Pseudohypoparathyroidism (PHP) is a rare disorder characterized by convulsions, tetany, and sensory abnormalities caused by hypocalcemia due to parathyroid hormone (PTH) resistance. Only few patients present with involuntary movements. We report the case of a 7-yr-old girl with PHP and involuntary movements triggered by running. Initially, she was suspected of having paroxysmal kinesigenic dyskinesia and was treated with carbamazepine (CBZ). Involuntary movements were reduced. However, 2 months post-treatment, she experienced convulsions during a fever. Blood tests and brain computed tomography revealed hypocalcemia, hyperphosphatemia, elevated intact PTH, and calcifications in the frontal cortex and basal ganglia. The patient showed no features of Albright\'s hereditary osteodystrophy. The involuntary movements disappeared after the discontinuation of CBZ and initiation of calcium and active vitamin D preparations. Methylation-specific multiplex ligation-dependent probe amplification for the GNAS region and microsatellite analysis of chromosome 20 led to the diagnosis of PHP1B caused by epimutation. In 15 reported cases, with or without intracranial calcification, PHP-associated involuntary movements disappeared or became less severe with treatment for hypocalcemia; in eight of 11 cases, they were triggered by exercise or movement. PHP-associated hypocalcemia can trigger exercise-induced involuntary movements owing to lowered serum ionized calcium levels. In such patients, early blood tests are vital for the differential diagnosis of PHP.

Pseudohypoparathyroidism 1B (PHP1B) is caused by maternal epigenetic defects in the imprinted GNAS cluster. PHP1B can follow an autosomal dominant mode of inheritance or occur sporadically (spor-PHP1B). These latter patients present broad methylation changes of two or more differentially methylated regions (DMR) that, when mimicking the paternal allele, raises the suspicious of the occurrence of paternal uniparental disomy of chromosome 20 (upd(20)pat). A cohort of 33 spor-PHP1B patients was screened for upd(20)pat using comparative genomic hybridization with SNP-chip. Methylation analyses were assessed by methylation specific-multiplex ligation-dependent probe amplification. Upd(20)pat was identified in 6 patients, all exhibiting typical paternal methylation pattern compared to normal controls, namely a complete loss of methylation of GNAS A/B:TSS-DMR, negligible methylation at GNAS-AS1:TSS-DMR and GNAS-XL:Ex1-DMR and complete gain of methylation at GNAS-NESP:TSS-DMR. The overall frequency of upd(20) is 18% in our cohort when searched considering both severe and partial loss of imprinting. However, twenty five patients displayed severe methylation pattern and the upd(20)pat frequency reaches 24% when searching in this group. Consequently, up to day, upd(20)pat is the most common anomaly than other genetic alterations in spor-PHP1B patients. Upd(20)pat occurrence is not linked to the parental age in contrast to upd(20)mat, strongly associated with an advanced maternal childbearing age. This study provides criteria to guide further investigations for upd(20)pat needed for an adequate genetic counseling.

Bone responsiveness to serum parathyroid hormone (PTH) in pseudohypoparathyroidism 1B (PHP1B) is controversial. Forty-eight PHP1B patients diagnosed by molecular analysis were recruited from 2000 to 2016 from the Peking Union Medical College Hospital. Fifty-five sex-matched nonsurgical hypoparathyroidism (NS-HP) patients were selected and included for comparison. Basic information, laboratory test, and dual-energy X-ray absorptiometry (DXA) results were collected. Linear regression was performed to identify independent predictors of lumbar spine (LS), femoral neck (FN), and total hip (TH) bone mineral density (BMD) Z-scores in PHP1B patients. BMD and related markers were compared between PHP and NS-HP patients. Longitudinal observation of 10 PHP1B patients was performed. The BMD Z-score for the LS (1.14 ± 1.41) was higher than that for the FN (-0.20 ± 1.00, p < 0.001) and the TH (0.03 ± 1.06, p < 0.001) in PHP1B patients. Despite lower serum calcium levels in untreated patients (1.72 mmol/L in untreated patients versus 2.14 mmol/L in treated patients, p = 0.024), the PTH levels as well as BMD Z-scores were comparable between treated and untreated patients at baseline. PTH was a negative predictor for LS-BMD Z-score (B = -0.004, p = 0.028) for sporadic PHP1B patients, and a similar result was obtained for all the PHP1B patients (B = -0.002, p = 0.053). Z-scores for FN- and LS-BMDs after treatment increased by 0.31 ± 0.10 and 0.58 ± 0.12, respectively, where the increase in LS-BMD correlated with a decrease in PTH (r = -0.72, p = 0.044). All BMD Z-scores were significantly lower in PHP1B patients than in IHP patients for the FN, LS, and TH (-0.20 ± 1.00 versus 1.57 ± 1.07, 1.14 ± 1.41 versus 1.96 ± 1.32, 0.03 ± 1.06 versus 1.67 ± 1.01, respectively, all p < 0.05). Skeletal tissue in PHP1B patients responds to PTH, where heterogenous sensitivities to PTH may exist in different regions of bone. Therefore, it is reasonable to normalize PTH levels when treating PHP1B to avoid negative effects of PTH on bone. © 2017 American Society for Bone and Mineral Research.