Click here to view next page of this article

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.

I. Multiple endocrine neoplasia Type I

A. Pathology

• Benign and malignant tumors and/or hyperplasia in pituitary, parathyroid, and

B. Clinical syndromes

• Pituitary: Acromegaly, hyperprolactinemia, hypopituitarism

• Parathyroid: Hyperparathyroidism

• Pancreas: Hypoglycemia with hypednsulinemia; Zollinger-Ellison Syndrome

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"

D. Molecular genetics:

1.Linkage analysis in 1988 led to localization of gene on chromosome 11
2.Molecular dissection in 2006 led to identification of MEN1 gene in 11q13 region
3.Role of the encoded protein (menin) is not yet known

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

1. Recognizing the disorder

2. interpreting sporadic eases

3. What is a real "family history"

4.Screening

Calcium

Clinical story (eg, MENI Budn-Prolactinomas)

II.Multiple endocrine neoplasia Type 2A

A. Pathology

• Medullory carcinoma of the thyroid (on a background of hyperplasia)

• Pheochromocytoma (on a background of hyperplasia)

• Parathyroid hyperplasia

B. Clinical syndromes

• Thyroid: palpable tumors(s) Exuberant calcitonin secretion without abnormal calcium levels

• Episodic, provoked, or sustained hypertension

• Hypercalcemia

C. Clinical genetics: Autosomal dominant

• Considerable variations in time of onset, but can be very early

• First human cancer discovered (and cured) by endocrine screening of relatives

• Three variants emerged

MEN 2a - see above MTC, pheo, parathyroid tumors

MEN 2b - MTC, pheo, plus extensive mucosal abnormalities; no parathyroid tumors ivrl'c only

D. Molecular Genetics

1.Linkage analysis led to assignment to chromosome 10 cen-10q11.2

2.Responsible gene is c-ret protooncogene (c-ret) which encodes a tyrosine-kinase receptor

E. Pathogenesis

An oncogene that, escaping from normal inhibition, stimulates uncontrolled hyperplasia and malignant proliferation

Similar 2 hit background (but note difference from MEN 1)

Variety of mutations leads to variety of syndromes

F. Clinical implications

1.Cancer more of an issue here especially in thyroid

2.Earlier, silent onset more frequent than with MEN 1, including childhood and infancy

3.Silent because no endocrine consequence of MTC

4.Therefore aggressive screening of asymptomatic relatives is central to management of MEN 2