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Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.

Pseudohypoparathyroidism (PHP) is a rare hormone resistance syndrome caused by mutations in GNAS. This cross-sectional study investigated whether PHP patients with parathyroid hormone (PTH), thyrotropin (thyroid stimulating hormone; TSH), and free thyroxine (T4) levels at goal required higher doses of levothyroxine and calcitriol than recommended by current guidelines to overcome mineral ion abnormalities due to hormone resistance. Baseline demographic and clinical data of participants enrolled in PHP research studies between 2012-2021 were collected via retrospective chart review. Longitudinally, data were recorded at a maximum frequency of once a year starting at 1 year of age. The PTH at goal (PAG) group was defined as PTH The PAG group (n = 74) was prescribed higher calcitriol doses than the PTH not at goal (PNAG) group (n = 50) (0.9 ± 1.1 vs 0.5 ± 0.9 mcg/day, P = 0.04) and 21% of individual patients were prescribed ≥ 1.5 mcg of calcitriol daily. This remained true after normalization for body weight (0.013 ± 0.015 vs 0.0067 ± 0.0095 mcg/kg/day, P = 0.008). There was no statistically significant difference in levothyroxine dosing between the TAG group (n = 122) and TSH and free T4 not at goal (TNAG) group (n = 45) when normalized for weight (2.0 ± 0.7 vs 1.8 ± 0.7 mcg/kg/day, P = 0.2). More than one-third of patients with PHP had PTH levels not at goal and some patients required calcitriol doses ≥ 1.5 mcg/day to meet current treatment goals.

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

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 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.

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.

This Consensus Statement covers recommendations for the diagnosis and management of patients with pseudohypoparathyroidism (PHP) and related disorders, which comprise metabolic disorders characterized by physical findings that variably include short bones, short stature, a stocky build, early-onset obesity and ectopic ossifications, as well as endocrine defects that often include resistance to parathyroid hormone (PTH) and TSH. The presentation and severity of PHP and its related disorders vary between affected individuals with considerable clinical and molecular overlap between the different types. A specific diagnosis is often delayed owing to lack of recognition of the syndrome and associated features. The participants in this Consensus Statement agreed that the diagnosis of PHP should be based on major criteria, including resistance to PTH, ectopic ossifications, brachydactyly and early-onset obesity. The clinical and laboratory diagnosis should be confirmed by a molecular genetic analysis. Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes mellitus, and hypertension, as well as subcutaneous and/or deeper ectopic ossifications and neurocognitive impairment. Overall, a coordinated and multidisciplinary approach from infancy through adulthood, including a transition programme, should help us to improve the care of patients affected by these disorders, This Consensus Statement and the series of consensus meetings were supported by funds from the European Cooperation in Science and Technology (COST) action BM1208 on imprinting disorders (www.imprinting- disorders.eu), the European Society for Paediatric Endocrinology (ESPE) and the European Society for Endocrinology (ESE). Travel costs and housing of the representatives of the Asian Pacific Paediatric Endocrine Society (APPES) and of the Pediatric Endocrine Society (PES) were supported by their societies. The authors received no funding from pharmaceutical companies

Madelung deformity, a congenital anomaly of the wrist with subluxation of the ulna head, is not a widely recognized feature of Albright hereditary osteodystrophy. Here, we describe a young female with a bilateral Madelung deformity, mild cognitive disability, some dysmorphic facial features, and a type E-like brachydactyly, in whom we identified a novel and de novo mutation (c.476T>C; p.Val159Ala) in exon 6 of the GNAS gene. (C) 2011 Wiley-Liss, Inc.

Context: Loss-of-function GNAS mutations lead to hormone resistance and Albright's hereditary osteodystrophy (AHO) when maternally inherited, i.e. pseudohypoparathyroidism-Ia (PHPIa), but cause AHO alone when located on the paternal allele, i.e. pseudoPHP (PPHP). Objective: We aimed to establish the molecular diagnosis in a patient with AHO and evidence of hormone resistance. Case: The patient is a female who presented at the age of 13.5 years with short stature and multiple AHO features. No evidence for TSH or gonadotropin-resistance was present. Serum calcium and vitamin D levels were normal. However, serum PTH was elevated on multiple occasions (64-178 pg/mL, normal: 9-52) and growth hormone response to clonidine or L-DOPA was blunted, suggesting hormone resistance and PHP-Ia. The patient had diminished erythrocyte Gm activity and a novel heterozygous GNAS mutation (c.328 G>C; p.A109P). The mother lacked the mutation, and the father's DNA was not available. Hence, a diagnosis of PPHP also appeared possible, supported by low birth weight and a lack of AHO features associated predominantly with PHP-Ia, i.e. obesity and cognitive impairment. To determine the parental origin of the mutation, we amplified the paternally expressed A/B and biallelically expressed Gs alpha transcripts from the patient's peripheral blood RNA. While both wild-type and mutant nucleotides were detected in the Gs alpha amplicon, only the mutant nucleotide was present in the A/B amplicon, indicating that the mutation was paternal. Conclusion: These findings suggest that PTH and other hormone resistance may not be an exclusive feature of PHP-Ia and could also be observed in patients with PPHP. (C) 2014 Elsevier Inc. All rights reserved.

A dental practitioner with an eagle’s eye can diagnose many hidden disease through careful examination of the oral cavity. One such hereditary metabolic disorder is Albright hereditary osteodystrophy (AHO). Characteristic presentations in an individual affected by AHO were short stature, obesity and brachydactyly especially of 4th and 5th digits, which are the phenotypic features of genetic mutation. Pseudohypoparathyroidism (PHP) is characterized by inability of the body to respond appropriately to parathormone, mainly characterized by hypocalcemia, increased serum parathormone concentration, insensitivity to the biological activity of parathormone and hyperphosphatemia. AHO when seen in association with resistance to parathormone (PTH), it is called PHP. Here is, a case report of 32-year-old male patient with AHO with distinctive physical characteristics and oral manifestations.

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

Albright hereditary osteodystrophy with pseudohypoparathyroidism is due to maternal loss-of-function mutations in the GNAS gene. Its typical clinical features encompass obesity, a round face and a short neck, osteoma of the skin, endocrinological abnormalities, and psychomotoric retardation. Here we present a 10-month-old Tunisian boy with a classical course of this rare disease.

Chapter 77 covers Albright hereditary osteodystrophy (MIM 103580, 600430, 612462, 612463), including major clinical findings, radiographic features, and differential diagnoses.

Albright hereditary osteodystrophy (AHO) is a rare hereditary metabolic disorder that may be associated with or without resistant to parathyroid hormone (pseudohypoparathyroidism). It is commonly characterized by a constellation of physical features of short stature, round face, short neck, and small metacarpals and metatarsals, mild mental retardation, osteoporosis, subcutaneous calcification, and sometimes olfactory and hearing functional defect. Hypocalcaemia and hyperphosphatemia are the most important manifestations of the case. We report a clinical case of siblings with AHO with reduced Gs-alpha activity and we discuss their clinical features with oral manifestations, radiographic findings, laboratory tests along with treatment.

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

Pseudohypoparathyroidism (PHP) is a metabolic disorder characterized by organ resistance to the action of parathyroid hormone. PHP type 1 is subclassified into two apparent disorders, type 1a (PHP1a) and type 1b (PHP1b). Patients with PHP1a show Albright hereditary osteodystrophy including short stature. Patients with PHP1b have no such skeletal defects, however, literature regarding the growth of PHP1b is not currently available. We evaluated growth charts of PHP patients, including four PHP1a patients and six PHP1b patients. Growth patterns were different between PHP type 1a and 1b. Adult height was abnormally low in all PHP1a patients. The growth pattern of PHP1a was characterized by mild growth impairment in the prepubertal period, a blunted growth spurt and premature cessation of the growth spurt. The adult height of male PHP1b was slightly lower than average. An early growth spurt was observed only in male patients with PHP1b and it may reduce the adult height of male patients with PHP1b. This warrants further investigation into the growth and pubertal development of PHP1b patients.

Pseudohypoparathyroidism (PHP) is a term that refers to a heterogeneous group of metabolic disorders in which resistance to parathyroid hormone (PTH), characterized by hypocalcemia, hyperphosphatemia, and elevation of serum PTH in the setting of normal renal function, is the major clinical feature. In the original report by Fuller Albright, PHP patients showed reduced calcemic and phosphaturic responses to injected bovine parathyroid extract compared to patients with primary hypoparathyroidism (1). This observation led to the speculation that PHP is caused by a defect in PTH action within its target tissues, and was the first description of a hormone resistance syndrome. Subsequent studies describing parathyroid hyperplasia and elevation of immunoreactive serum PTH in untreated PHP patients confirmed that PTH resistance was the underlying defect (2,3).

Physiology A mutation in the α subunit of the guanine nucleotide–binding protein Gs, which transduces signals from various hormone receptors, causes obesity and insulin resistance in the human disorder Albright hereditary osteodystrophy. These disease manifestations occur in individuals with

Albright Hereditary Osteodystrophy is characterized by short stature, obesity, rounded facies, shortened metacarpal and/or phalangeal bones, developmental delay/mental retardation and hypocalcemia in some forms which can be symptomatic. In 5 patients, a typical facies was identified with round shape largely due to remarkably full cheeks, flat midface, depressed nasal bridge and upturned nose. During infancy the cheeks and face are reminiscent of a “Campbell Soup Kid,” and the round shape and fullness of the cheeks persist through early childhood. By late childhood, the face remains round and full, but the remarkable fullness of the cheeks subsides and the “soup kid” facies becomes less apparent. Undiagnosed older patients are usually evaluated because of a family member's concern about risks for mental retardation. Older affected individuals are short and obese and have small hands and feet with a round face. Review of photographs during infancy and childhood indicate the characteristic facial appearance and enable confirmation of the diagnosis. Early diagnosis with prompt intervention or accurate diagnosis in later years is desirable and allows for appropriate genetic evaluation and counseling.

Evidence of Genomic Imprinting of Pseudohypoparathyroidism in a Family with Albright Hereditary Osteodystrophy ♦ 745

BACKGROUND: Genetic 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. METHODS: The 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. RESULTS: In 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. CONCLUSIONS: A 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.