A 4-year-old girl presents with vaginal bleeding, breast development, and multiple bone lesions with a characteristic ground-glass appearance on X-ray. Physical examination reveals irregular, jagged brown macules on her trunk that respect the midline. Genetic testing of affected bone tissue reveals a post-zygotic somatic activating mutation in the gene marked **A** in the diagram. Which of the following best explains why this mutation causes autonomous hormone secretion in affected tissues?
A. Biallelic loss of TSC1 disrupts mTOR pathway inhibition, promoting uncontrolled cell proliferation
B. Loss of PTPN11 phosphatase activity impairs negative feedback on receptor tyrosine kinase signaling
C. Constitutively active Gsα leads to chronic elevation of intracellular cAMP, driving autonomous endocrine cell proliferation and hormone production
D. Inactivation of NF1 tumor suppressor removes inhibition of RAS-mediated growth signaling
Explanation
Why "Constitutively active Gsα leads to chronic elevation of intracellular cAMP, driving autonomous endocrine cell proliferation and hormone production" is right
The gene marked A (GNAS 20q13.32) encodes the alpha subunit of the stimulatory G-protein (Gsα). Post-zygotic somatic activating mutations in GNAS cause constitutive activation of adenylate cyclase, resulting in chronically elevated intracellular cAMP in affected tissues. This sustained elevation of cAMP drives autonomous hormone secretion (particularly gonadotropin-independent precocious puberty from autonomous ovarian estrogen production) and dysregulated cellular proliferation, explaining the endocrinopathies and fibrous dysplasia seen in McCune-Albright syndrome. This mechanism is pathognomonic for GNAS mutations and is the fundamental driver of the disease phenotype (Nelson Pediatrics 22e, Ch 595).
Why each distractor is wrong
Loss of PTPN11 phosphatase activity impairs negative feedback on receptor tyrosine kinase signaling: PTPN11 mutations cause Noonan syndrome, not McCune-Albright syndrome. While PTPN11 does regulate RTK signaling, it is not involved in the cAMP pathway that drives MAS pathology.
Inactivation of NF1 tumor suppressor removes inhibition of RAS-mediated growth signaling: NF1 mutations cause neurofibromatosis type 1, which can present with café-au-lait macules (but with smooth "coast of California" borders, not jagged "coast of Maine" borders). NF1 acts on RAS signaling, not the Gsα-cAMP axis central to MAS.
Biallelic loss of TSC1 disrupts mTOR pathway inhibition, promoting uncontrolled cell proliferation: TSC1 mutations cause tuberous sclerosis complex. Although TSC can cause bone lesions and skin manifestations, the mechanism involves mTOR dysregulation, not Gsα-mediated cAMP elevation, and TSC does not cause gonadotropin-independent precocious puberty.
