Pseudohypoparathyroidism type I‐b with neurological involvement is associated with a homozygous PTH1R mutation

Abstract

Pseudohypoparathyroidism type 1b (PHP1b) is characterized by hypocalcemia, hyperphosphatemia, increased levels of circulating parathyroid hormone (PTH), and no skeletal or developmental abnormalities. The goal of this study was to perform a full characterization of a familial case of PHP1b with neurological involvement and to identify the genetic cause of disease. The initial laboratory profile of the proband showed severe hypocalcemia, hyperphosphatemia and normal levels of PTH, which was considered to be compatible with primary hypoparathyroidism. With disease progression the patient developed cognitive disturbance, PTH levels were found to be slightly elevated and a picture of PTH resistance syndrome seemed more probable. The diagnosis of PHP1b was established after the study of family members and blunted urinary cAMP results were obtained in a PTH stimulation test. Integration of whole genome genotyping and exome sequencing data supported this diagnosis by revealing a novel homozygous missense mutation in PTH1R (p.Arg186His) completely segregating with the disease. Here, we demonstrate segregation of a novel mutation in PTH1R with a phenotype of PHP1b presenting with neurological symptoms, but no bone defects. This case represents the extreme end of the spectrum of cognitive impairment in PTH dysfunction and defines a possible novel form of PHP1b resulting from the impaired interaction between PTH and PTH1R.

Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism

“…This interpretation is consistent with the hypothesis that the R186H mutation in vivo causes a selective deficiency in responsiveness to endogenous PTH but not PTHrP. (19) Somewhat surprisingly, we found that the PTH1R-R186H mutant exhibited a more significant reduction in cAMP signaling response potency to PTHrP than to PTH . The reason for this apparent change in the relative impact of the receptor mutation on the interaction with the C-terminally truncated PTH and PTHrP(1-28) fragment peptides, as compared to the relative impact seen with the intact PTH and PTHrP (1-36) peptides, is not clear.…”

“…distinct patient phenotypes-a hypocalcemia/hyperphosphatemia phenotype similar to that seen pseudohypoparathyroidism type 1b (PHP1B) for R186H (19) and a skeletal/dental phenotype for V204E in which the PFE appears similar to that seen in patients with Eiken syndrome caused by other homozygous PTH1R missense mutations. (17,18,21) The structural model of the PTH1R-ligand complex shown in Fig.…”

Clinical and genetic characteristics of Pseudohypoparathyroidism in the Chinese population

“…Overlapping 4.4, 18.6 and 24.6 kb STX16 deletions and deletions involving NESP and AS that affect either GNAS A/B:TSS‐DMR alone or all four DMRs have also been reported in PHP1B families . Interestingly, the PTH receptor was not considered the candidate causative gene of PHP until recent confirmation demonstrating it as a cause of familial PHP1B in one family …”

Pseudohypoparathyroidism type 1B – a rare cause of tetany: case report

“…Pseudohypoparathyroidism (PHP) is an heterogeneous group of disorders characterised by hypocalcaemia and hyperphosphataemia resulting from end-organ resistance to parathyroid hormone (PTH) [1][2][3][4][5][6][7][8][9]. It is a rare disease with an estimated prevalence worldwide of approximately 7.9 cases per million [1,8].…”

“…Since parathyroid action is only affected at the renal proximal tubule level, some individuals are asymptomatic and may show only mild elevation of PTH as evidence of hormone resistance [2,10,11,14]. However, at some point, most patients present with hypocalcaemia and develop symptoms such as tetany, muscle spasms or even seizures [2,5,11]. No deletion in the STX16 region (upstream of the GNAS cluster) was detected.…”