Features Of Albright Hereditary Osteodystrophy Research Articles

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.

ODP117 Pseudohypoparathyroidism Type IB: A Rare Cause of Hypocalcemia

Abstract Introduction Pseudohypoparathyroidism (PHP) describes disorders of hypoparathyroidism that are the result of resistance of target tissues to the actions of parathyroid hormone (PTH). Studies have estimated the prevalence of PHP to be 0.34 in 100,000 in Japan and 1.1 in 100,000 in Denmark. The first biochemical abnormalities to become apparent are elevated serum levels of PTH and elevated serum levels of phosphorus, followed by hypocalcaemia. We present a patient diagnosed with PHP Type 1B (PHP1B), which was presented to us many years after her initial diagnosis, with other major comorbidities now present. Case description This patient is an 81 year old female presenting to the clinic to discuss her previously diagnosed PHP1B. Her past medical history revealed she began having symptoms of intermittent muscle cramping at the age of 22, followed by carpopedal spasms and periorbital paresthesia a year later. She has also had a physical examination significant for a positive Trousseau sign, but no phenotypical signs of Albright hereditary Osteodystrophy (AHO). Lab evidence from 1977 was recovered showing urinary cyclic AMP level <20 nmol/mg after administration of PTH, consistent with PHP1B. The family history in her parents and children has revealed no similar genetic history so far. Other comorbidities she has developed since her diagnosis are hypokalemia, hypothyroidism, osteoporosis with a femur fracture, obesity, chronic kidney disease and nephrolithiasis. She has been continuing treatment throughout her life with calcium, calcitriol and vitamin D supplementation for hypocalcemia. She has been mostly eucalcemic since then, and complains of occasional carpopedal spasms and perioral numbness. Discussion PHP1B is isolated resistance to PTH in the kidney and normal PTH response in bone without features of AHO. PHP1A and 1C have PTH resistance in bone, and both express AHO. These various forms of PHP are due to defects in the GNAS gene that lead to decreased expression of the alpha-subunit of G protein (Gsa). In the absence of molecular analysis, the clinical and biochemical overlap between PHP and related disorders can lead to challenges in diagnostic classification. There are 2 types of PHP1B cases- autosomal dominant (AD) and sporadic. However, the majority of Patients with PHP1B do not have mutations within the GNAS but they have methylation and imprinting defects that result in absence of maternal Gsa. To emphasize, epimutation study rather than sequencing of the coding region in GNAS should be performed for genetic investigation, which has now become standard practice. Although there is no difference in clinical presentation between AD PHP1B and sporadic PHP1B, their differentiation early during the disease onset can help providers give patients more reliable genetic and reproductive counseling and provide optimal medical management of complications such as hypocalcemia. Presentation: No date and time listed

Vitamin D Deficiency Mimicking Pseudohypoparathyroidism Type II in an Adolescent Boy: A Case Report

Background: Vitamin D deficiency in children is common and usually characterized by hypocalcemia, hypophosphatemia, and elevated serum parathyroid hormone level. However, vitamin D deficiency can be associated with parathyroid hormone resistance in the kidneys which may cause hyperphosphatemia instead, mimicking thus pseudohypoparathyroidism type II. The exact pathogenesis for parathyroid hormone resistance remains unclear, and the distinction between the two conditions remains difficult. We describe the case of an adolescent who presented with seizures and was found to have biochemical features consistent with pseudohypoparathyroidism, likely related to vitamin D deficiency. Case Report: A 13-year-old previously healthy adolescent presented with seizures. He experienced back pain during the previous month prior to the presentation. He did not have features of Albright hereditary osteodystrophy. His laboratory studies were significant for hypocalcemia, hyperphosphatemia, elevated serum alkaline phosphatase level, elevated parathyroid hormone level, and a deficient vitamin D level. Magnetic resonance imaging of the spine revealed multiple compression fractures. The child was treated with intravenous calcium and vitamin D administration with rapid improvement and his seizures resolved. Conclusion: Hypocalcemia from vitamin D deficiency can mimic pseudohypoparathyroidism type II. The principles of treatment for hypocalcemia in both conditions are similar and patients require timely intervention with close follow-up to ensure the resolution of symptoms. Patients with resolution of symptoms after adequate treatment may not require further evaluation for other types of pseudohypoparathyroidism.

Mild progressive osseous heteroplasia overlap syndrome with PTH and TSH resistance appearing during adolescence and not early childhood

Progressive osseous heteroplasia (POH), a genetic disorder, is associated with Albright's hereditary osteodystrophy (AHO), pseudohypoparathyroidism, and primary osteoma cutis and has common features of superficial ossification and GNAS-inactivating mutations. Disorders due to GNAS-inactivating mutations are classified as "inactivating parathyroid hormone (PTH)/PTHrP signaling disorder type 2." This study reports a case of mild POH overlap syndrome to improve understanding of genotype-phenotype correlations. A 13-year and 6-month-old Japanese boy was referred to our hospital with a chief complaint of the lower limb length difference. He underwent clinical, biochemical, radiological, and genetic studies. He showed sporadic GNAS mutation, deep ectopic ossification, small for gestational age (SGA), congenital tooth defect, and lack of AHO features; he met the diagnostic criteria for POH, and mild PTH and TSH resistance was detected. He had constant hyperphosphatasemia and hypocalciuria. At the age of 10 years, he occasionally experienced high iPTH levels. The pituitary stimulation test showed a normal response of all hormones at 3 years of age, but TSH response was decreased (previously 0.770, peak value 4.144 μIU/mL) in the TRH loading test at age 13 years and 6 months. DNA analysis showed a heterozygous p.D189MfsTer14 mutation of GNAS. The parents did not carry this mutation. We report a rare case of POH overlap syndrome with PTH/TSH resistance that appeared in adolescence rather than early childhood. Cases diagnosed with POH in early childhood also require reassessment during adolescence. Further studies of the GNAS heterozygous mutation p.D189MfsTer14 may reveal factors involved in POH overlap syndrome.

A Case of Pseudohypoparathyroidism Type 1b in Pregnancy

Introduction: Pseudohypoparathyroidism (PHP) type 1b is characterized by target organ resistance to PTH leading to hypocalcemia and hyperphosphatemia in the setting of elevated PTH due to abnormal imprinting that affects the regulatory elements of GNAS1. It poses challenges in management during pregnancy and lactation. We report the case of a patient who was diagnosed with PHP type 1b while pregnant. Case Presentation: A 30 year old woman, 16 weeks pregnant was referred for the evaluation of hypocalcemia. She had a history of traumatic fracture of her lower extremity and hypothyroidism treated with levothyroxine. She was noted to have hypocalcemia 1 year prior during routine labs. Family history was significant for hypothyroidism in her sister. On physical examination, she did not have phenotypic features of Albright hereditary osteodystrophy except for short stature. Before pregnancy her labs were significant for Ca 8.1 mg/dL(8.6–10.2), iCa 4.2 mg/dL(4.8–5.6), iPTH 289 pg/mL (14–64), creatinine 0.6 mg/dL(0.8–1.2), 25 vitamin D 22 ng/mL and 24 hr urine Ca 80 mg/24 hr (65-250mg). She was started on a combination of calcium citrate and carbonate 600 mg daily and vitamin D 1000 units daily. Labs while pregnant showed Ca 8.1 mg/dL, iCa 4.1 mg/dL, iPTH 184 pg/mL, PO4 4.9 mg/dL(2.5–3.5), 1,25 Vitamin D 53 pg/mL(18–72) and 25 Vitamin D 38 ng/mL. She had mild paresthesia and muscle cramps. Calcium supplements were increased to 1800 mg daily. While the urine Ca increased to 315 mg/24 hr, other biochemical parameters did not improve. Given her low Ca, high iPTH, high PO4, normal GFR and 25 vitamin D, PHP was suspected. Genetic testing showed loss of methylation at GNAS locus down to 5% (NL >43%) Diagnosis of PHP type 1b was made. Her Ca decreased the next months to a nadir of 7.9 mg/dL despite increased doses of calcium up to 1200 mg BID. Calcitriol 0.25 mcg BID was added. The rest of her pregnancy the serum Ca stayed between 8.1–8.6 mg/dL. She delivered a boy. At birth his Ca was 8.0 mg/ dL and PTH 81pg/mL. Genetic testing showed 41% methylation of GNAS. While breast feeding her Ca was 9.4 mg/dL, her calcitriol and calcium supplements were decreased. She continues to do well on calcium 630 mg daily and calcitriol 0.25 mcg daily with serum Ca between 8.5–8.8 mg/dL. Conclusion: The literature on PHP in pregnancy is scarce due to its rarity and the management is challenging due to altered calcium and vitamin D metabolism during pregnancy and lactation. The fetus draws calcium from maternal circulation and predisposes mother to hypocalcemia. Some patients may become normocalcemic during pregnancy due to placental secretion of 1,25 Vitamin D and PTHrp. There is also increased demand for calcium with lactation. There are genetic implications on the baby as it is inherited in an autosomal dominant mode. It is important to monitor calcium levels closely as there are multiple factors that could influence calcium metabolism in pregnancy.

Pseudohypoparathyroidism: Focus on Cerebral and Renal Calcifications.

Pseudohypoparathyroidism (PHP) is a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) levels as a result of end-organ resistance to PTH. To describe a cohort of 26 patients with PHP followed in a single tertiary center. Clinical, biochemical, radiological, and genetic analysis of the GNAS gene in 26 patients recruited since 2002. Ten patients harbored a GNAS mutation, 15 epigenetic abnormalities at the GNAS locus, and 1 did not show genetic or epigenetic abnormalities. According to clinical, biochemical, and genetic features, patients were classified as PHP1A, PHP1B, and pseudopseudohypoparathyroidism. Patients with PHP1A had an earlier diagnosis and more cases with family history, Albright hereditary osteodystrophy (AHO) features, hormonal resistance, and hypertension. Obesity was a common feature. No difference in biochemical values was present among PHP1A and PHP1B. Intracerebral calcification occurred in 72% of patients with no difference among PHP1A and PHP1B subgroups. No significant difference was observed between patients with and without intracerebral calcification for the time-weighted average values of total serum calcium, phosphate, calcium-phosphate product, and PTH fold increase. A borderline association between cerebral calcification and age at the time of diagnosis (P = .04) was found in the whole cohort of patients. No renal calcifications were found in the overall cohort. Patients with PHP1A more frequently have AHO features as well as hypertension than patients with PHP1B. Patients with PHP presented a high rate of intracerebral calcification with no significant difference between subgroups. No increased risk of renal calcifications was also found in the entire cohort.

Progressive Osseous Heteroplasia is not an Autosomal Dominant Trait but Reflects Superimposed Mosaicism in Different GNAS Inactivation Disorders.

Progressive osseous heteroplasia (POH) is a rarely occurring genetic condition characterized by severe segmental ossification involving the skin and deep connective tissues including the muscles. So far, the disorder is generally described as an autosomal dominant trait. By contrast, the following arguments are in favor of the alternative concept that POH should rather be taken as a non-specific segmental manifestation of different GNAS inactivation disorders such as Albright hereditary osteodystrophy (AHO) with hormone resistance, AHO without hormone resistance, and osteomatosis cutis. Presently, POH has got its own OMIM number 166350 but this is obviously wrong because the disorder does not reflect heterozygosity for a GNAS mutation. Conversely, the disorder is most likely due to an early event of postzygotic loss of heterozygosity with loss of the corresponding wild-type allele. This alternative concept, as proposed in 2016, offers a plausible explanation for the following features of POH. Familial occurrence is usually absent. POH is usually observed in families with one of the three GNAS inactivation disorders as mentioned above. Mosaicism is suggested by the pronounced segmental manifestation of POH and by its lateralization. Some patients have, in addition to POH, bilaterally disseminated features of osteomatosis cutis or AHO, and other patients have family members with one of these nonsegmental disorders. Remarkably, POH tends to appear much earlier than the nonsegmental GNAS inactivation disorders. – Molecular support of the concept was documented in a superficial variant of POH called 'plate-like osteoma cutis'. In several other autosomal dominant skin disorders, molecular corroboration of the theory of superimposed mosaicism has been provided. – For all of these reasons, it is unlikely that POH can further be taken as a distinct autosomal dominant trait. Generation of more molecular data in multiple cases of POH occurring in GNAS inactivation disorders will be crucial to corroborate the proposed concept.

Maternal Transmission Ratio Distortion of GNAS Loss-of-Function Mutations.

Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are two rare autosomal dominant disorders caused by loss-of-function mutations in the imprinted Guanine Nucleotide Binding Protein, Alpha Stimulating Activity (GNAS) gene, coding Gs α. PHP1A is caused by mutations in the maternal allele and results in Albright's hereditary osteodystrophy (AHO) and hormonal resistance, mainly to the parathormone (PTH), whereas PPHP, with AHO features and no hormonal resistance, is linked to mutations in the paternal allele. This study sought to investigate parental transmission of GNAS mutations. We conducted a retrospective study in a population of 204 families with 361 patients harboring GNAS mutations. To prevent ascertainment bias toward a higher proportion of affected children due to the way in which data were collected, we excluded from transmission analysis all probands in the ascertained sibships. After bias correction, the distribution ratio of the mutated alleles was calculated from the observed genotypes of the offspring of nuclear families and was compared to the expected ratio of 50% according to Mendelian inheritance (one-sample Z-test). Sex ratio, phenotype of the transmitting parent, and transmission depending on the severity of the mutation were also analyzed. Transmission analysis was performed in 114 nuclear families and included 250 descendants. The fertility rates were similar between male and female patients. We showed an excess of transmission from mother to offspring of mutated alleles (59%, p = .022), which was greater when the mutations were severe (61.7%, p = .023). Similarly, an excess of transmission was found when the mother had a PHP1A phenotype (64.7%, p = .036). By contrast, a Mendelian distribution was observed when the mutations were paternally inherited. Higher numbers of females within the carriers, but not in noncarriers, were also observed. The mother-specific transmission ratio distortion (TRD) and the sex-ratio imbalance associated to PHP1A point to a role of Gs α in oocyte biology or embryogenesis, with implications for genetic counseling. © 2019 American Society for Bone and Mineral Research.

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

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

MON-252 An Unusual Presentation of Pseudohypoparathyroidism Type 1a Associated with a Novel GNAS Mutation and Vitamin D Deficiency

Title: An Unusual Presentation of Pseudohypoparathyroidism Type 1a Associated with a Novel GNAS Mutation and Vitamin D Deficiency Background: Pseudohypoparathyroidism type 1a is caused by inactivating mutations in GNAS and is characterized by PTH resistance, resistance to other hormones acting on Gs-coupled receptors, and features of Albright hereditary osteodystrophy (AHO). Type 1b presents with PTH resistance but lacks clinical features of AHO and is caused by methylation defects within GNAS. Pseudohypoparathyroidism is best diagnosed in the setting of normal 25-OH vitamin D levels, as several cases have been reported in the literature that the first stage of vitamin D deficient rickets may mimic pseudohypoparathyroidism, with hypocalcemia, hyperphosphatemia, elevated PTH, and no signs of rickets. Clinical Case: Our patient was a three-year-old female who presented with tonic-clonic seizure activity and tetany and was found to have a calcium of 4.7 mg/dL (8.8-10.8), ionized calcium of 0.5 mmol/L (1-1.5), phosphorus of 10.2 mg/dL (3.2-5.8), PTH of 2597 pg/mL (12-88), alkaline phosphatase of 643 IU/L (100-320), 25-OH Vitamin D of 8.69 ng/mL (20-120), and 1,25-OH Vitamin D of 78.5 pg/mL (19.9-78.5) consistent with both PTH resistance and vitamin D deficiency. TSH was within range but free T4 was low at 0.76 ng/dL (1.08-1.66). Height and growth velocity were normal with obese BMI at the 97%ile. No cataracts, brachydactyly, or subcutaneous calcifications were present, normal dentition was noted, and she was without depressed nasal bridge or round facies. X-rays of bilateral hands and wrists were without brachydactyly or rickets, however, osteopenia was present. Our patient had cut out intake of dairy and eggs one year prior due to a presumed allergy without supplemental vitamin D or calcium intake. She had notable speech and fine motor delays. Family history was significant only for vitamin D deficiency in the maternal grandmother but no history of AHO. Calcium was normalized with a calcium chloride infusion and treatment with calcium carbonate, calcitriol, and cholecalciferol was initiated. Despite 25-OH vitamin D repletion, PTH remained elevated at 1202 pg/mL (12-88), phosphorus remained elevated, and calcium remained slightly low and thus the diagnosis of pseudohypoparathyroidism was confirmed. Genetic testing revealed a novel pathogenic inactivating GNAS mutation at an exon 8 donor splice site consistent with a diagnosis of pseudohypoparathyroidism type 1a. Clinical Lessons: Pseudohypoparathyroidism 1a is most commonly associated with classic signs of AHO such as brachydactyly and subcutaneous calcifications. However, in our patient this disorder presented with only more subtle associated signs. Vitamin D deficiency also clouded the clinical picture, however, laboratory testing in the setting of vitamin D repletion confirmed the diagnosis of pseudohypoparathyroidism.

SUN-510 Pseudohypoparathyroidism Type 1b Presenting With Fahr Syndrome In An Adolescent.

Background: Fahr syndrome is a condition characterized by the presence of abnormal calcifications in the basal ganglia and cerebral cortex, and has been linked with parathyroid disorders. We report a case of pseudohypoparathyroidism (PHP) type 1b in an adolescent presenting with recurrent seizures and intracranial calcifications. Clinical Case: A 15-year old boy presented with recurrent seizures that were uncontrolled despite treatment with anti-epileptic medications. He was diagnosed with epilepsy at the age of 9 overseas and had also been started on levothyroxine 25 mcg daily for hypothyroidism. He arrived in the US for further evaluation and management. He was initially seen by pediatric neurology wherein lab work-up showed hypocalcemia with a total calcium of 6.6 mg/dL (n 8.5-10.5). CT scan of the brain showed disseminated intracranial cortical and basal ganglia calcifications, consistent with Fahr syndrome. EEG showed generalized background slowing compatible with mild diffuse cerebral dysfunction. He was referred to pediatric endocrinology. At his endocrine visit, growth parameters were normal with height at 81st percentile, weight at 88th percentile, and BMI at 84th percentile. Family history was negative of seizures, thyroid or calcium disorders. He does not have intellectual disability. Physical exam did not reveal any features of Albright hereditary osteodystrophy. Additional lab testing showed ionized calcium 0.79 mmol/L (n 1.1-1.35), phosphorus 8.7 mg/dL (n 2.9-5.1), PTH 439 pg/mL (n 10.0-65.0), alkaline phosphatase (ALP) 308 U/L (n 60-270) and 25-hydroxy vitamin D 25.8 ng/mL (n 30-83). Renal function was normal. Findings were suggestive of PTH resistance. Thyroid function showed TSH 4.74 uU/mL (n 0.4-4.6), free T4 1.15 ng/dL (n 0.8-1.7) and negative thyroid antibodies (TPO, TG), suggestive of partial TSH resistance. He was treated with calcium carbonate, calcitriol and ergocalciferol. Levothyroxine was continued. Genetic testing was done which showed a partial loss of methylation in the GNAS exon 1A locus (patient 28%, [normal methylation ≥44%, complete loss of methylation ≤ 12%]), confirming the diagnosis of PHP type 1b. Calcium, phosphorus and ALP levels subsequently normalized with calcium and vitamin D supplementation. PTH improved though remains to be elevated (PTH 67.9 pg/mL). Anti-epileptic medications were weaned off after being seizure-free for more than 2 years. Conclusion: In this case, our patient presented with a distinct triad of epileptic seizure, extensive brain calcification, and hypocalcemia. This clinical scenario should prompt diagnostic evaluation for PHP as a treatable cause of epileptic seizures in children. Genetic testing for PHP type 1b showed partial loss of methylation in the GNAS locus, which was sufficient to cause disease.

Association of GNAS imprinting defects and deletions of chromosome 2 in two patients: clues explaining phenotypic heterogeneity in pseudohypoparathyroidism type 1B/iPPSD3

BackgroundThe term pseudohypoparathyroidism (PHP) describes disorders derived from resistance to the parathyroid hormone. Albright hereditary osteodystrophy (AHO) is a disorder with several physical features that can occur alone or in association with PHP.The subtype 1B, classically associated with resistance to PTH and TSH, derives from the epigenetic dysregulation of the GNAS locus. Patients showing features of AHO were described, but no explanation for such phenotypic heterogeneity is available.An AHO-like phenotype was associated with the loss of genetic information stored in chromosome 2q37, making this genomic region an interesting object of study as it could contain modifier genes involved in the development of AHO features in patients with GNAS imprinting defects.The present study aimed to screen a series of 65 patients affected with GNAS imprinting defects, with or without signs of AHO, for the presence of 2q37 deletions in order to find genes involved in the clinical variability.ResultsThe molecular investigations performed on our cohort of patients with GNAS imprinting defects identified two overlapping terminal deletions of the long arm of chromosome 2. The smaller deletion was of approximately 3 Mb and contained 38 genes, one or more of which is potentially involved in the clinical presentation. Patients with the deletions were both affected by a combination of the most pathognomic AHO-like features, brachydactyly, cognitive impairment and/or behavioural defects. Our results support the hypothesis that additional genetic factors besides GNAS methylation defects are involved in the development of a complex phenotype in the subgroup of patients showing signs of AHO.ConclusionsFor the first time, the present work describes PHP patients with hormone resistance and AHO signs simultaneously affected by GNAS imprinting defects and 2q37 deletions. Although further studies are needed to confirm the cause of these two rare molecular alterations and to identify candidate genes, this finding provides novel interesting clues for the identification of factors involved in the still unexplained clinical variability observed in PHP1B.

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

BackgroundPseudohypoparathyroidism type 1A (PHP1A) is a rare genetic disease primarily characterized by resistance to parathyroid hormone along with hormonal resistance and other features of Albright hereditary osteodystrophy (AHO). It is caused by heterozygous inactivating mutations in the maternal allele of the GNAS gene, which encodes the stimulatory G-protein alpha subunit (Gsα) and regulates production of the second messenger cyclic AMP (cAMP). Herein, we report a case of of PHP1A with atypical clinical manifestations (oligomenorrhea, subclinical hypothyroidism, and normocalcemia) and explore the underlying genetic cause in this patient.MethodsBlood samples were collected from the patient, her family members, and 100 healthy controls. The 13 exons and flanking splice sites of the GNAS gene were amplified by PCR and sequenced. To further assess whether the novel mutation resulted in gain or loss of function of Gsα, we examined the level of cAMP activity associated with this mutation through in vitro functional studies by introducing the target mutation into a human GNAS plasmid.ResultsA novel heterozygous c.715A > G (p.N239D) mutation in exon 9 of the GNAS gene was identified in the patient. This mutation was also found in her mother, who was diagnosed with pseudopseudohypoparathyroidism. An in vitro cAMP assay showed a significant decrease in PTH-induced cAMP production in cells transfected with the mutant plasmid, compared to that in the wild-type control cells (P < 0.01), which was consistent with loss of Gsa activity.ConclusionWe identified a novel GNAS mutation that altered Gsα function, which furthers our understanding of the pathogenesis of this disease. Screening for GNAS mutations should be considered in suspected cases of PHP1A even if the classical signs are not present.

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.

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.

Variable phenotype of pseudohypoparathyroidism in children

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

Multiple miliary osteoma cutis of the face associated with Albright hereditary osteodystrophy in the setting of acne vulgaris: a case report

Osteoma cutis is a condition characterized by theformation of bone within the skin. Such aberrantossification of the skin and subcutaneous tissue isconsidered primary when it arises in the absence ofunderlying tissue damage or a preceding cutaneouslesion. Conversely, secondary osteoma cutis occurswhen skin ossification is the result of a pre-existingskin lesion, trauma, or inflammatory process [1,2].Although rare, primary osteoma cutis has beenassociated with a number of different geneticdisorders. Albright hereditary osteodystrophy (AHO),a condition first described in 1942 by Fuller Albright,is an autosomal dominant metabolic disorder causedby a mutation in the GNAS1 gene [3]. This disease isassociated with a variety of phenotypic traits includingcutaneous ossification, short stature, brachydactyly,obesity, and mental retardation. It should be notedthat brachydactyly is the most specific feature of AHO[4]. However, owing to variable expressivity individualsmay present only with a subset of these symptoms [5,6]. The cutaneous ossification observed in patientswith AHO may be seen in infancy or early childhoodand is sometimes the earliest presenting symptom.Nonetheless, because clinical features of AHO canbe seen in the absence of metabolic derangements(i.e. normal serum calcium, phosphorus, and PTHlevels) an early diagnosis is often missed and delayedfor many years. Herein, we present a case of miliaryosteoma cutis of the face in a 68 year-old woman withphenotypic features of AHO and laboratory studiesconsistent with type 1a PHP.

2q37 Deletion syndrome confirmed by high-resolution cytogenetic analysis

Chromosome 2q37 deletion syndrome is a rare chromosomal disorder characterized by mild to moderate developmental delay, brachydactyly of the third to fifth digits or toes, short stature, obesity, hypotonia, a characteristic facial appearance, and autism spectrum disorder. Here, we report on a patient with 2q37 deletion presenting with dilated cardiomyopathy (DCMP). Congenital heart malformations have been noted in up to 20% of patients with 2q37 deletions. However, DCMP has not been reported in 2q37 deletion patients previously. The patient exhibited the characteristic facial appearance (a flat nasal bridge, deep-set eyes, arched eyebrows, and a thin upper lip), developmental delay, mild mental retardation, peripheral nerve palsy, and Albright hereditary osteodystrophy (AHO)-like phenotypes (short stature and brachydactyly). Conventional chromosomal analysis results were normal; however, microarray-based comparative genomic hybridization revealed terminal deletion at 2q37.1q37.3. In addition, the patient was confirmed to have partial growth hormone (GH) deficiency and had shown a significant increase in growth rate after substitutive GH therapy. Chromosome 2q37 deletion syndrome should be considered in the differential diagnosis of patients presenting with AHO features, especially in the presence of facial dysmorphism. When patients are suspected of having a 2q37 deletion, high-resolution cytogenetic analysis is recommended.

Abnormal Methylation Status of the GNAS Exon 1A Region in Pseudohypohyperparathyroidism Combined With Turner Syndrome

Pseudohypohyperparathyroidism (PHHP) is a rare type of pseudohypoparathyroidism (PHP), which seems to have a normal skeletal response to parathyroid hormone but shows renal resistance. Almost all patients with PHHP have PHP Ib, a subtype of PHP that is usually caused by GNAS methylation defects, often in exon 1A. Some features of Albright hereditary osteodystrophy can occasionally be found in patients with PHHP, but these features are also common in Turner syndrome. The authors report on an extremely rare case of a patient with PHHP and Turner syndrome, a 47-year-old woman who sought medical attention for hypocalcemia and elevated parathyroid hormone. She had no family history of hypocalcemia and no STX16 gene deletions. She had a mosaic karyotype of 46, X, del(X)(p11.4)/45, XO. Pyrosequencing was performed to determine the GNAS exon 1A methylation. The degree of methylation found in exon 1A of the patient was lower than her unaffected relatives.

Similar frequency of paternal uniparental disomy involving chromosome 20q (patUPD20q) in Japanese and Caucasian patients affected by sporadic pseudohypoparathyroidism type Ib (sporPHP1B)

Pseudohypoparathyroidism type Ib (PHP1B) is caused by proximal tubular resistance to parathyroid hormone that occurs in most cases in the absence of Albright's Hereditary Osteodystrophy (AHO). Familial forms of PHP1B are caused by maternally inherited microdeletions within STX16, the gene encoding syntaxin 16, or within GNAS, a complex genetic locus on chromosome 20q13.3 encoding Gsα and several splice variants thereof. These deletions lead either to a loss-of-methylation affecting GNAS exon A/B alone or to epigenetic changes involving multiple differentially methylated regions (DMRs) within GNAS. Broad GNAS methylation abnormalities are also observed in most sporadic PHP1B (sporPHP1B) cases. However, with the exception of paternal uniparental disomy involving chromosome 20q (patUPD20q), the molecular mechanism leading to this disease variant remains unknown. We now investigated 23 Japanese sporPHP1B cases, who presented with hypocalcemia, hyperphosphatemia, elevated PTH levels, and occasionally with TSH elevations and mild AHO features. Age at diagnosis was 10.6±1.45years. Calcium, phosphate, and PTH were 6.3±0.23mg/dL, 7.7±0.33mg/dL, and 305±34.5pg/mL, respectively, i.e. laboratory findings that are indistinguishable from those previously observed for Caucasian sporPHP1B cases. All investigated patients showed broad GNAS methylation changes. Eleven individuals were homozygous for SNPs within exon NESP and a pentanucleotide repeat in exon A/B. Two of these patients furthermore revealed homozygosity for numerous microsatellite markers on chromosome 20q raising the possibility of patUPD20q, which was confirmed through the analysis of parental DNA. Based on this and our previous reports, paternal duplication of the chromosomal region comprising the GNAS locus appears to be a fairly common cause of sporPHP1B that is likely to occur with equal frequency in Caucasians and Asians.