Evaluating the variety of GNAS inactivation disorders and their clinical manifestations in 11 Chinese children.

BACKGROUND: The GNAS gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of GNAS inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis. METHODS: We enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations. RESULTS: Among these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright's hereditary osteodystrophy (AHO) phenotype. GNAS abnormalities were detected in all 11 patients, including nine cases with GNAS gene variations and two cases with GNAS methylation defects. These GNAS variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > A, were found to be novel. This data was then used to assign a GNAS subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH. CONCLUSIONS: Evaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of GNAS mutations significantly. In addition, our results suggest that when GNAS gene sequencing is negative, GNAS methylation study should be performed. Early genetic detection is required for the differential diagnosis of GNAS disorders and is critical to the clinician's ability to distinguish between heterotopic ossification in the POH and AHO phenotype.

A Case of Soft Tissue Ossifications: A Case Report.

CASE: A patient who had previously been diagnosed with fibrodysplasia ossificans progressiva was seen for hip pain and progressive soft tissue ossifications. Through a careful clinical examination, by which a subtype of brachydactyly was noted, the Albright hereditary osteodystrophy phenotype was recognized, and a new diagnosis of pseudopseudohypoparathyroidism was established. This paucisymptomatic condition often remains unidentified; however, its transmission can lead to more potentially serious diseases. CONCLUSIONS: A careful diagnostic process, including physical examination, is essential. Even if advanced tests exist, small clinical findings can lead to the proper conclusion. In our case, a finger pointed us in the right direction.

Management of pseudohypoparathyroidism.

PURPOSE OF REVIEW: This review is timely given the 2018 publication of the first international Consensus Statement for the diagnosis and management of pseudohypoparathyroidism (PHP) and related disorders. The purpose of this review is to provide the knowledge needed to recognize and manage PHP1A, pseudopseudohypoparathyroidism (PPHP) and PHP1B - the most common of the subtypes - with an overview of the entire spectrum and to provide a concise summary of management for clinical use. This review will draw from recent literature as well as personal experience in evaluating hundreds of children and adults with PHP. RECENT FINDINGS: Progress is continually being made in understanding the mechanisms underlying the PHP spectrum. Every year, through clinical and laboratory studies, the phenotypes are elucidated in more detail, as are clinical issues such as short stature, brachydactyly, subcutaneous ossifications, cognitive/behavioural impairments, obesity and metabolic disturbances. Headed by a European PHP consortium, experts worldwide published the first international Consensus that provides detailed guidance in a systematic manner and will lead to exponential progress in understanding and managing these disorders. SUMMARY: As more knowledge is gained from clinical and laboratory investigations, the mechanisms underlying the abnormalities associated with PHP are being uncovered as are improvements in management.

Presentation of pseudohypoparathyroidism and pseudopseudohypoparathyroidism with skin lesions: Case reports and review.

We report three cases of patients with pseudohypoparathyroidism or pseudopseudohypoparathyroidism. These diseases are considered GNAS inactivating mutation syndromes that are characterized by a diversity of alterations among which a particular phenotype and specific endocrine or ossification abnormalities may be found. These patients may present with hard cutaneous nodules, which can represent osteoma cutis. The presence of these lesions in pediatric patients should prompt the dermatologist's consideration of this group of diseases when reaching a diagnosis. A multidisciplinary team of pediatricians, endocrinologists, geneticists, and dermatologists should carefully evaluate these patients.

Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed With Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism.

The cyclic adenosine monophosphate (cAMP) intracellular signaling pathway mediates the physiological effects of several hormones and neurotransmitters, acting by the activation of G-protein coupled receptors (GPCRs) and several downstream intracellular effectors, including the heterotrimeric stimulatory G-protein (Gs), the cAMP-dependent protein kinase A (PKA), and cAMP-specific phosphodiesterases (PDEs). Defective G-protein-mediated signaling has been associated with an increasing number of disorders, including Albright hereditary osteodistrophy (AHO) and pseudohypoparathyroidism (PHP), a heterogeneous group of rare genetic metabolic disorders resulting from molecular defects at the GNAS locus. Moreover, mutations in PRKAR1A and PDE4D genes have been recently detected in patients with acrodysostosis (ACRDYS), showing a skeletal and endocrinological phenotype partially overlapping with AHO/PHP. Despite the high detection rate of molecular defects by currently available molecular approaches, about 30% of AHO/PHP patients still lack a molecular diagnosis, hence the need to screen patients negative for GNAS epi/genetic defects also for chromosomal regions and genes associated with diseases that undergo differential diagnosis with PHP. According to the growing knowledge on Gsα-cAMP signaling-linked disorders, we investigated our series of patients (n = 81) with a clinical diagnosis of PHP/AHO but negative for GNAS anomalies for the presence of novel genetic variants at PRKAR1A and PDE4D genes. Our work allowed the detection of 8 novel missense variants affecting genes so far associated with ACRDYS in 9 patients. Our data further confirm the molecular and clinical overlap among these disorders. We present the data collected from a large series of patients and a brief review of the literature in order to compare our findings with already published data; to look for PRKAR1A/PDE4D mutation spectrum, recurrent mutations, and mutation hot spots; and to identify specific clinical features associated with ACRDYS that deserve surveillance during follow-up. © 2016 American Society for Bone and Mineral Research.

Pseudohypoparathyroidism vs. tricho-rhino-phalangeal syndrome: patient reclassification.

OBJECTIVES: Given that tricho-rhino-phalangeal syndrome (TRPS) and pseudohypoparathyroidism/pseudopseudohypoparathyroidism (PHP/PPHP) are very rare monogenic disorders that share some features (distinctive facies, short stature, brachydactyly and, in some patients, intellectual disability) that lead to their misdiagnosis in some cases, our objective was to identify clinical, biochemical or radiological signs that could help to distinguish these two syndromes. METHODS AND RESULTS: We report on two cases, which were referred to the Endocrinology and Pediatric Endocrinology Services for obesity. Clinical evaluation initially suggested the diagnosis of PHP-Ia [phenotype suggestive of Albright hereditary osteodystrophy (AHO) with parathyroid hormone (PTH) resistance] and PPHP (phenotype resembling AHO, without PTH resistance), but (epi)genetic analysis of the GNAS locus ruled out the suspected diagnosis. Further clinical re-evaluation prompted us to suspect TRPS, and this was confirmed genetically. CONCLUSION: TRPS was mistakenly identified as PHP/PPHP because of the coexistence of obesity and brachydactyly, with PTH resistance in one of the cases. Specific traits such as sparse scalp hair and a pear-shaped nose, present in both cases, can be considered pathognomonic signs of TRPS, which could help us to reach a correct diagnosis.

Brachydactyly mental retardation syndrome in differential diagnosis of pseudopseudohypoparathyroidism.

Patients with Albright hereditary osteodystrophy (AHO) phenotype are usually seen in pediatric endocrinology policlinics when they are evaluated for short stature and/or obesity. Brachydactyly mental retardation syndrome (BDMR, OMIM #600430) is a rare genetic disorder caused by aberrations of chromosomal region 2q37 and characterized with AHO-like phenotype without any hormone resistance. Diagnosis of BDMR is based on the detection of the deletion on the long arm of chromosome 2. Diagnosis can usually be made with karyotype analysis but sometimes chromosomal deletion can only be detected by fluorescent in situ hybridization (FISH) screening. We report a patient with the AHO phenotype whose karyotype was normal but who was diagnosed with BDMR with FISH analysis showing 2q deletion. In pediatric endocrinology practice, in patients with AHO phenotype but without parathormone (PTH) resistance, BDMR should be considered. For the diagnosis of BDMR, the subtelomeric region of chromosome 2 should be screened for deletion by FISH analysis even in patients with normal karyotypes.

Pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism: the growing spectrum of GNAS inactivating mutations.

Pseudohypoparathyroidism (PHP) is a rare heterogeneous genetic disorder characterized by end-organ resistance to parathyroid hormone due to partial deficiency of the α subunit of the stimulatory G protein (Gsα), encoded by the GNAS gene. Heterozygous inactivating GNAS mutations lead to either PHP type Ia (PHP-Ia), when maternally inherited, or pseudo-pseudohypoparathroidism (PPHP), if paternally derived. Both diseases feature typical physical traits identified as Albright's hereditary osteodystrophy in the presence or absence of multihormone resistance, respectively. GNAS mutations are detected in 60-70% of affected subjects, most patients/families harbor private mutations and no genotype-phenotype correlation has been found to date. We investigated Gsα-coding GNAS exons in a large panel of PHP-Ia-PPHP patients collected over the past decade in the two Italian referring centers for PHP. Of 49 patients carrying GNAS mutations, we identified 15 novel mutations in 19 patients. No apparent correlation was found between clinical/biochemical data and results of molecular analysis. Furthermore, we summarized the current knowledge of GNAS molecular pathology and updated the GNAS-locus-specific database. These results further expand the spectrum of GNAS mutations associated with PHP/PPHP and underline the importance of identifying such genetic alterations to supplement clinical evaluation and genetic counseling.

Clinical characterization and identification of two novel mutations of the GNAS gene in patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism.

OBJECTIVE: Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are rare disorders resulting from genetic and epigenetic aberrations in the GNAS locus. DESIGN: Investigation of clinical characteristics and molecular analysis in PHP and PPHP. PATIENTS: Fourteen subjects from 13 unrelated families including subjects with PPHP (n = 1), PHP-Ia (n = 6) and PHP-Ib (n = 7) were enrolled. MEASUREMENTS: Clinical data, including age at presentation, presenting symptom, auxological findings, family history, presence of Albright hereditary osteodystrophy (AHO) features and hormonal and biochemical findings, were analysed. The GNAS locus was subjected to direct sequencing and methylation analysis using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). RESULTS: Of the 13 PHP subjects, 10 (three PHP-Ia and seven PHP-Ib) presented with hypocalcemic tetany at ages ranging from 7 to 14·8 years. Subcutaneous calcification was observed as an early manifestation of AHO in one PHP-Ia patient (age, 2·9 years) and one PPHP patient (age, 7 months). Six PHP-Ia and one PPHP harboured four different heterozygous mutations within the coding region of GNAS, p.Asp189_Tyr190delinsMetfxX14, p.Val117fsX23, p.Tyr190CysfsX19, and a splicing mutation (c.659 + 1G>A), of which the latter two were novel. Five subjects with PHP-Ib exhibited complete loss of the maternal-specific methylation pattern. The remaining two PHP-Ib showed a loss of methylation of exon 1A on the maternal allele as a consequence of heterozygous 3-kb microdeletions within the STX16 gene. CONCLUSIONS: GNAS mutation analyses and MS-MLPA assays are useful molecular tools for understanding the molecular bases and confirming the diagnosis of PHP and PPHP.

Psoríase e pseudo-hipoparatireoidismo / Psoriasis and pseudohypoparathyroidism

Relato de caso clínico de paciente do sexo masculino, de 24 anos de idade, com psoríase pustulosa havia dois meses. Apresentava antecedentes de crises convulsivas e retardo do desenvolvimento neuropsicomotor. Ao exame físico o sinal de Trousseau foi positivo, e a dosagem de cálcio no soro estava acentuadamente diminuída. O diagnóstico foi de psoríase pustulosa generalisada associada a pseudo-hipoparatireoidismo. Inicialmente o paciente foi tratado com etretinato, sem controle do quadro; porém, com detecçäo da hipocalcemia e a reposiçäo do cálcio, houve melhora acentuada das lesöes cutâneas. A remissäo completa foi obtida com a correçäo da hipocalcemia. Esses resultados indicam que a hipocalcemia estava diretamente relacionada com a manutençäo das lesöes de psoríase pustulosa generalizada e pseudo-hipoparatireoidismo