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We report a case of pseudohypoparathyroidism type 1b (PHP1b) manifesting in childhood with hypocalcemic seizures. Symptomatic hypocalcemia is a common emergency in the pediatric age group with vitamin D deficiency being a frequent underlying etiology and PHP is rare. Patients with PHP1b do not depict the Albright’s hereditary osteodystrophy (AHO) phenotype typical of patients with PHP1a and pseudopseudohypoparathyroidism (PPHP). The resistance to parathyroid hormone (PTH) is documented mostly at renal tubular site of action in patients with PHP1b. Hypothyroidism is reported occasionally, signifying resistance to thyroid-stimulating hormone (TSH). Individuals with autosomal dominant and maternally inherited form of PHP harbor methylation defects at GNAS exon A/B, while sporadic and non-familial cases harbor methylation defects at other locus sites, including differentially methylated regions (GNAS-DMR). A novel heterozygous stop gain mutation c.C910T/p.Arg304X in exon 8 of the STX16 gene (Syntaxin 16) was observed in our case. Resistance seems limited to the renal action of PTH alone as currently, TSH level is normal. Maternal STX16 gene analysis results confirmed the modality of inheritance.

We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carried pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity, using an inhouse computational staged approach. This included analysis of whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistani PROMIS study, and 200K participants of the UK Biobank, to prioritize genes harbouring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding Prolyl 4-Hydroxylase Transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment and/or developmental delay. Three of the five probands died of pneumonia during the ∼2 years of the follow up. P4HTM deficiency is a novel form of syndromic obesity affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia inducible factor that is necessary for survival and adaptation under oxygen deprivation but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated.

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