This document summarizes several genetic disorders including Down syndrome, Klinefelter's syndrome, Turner syndrome, Marfan syndrome, Ehlers-Danlos syndrome, cystic fibrosis, phenylketonuria, neurofibromatosis, tuberous sclerosis, and Friedreich's ataxia. It describes the genetic causes, characteristic physical features, complications, methods of diagnosis, and treatment options for each condition where relevant. The purpose is to provide an overview of common genetic disorders encountered in clinical practice.

1. Genetic disorders in practice

2. Down syndrome
 Extra chromosome 21
 1 per 1000 births, > with older moms
 Mental retardation, impaired physical growth
& infertility
 Round facies, macroglossia, epicanthic fold of
eyelid, single palmer crease, shorter limbs
 Increases risk of CHD (VSD), GERD, OSA
 Screening-
 1st
trimester US for nuchal translucency
 2nd
trimester quad screen- AFP, estriol, hCG, inhibin-alpha

3. Klinefelter’s syndrome
 47,XXY; most common sex chr.
disorder
 1 per 1000 males
 Small testes & reduced fertility
 Gynecomastia is common
 Testosterone low, FSH & LH high
 Dx- karyotyping

4. Turner syndrome
 45,X; 1 per 2500 girls
 Short stature, webbed neck, low
hairline, low-set ears, broad chest
 Amenorrhoea & sterility
 Asso. with coarctation of Aorta, learning
difficulties, Hashimoto’s thyroiditis
 Dx- karyotyping

5. Marfan syndrome
 Autosomal dominant
 Patients are tall with long limbs &
fingers (arachnodactyly), dislocated
lens, aortic root dilatation
 Complication- early OA, astigmatism,
MVP, aortic dissection, pneumothorax

6. Ehlers-Danlos syndrome
 Autosomal dominant
 Defect in collagen synthesis
 Causes hypermobile joints, flat feet,
aneurysm, MVP, velvety stretchy skin,
easy bruisability

7. 21-hydroxylase deficiency
 Autosomal recessive
 Causes congenital adrenal hyperplasia
 Leads to reduced cortisol & excess
androgens
 Classical- ambiguous genitalia in
newborn females & virilization of
prepubertal females
 High ACTH & 17-hydroxyprogesterone

8. Porphyria
 Defect in heme biosynthetic pathway
 Acute inter.- AD- abd. pain, peri. n’pathy
 Cong. erythropoeitic- AR- severe
photosensitivity (P), hemo. anemia
 PCT- AD- P
 Hereditary coproporphyria- AD- P, neurologic
symptoms (N), colic
 Variegate porphyria- AD- P, N, MR
 Erythro. protoporphyria- AD- P, gallstones

9. Cystic fibrosis
 Automal recessive, defect in CFTR gene
 Regulates components of sweat, mucus &
digestive juices
 Causes growth retardation, malabsorption,
pancreatitis, cirrhosis & infertility
 Frequent lung infections & bronchiectasis
lead to early death
 Dx- sweat test- Cl >60 mEq/L

10. Alpha-1 antitrypsin deficiency
 Autosomal recessive
 A1AT produced in liver, protects lungs
from neutrophil elastase enzyme
 Deficiency causes emphysema &
cirrhosis (accumulation of A1AT in liver)
 Sufferers should avoid smoking

11. Phenylketonuria
 Autosomal recessive
 Defect in enzyme that converts phenylalanine
to tyrosine
 Phenylalanine increases in blood &
phenylpyruvate in urine
 Untreated causes albinism, ADHD, mental
retardation & seizures
 Rx- low phenylalanine diet & oral
tetrahydrobiopterin

12. Hemochromatosis type 1
 Autosomal recessive
 Causes iron overload leading to organ
dysfunction
 Cirrhosis, diabetes, cardiomyopathy,
arthritis, testicular failure, skin tan
 1/3rd
untreated develop HCC

13. Wilson’s disease
 Autosomal recessive
 Copper accumulates in liver & brain
 Causes cirrhosis, portal HT, rarely HCC,
parkinsonism, ataxia, dystonia, behavioral
changes
 KF ring- due to copper deposition in
Descemet’s membrane of cornea
 Renal tubular acidosis & nephrocalcinosis

14. Lesch-Nyhan syndrome
 X-linked recessive
 Symptomatic in boys only
 Deficiency of enzyme HGPRT
increases uric acid in body
 Mental retardation, hypotonia, dystonia,
self mutilation, hyperuricemia- arthritis &
renal calculi, macrocytic anemia,
testicular atrophy

15. Duchenne muscular dystrophy
 X-linked
 Males affected, females carrier
 Progressive muscle wasting, starting in
childhood  frequent falls, waddling
gait, calf pain & hypertrophy
 Dx- CPK & muscle biopsy
 Death due to respiratory complications

16. Neurofibromatosis
 Autosomal dominant
 Effects all neural crest cells i.e. schwann
cells, melanocytes, endoneurial fibreblasts
 Type 1- multiple neurofibromas causing
mental retardation, epilepsy, symptoms due
to nerve damage/compression
 Type 2- deafness due to acoustic neuromas

17. Tuberous sclerosis
 Autosomal dominant
 Classical intracranial manifestation are
cortical/subcortical tubers (malformed tissue)
 Lead to mental retardation, hydrocephalus,
angiomyolipomas, rhabdomyoma
 Ash leaf spots (hypomelanic macules) &
Shagreen patch over neck/back

18. Friedreich’s ataxia
 Autosomal recessive
 Onset between 5-15 years
 Progressive staggering gait & frequent
falls
 Nystagmus, -nt DTR, ext. plantars, loss
of post. column sensation
 Cardiomegaly, hypertrophy, arrythmias
 Median age of death- 35 years

19. Storage disorders
 Autosomal recessive
 Gaucher- glucocerebroside- HSmegaly
 Niemann-Pick- sphingolipid- HSmegaly,
ataxia
 Tay-Sachs- gangliosides- ataxia, HSmegaly
 Hurler/Hunter- mucopolysaccharides- MR
 von Gierke/Pompe/Cori/McArdle/Her/Tarui-
glycogen- hepatomegaly, hypoglycemia,
hyperlipidemia, myopathy, GR/MR

20. Hematological
 Hemophilia- X linked- factor VIII deficiency-
bleeding
 Thallasemia- auto. recessive- reduced
synthesis of globin chain of Hb- anemia
 Sickle cell disease- auto. recessive- defective
globin chain production- anemia+