Selected Genetic Disorders & Primary Immunodeficiency States

1. Selected Genetic Disorders &Primary Immunodeficiency States Janice M. Lage, M.D. MUSC Pathology

2. Marfan’s Syndrome • Autosomal dominant • 1/10,000-1/20,000 incidence • 70-85% familial, remainder sporadic mutation

3. Marfan’s Syndrome • Autosomal dominant • Defective fibrillin synthesis • Support scapholding for tropoelastin deposition resulting in elastin fiber formation

4. Marfan’s Syndrome • Autosomal dominant • Defective fibrillin synthesis • Skeletal abnormalities • Short-waisted (long legs, long armspan, short upper body) • Pectus excavatum, pigeon chest deformity • Kyphosis, scoliosis

6. Marfan’s Syndrome • Autosomal dominant • Defective fibrillin synthesis • Skeletal abnormalities • Subluxation of lens • Deflected upward and outward—ectopia lentis, • Bilateral ectopia lentis is a strong clue raising suspicion for Marfan’s syndrome

8. Marfan’s Syndrome • Autosomal dominant • Defective fibrillin synthesis • Skeletal abnormalities • Subluxation of lens • Aortic dissection

12. Ehlers-Danlos Syndromes • Similar to Marfan’s

13. Ehlers-Danlos Syndromes • Similar to Marfan’s • Defective collagen synthesis • Lack tensile strength • Extremely fragile • Vulnerable to trauma

14. Ehlers-Danlos Syndromes • Similar to Marfan’s • Defective collagen synthesis • Tissues become rubbery/elastic like—contortionists • Joints, skin, internal structures • Joint dislocation, skin trauma, rupture colon, large arteries, cornea; retinal detachment, diaphragmatic hernia

17. Lysosomal Storage Diseases • Defect of a a lysosomal enzyme • Leads to accumulation of substrate • How do lysosomal enzymes get directed to the lysosome without digesting their own cells first (autodigestion)? • Mannose-6-phosphate (a Fedex address) directs the package to fuse with the lysosome before releasing its contents (RER—> Golgivesicle tagged with address lysosome)

18. Tay-Sachs • Hexosamindase A a-subunit deficiency • More common among Ashkenazi Jews—Eastern European origins • Heterozygote carrier 1 in 30 • Normal appearing at birth, then develop profound retardation • Blindness • Neurologic defects • DEATH 2 to 3 years of age

22. Niemann-Pick Disease • Accumulation of sphingolipid (Types A and B) and, in an unrelated disease, cholesterol (Type C) • Types A (infantile) and B (adult) due to deficiency of sphingomyelinase, thus can’t break down sphingomyelin • Types A and B more frequent in Ashkenazi Jews • Products accumulate in neurons in brain, and in phagocytic cells in spleen, liver, bone marrow, lungs, lymph nodes

23. Niemann-Pick Disease • Type A, 75-80%, severe infantile form with extensive neuronal involvement, visceromegaly, progressive wasting; spingomyelin accumulates due to a deficiency of spingomyelinase • Neurologic deterioration with DEATH about 5 years in type A. • Type B: adults with organomegaly alone

27. Gaucher’s Disease • Deficiency in glucocerebrosidase—cleaves glucose from ceramide residue • Type I due to accumulation of glucocerebroside in RE cells—Gaucher cells, Ashkenazi Jews • Source is usually degrading RBC and WBC membranes

28. Gaucher’s Disease • 99% are Type I, chronic non-neuronopathic form, big spleen, accumulates in bones, longevity only somewhat shortened • Type II, infantile form, lethal in 6 months, no predilection for Jews • Depending on variant, death may occur

32. Mucopolysaccharidoses(Hurler Syndrome) • Hurler Syndrome (MPS 1H) due to deficiency of a-L-iduronidase • Hurler Syndrome, failure to remove terminal sugar from proteoglycans--Dermatan sulfate and heparan sulfate accumulate • MPS disorders develop profound facial changes (gargoylism), joint stiffness, clouding cornea and mental retardation • Death within 10 years

36. Bruton’s Disease • Failure of B cells to differentiate • Light chains not produced • Free heavy chains in cytoplasm

37. Bruton’s Disease • X-linked (males) • Presents about 6 mo after birth • Numerous childhood infections • Bacterial infections include H. flu, Strep pneu, S. aureus • Viral infections include enteroviruses: echo, polio, and coxsackievirus • Absence of plasma cells

38. DiGeorge’s Syndrome • Failure of 3rd and 4th pharyngeal pouches to develop—parathyroids, thymus, clear cells of thyroid, ultimobranchial body • Congenitally small or absent thymus, tetany, other anomalies • T cells reduced or absent • Paracortex of lymph nodes depleted • Periarteriolar sheaths of spleen depleted

39. DiGeorge’s Syndrome • Numerous viral, fungal or protozoal infections • May have multiple congenital defects

41. SCID • May have both cell mediated and humoral related defects • Classic form—severe B and T cell deficiencies, described in Swiss children

42. SCID • Classic form: BOTH T and B cells affected: • Thrush (oral candida) • Diaper rash, extensive • Failure to thrive • Mobiliform skin rash due to graft-versus-host disease from mother’s T cells going through placenta destroying baby’s skin cells • Death 1st year of life

43. SCID • Most common form: X-linked T cell impairment (boys>>girls) • 50-60% of cases • Mutation in gamma chain subunit of several cytokine receptors IL2, IL4, IL7, IL9, IL11, IL15 • Defects: earliest T cell development, late stages of B cell development

44. SCID • T cells greatly reduced, B cells normal in number but with impaired antibody synthesis • Small thymus, no lymphoid cells • Multiple opportunistic infections