Pseudohypoparathyroidism Research Articles

Pseudohypoparathyroidism - epidemiology, mortality and risk of complications.

Pseudohypoparathyroidism (PHP) is caused by a mutation within the GNAS gene or upstream of the GNAS complex locus. It is characterized by target organ resistance to PTH, resulting in hypocalcaemia and hyperphosphataemia. Studies in patients with PHP are limited. We sought to identify all patients in Denmark with PHP and access their mortality data and risk of complications. Patients were identified through the Danish National Patient Registry and a prescription database, with subsequent validation by investigation of patient charts. For each case, three age- (±2 years) and gender-matched controls were randomly selected from the general background population. We identified a total of 60 cases, equal to a prevalence of 1·1/100 000 inhabitants. The average age at diagnosis was 13 years (range 1-62 years), and 42 were women. Only 14 patients had an identified mutation in the GNAS1 gene. Compared with controls, patients with PHP had an increased risk of neuropsychiatric disorders (P < 0·01), infections (P < 0·01), seizures (P < 0·01) and cataract (P < 0·01), whereas their risk of renal, cardiovascular, malignant disorders and fractures was compatible with the general background population. The same tendencies were found in a subgroup analysis in cases with genetically verified PHP. Patients with PHP have an increased risk of neuropsychiatric disorders, infections, cataract and seizures, whereas mortality among PHP patients is compatible with that in the background population.

Pseudohypoparathyroidism: a case of delayed diagnosis

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Progress of diagnosis and clinical management of pseudohypoparathyroidism

Pseudohypoparathyroidism(PHP) is a rare genetic disorder.The main character is parathyroid hormone resistance, and some with typical Albright's Hereditary Osteodystrothy malformation.The wide range of PHP symptom spectrum may lead to miss or misdiagnosis.This paper reviewed and summarized the pathogenesis, manifestation and the progress on the diagnosis and treatment of PHPⅠ, so as to improve the diagnostic level of this disease. Key words: Pseudohypoparathyroidism; Albright's hereditary osteodystrothy; Hypocalcemia; GNAS1 gene; Diagnosis; Treatment

Mutations paternelles de GNAS : quels phénotypes ? Quel conseil génétique ?

Parental imprinting and the type of the genetic alteration play a determinant role in the phenotype expression of GNAS locus associated to pseudohypoparathyroidism (PHP). GNAS locus gives rise to several different messenger RNA transcripts that are derived from the paternal allele, the maternal allele, or both and can be either coding or non-coding. As a consequence, GNAS mutations lead to a wide spectrum of phenotypes. An alteration in the coding sequence of the gene leads to a haplo-insufficiency and a dysmorphic phenotype (Albright's syndrome or AHO). AHO is a clinical syndrome defined by specific physical features including short stature, obesity, round-shaped face, subcutaneous ossifications, brachymetarcapy (mainly of the 4th and 5th ray). If the alteration is on the maternal allele, there is a hormonal resistance to the PTH at the kidney level and to the TSH at the thyroid level. The phenotype is known as pseudohypoparathyroidism type 1a (PHP1a). If the alteration is on the paternal allele, there are few clinical signs with no hormonal resistance and the phenotype is known as pseudopseudo hypoparathyroidism (pseudo-PPHP). Heterozygous GNAS mutations on the paternal GNAS allele were associated with intra uterin growth retardation (IUGR). Moreover, birth weights were lower with paternal GNAS mutations affecting exon 2-13 than with exon 1/intron 1 mutations suggesting a role for loss of function XLαs. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, characterized by cutaneous and subcutaneous ossifications progressing towards deep connective and muscular tissues. POH is caused by a heterozygous GNAS inactivating mutation and has been associated with paternal inheritance. However, genotype/phenotype correlations suggest that there is no direct correlation between the ossifying process and parental origin, as there is high variability in heterotopic ossification. Clinical heterogeneity makes genetic counseling a very delicate matter, specifically where paternal inheritance is concerned as it can lead either to a mild expression of pseudo-PHP or to a severe one of POH.

Pseudohypoparathyroidism: phenotypic spectrum in kindred

Pseudohypoparathyroidism (PHP) encompasses a heterogeneous group of disorders due to an inactivating mutation in the GNAS gene which encodes the α subunit of Gs proteins (Gsα). Gsα plays a crucial role in intracellular signal transduction of peptides, hormones and neurotransmitter receptors in multiple tissues. Key features of PHP include Albright Hereditary Osteodystrophy (AHO) and biochemical evidence of multiple hormone resistances. There are several conflicting mechanisms for its heterogeneity; a possible explanation is a tissue-specific differential imprinting of Gsα protein. PHP type1a has AHO with multiple hormone resistance and is inherited as maternal imprinting defect. PHP type 1b presents with hormone resistance but no AHO features and is probably due to epigenetic methylation defects. Peudopseudohypoparathyroidism is another subtype with AHO but absence of hormone resistance and is inherited as paternal inactivating mutation. We describe a family with female members having PHP with variable clinical and biochemical features. Two female siblings from non-consanguineous parents, patient A (15 year) & patient B (13 year) presented at birth with raised TSH levels and were diagnosed to have congenital hypothyroidism and treated with thyroxine replacement. Patient A was noted to have infantile obesity with short stature and evolving phenotypic features consistent with AHO. Further history revealed that her sister patient B has similar phenotypic appearance and was confirmed on clinical exam. Biochemical evaluation for Patient A showed a borderline low calcium and normal phosphate level with elevated PTH while Patient B had normal calcium and phosphate levels with high PTH. Both patients entered puberty at 11 years and patient A progressed to breast tanner 4 but has no menarche at 15 years despite pubertal gonadotropin levels (Table ​(Table1),1), advanced bone age (18 years) & mature uterus. Patient B is currently 12.5 years old and has progressed to tanner 3 breasts with no menarche. Mother exhibits features of AHO without hormone resistance. The father and younger brother do not have any features of AHO. Table 1 The two patients with PHP described above had an interesting presentation as congenital hypothyroidism with features of AHO evolving later in life. They exhibit clinical evidence of maternal transmission with end-organ resistance. This family illustrates heterogeneity of presentation of GNAS mutation. Written informed consent was obtained from the patients for publication of this abstract. A copy of the written consent is available for review by the Editor of this journal.

Monitoring of hypo- and pseudohypoparathyroidism

Monitoring of hypo- and pseudohypoparathyroidism

Case Report of GNAS Epigenetic Defect Revealed by a Congenital Hypothyroidism

Pseudohypoparathyroidism (PHP) is a group of disorders characterized by end-organ resistance to the parathyroid hormone (PTH). PHP type 1A includes multihormone resistance syndrome, Albright's hereditary osteodystrophy, and obesity and is caused by mutations in GNAS exon 1 through 13. PHP type 1B (PHP1B), caused by epigenetic changes in the GNAS locus, was initially described as an isolated resistance to PTH. Epigenetic changes in GNAS have also been reported in patients who display mild Albright's hereditary osteodystrophy or mild thyroid-stimulating hormone (TSH) resistance without mutation of GNAS. Here we report a case of PHP caused by epigenetic changes in GNAS in a patient with congenital hypothyroidism. The patient was referred for a positive newborn screening for hypothyroidism (TSH 50 mIU/L). She exhibited severe clinical features of congenital hypothyroidism. The thyroid was in place, and etiologic explorations were negative. TSH was normalized under L-thyroxin, and the symptoms disappeared, except for a macroglossia. In childhood, PHP was suspected in addition to elevated PTH, obesity, brachydactyly, and a rounded face. Sequencing, methylation analysis, and large deletion research were performed in GNAS. No genetic mutations were found. Methylation analysis revealed a broad epigenetic defect without deletion in GNAS consistent with sporadic PHP1B. The multilocus methylation analysis were negative. This finding expands the known onsets of PHP1B and emphasizes the need for a new PHP classification system. This case report has important consequences for the etiologic diagnosis of congenital hypothyroidism because it adds a new cause of the disease.

Loss of Methylation at GNAS Exon A/B Is Associated With Increased Intrauterine Growth

GNAS is one of few genetic loci that undergo allelic-specific methylation resulting in the parent-specific expression of at least four different transcripts. Due to monoallelic expression, heterozygous GNAS mutations affecting either paternally or maternally derived transcripts cause different forms of pseudohypoparathyroidism (PHP), including autosomal-dominant PHP type Ib (AD-PHP1B) associated with loss of methylation (LOM) at exon A/B alone or sporadic PHP1B (sporPHP1B) associated with broad GNAS methylation changes. Similar to effects other imprinted genes have on early development, we recently observed severe intrauterine growth retardation in newborns, later diagnosed with pseudopseudohypoparathyroidism (PPHP) because of paternal GNAS loss-of-function mutations. This study aimed to determine whether GNAS methylation abnormalities affect intrauterine growth. Birth parameters were collected of patients who later developed sporPHP1B or AD-PHP1B, and of their healthy siblings. Comparisons were made to newborns affected by PPHP or PHP1A. As newborns, AD-PHP1B patients were bigger than their healthy siblings and well above the reference average; increased sizes were particularly evident if the mothers were unaffected carriers of STX16 deletions. SporPHP1B newborns were slightly above average for weight and length, but their overgrowth was less pronounced than that of AD-PHP1B newborns from unaffected mothers. LOM at GNAS exon A/B due to maternal STX16 deletions and the resulting biallelic A/B expression are associated with enhanced fetal growth. These findings are distinctly different from those of PPHP patients with paternal GNAS exons 2-13 mutations, whose birth parameters are almost 4.5 z-scores below those of AD-PHP1B patients born to healthy mothers.

Diagnosis and Management of Congenital Hypothyroidism Associated with Pseudohypoparathyroidism

Hypothyroidism is a particular condition observed in pseudohypoparathyroidism (PHP), a rare disorder characterized by parathyroid (PTH) resistance leading to hypocalcemia and hyperphosphatemia associated with a GNAS (guanine nucleotide-binding protein α-subunit) mutation (PHP1A) or epimutation (PHP1B). To determine the presence of hypothyroidism at birth we conducted a retrospective study in our cohort of patients presenting with either PHP1A (n = 116) or PHP1B (n = 99). We also investigated patients presenting at birth with congenital hypothyroidism (CH) and a eutopic thyroid gland for phosphocalcium abnormalities suggesting PTH resistance and PHP. Our study reveals CH as the earliest diagnostic clue for PHP1A, but not for PHP1B. We estimated the frequency of CH at birth to be between 8 and 34% in patients presenting with PHP1A. The elevation of phosphatemia and PTH concentration precedes hypocalcemia in PHP1A. Conversely, the frequency of PHP1A in patients presenting CH is dramatically low. This may be due to the low prevalence of PHP1A which remains unknown. Conclusions: Subclinical and overt hypothyroidism can occur in PHP1A patients at birth many years before PTH resistance becomes clinically apparent. Although such cases appear to be rare, some pediatric patients with unexplained CH are likely to benefit from measuring calcium, phosphorus, and PTH for extended periods of time.

Hypocalcemia caused by type 1b pseudohypoparathyroidism

Hypocalcemia caused by type 1b pseudohypoparathyroidism

Albright Hereditary Osteodystrophy: A Case Report

A dental practitioner with an eagle's eye can diagnose many hidden disease through careful examination of the oral cavity. One such hereditary metabolic disorder is Albright hereditary osteodystrophy (AHO). Characteristic presentations in an individual affected by AHO were short stature, obesity and brachydactyly especially of 4(th) and 5(th) digits, which are the phenotypic features of genetic mutation. Pseudohypoparathyroidism (PHP) is characterized by inability of the body to respond appropriately to parathormone, mainly characterized by hypocalcemia, increased serum parathormone concentration, insensitivity to the biological activity of parathormone and hyperphosphatemia. AHO when seen in association with resistance to parathormone (PTH), it is called PHP. Here is, a case report of 32-year-old male patient with AHO with distinctive physical characteristics and oral manifestations.

Pseudohypoparathyroidism type 1a in pregnancy

Pseudohypoparathyroidism (PHP) refers to end-organ resistance that impairs the renal actions of the parathyroid hormone (PTH). PHP-1a, inherited as an autosomal dominant trait, is characterised by ...

Approach to the type pseudohypoparathyroidism I b patient with multiple endocrine dysfunctions and multiple organ abnormalities

[Summary] A 24 years old male patient with growth retardation revealed,anemia,obvious fluctuation of serum calcium,phosphorus and intact parathyroid hormone and obvious elevation of adrenocorticotropic hormone (ACTH) and gonadotropin.The dysplasia of adrenal gland,testis and skeleton,accompanied with pulmonary hypertension were shown by the imaging examination.The gene test showed loss of exon 1 A methylation,the patient was diagnosed as a case of pseudohypoparathyroidism (PHP) Ⅰ b.This case suggests that a new patient with growth retardation should be approached with the possibility of PHP,with regard of complicated clinical manifestation and needs further gene testing. Key words: Pseudohypoparathyroidism; GNASI gene ; Calcium/phosphorus; Methylation specific polymerase chain reaction

Clinical Characterization and Molecular Classification of 12 Korean Patients with Pseudohypoparathyroidism and Pseudopseudohypoparathyroidism

Pseudohypoparathyroidism (PHP) is defined as resistance toward parathyroid hormones. PHP and pseudopseudohypoparathyroidism (PPHP) are rare disorders resulting from genetic and epigenetic aberrations within or upstream of the GNAS locus. This study investigated the clinical characteristics and performed a molecular analysis of PHP and PPHP. A total of 12 patients with (P)PHP from 11 unrelated families (4 with PHP-Ia, 6 with PHP-Ib, and 2 with PPHP) were characterized using both clinical and molecular methods. Clinical features included the presenting symptoms, Albright hereditary osteodystrophy features, and resistance to hormones. Comprehensive analysis of the GNAS and STX16 loci was undertaken to investigate the molecular defects underlying (P)PHP. All PHP-Ib patients displayed hypocalcemic symptoms. All PHP-Ia patients showed resistance toward TSH, in addition to PTH. In most patients with PHP, when the diagnosis of PHP was first established, hypocalcemia and hyperphosphatemia were associated with a significant increase in serum PTH levels. One patient with PHP-Ia was diagnosed with growth hormone deficiency and showed a good response to human recombinant growth hormone therapy. 6 patients with PHP-Ia and PPHP showed 5 different mutations in the GNAS gene. 5 patients with PHP-Ib displayed a loss of differentially methylated region (DMR) imprints of the maternal GNAS. One PHP-Ib patient showed a de novo microdeletion in STX16 and a loss of methylation of exon A/B on the maternal allele. No patients revealed paternal disomy among 4 patients with PHP-Ib. Identification of the molecular causes of PHP and PPHP explains their distinctive clinical features and enables confirmation of the diagnosis and exact genetic counseling.

The first reported case of pseudoparathryoidism type IB in Hong Kong: hypocalcemia in an adolescent boy with recurrent seizures

Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders characterized by hypocalcemia, hyperphoshatemia and inappropriately elevated serum parathyroid hormone (PTH) level due to end-organ resistance of biological activity of parathyroid hormone. It is due to epigenetic change at the GNAS locus and is divided into types Ia, Ib, Ic and II. We hereby describe the first reported case of pseudohypoparathyroidism type Ib Hong Kong.

Reduced Insulin Sensitivity in Adults With Pseudohypoparathyroidism Type 1a

Disruption of the Gsα maternal allele leads to severe obesity and insulin resistance in mice and early-onset obesity in patients with pseudohypoparathyroidism (PHP) type 1a. However, insulin resistance and glucose metabolism have not been systematically characterized in patients with PHP1a. In a cross-sectional, case-control study, we examined insulin sensitivity, β-cell function, energy expenditure (EE), and sympathetic nervous system activity in adults with PHP1a. PHP1a patients (n = 8) and healthy control subjects (n = 24) matched for age (41 ± 7 vs 41 ± 7 years [mean ± SD]), gender, and percent body fat. Insulin sensitivity (SI), acute insulin response to glucose, and disposition index were assessed during a frequently sampled iv glucose tolerance test. Oral glucose insulin sensitivity (OGIS) was measured during a mixed meal. EE was measured using whole-room indirect calorimetry. Body composition was assessed via dual-energy x-ray absorptiometry and sympathetic nervous system activity by measuring 24-hour urinary catecholamine concentrations. PHP1a patients were less insulin-sensitive than their matched controls based upon SI and OGIS. Nondiabetic PHP1a patients tended to have a lower SI (P = .09) and reduced OGIS (P = .03). Disposition index, a composite measure of β-cell function, also tended to be lower in patients (P = .07). Total caloric intake, resting EE, total EE, meal-induced thermogenesis, and 24-hour urinary catecholamine concentrations were not significantly different between the groups. Adults with PHP-1a have reduced insulin sensitivity compared with their matched controls that may contribute to the pathogenesis of glucose intolerance and diabetes in these patients.

One case of pseudohypoparathyroidism, clinical characterisation, follow up and treatment

One case of pseudohypoparathyroidism, clinical characterisation, follow up and treatment

Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: First Italian series

Progressive osseous heteroplasia (POH) is a rare autosomal dominant disorder of mesenchymal differentiation characterized by progressive heterotopic ossification (HO) of dermis, deep connective tissues and skeletal muscle. Usually, initial bone formation occurs during infancy as primary osteoma cutis (OC) then progressively extending into deep connective tissues and skeletal muscle over childhood.Most cases of POH are caused by paternally inherited inactivating mutations of GNAS gene. Maternally inherited mutations as well as epigenetic defects of the same gene lead to pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO).During the last decade, some reports documented the existence of patients with POH showing additional features characteristic of AHO such as short stature and brachydactyly, previously thought to occur only in other GNAS-associated disorders. Thus, POH can now be considered as part of a wide spectrum of ectopic bone formation disorders caused by inactivating GNAS mutations.Here, we report genetic and epigenetic analyses of GNAS locus in 10 patients affected with POH or primary OC, further expanding the spectrum of mutations associated with this rare disease and indicating that, unlike PHP, methylation alterations at the same locus are absent or uncommon in this disorder.

Aspectos clínicos en dos casos de seudohipoparatiroidismo (ia y ib) y estudio molecular del locus GNAS

Pseudohypoparathyroidism (PHP) is a rare disorder, characterized by a tissue resistance to parathyroid hormone (PTH). The two main subtypes of PHP, PHPIa and PHPIb, are caused by alterations in the GNAS locus (20q13.3), which encodes the Gsα protein, essential for the action of PTH and other hormones.PHP-Ia is associated with several hormone resistances, Albright hereditary osteodystrophy (AHO), and reduced Gsα activity. It is caused by inactivating mutations in the GNAS gene. PHP-Ib presents with isolated resistance to PTH, without AHO and with normal to low Gsα activity. It is related to imprinting defects in GNAS.Two unrelated cases of PHP-Ia and PHP-Ib are presented here, focusing on their clinical aspects and in the differential diagnosis with similar pathologies.

Endocrine Profile and Phenotype-(Epi)Genotype Correlation in Spanish Patients with Pseudohypoparathyroidism

Recent advances in genetics and epigenetics have revealed an overlap between molecular and clinical features of pseudohypoparathyroidism (PHP) subtypes, broadening the previous spectrum of PHP genotype-phenotype correlations and indicating limitations of the current classification of the disease. The aim of the study was to screen patients with clinical diagnoses of PHP type I or pseudo-PHP for underlying molecular defects and explore possible correlations between molecular findings and clinical features. We investigated the GNAS locus at the molecular level in 72 affected patients (46 women and 26 men) from 56 nonrelated families. Clinical data were obtained for 63 of these patients (38 women and 25 men). The molecular analysis showed that 35 patients carried structural mutations, 32 had loss of methylation, and 2 had a 2q37 deletion but did not reveal any (epi)mutation for 3 patients. Comparing these results and the clinical data, we observed that a younger age at diagnosis was associated with structural defects at the GNAS gene and epigenetic defects with a diagnosis later in life (9.19 ± 1.64 vs 24.57 ± 2.28 years, P < .0001). This first global review of PHP in Spain highlights the importance of a detailed clinical and genetic study of each patient and the integrated analysis of the findings from the two approaches. It may also help geneticists and clinicians to raise the suspicion of PHP earlier, reach more accurate diagnoses, and provide patients with PHP and their families with useful genetic information and counseling, thereby improving outcomes and quality of life.