Tertiary hyperparathyroidism in patients with pseudohypoparathyroidism type 1a.

Pseudohypoparathyroidism type 1a (PHP1a) is a genetic disorder caused by heterozygous loss-of-function mutations on the maternal allele of the GNAS gene. Patients with PHP1a predominantly exhibit parathyroid hormone (PTH) resistance and physical features of Albright's hereditary osteodystrophy. We report two unrelated cases with PHP1a who developed tertiary hyperparathyroidism (HPT). Molecular analyses of the GNAS gene identified a previously known heterozygous 4-bp deletion (c. 565_568delGACT) in exon 7 in case 1 and a novel heterozygous missense mutation (p.Lys233Glu) in exon 9 in case 2. Both patients developed tertiary HPT associated with hyperfunctioning parathyroid glands during long-term treatment of hypocalcemia. Case 1 had severe osteoporosis and underwent parathyroidectomy. Case 2 was asymptomatic with no evidence of bone diseases associated with tertiary HPT. PHP1a patients are at risk of developing tertiary HPT and should be treated with sufficient doses of calcium and vitamin D to achieve serum PTH levels within the mid - normal to double the upper limit of the normal range, regardless of serum calcium levels.

Pseudohypoparathyroidism type 1 B mimicking Fahr's disease in a 28-year-old female: A case report.

In virtue of precise clinical history, physical examinations, and biochemical/radiological investigations, pseudohypoparathyroidism can be effectively diagnosed, and its types can be differentiated even without exorbitant tests.

Lack of GNAS Remethylation During Oogenesis May Be a Cause of Sporadic Pseudohypoparathyroidism Type Ib.

CONTEXT: Pseudohypoparathyroidism type Ib (PHP1B) is characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone resistance in the proximal renal tubules. Maternal pathogenic STX16/GNAS variants leading to maternal epigenetic GNAS changes impair expression of the stimulatory G protein alpha-subunit (Gsα) thereby causing autosomal dominant PHP1B. In contrast, genetic defects responsible for sporadic PHP1B (sporPHP1B) remain mostly unknown. OBJECTIVE: Determine whether PHP1B encountered after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) causes GNAS remethylation defects similar to those in sporPHP1B. DESIGN: Retrospective analysis. RESULTS: Nine among 36 sporPHP1B patients investigated since 2000, all with loss of methylation (LOM) at the 3 maternal GNAS differentially methylated regions (DMRs) and gain of methylation at the paternal NESP DMR, had been conceived through IVF or ICSI. Besides abnormal GNAS methylation, IVF/ICSI PHP1B cases revealed no additional imprinting defects. Three of these PHP1B patients have dizygotic twins, and 4 have IVF/ICSI-conceived siblings, all with normal GNAS methylation; 2 unaffected younger siblings were conceived naturally. CONCLUSION: Sporadic and IVF/ICSI-conceived PHP1B patients revealed indistinguishable epigenetic changes at all 4 GNAS DMRs, thus suggesting a similar underlying disease mechanism. Given that remethylation at the 3 maternal DMRs occurs during oogenesis, male factors are unlikely to cause LOM postfertilization. Instead, at least some of the sporPHP1B variants could be caused by a defect or defects in an oocyte-expressed gene that is required for fertility and for re-establishing maternal GNAS methylation imprints. It remains uncertain, however, whether the lack of GNAS remethylation alone and the resulting reduction in Gsα expression is sufficient to impair oocyte maturation.

Pseudohypoparathyroidism: Focus on Cerebral and Renal Calcifications.

CONTEXT: Pseudohypoparathyroidism (PHP) is a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) levels as a result of end-organ resistance to PTH. OBJECTIVE: To describe a cohort of 26 patients with PHP followed in a single tertiary center. METHODS: Clinical, biochemical, radiological, and genetic analysis of the GNAS gene in 26 patients recruited since 2002. RESULTS: Ten patients harbored a GNAS mutation, 15 epigenetic abnormalities at the GNAS locus, and 1 did not show genetic or epigenetic abnormalities. According to clinical, biochemical, and genetic features, patients were classified as PHP1A, PHP1B, and pseudopseudohypoparathyroidism. Patients with PHP1A had an earlier diagnosis and more cases with family history, Albright hereditary osteodystrophy (AHO) features, hormonal resistance, and hypertension. Obesity was a common feature. No difference in biochemical values was present among PHP1A and PHP1B. Intracerebral calcification occurred in 72% of patients with no difference among PHP1A and PHP1B subgroups. No significant difference was observed between patients with and without intracerebral calcification for the time-weighted average values of total serum calcium, phosphate, calcium-phosphate product, and PTH fold increase. A borderline association between cerebral calcification and age at the time of diagnosis (P = .04) was found in the whole cohort of patients. No renal calcifications were found in the overall cohort. CONCLUSION: Patients with PHP1A more frequently have AHO features as well as hypertension than patients with PHP1B. Patients with PHP presented a high rate of intracerebral calcification with no significant difference between subgroups. No increased risk of renal calcifications was also found in the entire cohort.

High frequency of paternal iso or heterodisomy at chromosome 20 associated with sporadic pseudohypoparathyroidism 1B.

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.

Association of GNAS imprinting defects and deletions of chromosome 2 in two patients: clues explaining phenotypic heterogeneity in pseudohypoparathyroidism type 1B/iPPSD3.

BACKGROUND: The term pseudohypoparathyroidism (PHP) describes disorders derived from resistance to the parathyroid hormone. Albright hereditary osteodystrophy (AHO) is a disorder with several physical features that can occur alone or in association with PHP. The subtype 1B, classically associated with resistance to PTH and TSH, derives from the epigenetic dysregulation of the GNAS locus. Patients showing features of AHO were described, but no explanation for such phenotypic heterogeneity is available. An AHO-like phenotype was associated with the loss of genetic information stored in chromosome 2q37, making this genomic region an interesting object of study as it could contain modifier genes involved in the development of AHO features in patients with GNAS imprinting defects. The present study aimed to screen a series of 65 patients affected with GNAS imprinting defects, with or without signs of AHO, for the presence of 2q37 deletions in order to find genes involved in the clinical variability. RESULTS: The molecular investigations performed on our cohort of patients with GNAS imprinting defects identified two overlapping terminal deletions of the long arm of chromosome 2. The smaller deletion was of approximately 3 Mb and contained 38 genes, one or more of which is potentially involved in the clinical presentation. Patients with the deletions were both affected by a combination of the most pathognomic AHO-like features, brachydactyly, cognitive impairment and/or behavioural defects. Our results support the hypothesis that additional genetic factors besides GNAS methylation defects are involved in the development of a complex phenotype in the subgroup of patients showing signs of AHO. CONCLUSIONS: For the first time, the present work describes PHP patients with hormone resistance and AHO signs simultaneously affected by GNAS imprinting defects and 2q37 deletions. Although further studies are needed to confirm the cause of these two rare molecular alterations and to identify candidate genes, this finding provides novel interesting clues for the identification of factors involved in the still unexplained clinical variability observed in PHP1B.

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

Pseudohypoparathyroidism (PHP) is a rare group of disorders characterised by end-organ resistance to the parathyroid hormone (PTH). A 16-year-old boy presented with a 2-year history of involuntary dystonic movements involving mainly the left hand, initially after writing and later during physical exercise. Serum calcium was 1.37 mmol/L (2.20-2.69), phosphate 2.1 mmol/L (0.8-1.45) and PTH 302 ng/L (12-88). CT scan of the head demonstrated multiple subcortical and diffuse basal ganglia calcifications. Genetic analysis confirmed a methylation defect in the GNAS cluster on chromosome 20q13.32 which established the diagnosis. Treatment with calcitriol and calcium carbonate led to complete remission of symptoms. Causes of hypocalcaemia should be considered in evaluating patients with movement disorders. The diagnosis of PHP-1B is challenging but the overall prognosis is excellent.

Pseudohypoparathyroidism: one gene, several syndromes.

Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several sites. GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Heterozygous inactivating mutations involving the maternal GNAS exons 1-13 cause PHP type Ia (PHP1A). Because of much reduced paternal Gsα expression in certain tissues, such as the proximal renal tubules, thyroid, and pituitary, there is little or no Gsα protein in the presence of maternal GNAS mutations, thus leading to PTH-resistant hypocalcemia and hyperphosphatemia. When located on the paternal allele, the same or similar GNAS mutations are the cause of PPHP. Besides biochemical abnormalities, patients affected by PHP1A show developmental abnormalities, referred to as Albrights hereditary osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who typically show no laboratory abnormalities. Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss-of-methylation (LOM) at exon A/B alone or at all maternally methylated GNAS exons. LOM at exon A/B and the resulting biallelic expression of A/B transcripts reduces Gsα expression, thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, the most frequent disease variant, which remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q).