Pseudohypoparathyroidism Type Ia Research Articles

Clinical and Molecular Characteristics and Long-term Follow-up of Children With Pseudohypoparathyroidism Type IA.

Pseudohypoparathyroidism type IA (PHPIA) is a rare genetic disorder characterized by hormone resistance and a typical phenotype named Albright hereditary osteodystrophy. Unawareness of this rare disease leads to delays in diagnosis. The aims of this study were to describe the clinical and molecular characteristics of patients with genetically confirmed GNAS mutations and to evaluate their long-term outcomes. A retrospective search for all patients diagnosed with PHPIA in 2 referral centers in Israel was conducted. Nine children (8 females) belonging to 6 families were included in the study. Five patients had GNAS missense mutations, 2 had deletions, and 2 had frameshift mutations. Four mutations were novel. Patients were referred at a mean age of 2.4 years due to congenital hypothyroidism (5 patients), short stature (2 patients), or obesity (2 patients), with a follow-up duration of up to 20 years. Early obesity was observed in the majority of patients. Elevated parathyroid hormone was documented at a mean age of 3 years; however, hypocalcemia became evident at a mean age of 5.9 years, about 3 years later. All subjects were diagnosed with mild to moderate mental retardation. Female adult height was very short (mean -2.5 SD) and 5 females had primary or secondary amenorrhea. Long-term follow-up of newborns with a combination of congenital hypothyroidism, early-onset obesity, and minor dysmorphic features associated with PHPIA is warranted and molecular analysis is recommended since the complete clinical phenotype may develop a long time after initial presentation.

Overweight and obesity in children and adolescents with endocrine disorders.

Obesity has become a serious medical condition where many factors can contribute to excess weight gain. The most common type of childhood obesity is simple obesity, which is due to gene-obesogenic environment interaction. Only a minority are due to pathological causes. Secondary causes of obesity, while less common, include these: genetic syndromes, drug-related obesity, as well as endocrine disorders (hypothyroidism, Cushing's syndrome, growth hormone deficiency, hypogonadism, pseudohypoparathyroidism type Ia, insulinoma, hypothalamic obesity and polycystic ovary syndrome). Given that some conditions may be treatable, physicians must be aware of obesity due to endocrinopathies and distinguish them from simple obesity, and treat them properly. Although rare among children, early detection of the endocrine cause of obesity leads to reduced morbidity and, in some cases, reduced mortality in these individuals. The aim of this review is to summarize the current findings on obesity-related endocrinopathies in children (illustrated by clinical examples), highlighting aspects of pathogenetic mechanisms, genetics, the clinical diagnosis, growth, body mass index and possible therapeutic approaches. Early detection and correction of endocrine obesity is of paramount importance for obese children who could benefit from timely diagnosis and an improved management of obesity as many disturbances related to obesity can be reversed at the early stage, if weight loss is achieved.

Abstract #1413302: A Case of a 25-Year-Old Woman with Congenital Pseudohypoparathyroidism and Hypothyroidism with Prediabetes

Pseudohypoparathyroidism (PHP) is a group of rare disorders, with fewer than 60 clinically-confirmed cases worldwide by 2016. PHP and related disorders mostly result from the genetic and/or epigenetic changes that cause end-organ parathyroid hormone resistance with a cyclic adenosine monophosphate (cAMP) generator down-regulation. These changes are often associated with the GNAS gene. PHP type IA tends to present with hypocalcemia, hyperphosphatemia, elevated PTH levels and Albright hereditary osteodystrophy (AHO). Clinical features of AHO are obesity, round face, short stature, brachydactyly (BD), subcutaneous ossifications and mental retardation. PHP is associated with increased risk for metabolic syndrome and diabetes with related complications. We present a case of a 25-year-old woman, who was referred to the adult Endocrinology clinic for management of PHP type IA and hypothyroidism by her primary care provider who was managing her condition for the last 7 years. She was last evaluated by her pediatric endocrinologist at age 18. She was initially diagnosed with PHP and hypothyroidism at age 7 after a syncopal episode requiring hospitalization. She had severely low serum calcium and elevated thyroid stimulating hormone levels upon diagnosis. She has a past medical history of seizures as a child. There is no family history of PHP. On physical examination, she had a round face with short stature, shortened chubby extremities and absent knuckles in all except index fingers of both hands. She weighed 173 pounds with a height of 62 inches and a BMI of 31.64. She is currently taking 150 mcg oral once daily levothyroxine, 0.25 mcg oral once daily calcitriol and calcium carbonate 625 mg oral four times per day. Laboratory investigations: Her TSH is 3.4, serum calcium is 8.7mg/dl, intact parathyroid hormone level is 169.4 picograms/milliliter. Her 25-OH-vitamin D level is low at 14.8nanogram/milliliter. Her serum Phosphorus is high at 5.3 mg/dl and her HbA1c is high at 5.8 mg/dl. Her lipid profile is normal except for a low level of HDL at 35 mg/dl. Patients with PHP are at higher risk for weight gain, type 2 diabetes, dyslipidemia and hypertension. Our patient with PHP and prediabetes was referred to the dietitian for nutrition education. Increasing physical activity was recommended. Vitamin D deficiency was treated with a high dose vitamin D course. Calcium and calcitriol treatments were continued. We conclude that patients with PHP should transition from pediatric endocrinology to adult endocrinology in a timely fashion for regular follow-ups to avoid morbidity and mortality. Educational programmes, as well as psychological support, should be provided to patients and families even in the presence of a normal BMI as a preventive strategy.

Preferential Maternal Transmission of STX16-GNAS Mutations Responsible for Autosomal Dominant Pseudohypoparathyroidism Type Ib (PHP1B): Another Example of Transmission Ratio Distortion.

Preferential transmission of a genetic mutation to the next generation, referred to as transmission ratio distortion (TRD), is well established for several dominant disorders, but underlying mechanisms remain undefined. Recently, TRD was reported for patients affected by pseudohypoparathyroidism type Ia or pseudopseudohypoparathyroidism. To determine whether TRD is observed also for autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP1B), we analyzed kindreds with the frequent 3-kb STX16 deletion or other STX16/GNAS mutations. If inherited from a female, these genetic defects lead to loss-of-methylation at exon A/B alone or at all three differentially methylated regions (DMR), resulting in parathyroid hormone (PTH)-resistant hypocalcemia and hyperphosphatemia and possibly resistance to other hormones. In total, we investigated 212 children born to 80 females who are unaffected carriers of a STX16/GNAS mutation (n = 47) or affected by PHP1B (n = 33). Of these offspring, 134 (63.2%) had inherited the genetic defect (p = .00012). TRD was indistinguishable for mothers with a STX16/GNAS mutation on their paternal (unaffected carriers) or maternal allele (affected). The mechanisms favoring transmission of the mutant allele remain undefined but are likely to include abnormalities in oocyte maturation. Search for mutations in available descendants of males revealed marginally significant evidence for TRD (p = .038), but these analyses are less reliable because many more offspring of males than females with a STX16/GNAS mutation were lost to follow-up (31 of 98 versus 6 of 218). This difference in follow-up is probably related to the fact that inheritance of a mutation from a male does not have clinical implications, whereas inheritance from an affected or unaffected female results in PHP1B. Lastly, affected PHP1B females had fewer descendants than unaffected carriers, but it remains unclear whether abnormal oocyte development or impaired actions of reproductive hormones are responsible. Our findings highlight previously not recognized aspects of AD-PHP1B that are likely to have implications for genetic testing and counseling. © 2020 American Society for Bone and Mineral Research (ASBMR).

Impaired iloprost-induced platelet inhibition and phosphoproteome changes in patients with confirmed pseudohypoparathyroidism type Ia, linked to genetic mutations in GNAS

Patients diagnosed with pseudohypoparathyroidism type Ia (PHP Ia) suffer from hormonal resistance and abnormal postural features, in a condition classified as Albright hereditary osteodystrophy (AHO) syndrome. This syndrome is linked to a maternally inherited mutation in the GNAS complex locus, encoding for the GTPase subunit Gsα. Here, we investigated how platelet phenotype and omics analysis can assist in the often difficult diagnosis. By coupling to the IP receptor, Gsα induces platelet inhibition via adenylyl cyclase and cAMP-dependent protein kinase A (PKA). In platelets from seven patients with suspected AHO, one of the largest cohorts examined, we studied the PKA-induced phenotypic changes. Five patients with a confirmed GNAS mutation, displayed impairments in Gsα-dependent VASP phosphorylation, aggregation, and microfluidic thrombus formation. Analysis of the platelet phosphoproteome revealed 2,516 phosphorylation sites, of which 453 were regulated by Gsα-PKA. Common changes in the patients were: (1) a joint panel of upregulated and downregulated phosphopeptides; (2) overall PKA dependency of the upregulated phosphopeptides; (3) links to key platelet function pathways. In one patient with GNAS mutation, diagnosed as non-AHO, the changes in platelet phosphoproteome were reversed. This combined approach thus revealed multiple phenotypic and molecular biomarkers to assist in the diagnosis of suspected PHP Ia.

GNAS, PDE4D, and PRKAR1A Mutations and GNAS Methylation Changes Are Not a Common Cause of Isolated Early-Onset Severe Obesity Among Finnish Children.

Context: Pseudohypoparathyroidism type Ia (PHP1A) is caused by inactivating mutations involving GNAS exons 1–13, encoding the alpha-subunit of the stimulatory G protein (Gsα). Particularly PHP1A, but also other disorders involving the Gsα-cAMP-signaling pathway, have been associated with early-onset obesity. Thus, patients with mutations in the genes encoding PDE4D and PRKAR1A can also be obese. Furthermore, epigenetic GNAS changes, as in pseudohypoparathyroidism type Ib (PHP1B), can lead to excessive weight.Objective: Search for genetic variants in GNAS, PDE4D, and PRKAR1A and for methylation alterations at the GNAS locus in Finnish subjects with isolated severe obesity before age 10 years.Methods: Next generation sequencing to identify pathogenic variants in the coding exons of GNAS, PDE4D, and PRKAR1A; Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-sensitive MLPA (MS-MLPA) to search for deletions in GNAS and STX16, and for epigenetic changes at the four differentially methylated regions (DMR) within GNAS.Results: Among the 88 subjects (median age 13.8 years, median body mass index Z-score +3.9), we identified one rare heterozygous missense variant of uncertain significance in the XL exon of GNAS in a single patient. We did not identify clearly pathogenic variants in PDE4D and PRKAR1A, and no GNAS methylation changes were detected by MS-MLPA.Conclusions: Our results suggest that coding GNAS mutations or methylation changes at the GNAS DMRs, or coding mutations in PDE4D and PRKAR1A are not common causes of isolated childhood obesity in Finland.

以早发性皮肤结节为诊断线索的假性甲状旁腺功能减退Ⅰa型二例临床特点和基因分析

Clinical features of and genetic mutations in two cases of pseudohypoparathyroidism type Ⅰa (PHPⅠa) with early-onset skin nodules were analyzed. Both of the two patients were males, and their ages at onset were 2 and 3 months respectively. They both presented with early-onset skin nodules as the main clinical manifestation, and were clinically characterized by a round face, short neck and early obesity. Histopathological examination of skin lesions showed subcutaneous ectopic osteogenesis in both patients. The first patient had low blood calcium, high blood phosphorus, high parathyroid hormone (PTH) , and gene sequencing showed a heterozygous mutation c.399delT causing a T base deletion at position 399 in exon 5 of the GNAS gene. The second patient had normal blood calcium and phosphorus levels as well as normal PTH levels at early stage, and gene sequencing showed a heterozygous mutation c.939delT causing a T base deletion at position 939 in exon 9 of the GNAS gene. The blood PTH level was found to increase in the second patient after 1-year follow-up. Both the patients were confirmedly diagnosed with PHPⅠa. After treatment with vitamin D3, no new skin nodules occurred, and the blood calcium and phosphorus levels returned to normal. Key words: Pseudohypoparathyroidism; Cholecalciferol; DNA mutational analysis; Skin manifestations; GNAS gene

Central precocious puberty in a boy with pseudohypoparathyroidism type Ia due to a novel GNAS mutation.

Central precocious puberty in a boy with pseudohypoparathyroidism type Ia due to a novel GNAS mutation.

Fahrov sindrom - neurološka manifestacija endokrinološkog oboljenja

Syndrome Fahr is described as calcification of the basal ganglia and is a rare inherited or sporadic neurological disease with a prevalence of 1:1000000 (1). For the first time described in 1930 in the works of Dr. Karl Theodor Fahr, it is characterized by calcium deposition in areas of the brain to control movement: basal gamma, thalamus, cerebral cortex, cerebellum, dentate nucleus, subcortical white matter and hippocampus (2). The diagnostic criteria were revised and modified by Moskowitz et al. in 1971., Ellie et al. in 1989. and Manyam in 2005. and include: bilateral calcifications of the basal ganglia confirmed by neuroradiological visualization, progressive neurological dysfunction and neuropsychiatric manifestations, absence of biochemical and somatic entities of mitochondrial disease, absence of infectious, traumatic, or toxic etiology, and autosomal dominant inheritance (2,3,4). Etiologically, endocrine diseases, and especially parathyroid gland dysfunction, are closely related to Farr's syndrome, including idiopathic hypoparathyroidism, secondary hypoparathyroidism, pseudohypoparathyroidism, pseudo-pseudohypoparathyroidism, and hyperparathyroidism. Pseudo and pseudo-pseudohypoparathyroidism are defined by a phenotypic spectrum induced by a mutation in RNA. They manifest on average at the age of 8 to 10, with clinical manifestations very similar to hypoparathyroidism, except for a slightly more pronounced intellectual declension. The term pseudohypoparathyroidism (PHP) for subtypes PHP type IA and PHP type 1C includes diseases that share the biochemical characteristics of hypoparathyroidism (hypocalcemia and hyperphosphatemia), and which are the consequences of resistance of target tissues to the action of parathyroid hormone. In some cases, resistance to TSH, gonadotropins, GHRH and calcitonin, which have receptors bound to the Gs Alpha subunit, is detected. Patients with type 1A and type 1C PHP show diverse phenotypic expression combined by the term Albright hereditary osteodystrophy (AHO), which includes premature closure of bone and short bone growth zones, low growth, ectopic calcifications. More specifically, based on the dissemination of ectopic calcifications, patients were classified into three categories: pseudohypoparathyroidism, progressive bone heteroplasia, and osteoma cutis. Our patient was diagnosed as pseudohypoparathyroidism at an early age based on the phenotype characteristics of AHO and the biochemical findings of hypocalcemia. Substitution therapy with vitamin D and calcium was introduced, and after pronounced changes in behavior, feelings of being followed and extreme anxiety, he was hospitalized in the Clinic for Neurology and in the Clinic for Endocrinology, Clinical Center of Serbia. Neurofunctional studies have shown progressive decline in intellectual function, neuroradiologically were detected zones of calcification of the basal ganglia and frontal subcortical white matter, as well as hypothyroidism as a consequence of TSH resistance. High concentrations of calcitonin were detected, also as a consequence of resistance of target tissues to calcitonin.

Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis.

The stimulatory G-protein α-subunit encoded by GNAS exons 1-13 (GNAS-Gsα) mediates signal transduction of multiple G protein-coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function GNAS-Gsα variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function GNAS-Gsα variants have been detected in McCune-Albright syndrome and may result in phosphate wasting. However, no germline-derived gain-of-function variant has been identified, implying that such a variant causes embryonic lethality. We performed whole-exome sequencing in two families with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD) as a salient phenotype after excluding a gain-of-function variant of AVPR2 and functional studies for identified variants. Whole-exome sequencing revealed two GNAS-Gsα candidate variants for NSIAD: GNAS-Gsα p.(F68_G70del) in one family and GNAS-Gsα p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, GNAS-Gsα alone was involved in AVPR2 signaling and shared by the families. Protein structural analyses revealed a gain-of-function-compatible conformational property for p.M255V-Gsα, although such assessment was not possible for p.F68_G70del-Gsα. Both variants had gain-of-function effects that were significantly milder than those of McCune-Albright syndrome-specific somatic Gsα variants. Model mice for p.F68_G70del-Gsα showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gsα exhibited severe failure to thrive. This study shows that germline-derived gain-of-function rare variants of GNAS-Gsα exist and cause NSIAD as a novel Gsα-mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to GNAS-Gsα's gain-of-function effects.

A case of pseudohypoparathyroidism type Ia with a novel frameshift mutation in the GNAS gene: early diagnosis of osteoma cutis by skin biopsy.

A case of pseudohypoparathyroidism type Ia with a novel frameshift mutation in the GNAS gene: early diagnosis of osteoma cutis by skin biopsy.

A Heterozygous Splice-Site Mutation in PTHLH Causes Autosomal Dominant Shortening of Metacarpals and Metatarsals.

Short metacarpals and/or metatarsals are typically observed in pseudohypoparathyroidism (PHP) type Ia (PHP1A) or pseudo-PHP (PPHP), disorders caused by inactivating GNAS mutations involving exons encoding the alpha-subunit of the stimulatory G protein (Gsα). Skeletal abnormalities similar to those in PHP1A/PPHP were present in several members of an extended Belgian family without evidence for abnormal calcium and phosphate regulation. Direct nucleotide sequencing of genomic DNA from an affected individual (190/III-1) excluded GNAS mutations. Instead, whole exome analysis revealed a novel heterozygous A>G change at nucleotide -3 upstream of PTHLH exon 3 that encodes the last two amino acids of the prosequence and the mature PTHrP. The same nucleotide change was also found in her affected mother and maternal aunt (190/II-2, 190/II-1), and her affected twin sons (190/IV-1, 190/IV-2), but not in her unaffected daughter (190/IV-3) and sister (190/III-2). Complementary DNA derived from immortalized lymphoblastoid cells from 190/IV-2 (affected) and 190/IV-3 (unaffected) was PCR-amplified using forward primers located either in PTHLH exon 1 (noncoding) or exon 2 (presequence and most of the prosequence), and reverse primers located in the 3'-noncoding regions of exons 3 or 4. Nucleotide sequence analysis of these amplicons revealed for the affected son 190/IV-2, but not for the unaffected daughter 190/IV-3, a heterozygous insertion of genomic nucleotides -2 and -1 causing a frameshift after residue 34 of the pre/prosequence and thus 29 novel residues without homology to PTHrP or any other protein. Our findings extend previous reports indicating that PTHrP haploinsufficiency causes skeletal abnormalities similar to those observed with heterozygous GNAS mutations. © 2018 American Society for Bone and Mineral Research.

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.

GNAS mutations and heterotopic ossification.

GNAS is a complex imprinted gene encoding the alpha-subunit of the stimulatory heterotrimeric G protein (Gsα). GNAS gives rise to additional gene products that exhibit exclusively maternal or paternal expression, such as XLαs, a large variant of Gsα that shows exclusively paternal expression and is partly identical to the latter. Gsα itself is expressed biallelically in most tissues, although the expression occurs predominantly from the maternal allele in a small set of tissues, such as renal proximal tubules. Inactivating mutations in Gsα-coding GNAS exons are responsible for Albright's hereditary osteodystrophy (AHO), which refers to a constellation of physical and developmental disorders including obesity, short stature, brachydactyly, cognitive impairment, and heterotopic ossification. Patients with Gsα mutations can present with AHO in the presence or absence of end-organ resistance to multiple hormones including parathyroid hormone. Maternal Gsα mutations lead to AHO with hormone resistance (i.e. pseudohypoparathyroidism type-Ia), whereas paternal mutations cause AHO alone (i.e. pseudo-pseudohypoparathyroidism). Heterotopic ossification associated with AHO develops through intramembranous bone formation and is limited to dermis and subcutis. In rare cases carrying Gsα mutations, however, ossifications progress into deep connective tissue and skeletal muscle, a disorder termed progressive osseous heteroplasia (POH). Here I briefly review the genetic, clinical, and molecular aspects of these disorders caused by inactivating GNAS mutations, with particular emphasis on heterotopic ossification.

A novel deletion involving GNAS exon 1 causes PHP1A and further refines the region required for normal methylation at exon A/B

GNAS exons 1–13 encode the biallelically expressed alpha-subunit of the stimulatory G protein (Gαs). Additional transcripts derived from this locus use alternative first exons that undergo parent-specific methylation, thus allowing transcription only from the non-modified allele. Pseudohypoparathyroidism type Ia (PHP1A) is characterized by Albright's Hereditary Osteodystrophy (AHO) and resistance to multiple hormones; this disorder is caused by maternal inactivating mutations involving Gαs exons. In contrast, pseudohypoparathyroidism type Ib (PHP1B) is characterized mostly by resistance to PTH and often mild TSH resistance, usually without AHO features. The autosomal dominant variant of PHP1B (AD-PHP1B) is caused by maternal deletions in GNAS or STX16 that reduce Gαs expression through loss-of-methylation at GNAS exon A/B alone or at multiple differentially methylated regions (DMR). Several large maternal deletions involve not only GNAS exons 1–13, but also one or several GNAS DMRs, thus causing PHP1A combined with apparent GNAS epigenetic changes that are indistinguishable from those observed in PHP1B. Some of these deletions include a large CpG island extending from exon A/B to the intron between GNAS exons 1 and 2, but there is no evidence for parent-specific exon 1 methylation. We now describe a family in which the female proband and her daughter presented with hypocalcemia, elevated PTH levels, shortened metacarpals, and obesity, but without obvious neurocognitive abnormalities. A maternally inherited 2015-bp deletion that includes GNAS exon 1 was identified thereby establishing the diagnosis of PHP1A. The centromeric deletion breakpoint is located 178bp upstream of exon 1, yet no methylation changes were observed at exon A/B. This novel deletion therefore refines further the region between exon A/B and exon 1 that is critical for establishing or maintaining normal methylation at GNAS exon A/B.

Mice maintain predominantly maternal Gαs expression throughout life in brown fat tissue (BAT), but not other tissues

The murine Gnas (human GNAS) locus gives rise to Gαs and different splice variants thereof. The Gαs promoter is not methylated thus allowing biallelic expression in most tissues. In contrast, the alternative first Gnas/GNAS exons and their promoters undergo parent specific methylation, which limits transcription to the non-methylated allele. Pseudohypoparathyroidism type Ia (PHP1A) or type Ib (PHP1B) are caused by heterozygous maternal GNAS mutations suggesting that little or no Gαs is derived in some tissues from the non-mutated paternal GNAS thereby causing hormonal resistance. Previous data had indicated that Gαs is mainly derived from the maternal Gnas allele in brown adipose tissue (BAT) of newborn mice, yet it is biallelically expressed in adult BAT. This suggested that paternal Gαs expression is regulated by an unknown factor(s) that varies considerably with age. To extend these findings, we now used a strain-specific SNP in Gnas exon 11 (rs13460569) for evaluation of parent-specific Gαs expression through the densitometric quantification of BanII-digested RT-PCR products and digital droplet PCR (ddPCR). At all investigated ages, Gαs transcripts were derived in BAT predominantly from the maternal Gnas allele, while kidney and liver showed largely biallelic Gαs expression. Only low or undetectable levels of other paternally Gnas-derived transcripts were observed, making it unlikely that these are involved in regulating paternal Gαs expression. Our findings suggest that a cis-acting factor could be implicated in reducing paternal Gαs expression in BAT and presumably in proximal renal tubules, thereby causing PTH-resistance if the maternal GNAS/Gnas allele is mutated.

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.

Endocrinological and phenotype evaluation in a patient with acrodysostosis.

.Acrodysostosis is characterized by distinctive facial features and severe brachydactyly. Mutations in PRKAR1A or PDE4D are known to be responsible for this disease. Cases of hormonal resistance have been reported, particularly in patients with PRKAR1A mutations. The physical characteristics and endocrine function of pseudohypoparathyroidism type Ia is known to resemble acrodysostosis. We report the case of a 4-yr-old patient with a PRKAR1A mutation. He had characteristic facies with an upturned nose and cone-shaped epiphyses of most phalanges. These findings have not been reported as extensive for cases of pseudohypoparathyroidism type Ia. He also had TSH resistance from birth. We performed endocrinological stimulation tests to further evaluate his endocrine status. These examinations revealed resistance to TSH and PTH, but there was normal secretion of ACTH, GH, and cortisol. An Ellsworth-Howard test resulted in normal urinary cAMP excretion. This response differs from that of pseudohypoparathyroidism type Ia. In summary, the constellation of an upturned nose, cone-shaped epiphyses of most if not all phalanges, and PTH resistance with a normal urinary cAMP response may satisfactorily enable clinical diagnosis of acrodysostosis.

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).

The Association of Pseudohypoparathyroidism Type Ia with Chiari Malformation Type I: A Coincidence or a Common Link?

A 19-month-old boy was referred for progressive weight gain. His past medical history included congenital hypothyroidism and developmental delay. Physical examination revealed characteristics of Albright Hereditary Osteodystrophy, macrocephaly, and calcinosis cutis. He had hypocalcemia, hyperphosphatemia, and elevated Parathyroid Hormone levels. Genetic testing revealed a known mutation of GNAS gene, confirming the diagnosis of Pseudohypoparathyroidism Type Ia (PHP-Ia) (c.34C>T (p.G1n12X)). He had a normal brain MRI at three months, but developmental delay prompted a repeat MRI that revealed Chiari Malformation Type I (CM-I) with hydrocephalus requiring neurosurgical intervention. This was followed by improvement in attaining developmental milestones. Recently, he was diagnosed with growth hormone deficiency. This case suggests the potential association of CM-I with PHP-Ia. Larger studies are needed to assess whether CM-I with hydrocephalus are common associations with PHP-Ia and to define potential genetic links between these conditions. We propose a low threshold in performing brain MRI on PHP-1a patients, especially those with persistent developmental delay to rule out CM-I. Early intervention may improve neurodevelopmental outcomes and prevent neurosurgical emergencies.