偽性副甲状腺機能低下症

Pseudohypoparathyroidism is a really rare inherited disorder characterized by either unresponsiveness or targeted organ resistance to the parathyroid hormone, classified either biochemically or by phenotype characteristics. Here, we report an atypical presentation of Albright hereditary osteodystrophy. An underweight 18-year-old male presented with painful subcutaneous nodules that progressively appeared over a period of 10 years and were confirmed by fine needle aspiration, and the pathology report indicated osteoma cutis.

Pseudohypoparathyroidism type 1A (PHP1A) is an uncommon inherited condition caused by loss‑of‑function mutations in the guanine nucleotide-binding protein, alpha-stimulating activity polypeptide (GNAS) gene, which results in hormone resistance to parathyroid hormone (PTH) and other hormones that signal through the stimulatory alpha subunit of the G protein (Gsα). The disorder is classically associated with Albright hereditary osteodystrophy (AHO), although marked phenotypic and biochemical variability has been increasingly recognized, particularly in children. We report three siblings from an Omani family diagnosed with PHP1A, aged 2.6-9 years, demonstrating substantial intrafamilial heterogeneity. The eldest sibling presented with severe multisystem involvement, including congenital aortic stenosis, extensive osteoma cutis, and neurocognitive impairment. The proband had a more classical endocrine phenotype with progressive PTH elevation and symptomatic soft tissue ossifications. The youngest sibling was identified through family screening during infancy and remained largely asymptomatic despite evolving biochemical abnormalities. All siblings demonstrated characteristic AHO features including round facies, brachydactyly, and shortening of the fourth and fifth metacarpals and metatarsals. Longitudinal biochemical evaluation showed progressive PTH elevation with persistent normocalcemia and hyperphosphatemia. Genetic testing in one sibling confirmed a heterozygous pathogenic GNAS mutation. This familial case series highlights the broad phenotypic spectrum and dynamic biochemical evolution of PHP1A. AHO manifestations may precede overt biochemical abnormalities for several years, particularly during childhood. Recognition of subtle early features, proactive family screening, and longitudinal biochemical monitoring are essential for timely diagnosis and management.

Genetic defects in GNAS on the maternal allele cause pseudohypoparathyroidism type 1A (PHP1A) with PTH resistance. Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome caused by aberrant methylation in the KCNQ1OT1:transcription start site (TSS)-differentially methylated region (DMR). PHP1A and BWS exhibit postnatal overgrowth. Recently, multi-locus imprinting disturbance (MLID) has been observed in cases with BWS. Deleterious variants in genes encoding proteins that maintain CpG methylation at DMRs have been found in MLID cases and/or their mothers, and ZAR1 is supposed to be one of the MLID causative genes. In this study, we identified a patient with a deletion involving Gsα-coding region and MLID including hypomethylation of the KCNQ1OT1:TSS-DMR by genome-wide copy number variation analysis, genome-wide methylation analysis, and whole-exome sequencing. The patient's mother had a deletion of the same region on the paternal allele and carried a ZAR1 missense variant considered benign. The patient exhibited severe infantile obesity with a body mass index greater than 33 kg/m2 and PTH resistance due to the comorbidity of PHP1A and MLID including hypomethylation of the KCNQ1OT1:TSS-DMR. This study highlights the importance of screening for PHP1A and imprinting disorders with overgrowth, in cases with severe infantile obesity, and for MLID causative genes in MLID cases.

The parental imprinted GNAS complex locus encodes the α-subunit of the stimulatory G protein. Pseudohypoparathyroidism type Ib (PHP1B) is characterized by renal resistance to parathormone and is caused by epigenetic anomalies, ie, at least the loss of methylation (LOM) at the A/B differentially methylated region (DMR). LOM or gain of methylation (GOM) may also affect other DMRs and different transcripts expressions within the locus (NESP, exon H, AS1, XLαs, A/B). Most PHP1B are sporadic and result from abnormal methylation of all DMRs in the regulatory region of GNAS. Autosomal dominant PHP1B (AD-PHP1B) is usually caused by a recurrent STX16 gene microdeletion in the maternal allele which leads to isolated LOM at the A/B DMR. In this study, we investigated an AD-PHP1B family without STX16 deletion using whole genome sequencing (WGS). The two affected siblings presented a LOM at the A/B DMR and the half telomeric portion of the XLαs DMR and their healthy mother presented a partial GOM at the AS1 DMR and the half centromeric portion of the XLαs DMR. The WGS analysis revealed a 140-kb paracentric inversion with breakpoints located in the NPEPL1 gene and XLαs DMR. We identified the first inversion involving the regulatory region of GNAS locus leading to a maternally inherited AD-PHP1B. This observation provides additional insight into the methylation regulatory elements in the GNAS locus on both alleles, especially on NESP and exon H transcription-mediated methylation. This study will help design subsequent strategies for further studies.

Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders defined by resistance to parathyroid hormone (PTH), typically stemming from GNAS locus abnormalities. This report describes an unusual case of a 32-year-old Han Chinese male with sporadic PHP Type 1B (PHP1B) who presented with paroxysmal numbness and significant hypokalemia. Despite elevated PTH levels, the patient maintained normocalcemia and showed no evidence of globus pallidus calcification on brain imaging. Diagnosis was confirmed using methylation-specific multiplex ligation-dependent probe amplification, which identified characteristic GNAS imprinting defects: a gain of methylation at the NESP55 exon and loss of methylation at the AS, XL, and A/B exons. With a normal copy number, no detectable GNAS mutations, and a negative family history, the case was classified as sporadic PHP1B. This rare presentation highlights the broad phenotypic spectrum of PHP and emphasizes the clinical importance of monitoring diverse electrolyte disturbances, such as hypokalemia, even when calcium levels appear normal.