheritance, each gene has a small additive effect, and the effect of a combination of genetic errors in a person is unpredictable. Multifactorial disorders can result from a less-than-optimum expression of many different genes, not from a specific error.

Some multifactorial disorders are apparent at birth, such as cleft lip, cleft palate, congenital heart disease, anencephaly, clubfoot, and myelomeningocele. Others don't become apparent until later, such as type 2 diabetes mellitus, hypertension, hyperlipidemia, most autoimmune diseases, and many cancers. Multifactorial disorders that develop during adulthood are commonly believed to be strongly related to environmental factors, not only in incidence but also in the degree of expression.

Chromosome defects

Aberrations in chromosome structure or number cause a class of disorders called congenital anomalies, or birth defects. The aberration may be loss, addition, or rearrangement of genetic material. If the remaining genetic material is sufficient to maintain life, an endless variety of clinical manifestations may occur. Most clinically significant chromosome aberrations arise during meiosis. Meiosis is an incredibly complex process that can go wrong in many ways. Potential contributing factors include maternal age, radiation, and use of some therapeutic or recreational drugs.

Translocation, the relocation of a segment of a chromosome to a nonhomologous chromosome, occurs when chromosomes split apart and rejoin in an abnormal arrangement. The cells still have a normal amount of genetic material, so usually there are no visible abnormalities. However, because of the potential for these individuals to produce unbalanced gametes, the children of parents with translocated chromosomes may have serious genetic defects, such as monosomies or trisomies.

During both meiosis and mitosis, chromosomes normally separate in a process called disjunction. Failure to separate, called nondisjunction, causes an unequal distribution of chromosomes between the two resulting cells. If nondisjunction occurs during mitosis soon after fertilization, it may affect all the resulting cells. If nondisjunction occurs later during embryogenesis, a portion of the cells may be abnormal, resulting in mosaicism, which is the presence of two or more cell lines in the same person. Gain or loss of chromosomes is usually caused by nondisjunction of autosomes or sex chromosomes during meiosis. The incidence of nondisjunction increases with parental age.

The presence of one chromosome fewer than the normal number is called monosomy for that particular chromosome; an autosomal monosomy is nonviable. The presence of an extra chromosome is called a trisomy for that particular chromosome. A mixture of both abnormal and normal cells results in mosaicism. The effect of mosaicism depends on the proportion and anatomic location of abnormal cells.

Genetic disorders

Genetic disorders are commonly classified by pattern of inheritance, as shown in the accompanying chart. (See Common genetic disorders, pages 24 to 27.)





Common Genetic Disorders




Autosomal recessive disorders

Cystic fibrosis
Inborn error in a cell-membrane transport protein. Dysfunction of the exocrine glands affects multiple organ systems. The disease affects males and females. It's the most common fatal genetic disease in white children.

Most cases arise from the mutation that affects the genetic coding for a single amino acid, resulting in a protein (cystic fibrosis transmembrane regulator [CFTR]) that doesn't function properly. This mutant CFTR resembles other transmembrane transport proteins, but it lacks the phenylalanine at position 508 in the protein produced by normal genes. This regulator interferes with cyclic adenosine monophosphate (cAMP)–regulated chloride channels and transport of other ions by preventing adenosine triphosphate from binding to the protein or by interfering with activation by protein kinase. The mutation affects volume-absorbing epithelia in the airways and intestines, salt-absorbing epithelia in sweat ducts, and volume-secretory epithelia in the pancreas. Mutations in CFTR lead to dehydration, which increases the viscosity of mucous gland secretions and consequently obstructs glandular ducts. Cystic fibrosis has varying effects on electrolyte and water transport.

·         Chronic airway infections leading to bronchiectasis

·         Bronchiolectasis

·         Exocrine pancreatic insufficiency

·         Intestinal dysfunction

·         Abnormal sweat-gland function

·         Reproductive dysfunction

Phenylketonuria (PKU)
Inborn error in metabolism of the amino acid phenylalanine. PKU has a low incidence among Blacks and Ashkenazic Jews and a high incidence among people of Irish and Scottish descent.

Patients with classic PKU have almost no activity of phenylalanine hydroxylase, an enzyme that helps convert phenylalanine to tyrosine. As a resuIt, phenylalanine accumulates in the blood and urine, and tyrosine levels are low.

Treatment includes early diagnosis and avoidance of phenylalanine in the diet; however, if left untreated, these signs and symptoms can occur:

·         By age 4 months, signs of arrested brain development, including mental retardation

·         Personality disturbances

·         Seizures

·         Decreased IQ

·         Macrocephaly

·         Eczematous skin lesions or dry, rough skin

·         Hyperactivity

·         Irritability

·         Purposeless, repetitive motions

·         Awkward gait

·         Musty odor from skin and urine excretion of phenylacetic acid

Sickle cell anemia
Congenital hemolytic anemia resulting from defective hemoglobin molecules. In the United States, sickle cell anemia occurs primarily in persons of African and Mediterranean descent. It also affects populations in Puerto Rico, Turkey, India, and the Middle East.

Abnormal hemoglobin S in red blood cells becomes insoluble during hypoxia. As a result, these cells become rigid, rough, and elongated, forming a crescent or sickle shape. The sickling produces hemolysis. The altered cells also pile up in the capillaries and smaller blood vessels, making the blood more viscous. Normal circulation is impaired, causing pain, tissue infarctions, and swelling. Each patient with sickle cell anemia has a different hypoxic threshold and different factors that trigger a sickle cell crisis. Illness, exposure to cold, stress, acidotic states, or a pathophysiologic process that pulls water out of the sickle cells precipitates a crisis in most patients. The blockages then cause anoxic changes that lead to further sickling and obstruction.

·         Symptoms of sickle cell anemia don't develop until after age 6 months because fetal hemoglobin protects infants for the first few months after birth

·         Chronic fatigue

·         Unexplained dyspnea on exertion

·         Joint swelling

·         Aching bones

·         Severe localized and generalized pain

·         Leg ulcers

·         Frequent infections

·         Priapism in males

In sickle cell crisis:

·         Severe pain

·         Hematuria

·         Lethargy

Tay-Sachs disease
Also known as GM2 gangliosidosis, the most common lipid-storage disease. Tay-Sachs affects Ashkenazic Jews about 100 times more often than the general population.

The enzyme hexosaminidase A is absent or deficient. This enzyme is necessary to metabolize gangliosides, water-soluble glycolipids found primarily in the central nervous system (CNS). Without hexosaminidase A, lipid molecules accumulate, progressively destroying and demyelinating CNS cells.

·         Exaggerated Moro's (startle) reflex at birth and apathy (response only to loud sounds) by age 3 to 6 months

·         Inability to sit up, lift head, or grasp objects; difficulty turning over; progressive vision loss

·         Deafness, blindness, seizures, paralysis, spasticity, and continued neurologic deterioration (by age 18 months)

·         Recurrent bronchopneumonia

Autosomal dominant disorders

Marfan syndrome
Rare degenerative, generalized disease of the connective tissue that results from elastin and collagen defects. The syndrome occurs in 1 of 20,000 individuals, affecting males and females equally. Approximately 25% of cases represent new mutations.

Marfan syndrome is caused by mutation in a single gene on chromosome 15, the gene that codes for fibrillin, a glycoprotein component of connective tissue. These small fibers are abundant in large blood vessels and the suspensory ligaments of the ocular lenses. The effect on connective tissue is variable and includes excessive bone growth, ocular disorders, and cardiac defects.

·         Increased height, long extremities, and arachnodactyly (long, spiderlike fingers)

·         Defects of sternum (funnel chest or pigeon breast, for example), chest asymmetry, scoliosis, or kyphosis

·         Hypermobile joints

·         Myopia

·         Lens displacement

·         Valvular abnormalities (redundancy of leaflets, stretching of chordae tendineae, or dilation of valvulae anales)

·         Mitral valve prolapse

·         Aortic regurgitation

X-linked recessive disorders

Fragile X syndrome
The most common inherited cause of mental retardation. Approximately 85% of males and 50% of females who inherit the fragile X mental retardation 1 (FMR1) mutation will demonstrate clinical features of the syndrome. It's estimated to occur in about 1 in 1,500 males and 1 in 2,500 females. It has been reported in almost all races and ethnic populations.

Fragile X syndrome is an X-linked condition that doesn't follow a simple X-linked inheritance pattern. The unique mutation that results consists of an expanding region of a specific triplet of nitrogenous bases: cytosine, guanine, and guanine (CGG) within the gene's DNA sequence. Normally, FMR1 contains 6 to 49 sequential copies of the CGG triplet. When the number of CGG triplets expands to the range of 50 to 200 and repeats, the region of DNA becomes unstable and is referred to as a premutation. A full mutation consists of more than 200 CGG triplet repeats. The full mutation typically causes abnormal methylation (methyl groups attach to components of the gene) of FMR1. Methylation inhibits gene transcription and, thus, protein production. The reduced or absent protein product is responsible for the clinical features of fragile X syndrome.

Postpubescent males with fragile X syndrome commonly have distinct physical features, behavioral difficulties, and cognitive impairment. Other signs and symptoms include:

·         Prominent jaw and forehead and a head circumference exceeding the 90th percentile

·         Long, narrow face with long or large ears that may be posteriorly rotated

·         Connective tissue abnormalities, including hyperextension of the fingers, a floppy mitral valve (in 80% of adults), and mild to severe pectus excavatum

·         Unusually large testes

·         Average IQ of 30 to 70

·         Hyperactivity, speech difficulties, language delay, and autisticlike behaviors

Females with fragile X syndrome tend to have more subtle symptoms, including:

·         Learning disabilities

·         IQ scores in the mental retardation range

·         Excessive shyness or social anxiety

·         Prominent ears and connective tissue manifestations

Bleeding disorder; severity and prognosis vary with the degree of deficiency, or nonfunction, and the site of bleeding. Hemophilia occurs in 20 of 100,000 male births. Hemophilia A, or classic hemophilia, is a deficiency of clotting factor VIII; it's more common than type B, affecting more than 80% of all hemophiliacs. Hemophilia B, or Christmas disease, affects 15% of all hemophiliacs and results from a deficiency of factor IX. There's no relationship between factor VIII and factor IX inherited defects.

Abnormal bleeding occurs because of specific clotting factor malfunction. Factors VIII and IX are components of the intrinsic clotting pathway; factor IX is an essential factor, and factor VIII is a critical cofactor. Factor VIII accelerates the activation of factor X by several thousand times. Excessive bleeding occurs when these clotting factors are reduced by more than 75%.
Hemophilia may be severe, moderate, or mild, depending on the degree of activation of clotting factors. A person with hemophilia forms a platelet plug at a bleeding site, but clotting factor deficiency impairs the ability to form a stable fibrin clot. Delayed bleeding is more common than immediate hemorrhage.

·         Spontaneous bleeding in severe hemophilia

·         Excessive or continued bleeding or bruising

·         Large subcutaneous and deep intramuscular hematomas

·         Prolonged bleeding in mild hemophilia after major trauma or surgery, but no spontaneous bleeding after minor trauma

·         Pain, swelling, and tenderness in joints

·         Internal bleeding, commonly manifested as abdominal, chest, or flank pain

·         Hematuria

·         Hematemesis or tarry stools

Polygenic (multifactorial) disorders

Cleft lip and cleft palate
May occur separately or together. Cleft lip with or without cleft palate occurs twice as often in males as in females. Cleft palate without cleft lip is more common in females. Cleft lip deformities can occur unilaterally, bilaterally or, rarely, in the midline. Only the lip may be involved, or the defect may extend into the upper jaw or nasal cavity. Incidence is highest in children with a family history of cleft defects.

During the 2nd month of pregnancy, the front and sides of the face and the palatine shelves develop. Because of a chromosomal abnormality, exposure to teratogens, genetic abnormality, or environmental factors, the lip or palate fuses imperfectly. The deformity may range from a simple notch to a complete cleft.
A cleft palate may be partial or complete. A complete cleft includes the soft palate, the bones of the maxilla, and the alveolus on one or both sides of the premaxilla.
A double cleft is the most severe of the deformities. The cleft runs from the soft palate forward to either side of the nose. A double cleft separates the maxilla and premaxilla into freely moving segments. The tongue and other muscles can displace the segments, enlarging the cleft.

·         Obvious cleft lip or cleft palate

·         Feeding difficulties due to incomplete fusion of the palate

Neural tube defects
Serious birth defects that involve the spine or skull; they result from failure of the neural tube to close at approximately 28 days after conception. The most common forms of neural tube defects are spina bifida (50% of cases), anencephaly (40% of cases), and encephalocele (10% of cases). Spina bifida occulta is the most common and least severe spinal cord defect. The incidence of neural tube defects varies greatly among countries and by region in the United States. For example, the incidence is significantly higher in the British Isles and low southern China and Japan. In the United States, North and South Carolina have at least twice the incidence of neural tube defects as most other parts of the country. These birth defects are also less common in Blacks than in Whites.

Neural tube closure normally occurs at 24 days gestation in the cranial region and continues distally, with closure of the lumbar regions by 28 days.
Spina bifida occulta is characterized by incomplete closure of one or more vertebrae without protrusion of the spinal cord or meninges.
However, in more severe forms of spina bifida, incomplete closure of one or more vertebrae causes protrusion of the spinal contents in an external sac or cystic lesion (spina bifida cystica). Spina bifida cystica has two classifications: myelomeningocele (meningomyelocele) and meningocele. In myelomeningocele, the external sac contains meninges, cerebrospinal fluid (CSF), and a portion of the spinal cord or nerve roots distal to the conus medullaris. When the spinal nerve roots end at the sac, motor and sensory functions below the sac are terminated. In meningocele, less severe than myelomeningocele, the sac contains only meninges and CSF. Meningocele may produce no neurologic symptoms.
In encephalocele, a saclike portion of the meninges and brain protrudes through a defective opening in the skull. Usually, it occurs in the occipital area, but it may also occur in the parietal, nasopharyngeal, or frontal area.
In anencephaly, the most severe form of neural tube defect, the closure defect occurs at the cranial end of the neuroaxis and, as a result, part or the entire top of the skull is missing, severely damaging the brain. Portions of the brain stem and spinal cord may also be missing. No diagnostic or therapeutic efforts are helpful; this condition is invariably fatal.

Signs and symptoms depend on the type and severity of the neural tube defect:

·         Possibly, a depression or dimple, tuft of hair, soft fatty deposits, port wine nevi, or a combination of these abnormalities on the skin over the spinal defect (spina bifida occulta)

·         Foot weakness or bowel and bladder disturbances, especially likely during rapid growth phases (spina bifida occulta)

·         Saclike structure that protrudes over the spine (myelomeningocele, meningocele)

·         Depending on the level of the defect, permanent neurologic dysfunction, such as flaccid or spastic paralysis and bowel and bladder incontinence (myelomeningocele)

Disorders of chromosome number

Down syndrome (trisomy 21)
Spontaneous chromosome abnormality that causes characteristic facial features, other distinctive physical abnormalities (cardiac defects in 60% of affected persons), and mental retardation. It occurs in 1 of 650 to 700 live births.

Nearly all cases of Down syndrome result from trisomy 21 (three copies of chromosome 21). The result is a karyotype of 47 chromosomes instead of the usual 46. In 4% of patients, Down syndrome results from an unbalanced translocation or chromosomal rearrangement in which the long arm of chromosome 21 breaks and attaches to another chromosome. Some affected persons and some asymptomatic parents may have chromosomal mosaicism, a mixture of two cell types, some with the normal 46 and some with an extra chromosome 21.

·         Distinctive facial features (low nasal bridge, epicanthic folds, protruding tongue, and low-set ears); small open mouth and disproportionately large tongue

·         Single transverse crease on the palm (Simian crease)

·         Small white spots on the iris (Brushfield's spots)

·         Mental retardation (estimated lQ of 20 to 50)

·         Developmental delay

·         Congenital heart disease, mainly septal defects and especially of the endocardial cushion

·         Impaired reflexes

Trisomy 18 syndrome
Also known as Edwards' syndrome, it's the second most common multiple malformation syndrome. Most affected infants have full trisomy 18, involving an extra (third) copy of chromosome 18 in each cell, but partial trisomy 18 (with varying phenotypes) and translocation types have also been reported. Full trisomy 18 syndrome is generally fatal or has an extremely poor prognosis. Most trisomic conceptions are spontaneously aborted; 30% to 50% of infants die within the first 2 months of life, and 90% die within the first year. Most surviving patients are profoundly mentally retarded. Incidence ranges from 1 in 3,000 to 8,000 neonates, with 3 to 4 females affected for every 1 male.

Most cases result from spontaneous nondisjunction meiotic, leading to an extra copy of chromosome 18 in each cell.

·         Growth retardation, which begins in utero and remains significant after birth

·         Initial hypotonia that may soon cause hypertonia

·         Microcephaly and dolichocephaly

·         Micrognathia

·         Short and narrow nose with upturned nares

·         Unilateral or bilateral cleft lip and palate

·         Low-set, slightly pointed ears

·         Short neck

·         Conspicuous clenched hand with overlapping fingers (commonly seen on ultrasound in utero as well)

·         Cystic hygroma

·         Choroid plexus cysts (also seen in some normal infants)

Trisomy 13 syndrome
Also known as Patau's syndrome, it's the third most common multiple malformation syndrome. Most affected infants have full trisomy 13 at birth; a few have the rare mosaic partial trisomy 13 syndrome (with varying phenotypes) or translocation types. Full trisomy 13 syndrome is fatal. Many trisomic zygotes are spontaneously aborted; 50% to 70% of infants die within 1 month after birth, and 85% by the first year. Only isolated cases of survival beyond 5 years have been reported in full trisomy 13 patients. Incidence is estimated to be 1 in 4,000 to 10,000 neonates.

Approximately 75% of all cases result from chromosomal nondisjunction. About 20% result from chromosomal translocation, involving a rearrangement of chromosomes 13 and 14. About 5% of cases are estimated to be mosaics; the clinical effects in these cases may be less severe.

·         Microcephaly

·         Varying degrees of holoprosencephaly

·         Sloping forehead with wide sutures and fontanel

·         Scalp defect at the vertex

·         Bilateral cleft lip with associated cleft palate (in 45% of cases)

·         Flat and broad nose

·         Low-set ears and inner ear abnormalities

·         Polydactyly of the hands and feet

·         Club feet

·         Omphaloceles

·         Neural tube defects

·         Cystic hygroma

·         Genital abnormalities

·         Cystic kidneys

·         Hydronephrosis

·         Failure to thrive, seizures, apnea, and feeding difficulties






Respiratory acidosis

·         Airway obstruction or parenchymal lung disease

·         Mechanical ventilation

·         Chronic metabolic alkalosis as respiratory compensatory mechanisms try to normalize pH

·         Chronic bronchitis

·         Extensive pneumonia

·         Large pneumothorax

·         Pulmonary edema

·         Asthma

·         Chronic obstructive pulmonary disease (COPD)

·         Drugs

·         Cardiac arrest

·         Central nervous system (CNS) trauma

·         Neuromuscular diseases

·         Sleep apnea

When pulmonary ventilation decreases, partial pressure of carbon dioxide in arterial blood (PaCO2) increases and carbon dioxide (CO2) level rises. Retained CO2combines with water (H2O) to form carbonic acid (H2CO3), which dissociates to release free hydrogen (H+) and bicarbonate (HC03) ions. Increased Paco2 and free H+ ions stimulate the medulla to increase respiratory drive and expel CO2.
As pH falls, 2,3-diphosphoglycerate (2,3-DPG) accumulates in red blood cells, where it alters hemoglobin (Hb) to release oxygen. The Hb picks up H+ ions and CO2 and removes them from the serum. As respiratory mechanisms fail, rising PaCO2stimulates kidneys to retain HCO3 and sodium (Na+) ions and excrete H+ ions.
As the H+ ion concentration overwhelms compensatory mechanisms, H+ ions move into cells and potassium (K+) ions move out. Without enough oxygen, anaerobic metabolism produces lactic acid.

·         Restlessness

·         Confusion

·         Apprehension

·         Somnolence

·         Asterixis

·         Headaches

·         Dyspnea and tachypnea

·         Papilledema

·         Depressed reflexes

·         Hypoxemia

·         Tachycardia

·         Hypertension/hypotension

·         Atrial and ventricular arrhythmias

·         Coma

Arterial blood gas (ABG) analysis: PaCO2 > 45 mm Hg; pH <7.35 to 7.45; and normal HCO3 in the acute stage and elevated HCO3 in the chronic stage

For pulmonary causes

·         Removal of foreign body obstructing the airway

·         Mechanical ventilation

·         Bronchodilators

·         Antibiotics for pneumonia

·         Chest tubes for pneumothorax

·         Thrombolytics or anticoagulants for pulmonary emboli

·         Bronchoscopy to remove excess secretions


·         Bronchodilators

·         Oxygen at low flow rates

·         Corticosteroids

For other causes

·         Drug therapy

·         Dialysis or activated charcoal to remove toxins

·         Correction of metabolic alkalosis

·         I.V. sodium bicarbonate

Respiratory alkalosis

·         Acute hypoxemia, pneumonia, interstitial lung disease, pulmonary vascular disease, or acute asthma

·         Anxiety

·         Hypermetabolic states, such as fever and sepsis

·         Excessive mechanical ventilation

·         Salicylate toxicity

·         Metabolic acidosis

·         Hepatic failure

·         Pregnancy

As pulmonary ventilation increases, excessive CO2 is exhaled. Resulting hypocapnia leads to reduction of H2CO3 excretion of H+ and HCO3 ions, and rising serum pH.
Against rising pH, the hydrogen-potassium buffer system pulls H+ ions out of cells and into blood in exchange for K+ ions. H+ ions entering blood combine with HC03ions to form H2CO3, and pH falls.
Hypocapnia causes an increase in heart rate, cerebral vasoconstriction, and decreased cerebral blood flow. After 6 hours, kidneys secrete more HCO3 and less H+.
Continued low Paco2 and vasoconstriction increases cerebral and peripheral hypoxia. Severe alkalosis inhibits calcium (Ca+) ionization, increasing nerve and muscle excitability.

·         Deep, rapid breathing

·         Light-headedness or dizziness

·         Agitation

·         Circumoral and peripheral paresthesias

·         Carpopedal spasms, twitching, and muscle weakness

ABG analysis showing PaCO2 < 35 mm Hg; elevated pH in proportion to decrease in Paco2in the acute stage but decreasing toward normal in the chronic stage; normal HCO3 in the acute stage but less than normal in the chronic stage

·         Removal of ingested toxins, such as salicylates, by inducing emesis or using gastic lavage

·         Treatment of fever or sepsis

·         Oxygen for acute hypoxemia

·         Treatment of CNS disease

·         Having patient breathe into a paper bag

·         Adjustments to mechanical ventilation to decrease minute ventilation

Metabolic acidosis

·         Excessive acid accumulation

·         Deficient HCO3scores

·         Decreased acid excretion by the kidneys

·         Diabetic ketoacidosis

·         Chronic alcoholism

·         Malnutrition or a low-carbohydrate, high-fat diet

·         Anaerobic carbohydrate metabolism

·         Underexcretion of metabolized acids or inability to conserve base

·         Diarrhea, intestinal malabsorption, or loss of sodium bicarbonate from the intestines

·         Salicylate intoxication, exogenous poisoning or, less frequently, Addison's disease

·         Inhibited secretion of acid

As H+ ions begin accumulating in the body, chemical buffers (plasma HCO3 and proteins) in cells and extracellular fluid bind them. Excess H+ ions decrease blood pH and stimulate chemoreceptors in the medulla to increase respiration. Consequent fall of partial pressure of Paco2 frees H+ ions to bind with HCO3 ions. Respiratory compensation occurs but isn't sufficient to correct acidosis.
Healthy kidneys compensate, excreting excess H+ ions, buffered by phosphate or ammonia. For each H+ ion excreted, renal tubules reabsorb and return to blood one Na+ ion and one HCO3 ion.
Excess H+ ions in extracellular fluid passively diffuse into cells. To maintain balance of charge across cell membrane, cells release K+ ions. Excess H+ ions change the normal balance of K+, Na+, and Ca+ ions, impairing neural excitability.

·         Headache and lethargy progressing to drowsiness, central nervous system (CNS) depression, Kussmaul's respirations, hypotension, stupor, and coma and death

·         Associated GI distress leading to anorexia, nausea, vomiting, diarrhea, and possibly dehydration

·         Warm, flushed skin

·         Fruity-smelling breath

·         Arterial pH <7.35; PaCO2 normal or < 35 mm Hg as respiratory compensatory mechanisms take hold; HCO3 may be < 22 mEq/L

·         Urine pH < 4.5 in the absence of renal disease

·         Elevated plasma lactic acid in lactic acidosis

·         Anion gap >14 mEq/L in high anion gap metabolic acidosis, lactic acidosis, ketoacidosis, aspirin overdose, alcohol poisoning, renal failure, or other disorder characterized by accumulation of organic acids, sulfates, or phosphates

·         Anion gap 12 mEq/L or less in normal anion gap metabolic acidosis from HCO3 loss, Gl or renal loss, increased acid load, rapid I.V. saline administration, or other disorders characterized by HCO3 loss

·         Sodium bicarbonate I.V. for severe high anion gap

·         I.V. lactated Ringer's solution

·         Evaluation and correction of electrolyte imbalances

·         Correction of underlying cause

·         Mechanical ventilation to maintain respiratory compensation, if needed

·         Antibiotic therapy to treat infection

·         Dialysis for patients with renal failure or certain drug toxicities

·         Antidiarrheal agents for diarrhea-induced HCO3 loss

·         Position patient to prevent aspiration

·         Seizure precautions

Metabolic alkalosis

·         Chronic vomiting

·         Nasogastric tube drainage or lavage without adequate electrolyte replacement

·         Fistulas

·         Use of steroids and certain diuretics (furosemide [Lasix], thiazides, and ethacrynic acid [Edecrin])

·         Massive blood transfusions

·         Cushing's disease, primary hyperaldosteronism, and Bartter's syndrome

·         Excessive intake of bicarbonate of soda, other antacids, or absorbable alkali

·         Excessive amounts of I.V. fluids; high serum concentrations of bicarbonate or lactate

·         Respiratory insufficiency

·         Low serum chloride

·         Low serum potassium