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Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorder with parathormone target organ resistance, characterized by hypocalcemia, hyperphosphatemia and high blood parathormone (PTH). Typical phenotypic symptoms and additional hormonal resistance can be observed in type Ia, which is also known as Albright hereditary osteodystrophy. Our patient was an eight-year and nine-month old girl with typical Albright-s hereditary osteodystrophy phenotype including short stature, obesity, round face, low nasal bridge, shortened metacarpals, and mild mental retardation. In her biochemical examination, high PTH level and hypothyroidism is detected in spite of normal calcium and phosphor levels. As a result of clinic and laboratory tests, the findings were consistent with PHP type Ia with normocalcemia. In her guanine nucleotide binding protein (G protein), alpha stimulating activity polypeptide 1 (GNAS 1) gene serial analysis, C-308T>C (p1103T) transformation was detected, which was previously reported in a PHP type Ia patient. In this report, we-ve aimed to emphasize the fact that calcium and phosphor level in the blood of the patient with PHP type Ia can be measured normal.

Introduction: Pseudohypoparathyroidism (PHP) indicates a group of rare disorders characterized by end-organ resistance to various hormones, primarily parathyroid hormone (PTH). One of its most common type is PHP-Ia, which is caused by maternally inherited inactivating mutations in GNAS. In this report, we present a Chinese girl with typical features of PHP-Ia and a novel mutation of the GNAS gene. Patient concerns: A 9-year-old Chinese girl presented with recurrent epileptic seizure. Diagnosis: Biochemical and imaging findings were consistent with PHP-Ia, including typical Albright hereditary osteodystrophy phenotype (short stature, round face, brachydactyly, and mild mental retardation), PTH resistance (hypocalcemia, hyperphosphatemia, elevated serum PTH, and multiple intracranial calcification) and thyroid stimulating hormone resistance (elevated serum thyroid stimulating hormone). Interventions: The patient was given 1α-hydroxylated vitamin D (calcitriol, 0.5 ug/d), calcium carbonate and vitamin D3 tablets (1.5 g/d, including 600 mg calcium and 125 IU vitamin D3). DNA analysis of the GNAS gene was performed for the whole family. Outcomes: Investigation of the GNAS gene revealed a novel mutation c.313delG (p.Glu105Lysfs∗7) in the patient, as well as her mother. So the diagnosis of PHP-Ia was confirmed. Conclusion: The study further expands the spectrum of known GNAS mutations associated with PHP and lay emphasis on the genetic analysis of GNAS gene for identifying genetic abnormalities as well as making diagnosis and differentiation of various subtypes of PHP.

BACKGROUND: Pseudohypoparathyroidism type Ia (PHP Ia) is a rare hereditary syndrome, and patients with early PHP Ia are generally not diagnosed based on the presentation of cutaneous nodules as the main clinical feature. Here, we describe a Chinese boy with PHP Ia in whom the main clinical feature was cutaneous nodules, and the patient exhibited a novel GNAS mutation. CASE SUMMARY: A 5-year-old boy presented with a 5-year history of cutaneous nodules scattered over his entire body. The patient had a short stature, round face, short neck, and slightly flattened nose; he also had multiple hard papules and cutaneous nodules scattered over his entire body. The patient had a significantly elevated parathyroid hormone level. His serum calcium level was reduced, while his serum phosphorus level was increased and his serum thyroid-stimulating hormone level was elevated. Skin biopsy showed osteoma cutis in subcutaneous tissue. Sanger sequencing revealed a frameshift mutation, c.399delT (p.Ser133Argfs*2) in exon 5 of the GNAS gene. The patient was diagnosed with PHP Ia and subclinical hypothyroidism. He was given 1,25-dihydroxyvitamin D, calcium carbonate, and synthetic L-thyroxine. After 3 months of treatment, the patient’s parathyroid hormone level decreased, and his serum calcium and serum phosphorus levels were normal. Moreover, his thyroid-stimulating hormone level decreased. CONCLUSION: These findings can help dermatologists to diagnose PHP Ia in patients with cutaneous nodules as the main early clinical feature.

Maternally inherited inactivating GNAS mutations are the most common cause of parathyroid hormone (PTH) resistance and Albright hereditary osteodystrophy (AHO) leading to pseudohypoparathyroidism type Ia (PHPIa) due to Gsα deficiency. Paternally inherited inactivating mutations lead to isolated AHO signs characterizing pseudo-pseudohypoparathyroidism (PPHP). Mutations are distributed throughout the Gsα coding exons of GNAS and there is a lack of genotype–phenotype correlation. In this study, we sequenced exon 1–13 of GNAS in a large cohort of PHPIa- and PPHP patients and identified 58 different mutations in 88 patients and 27 relatives. Thirty-three mutations including 15 missense mutations were newly discovered. Furthermore, we found three hot spots: a known hotspot (p.D190MfsX14), a second at codon 166 (p.R166C), and a third at the exon 5 acceptor splice site (c.435 + 1G>A), found in 15, 5, and 4 unrelated patients, respectively. Comparing the clinical features to the molecular genetic data, a significantly higher occurrence of subcutaneous calcifications in patients harboring truncating versus missense mutations was demonstrated. Thus, in the largest cohort of PHPIa patients described to date, we extend the spectrum of known GNAS mutations and hot spots and demonstrate for the first time a correlation between the genetic defects and the expression of a clinical AHO-feature.

A case report of a 2-year-old female satin guinea pig with a history of dental overgrowth and lameness and radiological lesions of fibrous osteodystrophy is presented. The most relevant clinical findings were bone demineralization, high level of parathyroid hormone (PTH), normophosphatemia, normal ionized calcium, and low total thyroxine (tT4) with a normal renal function. Long-term treatment was based on teeth coronal reduction and maintaining a balanced diet. PTH measurement was performed with a kit suitable for rats to test 4 different paired samples of guinea pigs and resulted in similar results for each pair of measurements. Two kits routinely employed in dogs and cats failed in measuring PTH in guinea pig serum samples. The ionized calcium, PTH, and tT4 values, not previously reported in similar cases, were obtained. The determination of tT4 could be useful in the diagnosis of fibrous osteodystrophy in guinea pigs. The observed findings show similarity with human pseudohypoparathyroidism type Ia, a disease caused by an inactivating heterozygous mutation of the stimulatory G proteinαsubunit from the maternal genome that induces multiple hormone resistance and that courses with a syndrome called Albright hereditary osteodystrophy. Naturally occurring pseudohypoparathyroidism in animals has been reported previously only in a ferret.

The objective of this study was to describe a new mutation in GNAS in a family with pseudohypoparathyroidism type Ia (PHP Ia), a rare osteometabolic disease. An 8-month-old boy was seen by an Endocrinologist due to obesity and low growth velocity. Noteworthy, his mother exhibited typical Albright hereditary osteodystrophy (AHO) phenotype. The clinical diagnosis of PHP Ia was suspected. The GNAS coding region from mother and son was amplified and directly sequenced. A novel heterozygous missense mutation (c.673T>C) was identified in exon 5 in both patients. In this family, the mother's clinical picture was the clue for the son's diagnosis. Molecular analysis of GNAS confirmed the diagnosis of PHP Ia in both patients and the child's early diagnosis was possible. Moreover, this novel missense substitution expands the spectrum of GNAS mutations associated with this disorder and allows for genetic counseling of this family.

Pseudohypoparathyroidism (PHP) type Ia is characterized by hypocalcemia due to PTH resistance and by features of Albright's hereditary osteodystrophy, including short stature, obesity, subcutaneous calcification and brachydactyly. A wide variety of clinical and biochemical manifestations have been reported. We report two cases of PHP type Ia in duozygotic twins with different phenotypes. The proband was a 10-yr-old girl. She showed subcutaneous ossification, shortening of the metacarpal bone, short stature, obesity and round face. She had normocalcemia (8.9 mg/dl), high-normal phosphate (5.0 mg/dl) and increased levels of serum intact PTH (152 pg/ml) and TSH (9.17 μIU/ml) levels. Her twin younger brother had atypical Albright's hereditary osteodystrophy with only mild obesity and subcutaneous calcifications, but he showed a low level of serum calcium (7.0 mg/dl) and high levels of serum phosphate (7.6 mg/dl), intact PTH (377 pg/ml) and TSH (6.9 μIU/ml). We diagnosed them as having PHP type Ia on the basis of clinical and biochemical findings, Ellsworth-Howard test and family history. There is considerable variability in clinical and biochemical features of PHP type Ia even among affected duozygotic twins. The differences of intrauterine environment and growth history cannot account for the variable phenotypes of PHP type Ia. Even if a patient shows no AHO features, examination of all family members should be undertaken.

A 22-year-old woman presented to us with seizures of a few minutes duration. She had clinical features of Albright hereditary osteodystrophy (AHO), including hypocalcemia, hyperphosphatemia and resistance to parathyroid hormone. Genetic testing revealed a sporadic form of pseudohypoparathyroidism type Ib (PHP-Ib). This is the first Japanese case involving overlap between pseudohypoparathyroidism type Ia (PHP Ia) associated with AHO and PHP Ib. It is important to perform both DNA sequencing and methylation status analyses in cases of suspected PHP in patients with signs of AHO.

PubMed: 21274345 Pseudohypoparathyroidism (PHP) refers to end-organ resistance that primarily impairs the renal actions of parathyroid hormone (PTH). The patients with PHP type Ia (PHP-Ia), one of the 4 types of PHP, show resistance to other peptide hormones as well as clinical features of Albright hereditary osteodystrophy (AHO), a constellation of short stature, obesity, brachydactyly, ectopic ossifications, and/or mental retardation. Here we report clinical follow-up for a long-term period in a PHP-Ia case who had a missense mutation leading to the substitution of proline by serine (Prol115Ser) in exon 5 which has been reported previously in only two patients. An 11-year-old boy applied for hand spasm to our hospital. On physical examination, he had short stature, round-shaped face and brachydactly. Laboratory evaluation revealed PTH and TSH resistance. Molecular genetic analysis of the GNAS gene revealed a P115S substitution. The patient was followed up for 13 years. Normocalcaemia was achieved with reduced doses of calcitriol (0.25 ?g/day) and calcium supplements (40 mg/kg/day). Daily requirement for levothyroxine supplementation was still high (2.3 ?g/kg) to achieve euthyroidism. His pubertal development was Tanner stage V and he has no gonadotropin resistance. To our knowledge, this is the first report concerning long-term follow-up of this rare mutation. We believe that despite the genetic heterogeneity of AHO, phenotype/genotype correlations of this kind of rare mutations may help to understand progress of the disease. © Journal of Clinical Research in Pediatric Endocrinology.

Since the identification of GH deficiency due to resistance to GHRH in patients with pseudohypoparathyroidism type Ia (PHP-Ia), no study investigated the effects of recombinant human GH (rhGH) therapy on height velocity (HV) in these patients.To address this question, eight prepubertal PHP-Ia children with GH deficiency (seven girls and one boy, aged 5.8-12 yr) underwent a 3- to 8-yr treatment with rhGH. Height and HV were measured before and at 6-month intervals during therapy. Nine sex- and age-matched children with idiopathic GH deficiency were monitored during rhGH therapy for comparison.In PHP-Ia children, height sd scores increased from -2.4 ± 0.58 to -1.8 ± 0.47 (P = 0.04) after 12 months, this increase being maintained after the second (-1.6 ± 0.6) and third (-1.15 ± 0.6) year of therapy, similarly to what recorded in children with idiopathic GH deficiency. The HV and HV sd scores after 3 yr maintained a significant increase from 3.5 ± 0.6 to 7.0 ± 0.9 cm/yr (P0.0001) and from -2.8 ± 0.8 to +2.2 ± 1.0 (P0.0001), respectively. Six patients treated for 4-8 yr had a reduced pubertal spurt and did not improve their near-adult height, with the only exception of one patient in whom estrogen production was blocked by GnRH analogs.We report the first study on the efficacy of rhGH replacement therapy in prepubertal children with PHP-Ia and provide indication that treatment of GH deficiency should be started soon due to the rather limited time window for a potentially effective therapy.

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가성부갑상선기능저하증은 신장의 부갑상선 호르몬에 대한 반응저하를 유발하는 유전질환이다. 가성부갑상선기능저하증 Ia형에서 다양한 GNAS 복합부위의 결손들이 발견되었으며, GNS1 유전자 돌연변이는 Gsα 단백 활성도를 감소시킨다. 대부분의 가성부갑상선기능저하증 Ia형 환자는 특징적으로 알브라이트 유전성 골이영양증(Albright hereditary osteodystrophy)과 저칼슘혈증, 부갑상선호르몬의 증가, Gsα 단백이 매개하는 여러 호르몬들에 대한 저항성을 보인다. 알브라이트 유전성 골이영양증은 작은 신장, 비만, 둥근얼굴형, 피하 석회결절 그리고 발과 손의 단지증 등의 다양한 증상이 발현되는 증후군이다. 저자들은 알브라이트 유전성 골이영양증, 근강축, 어지러움, 빛에 대한 과민성과 시력저하, 인지 및 운동기능의 장애를 보이는 47세 여자환자에서 직접염기서열분석을 통해 국내에서는 최초로 GNAS1 유전자 엑손 6에서 과오돌연변이(c.466G>A,p.Asp156Asn)를 증명하여 가성부갑상선기능저하증 Ia형으로 진단한 증례를 경험하였기에 보고하는 바이다.

Shortening of metacarpals is a useful diagnostic marker in patients with pseudohypoparathyroidism type Ia (PHP-Ia) with Albright′s hereditary osteodystrophy (AHO) phenotype or pseudopseudohypoparathyroidism (PPHP). There are very rare reports of metacarpals shortening in idiopathic primary hypoparathyroidism (IPH) cases in the literature. Here we described a young woman with IPH who presented with hypocalcaemia and generalized tonic-clonic seizure. She had shortening of forth and fifth metacarpals which was prominent in her right hand. Based on our finding and other previous case reports we conclude that metarpals shortening is not a specific finding of PHP-Ia or PPHP and it may be found in IPH cases.