Developmental and Genetic Diseases

Chapter 6 Developmental and Genetic Diseases



Bruce A. Fenderson, PhD




1 How common are birth defects?


Developmental and genetic diseases account for half of all infant mortality in the United States. It is estimated that 1 in 50 children worldwide is born with a major birth defect. Approximately 1 in 100 has a single gene defect, and 1 in 200 has a major chromosomal defect. If one also considers diseases with polygenic patterns of inheritance (e.g., atherosclerosis and hypertension), the lifetime risk of genetic disease may be as high as 65 in 100.



2 What are the major causes of birth defects?


The causes of most birth defects are unknown (70%). Approximately 25% are due to cytogenetic or hereditary diseases. The remaining birth defects (5%) are associated with maternal exposure to chemicals, radiation, or infections or are related to maternal metabolic factors or birth trauma. The major causes of birth defects can be classified as follows:


image Errors of morphogenesis

image Chromosomal abnormalities

image Single gene defects

image Polygenic defects

image Transplacental and birth injury


3 Define hereditary, familial, and congenital disease



image Hereditary diseases are passed from parents to their offspring. The risk of inheritance depends on whether the trait is carried on a sex chromosome or autosome and on whether the trait is dominant or recessive.

image Familial diseases run in families and represent examples of multifactorial (polygenic) inheritance. There is no reliable pattern of inheritance because of the low probability of inheriting all of the mutations necessary for clinical disease. If an individual is a member of a family with a history of a familial disease, he or she has a greater probability than the general population of inheriting this disease. For first-degree relatives of affected individuals, the risk is 5% to 10%.

image Congenital diseases are present at birth. They may be due to structural changes in DNA (mutations) or by direct injury to the fetus in utero.


4 List congenital malformations that occur at least once in 1000 newborn children



image Anencephaly (0.3/1000 in the United States and 5–6/1000 in Wales and Ireland)

image Fetal alcohol syndrome (1–3/1000 in the United States and Europe)

image Down syndrome (1/1000 for women up to their mid-30s; 1/30 for women age 45)

image Klinefelter syndrome (1/1000 males)

image TORCH complex (1–5/1000 of all live-born infants in the United States)

image Cleft lip with or without cleft palate (1/1000)


ERRORS OF MORPHOGENESIS



5 What are teratogens?


Teratogens are chemical, physical, or biologic agents that are able to induce developmental abnormalities. Some teratogens are toxic and cause necrosis, whereas others trigger programmed cell death (apoptosis). Teratogens may also induce developmental abnormalities by altering patterns of gene expression, inhibiting cell interactions, or blocking morphogenetic cell movements.



6 List proved human teratogens



image Radiation (atomic weapons and radioiodine)

image Infections (cytomegalovirus, herpes virus, syphilis, Toxoplasma, and rubella virus)

image Maternal metabolic factors (alcoholism, diabetes, folic acid deficiency, and endemic cretinism)

image Drugs (aminopterin, busulfan, cocaine, coumarin anticoagulants, cyclophosphamide, lithium, mercury, thalidomide, and retinoic acid)


7 List basic principles of teratology


Approximately 5% of birth defects are linked to maternal exposure to chemicals, drugs, or radiation or linked to maternal metabolic disturbances or infections. The biochemical mechanisms of teratogenesis in these cases are varied. Indeed, exposure to a proved teratogen does not always cause a congenital malformation. General principles of teratology include the following:


image Teratogens produce growth retardation or malformation. The outcome depends on complex interactions between the mother, placenta, and fetus.

image Genes of the mother and fetus determine susceptibility to a teratogen (e.g., there is variable susceptibility to the effects of alcohol).

image Most teratogens are harmful only during a critical window of development (e.g., thalidomide is teratogenic only between days 28 and 50 of pregnancy).

image Teratogenic agents inhibit specific receptors or enzymes or disrupt specific developmental pathways (e.g., some agents show neurotropism or cardiotropism).

image Effects of teratogens are dose-dependent. A “safe” dosage may exist; however, in the absence of certain knowledge, teratogens should be avoided by pregnant women.


8 Define agenesis, aplasia, hypoplasia, dysraphic anomaly, involution failure, division failure, atresia, dysplasia, ectopia, and dystopia



image Agenesis is the complete absence of an organ or lack of specific cells within an organ (e.g., lack of germ cells in “Sertoli cell only syndrome”).

image Aplasia is the absence of an organ with retention of the organ rudiment (e.g., aplasia of the lung).

image Hypoplasia is incomplete development of an organ (e.g., microphthalmia and microcephaly).

image Dysraphic anomaly is caused by failure of opposed structures to undergo adhesion and fusion (e.g., spina bifida and anencephaly are dysraphic anomalies of the neural tube).

image Involution failure is persistence of an embryonic structure that normally disappears during development (e.g., persistent thyroglossal duct).

image Division failure is incomplete cleavage of embryonic tissues owing to lack of programmed cell death (e.g., incomplete separation of digits in syndactyly).

image Atresia is failure of an organ rudiment to form a lumen (e.g., esophageal atresia).

image Dysplasia is abnormal organization of cells in a tissue (e.g., congenital cystic renal dysplasia).

image Ectopia is an error of morphogenesis in which an organ is located outside its correct anatomic site (e.g., ectopic parathyroid glands can be located within the thymus).

image Dystopia is an error of morphogenesis in which an organ is retained at a site where it resided during a stage of development (e.g., cryptorchidism occurs when dystopic testes are retained in the inguinal canal).


9 What is Potter complex?


Potter complex is an example of a “developmental sequence anomaly” in which multiple disorders lead to the same birth defect through a common pathway. Signs of Potter complex include pulmonary hypoplasia and abnormal position of hands and legs (signs of fetal compression). These abnormalities are caused by reduced amniotic fluid level (oligohydramnios). Because fetal urine serves to maintain the normal volume of amniotic fluid, the causes of oligohydramnios include renal agenesis and urinary tract obstruction. Oligohydramnios may also be caused by chronic leakage of amniotic fluid through the cervical plug.



10 List dysraphic anomalies of the neural tube


Dysraphic anomalies are caused by a failure of apposed edges of the presumptive neural plate to fuse properly during early development (days 25–35). Neural tube defects follow multifactorial (polygenic) inheritance. Maternal serum alpha-fetoprotein levels and ultrasonography are used to diagnose dysraphic anomalies in utero. Examples of dysraphic anomalies include the following:


image Spina bifida is incomplete closure of the spinal cord and vertebral column. It occurs most frequently in the lumbar region and represents a defect in neural tube closure on days 25–30.

image Meningocele is a herniation of the meninges through a defect in the vertebral column in patients with spina bifida.

image Myelomeningocele is a herniation of both the meninges and the spinal cord through a defect in the vertebral column in patients with spina bifida.

image Acrania is complete or partial absence of the cranium.

image Anencephaly is the absence of the cranial vault with reduced or missing cerebral hemispheres.

image Craniorachischisis is a more extensive dysraphic anomaly that may extend from the cranium to the vertebral column.


11 Explain the role of folic acid in the pathogenesis of neural tube defects


Pharmacologic doses of folic acid have been shown to reduce the incidence of neural tube defects by lowering plasma levels of homocysteine. Homocysteine is a teratogen for the central nervous system and heart. Women with reduced activity of 5,10-methylenetetrahydrofolate reductase exhibit elevated plasma levels of homocysteine and are at risk for bearing children with neural tube and other birth defects.



12 What are the typical clinical features of thalidomide-induced malformations?


Thalidomide is a sedative (derivative of glutamic acid) that has been found to cause birth defects when used by women between days 28 and 50 of pregnancy. Approximately 3000 children were born with birth defects during the 1960s to women who used thalidomide during early pregnancy. Clinical features of thalidomide-induced birth defects include:


image Phocomelia (foreshortening of the arms)

image Amelia (lack of arms)

image Microtia (small ears)

image Anotia (lack of ears)

image Congenital heart disease


13 What are the typical clinical features of fetal alcohol syndrome?


Clinical features of fetal alcohol syndrome include facial dysmorphology, growth retardation, and mental deficiency/emotional instability. Specific anatomic findings include microcephaly, epicanthal folds, short palpebral fissure, maxillary hypoplasia, thin upper lip, micrognathia, poorly developed philtrum, and septal defects of the heart. Most children with fetal alcohol syndrome have IQs below 85. Additional psychological findings include short memory spans, impulsiveness, and emotional instability.



14 Is fetal alcohol syndrome a common cause of mental retardation?


Yes. Fetal alcohol syndrome has an incidence of 1 to 3 in 1000 live births in the United States. It is a major cause of mental retardation and emotional instability. Studies in animal models indicate that ethanol triggers massive, programmed cell death (apoptosis) in the developing central nervous system.



15 What is the TORCH complex?


TORCH is an acronym that refers to the signs and symptoms of congenital infection with Toxoplasma, others, rubella, cytomegalovirus, and herpes. Syphilis, tuberculosis, Epstein-Barr virus, varicella-zoster virus, and human immunodeficiency virus (HIV) are included in the “other” category. This acronym was coined to alert pediatricians to the fact that a search for one etiologic agent should include a search for all TORCH agents.



16 How common is the TORCH complex?


The TORCH complex is seen in 1% to 5% of all live births in the United States, so it is a major cause of infant mortality and morbidity. Congenital syphilis is estimated to affect 1 in 2000 live-born infants in the United States. Infants infected with TORCH agents may be asymptomatic at birth but develop typical signs and symptoms over the ensuing months.



17 What are the typical clinical features of the TORCH complex?


Signs and symptoms of TORCH infections in the fetus or newborn include ocular defects (microphthalmia, glaucoma, cataracts, retinitis, and conjunctivitis), brain lesions (focal cerebral calcification and microcephaly), cardiac anomalies (patent ductus arteriosus and septal defects), and other systemic manifestations (pneumonitis, hepatomegaly, splenomegaly, petechiae, purpura, and jaundice). Late complications of congenital syphilis include rhinitis (snuffles), skin rash, pneumonia, vascularization of the cornea (interstitial keratitis), notched incisors, inflammation of the periosteum, meningitis, and deafness. The clinical finding of notched incisors, deafness, and interstitial keratitis is referred to as Hutchinson triad.



CHROMOSOMAL ABNORMALITIES



18 What is the normal human karyotype?


Somatic cells of the human body possess 22 pairs of autosomes and two sex chromosomes (46,XX or 46,XY). The normal karyotype is diploid (two copies of each chromosome). Sperm and eggs carry 23 chromosomes and are haploid (one copy of each chromosome). Sperm determines genotypic sex by contributing either an X or a Y chromosome during fertilization.



19 How is karyotype analysis used in medical genetics?


Cytogenetic studies are routinely performed on fetal cells collected from amniotic fluid (amniocentesis) or from chorioallantoic villus sampling. Cultured cells are treated with colchicine to obtain metaphase chromosome spreads. Chromosomes are stained with dyes (e.g., Giemsa) to reveal banding patterns under the microscope (G bands). These bands permit the identification of both numeric and structural chromosomal abnormalities. Fluorescence in situ hybridization (FISH) is also used for cytogenetic studies. In this assay, fluorescent dye-conjugated DNA probes are used to mark interphase chromosomes, map structural defects, and identify specific genes. Karyotype analysis can be used to determine:


image Genotypic sex (i.e., identification of X and Y chromosomes)

image Ploidy (i.e., euploid, aneuploid, or polyploid)

image Chromosomal structural defects (e.g., translocation, isochromosome, and deletion)


20 Define haploid, diploid, euploid, polyploid, aneuploid, monosomy, and trisomy



image Haploid (n) refers to a single set of chromosomes (23 in humans). Postmeiotic germ cells (sperm and eggs) are haploid.

image Diploid (2n) refers to a double set of chromosomes (46 in humans). Somatic cells are diploid.

image Euploid refers to any multiple of the haploid set of chromosomes (from n to 8n).

image Polyploid refers to any multiple of the haploid set of chromosomes greater than diploid (>2n).

image Aneuploid refers to karyotypes that do not have multiples of the haploid set of chromosomes.

image Monosomy refers to an aneuploid karyotype with one missing chromosome (e.g., monosomy X in Turner syndrome).

image Trisomy refers to an aneuploid karyotype with one extra chromosome (e.g., trisomy 21 in Down syndrome).


Key Points: Chromosomal Abnormalities



1. Chromosomal abnormalities can be classified as structural or numeric.

2. Down syndrome is an autosomal trisomy characterized by mental retardation and characteristic facial features, as well as several abnormalities of internal organs.

3. Klinefelter syndrome and Turner syndrome are the two most important numeric abnormalities of sex chromosomes.


21 How are chromosomal abnormalities classified?


Chromosomal abnormalities are classified as either structural or numeric. They affect both sex chromosomes and autosomes. Examples of structural abnormalities include deletion and translocation. The most common cause of numeric chromosomal abnormalities is nondisjunction, resulting in either monosomy or trisomy. Chromosomal abnormalities may arise during somatic cell division (mitosis) or gametogenesis (meiosis). Abnormalities that originate during gametogenesis are transmitted to all somatic cells of the offspring. Chromosomal abnormalities are common and usually result in spontaneous abortion during early pregnancy. Major chromosomal abnormalities are incompatible with life.



22 List structural abnormalities of chromosomes



image Deletion is loss of a portion of a chromosome. Examples include cri du chat syndrome (5p-), Wilms tumor aniridia syndrome (11p-), and retinoblastoma (13q-).

image Reciprocal translocation is exchange of chromatin (crossing over) between nonhomologous chromosomes. Balanced translocations do not result in the loss of genetic material. Most carriers of balanced translocations have a normal phenotype.

image Robertsonian translocation is centric fusion of two acrocentric chromosomes resulting in the formation of one large metacentric chromosome and one small fragment. This fragment is usually lost during subsequent cell divisions.

image Isochromosomes are formed by faulty division of the centromere. If the centromere divides in a plane perpendicular to the long axis of the chromosome, pairs of isochromosomes are formed. One pair is composed of two short arms; the other pair is composed of two long arms. Approximately 15% of women with Turner syndrome have an isochromosome of the long arm of the X chromosome and are monosomic for genes on the missing short arm.

image Inversion is the breaking of a chromosome at two points, followed by rejoining of the broken ends.

image Ring chromosome involves breaking both telomeric ends of a chromosome, followed by end-to-end fusion of the centric portion. Ring chromosomes usually have no phenotypic consequence.


23 Explain chromosomal breakage syndromes


Chromosomal breakage and translocation may be acquired or hereditary. Acquired chromosomal breakage and translocation is commonly associated with development of leukemias and lymphomas. Examples include chronic myelogenous leukemia t(9;22) and Burkitt lymphoma t(8;14). Hereditary syndromes associated with DNA damage and loss of cellular growth control include xeroderma pigmentosum, Bloom syndrome, Fanconi anemia, and ataxia telangiectasia. These hereditary syndromes exhibit autosomal recessive inheritance.



24 What is nondisjunction, and how does it cause a numeric chromosomal abnormality?


Nondisjunction is failure of paired chromosomes to move to opposite poles of the spindle during mitosis or meiosis. If nondisjunction occurs during meiosis, the resulting embryo inherits an extra chromosome (trisomy) or lacks a chromosome (monosomy). Nondisjunction occurs more commonly in people with structural chromosomal abnormalities, such as nonbalanced translocations. The incidence of nondisjunction increases dramatically with maternal age.



25 List the most common birth defects caused by a numeric chromosomal abnormality


Most numeric chromosomal abnormalities are caused by nondisjunction. Examples include:


image Down syndrome (trisomy 21): The incidence is 1 in 1000 for women up to their mid-30s, but 1 in 30 for women at age 45 years. Most cases are accounted for by nondisjunction during the first meiotic division (meiosis I) of oogenesis.

image Klinefelter syndrome (sex chromosome trisomy, XXY): The incidence is 1 in 1000 in newborn males. Most cases are accounted for by maternal nondisjunction during the first meiotic division of oogenesis.

image Turner syndrome (monosomy X): Turner syndrome is one of the most common chromosomal abnormalities; however, most fetuses are aborted spontaneously. The incidence in newborn females is 1 in 5000. The missing X is usually of paternal origin.

image Edward syndrome (trisomy 18): The incidence is 1 in 8000. Most children die in infancy.


26 What are the typical clinical features of Down syndrome?


Down syndrome (trisomy 21) is the most common cause of mental retardation. The incidence strongly correlates with advancing maternal age, increasing to 1 in 30 by age 45. Two thirds of all conceptions with the trisomy 21 karyotype end in spontaneous abortion. Typical clinical features of Down syndrome are summarized as follows:


image The face and occiput tend to be flat, with a low-bridged nose, reduced interpupillary distance, oblique palpebral fissures, epicanthal folds, Brushfield spots of the iris, and a protruding tongue.

image Children suffer severe mental retardation and exhibit a progressive decline in IQ with age (from 70 to 30 by age 10).

image One third of children suffer from congenital heart disease. Anomalies include atrioventricular canal, ventricular and atrial septal defects, tetralogy of Fallot, and patent ductus arteriosus.

image Children are small, with shorter than normal bones of the ribs, pelvis, and extremities. Hands exhibit a simian crease, and the fifth finger usually curves inward (clinodactyly).

image Duodenal stenosis, imperforate anus, and congenital megacolon (Hirschsprung disease) occur in 2% to 3% of children.

image Men are sterile because of arrested spermatogenesis. Some women with Down syndrome have given birth, and 40% of these children exhibit trisomy 21.

image Children are at high risk of developing leukemia. For children younger than 15 years, the risk is approximately 15-fold greater than normal.

image Morphologic lesions characteristic of Alzheimer’s disease (neurofibrillary tangles and senile plaques) appear in all patients with Down syndrome by age 35.


27 What is the life expectancy for patients with Down syndrome?


The most common causes of death in patients with Down syndrome are congenital heart disease and leukemia. With a normal heart, only 5% of children with Down syndrome die before age 10. After age 10, the estimated life expectancy is 55 years.



28 Describe two forms of chromosomal change in Down syndrome


Chromosome 21 is the smallest human autosome and encodes approximately 225 genes. The region critical for the development of Down syndrome has been mapped to a small segment of the long arm (21q). The most common forms of chromosomal change in Down syndrome are:


image Nondisjunction arising during the first meiotic division of gametogenesis (95% of cases); the incidence increases dramatically with maternal age, from 1 in 1000 during early reproductive years to 1 in 30 by age 45

image Translocation of an extra long arm of chromosome 21 to another chromosome (5% of cases)


29 How do the X and Y chromosomes regulate sex differentiation?


The presence of a Y chromosome determines male phenotypic sex, regardless of the number of X chromosomes. Thus individuals with Klinefelter syndrome (47,XXY) are phenotypically male despite the presence of an extra X chromosome. The SRY gene on the Y chromosome is known to encode a transcription factor (SIP-1), which serves as a master switch to turn on male-determining genes that are present on the autosomes. Without an SRY gene, the phenotype is female.



30 What are Barr bodies?


Female embryos randomly inactivate either the paternal or the maternal X chromosome during embryogenesis to achieve dosage compensation for critical genes on the X chromosome. Thus females are mosaics for the maternal and paternal X chromosomes. X inactivation involves DNA methylation, gene repression, and chromatin condensation. Hyperchromatic X chromatin can be viewed under the light microscope and is referred to as a Barr body. In this connection, patients with Klinefelter syndrome (47,XXY) show a Barr body in all somatic cells, despite the fact that they are phenotypically male.



31 What are the typical clinical features of Klinefelter syndrome?


Klinefelter syndrome is an important cause of male hypogonadism and infertility. It affects approximately 1 in 1000 newborn males. It is defined as the presence of one or more extra X chromosomes in a phenotypic male (e.g., 47,XXY). The principal clinical features during childhood are behavioral. Klinefelter syndrome should be suspected in all boys with some degree of mental deficiency or behavioral abnormality. As they mature, boys with Klinefelter syndrome exhibit a eunuchoid body habitus (tall and thin) and develop certain feminine characteristics, including a high-pitched voice, gynecomastia, and female escutcheon. Testes and penis remain small. After puberty, the testes begin to atrophy, with loss of germ cells and Sertoli cells. Aspermia and peritubular fibrosis lead to infertility. Leydig cell function is impaired, leading to low serum levels of testosterone (increased estradiol-to-testosterone ratio). Follicle-stimulating hormone and luteinizing hormone levels are high, indicating that the pituitary gland is functioning normally. Testosterone can be used to virilize these patients, but it cannot restore fertility.

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Jul 23, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Developmental and Genetic Diseases

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