Ghai Essential Pediatrics8th

Physiological Considerations

The pattern of inheritance is determined by the genetic material in the nuclei of cells, which is distributed into 23 pairs of chromosomes. The two members of 22 pairs of chromosomes that are apparently alike (or homologous) are called autosomes. The 23rd pair is homologous only in females with two X chromosomes. In the male, the 23rd pairhas one X chromosomeand a much smallerY chromo­ some. In the germ cells of both sexes, the cell division is not of theusualmitoticvariety, but is a reduction division or meiosis. The cells which are obtained after meiosis have only one representative of each pair of chromosomes, so that in human beings they have only 23 chromosomes. In the course of meiosis, not only is the number of chromo­ somes halved, there is also some exchange of genetic material between the two members of a pair. This pheno­ menon is called crossover. Since the progeny inherits half their chromosomes from the father and half from the mother, they have some characteristics of both.

Theportionofachromosomewhichcodesfora'character' is called a gene. The position of a gene on a chromosomeis calleditslocus. Correspondinglocionthetwomembersof apaircarrygenesforthesamecharacter. Thecharactercoded by the two chromosomes may have different forms. For instance, one of them may code for black iris and another for blue iris. Such alternative forms of a gene are known as alleles. If the alleles code for the same forms, these are said to be present in the homozygous state; if they code for different traits, they are in heterozygous state. If an allele clinically manifests itself even in theheterozygous state, it iscalledadominantgeneor character. Itsalternateformor allelewhichdoesnotexpressitselfclinicallywhentheother allele from the other parent is normal is called a recessive gene. Recessive genes will manifest features of the disease only when present on both chromosomes in the pair (homozygous state) or whenthespecific abnormal gene is inheritedfrombothparents.Thegeneticmakeupofaperson

Neerja Gupta, Madhulika Kabra

is called thegenotype andthe clinically manifest characters areknown asthephenotype. Sometimesagene may express itself in several slightly modified forms without adverse effect on the health of the individual, known as genetic

polymorphism.

From Chromosomes to Characters

Chemically, the chromosomes are made up of deoxyribo­ nucleic acid (DNA) and histones. Only about 3% of DNA in the human genome symbolizes genes. About 93% has apparentlynoclear-cutfunctionandisoftentermedasjunk DNA Many copies of the latter type of DNA are scattered atrandomoverthechromosomesintermingledwithgenes. These are called repetitive sequences. There are about 30,000 genesin thehuman genome. Roughly 20% of these are specific genes which regulate the production of structural or functional proteins. About 80% genes are housekeepinggenesresponsible for basiccellfunctioning. DNA determines the type of messenger ribonucleic acid (mRNA) thatissynthesized bya cell; mRNAisresponsible for the type of protein manufactured by the cell.

Molecular Genetics

It is possible to cleave DNA at specific points by restriction endonucleases derived from bacteria. DNA probes can be made to detect specific base sequences in the DNA The most fascinating technique in molecular genetics is the ability to form large number of copies of DNA sequences in a short time. This amplification of genetic material is now possible with polymerase chain reaction (PCR). In high throughput microarray techniques, thousands of samples can be analyzed in a very short time. A microarray is a collection of microscopic DNA spots attached to a solid surface. DNA microarrays can be used to measure the expression of a large numbers of gene simultaneously or to genotype multiple regions of a genome. Since an array maycontainthousandsofprobes, amicroarrayexperiment

CHROMOSOMAL DISORDERS

Mechanisms of Chromosomal An omalies

Chromosomes contain a large number of genes. Loss or gain of a whole chromosome due to abnormalities in cell division may cause profound disturbances in the genetic constitution of the fetus and affect its survival. If the fetus is born alive it may die soon after birth. Even if the disturbances are not lethal, the fetus may be malformed or have intellectual disability later in life. At times, only a part of the chromosome may be deleted or lost, causing less severe genetic disturbances. Generally, loss of a whole chromosome except one X chromosome (as in Turner syndrome) is lethal. Surveys in still-born or abortuses (aborted fetuses) have shown large proportion of chromosomal anomalies. Of all live newborns, 0.5% may have a chromosomal anomaly.

Each chromosome has a short arm (p) and a long arm (q) joined by a centromere. Chromosomes are numbered based on their size and position of the centromere (Fig. 22.1). Chromosomal abnormalities are generally sporadic and therefore, the risk of their recurrence in the offsprings is low (except in situations when either parent is a balanced translocation carrier). There are two types

1

)6

13

19

7 8 9 10 11 12

Fig. 22.1: Conventional G band karyotype

of chromosomalabnormalities-numerical (aneuploidies) and structural. There are several mechanisms which lead to chromosomal abnormalities.

Inversion. One or two breaks may occur along the lengthof the chromosome arm. The broken pieces may rearrange themselvesin anewway.If thereisnolossorgainofgenetic material, there may be no significant clinical manifes­ tations. Break point is important if it disrupts a vital gene.

Isochromosome. During mitotic cell division, the chromo­ some divides longitudinally. Rarely it may divide trans­ versely across the centromere. Half of the chromosome replicates to form its complement. Thus instead of normal chromosomes, two new types of chromosomes are formed-onehaving both thelongarmsandtheother with both the short arms. These are known as isochromosomes. Each isochromosome thus has excess of some genetic materialanddeficiencyof some othergenetic material,e.g. in some cases of Turner syndrome.

Anaphase lag. In the firstmeioticdivision, the chromosomes are arranged in pairs in the equatorial plane during the metaphase. During anaphase if one of the chromosomes is slowin its migration, it might be excluded andthusbe lost.

Nondisjunction. During the first meiotic division, both members of a pair of chromosomes may move jointly dur­ ing anaphaseto either of the daughter cells. Thus, whereas one daughter cell may have both members of a pair of chromosomes, i.e. 22 + 2 or 24 chromosomes, the other cell may have only 22chromosomeswithout any represen­ tation of the erring pair. When such gametes mate with other gameteswith normalchromosomal complement, the zygote will either have 47 or 45 chromosomes. Non­ disjunction leads to aneuploidies. Common aneuploidies seen in live born babies include Down syndrome (trisomy 21), Edward syndrome (trisomy 18), Patau syndrome (trisomy 13) and Turner syndrome (monosorny X).

Mosaicism. If the nondisjunction occurs in the first mitotic division instead of meiosis, of the two new cells which are formed, one has 47 chromosomes and the other cell has 45 chromosomes. The error is perpetuated by repeated mitotic divisions. Thus, two cell lines with 47 and 45 chromosomes are observed in the same individual. If the nondisjunction occurs after a few mitotic divisions have already occurred, more than two cell lines may be observed, some withnormaland the otherswith abnormal complement of chromosomes.

Translocation. A chromosome or a segment of a chromo­ some may break off from the parent chromosome and be joinedtoanotherchromosome. Thisphenomenon iscalled translocation. Thus one chromosome may appear shor­ tenedin this process, no lossorgain of the genetic material occurs, the translocation is balanced and the person is phenotypically normal. Translocated chromosome may be transmitted to either gamete during meiosis and when it mateswithnormal gamete,theresultingzygotemayeither

Genetic Disorders -

have excess or deficiency of the genetic material. Such an offspring is abnormal. Viability of such zygotes would depend on the essentiality of the genes carried on translocated portion of the chromosome.

Deletion. A segment of chromosome may break off and be lost. Loss of a portion of chromosomal material large enough to be seen by light microscope is often lethal or poorly tolerated. Submicroscopic deletions are detected on special chromosomal staining or fluorescent in situ hybridization (FISH) (Fig. 22.2). DNA probes have been developed that make it possible for FISH to be used for diagnosisfor aneuploidies andmicrodeletion syndromes. Gene deletion syndromes are characterized by loss of a cluster of genes, giving rise to a consistent pattern of con­ genitalanomaliesand developmentalproblems.Examples of these are William syndrome (7qll.23); retinoblastoma with mental retardation and dysmorphic facies (13q14.1); Prader-Willi syndrome (hypotonia, mental retardation and obesity, 15qll); Rubinstein Taybi syndrome (micro­ cephaly, broad thumbs and big toes, dysmorphism and mental retardation; 16q13); and DiGeorge syndrome (congenital heart defect, hypoplasia of parathyroid and thymus, facial and palate anomalies; 22qll).

Genomic imprinting. Maternal and paternal setsof genes are not alwaysfunctionallyequal.Somegenesare preferentially expressedfrommaternalorpaternalside. Examplesinclude Prader-Willi syndrome (microdeletion on paternal side or inheritance of both copies from maternal side) and Angelman syndrome (microdeletion on maternal side or inheritance of both copies from paternal side).

Down Syndrome

Down syndrome is the most common chromosomal disorder, occurring with a frequency of 1:800 to 1:1000 newborns. Chromosomenumber 21ispresentin triplicate, the origin of theextrachromosome21 being either maternal or paternal. In most cases the extrachromosome is from the mother. Down syndrome occurs more often in offspring of

Fig. 22.2: Signals on fluorescent in situ hybridization (FISH) testing. Reduction or increased number of signals indicates aneuploidy

mothers conceiving at older age; the risk in the newborn is 1:1550 if maternal age is between 15 and 29 yr, 1:800 at 30-34 yr, 1:270 at 35 to 39 yr, 1:100 at 40 to 44 yr and 1:50 after 45yr.Thisis attributed totheexposure ofthe maternal oocyte to harmful environmental influences for a longer period since Graafian follicles are present in the fetal life and exist through female reproductive life. 1l1e sperm has a short lifespan and therefore has less chances of injurious exposure.

Cytogenetics

Trisomy 21 is found in 94% cases. Approximately 1% of cases aremosaicand the rest (5%) are due totranslocations, most commonly involving chromosomes 21 and 14. Karyotype of the parents is only required if the affected child has translocation underlying Down syndrome.

Clinical Features and Diagnosis

Patients with Down syndrome have mental and physical retardation, flat facial profile, anupward slant of eyes and epicanthic folds (Figs 22.3A and B). Oblique palpebral fissure is obvious only when the eyes are open. The nose is small with flat nasal bridge. Mouth shows a narrow

Figs 22.3A and 8: Two young children with Down syndrome. Note the flat facies, upward eye slant and open mouth appearance

short palate with small teeth and furrowed protruding tongue. There is significant hypotonia. The skull appears small and brachycephalic with flat occiput. Ears are small and dysplastic. There is a characteristic facial grimace on crying. Hands are short and broad. Clinodactyly (hypo­ plasia of middle phalanx of fifth finger) and simian crease are usual. There is a wide gap between the first and the second toe (sandle gap).

Associated Abnormalities

Congenital heart disease. Approximately 40% children have congenital heart disease. Endocardial cushion defects account for about 40-60% cases. Presence of heart disease is the most significant factor in determining survival. All children should have a cardiac evaluation before 9months of age, including echocardiography.

Gastrointestinal malformations. Atresias are present in 12% of cases, especially duodenal atresia.There is an increased risk of annular pancreas and Hirschsprung disease.

Ophthalmic problems. There is an increased risk of cataract, nystagmus, squint and abnormalities of visual acuity. Routine evaluation is performed in infancy and then yearly.

Hearing defects. 40-60% patients have conductive hearing loss and are prone to serous otitis media (most commonly during the first year).Routineevaluation before 6 months of age and then every year is advisable.

Thyroid dysfunction. About 13-54% patients with Down syndrome have hypothyroidism. Thyroid function tests (T3, T4 and TSH) are recommended once in the neonatal period or at first contact, and then every year. This should ideally include antithyroid antibodies specially in older children as etiology is more likely to be autoimmune.

Atlanto-occipital subluxation. The incidence is variable, reported in 10-30% of cases. Lateral neck radiograph is recommended once between 3 and 5 yr, before surgery, for participation in special games, or earlier, if signs and symptoms suggest cord compression.

Physical growth. Regular followup for height and weight is necessary. Linear growth is retarded as compared to normal, children tend to become obese with age. Muscle tone tends to improve with age, whereas the rate of deve­ lopmental progressslows with age.

Malignancies. Patients with Down syndrome are at increa­ sed riskof developmentof lymphoproliferativedisorders, including acute lymphoblastic leukemia, acute myeloid leukemia, myelodysplasia and transient lympho­ proliferative syndrome.

Management and Prognosis

The principles of management are early stimulation, physiotherapy and speech therapy. Associated problems

need to be treated as rey_uued. Social perto1mance is usually achieved beyond that expected for mental age. Generally, they behave as happy children, like mimicry, are friendly, have good sense of rhythm and enjoy music.

The major cause for early mortality is congenital heart disease, and almost 50% of those with cardiac anomalies die in infancy. Chronic rhinitis, conjunctivitis and perio­ dontal disease are common. Lower respiratory tract infections pose a threat tolife. Hematological malignancies are another cause of increased mortality.

Counseling

The parents of a child with Down syndrome should be counseled withtact, compassion and truthfulness. Briefly one should: (i) inform about the disorder as early as possi­ ble after diagnosis is confirmed; (ii) counsel in presence of both the parents in privacy; (iii) talk in simple andpositive language giving hope and allow sufficient time to the parentstoaskquestions;(iv)discuss known problemsand associated disorders; (v) highlight the importance of early stimulation; (vi) not discuss institutionalization and adoption, wuess asked, and discourage both the options; (vii) ask the parents to contact the local Down syndrome association,ifoneexists; (viii) talkaboutgeneticsonlyafter chromosomal analysis; (ix) inform about recurrence risks and possibilities of prenatal diagnosis; and (x) schedule future appointments.

Risk ofrecurrence. Women 35 yr of age or less who have a child with trisomy 21 have a 1% risk of having another, which is significantlygreater than the general population. The risk is little increased, if any, over the usual maternal age dependent frequency if the mother at risk is 35 yr or older. For translocations inherited from the mother, the risk is about 10%, whereas it is about 4-5% when father is the carrier. Balanced translocation 21; 21 is the only situation where all viable fetuses will have Down syndrome.

Prenatal diagnosis. Parents who wish to get a prenatal diagnosis have a number ofoptions.They candirectlyget a fetal karyotype by chorionic villus sampling or amniocentesis. Alternatively (if the parents do not want invasive testing) an initial screening may be performed with maternal serum markers and ultrasonography (as discussed later). Prenatal karyotyping can be done by chorionic villus sampling (CVS)between 10 and 12 weeks of pregnancy (by transcervical or transabdominal route) and allows diagnosis in the first trimester. Options for couples who come late or opt for initial screening with serum markers and ultrasonography are karyotyping by amniocentesis at 16-18 weeks, transabdominal chorionic villus sampling and cordocentesis after 18 weeks. Karyotype results are available within a week with cord blood samples and direct chorionic biopsy preparations. The results of amniotic fluid cultures take about 10-14 days.

Genetic Disorders -

Trisomy 18 (Edward Syndrome)

This is the second most common autosomal trisomy amonglivebirths after Down syndrome,witha frequency of 1:3000 births. This disorder is characterized by failure to thrive, developmental retardation, hypertonia, elon­ gated skull, low set and malformed ears, rnicrognathia, shield-shaped chest, short sternum, joint abnormalities including flexion deformity of fingers, limited hip abduction and short dorsiflexed hallux. Congenital heart disease is common, occurring mostly as ventricular septa! defect or patent ductus arteriosus. Most subjects have simple dermalarches on nearlyallof the digits. Theyoften have short fourth digits with only a single crease (Figs 22.4A to C).

Figs 22.4A to C: Note the (A) facial dysmorphism and (B and C) overlapping of fingers in an infant with trisomy 18

Majority of patients are postmature with a low birth weight. Resuscitation is oftenrequired at birth andapneic episodesarecommoninthe neonatalperiod.Poor sucking capability may necessitate nasogastric feeding, but most infants fail to thrive despite optimal management. The median survival is about 3 months.

Trisomy 13 (Patau Syndrome)

Theincidenceofthissyndromeisaboutoneper5000births. It is characterized by severe developmental and physical retardation, microcephaly and sloping forehead. Holo­ prosencephaly with varying degrees of incomplete development of forebrain and olfactory and optic nerves, is common. Eye anomalies include microphthalrnia, colo­ bomaof iris, retinaldysplasiaandcataract.Malformations ofearsandcleftlipwithorwithoutcleftpalatearecommon; many babies are deaf. Capillary hemangiomata are characteristic (Fig. 22.5). Fingers and toes are frequently abnormal, with polydactyly, flexion deformitiesand long andhyperconvexnails. Congenitalheartdiseaseispresent in almost80% ofpatients. Common defectsareventricular septal defect, patent ductus arteriosus and atrial septal defect. Majority of casesdie in the first six months of life. Survivorshaveseverementaldefectsandseizuresandthey fail to thrive.

Fig. 22.5: Note postaxial polydactyly and forehead hemangioma in an infant with trisomy 13

Klinefelter Syndrome

Klinefelter syndrome refers to a form of hypogonadism comprising small testes, failure of development of secondary sex characters and increased gonadotropins. The frequency of this syndrome is about 1.32 per 1000 live newborns and about 79 per 1000 among mentally subnormal population; almost 10-20% ofmales attending infertility clinics have this syndrome. Cases of Klinefelter syndrome usuallyseek medical consultation near puberty due to the failure of appearance of secondary sexual char­ acters.The diagnosis should also be considered in all boys with mental retardation, as well as in children with psychosocial, learning disability or school adjustment problems.

Even in the prepubertal age, the testes and penis are smaller in size for age. These patients tend to be tall and underweight, have relatively elongated legs and more eunuchoid proportions. Occasionally, hypospadias or cryptorchidism is present. Pubertal development is delayed. The growth of pubic and facial hair is often late; and the pubic hair is generally feminine in distribution. About 40% adults have gynecomastia, appearing usually soon after puberty between the ages of 14 and 16 yr. Characteristically, the testes are small and show small, shrunken and hyalinized seminiferous tubules, while some are lined exclusively by Sertoli cells. Leydig cells show hypertrophy and clumping.

Chromosomal analysis reveals 47 XXY karyotype. Individuals with XXY/XY mosaicism have better prog­ nosis. As the number of Xchromosomesincreasesbeyond two, the clinical manifestations increase correspondingly. Management includes behavioral and psychosocial rehabilitation. Testosterone therapy should be started in middle to late adolescence with monitoring of levels.

Turner Syndrome

Turner syndrome having 45 X chromosomal constitution, has an incidence of about 1:3000 newborns. However, chromosomal studies of spontaneous abortions have clearly shown that majority of 45 X fetuses are likely to be aborted; the precise reason for this is not known. Many patients with Turner syndrome shows a considerable degree of chromosomal mosaicism, i.e. 45 X/46 XX. Formation of isochromosome of long arms of X chromosome may lead to Turner phenotype with 46 chromosomesbecause of absence of short arms. Since there is no apparent relationship to advanced maternal age, it is likely, that this syndrome does not arise from gametic nondisjunction.

Clinical Features

Turner syndrome may be recognizable at birth. lymphe­ dema of the dorsum of hands and feet and loose skin folds at the nape of neck. Other manifestations include short stature, short neck with webbing and low posterior hair­ line. Anomalous ears, prominent narrow and high arched palate, small mandible and epicanthal folds may be noted. Chest is broad shield-like with widely spaced hypoplastic nipples (Figs22.6A and B).Thereis increased carrying angle at elbow. Bony anomalies include medial tibial exostosis, and short fourth metacarpals and metatarsals. Pigmented nevi mayappear whenolder.Atpuberty,sexualmaturation fails to occur. The phenotype is highly variable. It has been recommended that the diagnosis of Turner syndrome should be considered in all girls with short stature.

Ultrasound may show streak ovaries and hypoplastic uterus. Levels of FSH and LH are increased (hypergonado­ tropic hypogonadism). Adult stature is less than 145 cm. Associated congenital defects are common in the kidney (horseshoe kidney, double or cleft renal pelvis), heart (coarctation ofaorta) and ears (perceptivehearing defect). Congenitallymphedemausually recedes in early infancy, leaving onlypuffinessover thedorsumoffingers and toes.

Figs 22.6A and B: Turner syndrome. Note (A) ptosis in right eye, shield chest, increased carrying angle, webbed neck and short neck with (8) low posterior hair line

Linear growth proceeds at about half to three-fourths the usual rate.

Hypothyroidism occurs in about 15-30% of adults with Turner syndrome.The clinical manifestations are milder in Turnersyndromewithmosaicism. These patientsmayhave normal stature and present with secondary amenorrhea.

Management

Height monitoring should be done using growth charts forTurner syndrome. Cardiacevaluation isrecommended at baseline and every year. Regular measurement of blood pressure at baseline and every year is advisable.

Growth hormone therapy is useful and is approved. Therapy may increase the final height by 8-10 cm, but decisionto treat should be left to the parents as the cost of treatment is prohibitive. Thyroid testing should be done in infancy or early childhood if the child is lagging in growthas pergrowthcharts forTurnersyndrome. Routine evaluation every other year should be done after 10 yr of age. Counseling regarding behavioral problems due to short stature, amenorrhea and sterility is an integral part of management. Ovarian hormone replacement should bestartedaround14 yr. Tostartwith,conjugatedestrogen at 0.3 mg/day or ethinyl estradiol 5-10 mg/day is given for 3-6 months, then increased to 0.625-1.25 mg of (conjugatedestrogen)or20-50 µg/day ofethinylestradiol. After 6-12 months cyclical therapy with estrogen and progesterone is started.

Regular audiometry should done in adulthood orearlier if indicated. Evaluation for renal malformation by ultra­ sonography should be done at first contact. Prophylactic gonadectomy is advised for patients with Y chromosome due to the risk of developing gonadoblastoma.

SINGLE GENE DISORDERS

Drawing and interpreting a pedigree is an integral part of genetic diagnosis. Table 22.1 gives symbols used for pedigree drawing.

Genetic Disorders -

chorea and connective tissue disorders. These disorders manifestevenif onlyoneoftheallelesoftheabnormalgene

is affected. The autosomal dominant disorders are gene- I rally milder than autosomalrecessive disorders. Physical examination of other siblings and parents should be done

to uncover milderformsofthe disorder. Homozygotesfor thedominantmutantgenesusuallydie prenatally, asinthe case of the gene forachondroplasia. If the child is the only affected member, it is very likely that the observed muta- tionhasoccurredde nova and is notinherited. In such cases other siblings are not likely to be affected. However, onehalf of the offspring of the affected individual are likely to inherit the disorder. New dominant gene mutations are more likely to occur if the paternal age is high. Examples include neurofibromatosis, achondroplasia, Marfan syndrome and Crouzon disease. A typical pedigree is shownin Fig.22.7.

Autosomal Recessive Disorders

Autosomal recessive disorders manifest only in homo­ zygousstate, i.e. both the alleles are mutant genes. Gene­ rally, autosomal recessive mutations affect synthesis of enzyme, leading to inborn errors of metabolism. The parents of the affected individuals are apparently normal but carry the mutant genes. As they are heterozygous, the mutant recessive gene does not express itself in the phenotype.In suchmatings,one-fourthoftheoffspringare affected (homozygous for the mutant genes), one-fourth are normal (both normal alleles) and half are carriers (heterozygote with one mutant allele and one normal allele). A classical pedigree is shown in Fig. 22.8. For obvious reasons, recessive disordersare more common in consanguineous marriage or in closed communities. It is now possible to detect carrier status by biochemical and molecular techniques in a number of autosomal recessive disorders. Common examples of autosomal recessive disorders are beta-thalassemia, sickle cell disease, spinal muscular atrophy, phenylketonuria and galactosemia.

Con1111ents

Assign gender by phenotype. Square represents male; circlerepresents a female; a diamond represents onewhose sex is not known. Age/date of birth can be given at the bottom or right hand corner

Affected 'Ill

individual

Multiple IT] individuals; number

known

Multiple ciJ individuals; number

unknown

Fillings can be shading, hatches, dots or lines

For z.2 conditions the symbols are partitioned correspondingly,eachquadrant with different fillings/patterns representing different features

Number of the siblings is written inside the symbols;affectedindividualsshouldnot be grouped

'?' is used in the place of 'n'

Proband

p)I

Consultand []

First affected family member coming to medical attention

Individual(s) seeking genetic counseling or testing

Comments

If ectopic pregnancy, write ECT below symbol

If gestational age known, write below symbol. Key or legend used to define shading

Key or legend used to define shading

the mutant X-linked recessive gene expresses as a clinical disorderinthemalechild because itisnotbeingsuppressed byanormalallele. Inthefemale,thedisorderdoesnotmani­ fest clinically since the mutant gene is compensated for by the normal allele in the other X chromosome. Females thus actascarriersofthemutantallele.Halfoftheirmalechildren inherit themutantallele and are affected. Figure22.9 shows a family with X-linked recessive inheritance. It is now possible to detect carrier state in the female child in case of somedisorders,e.g.hemophilia,Duchennemusculardystro­ phyandmucopolysaccharidosistypeII(Huntersyndrome). Color blindness also has an X-linked recessive inheritance.

Diseases with X-Linked Dominant Inheritance

Dominant X-linked conditions are rare. Both the hetero­ zygous female and hemizygous males are affected. All the sons of the affected males are normal and all the daughters are affected. The affected females transmit the disease to half of the sons and half of the daughters. Examples: Hypophosphatemic type of vitamin D resistant rickets, orofaciodigital syndrome and incontinentia pigmenti. In some cases, the effect of the mutant gene on development is severe, and affected males are seldom born alive. Majority of patientsareheterozygous females (Fig. 22.10).

Fig. 22.8: Autosomal recessive inheritance. Carriers are indicated by partly shaded symbols

Fig. 22.9: X-linked recessive inheritance. Carriers are indicated by symbols with bold dot in the center

Mitochondrial Inheritance

Mutations within a mitochondrial gene can lead to phenotypic defects and show a patternof maternal genetic transmission.Since mitochondria are only presentin ovum and not sperms, the inheritance is maternal. All offspring of an affected female will be affected. All affected daughters will transmit the disease. Sons will be affected but will not transmit the disease (Fig. 22.11). Examples includeLeighdiseaseand mitochondrial encephalopathy, lactic acidosis and stroke (MELAS) like syndrome.

Somatic Cell Genetic Disorders

These include cancers which can arise due to genetic changes in somatic cells.

POLYGENIC INHERITANCE

In a number of conditions, the affected individuals do not have a sharp division between the normal and the

D D

Fig. 22.1O: X-linked dominant inheritance

Fig. 22.11: Mitochondrial inheritance

abnormal, but merely represent a spectrum of a continuously varying attribute. Such conditions are likely to be inherited by alterations in many gene loci, each of themindividuallyhaving only a small effect. Many of these conditions are also affected by numerous environmental factors, individually of small effect. Examples of polygenic disorders are: neural tube defect, cleft lip, cleft palate, Hirschsprung disease, congenital hypertrophic pyloric stenosis, diabetes mellitus, ischemic heart disease, hypertension and schizophrenia.

In diseases with multifactorial etiology, the risk to progeny and siblings is higher if the malformation is more severe, because a more severe malformation is a bigger deviation from the normal threshold, e.g. the risk of recurrence of Hirschsprung disease in a family is higher if the aganglionic segment of the colon is longer. When these diseases have a marked sex predilection, the risk of recurrenceinthefamilyishigher iftheindexpatientbelongs to the less often affected sex. This is so, because the mutant genes are likely to be more severe so as to produce the disease in the sex with an inherent resistanceto the disease. The usual risk of recurrence for malformations caused by a polygenic or multifactorial cause is 2-5%.

THERAPY FOR GENETIC DISORDERS

Genetic disorders cannot generally be cured completely. However, symptomsof many disorders can be ameliorated