Albright Hereditary Osteodystrophy Research Articles

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.

#191 An unusual cause of hypocalcemia in a young patient

Abstract Background and Aims A 33-year-old man visited the Nephrology Department outpatient clinic with abnormal laboratory findings: his serum calcium level was 5.9 mg/dL in a recent health examination. He denied any underlying disease and was on no medications. He complained of a tingling sensation in his hands and of eyelid twitching. On physical examination, he showed Chvostek's sign. His laboratory findings including serum calcium level are shown in Table 1. He did not have any morphological abnormalities, such as a round face, brachydactyly, or dental anomalies. Method Since he showed hypocalcemia, normal 25-hydroxyvitamin D, and elevated parathyroid hormone (PTH) levels, the presence of PTH resistance was presumed. Under strong suspicion of pseudohypoparathyroidism (PHP) in this patient, DNA sequence analysis and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) of GNAS and STX16, genetic regions that are often affected by mutations or imprinting changes in PHP, was performed. No pathogenic mutations in GNAS and STX16 were detected by sequencing. Results Results of MS-MLPA of the GNAS locus demonstrated abnormal methylation patterns in the patient after HhaI restriction enzyme treatment. The methylation ratio showed a gain of methylation in the NESP55 region and loss of methylation in the AS, XL, and A/B differentially methylated regions (DMRs) in the patient as compared to a healthy control (Fig. 1). The patient was diagnosed with PHP type 1B (PHP1B) due to the methylation abnormalities in multiple DMRs. His parents both showed normal serum calcium levels; thus, no further genetic testing was conducted. He is on outpatient follow-up with adequate calcium replacement and no specific symptoms. Conclusion PHP is a rare disorder of unknown prevalence. It is characterized by hypocalcemia, hyperphosphatemia, and increased PTH levels. PHP1B is a subtype of PHP characterized by isolated renal PTH resistance, usually without physical abnormalities such as Albright hereditary osteodystrophy or other endocrine abnormalities. PHP1B can be sporadic or familial. The genetic characteristics of most sporadic PHP1B remains unclear, but GNAS imprinting abnormalities and hypomethylation at the A/B DMRs have been reported. Symptoms of PHP1B usually begin in childhood due to low calcium levels and may include numbness, seizures, tetany, cataracts, and dental problems. However, as in our case, specific symptoms may not occur until adulthood. Therefore, when evaluating the cause of hypocalcemia, it is necessary to differentiate PHP1B, even in adults, and particularly in cases with hyperphosphatemia and high PTH levels.

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.

Pseudohypoparathyroidism type 1A and Albright hereditary osteodystrophy: A genetic conundrum of multiple hormonal resistances in a family

We present a case series of pseudohypoparathyroidism type 1A (PHP1A) from a single family characterized by a notable pattern of inheritance and intrafamilial variability. The affected siblings exhibited clinical manifestations of PHP1A, including short stature, skeletal abnormalities, and hypocalcemia. Clinical exome sequencing revealed heterozygous inactivating mutations in the GNAS gene, leading to haploinsufficiency of the functional GNAS gene product. The proband, a 14-year-old male patient, demonstrated features such as short stature, obesity, skeletal anomalies, hypocalcemia, and hypothyroidism. The 12-year-old female sibling presented with bone pains, and carpopedal spasm with hypocalcemia without hypothyroidism. The mother had short 3rd and 4th metacarpals (Archibald sign), but biochemical profile was normal. This case report highlights the complex endocrine abnormalities and biochemical imbalances associated with PHP1A, emphasizing the genetic nature and variable expression of the disorder within the family.

Novel 4.18 Mb deletion resulting in 2q37 microdeletion syndrome combined with PTH resistance found in one Chinese patient.

2q37 microdeletion syndrome is a rare clinical condition characterized by a series of physical abnormalities. Its Albright hereditary osteodystrophy (AHO)-like manifestations and possible complication of biochemical abnormalities indicating PTH resistance greatly increased the likelihood of misdiagnosis with classic pseudohypoparathyroidism (PHP) caused by GNAS mutation or methylation alteration, even though there have only been six reports of such clinical occasions. to investigate the underlying genetic defect in a male patient presenting hypocalcemia, elevated PTH and with a history of kyphosis. clinical information was collected, while the DNA was extracted from peripheral blood and subjected to methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and exome sequencing. Physical characteristics featuring short stature, obesity, round face, short neck, and shortened 4th metacarpal and laboratory examination of the patient suggested the presence of PTH resistance, which is indicative of PHP. MS-MLPA did not reveal methylation alterations or deletions of GNAS, STX16 or other monogenetic alterations responsible for iPPSDs, but WES revealed a long-range deletion of approximately 4.18 Mb of the 2q37 region that spanned AGAP1 to NDUFA10, indicating that the patient had 2q37 microdeletion syndrome with PTH resistance. After undergoing MS-MLPA and exome sequencing, a novel deletion spanning 4.18 Mb on the 2q37 region was identified in one male patient, clarifying the diagnosis of 2q37 microdeletion syndrome with PTH resistance. The new genetic discovery added to our understanding of the molecular defects that cause inactivating PTH/PTH-related protein signaling disorders (iPPSDs).

(Epi)genetic and clinical characteristics in 84 patients with pseudohypoparathyroidism type 1B.

Pseudohypoparathyroidism type 1B (PHP1B) caused by methylation defects of differentially methylated regions (DMRs) on the GNAS locus can be categorized into groups according to etiologies and methylation defect patterns of the DMRs. The aim of this study was to clarify the clinical characteristics in each group. Comprehensive molecular analyses consisting of methylation, copy number, and microsatellite analyses. Eighty-four patients with PHP1B were included in this study. We classified them into five groups, namely, autosomal dominant inheritance-PHP1B (Group 1, G1), sporadic-PHP1B (G2), and atypical-PHP1B (G3-G5), based on the methylation defect patterns in four DMRs on the GNAS locus and etiologies and evaluated the clinical findings in each group and compared them among the groups. G2 had the youngest age and the highest serum intact parathyroid hormone levels among the five groups at the time of diagnosis. The most common symptoms at the time of diagnosis were tetany in G1, and seizures or loss of consciousness in G2. Albright's hereditary osteodystrophy and PHP-suggestive features were most frequently observed in the G2 proband. Nine patients had neurodevelopmental disorders (NDs) consisting of mild to borderline intellectual disability and/or developmental delay. There were no significant correlations between the average methylation ratios of seven CpG sites in the GNAS-A/B:TSS-DMR and hormonal and biochemical findings. This study revealed the differences in some clinical characteristics, particularly clinical features and ages at the time of diagnosis between G2 and other groups and detailed NDs observed in some patients with PHP1B.

GNAS locus: bone related diseases and mouse models.

GNASis a complex locus characterized by multiple transcripts and an imprinting effect. It orchestrates a variety of physiological processes via numerous signaling pathways. Human diseases associated with the GNAS gene encompass fibrous dysplasia (FD), Albright's Hereditary Osteodystrophy (AHO), parathyroid hormone(PTH) resistance, and Progressive Osseous Heteroplasia (POH), among others. To facilitate the study of the GNAS locus and its associated diseases, researchers have developed a range of mouse models. In this review, we will systematically explore the GNAS locus, its related signaling pathways, the bone diseases associated with it, and the mouse models pertinent to these bone diseases.

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.

SAT230 A Case Of Pseudohypoparathyroidism Without Any Hereditary Features

Abstract Disclosure: I. Haque: None. L.A. Robles: None. Background: Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of disorders characterized by resistance to parathyroid hormone. PHP type Ib is characterized clinically by isolated renal PTH resistance manifesting as hypocalcemia, hyperphosphatemia, and increased serum PTH. About 60-70% of patients also present with elevated TSH levels due to TSH resistance. We present a unique case of adult onset PHP. Clinical Case: A 30-year-old woman admitted to the hospital for recent onset recurrent hypocalcemia with symptoms of weakness, muscle spasm and cramps. Until recently she was in a normal state of health. Admission labs revealed ionized calcium 0.78 (1.15 - 1.30 MM/L) , serum Ca 6.2 (Albumin 4.3). PTH elevated to 364. Creatinine 0.54 mg/dl, GFR 131 ml/min. Vit D level 35, Bone ALP 49.3 (premenopausal female :4.5-16.9 UG/L), Mag 1.9 , Ph 6.6. A 24-hour urine collection for Ca showed a value of 14 mg/24hr (50 - 400 MG/24H). Additionally, she was found to have a TSH &amp;lt;0.01 and Free T4 1.1. These labs confirmed PTH-resistant hypocalcemia and hyperphosphatemia with concurrent hyperthyroidism. Thyroid Ultrasound demonstrated a possible parathyroid adenoma on the left measuring 0.8x0.4x0.7 cm, which we suspect was a result of hyperplasia from PTH hypersecretion secondary to PTH resistance. TSI and TRAB antibodies were later found to be positive confirming grave’s hyperthyroidism. She had a similar presentation about 3 months earlier with symptomatic hypocalcemia and was discharged on Calcitriol, Ca CO3, and Cholecalciferol. Prior to this including through childhood, patient denies symptoms or lab abnormalities. Patients’ physical exam shows a height of 5ft 4-inch, weight 78kg, BMI 29.7. She had no abnormal facial features or skeletal/digit abnormalities. Patient reached all physical and cognitive milestones at expected times through childhood. Her calcium supplementation was adjusted to calcium carbonate 2000 mg every 8 hours, calcitriol 1 mcg twice daily, cholecalciferol 1000 units daily. Her total calcium improved to 7.4, ionized calcium improved to 0.93, phosphorus remained elevated at 6.1. Patient was discharged at her will due to personal social commitment. She was also started on Methimazole 5mg daily on discharge. Follow up labs showed Ca remained stable and eventually normalized on the above Ca supplementation 6 months after discharge. Conclusion: Unlike PHP Ia, patients with PHP Ib usually lack the physical characteristics of Albright hereditary osteodystrophy (round facies, short stature, short metacarpal bones (especially III-V), obesity, subcutaneous calcifications, and developmental delay), and typically show no other endocrine abnormalities, although our patient presented with subclinical hyperthyroidism. Typically, PTH-resistance disorders present as symptomatic hypocalcemia in childhood, however our patient presented in adulthood. Presentation: Saturday, June 17, 2023

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

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

Prevalence Allusions of Albright’s Hereditary Osteodystrophy Syndrome in South Asia

Albright's Hereditary Osteodystrophy (AHO) is a rare, complex genetic metabolic disorder that was first delineated by American endocrinologist Fuller Albright in 1942. This syndrome is characterized by physical features such as short stature, abnormal finger and toe bones, skin ossification, obesity, rounded facial appearance, flat nasal bridge, and in some cases, developmental and mental abnormalities. AHO is classified as a subtype of pseudohypoparathyroidism type 1A due to its association with resistance to parathyroid hormone. When AHO is inherited from parents, it leads to the development of the syndrome without hormonal issues, resulting in a condition known as Pseudo-Pseudo Hypoparathyroidism (PPHP). PPHP is inherited in an autosomal dominant manner, caused by a mutation in the GNAS gene. This gene is responsible for producing a subunit of a protein called a G protein, which regulates the activity and production of specific hormones, including parathyroid hormone. Globally, AHO is considered a rare syndrome, with a prevalence of 0.7 in 100 individuals. It is further classified into subtypes 1a, 1b, 1c, and 2 based on different phenotypes and underlying mechanisms. However, the purpose of this study is to investigate the rarity of the syndrome in the Asian subcontinent, specifically examining its prevalence, recent trends, and awareness within the selected demographic population. A survey-based approach was employed to gather data from several Asian countries. The findings of this study revealed significant variations in terms of gender distribution, family history, associated complications, Gs alpha subunit deficiency, and the age at which individuals are diagnosed with the syndrome. These variations underscore the need for a versatile approach to accurately diagnose and promptly treat individuals at risk of or already affected by the syndrome.

GNAS gene mutations affecting XLαs and bone health: A long neglected relationship.

The GNAS locus is an imprinted site. The α-subunit of the stimulatory G protein (Gsα) and extralarge variant (XLαs) are the two important products of the GNAS locus. The abnormal expression of Gsα is associated with pseudohypoparathyroidism (PHP) and related disorders, including Albright hereditary osteodystrophy (AHO), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH). XLαs protein can mimic the catalytic intracellular synthesis of cyclic adenosine monophosphate (cAMP) by Gsα in response to parathyroid hormone (PTH) stimulation, which may be involved in the pathogenesis of PPHP and POH in patients with paternal GNAS defects. A paternally inherited nonsense variant in the first exon of XLαs in an adult patient may be associated with fractures and osteopetrosis. The relationship between the XLαs product of the GNAS locus and bone remodeling may have been overlooked. Here, we summarize the phenotypes of genetic mouse models and clinical cases of XLαs variations and suggest that the abnormal paternal expression of XLαs may be associated with the development of POH and affect osteoblast and osteoclast differentiation.

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.

Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy: A Case Report and Literature Review

Introduction: Pseudohypoparathyroidism (PHP) is a rare disease and the first example of hormone resistance to be observed. It combines a particular morphotype, subcutaneous calcifications and bone and kidney resistance to parathyroid hormone. Other hormone resistances are possible. Case Presentation: Patient of 16 years old, had a progressive onset of right foot/ankle deformity at age of 12 years, then 6 months later contralateral ankle deformity, associated to Macrocrania, rounded forehead, enlarged nose, micrognatism, short neck, brachydactyly, deformities, Genu valgum. Workup; corrected hypocalcaemia 46.9mg/l hyperphosphaemia 66mg/l high PTH 1739pg/ml, normal renal function. Diagnosis retained: Pseudohypo-parathyroidism Type 1A or 1C associated with Albright hereditary osteodystrophy (AHO), genetic confirmation in progress. Discussion &amp; Conclusion: PHP is a rare autosomal dominant inherited disorder of variable penetrance and expression, most severe when maternally inherited. Genetic studies have identified inactivating mutations in Gs-alpha, encoded by the GNAS gene, responsible for several phenotypes. Management consists of multidisciplinary follow-up and early and specific interventions. Prognosis is variable, normal life expectancy in mild forms, significant morbidity and mortality in severe forms.

Atrophic macules containing mesenchymal cells are precursor lesions of osteoma cutis in Albright hereditary osteodystrophy.

A newborn presented numerous small violaceous and atrophic macules randomly distributed over the body surface, with no other skin or relevant systemic signs. A skin biopsy showed mild hypercellularity with spindle-shaped cells that stained positively for alpha smooth muscle actin (SMA) and were negative for CD34 and S100. By the age of 18 months, the patient developed obesity, multi-hormone resistance and his skin lesions became indurated; a skin biopsy at this time showed osteoma cutis. The diagnosis of Albright hereditary osteodystrophy (AHO) was made and confirmed by GNAS sequencing. We characterize the skin lesions preceding osteoma cutis as atrophic violaceous macules containing a proliferation of SMA+ mesenchymal cells similar to myofibroblasts in the upper and mid dermis. We speculate that these cells may represent primitive mesenchymal osteoprogenitor cells, from which intramembranous ossification develops as direct conversion of mesenchyme into bone. This article is protected by copyright. All rights reserved.

PSAT183 Severe Hypocalcemia Precipitated by COVID-19 Infection in a Patient with Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism

Abstract Background Hypocalcemia is a common endocrine manifestation of COVID 19 infection. We present a rare case of severe hypocalcemia in a patient with a history of Pseudohypoparathyroidism (PHP) type 1A after COVID-19 infection. PHP is a genetic disorder that presents with hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism due to marked target-organ unresponsiveness to parathyroid hormone (PTH). PHP type 1A also has a characteristic somatic phenotype known as Albright Hereditary Osteodystrophy (AHO), including short stature, brachydactyly, shortened metatarsals, and often reduced intelligence. Case Presentation This is a 53-year-old female with PHP type 1A, diabetes mellitus type 2, hypothyroidism, vitamin D deficiency, mild intellectual disability, and hypertension. She presented with new onset of seizures. She was also found to be positive for COVID-19 infection. On Review of systems, she had diarrhea but denied perioral or extremity paresthesia, palpitations, muscle spasms and bone pain. She reported compliance with calcitriol and calcium supplements at home. She had short stature, round face, short neck, obesity, brachydactyly (short digits of right 4th and 5th fingers) and shortened left 4th metacarpal. Labs revealed corrected serum calcium from baseline of 7.8 mg/dL to 4.4 mg/dL, ionized calcium 2.9 mg/dL, vitamin D 12.8ng/ml, PTH 142pg/ml and phosphorus 6.2mg/dl. EKG showed T wave inversions and prolonged QT interval. She did not have tetany, carpopedal spasm, paresthesia, Chvostek's sign, or Trousseau's sign. After receiving a total of 11 grams of elemental calcium, calcitriol, and ergocalciferol, her corrected calcium level improved to 7.4 mg/dL and EKG normalized. She was discharged home with calcium carbonate 1,250 mg twice a day and calcitriol 0.5 mcg daily. Discussion PHP type 1A is an autosomal dominant mutation of the stimulatory G protein alpha subunit (G alpha or GNAS) derived from the mother due to genomic imprinting which leads to PTH resistance in the kidneys and parathyroid glands. Our patient had a long-standing history of mild hypocalcemia with calcium and calcitriol supplements. Sudden worsening of hypocalcemia was likely related poor calcium and calcitriol absorption induced by COVID-19 infection. Patient with chronic hypocalcemia may not present with typical hypocalcemia signs or symptoms due to their tolerance. Conclusion Clinicians should be aware of the risk of developing severe hypocalcemia in patients who are calcium dependent or vitamin D deficient, malnourished during critical illness, or have COVID-19 infection which may decrease serum albumin and reduce total serum calcium level. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

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 &amp;lt;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

PSAT185 Pseudohypoparathyroidism Type 1B: A Medication Compliance Challenge

Abstract Introduction Pseudohypoparathyroidism (PHP) encompasses five metabolic disorders characterized by target organ PTH resistance. The focus of this paper is PHP Type 1B (PHP1B), a disease that typically presents in children with symptomatic hypocalcemia. Only 15-20% of cases are genetic, making our case of Familial PHP1B even rarer. Case Presentation A 23-year-old African-American female with hypothyroidism and PHP1B diagnosed in 2005 presented to the emergency department with symptomatic hypocalcemia. As a child, she was evaluated for progressive femur, tibia, radius, and ulna bowing in the setting of short stature without phenotypic features of Albright's Hereditary Osteodystrophy. Her biochemical profile was consistent with pseudohypoparathyroidism and imaging showed costochondral junction enlargement. Genetic testing revealed STX mutation confirming PHP1B diagnosis. Extensive studies of her family revealed several affected members, including one of her two children.Patient has history of multiple hospitalizations for symptomatic hypocalcemia. During this admission, her laboratories demonstrated: calcium 4.4 mg/dL (8.6-10.3 mg/dL), phosphorus 7.3 mg/dL (2.5-4.5 mg/dL), PTH 574 pg/mL (16-65 pg/mL), 1,25-dihyroxyvitamin D &amp;lt; 8 ng/mL (18-78 ng/mL), and 25-hydroxyvitamin D 7.6 ng/mL (30-100 ng/mL).She has an extensive history of non-compliance with medications and endocrinology appointments. During the last visit, she complained of ostealgia, particularly in long bones. While discussing the importance of maintaining adequate calcium levels, the patient expressed feeling overwhelmed by her regimen (calcitriol 1 mcg QAM and 0.5 mcg QHS, calcium carbonate 1,200 mg TID). After a lengthy conversation regarding the need for long-term medical therapy, she became increasingly distraught. Conclusion When normocalcemia is achieved with high doses of calcium and calcitriol, patients with PHP1B have an average life expectancy. Given that patients are typically diagnosed in childhood, taking several medications multiple times a day can be challenging and lead to poor compliance. When this occurs, PHP1B becomes a life-altering disease with a significant decrease in quality of life.In 2018 Wierenga et al. reported that being emotionally overwhelmed by chronic disease prevents a patient from appropriately caring for themselves. Their research shows that older males with higher levels of education have better emotional regulation than young females with low educational levels. Providing patients at high risk of psychological stress with a multidisciplinary team including cognitive-behavioral therapists can improve their quality of life and compliance while decreasing the healthcare costs associated with poorly controlled chronic diseases. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Clinical and genetic characteristics for 4 patients with Type Ib pseudohypoparathyroidism.

Pseudohypoparayhyroidism (PHP) is a rare autosomal dominant or recessive genetic disorder characterized by low calcium, high phosphorus, and target organ resistance to parathyroid. The clinical characteristics and genetic features in 4 patients with Type Ib PHP in the Third Xiangya Hospital, Central South University, have been reviewed. All 4 patients had low calcium, high phosphorus, and parathyroid resistance. Among them, 2 patients had slightly elevated thyroid stimulating hormone and mild features of Albright's hereditary osteodystrophy, and one patient had hypokalemia. No guanine nucleotide-binding protein alpha-stimulating activity polypeptide 1 (GNAS) and gene variant associated with hypokalemia were identified using the whole exome sequencing. The results of the methylation-specific multiple ligation-dependent probe amplification showed that there were abnormal methylation of the upstream differentially methylated regions of GNAS in the 4 patients. There were phenotype overlap among the various subtypes of PHP. Detection of GNAS gene methylation in patients with clinical suspicion of Type Ib PHP is helpful for the diagnosis and treatment of PHP.

Genetics of Obesity in Humans: A Clinical Review.

Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and developing countries. The development of genome-wide association studies (GWAS) and next-generation sequencing (NGS) has increased the discovery of genetic associations and awareness of monogenic and polygenic causes of obesity. The genetics of obesity could be classified into syndromic and non-syndromic obesity. Prader–Willi, fragile X, Bardet–Biedl, Cohen, and Albright Hereditary Osteodystrophy (AHO) syndromes are examples of syndromic obesity, which are associated with developmental delay and early onset obesity. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin. Monogenic obesity is caused by variants of single genes while polygenic obesity includes several genes with the involvement of members of gene families. New advances in genetic testing have led to the identification of obesity-related genes. Leptin (LEP), the leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PCSK1), the melanocortin 4 receptor (MC4R), single-minded homolog 1 (SIM1), brain-derived neurotrophic factor (BDNF), and the neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) have been reported as causative genes for obesity. NGS is now in use and emerging as a useful tool to search for candidate genes for obesity in clinical settings.