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Endocrine Abstracts (2015) 39 OC5.6 | DOI: 10.1530/endoabs.39.OC5.6

BSPED2015 ORAL COMMUNICATIONS Oral Communications 5 (10 abstracts)

Bone histomorphometry in patients with TMEM38B mutations suggests a novel patho-mechanism leading to increased bone fragility

Emma Webb 1 , Meena Balasubramanian 2 , N Fratzl-Zelman 3, , H Titheradge 5 , Trevor Cole 5 , S Stewart 5 , Nicola Crabtree 1 , W B Cabral 6 , B Owens 6 , P Roschger 3, , K Klaushofer 3, , J C Marini 6 , N Shaw 1 & W Hogler 1


1Department of Endocrinology and Diabetes, Birmingham Children’s Hospital, Birmingham, UK; 2Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK; 3Ludwig Boltzmann Institute of Osteology, Hanusch Hospital of WGKK, Vienna, Austria; 4AUVA Trauma Centre Meidling, Vienna, Austria; 5Department of Clinical Genetics, Birmingham Women’s Hospital, Birmingham, UK; 6Bone and Extracellular Matrix Branch, NICHD, National Institutes of Health, Bethesda, Maryland, USA.


Background: TMEM38B is a ubiquitously expressed monovalent cation-specific channel protein hypothesized to play a role in intracellular calcium homeostasis. To date, only two unique recessively inherited exon deletions in TMEM38B have been reported in 17 individuals with osteogenesis imperfecta (OI). Data on bone histomorphometry and bone material property have not previously been presented.

Cases: Targeted next generation sequencing was performed using a custom designed gene panel in seven children who presented with increased bone fragility and fractures. Pre-bisphosphonate bone biopsies were performed in three affected individuals. Patient 2 had an unusual skeletal phenotype with postnatal radiographs at 2 months of age identifying excessive periosteal reaction (cloaking) in all long bones, which later consolidated to form rather wide bones and significant coxa vara. Patient 4 presented with an extensive anterior myocardial infarct aged 16 years.

Results: Individuals 1–4 were homozygous for the same c.507G>A mutation in exon 4 of TMEM38B. Patient 7 was compound heterozygous for an exons 1 and 2 deletion and c.63dupT, which introduces a premature termination codon. In contrast to classical OI, iliac crest bone histomorphometry identified markedly reduced bone resorption with normal or slightly increased bone matrix mineralization density.

Discussion: Our studies suggest that TMEM38B mutations create a unique bone material phenotype of increased bone fragility. Histomorphometrically, this condition not typical of OI caused by collagen-gene being instead characterized by, low bone turnover and formation and relatively normal bone matrix mineralization. We describe the first cardiac abnormalities in a patient with a mutation in TMEM38B. TRIC channels encoded by TMEM38B contribute to calcium flux across the endoplasmic reticulum. Abnormalities in the function of this channel may predispose affected individuals to stress-induced heart failure. This report indicates the need for careful cardiovascular risk assessment in OI caused by TMEM38B mutations, at least until the risk profile becomes clearer.

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Volume 39

43rd Meeting of the British Society for Paediatric Endocrinology and Diabetes

British Society for Paediatric Endocrinology and Diabetes 

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