Genetics E2- Hepatic, HLD, Rheum

What is an autosomal recessive disorder of copper metabolism resulting from ATP7B mutations on chromosome 13?

Wilson’s disease

What are the major organs affected by copper accumulation in Wilson’s disease?

Liver, brain, cornea

When is Wilson’s disease typically diagnosed?

Between ages 5-35 (avg 13)

What manifestations of Wilson’s disease are children more likely to have?

Hepatic

What manifestations of Wilson’s disease are adolescents & adults most likely to have?

Neurologic

What are golden brown or greenish collarettes at corneal margins due to copper accumulation in Wilson’s disease?

Kayser-fleischer rings

What clinical features can be seen in Wilson’s disease?

Hepatic (jaundice, abd pain, ascites, UGI), neurologic(dysarthria, ataxia, dystonia, tremor), psychiatric (AMS, depression, irritability), kayser-fleischer rings

What lab findings are seen in Wilson’s disease?

Low ceruloplasmin, inc LFTs, thrombocytopenia, coagulopathy

What is the confirmatory testing for Wilson’s disease?

Elevated 24 hr urinary copper excretion, slit lamp for KF rings, genetic testing for ATP7B mutations, liver bx w/ quantitative copper analysis, abd US

What is the treatment for Wilson’s disease?

1st line: D-penicillamine & trientine chelation

Maintenance: oral zinc

What inheritance pattern does hereditary hemochromatosis have?

Autosomal recessive with low penetrance

What disorder is characterized by increased intestinal iron absorption leading to total-body iron overload, MC in caucasians?

*”iron elephant”

Hereditary hemochromatosis

What gene is involved in hereditary hemochromatosis?

HFE gene on chromosome 6

What clinical features are seen with hereditary hemochromatosis?

Hyperpigmentation, insulin resistance, “bronze diabetes”, cirrhosis

What lab studies are seen in hereditary hemochromatosis?

Inc transferrin saturation (earliest sign), inc ferritin, normal-inc iron, normal-dec TIBC

What testing is done for hereditary hemochromatosis?

PCR for HFE gene

What are hemochromatosis patients at an increased risk of developing?

HCC

What is the treatment for hereditary hemochromatosis?

Therapeutic phlebotomy; liver transplant for ESLD

What autosomal dominant condition is d/t defective LDL receptors and impaired LDL clearance, leading to elevated cholesterol levels from birth & an increase risk of premature CAD?

Familial hypercholesterolemia

How does the homozygous form of familial hypercholesterolemia present?

Detectable at birth; atherosclerosis develops in early childhood; cholesterol may be 8x ULN

How does the heterozygous form of familial hypercholesterolemia present?

Atherosclerosis begins in 3rd or 4th decade; LDL-C levels 2x ULN

What clinical features are seen with familial hypercholesterolemia?

Tendon xanthomas, xanthelasmata, arcus corneus (cholesterol in peripheral border of cornea)

What is the diagnostic criteria for heterozygous familial hypercholesterolemia?

LDL > 190 and either 1st degree relative w/ positive genetic testing or known premature CAD (< 55 for M, < 60 for F)

What is the diagnostic criteria for homozygous familial hypercholesterolemia?

LDL-C > 500 untreated or > 300 treated; xanthomas before age 10 or CAD at an early age; family history (heterozygous parents or genetic mutations)

When should children and adolescents be screened for familial hypercholesterolemia?

FHX of coronary heart disease, 1 parent with TC > 240, or one other RF (HTN, smoking, sedentary, obesity, drug use, DM)

What is the treatment for familial hypercholesterolemia?

Statins, ezetimibe, PCSK9 inhibitors, diet low in sat/trans fats & cholesterol, regular exercise

What is the MC form of skeletal dysplasia leading to disproportionate short stature?

Achondroplasia

What autosomal dominant condition is caused by a gain-of-function variant in the FGFR3 gene?

Achondroplasia

What inheritance pattern does achondroplasia have?

Autosomal dominant, but 80% of cases are de novo mutations

What is rhizomelic?

Shortened proximal long bones (humeri, femora)

What is brachydactyly?

Short digits

What is a flattening of the nasal bridge in association with mid face hypoplasia?

Saddle nose deformity

What is a deformity of the knee with outward deviation d/t bowing and/or joint laxity?

Varus

What are clinical manifestations of achondroplasia?

Rhizomelic shortening, brachydactyly, kyphosis in mid thoracic-lumbar region, accentuated lordosis, saddle nose, varus knee

What is the treatment for achondroplasia?

Vosoritide to inc linear growth in kids w/ open epiphyses

PT, OT, limb-lengthening procedures

What obstetric care is required for pregnant patients with achondroplasia?

Delivery by cesarean section d/t anatomy & size of pelvis

What typically autosomal dominant condition is a connective tissue disorder d/t mutations in COL1A1/2 & is characterized by abnormal collagen structure, leading to “brittle bones”?

Osteogenesis imperfecta

What is the mildest form of osteogenesis imperfecta?

Type 1

What clinical manifestations are seen with osteogenesis imperfecta?

Excess or atypical features, short stature, basilar skull deformities, opalescent teeth that wear quickly, easy bruising, inc laxity of ligaments & skin, blue sclera

What is the management for osteogenesis imperfecta?

Bisphosphonates, PT, OT, intramedullary rodding & telescoping rods for fx prevention