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Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.

ABSTRACT: BACKGROUND:Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS:We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. RESULTS:We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells. CONCLUSIONS:We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

SUBMITTER: Trivellin G

PROVIDER: S-EPMC4291174 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.

Trivellin Giampaolo G Daly Adrian F AF Faucz Fabio R FR Yuan Bo B Rostomyan Liliya L Larco Darwin O DO Schernthaner-Reiter Marie Helene MH Szarek Eva E Leal Letícia F LF Caberg Jean-Hubert JH Castermans Emilie E Villa Chiara C Dimopoulos Aggeliki A Chittiboina Prashant P Xekouki Paraskevi P Shah Nalini N Metzger Daniel D Lysy Philippe A PA Ferrante Emanuele E Strebkova Natalia N Mazerkina Nadia N Zatelli Maria Chiara MC Lodish Maya M Horvath Anelia A de Alexandre Rodrigo Bertollo RB Manning Allison D AD Levy Isaac I Keil Margaret F MF Sierra Maria de la Luz Mde L Palmeira Leonor L Coppieters Wouter W Georges Michel M Naves Luciana A LA Jamar Mauricette M Bours Vincent V Wu T John TJ Choong Catherine S CS Bertherat Jerome J Chanson Philippe P Kamenický Peter P Farrell William E WE Barlier Anne A Quezado Martha M Bjelobaba Ivana I Stojilkovic Stanko S SS Wess Jurgen J Costanzi Stefano S Liu Pengfei P Lupski James R JR Beckers Albert A Stratakis Constantine A CA

The New England journal of medicine 20141203 25

<h4>Background</h4>Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.<h4>Methods</h4>We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.<h4>Results</h4>We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these sampl ...[more]

PMID: 25470569

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Project description:SUMMARY:A 20-year-old man with an 8-year history of progressive enlargement of his hands and feet, coarsening facial features, painful joints and thickened, oily skin was referred for investigation of acromegaly. On examination, the subject was of normal height and weight. He had markedly increased skin thickness around the forehead, eyelids and scalp with redundant skin folds. Bilateral painful knee swelling was accompanied by enlargement of the extremities, and his fingers were markedly clubbed. Routine hematological, biochemical and hormonal blood tests, including GH and IGF-1 were normal. The clinical picture suggested primary hypertrophic osteoarthropathy (PHOA) rather than acromegaly and radiological studies were supportive of this, demonstrating increased subperiosteal bone formation and increased bone density and cortical thickening. There was widespread joint disease, with narrowing of joint spaces, whereas the knees demonstrated effusions and calcification. A skull X-ray revealed calvarial hyperostosis and a normal sellar outline. Family history was negative. Genetic studies were performed on peripheral blood leukocyte DNA for mutations in the two genes associated with PHOA, 15-hydroxyprostaglandin dehydrogenase (HPGD; OMIM: 601688) and solute carrier organic anion transporter family member 2A1 (SLCO2A1; OMIM: 601460). The sequence of HPGD was normal, whereas the subject was homozygous for a novel pathological variant in SLCO2A1, c.830delT, that predicted a frameshift and early protein truncation (p.Phe277Serfs*8). PHOA, also known as pachydermoperiostosis, is a rare entity caused by abnormal prostaglandin E2 metabolism, and both HPGD and SLCO2A1 are necessary for normal prostaglandin E2 handling. High prostaglandin levels lead to bone formation and resorption and connective tissue inflammation causing arthropathy, in addition to soft tissue swelling. LEARNING POINTS:The differential diagnosis of enlarged extremities, coarsened facial features, skin changes and increased sweating in suspected acromegaly is quite limited and primary hypertrophic osteoarthropathy (PHOA) is one of the few conditions that can mimic acromegaly at presentation.PHOA is not associated with abnormalities in GH and IGF-1 secretion and can be readily differentiated from acromegaly by hormonal testing.Clubbing in the setting of diffuse enlargement of joints and extremities in addition to skin changes should alert the physician to the possibility of PHOA, as clubbing is not a usual feature of acromegaly. Underlying causes of secondary hypertrophic osteoarthroapthy (e.g. bronchial neoplasia) should be considered.PHOA is a very rare condition caused by abnormalities in prostaglandin metabolism and has two known genetic causes (HPGD and SLCO2A1 mutations). SLCO2A1 gene mutations lead usually to autosomal recessive PHOA; fewer than 50 SLCO2A1 mutations have been described to date and the current case is only the second in a Hispanic patient.Treatment of primary hypertrophic osteoarthropathy is focused on the management of joint pain usually in the form of non-steroidal anti-inflammatory drug therapy.

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Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.

Publications

Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.

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