Subcutaneous Ossifications Research Articles

Characterization of Digestive Manifestations in Patients with Impaired PTH/PTHrP Signaling Disorder/Pseudohypoparathyroidism.

Pseudohypoparathyroidism, newly classified as inactivating PTH/PTHrP signaling disorder (iPPSD) type 2 or type 3, is a rare disease caused by defects in the GNAS imprinted gene that encodes Gsα. The most common phenotype comprises resistance to hormones binding to G protein-coupled receptors such as PTH, PTHrP, or TSH, subcutaneous ossifications, short stature, brachydactyly, and early onset obesity. Uncommon features have been described including sleep apnea, asthma, and resistance to calcitonin. At the national French reference center for rare calcium and phosphate metabolism diseases, a large cohort of patients with iPPSD type 2 and type 3 is followed. Interestingly, digestive manifestations and in particular intractable constipation were regularly reported by families of children with iPPSD type 2 or type 3. The aim of our study was therefore to specify the frequency and characteristics of digestive manifestations in children followed up for iPPSD2 or iPPSD3 in our reference center. Thirty-six patients aged between 2 and 18 years (32 followed up for iPPSD2 and 4 for iPPSD3) were included. Parents completed a specific questionnaire to assess any digestive disorders in their child. The diagnosis of constipation was established using the Bristol visual scale in the event of a score of less than 2 according to stool appearance. Parents reported constipation through the questionnaires in 22/36 (over 60%) of the children. It was the most frequently reported digestive disorder. Among these 22 children, 19 (87%) had a Bristol score for stool shape and texture between 1 and 2 on a scale of 7, confirming constipation. Dedicated treatment had been initiated for 10 (55%) of them, yet only 3 families (16%) considered this treatment effective. Neonatal vomiting and eating disorders, such as lack of satiety or food selectivity, were also noted in 18 (50%) of patients, as was gastroesophageal reflux present in the neonatal period in 14 (40%) of children. There were no significant differences according to the type of iPPSD or patient age. Our work shows for the first time that digestive manifestations, including constipation, occur frequently in children followed for iPPSD, suggesting a potential role of Gsα and G protein receptors in the digestive tract. It is well known that constipation and digestive symptoms alter quality of life. Early management is therefore essential to improve the quality of life of children followed for iPPSD. Our data need to be confirmed on a larger cohort.

Hair follicle-resident progenitor cells are a major cellular contributor to heterotopic subcutaneous ossifications in a mouse model of Albright hereditary osteodystrophy.

Heterotopic ossifications (HOs) are the pathologic process by which bone inappropriately forms outside of the skeletal system. Despite HOs being a persistent clinical problem in the general population, there are no definitive strategies for their prevention and treatment due to a limited understanding of the cellular and molecular mechanisms contributing to lesion development. One disease in which the development of heterotopic subcutaneous ossifications (SCOs) leads to morbidity is Albright hereditary osteodystrophy (AHO). AHO is caused by heterozygous inactivation of GNAS, the gene that encodes the α-stimulatory subunit (Gαs) of G proteins. Previously, we had shown using our laboratory's AHO mouse model that SCOs develop around hair follicles (HFs). Here we show that SCO formation occurs due to inappropriate expansion and differentiation of HF-resident stem cells into osteoblasts. We also show in AHO patients and mice that Secreted Frizzled Related Protein 2 (SFRP2) expression is upregulated in regions of SCO formation and that elimination of Sfrp2 in male AHO mice exacerbates SCO development. These studies provide key insights into the cellular and molecular mechanisms contributing to SCO development and have implications for potential therapeutic modalities not only for AHO patients but also for patients suffering from HOs with other etiologies.

Identification of a novel GNAS mutation in a family with pseudohypoparathyroidism type 1A

BackgroundPseudohypoparathyroidism (PHP) is caused by loss-of-function mutations at the GNAS gene (as in the PHP type 1A; PHP1A), de novo or inherited at heterozygous state, or by epigenetic alterations at the GNAS locus (as in the PHP1B). The condition of PHP refers to a heterogeneous group of disorders that share common clinical and biological features of PTH resistance. Manifestations related to resistance to other hormones are also reported in many patients with PHP, in association with the phenotypic picture of Albright hereditary osteodystrophy characterized by short stature, round facies, subcutaneous ossifications, brachydactyly, mental retardation and, in some subtypes, obesity. The purpose of our study is to report a new mutation in the GNAS gene and to describe the significant phenotypic variability of three sisters with PHP1A bearing the same mutation.Case presentationWe describe the cases of three sisters with PHP1A bearing the same mutation but characterized by a significantly different phenotypic picture at onset and during follow-up in terms of clinical features, auxological pattern and biochemical changes. Clinical exome sequencing revealed a never before described heterozygote mutation in the GNAS gene (NM_000516.5 c.118_139 + 51del) of autosomal dominant maternal transmission in the three siblings, confirming the diagnosis of PHP1A.ConclusionsThis study reported on a novel mutation of GNAS gene and highlighted the clinical heterogeneity of PHP1A characterized by wide genotype–phenotype variability. The appropriate diagnosis has crucial implications for patient care and long-term multidisciplinary follow-up.

Genotype phenotype correlations in pseudohypoparathyroidism type 1a patients: a systemic review.

Pseudohypoparathyroidism type 1a (PHP1a) is a rare endocrine disease caused by partial defects of the α subunit of the stimulatory GTP binding protein (Gsα) resulting from maternal GNAS gene variation. The clinical manifestations are related to PTH resistance (hypocalcemia, hyperphosphatemia, and elevated serum intact PTH) in the presence or absence of multihormone resistance, and Albright's hereditary osteodystrophy (AHO). To summarize the molecular genetics results and clinical characteristics as well as to explore the correlations between them. Articles pertaining to PHP1a until May 31, 2021 were reviewed and 527 patients with genetic diagnosis were included in the data analysis. The clinical characteristics and molecular genetics results of these patients were analyzed and compared to explore the correlations between them. A total of 258 GNAS rare variants (RVs) were identified in 527 patients. The RVs were most commonly found in exons 1 and 7 (17.6% each), with frameshift (36.8%) and missense (31.3%) being the main types of RVs. The median age of onset was 5.0 years old. The most common clinical manifestations were elevation of PTH (86.7%) and AHO (87.5%). TSH resistance was the most common hormone resistance (75.5%) other than PTH resistance. Patients with missense and in-frame RVs had lower incidence rates of round face (P = 0.001) and subcutaneous ossifications (P < 0.001) than those with loss-of-function (nonsense, frameshift, splicing site variants and large deletions) variants. This study revealed the correlation between loss-of-function RVs with round face and subcutaneous ossifications in PHP 1a patients. Further exploration on genotype phenotype correlations through more standardized and prospective studies with long-term follow-up is necessary.

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.

LB965 Sonic hedgehog signaling promotes aberrant hair follicle stem cell differentiation and subcutaneous ossification formation in a mouse model of albright hereditary osteodystrophy

Albright hereditary osteodystrophy (AHO) is a disorder caused by GNAS heterozygous inactivation, and results in the spontaneous development of subcutaneous ossifications (SCOs) in the dermis and subcutaneous tissue. We have generated an AHO mouse model through global Gnas heterozygous inactivation (Gnas+/-) that phenocopies the human disorder and develops SCOs that consistently surround hair follicles (HF). Therefore, this study examined the cellular and molecular etiologies contributing to SCO formation within the HF microenvironment of Gnas+/- mice.

Aberrant Bone Regulation in Albright Hereditary Osteodystrophy dueto Gnas Inactivation: Mechanisms and Translational Implications.

This review highlights the impact of Gnas inactivation on both bone remodeling and the development of heterotopic subcutaneous ossifications in Albright hereditary osteodystrophy (AHO). Here we discuss recent advancements in understanding the pathophysiologic mechanisms of the aberrant bone development in AHO as well as potential translational implications. Gnas inactivation can regulate the differentiation and function of not only osteoblasts but also osteoclasts and osteocytes. Investigations utilizing a mouse model of AHO generated by targeted disruption of Gnas have revealed that bone formation and resorption are differentially affected based upon the parental origin of the Gnas mutation. Data suggest that Gnas inactivation leads to heterotopic bone formation within subcutaneous tissue by changing the connective tissue microenvironment, thereby promoting osteogenic differentiation of tissue-resident mesenchymal progenitors. Observed variations in bone formation and resorption based upon the parental origin of the Gnas mutation warrant future investigations and may have implications in the management and treatment of AHO and related conditions. Additionally, studies of heterotopic bone formation due to Gnas inactivation have identified an essential role of sonic hedgehog signaling, which could have therapeutic implications not only for AHO and related conditions but also for heterotopic bone formation in a wide variety of settings in which aberrant bone formation is a cause of significant morbidity.

Parental Origin of Gsα Inactivation Differentially Affects Bone Remodeling in a Mouse Model of Albright Hereditary Osteodystrophy.

ABSTRACTAlbright hereditary osteodystrophy (AHO) is caused by heterozygous inactivation of GNAS, a complex locus that encodes the alpha‐stimulatory subunit of heterotrimeric G proteins (Gsα) in addition to NESP55 and XLαs due to alternative first exons. AHO skeletal manifestations include brachydactyly, brachymetacarpia, compromised adult stature, and subcutaneous ossifications. AHO patients with maternally‐inherited GNAS mutations develop pseudohypoparathyroidism type 1A (PHP1A) with resistance to multiple hormones that mediate their actions through G protein‐coupled receptors (GPCRs) requiring Gsα (eg, parathyroid hormone [PTH], thyroid‐stimulating hormone [TSH], growth hormone–releasing hormone [GHRH], calcitonin) and severe obesity. Paternally‐inherited GNAS mutations cause pseudopseudohypoparathyroidism (PPHP), in which patients have AHO skeletal features but do not develop hormonal resistance or marked obesity. These differences between PHP1A and PPHP are caused by tissue‐specific reduction of paternal Gsα expression. Previous reports in mice have shown loss of Gsα causes osteopenia due to impaired osteoblast number and function and suggest that AHO patients could display evidence of reduced bone mineral density (BMD). However, we previously demonstrated PHP1A patients display normal‐increased BMD measurements without any correlation to body mass index or serum PTH. Due to these observed differences between PHP1A and PPHP, we utilized our laboratory's AHO mouse model to address whether Gsα heterozygous inactivation differentially affects bone remodeling based on the parental inheritance of the mutation. We identified fundamental distinctions in bone remodeling between mice with paternally‐inherited (GnasE1+/−p) versus maternally‐inherited (GnasE1+/−m) mutations, and these findings were observed predominantly in female mice. Specifically, GnasE1+/−p mice exhibited reduced bone parameters due to impaired bone formation and enhanced bone resorption. GnasE1+/−m mice, however, displayed enhanced bone parameters due to both increased osteoblast activity and normal bone resorption. These in vivo distinctions in bone remodeling between GnasE1+/−p and GnasE1+/−m mice could potentially be related to changes in the bone microenvironment driven by calcitonin‐resistance within GnasE1+/−m osteoclasts. Further studies are warranted to assess how Gsα influences osteoblast–osteoclast coupling. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Pseudohypoparathyroidism and its various phenotypes: three sisters with three different clinical presentations

Pseudohypoparathyroidism (PHP) is a heterogeneous group of hereditary disorders characterized by clinical and biological characteristics of resistance to parathyroid hormone (PTH) caused by impaired hormonal signalling via receptors that are coupled, through the α- subunit of the stimulatory G protein (Gsα). In some cases, resistance to other hormones (such as TSH, gonadotropins, GHRH and calcitonin) that have receptors coupled via Gsα is observed. A subset of patients with PHP are characterized by the variable expression of a collection of physical features, termed Albright hereditary osteodystrophy (AHO), which includes brachydactyly, rounded face, short stature, central obesity, subcutaneous ossifications, and variable degrees of mental retardation. These patients face a wide range of problems from early childhood to adulthood, which include potentially severe alterations in mineral metabolism, which could be associated with seizures; other endocrine deficiencies due to hormone resistance that lead to hypothyroidism, hypogonadism and GH deficiency; growth impairment independently of hormonal status; ectopic ossifications with potential severe limitation of mobility; skeletal issues and cognitive and psychomotor impairment. Here we report three sisters affected by pseudohypoparathyroidism but with remarkably differences from each other in terms of phenotypic and clinical-auxological characteristics, a demonstration of how this disease is characterized by a very heterogeneous phenotype, even among patients carrying the same genetic alteration.

GNAS Heterozygous Inactivation Differentially Affects Osteoclast-Specific Calcitonin Receptor Bioactivity in a Mouse Model of Albright Hereditary Osteodystrophy Based Upon Parental Inheritance

Abstract Albright hereditary osteodystrophy (AHO) is caused by the heterozygous inactivation of GNAS, encoding the α-stimulatory subunit (Gαs) of G protein-coupled receptors. Skeletal manifestations of AHO include adult short stature, brachydactyly and subcutaneous ossifications. AHO patients with maternally-derived GNAS mutations develop pseudohypoparathyroidism type 1A (PHP1A) and are obese with resistance to hormones requiring Gαs (eg., PTH, TSH and GHRH) due to tissue-specific GNAS imprinting. Paternally-derived GNAS mutations cause pseudopseudohypoparathyroidism (PPHP) in which patients have AHO skeletal features but do not develop severe obesity or hormonal resistance. Mouse models have shown loss of Gα s signaling in osteoblasts or osteoclasts leads to osteopenia, and suggest AHO patients would display a reduced bone mineral density (BMD). Interestingly, PHP1A patients have been shown to have normal to increased BMD without any correlation to body mass index or serum PTH measurement. Based on the differences observed clinically and hormonally between PHP1A and PPHP, we hypothesize that there may also be distinctions in overall bone remodeling between these two disorders due to GNAS imprinting. This study addressed whether the heterozygous inactivation of Gnas differentially affects Gα s-receptor bioactivity within osteoclasts (OCs) based upon parental inheritance. Bone Marrow Macrophages (BMMs) were harvested from our laboratory’s AHO mouse model with either maternally-inherited (Gnas+/-m) mutations correlating to PHP1A or paternally-inherited (Gnas+/-p) mutations correlating to PPHP. BMMs were exposed to 10-7M salmon calcitonin (sCT), 10-5M forskolin or PBS for 6 hrs. OC receptor activity was measured by fluorescent microscopy to visualize actin ring morphology and RT-PCR analysis of Gα s-PKA signaling transcripts Crem and Ramp3. Forskolin treatment displayed no significant variations in OC ring morphology or Crem and Ramp3 mRNA expression between Gnas+/-m, Gnas+/-p and WT cultures. Both WT and Gnas+/-p OCs displayed appropriate responses to sCT, as indicated by a significant disruption in actin ring morphology and increased Crem and Ramp3 mRNA expression when compared to vehicle-treated controls. SCT-treated Gnas+/-m OCs, however, displayed only mild disruptions in actin ring morphology, and we observed significant reductions in Ramp3 expression compared to WT as well as reductions in Crem compared to WT and Gnas+/-p. These data suggest evidence of partial calcitonin resistance within Gnas+/-m OCs due to impaired Gα s- signaling. These data correlate with previous clinical observations of calcitonin resistance in PHP1A patients. Because these findings were observed only within Gnas+/-m cultures, future work is warranted to determine whether this impaired receptor activity may be attributed to partial Gnas imprinting within OCs or the myeloid lineage.

Pseudohypoparathyroidism: application of the Italian common healthcare-pathway for a homogeneous clinical approach and a shared follow up

BackgroundPseudohypoparathyroidism (PHP) represents a heterogeneous group of rare endocrine disorders caused by (epi) genetic abnormalities affecting the GNAS locus. It is mainly characterized by resistance to PTH and TSH, and by peculiar clinical features such as short stature, obesity, cognitive impairment, subcutaneous ossifications and brachydactyly. Delayed puberty, GHRH and calcitonin resistances have also been described. The healthcare-pathway recently proposed by the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) has provided a standardized clinical approach to these conditions. The purpose of the present study was to evaluate its application in clinical practice, and to collect data for setting future specific studies.MethodsThrough a semi-structured survey, based on the indications of the care-pathway, data on PHP clinical management were collected. The compilation of each data in the survey was read as an index of the adoption of the healthcare-pathway in clinical practice.ResultsIn addition to the proposing Center, 4 Centers joined the study, thus obtaining a large collection of data on 48 PHP patients. Highest rates in the completion of data were obtained for diagnostic history, auxological measurements and subcutaneous ossifications evaluation. As expected, the availability of data for the other investigated fields was lower, coming from recent research studies. More information has been obtained on hormonal resistance classically involved in PHP (PTH, TSH, GHRH and GnRH) and on cognitive impairment, while a few data has been collected on bone mineral status, calcitonin levels and glucolipid metabolism.ConclusionsThe presented data show that the ISPED healthcare-pathway could represent a valid tool both to confirm the clinical approach to PHP patients and to allow homogeneous data collection; however, it has not yet been fully adopted. The strengthening of the network among the major Italian Endocrine Centers will contribute to improve its application in clinical practice, optimizing the follow-up of these patients and increasing knowledge on PHP.

Implication in Paediatrics of the First International Consensus Statement for the Diagnosis and management of pseudohypoparathyroidism and related disorders

Since Albright and co-workers described pseudohypoparathyroidism in 1942 as the combined presence of hypocalcaemia and hyperphosphataemia associated with the existence of tissue resistance to parathyroid hormone (PTH) action upon normal renal function, great advances have been made in the clinical and genetic profile of patients affected by this condition. Furthermore, not only have genetic bases of pseudohypoparathyroidism been unravelled, but also variants in other genes involved in the PTH/PTHrP signalling pathway through Gsα, have been identified as the cause of diseases that share clinical features with pseudohypoparathyroidism.In the paediatric setting, the first symptoms suggesting the impairment of this signalling pathway are the presence of subcutaneous ossifications, brachydactyly and/or early onset obesity, followed by the possible development of PTH resistance. This clinical suspicion should be confirmed by an accurate molecular diagnosis to allow for coordinated multidisciplinary clinical management. Among the features of this group of disorders, physicians should pay attention to evaluation of PTH and/or thyrotropin (TSH) resistance at diagnosis and throughout follow-up, as well as growth hormone deficiency, hypogonadism, skeletal deformities, dental impairment, obesity, insulin resistance, impaired glucose tolerance or type 2 diabetes mellitus and hypertension, as well as ectopic ossifications (either subcutaneous or affecting deeper tissues) and impairment of neurocognitive development.

What to consider when pseudohypoparathyroidism is ruled out: iPPSD and differential diagnosis

BackgroundPseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright’s hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing.MethodsWe reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case.ResultsA review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH.ConclusionsThis study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with “AHO-like phenotype” with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes.

Current Nomenclature of Pseudohypoparathyroidism: Inactivating Parathyroid Hormone/Parathyroid Hormone-Related Protein Signaling Disorder.

Disorders related to parathyroid hormone (PTH) resistance and PTH signaling pathway impairment are historically classified under the term of pseudohypoparathyroidism (PHP). The disease was first described and named by Fuller Albright and colleagues in 1942. Albright hereditary osteodystrophy (AHO) is described as an associated clinical entity with PHP, characterized by brachydactyly, subcutaneous ossifications, round face, short stature and a stocky build. The classification of PHP is further divided into PHP-Ia, pseudo-PHP (pPHP), PHP-Ib, PHP-Ic and PHP-II according to the presence or absence of AHO, together with an in vivo response to exogenous PTH and the measurement of Gsα protein activity in peripheral erythrocyte membranes in vitro. However, PHP classification fails to differentiate all patients with different clinical and molecular findings for PHP subtypes and classification become more complicated with more recent molecular characterization and new forms having been identified. So far, new classifications have been established by the EuroPHP network to cover all disorders of the PTH receptor and its signaling pathway. Inactivating PTH/PTH-related protein signaling disorder (iPPSD) is the new name proposed for a group of these disorders and which can be further divided into subtypes - iPPSD1 to iPPSD6. These are termed, starting from PTH receptor inactivation mutation (Eiken and Blomstrand dysplasia) as iPPSD1, inactivating Gsα mutations (PHP-Ia, PHP-Ic and pPHP) as iPPSD2, loss of methylation of GNAS DMRs (PHP-Ib) as iPPSD3, PRKAR1A mutations (acrodysostosis type 1) as iPPSD4, PDE4D mutations (acrodysostosis type 2) as iPPSD5 and PDE3A mutations (autosomal dominant hypertension with brachydactyly) as iPPSD6. iPPSDx is reserved for unknown molecular defects and iPPSDn+1 for new molecular defects which are yet to be described. With these new classifications, the aim is to clarify the borders of each different subtype of disease and make the classification according to molecular pathology. The iPPSD group is designed to be expandable and new classifications will readily fit into it as necessary.

Ossifications in Albright Hereditary Osteodystrophy: Role of Genotype, Inheritance, Sex, Age, Hormonal Status, and BMI.

Albright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Depending on the parental origin of the mutated allele, patients develop either pseudohypoparathyroidism type 1A (PHP1A), with multihormone resistance and severe obesity, or pseudopseudohypoparathyroidism (PPHP), without hormonal abnormalities or marked obesity. Subcutaneous ossifications (SCOs) are a source of substantial morbidity in both PHP1A and PPHP. This study investigated the previously undetermined prevalence of SCO formation in PHP1A vs PPHP as well as possible correlations with genotype, sex, age, hormonal resistance, and body mass index (BMI). This study evaluated patients with AHO for SCOs by physical examination performed by one consistent physician over 16 years. Albright Clinic, Kennedy Krieger Institute; Institute for Clinical and Translational Research, Johns Hopkins Hospital; Albright Center, Connecticut Children's Medical Center. We evaluated 67 patients with AHO (49 with PHP1A, 18 with PPHP) with documented mutations in GNAS. Relationships of SCOs to genotype, sex, age, hormonal resistance, and BMI. Forty-seven of 67 participants (70.1%) had SCOs. Patients with PHP1A and PPHP had similar prevalences and degrees of ossification formation. Patients with frameshift and nonsense mutations had much more extensive SCOs than those with missense mutations. Males were affected more than females. There was no correlation with hormonal status or BMI. There is a similar prevalence of SCOs in PHP1A and PPHP, and the extent of SCO formation correlates with the severity of the mutation. Males are affected more extensively than females, and the SCOs tend to worsen with age.

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.

Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption.

BackgroundGenetic and epigenetic alterations in the GNAS locus are responsible for the Gsα protein dysfunctions causing Pseudohypoparathyroidism (PHP) type Ia/c and Ib, respectively. For these heterogeneous diseases characterized by multiple hormone resistances and Albright’s Hereditary Osteodystrophy (AHO) the current classification results inadequate because of the clinical overlap between molecular subtypes and a standard clinical approach is still missing.In the present paper several members of the Study Group Endocrine diseases due to altered function of Gsα protein of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) have reviewed and updated the clinical-molecular data of the largest case series of (epi)/genetically characterized AHO/PHP patients; they then produced a common healthcare pathway for patients with these disorders.MethodsThe molecular analysis of the GNAS gene and locus identified the causal alteration in 74 subjects (46 genetic and 28 epigenetic mutations). The clinical data at the diagnosis and their evolution during up to 15 years follow-up were collected using two different cards.ResultsIn patients with genetic mutations the growth impairment worsen during the time, while obesity prevalence decreases; subcutaneous ossifications seem specific for this group. Brachydactyly has been detected in half of the subjects with epigenetic alterations, in which the disease overts later in life, often with symptomatic hypocalcaemia, and also early TSH and GHRH resistances have been recorded.ConclusionsA dedicated healthcare pathway addressing all these aspects in a systematic way would improve the clinical management, allowing an earlier recognition of some PHP features, the optimization of their medical treatment and a better clinical-oriented molecular analysis. Furthermore, standardized follow-up data would provide new insight into less known aspects.

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

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

Endochondral ossification in a case of progressive osseous heteroplasia in a young female child

Progressive osseous heteroplasia (POH) (OMIM 166350) is a rare autosomal dominant condition, characterized by heterotopic ossification of the skin, subcutaneous fat, and deep connective tissue. This condition is distinct from Albright's hereditary osteodystrophy or McCune Albright syndrome (OMIM 103580) and fibrodysplasia ossificans progressiva (OMIM 135100). We present an unusual presentation of POH in a 7-year-old female child. The clinical features included a painful swelling on the left foot, with mechanical complaints. There was no congenital hallux valgus. Family anamnesis was positive in the father. There were subcutaneous ossifications of his left upper arm, right-sided thorax, and lateral side of the right ankle. The father did not allow any radiographs or further examinations. Radiographic examination of the patient revealed ossified subcutaneous plaques on the left foot, lumbar spine, and left scapulae. Additional blood samples were analyzed, revealing no pseudohypoparathyroidism. Sequence analysis of the gene associated with POH, the GNAS1 gene, revealed the heterozygote mutation c.565_568del, previously found in Albright's hereditary osteodystrophy. Histopathological examination of the subcutaneous ossification showed presence of chondrocyte clusters, a feature usually found in fibrodysplasia ossificans progressiva. The combination of the clinical features, the absence of pseudohypoparathyroidism, histology revealing chondrocyte clusters, and the specific GNAS mutation in this patient makes this a truly unusual presentation of POH. The findings in the described case might denote subdivisions of POH. The condition is associated with progressive superficial to deep ossification, progressive restriction of range of motion, and recurrence if excised. We hope to inform pediatricians and orthopedic surgeons to create more awareness of this disorder so that unnecessary treatments can be avoided and proper counseling offered.

Albright hereditary osteodystrophy: Current progress and new frontiers

Albright hereditary osteodystrophy (AHO) is a rare genetic disorder characterized by phenotypic abnormalities including brachydactyly , brachymetacarpia, short stature , subcutaneous ossifications , and dental abnormalities. This disorder is caused by heterozygous, inactivating mutations in GNAS , the gene encoding the alpha chain of the heterotrimeric G protein, Gs, that couples with receptors for many hormones and neurotransmitters for the activation of adenylyl cyclase. Transcripts encoding Gαs are preferentially expressed from the maternally inherited allele in the renal proximal tubule, thyroid, gonad, and pituitary. AHO patients who have GNAS mutations on maternally inherited alleles manifest resistance to multiple hormones (including PTH, TSH, gonadotropins, and GHRH) as well as obesity and cognitive deficits. This condition is termed pseudohypoparathyroidism type Ia (PHP Ia) and is due to tissue-specific paternal imprinting. Conversely, patients with AHO and GNAS mutations on their paternally inherited alleles have no evidence of hormonal resistance, are typically not obese, and cognitive function may be normal. This condition is termed pseudopseudohypoparathyroidism (PPHP). Current knowledge as well as the research in progress in both humans and mouse models regarding the major clinical problems in AHO will be reviewed. Dr. Germain-Lee will focus on her past and current research involving clinical trials with growth hormone in patients with AHO, as well as her research on the heterotopic ossifications that develop in this condition, which she is examining through the use of a mouse model. Her research on the etiology and mechanisms underlying the formation of the heterotopic ossifications has broader implications in terms of the potential to understand more about the mechanisms of osteogenesis overall. In addition, Dr. Germain-Lee will discuss her clinical findings related to the severe obesity in pseudohypoparathyroidism type Ia; this severe obesity is not present in pseudopseudohypoparathyroidism. Dr. Weinstein will discuss his basic science research on metabolism and obesity in AHO, which is based on his studies of his mouse models of this condition. In addition, he will discuss his current ongoing clinical studies of obesity and metabolism in AHO.