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New Mechanisms of Endocrine Disease: Hereditary Disorders

The advances in molecular genetics have led to a greatly strengthened understanding of the mechanisms of certain of the hereditary endocrine disorders. In this lecture we will cover three such syndromes to illuminate the clinical decision-making now required as the genetic predisposition is

I. Multiple endocrine neoplasia Type I

A. Pathology

B. Clinical syndromes

C. Clinical Genetics: Autosomal dominant

Affects 50 % of first-order relatives

Relatively high rate of new mutations (~10 %)

Hence antecedent family history often negative
But sometimes "falsely negative"

E. Pathogenesis

1.The Knudsen hypothesis: development of tumor requires "two hits"--the same locus on a pair of chromosomes. This will be a rare event when both hits occur in somatic tissues.
2.But if one hit is in the germlinc hence present in all cells--a second hit is needed to produce tumor.
3.Above is general story for tumor suppressor genes such as Rb (Retinoblastoma) and p53 (Li-Fraumeni syndrome)
4.Second hit confers loss of heterozygosity and leads to tumor manifestation

F. Clinical Implications

II.Multiple endocrine neoplasia Type 2A

A. Pathology

B. Clinical syndromes

C. Clinical genetics: Autosomal dominant

D. Molecular Genetics

E. Pathogenesis