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Difficulty: HardGenetic and Molecular Mechanisms

An outpatient evaluation is conducted for a 2424-year-old male who reports a two-month history of episodic, severe headaches accompanied by palpitations, profound diaphoresis, and anxiety. During the visit, his blood pressure is measured at 185/110185/110 mm Hg with a heart rate of 115115/min. Physical examination is notable for an unusually tall and slender body habitus with arachnodactyly. Examination of the oral cavity reveals multiple firm, painless, yellow-white nodules distributed across the lips and the anterior tip of the tongue. Palpation of the anterior neck identifies a firm, 22-cm nodule in the right thyroid lobe. Diagnostic laboratory studies show markedly elevated plasma free metanephrines. A review of his family history indicates that his mother passed away from a rapidly progressive neck tumor at age 3535, and his 1212-year-old brother recently underwent an elective prophylactic total thyroidectomy. Based on these clinical findings, the genetic defect responsible for this patient's condition causes which of the following molecular alterations?

  1. Constitutive ligand-independent activation of a transmembrane receptor tyrosine kinaseAnswer
  2. B
    Dysfunctional assembly of extracellular matrix glycoprotein microfibrils
  3. C
    Impaired ubiquitin-mediated degradation of hypoxia-inducible transcription factors
  4. D
    Loss of heterozygosity of a nuclear protein that normally suppresses gene transcription
  5. E
    Loss of GTPase-activating protein function resulting in sustained intracellular Ras signaling

Answer

Constitutive ligand-independent activation of a transmembrane receptor tyrosine kinase
The patient's clinical presentation is highly characteristic of Multiple Endocrine Neoplasia type 2B (MEN2B). This syndrome is distinguished by the development of medullary thyroid cancer (MTC) and pheochromocytomas, accompanied by a marfanoid body habitus and mucosal neuromas (often on the lips and tongue). The family history of an early fatal 'thyroid tumor' and a brother undergoing a prophylactic total thyroidectomy strongly supports the presence of a highly penetrant, aggressive familial MTC syndrome. MEN2B is an autosomal dominant condition caused by a gain-of-function germline mutation in the RET proto-oncogene. The RET gene encodes a transmembrane receptor tyrosine kinase. Normally, this receptor requires binding by glial cell line-derived neurotrophic factor (GDNF) family ligands to dimerize and activate. However, in MEN2B (most commonly due to an M918T point mutation in the kinase domain), the receptor undergoes constitutive, ligand-independent auto-phosphorylation. This leads to persistent downstream mitogenic signaling, driving the neoplastic transformation of neural crest-derived tissues such as parafollicular C-cells and adrenal medullary chromaffin cells.

Step-by-Step Solution

1
Analyze the clinical presentation and physical exam findings.
The patient has signs of a pheochromocytoma (hypertension, headaches, elevated metanephrines), a marfanoid habitus, mucosal neuromas, and a thyroid nodule.
Identifying the complete constellation of signs is necessary to formulate an accurate syndromic diagnosis rather than anchoring on one isolated finding.
2
Synthesize the family history with the patient's presentation to establish a diagnosis.
A family history of early fatal neck tumors and prophylactic thyroidectomy indicates hereditary medullary thyroid cancer. Combined with the patient's physical findings, the diagnosis is definitively Multiple Endocrine Neoplasia type 2B (MEN2B).
Prophylactic thyroidectomy in an asymptomatic relative is a hallmark management strategy for kindreds with high-risk RET mutations, confirming the MEN2 familial pattern.
3
Determine the molecular mechanism of the genetic defect associated with MEN2B.
MEN2B is caused by an activating germline mutation in the RET proto-oncogene, which encodes a receptor tyrosine kinase that becomes constitutively active without ligand binding.
The question specifically asks for the molecular alteration caused by the genetic defect.

Key Concept

Multiple Endocrine Neoplasia type 2B (MEN2B) is caused by a gain-of-function germline mutation in the RET proto-oncogene, resulting in constitutive, ligand-independent activation of its receptor tyrosine kinase.
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Topics

Genetic and Molecular Mechanisms

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