INTRODUCTION Diseases due to dysfunction of hereditary material, like chromosomes and genes, are the oldest, most widespread

and probably the most burdensome of all human afflictions. Birth defects, about 80 per cent of which are thought to be due to genetic defects, are amongst the leading causes of infant mortality and fetal loss. Several studies have shown that genetic disease has a severe impact on the newborn. However, the clinical manifestation of hereditary defects can occur at any age from birth to maturity. he basis for all forms of genetic disease is determined at conception, and can be passed on to subse!uent generations. Some genetic defects recognised at birth, or may present in childhood while others manifest themselves only in late years. HUMAN CHROMOSOMES he diploid chromosome number "#$ % in men was believed to be &8 until '()*, when +oe,+ind -io and .lbert /evan demonstrated that the correct number of chromosomes was &*. his diploid number represents ## pairs of autosomes and two se0 chromosomes, 12 in the male and 11 in the female.

GENETIC DISORDERS

CHROMOSOMAL

SINGLE GRNE

POLYGENIC

0.& 3 /ive births 4ultiple cangential anomalies 4ental retardation 5epeated fetal loss .bnormal se0ual development 6nfertility

'.8 to #3 /ive births Dominant 5ecessive Se0,linked or 1,linked

'.7,#.*3 /ive births $eural tube defects 8left lip. 8left palate 8ongenital microcephaly Skeletal deformities Some forms of diabetes Hydrocephalus Several forms of cancer

Soon after the discovery of the correct number of chromosomes in man, a standard system for identifying the #9 pairs of chromosomes was proposed at a conference of human genetics, held at Denver, :S., in '(*). his classification was termed the Denver 8lassification .ccording to this system, the chromosomes are identified and arranged in the descending order of length, the largest chromosome being the first and the smallest being the twenty third. he &* chromosomes were organised into seven groups, . to ;, according to their si<e and the position of the 8entromere. his system was useful for the detection of gross abnormalities in chromosomal numbers. During the early '(70=s several new staining techni!ues which helped in the precise identification of each pair of chromosomes were developed. hese techni!ues consisted of treating the chromosome preparations with en<ymes "trypsin%, buffered salt solutions "sodium citrate, phosphate buffered saline%, barium hydro0ide, and D$. binding fluorochromes "!uinacrine dihydrochloride, acridine orange% which resulted in

linear differential staining "dark and light, or positive and negative, bands of the chromosomes%. he application of the banding techni!ues helped the precise hus it became possible to detect minor chromosomal identification of not only each chromosome pair, but also of the different regions of the chromosomes. aberrations "deletions, structural aberrations% which had not been identified by routine staining procedures. CHROMOSOMAL ABERRATIONS IN MAN 6t is estimated that in every one of #)0 live births, a chromosomal abnormality occurs, leading to multiple congenital malformations and mental retardation. .bout 9* per cent of spontaneous abortions are due to gross chromosomal defects. .bout one third of all patients admitted to pediatric wards in hospitals suffer from genetic disorders. 8hromosomal aberrations may be numerical or structural. $umerical defects arise due to non,dis-unction "misdivision% either at meiosis or mitosis, during gametogenesis or after fertilisation. Structural aberrations occur due to the union "fusion% of the broken ends of two chromosomes "translocation%. riploidy, and tetraploidy "polyploidy% are relatively fre!uent in abortuses and stillbirths. he fetus in these conditions will have *( chromosomes "9 $% and (# "& $%chromosomes, respectively. >olyploidy arises due to the fertilisation of a diploid gamete or due to double fertili<ation.

S?4@ 8?44?$ 8H5?4?S?4./ S2$D5?4@S 6$ H:4.$ 4./A?54. 6?$S 8linical Diagnosis $umericalB '. Down=s syndrome "4ongolism% 8hromosomal .bnormalities &7, 11 or 12, D #' &*, 11 or 12, t "'&E#'% &*,11 or 12 t "#'E#' or #'E##% mos &*C&7.11 or 12 D #' other Structural anomalies. &7,11 or 12 D '9 &7,11 or 12, D '8

#. >atau=s syndrome 9. @dward=s syndrome Structural: &. 8ri,du,chatCsyndrome "8at cry syndrome% ). 5etinoblastoma *. 8hronic 4yeloid /eukaemia "84/% 7. .ta0ia telangectasia C 1eroderma pigmentosaC Aanconi=s anemia 8.1,linked mental retardation

&*, or 12 deletion ")p% 6nterstitial deletion "'9% >hiladelphia 8hromosome ">h= 8hromosome ##!,(! D % 4ultiple chromosome breakage syndrome Aragile site 1,chromosome "fra 1! #7%

ANEUPLOIDY .ddition "D% or loss ",% of an individual chromosome "autosome or se0 chromosome% is termed aneuploidy. . diploid "# $ F &*% cell with an e0tra chromosome is referred to as trisomy. 8onversely, a cell with the loss of a chromosome is referred to as monosomy. hus a cell with trisomy will have &7 chromosomes and a monosomic cell will have &) chromosomes. risomic or monosomic <ygotes are formed by the fertilisation of abnormal gametes. . gamete

with ## or #& chromosomes fertilised by a normal gamete with #9 chromosomes will result in the formation of a <ygote with &) and &7 chromosomes, respectively. 6t is well known that trisomic fetuses are more viable than those with monosomy. DOWNS SYNDR0ME (TRISOMY 2 ! his chromosomal abnormality was the first to be recogni<ed and is the. most widely studied in the world. Down=s syndrome occurs in one out of *00,800 live births. >atients with Down=s syndrome are mentally retarded and manifest a number of specific clinical features. he typical features observed are, flat facies, brachycephaly and flattening of the occiput, obli!ue palpebral fissures, epicanthic folds, low set malformed ears, Brushheld=s spots "speckled iris, which is not a common finding ill 6ndia%, thick furrowed protruding tongue "fissured%, short neck with e0cess fat at the nape, short and stubby hands, incurving of the little finger "clinodactyly% and a single transverse palmar crease commonly referred to as the simian crease. 6nfants with trisomy #' are markedly hypotonic, and their -oints are la0 and hypere0tensible. :sually, post,natal growth is relatively slow and skeletal maturation is delay. 8ongenital heart defects are present in 9),&0 per cent of children with Down=s syndrome. Duodenal atresia and annular pancreas are also fre!uently observed in them. hey are highly susceptible to infections and often develop lymphoblastic leukemia. 5adiological abnormalities include a flat acetabulum and lateral flaring of the iliac wings. 4ost patients have &7 chromosomes, and in about 9,) per cent of cases the e0tra chromosome #' is translocated to other chromosomes, more often to chromosomes '& or #'.

risomy #' has also been reported in association with other chromosomal abnormalities, such as trisomy '8, Glinefelter=s syndrome and urner=s syndrome. he incidence of Down=s syndrome has been found to be higher in stillbirths, sponneous abortions and among children born to mothers over 9). TRISOMY " (E#$ar#%& &'(#r)*+! his is the second autosomal trisomy occurring in infants with multiple congenital abnormalities and was described by @dward in '(*0. he incidence of trisomy '8 is one in 8,000 births. he male to female ratio is 'B &. Cl,(,cal -+atur+&: 4icrocephaly, prominent occipital protuberances, faun,like ears, micrognathia, an upturned nose, bilateral epicanthic folds, hypoplasia of the orbital ridges, corneal opacities and micro,ophthalmia are the principal features seen in this condition. he mouth is small and the palate narrow. he neck is often short, with an e0cess of skin. he fists are closed and cannot be e0tended, the inde0 finger overlaps with the third digit and the fifth overlaps with the fourth. :nlike trisomy #', children with trisomy '8 have a sort lifespan. he mean survival span is #,9 months for the male child and '0,'# months for the female. TRISOMY . (Palau%& &'(#r)*+! >atau and his co,workers reported the first case of trisomy '9 "trisomy D% in '(*0. he prevalence of trisomy '9 is estimated to be about one in &,000 to one in '0,000 births . Clinical features: Harelip, micro,ophthalmia, he0adactyly, broad and flat nose, low set ears with abnormal heli0, and the presence of one or multiple hemangiomas which are often on the face or nape of the neck are characteristic features. he fingers are fle0ed. he feet are usually deformed "rockerbottom%. 6n

male children, the testes are undescended and the scrotum is abnormally developed. 6n the female, hypertrophy of the clitoris, bicornuate uterus and double vagina are observed. .s in trisomy '8, failure to thrive and an early death are usual. he lifespan is as short as '90 days in both the se0es. 4ore than )0 per cent die within 90 day. Structural c/r)*)&)*al a0()r*al,t,+& . number of structural chromosomal aberrations resulting in mental retardation, congenital defects, fetal wastage and infertility have been observed. he following types of structural abnormalities have been foundB '% Deletion ")p%, #% Duplication,'8! trisomy 9% 5eciprocal translocation "balanced or unbalanced%, &% 5ing chromosome "chromosome '9%, )% 6sochromosomes "#'C#'%, *% 6nversions "peri or paracentric,chromosome (%, 7% 8hromosomal breakage syndrome "e.g. 1eroderma pigmentosa, ata0ia telangectasia. Aanconi=s anemia%, and 8% Aragile sites "1! #7, 1,linked mental retardation. Tu+(+r%& &'(#r)*+1 his condition was formerly referred to as gonadal dysgenesis or primary ovarian dysgenesis. Aemales with &) 1, karyotype are usually short, with underdeveloped secondary se0ual characters. he characteristic features of this syndrome are webbing of the neck, widely spaced nipples, low hair,line, wide carrying angle at elbow, marked oedema of the limbs, particularly in infants and children, and infertility. here is no mental sub,normality associated with &,) 1, karyotype. Hhile the ma-ority of &) 1 females are infertile, conception has been reported in a few cases. 4osaicism &) 1C&* 11 is not uncommon. he prognosis and possibility of fertility is better in mosaic case.

22Y *al+& (3l,(+-+lt+r:& &'(#r)*+! he clinical features of this syndrome were well established as early as in '(&# by Glinefelter. his syndrome represents pubertal hypogonadism or pubertal seminiferous tubular failure in the male. 6t has been estimated that about one in ',000 male births have the &7, 112 karyotype. he incidence has been reported to be much higher among mentally retarded and infertile males. he defect is most often diagnosed after puberty or marriage. he typical features of this syndrome include tall stature, obesity, gynecomastia, testicular atrophy and sterility. >ost,pubertal hormone levels show high levels of /H and ASH and low testosterone. 6n 80 per cent of cases the karyotype is &7, 112, the =classic= Glinefelter=s syndrome. GENETIC DISORDERS 8hromosomes are composed of genes, which are tile pnmary units that determine hereditary traits. hese genes are distributed in an orderly manner along the entire length of the chromosome. he number of genes in man is estimated to be more than '00,000. So far, ',800 genes have been mapped. he pattern of in heritance of the different characteristics of an individual is controlled by the genes on the autosomes and se0 chromosomes. hey are categorised into three ma-or typesB '% dominant, #% recessive, and 9% se0,linked. DOMINANT4 SINGLE GENE DE5ECTS hese are transmitted to the offspring through one of the affected parents. 4ore than (&0 such disorders have been identified. .n individual carrying a

dominant gene has a )0 per cent risk of transmitting the defect to his progeny. 6f both parents are affected, the risk is 7) per cent. @0amples of dominant single gene defects are dwarfism, achondroplasia and Huntington=s disease. RECESSI6E4 SINGLE GENE DE5ECTS 5ecessive disorders manifest in the offspring, if t e recessive gene is transmitted from both the parents. 6f both parents are carriers of a recessive trait there is a #) per cent chance of a child being affected in each pregnancy. $early 780 recessive single gene defects have been identified in man, including sickle cell anemia, ay,Sachs disease, cystic fibrosis >henyl,ketinuriam and galactisemia SE2 LIN3ED SINGLE GENE DISORDERS 4ost se0 linked disorders are from the 1,chromosome. Hence se0 linked disorders are also commonly referred to as 1,linked defects. here are more than ')0 1,linked disorders in man. 8hromosome segregation studies in the germ cells o males and females have demonstrated that males transmit their 1,chromosome to daughters and never to sons, who always receive the 2,chromosome. hus a female may carry the trait but not be =affected= since she has a normal 1chromosome which nullifies the effect of the trait. . male, however, is always affected if he receives an 1,chromosome bearing the abnormal gene from his mother. he risk of a carrier mother having an affected child is )0 per cent for each male child. Aemale children born to carrier females may be normal or carriers. @0amples of 1,linked disorders are hemophilia, Hunter=s disease, Duchenne muscular dystrophy, /esch,$yhan syndrome, diabetes insipidus and ata0ia.

Y7l,(8+# ,(/+r,ta(c+ ;enes located on the 2,chromosomes are transmitted from father to son, while daughters always receive the 1,chromosome. .ll sons of affected males are in turn affected. Some male,specific traits, also termed 2,limited traits, such as hypertrichosis "hairy pinnae%, baldness, etc. have been shown to be 2,linked, as they are observed only in men. P)l'9+(,c tra,t& he fourth group of genetic diseases are the comple0, polygenic or multigene disorders. he incidence of polygenic disorders has been estimated to be '.7,#.* per cent of all live births. :nlike the well established 4endelian traits, the mode of transmission in this group is very comple0. Some of the defects that are transmitted as polygenic traits are club foot, congenital dislocation of the hip, spina bifida, open meningomyelocele, etc. he first constant chromosomal abnormality in a human cancer was reported by $owell and Hungerford in '(*0. hey observed an unusually small ; group chromosome "now confirmed to be number ##% in leukemic cells from patients with chronic myeloid leukemia. his chromosome showed deletion of the long arm, and was named the >hiladelphia chromosome or >hi chromosome, in honour of the .merican city where it was discovered. Studies carried out all over the world have conclusively demonstrated the causal relationship between chromosomal abnormalities and cancer. PENATAL DIAGNOSIS DISORDERS O5 GENETIC AND CHROMOSOMAL

6t is known that there is no permanent cure or therapy for a ma-ority of chromosomal and genetic defects. However, it is possible to prevent the birth of

children with gross chromosomal and genetic defects by selective 4 > in the early stages of pregnancy. .mniocentesis, the techni!ue of withdrawing the amniotic fluid during mid, trimester pregnancy. .mniocentesis performed under ultrasonographic guidance helps in minimising the risk of damage to the fetus and placenta. Homen over 9) years and those with a personal or family history of chromosomal or genetic defects need to be submitted to this techni!ue. .mniocentesis also helps the accurate determination of the se0 of the fetus. C/)r,)(,c :,ll, c+ll cultur+ :ntil recently a prenatal diagnosis could be made only by amniotic fluid cell culture. oday the fact that samples of chorionic villi can be collected and studied, permits ante,natal diagnosis as early as in the ninth week. his techni!ue involves the removal of a small sample of chorionic villi from the developing placenta at the site of implantation. he aspirated cells can be cultured for chromosome, D$. or en<ymatic analysis. 5+t)&c);' a(# -+tal 0l))# &a*;l,(9 Aetoscopy was one of the first methods of prenatal diagnosis and was introduced in clinical practice in the early seventies. 6ndicationsB '. Before the advent of ultrasound, indications for the visuali<ation of the fetus were isolated e0ternal malformations and 4ultiple malformation syndromes. 4inor anomalies of the orofacial area are seen better with the fetoscope than with ultrasound.

#.

he most common indication is fetal blood sampling. .t present it is most commonly obtained for detecting hemoglobinopathies. ?ther uses of fetal blood sampling are detection of 5B8 morphology defects, coagulation disorders, metabolic disorders and fetal infections, karyotyping, 5h isoimmunisation, fetal se0 determination, detecting Duchenne muscular dystrophy and severe combined immunodeficiency.

9. Diagnosis of some genetic skin diseases, e.g., albinism, congenital icthyosis, etc. &. Aor the study of hepatic en<ymes, a liver biopsy is performed. ). .long with ultrasound, fetoscopy is used for performing intra,uterine fetal surgery. *. Direct intra,vascular fetal blood transfusion performed guided by the fetoscope. 7. Aetoscopy can also be used for the intrau erine administration of drugs. A*(,)9ra;/' .mniography permits intra,uterine diagnosis of anomalies such as e0 trophy of the bladder, men ingocele, tracheo,oesophageal fistula, oesophageal atresia, diaphragmatic hernia, etc. Ultra&)()9ra;/' he advent and application of ultrasound has I or obviated the need for certain traditional diagnostic procedures. 6t is useful for the early diagnosis of pregnancy, localisation of placenta for performing amniocentesis, detecting placental anomaly, etc. :terine malformations, incompetent os, polyhydramnios and oligohydramnios can be.

diagnosed.

he number and position of the fetus can be easily -udged. 4a-or

congenital malformations can also be diagnosed. ASSESSMENT O5 5ETAL GROWTH4 MATURITY AND 5UNCTION I1 G+&tat,)(al a9+ a(# 9r)$t/ History: 8onventionally, #80 days are added to the date of the last menstrual period in order to obtain the e0pected date of delivery. 6n case of irregular menstrual cycles, oral contraceptives intake etc., this is not reliable. Uterine size , .ssessment of uterine si<e by vaginal e0amination is fairly accurate :pto '# weeks of gestation. /ater, gestational age in weeks can be calculated by multiplying the fundal height in cm by a factor of 8C7. Aundal height patterns are also now used to detect intra,uterine growth retardation. Abdominal girth: here is an increase of one inch every week, after 90 weeks. Maternal weight gain: he weekly gain is 0.' kgCweek in the first trimester, 0.# kgCweek in the second trimester and 0.9,0.) kgCweek in the third trimester, totaling ),( kg during the entire pregnancy. Radiological examination: he epiphyseal centers at the lower end of the femur and upper end of the tibia appear usually at 9* and 98 weeks, respectively. 6n addition, at full term, centres for #,9 tarsal bones may be present. :ltrasound in the third trimester is more useful as a means of identifying intra,uterine growth and predicting weight. Serial measurements of biparietal diameter given some indication of fetal growth. Aetal anomalies like neural tube defects fetal presentation and 6J;5 can de deterred.