Neonatal McCune‐Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome
ABSTRACT Somatic 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), c...
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doaj-f8af931cc2394d96b8c1a0d938ea20a82021-05-02T15:56:39ZengWileyJBMR Plus2473-40392019-08-0138n/an/a10.1002/jbm4.10134Neonatal McCune‐Albright Syndrome: A Unique Syndromic Profile With an Unfavorable OutcomeAlessandro Corsi0Natasha Cherman1David L Donaldson2Pamela G Robey3Michael T Collins4Mara Riminucci5Department of Molecular MedicineSapienza UniversityRome ItalySkeletal Biology SectionNational Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesda MD USADepartment of PediatricsUniversity of Utah, School of MedicineSalt Lake City UT USASkeletal Biology SectionNational Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesda MD USASkeletal Disorders and Mineral Homeostasis SectionNational Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesda MD USADepartment of Molecular MedicineSapienza UniversityRome ItalyABSTRACT Somatic 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.https://doi.org/10.1002/jbm4.10134MCCUNE‐ALBRIGHT SYNDROMEGNASCUSHING SYNDROMECHOLESTASISNEONATAL |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alessandro Corsi Natasha Cherman David L Donaldson Pamela G Robey Michael T Collins Mara Riminucci |
spellingShingle |
Alessandro Corsi Natasha Cherman David L Donaldson Pamela G Robey Michael T Collins Mara Riminucci Neonatal McCune‐Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome JBMR Plus MCCUNE‐ALBRIGHT SYNDROME GNAS CUSHING SYNDROME CHOLESTASIS NEONATAL |
author_facet |
Alessandro Corsi Natasha Cherman David L Donaldson Pamela G Robey Michael T Collins Mara Riminucci |
author_sort |
Alessandro Corsi |
title |
Neonatal McCune‐Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome |
title_short |
Neonatal McCune‐Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome |
title_full |
Neonatal McCune‐Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome |
title_fullStr |
Neonatal McCune‐Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome |
title_full_unstemmed |
Neonatal McCune‐Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome |
title_sort |
neonatal mccune‐albright syndrome: a unique syndromic profile with an unfavorable outcome |
publisher |
Wiley |
series |
JBMR Plus |
issn |
2473-4039 |
publishDate |
2019-08-01 |
description |
ABSTRACT Somatic 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. |
topic |
MCCUNE‐ALBRIGHT SYNDROME GNAS CUSHING SYNDROME CHOLESTASIS NEONATAL |
url |
https://doi.org/10.1002/jbm4.10134 |
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