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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), 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.

SUBMITTER: Corsi A

PROVIDER: S-EPMC6715781 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Neonatal McCune-Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome.

Corsi Alessandro A Cherman Natasha N Donaldson David L DL Robey Pamela G PG Collins Michael T MT Riminucci Mara M

JBMR plus 20190115 8

Somatic gain-of-function mutations of <i>GNAS</i> 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 di ...[more]

PMID: 31485549

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Project description:McCune-Albright syndrome (MAS) is classically defined by the clinical triad of fibrous dysplasia of bone (FD), café-au-lait skin spots, and precocious puberty (PP). It is a rare disease with estimated prevalence between 1/100,000 and 1/1,000,000. FD can involve a single or multiple skeletal sites and presents with a limp and/or pain, and, occasionally, a pathologic fracture. Scoliosis is common and may be progressive. In addition to PP (vaginal bleeding or spotting and development of breast tissue in girls, testicular and penile enlargement and precocious sexual behavior in boys), other hyperfunctioning endocrinopathies may be involved including hyperthyroidism, growth hormone excess, Cushing syndrome, and renal phosphate wasting. Café-au-lait spots usually appear in the neonatal period, but it is most often PP or FD that brings the child to medical attention. Renal involvement is seen in approximately 50% of the patients with MAS. The disease results from somatic mutations of the GNAS gene, specifically mutations in the cAMP regulating protein, Gs alpha. The extent of the disease is determined by the proliferation, migration and survival of the cell in which the mutation spontaneously occurs during embryonic development. Diagnosis of MAS is usually established on clinical grounds. Plain radiographs are often sufficient to make the diagnosis of FD and biopsy of FD lesions can confirm the diagnosis. The evaluation of patients with MAS should be guided by knowledge of the spectrum of tissues that may be involved, with specific testing for each. Genetic testing is possible, but is not routinely available. Genetic counseling, however, should be offered. Differential diagnoses include neurofibromatosis, osteofibrous dysplasia, non-ossifying fibromas, idiopathic central precocious puberty, and ovarian neoplasm. Treatment is dictated by the tissues affected, and the extent to which they are affected. Generally, some form of surgical intervention is recommended. Bisphosphonates are frequently used in the treatment of FD. Strengthening exercises are recommended to help maintaining the musculature around the FD bone and minimize the risk for fracture. Treatment of all endocrinopathies is required. Malignancies associated with MAS are distinctly rare occurrences. Malignant transformation of FD lesions occurs in probably less than 1% of the cases of MAS.

Project description:AimThis study aimed to summarize and show the characteristics and evolutionary process of neonatal cholestasis caused by McCune-Albright syndrome (MAS), as neonatal cholestasis may be the initial manifestation of MAS before other classic clinical features appear.MethodsThe clinical characteristics, treatment methods, and outcomes of three neonatal cholestasis cases caused by MAS in our center were retrospectively studied. In addition, all the reported cases of MAS combined with cholestasis were reviewed and summarized to show the cholestatic features in them.ResultsWe have confirmed three MAS cases in our center, presenting onset symptoms of jaundice, pale stool, and neonatal cholestasis soon after birth. The cholestasis subsided spontaneously at around the sixth month. The literature review showed that the levels of total bilirubin, conjugated bilirubin, ALT, AST, and GGT in neonatal MAS cholestasis cases were 207 μmol/L (range 65-445 μmol/L), 162 μmol/L (range 46-412 μmol/L), 821 U/L (range 85-3,597 U/L), 532 U/L (range 127-3,633 U/L), and 244 U/L (range 79-3,800 U/L), respectively. Liver histology showed canalicular and hepatocellular cholestasis, giant hepatic cell transformation, and bile paucity. Extrahepatic manifestations such as café-au-lait pigmented skin lesions, Cushing's syndrome, hyperthyroidism, renal tubular dysfunction, and skeletal abnormalities could occur simultaneously when jaundice occurred. GNAS mutations had a high positive rate (83.3%-100%) in liver tissue with cholestasis. Neonatal cholestasis caused by MAS could be self-resolved, but hepatic lesions persist and have malignant potential.ConclusionMAS can be one of the causes of neonatal cholestasis, which may be the first manifestation of the disease. Extrahepatic coexisting symptoms of MAS and liver histology can help to distinguish MAS from other etiology of cholestasis. Detecting GNAS mutations in liver tissue may shorten diagnostic time and is of particular interest in the partial and atypical forms of MAS with neonatal cholestasis. Neonatal cholestasis in children with MAS can self-resolve, but liver dysfunction and malignant lesions persist.

Dataset Information

Neonatal McCune-Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome.

Publications

Neonatal McCune-Albright Syndrome: A Unique Syndromic Profile With an Unfavorable Outcome.

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