Endocrine Abstracts

A 24-year-old male was referred to endocrinology with multiple severe atraumatic vertebral fractures. In the preceding 10 years the patient had experienced a bimalleolar ankle fracture and numerous metacarpal and metatarsal breakages unrelated to trauma. There was no family history of osteoporosis and examination did not reveal any abnormalities in scleral colour, stature, dentition or facial/thoracic morphology. Dual-energy x-ray absorptiometry demonstrated severe densitometric spinal osteoporosis with a Z score of -4.5 (T score: -4.2). Bone mineralisation density (BMD) was estimated to be 44% below average for age. Femoral neck and total hip Z scores were -1.8 and -3.1, respectively. No disorders of calcium or phosphate homeostasis, thyroid disease, hypogonadism, malabsorption, or myeloma were identified, although 25-hydroxy vitamin D was deficient (22 nmol/l). C-terminal telopeptide (CTX) was elevated (0.95 mg/l) signifying increased bone turnover. DNA was extracted and demonstrated a novel hemizygous X-chromosome plastin 3 (PLS3) sequence variant (c.892-2A>G), which is predicted to abolish the acceptor splice site. PLS3 mutations are associated with X-linked male osteoporosis, however, the mechanism responsible is unclear. PLS3 is integral to cytoskeletal actin bundle formation and these variants may facilitate dysregulated osteocyte mechanosensing signalling pathways responsible for bone homeostasis. We report a previously unrecognised PLS3 splice variant (c.892-2A>G) responsible for the development of X-linked male osteoporosis. Subsequent cascade genetic testing confirmed the patient’s mother, who has normal BMD, to be a homozygous carrier, while the patient’s brother, who has significant history of fragility fractures, is heterozygous for this variant and awaiting densitometric assessment. Therefore, genetic analysis of PLS3 should be considered in all young men with evidence of bone fragility to facilitate the timely identification of osteoporosis aetiology and management of patients and affected family members. Moreover, further research is required to understand the role of PLS3 in bone health and disease.