Bone Abstracts

Osteogenesis imperfecta (OI) classification has recently been broadened to include genes that primarily affect osteoblast differentiation. TMEM38B encodes TRIC-B, a ubiquitously expressed monovalent cation-specific channel protein involved in calcium release from the endoplasmic reticulum. How alterations in TMEM38B cause OI remains poorly understood and bone matrix characteristics in affected patients have not previously been described.

We present skeletal and bone material characteristics of two children from apparently unrelated Pakistani families. Patient 1 presented with antenatal femoral bowing. Postnatal radiographs at 2 months of age identified excessive periosteal reaction (cloaking) in all long bones, which later consolidated to form rather wide bones and significant coxa vara. Multiple vertebral fractures showed spontaneous but incomplete reshaping over the first 22 months. Patient 2 presented at 11 years of age with multiple vertebral fractures, femoral bowing and low bone mass.

Clonal sequencing of genomic DNA was performed using a custom designed OI gene panel. Iliac bone biopsy was obtained from case 2 to evaluate histomorphometry and bone mineralization density distribution (BMDD) by quantitative backscattered electron imaging.

A novel homozygous point mutation in TMEM38B (c.507G>A), predicted to result in a p.Trp169 nonsense change in exon 4 leading to nonsense mediated decay of the protein, was identified in both individuals. Bone histomorphometry revealed thin and isolated trabecular features covered by an extended area of thin osteoid layer, a paucity of osteoblasts and osteoclasts. Concomitantly, mineralizing surface was rather low and mineralizing lag-time prolonged. Bone cortex had normal lamellar pattern, thickness and haversian canals. BMDD was within normal range.

In conclusion, we describe a novel skeletal phenotype associated with bone fragility caused by a TMEM38B point mutation. In contrast to OI with collagen-gene mutations characterized by high bone turnover and abnormally high bone matrix mineralization, we observed in our patient rather low bone turnover and apparently normal bone matrix mineralization. The fact that there was no hypermineralization of the mineralized bone matrix is consistent with previous findings in OI cases lacking direct or indirect abnormalities in collagen type I. The exact role of TRIC-B in bone formation and OI pathogenesis remains to be elucidated.

Disclosure: The authors declared no competing interests.