ESPE Abstracts

Background: Fetal skeletal bone development and mineralisation depends on placental calcium transfer. Although Parathyroid Hormone (PTH) pathway has some contribution, TRPV6 (the sixth member of the Transient Receptor Potential Vanilloid family) is a recently identified receptor involved in calcium transport and is predominantly expressed in the placenta. It has not previously been linked with skeletal development disorders.

Case: This infant had thoracic insufficiency with significant skeletal and biochemical abnormalities. Pregnancy featured polyhydramnios. Antenatal ultrasound identified a small chest, unusual rib configuration and short long bones. Antenatal CGH array and UPD14 testing showed no abnormalities. Delivery was by emergency caesarean due to fetal distress. Intubation and ventilation was required from birth. Conventional mechanical ventilation with maximal pressures of 30 cmsH20 and FiO2 0.6 was needed, followed by tracheostomy for long term ventilation. Postnatal skeletal survey showed generalised marked under-mineralisation, bell-shaped chest, fractures of ribs and metaphyses and extensive periosteal thickening of femoral, tibial and humeral diaphyses. Biochemistry featured markedly elevated PTH (53.4 progressing to 101 pmol/l), predominantly normocalcaemia (corrected calcium 2.43 mmol/l), although transient mild hypocalcaemia and hypophosphataemia weeks 3–4, normal ALP (289 IU/l), normal urinary Calcium/Creatinine ratio (1.05), Vitamin D insufficiency (29 nmol/l). Parental biochemistry was normal. PTH elevation with periosteal reaction suggested Neonatal Severe Hyperparathyroidism (NSHPT), although the absence of hypercalcaemia was uncharacteristic. Treatment of the metabolic bone abnormality included pamidronate, cinacalcet (calcimimetic), calcium and Vitamin D supplementation. NSHPT was subsequently excluded as molecular genetic analysis found no causative variants in CASR, GNA11, APS21; Mucolipidosis Type II also excluded biochemically and genetically (GNPTG). The significant skeletal abnormalities were investigated by whole exome sequencing (WES) and no abnormalities were found using a 336 gene skeletal dysplasia panel. Meanwhile, resolution of biochemical abnormalities and progressive mineralisation radiologically was evident by 8 weeks. This changing clinical picture suggested an alternative hypothesis of an in utero pathology with normalisation ex utero. Consequently, placental calcium transfer candidate genes TRPV6, CABP9K and VDR were explored. Trio exome analysis identified compound heterozygous TRPV6 likely pathogenic variants: a novel maternally inherited missense variant, c.1978G>C p.(Gly660Arg), and a paternally inherited nonsense variant, c.1528C>T p.(Arg510Ter), confirming recessive inheritance of this novel dysplasia.

Conclusion: We report the first case of TRPV6 compound heterozygous variants in a novel dysplasia. This rare bone disease case illustrates that astute clinical interpretation of evolving perinatal abnormalities remains valuable in complex calcium and bone pathophysiology and informs whole exome sequence interpretation.