Albright Hereditary Osteodystrophy Phenotype Research Articles

Abstract 34: A rare case of pseudohypoparathyroidism type 1a associated with albright hereditary osteodystrophy phenotype and with multiple hormonal resistance

Abstract 34: A rare case of pseudohypoparathyroidism type 1a associated with albright hereditary osteodystrophy phenotype and with multiple hormonal resistance

Pseudohypoparathyroidism and GNAS gene defects: clinical evaluation and molecular analysis in 20 children

Objective: To analyze the patients' clinical and genetic characteristics with pseudohypoparathyroidism (PHP) and investigate the correlation between clinical phenotypes and genotypes. Methods: Twenty PHP patients were ascertained at Children's Hospital Zhejiang University School of Medicine from January 2011 to July 2020. Clinical manifestation, laboratory examination and gene test results were retrospectively analyzed. Results: In these twenty patients, eighteen cases showed resistance to parathyroid hormone (PTH) and thirteen cases had Albright's hereditary osteodystrophy (AHO) phenotype. Gene abnormalities were found in all the twenty PHP patients, which included seven patients with GNAS gene variations (six frameshifts and one missense) and thirteen patients with GNAS gene methylation defects. Moreover, twelve children with both PTH resistance and AHO phenotype were clinically diagnosed as PHP-Ⅰa, meanwhile, seven carried GNAS variations and five had methylation abnormalities with a correct diagnosis of PHP-Ⅰb. Conclusions: Patients with AHO phenotype and PTH resistance may have a high genetic diagnosis rate. Because PHP-Ⅰb clinical phenotype may be similar to PHP-Ⅰa, early genetic detection is required for the differential diagnosis. In addition, children without PTH resistance should also be followed up regularly, which may help the early diagnosis.

2q37 Deletions in Patients With an Albright Hereditary Osteodystrophy Phenotype and PTH Resistance.

Pseudohypoparathyroidism (PHP) is a rare endocrine disorder derived from the defective activation of the cAMP pathway by the parathyroid hormone secondary to GNAS molecular defects. PHP subtypes are defined by the presence/absence of specific clinical/biochemical features. PHP1A is characterized by resistance to multiple hormones with features of Albright hereditary osteodystrophy (AHO), while pseudopseudohypoparathyroidism (PPHP) is characterized by AHO in the absence of PTH resistance. Small subsets of PHP and PPHP patients without known molecular defects have been re-diagnosed as being affected by the brachydactyly-mental retardation syndrome (BDMR), also known as the AHO-like syndrome. This study aimed to analyse 24 PHP1A and 51 PPHP patients without a molecular diagnosis for the presence of BDMR-associated 2q37 deletions to improve the differential diagnosis and to identify features that might help to avoid a misdiagnosis. Molecular investigations identified 4 deletions in 4 unrelated patients. The affected patients showed a combination of the most pathognomonic AHO features. Of note, 3 of the patients also displayed mild PTH resistance, and none of the patients developed ectopic ossifications. Our work confirmed the rarity of the misdiagnosis of BDMR in PHP patients through the identification of 4 patients bearing a 2q37 deletion in a cohort of 73 PHP patients (5.3%). Three patients with the deletion presented a PHP1A phenotype in the absence of any BDMR-specific findings. Further studies on larger case series are needed to elucidate the overlap between these clinical entities and to allow the early identification of patients.

Language delay and developmental catch-up would be a clinical feature of pseudohypoparathyroidism type 1A during childhood.

Pseudohypoparathyroidism type 1A (PHP1A) is characterized by resistance to multiple hormones, the Albright Hereditary Osteodystrophy phenotype, obesity, and developmental delay. Developmental delay usually appears prior to hypocalcemia due to parathyroid hormone resistance and could be a clinically important feature for early diagnosis of PHP1A. To date, however, the details have not been documented. With regard to developmental delays, we conducted a multicenter retrospective study of 22 PHP1A patients from 18 families who were diagnosed clinically or genetically from 2005 to 2015. For quantitative analysis of their development, we calculated the ratios of the milestone ages of the patients to those in normal reference data. The ratio of the ages with respect to speech development, i.e., speaking a first meaningful word (median: 1.67), was significantly higher than that for gross motor development, walking unassisted (median: 1.34). The ratio of age at stringing a two-word sentence (median: 1.32) was significantly lower than that of saying a first word (median: 1.84). Ten out of 11 (91%) patients exhibited two or three of the following clinical phenotypes: developmental delay, obesity, and hyperthyrotropinemia. These results suggest two possible clinical features of developmental delays in PHP1A patients: developmental delay is more obvious in speech acquisition than in gross motor skills, and speech delays could be attenuated during later childhood. Further, the presence of multiple of three clinical symptoms could be an important indicator to differentiate the diagnosis of PHP1A during early childhood.

Brachydactyly mental retardation syndrome with growth hormone deficiency.

SummaryDeletion of chromosome 2q37 results in a rare congenital syndrome known as brachydactyly mental retardation (BDMR) syndrome; a syndrome which has phenotypes similar to Albright hereditary osteodystrophy (AHO) syndrome. In this report, we describe a patient with AHO due to microdeletion in long arm of chromosome 2 [del(2)(q37.3)] who had growth hormone (GH) deficiency, which is a unique feature among reported BDMR cases. This case was presented with shortening of the fourth and fifth metacarpals which along with AHO phenotype, brings pseudopseudohypoparathyroidism (PPHP) and pseudohypoparathyroidism type Ia (PHP-Ia) to mind; however, a genetic study revealed del(2)(q37.3). We recommend clinicians to take BDMR in consideration when they are faced with the features of AHO; although this syndrome is a rare disease, it should be ruled out while diagnosing PPHP or PHP-Ia. Moreover, we recommend evaluation of IGF 1 level and GH stimulation test in patients with BDMR whose height is below the 3rd percentile.Learning points:Clinicians must have brachydactyly mental retardation (BDMR) syndrome in consideration when they are faced with the features of Albright hereditary osteodystrophy.Although BDMR syndrome is a rare disease, it should be ruled out while diagnosing PPHP or PHP-Ia.Evaluation of IGF1 level in patients diagnosed with BDMR whose height is below the 3rd percentile is important.

Pseudohypoparathyroidism Type 1B with Asymptomatic Hypocalcemia

<h2>ABSTRACT</h2> <b>Objective:</b> To report the rare case of an asymptomatic female patient with pseudohypoparathyroidism type 1b. <b>Methods:</b> The diagnosis of pseudohypoparathyroidism type 1b was confirmed by analysis of the methylation status by methylation-specific multiplex ligation-dependent probe amplification. <b>Results:</b> A 21-year-old female was referred to the endocrinology clinic due to an elevated parathyroid hormone level as an incidental finding. Her personal and family histories were unremarkable and there were no Albright hereditary osteodystrophy stigmata. Initially the patient only presented an elevated parathyroid hormone level, without hypocalcemia or hyperphosphatemia. The patient exhibited no signs or symptoms of hypocalcemia. After 6 months the patient presented hypocalcemia and treatment with calcium and calcitriol was commenced, despite her remaining asymptomatic. The genetic study was compatible with sporadic pseudohypoparathyroidism type 1b. <b>Conclusion:</b> An incidental finding of elevated parathyroid hormone with absence of Albright hereditary osteodystrophy phenotype raised the clinical suspicion of pseudohypoparathyroidism type 1b, which lead to careful monitoring of calcemia and therefore allowed timely management of hypocalcemia. <b>Abbreviations: AHO</b> Albright hereditary osteodystrophy <b>GNAS</b> guanine nucleotide binding protein, alpha stimulating gene <b>Gsα</b> alpha subunit of G protein <b>PHP</b> pseudohypoparathyroidism <b>PHP-1a</b> pseudohypoparathyroidism type 1a <b>PHP-1b</b> pseudohypoparathyroidism type 1b <b>PHP-1c</b> pseudohypoparathyroidism type 1c <b>PHP-2</b> pseudohypoparathyroidism type 2 <b>PTH</b> parathyroid hormone

Variable phenotype of pseudohypoparathyroidism in children

Background. Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders associated with tissue insensitivity to parathyroid hormone. PHP is characterized by genetic heterogeneity and variable phenotype. In addition to the hypocalcemic syndrome and resistance to parathyroid hormone, PHP is also characterized by phenotypic features and resistance to other hormones (TSH, LH, FSH, and GHRH), which are known as Albright Hereditary Osteodystrophy (AHO). Until recently, no analysis of large cohorts of patients with PHP has been performed in Russian literature.&#x0D; Objective — to examine a large cohort of patients with PHP and assess the clinical features of PHP.&#x0D; Material and methods. A group consisting of 32 patients with different variants of course of the disease who had been examined at the Endocrinology Research Center in 2014—2016 was analyzed.&#x0D; Results. Features of AHO phenotype in addition to hormonal resistance were identified in 16 (50%) patients; one of them had one feature (brachydactyly) and 15 patients had two and more features of AHO. Besides insensitivity to PTH, TSH resistance was found in 22 (68.75%) patients and one patient had resistance to PTH, TSH and LH/FSH. Hypothyroidism manifested before hypocalcaemia in 4 patients. Obesity was the first complaint in 8 patients; 5 of them had subclinical hypocalcaemia and the remaining 3 patients had an elevated PTH level with the normal level of calcium at the time of first examination. The most typical clinical signs of hypocalcaemia in 23 (72%) patients were seizures. Thirteen of them were misdiagnosed with epilepsy and had been followed by a neurologist for a period ranging between 2 months and 7 years before hypocalcaemia was revealed.&#x0D; Conclusions. Pseudohypoparathyroidism is a rare genetic disorder associated with resistance to parathyroid hormone, which can have a lot of other clinical features in addition to the symptoms of PTH resistance. Obesity or hypothyroidism can be the earliest manifestation of PHP preceding hypocalcaemia. Evaluation of serum calcium level is important for all pediatric patients with seizures to timely diagnose hypocalcaemia and avoid misdiagnosing.

Follow-up Findings in a Turkish Girl with Pseudohypoparathyroidism Type Ia Caused by a Novel Heterozygous Mutation in the GNAS Gene

Pseudohypoparathyroidism type Ia (PHP-Ia) is characterized by multihormone resistance and an Albright hereditary osteodystrophy (AHO) phenotype. It is caused by heterozygous mutations in GNAS gene. Clinical and biochemical findings of a female PHP-Ia patient were evaluated from age of diagnosis (6.5 years) to 14.5 years of age. The patient had short stature, brachydactyly, and subcutaneous heterotopic ossifications. Serum calcium and phosphorus levels were normal, but parathyroid hormone levels were high. Based on the typical clinical findings of AHO phenotype and biochemical findings, she was diagnosed as having PHP-Ia. A novel heterozygous mutation (c.128T>C) was found in the GNAS gene. Follow-up examinations revealed resistance to thyroid-stimulating hormone and a bioinactive growth hormone. Clinicians should take into consideration PHP-Ia in patients referred with short stature, and patients with an AHO phenotype must be further evaluated for hormone resistance, GNAS gene mutation, Gsα activity. To our knowledge, this is the first case report describing bioinactive growth hormone in PHP-Ia.

Nonclassic features of pseudohypoparathyroidism type 1A.

To provide readers with a review of contemporary literature describing the evolving understanding of the pseudohypoparathyroidism type 1A (PHP1A) phenotype. The classic features of PHP1A include multihormone resistance and the Albright Hereditary Osteodystrophy phenotype (round facies, short stature, subcutaneous ossifications, brachydactyly, and early-onset obesity. Obesity may be because of a decrease in resting energy expenditure because most patients do not report significant hyperphagia. Patients with PHP1A have an increased risk of type 2 diabetes. In addition to brachydactyly and short stature, orthopedic complications can include spinal stenosis and carpal tunnel syndrome. Hearing loss, both sensorineural and conductive, has been reported in PHP1A. In addition, ear-nose-throat findings include decreased olfaction and frequent otitis media requiring tympanostomy tubes. Sleep apnea was shown to be 4.4-fold more common in children with PHP1A compared with other obese children; furthermore, asthma-like symptoms have been reported. These new findings are likely multifactorial and further research is needed to better understand these nonclassic features of PHP1A. Along with the Albright Hereditary Osteodystrophy phenotype and hormone resistance, patients with PHP1A may have additional skeletal, metabolic, ear-nose-throat, and pulmonary complications. Understanding these nonclassic features will help improve clinical care of patients with PHP1A.

A Novel T55A Variant of Gs α Associated with Impaired cAMP Production, Bone Fragility, and Osteolysis.

G-protein coupled receptors (GPCRs) mediate a wide spectrum of biological activities. The GNAS complex locus encodes the stimulatory alpha subunit of the guanine nucleotide binding protein (Gsα) and regulates production of the second messenger cyclic AMP (cAMP). Loss-of-function GNAS mutations classically lead to Albright's Hereditary Osteodystrophy (AHO) and pseudohypoparathyroidism, often with significant effects on bone formation and mineral metabolism. We present the case of a child who exhibits clinical features of osteolysis, multiple childhood fractures, and neonatal SIADH. Exome sequencing revealed a novel de novo heterozygous missense mutation of GNAS (c.163A<G, p.T55A) affecting the p-loop of the catalytic Gsα GTPase domain. In order to further assess whether this unique mutation resulted in a gain or loss of function of Gsα, we introduced the mutation into a rat GNAS plasmid and performed functional studies to assess the level of cAMP activity associated with this mutation. We identified a 64% decrease in isoproterenol-induced cAMP production in vitro, compared to wild type, consistent with loss of Gsα activity. Despite a significant decrease in isoproterenol-induced cAMP production in vitro, this mutation did not produce a classical AHO phenotype in our patient; however, it may account for her presentation with childhood fractures and osteolysis.

Methylation Defect in Imprinted Genes Detected in Patients with an Albright's Hereditary Osteodystrophy Like Phenotype and Platelet Gs Hypofunction

BackgroundPseudohypoparathyroidism (PHP) indicates a group of heterogeneous disorders whose common feature is represented by impaired signaling of hormones that activate Gsalpha, encoded by the imprinted GNAS gene. PHP-Ib patients have isolated Parathormone (PTH) resistance and GNAS epigenetic defects while PHP-Ia cases present with hormone resistance and characteristic features jointly termed as Albright's Hereditary Osteodystrophy (AHO) due to maternally inherited GNAS mutations or similar epigenetic defects as found for PHP-Ib. Pseudopseudohypoparathyroidism (PPHP) patients with an AHO phenotype and no hormone resistance and progressive osseous heteroplasia (POH) cases have inactivating paternally inherited GNAS mutations.Methodology/Principal FindingsWe here describe 17 subjects with an AHO-like phenotype that could be compatible with having PPHP but none of them carried Gsalpha mutations. Functional platelet studies however showed an obvious Gs hypofunction in the 13 patients that were available for testing. Methylation for the three differentially methylated GNAS regions was quantified via the Sequenom EpiTYPER. Patients showed significant hypermethylation of the XL amplicon compared to controls (36±3 vs. 29±3%; p<0.001); a pattern that is reversed to XL hypomethylation found in PHPIb. Interestingly, XL hypermethylation was associated with reduced XLalphaS protein levels in the patients' platelets. Methylation for NESP and ExonA/B was significantly different for some but not all patients, though most patients have site-specific CpG methylation abnormalities in these amplicons. Since some AHO features are present in other imprinting disorders, the methylation of IGF2, H19, SNURF and GRB10 was quantified. Surprisingly, significant IGF2 hypermethylation (20±10 vs. 14±7%; p<0.05) and SNURF hypomethylation (23±6 vs. 32±6%; p<0.001) was found in patients vs. controls, while H19 and GRB10 methylation was normal.Conclusion/SignificanceIn conclusion, this is the first report of methylation defects including GNAS in patients with an AHO-like phenotype without endocrinological abnormalities. Additional studies are still needed to correlate the methylation defect with the clinical phenotype.

Intraarticular Heterotopic Ossification as the Initial Manifestation in a Child with Pseudohypoparathyroidism 1a

The authors describe a 6 year old girl who initially presented with limping due to intraarticular ossification of left knee joint but later developed carpopedal spasms. She had Albright's hereditary osteodystrophy phenotype with hypocalcemia and hyperphosphatemia with elevated parathyroid hormone. She was diagnosed to have pseudohypoparathyroidism 1a (PHP1a) with heterotopic intraarticular ossification. This case emphasizes the need for evaluation of PHP in patients with intraarticular ossification to facilitate early diagnosis of PHP.

A Family with Congenital Hypothyroidism Caused by a Combination of Loss-of-Function Mutations in the Thyrotropin Receptor and Adenylate Cyclase-Stimulating G Alpha-Protein Subunit Genes

Resistance to thyrotropin (TSH) causes congenital hypothyroidism (CH). TSH receptor (TSHR) and adenylate cyclase-stimulating G alpha protein subunit (GNAS) loss-of-function mutations cause TSH resistance. We describe a family with TSH resistance and CH bearing a combination of inactivating mutations in TSHR and GNAS genes. We describe studies to determine the molecular mechanisms involved in TSH resistance in this family. DNA sequencing to identify TSHR and GNAS gene mutations was performed. In vitro effects of the mutations on cAMP production and TSH binding were investigated in COS7 cells. cAMP production was evaluated by transfecting a cAMP response element (CRE)-luciferase reporter with pSVL-TSHR and pSVK3-GNAS vectors. For binding studies, cells transfected with pSVL-TSHR vectors were incubated with iodine-125 bovine TSH ((125)IbTSH). Family members with and without CH were heterozygous for the TSHR mutant p.E34K or the GNAS mutant c.750_751insA (=GNASMut). The propositus had CH and he was heterozygous for TSHR p.E34K; his mother, also heterozygous for TSHR p.E34K, did not have CH. The euthyroid propositus' wife was heterozygous for GNASMut. The propositus' two daughters had CH, one was heterozygous for GNASMut and the other a compound heterezygous for TSHR p.E34K and GNASMut. Albright's hereditary osteodystrophy phenotype was present in those with GNASMut mutation but only the daughters had pseudohypoparathyroidism type 1a. Cells transfected with TSHRE34K had lower TSH affinity and less CRE-luciferase response than cells transfected with TSHR wild-type (WT). Cells transfected with GNASMut did not stimulate CRE-luciferase activity, but when cells were transfected with GNASMut plus GNASWT, a similar response to GNASWT alone was observed. The combination of TSHRWT and GNASWT showed higher CRE-luciferase response than TSHRWT and TSHRE34K with either GNASWT or GNASWT plus GNASMut. CH was caused by loss-of-function mutations in TSHR and/or GNAS. The absence of CH in the propositus' mother argues against a role for TSHR p.E34K being the only cause of CH. The minimal thyroidal phenotypic differences between the sisters with pseudohypoparathyroidism type 1a and TSH resistance, both heterozygous for GNAS c.750_751insA but only one bearing the TSHR p.E34K mutant, suggest that the main cause for CH was preferential expression of the mutated maternal GNAS allele in the thyroid gland.

Selective Deficiency of Gsα and the Possible Role of Alternative Gene Products of GNAS in Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism Type Ia

Albright hereditary osteodystrophy (AHO) and Pseudohypoparathyroidism type Ia (PHPIa) are caused by an inherited deficiency of Gsalpha, encoded by the GNAS gene. Apart from an exclusive first exon, Gsalpha shares part of the transcribed regions with NESP55, Exon A/B and XLalphas, whose gene products utilize alternative promoter regions of this complex gene locus. However, it is not known, whether the deficiency of all gene products contributes to the AHO and PHPIa phenotype or if they are even causative for some specific symptoms. In these cases, mutations affecting selectively GNAS exon 1, coding only for Gsalpha, would lead to a different phenotype than mutations affecting the common exons 2-13. Clinical and molecular genetic analysis of a patient with features of AHO and review of exclusive exon 1 mutations of GNAS. We detected a novel heterozygous 1 bp deletion of a guanine in codon 31 in exon 1 of the GNAS gene leading to a frame shift and premature termination of Gsalpha. The female patient demonstrated a fully expressed AHO and PHPIa phenotype and a decreased Gsalpha protein activity of 62% compared to the wild type. Mutations in exon 1 are almost exclusively disruptive and lead to an AHO phenotype that does not show obvious differences from those provoked by missense or nonsense mutations in exon 2-13. Disruptive mutations in exon 1 indicate that exclusive deficiency of Gsalpha is sufficient for the expression of an AHO phenotype, which cannot be compensated by alternative products of GNAS.

Osteoma Cutis as the Presenting Feature of Albright Hereditary Osteodystrophy Associated with Pseudopseudohypoparathyroidism

Primary osteoma cutis is characterized by the formation of normal bone tissue in the dermis or subcutis without any underlying tissue abnormality or pre-existing calcification. This illness is associated with Albright hereditary osteodystrophy (AHO), which is characterized by such physical features as a short stature, round face, obesity, brachydactyly and osteoma cutis. Pseudohypoparathyroidism (PHP) is an inherited metabolic disorder that's characterized by resistance to parathyroid hormone, and PHP is present in most AHO patients. An AHO phenotype without hormonal resistance is called pseudopseudohypoparathyroidism (PPHP). Osteoma cutis is less common in patients with PPHP than in patients with PHP. We present here a case of osteoma cutis as the cardinal manifestation of AHO associated with PPHP. Osteoma cutis is an important sign of AHO and its significance should not be overlooked, even if the patient has normal values on the serum biochemical tests.

Patients with Mutations in Gsα Have Reduced Activation of a Downstream Target in Epithelial Tissues due to Haploinsufficiency

Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein signaling due to loss of function mutations in GNAS. The mechanism by which these mutations lead to the AHO phenotype has been difficult to establish due to the inaccessibility of the affected tissues. The objective of the study was to gain insight into the downstream consequences of abnormal stimulatory G protein signaling in human epithelial tissues. We assessed transcription of GNAS and Gsalpha-stimulated activation of the cystic fibrosis transmembrane conductance regulator (CFTR) in AHO patients, compared with normal controls and patients with cystic fibrosis. Relative expression of Gsalpha transcripts from each parental GNAS allele and cAMP measurements from nasal epithelial cells were compared among normal controls and AHO patients. In vivo measurements of CFTR function, pulmonary function, and pancreatic function were assessed in AHO patients. GNAS was expressed equally from each allele in normals and two of five AHO patients. cAMP generation was significantly reduced in nasal respiratory epithelial cells from AHO patients, compared with normal controls (0.4 vs. 0.6, P = 0.0008). Activation of CFTR in vivo in nasal (P = 0.0065) and sweat gland epithelia (P = 0.01) of AHO patients was significantly reduced from normal. In three patients, the reduction in activity was comparable with patients with cystic fibrosis due to mutations in CFTR. Yet no AHO patients had pulmonary or pancreatic disease consistent with cystic fibrosis. In humans, haploinsufficiency of GNAS causes a significant reduction in the activation of the downstream target, CFTR, in vivo.

Progressive osseous heteroplasia-like heterotopic ossification in a male infant with pseudohypoparathyroidism type Ia: A case report

Pseudohypoparathyroidism (PHP) Ia is a rare condition associated with multiple hormone resistance and the Albright Hereditary Osteodystrophy (AHO) phenotype. Progressive osseous heteroplasia (POH) is characterized by progressive ossifications of dermal, skeletal muscle and deep connective tissue during childhood. Both PHP Ia and POH are caused by heterozygous inactivating mutations in the GNAS gene. Maternal inheritance of a GNAS mutation leads to an AHO phenotype with hormonal resistance (PHP Ia), whereas paternal inheritance leads to an AHO phenotype without the hormonal resistance (pseudopseudo-hypoparathyroidism). Pure POH (no other AHO features) is also caused by a paternal inheritance of GNAS mutations. Mutations that cause PHP Ia when maternally inherited can cause POH when paternally inherited. We present an unusual case of a boy with clinical features of both POH and PHP Ia, and a GNAS inactivating mutation. Case presentation The patient was referred at 1 month of age with a “knot on his leg”. Plain radiographs revealed subcutaneous ossifications. PE at age 4 months included: length and weight > 95%, a round face, short 4th metacarpals, and extensive subcutaneous ossifications of the lower limbs, buttocks, and back. Studies at age 4 months included an elevated TSH 12.4 mIU/l, free T4 0.86 ng/dl (0.8–2.3), PTH 61 pg/ml (10–65), calcium 9. 8 mg/dl (9.0–11.0), and phosphorus 6. 4 mg/dl (3.8–6.5). By age 16 months, the PTH was elevated at 126 pg/ml. Biopsies of the skin lesions demonstrated osteoma cutis consistent with POH. GNAS analysis revealed a heterozygous deletion in exon 7. The mutation was not detected in either parent. Discussion POH and PHP Ia are rare genetic disorders caused by loss of function mutations of the GNAS gene. POH and PHP Ia do not commonly occur in the same individual as they are associated with paternal versus maternal inheritance (imprinting) of an affected GNAS gene. Our patient has evidence of both severe POH and PHP Ia, apparently due to a de novo mutation in GNAS.

Molecular delineation of deletions on 2q37.3 in three cases with an Albright hereditary osteodystrophy‐like phenotype

A minority of the reported cases of terminal 2q37 deletion clinically resemble Albright hereditary osteodystrophy (AHO)/pseudopseudohypoparathyroidism and have only mild-to-moderate mental retardation. Our molecular and cytogenetic fluorescence in situ hybridization (FISH) findings on an additional three patients further reduce the size of the minimal critical region deleted in this syndrome to about 3 Mb. This region includes the G-protein-coupled receptor 35 (GPR35), glypican 1 (GPC1), and serine/threonine protein kinase 25 (STK25) genes on 2q37.3. We have further defined several polymorphic variants within the coding region and flanking regions of GPR35 gene, which could potentially be useful for rapid detection of GPR35 gene deletion. We postulate that the absence of GPR35 may, at least partly, account for the phenotypic resemblance to the AHO. We also believe that the deletion of GPR35 could be responsible for the entity brachydactyly mental retardation syndrome (OMIM #600430), which was coined based on the above minority of patients with terminal 2q37 deletion. We recommend that every patient with AHO phenotype should undergo 2q subtelomeric FISH screen and subsequently a molecular study on the GPR35 gene. GPC1 and/or STK25 haploinsufficiency may also contribute to the AHO-like phenotype.

Progressive osseous heteroplasia resulting from a new mutation in the GNAS1 gene

Progressive osseous heteroplasia (OMIM 166350) is a rare autosomal dominant condition that presents in childhood as dermal ossification and may progress deeper to involve subcutaneous fat and connective tissue. Recently, paternally inherited inactivating mutations in the GNAS1 gene on chromosome 20q13 have been implicated in the pathogenesis, although sporadic cases have also been reported. We report a 9-year-old British Chinese girl with progressive osseous heteroplasia resulting from a de novo missense mutation (W281R) in the GNAS1 gene. She is of small stature (0.4th centile) and started to develop skin lesions at the age of 9 months. These have been confirmed histologically as osteoma cutis. She is of normal intelligence and development and has no dysmorphic features. The GNAS1 gene exhibits imprinting and maternally inherited mutations have previously been shown to result in Albright's hereditary osteodystrophy (OMIM 103580) with pseudohypothyroidism type 1a, whereas paternally inherited mutations result in progressive osseous heteroplasia or the Albright's hereditary osteodystrophy phenotype with pseudopseudohypothyroidism (OMIM 300800). With only nine mutations of the GNAS1 gene reported so far in progressive osseous heteroplasia, this new mutation helps to extend further the genotype-phenotype correlation.

Gs(alpha) mutations and imprinting defects in human disease.

Gs is the ubiquitously expressed heterotrimeric G protein that couples receptors to the effector enzyme adenylyl cyclase and is required for receptor-stimulated intracellular cAMP generation. Activated receptors promote the exchange of GTP for GDP on the Gs alpha-subunit (Gs(alpha)), resulting in Gs activation; an intrinsic GTPase activity of Gs(alpha) deactivates Gs by hydrolyzing bound GTP to GDP. Mutations of Gs(alpha) residues involved in the GTPase reaction that lead to constitutive activation are present in endocrine tumors, fibrous dysplasia of bone, and McCune-Albright syndrome. Heterozygous loss-of-function mutations lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, and skeletal defects, and are sometimes associated with progressive osseous heteroplasia. Maternal transmission of Gs(alpha) mutations leads to AHO plus resistance to several hormones (e.g., parathyroid hormone) that activate Gs in their target tissues (pseudohypoparathyroidism type IA), while paternal transmission leads only to the AHO phenotype (pseudopseudohypoparathyroidism). Studies in both mice and humans demonstrate that Gs(alpha) is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues and biallelically expressed in most other tissues. This likely explains why multihormone resistance occurs only when Gs(alpha) mutations are inherited maternally. The Gs(alpha) gene GNAS1 has at least four alternative promoters and first exons, leading to the production of alternative gene products including Gs(alpha), XL alphas (a novel Gs(alpha) isoform expressed only from the paternal allele), and NESP55 (a chromogranin-like protein expressed only from the maternal allele). The fourth alternative promoter and first exon (exon 1A) located just upstream of the Gs(alpha) promoter is normally methylated on the maternal allele and is transcriptionally active on the paternal allele. In patients with parathyroid hormone resistance but without AHO (pseudohypoparathyroidism type IB), the exon 1A promoter region is unmethylated and transcriptionally active on both alleles. This GNAS1 imprinting defect is predicted to decrease Gs(alpha) expression in tissues where Gs(alpha) is normally imprinted and therefore to lead to renal parathyroid hormone resistance.