Abstract
ABSTRACTSomatic gain‐of‐function mutations of GNAS cause a spectrum of clinical phenotypes, ranging from McCune‐Albright syndrome (MAS) to isolated disease of bone, endocrine glands, and more rarely, other organs. In MAS, a syndrome classically characterized by polyostotic fibrous dysplasia (FD), café‐au‐lait (CAL) skin spots, and precocious puberty, the heterogenity of organ involvement, age of onset, and clinical severity of the disease are thought to reflect the variable size and the random distribution of the mutated cell clone arising from the postzygotic mutation. We report a case of neonatal MAS with hypercortisolism and cholestatic hepatobiliary dysfunction in which bone changes indirectly emanating from the disease genotype, and distinct from FD, led to a fatal outcome. Pulmonary embolism of marrow and bone fragments secondary to rib fractures was the immediate cause of death. Ribs, and all other skeletal segments, were free of changes of typical FD and fractures appeared to be the result of a mild‐to‐moderate degree of osteopenia. The mutated allele was abundant in the adrenal glands and liver, but not in skin, muscle, and fractured ribs, where it could only be demonstrated using a much more sensitive PNA hybridization probe‐based FRET (Förster resonance energy transfer) technique. Histologically, bilateral adrenal hyperplasia and cholestatic disease matched the abundant disease genotype in the adrenals and liver. Based on this case and other sporadic reports, it appears that gain‐of‐function mutations of GNAS underlie a unique syndromic profile in neonates characterized by CAL skin spots, hypercortisolism, hyperthyroidism, hepatic and cardiac dysfunction, and an absence (or latency) of FD, often with a lethal outcome. Taken together, our and previous cases highlight the phenotypic severity and the diagnostic and therapeutic challenges of MAS in neonates. Furthermore, our case specifically points out how secondary bone changes, unrelated to the direct impact of the mutation, may contribute to the unfavorable outcome of very early‐onset MAS. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
Missense gain-of-function mutations of the GNAS gene, encoding the a-subunit of the stimulatory G protein, Gas, are known to cause a varied spectrum of clinical expressions, including the McCune-Albright syndrome (MAS), isolated monostotic or polyostotic fibrous dysplasia (FD) of bone, isolated endocrine tumors, the syndromic association of muscular myxomas with FD, and isolated myxomas.[1,2,3,4,5,6,7,8,9,10,11,12] Recently, the same mutations have been reported in a spectrum of low-grade and benign hepato-biliary, pancreatic, and gastrointestinal neoplasias occuring either with or without other clinical features of MAS.[11,12,13,14] In all the different clinical contexts, the GNAS mutation leads to activation and inappropriate activity of cells and tissues normally stimulated through receptors that are coupled to the Ga-cAMP-protein-kinase A dependent pathway.[1,2]
We report here a case of neonatal lethal multiorgan disease caused by a gain-of-function mutation (R201H) in the GNAS
The patient presented at birth with large cafe-́ au-lait (CAL) skin macules, hypercortisolism, hyperthyroidism, and liver and cardiac dysfunction
Summary
Missense gain-of-function mutations of the GNAS gene, encoding the a-subunit of the stimulatory G protein, Gas, are known to cause a varied spectrum of clinical expressions, including the McCune-Albright syndrome (MAS), isolated monostotic or polyostotic fibrous dysplasia (FD) of bone, isolated endocrine tumors, the syndromic association of muscular myxomas with FD, and isolated myxomas.[1,2,3,4,5,6,7,8,9,10,11,12] Recently, the same mutations have been reported in a spectrum of low-grade and benign hepato-biliary, pancreatic, and gastrointestinal neoplasias occuring either with or without other clinical features of MAS.[11,12,13,14] In all the different clinical contexts, the GNAS mutation leads to activation and inappropriate activity of cells and tissues normally stimulated through receptors that are coupled to the Ga-cAMP-protein-kinase A dependent pathway.[1,2]In MAS, affected tissues and cell types include derivatives of the different germ layers.[1,8] Even though polyostotic FD, cafe-́ au-lait skin spots, and hyperfunctional endocrinopathies (in particular, peripheral precocious puberty) represent the typical clinical features of the disease, other tissues and organs can be affected.[8,9,10,11,12,15] The variability in the pattern of tissue and organ involvement, the age of onset and the severity of the clinical -%05 3OXV :2$disease are generally thought to reflect the variable size and the random distribution to diverse tissues/organs of the clone of mutated embryonic cells arising from the postzygotic mutation.[3,8,16] other factors, such as [1] the level of expression of the mutant allele in different tissues[17], [2] the activity of counterregulatory molecular mechanisms such as relevant tissue-specific phosphodiesterases[1,18], [3] the cellspecific effects of the increased cAMP production[15], [4] the differential survival of mutated cells across the body and along development[8] and [5] epigenetic determinants such as tissuespecific imprinting of the GNAS gene,(19–21) may all represent important additional determinants of the different disease burden of MAS patients.Presentation of MAS in neonatal life is a rare and often lethal event.[3,22,23,24,25,26,27,28,29,30,31,32,33,34] We report here a case of multiorgan disease caused by a gain-of-function mutation of GNAS that presented at birth and had an unfavorable outcome. An osteopenic bone phenotype, most likely secondary to hypercortisolism, was the major determinant of lethality, with multiple pulmonary marrow emboli originating from fractures of osteopenic ribs. This case and previous reports of MAS with very early onset[3,22,23,24,25,26,27,28,29,30,31,32,33,34] highlight a syndromic profile of the disease that appears to be unique to the neonatal period, and requires a prompt diagnosis, but may be difficult to recognize. Our case highlights the importance of bone changes that, in the absence of FD or any other direct impact of the disease genotype on bone, may contribute to the lethal outcome of MAS in neonatal patients
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