CHAPTER IV GENETIC DISORDERS CHAPTER IV GENETIC DISORDER Following are the diseases which have been found in the present investigation. Their pattern of inheritance (Fig. 1) extent of burden and descriptions are dealt with in this chapter. Table 46 Frequency and Pattern of Inheritance of different genetic disorders I. SINGLE GENE DISORDERS (A) Autosomal Dominants 1. Talipes Equinovarus 5 2. Talipes equinovarus 1 flat Rocker bottoro foot and third toe syndactyly. 3. Talipes Equinovarus bilateral 1 4. Bilateral congenital Talipes 1 Equinovarus with syndactyly 5. A^.'fJi ts Syndrome 3 6. Ectodermal dysplasia 1 7. Marfan's syndrome 1 8. Waardenberg syndrome with hypoplastic 1 cardial and ulner nerves 9. MPS with hypoachondroplasia 1 Contd.., 110 10. Hypoachondroplasia 11. Achondroplasia 12. Achondroplasia with MR 13. Amniotic Constriction band 14. Polydactyly 15. Osteogenesis imperfecta 16. Nail Patella Syndrome 17. Limb reduction 18.. Williams disease 19. Hypoplasia of left hand 20. Noonan Syndrome 21. Facial Dysmorphism 22. Arthrogryposis multiplex Congentia 23. Ectopia Lentis 24. Tuberous Sclerosis 25. Heredomacular generation affecting eyes 34 (B) Autosomal Recessive 1 . Thalassemia 11 2 . Mucopolysacchridoses 5 3 . Microcephaly with obscure MR 8 4 . Microcephyaly 20 5 . Microcephaly with MR 3 6 . Delayed milestones with microcephaly 1 and MR Contd 111 7. Microcephaly with delayed milestones 8. Microcephaly with MR 9. Microcephaly with absence of forebrain 10. Microcephaly with MR and polydactyly 13. Microcephaly with short stature 14. Hypocystic Ischaemia Encephalopathy microcephaly 15. Microcephaly with deafness 16. Anencephaly 18. Congenital cataract 19. Congenital glaucoma 20. Macrocephaly with MR 21. Nightblindness with albinism 22. Congenital deaf and mute with MR 23. Congenital deaf and mute 24. Congenital hypertropic pyloric stenosis 25. Neurocutaneous syndrome (Naxia- Telangista) 26. F:i’'3le pseudohermaphrodite 27. Congenital adrenal dysplasia with abnormal genetalia 26. Adrenogenital syndrome 28. Polycystic Kidney 29. Smith-Lemile-oplitz syndrome 30. Lawrence moon-Bardel-Biedl- syndrome 77 Contd. 112 (C) X-Linked Recessive 1 . Duchenne muscular dystrophy i 2 . Pseudohypertropic muscular dystrophy 2 3 . Hydrocephaly 7 4 . Hydrocephalous with VP shunt block 2 Hydrocephalous with imperforated 1 anus and typical facies 6 . Congenital hydrocephalous due to 1 aqueductus syndrome 7 . Hydrocephalous with no left hand 1 8 . Hydrocephaly with optic atrophy 1 9 . Haemophilia 4 10. Bleeding disorder with mild 1 haemophilia 11. Hunter syndrome 2 12 . Tostj.cular feminization 2 13 . Lesch-Nyhan syndrome 1 26 I I . CHROMOSOMAL DISORDERS (A) Autosomal 1 . Down syndrome 39 2 . Down syndrome with seperation 1 in palate 3 . Down syndrome with congenital 1 heart disease Contd, 113 4. Down syndrome with HS megaly 5 . Down syndrome with microcephaly and MR 6 . Tiisomy 18 1 7 . Trisomy 13 1 8 , Trisomy 8 2 9 . Prader w illi syndrome 1 10 , Multiple congenital anomalies 2 11. Delayed development micrognathia 1 cleft, palate, Rolter, facies and cat cries (C) Sex chromosomes 1. Abnormal genitalia with incomplete 1 testicular feminization & dehydra- testosterone deficiency 2. Turner syndrome 3 3. Klinefelter syndrome 2 4. Ambiguous gent'talia with microcephaly 1 5. Ambiguous genitalia 7 6. Ambiguous gen'italia with 1 imperforated anus 7. Micropenis 1 8. Maldeveloped penis 1 68 Contd, 114 III. MULTIFACTORIAL 1. Congenital Aortic Stenosis 1 2. Congenital heart disease with CL & CP 1 3. Congenital cyanotic heart diisease 2 4. Congenital Acyanotic heart disease 3 5. Congenital heart diesese with AV 1 canal defect 6. Congenital heart disease 1 7. Rokitansky-Mayer-Kuster-Hauser 1 syndrome 8. Claw foot and spina bifida 1 9. Spina bifida and hydrocephaly 1 10. Meningomylocoel 1 11. Meningomylocoel with hydrocephaly 1 12. Cl2 ft palate bilateral 1 13. Cleft lip with cleft palate 3 14. Cleft palate 2 15. Mental retardation 31 16. Obscure MR 1 17. Obscure MR with squint 1 18. Obscure MR with dysmorphic features 1 55 IV. PROBABLY GENETIC 1. Primary amenorrhea 3 2. Delayed physical with mental 2 retardation Contd, 115 3. Delayed milestones 4. MR with physical retardation and hypotonia 5. Speech defect 6. Dwarfism 7 . Blind with MR 8. MR with hearing asnd visual defect 9. Depressed rudimentary ear with no cartilage and renal disorder 10. Short stature 11. Male with female features 12. Retarded Growth 13. Delayed milestones with dv'cmorphism hernia 14. Deformities leg with Inguinal hernia 15. Delayed milestones with obscure MR and deafness 16. Bilateral undescended testis 17. Minimal Brain Dysfunction Syndrome 28 V. UNCERTAIN 1. Goldenhar Syndrome 2. Hepatosplenomegly (HS megaly) with MR 3. Ectospadia with Ectopia vc3ciclG epispermia Contd 116 4. Both Kidneys on right side with l hydronephrosis 5. Rubinstein Taynbi syndrome i 6. Umbilical hernia 1 7. Cerebral Palsy 1 8. Cornelia de lange Syndrome 2 9. Congenital hypothyroidism 1 12 The above Table lists down the type of disorders that were available in the present investigation. Microcephaly followed by thalassemia and hydrocephaly were the most common single gene disorders. Most frequent chromosomal disorders were Downs Syndrome and cases of ambiguous genitalia. Among the disorders under multifactorial category cases of mental retardation were higher. Delayed milestones were more in number in the category of probable genetic. The accompanying Table shows an estimate of the years of impairment and the degree of impairment. Degree of impairment is difficult to define. According to Carter (1982) it may involve a life long constant handicap as with congenital blindness or a progressive deterioration as with Hundington's chorea which begins with only a minor handicap but ends as total disability. Carter's rough guide to handicap has been limitation of working capacity in adulthood or in 117 childhood educability. While determining the degree of impairment in the present investigation nature of disease, year of detection, possible treatment, kind of handicap and longevity (60 years in India) are taken into account. The burden of various genetic disorders in terms of its degree of disability or impairment and the number of years of life lost as a result of the disorder are given in the Table. It can be seen that most of the autosomal dominant disorders do not have any effect on the lifespan and have marginal d isa bility , except the disorder?, like Marfan's Syndrome, Achondroplasia with mental retardation, Nail-Patella Syndrome and tuberous sclerosis. But the recessive disorders involve greater disability and drastically reduce longevity. Conditions like anenceph^y, microcephaly with absence of forebrain are fatal, whereas those like thalassemia, mucopolysacchridoses, polycystic kidney and neurocutaneous syndrome reduce the life span by as many as 55 years. These also involve a greater degree of disability. Same is true for X-linked recessive disorders where conditions like Hunter Syndrome and Lesch-Nyhan Syndrome impose the greatest burden both in terms of reducing longevity and the degree of impairment. All other X-linked disorders also have reduced life spans and increased disability. As regards the autosomal chromosome disorders most of them are fatal 118 and do not warrant survival. They impose the highest degree of disability and reduction in the life span e.g. multiple congenital anomalies and the trisomies 18 and 13. While those involving a^berrations of sex chromosome are comparatively milder in their effect on disability and longevity. Multifactorial disorders can be placed fourth in the order of the extent of burden where the neural tube defects,congenital heart disease and mental retardation contribute major share of the burden. Most of the disorders placed in probably genetic category do not have reduced life span but have variable disability. Among the uncertain category the disability and life lost is comparatively greater in Rubinstein Taynbi Syndrome, Cornelia de lange Syndrome and Congenital hypothyroidism. 119 Table 47 Table showing the estimated burden of the various genetic disorders S.No. Condition Unimpai red Impai red Degree Lost Cause of life I ife of I i f e death impai re- ment percent AUTOSOMAL DOMINANT 1. Talipes Equinovarus 60 20 None (untreated) 2. Talipes Equinovarus, 60 25 None Rocker bottom foot and third toe Syndactyly 3. Talipes equinovarus 60 25 None bilateral with Syndactyly 4. Aperts Syndrome Unknown 40 Unknown 5. Ectodermal dysplasia 60 10 0 None 6. Marfan's Syndrome 20 40 15 Aortic complica­ tion 7. Waardenberg Syndrome 58 30 0 None 8 . Hypoachondroplasia 54 20 0 None 9. Achondroplasia 60 30 0 None 10. Achondroplasia with MR 40 60 20 If heterozygous without complica tions. 11. Afrniotic Constriction 60 10 0 None band Contd. 120 12. Polydactyly (untreated) 0 60 0 0 None 13. Osteogenesis Imperfecta 2 53 40 5 Infection 14. Nail Patella Syndrome 0 20 50 40 Rena I fa ilure 15. Limb reduction (upper limb) 0 60 40 0 None 16. Willi ams Disease 4 Unknown 50 Unknown 17. Hypoplasia of left hand 0 60 40 0 None 18. Noonan SymdruT.: 0 60 40 0 None 19. Facial dysmorphism 10 50 20 Unknown 20. Arthrogryposis Multiplex 0 55 20 After aggressive congent i a physical therapy and orthopedic procedures 21 . Ectopia lent is 60 20 None 22. Tuberous sclerosis 40 80 20 Dementia and i nfect i on 23. Heredomacular degenera- 15 60 40 0 None t i on affect i ng eyes AUTOSOMAL RfcCESS'VE 1. Thalassemia (without 20 40 40 Increased chelation therapy) i ron burden 2. Mucopolysacchridoses 10 80 50 Pneumonia or cardiac decompo­ sition 3. Microcephaly wi th 55 90 5 Retardation and obscure MR infection 4. Microcephaly 55 50 5 -do- 5. Microcephaly with MR 45 90 5 - do Contd..., 121 6, MlcrocephaIy with ^5 30 5 - do- delayed milestones 7. Microcephaly with 100 60 Fatal absence of forebrain 8. Microcephaly with 55 80 Retardation and MR and polydactyly i nfect i on 9. Mi crocephaly wi th 55 80 5 - do - short stature 10. Microcephaly with 55 90 5 -do- deafness 11.