In this study, we report a case involving an Indian family exhibiting features of TNHP. The proband, a term female neonate born to a consanguineous couple displayed diffuse osteopenia, bowing of ribs, narrow thorax, short bones, respiratory difficulty and fetal growth restriction. Genetic testing identified homozygous missense variant of TRPV6 in the proband, along with same heterozygous variant in both the parents.

TRPV6 variants are associated with TNHP, with total 11 cases documented in the literature across 5 studies (Table 1).

Neonatal hyperparathyroidism can be primary or secondary. Primary neonatal hyperparathyroidism is mostly caused by mutations in calcium sensing receptor (CASR) gene [7]. Secondary neonatal hyperparathyroidism can be caused by mutations in SLC12A1 gene encoding for sodium–potassium–chloride cotransporter-2 (NKCC2), mucolipidosis-II or maternal pseudohypoparathyroidism [8, 9]. Another variety of secondary neonatal hyperparathyroidism is linked with TRPV6 mutations. This variety is transient as it is due to poor placental transport of calcium leading to fetal calcium deficiency and features of hyperparathyroidism including biochemical and skeletal changes. TRPV6 is an energy-dependent calcium transport channel which facilitates active transport of maternal–fetal calcium against the gradient during antenatal period [1]. TRPV6 is a complex of four identical subunits; each subunit comprises of six transmembrane segments (S1–S6) forming an inwardly rectifying calcium channel [10]. This facilitates transcellular maternal–fetal calcium transport. This is the predominant mechanism of calcium transport across the placenta. After birth, paracellular non-energy-dependent calcium transport channel is the major mechanism of calcium transport across the intestine. Hence, the biochemical and skeletal changes in this condition normalize after postnatal calcium, phosphorus and vitamin D supplementation. There are several hotspots of TRPV6 mutations. Transmembrane segments S2–S3 and Ankyrin repeats are the major ones [10]. The biallelic mutations could be homozygous or compound heterozygous leading to loss of function of calcium transport channel. Table 1 displays the various reported variants of TRPV6. Clinical characteristics include antenatal polyhydramnios, narrow thoracic cavity, respiratory and feeding difficulties, diffuse defective bone mineralization, bowing of long bones, fractures, metaphyseal dysplasia and short stature with normal cognitive outcome. Biochemical abnormalities include low to normal calcium, low phosphorus, low vitamin D, high ALP and high PTH levels [2,3,4,5,6]. Postnatal supplementation with calcium, phosphorus and vitamin D (2000 IU/day) leads to gradual normalization of PTH and ALP levels and skeletal changes over a varying period of time (mostly by 1–2 years of age) [2,3,4,5,6]. Understanding the hotspots and variants of TRPV6 could raise the possibility of gene therapy by using small chaperones. Prenatal diagnosis of TRPV6 variant could help in deciding for the continuation of pregnancy with affected fetus, considering the transient nature of the condition as well as normal cognitive outcome in the affected individual. This also raises the possibility of intra-amniotic infusion of calcium in the affected pregnancy. However, this needs confirmation in large studies.

The current report broadens the genotypic spectrum of TNHP linked with TRPV6 variant. It also reviews the reported cases available in literature describing the variable clinical manifestations and time needed to normalize the skeletal changes associated with this condition.