PTH Resistance Research Articles

6408 Familial Hypoparathyroidism With Elevated Parathyroid Hormone Due To A PTH Mutation Responsive To Teriparatide

Abstract Disclosure: N. Mukhtar: None. B. Alghamdi: None. M. Alswailem: None. A.S. Alzahrani: None. Introduction: Apart from vitamin D disorders, causes of congenital hypocalcemia (HypoCa) include genetic defects causing familial hypoparathyroidism (FH), and defects in PTH receptor or its signalling pathway (PTH resistance). The former is typically characterized by low plasma PTH and the latter by elevated PTH levels. In this report, we describe a family with FH but with significant elevation of functionally inactive PTH due to a PTH mutation. We also show a positive therapeutic impact of recombinant human PTH (teriparatide) therapy on HypoCa in one of these siblings who was not well controlled on calcitriol and calcium replacement. Case description: The proband is a 34-year-old lady who has history of chronic HypoCa since birth with several admissions for severe HypoCa and recurrent seizures during childhood. She and her three brothers (a 32-year-old male twin and an 18-year-old male) were diagnosed to have Pseudohypoparathyroidism type 1b based on the presence of chronic HypoCa (serum Ca 1.6-1.85 mmol/l) since birth associated with significantly elevated plasma PTH levels in the range of 310-564 pg/dl (normal range 10-65) and absence of signs of Albright hereditary osteodystrophy. Laboratory workup of the proband recently showed: PTH 514 ng/L (NR 15-65) , calcium 1.81 mmol/l (NR 2.1-2.6), phosphate 1.67mmol/L (NR 0.8-1.4), magnesium 0.73 mmol/L (NR 0.7-1.0), albumin 38 g/L (NR 40-50), Alkaline phosphatase 56 U/L, eGFR >60 ml/min/1.73 m2, creatinine 78 umol/L and 25-hydroxyvitamin D 77 nmol/l (NR 50-120). Daily excretion of calcium was normal at 3.38 mmol and an ultrasound of the kidneys suggest nephrocalcinosis. Skeletal X-rays and bone mass densitometry were normal. Molecular studies: WES showed no potentially pathogenic variants in GNAS, PTHR, CASR, VDR, and CYP27B1 but a previously reported homozygous variant in the PTH, exon 3 (NM_000315.4: c.128G>A, p.Gly43Glu). This was confirmed by Sanger sequencing in the patient and two of her brothers. This variant was assessed to be likely pathogenic or likely damaging by several in silico analysis tools including Polyphen2, MutPred, PROVEAN, DEOGEN2 and VUS by ACMG, SIFT, Mutation Assessor and FATHMM. Management: Because the patient’s HypoCa was not controlled on large doses of calcitriol and calcium carbonate, a trial of teriparatide 20 mcg SC daily resulted in normalization of calcium and PTH levels. The patient reported significant improvement in her general wellbeing with loss of numbness, tingling, muscle spasms and tetany of the fingers. She has been on teriparatide for the last year with excellent improvement in her quality-of-life Conclusion: High PTH in the presence of congenital hypoCa is not always due to receptor or post-receptor defect and can be due to a mutated biologically inactive PTH. In such cases, treatment with Teriparatide may result in stabilization of biochemical profile and improve quality of life. Presentation: 6/2/2024

Bone responsiveness in PTH resistance syndromes: preliminary data of a single centre retrospective study

Bone responsiveness in PTH resistance syndromes: preliminary data of a single centre retrospective study

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.

COVID‐19‐Induced Refractory Symptomatic Hypocalcemia in a Patient With Parathyroid Gland Reimplantation

Background: Several cases of severe hypocalcemia in the setting of COVID‐19 have been reported. The proposed mechanisms include direct viral interaction with ACE2 receptors in the parathyroid gland, viral chelation of calcium, worsening hypovitaminosis D, critical illness leading to unbound fatty acids binding calcium, and inflammatory cytokines leading to PTH resistance. Given the life‐threatening nature of hypocalcemia, this underrecognized phenomenon should be on the forefront of the clinician’s attention. This case highlights a rare manifestation of COVID‐19 and further complicated by the patient’s reimplanted parathyroid gland.Presentation: A 73‐year‐old female with primary hyperparathyroidism status post parathyroidectomy with reimplantation in the left forearm presented with 4 days of viral syndrome, found to have tetany and Chvostek’s sign on physical exam. Pertinent laboratory abnormalities included calcium 5.3 mg/dL, ionized calcium 0.44 mmol/L, magnesium 1.4 mg/dL, phosphorous 5.5 mg/dL, PTH 242 pg/mL, and 25‐OH vitamin D 56 ng/mL. Chest CT revealed multifocal pneumonia consistent with positive COVID‐19 testing. She was subsequently admitted to the ICU for severe, symptomatic hypocalcemia and was initiated on a continuous calcium infusion, remdesivir, baricitinib, and steroids. Tetany resolved after 9 g calcium repletion, and she was transferred to the medical floor with an ionized calcium of 0.83 mmol/L. On hospital day 3, repeat ionized calcium was 0.78 mmol/L despite ongoing repletion. Given the persistence of hypocalcemia, a repeat PTH level was obtained which remained high at 487 pg/mL, suggesting ongoing PTH interference in the setting of COVID‐19. PTH was obtained from the right (nonimplanted) arm which was normal at 74 pg/mL. This indicated an appropriate PTH response from the reimplanted gland, and that ongoing hypocalcemia may be due to insufficient PTH function to maintain systemic calcium levels or a peripheral interference with PTH level. With continued calcium supplementation and treatment of COVID‐19, the patient’s calcium stabilized at 8.6 mg/dL. She was discharged on oral calcium supplementation with endocrinology follow‐up.Conclusion: Acute hypocalcemia strongly correlates with a profound inflammatory response in COVID‐19 patients. This case corroborates the cytokine/PTH hypothesis. This patient had a high PTH sampled near the reimplanted gland but an inappropriately normal PTH from the nonimplanted arm, indicating that direct viral interaction interfering with PTH release is an unlikely mechanism. This case represents a scenario where PTH can be sampled directly from the source and this type of model could aid in the process of determining the etiology of hypocalcemia in COVID‐19.

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

SAT229 Symptomatic Hypocalcemia In The Setting Of Crohn’s Disease With Severe Hypomagnesemia

Abstract Disclosure: K. Cuan: None. T. Reisman: None. Introduction: People with Crohn’s Disease (CD) are at risk for various nutritional deficiencies due to decreased oral intake, malabsorption, and increased intestinal losses. CD often causes a negative calcium balance, which does not usually cause hypocalcemia because the bones serve as a reservoir for calcium. However, symptomatic hypocalcemia may occur if a concurrent severe hypomagnesemic state is present. The factors resulting in hypocalcemia in patients with magnesium deficiency are impaired PTH secretion, PTH resistance, and vitamin D deficiency. Clinical Case: A 33-year-old man with CD and rheumatoid arthritis presented following a seizure with additional symptoms of hand cramping and facial twitching. He had previously undergone three small bowel resections and had a history of hypocalcemia due to malabsorption. Although this patient had previously been admitted due to a hypocalcemic seizure, he did not start oral calcium supplements at that time. No issues with magnesium were identified previously. On this encounter, he was found to have a corrected calcium (cCa) of 5.3 mg/dL, undetectably low magnesium at &amp;lt;0.7 mg/dL, normal phosphorus, 25-hydroxyvitamin D at 3.5 ng/mL, and an elevated intact PTH (iPTH) at 169 pg/mL. Aggressive intravenous calcium and magnesium repletion improved cCa to 7.4 mg/dL and magnesium to 2 mg/dL with no further seizure activity. He was discharged on calcium carbonate, calcitriol, and ergocalciferol. A month later, he presented to our endocrinology clinic asymptomatic but with a cCa of 6 mg/dL and magnesium at &amp;lt;0.7 mg/dL. Further biochemical workup revealed normal phosphorus, 25-hydroxyvitamin D at 7.9 ng/mL, and an inappropriately normal iPTH at 49 pg/mL. He was readmitted to the hospital where intravenous repletion improved cCa to 8.1 mg/dL and magnesium to 1.9 mg/dL. His recurrent hypomagnesemia was attributed to malabsorption. An increased dose of calcitriol and oral magnesium were added to his discharge medication regimen, in addition to his ergocalciferol and calcium carbonate. Three days later, he had a cCa level of 7.1 mg/dL as an outpatient. Conclusion: Patients with CD often have nutrient deficiencies, especially if they have had surgical resection within the intestinal tract. Our patient initially developed hypocalcemia from malabsorption, which was then exacerbated by the severely hypomagnesemic state. During his initial hospital encounter, the elevated iPTH level indicated PTH resistance. On his second encounter, the normal iPTH level suggested hypoparathyroidism. Given the relationship between magnesium and calcium homeostasis, addressing the hypomagnesemia eventually aided in achieving stabilization of serum calcium levels. Thus, in patients who are at risk for malabsorption and have recurrent symptomatic hypocalcemia, it is prudent to check magnesium levels as it can affect long term management of hypocalcemia. Presentation: Saturday, June 17, 2023

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.

Pseudohypoparathyroidism and variants: A translational medicine success story

Pseudohypoparathyroidism (PHP) is an uncommon disorder which is characterized by end-organ PTH resistance. The genetic defect is located at the GNAS locus that encodes the alpha-subunit of the stimulatory G protein (Gαs) and several splice variants thereof. This complex locus undergoes parental specific methylation changes that result in tissue-specific silencing of the paternal allele. Heterozygous inactivating mutations that disrupt Gαs function or epigenetics changes that impair Gαs expression contribute to a wide clinical spectrum of the disease: PHP1A, PHP1B, osseous heteroplasia, osteodystrophy, obesity, intrauterine growth retardation… whose mechanisms at the molecular level remain unresolved.

MO584TRABECULAR BONE SCORE AND BONE MICROARCHITECTURE IN HEMODIALYSIS PATIENTS. ITS POTENTIAL RELATIONSHIP WITH PTH-RESISTANCE : A PILOT STUDY

Abstract Background and Aims To explore:i)differences in predictive variables between TrabecularBoneScore(TBS)-derived and LumbarT-score derived bone types.ii)the relationship difference of TBS and LumbarT-score with various ranges of PTH levels in order to identify the levels of PTH that overcome PTH resistance iii) to conform normal upper limit of PTHi levels in hemodialysis patients recommended by K-DIGO guidelines. Method In twenty-five hemodialysis patients,following variables were recorded:biochemical variables,DXA derived variables(including TBS),FRAX-tool derived HRs.The relationship of variables with TBS-derived and LumbarTscore-derived bone types was tested by univariate analysis. The association of TBS,LumbarTscore and fracture HRs with PTHi was tested by univariate analysis and regression curve fitting(maximizing R²). Results Using univariate analysis,the predictive variables of lumbarT-score derived and TBS-derived bone types are different.By curve fitting regression TBS vs PTHi had a sinusoidal pattern with higher values,correlating to PTHi values in the 4th quartile(462 pg/ml (341 -696)corresponding to the normal levels recommended by K-DIGO guidelines.In the same range of values,LumbarT-score vs PTHi for BMD-derived bone type has a progressively increasing trend for osteopenia and osteoporosis,with a statistically significant difference(P0.008). Conclusion The predictive variables of TBs-derived and LumbarT-score derived bone types are different.Bone microarchitecture(MA),measured by TBS,correlates oppositely than LumbarT-score with higher PTHi values in the normal range of PTHi levels recommended by the K-DIGO-CKD-MBD2009-2017 guidelines.Within this range,PTHi values overcome PTH-resistance and improve the bone mineral metabolism. Results must not be extended to higher or lower levels of PTHi compared to those considered in the study for which there is a clear evidence of increase in the relative risk of mortality.

Bilateral Basal Ganglia Calcification; An Unusual Initial Presentation of Pseudohypoparathyroidism

Physiological intracranial calcification occurs in about 0.3–1.5% of cases. Hypoparathyroidism and pseudohypoparathyroidism are the most common causes of pathological basal ganglia calcification.A 21-year-old female who was initially evaluated by neurology team for headache and diplopia, underwent MRI of brain which revealed Calcifications involving the bilateral basal ganglia, thalami, dentate nuclei as well as juxtacortical frontal lobes. She reported Fatigue and muscle pain, usually in her arms especially after playing sports which had been going on for many years. She had no history of fractures, seizures, psychiatric disorders, developmental delay or obvious cognitive impairments. She denied any family history of calcium disorders or autoimmune diseases. As she had been generally healthy in her whole life, she never had any lab testing done. On examination, Height 5’1”, Chvostek’s sign was positive. Fundoscopy was normal. she had no dysmorphic features or shortened 4th metacarpal. Investigations revealed serum calcium less than 5.0 mg (N 8.3 - 10.1 mg/dl), PTH 205.1 pg/ml (N 18.4 - 80.1 pg/ml), phosphate 7.1 mg (N 2.5 - 5 mg), Vitamin-D 36.2 ng/ml (N 30.0 - 100.0 pg/ml),magnesium 2.0 m (N 1.6 - 2.6 mg/dl) with normal albumin, alkaline phosphatase and renal function test. She was diagnosed with pseudohypoparathyroidism and started on calcium and active vitamin D supplement and was referred for genetic testing study. She reported significant improvement in myalgia after a few weeks of starting calcium and active vitamin D supplementations and repeat lab testing showed improved hypocalcemia and hyperphosphatemia. This case illustrates unusual presentation of PTH resistance with basal ganglia calcification as initial presentation prompting further workup. She likely has pseudohypoparathyroidism type 1b.Since adequate treatment of hypoparathyroidism may lead to marked clinical improvement, determination of serum calcium, phosphorus, and parathyroid hormone is mandatory in all individuals with calcification of the basal ganglia to rule out hypoparathyroidism.

Evaluation of Serum Calcium Levels in Patients with Epileptic Seizure

ABSTRACT Introduction Epilepsy is a disorder of the central nervous system, characterized by an epileptic seizure. Epileptic seizures occur due to abnormal synchronous activity in the brain. Calcium is an essential component of bone. Hypocalcemia enhances neuronal excitability, and there are many causes of which include hypocalcemia, vitamin D deficiency, and PTH resistance. Materials and methods The study was conducted in Department of Biochemistry in association with the Department of Neurology of Mahatma Gandhi Medical College and Hospital, Jaipur. Fifty patients diagnosed for epileptic seizure and 50 controls, visiting the inpatient department (IPD) and outpatient department (OPD) of Neurology fulfilling the inclusion criteria, were enrolled for the study. Result The present study showed significantly lower level of serum calcium in patients with epileptic seizure when compared to controls. Conclusion The serum calcium was measured between epileptic seizure and controls. Our present study showed significantly lower value of calcium. It is therefore suggested that there should be regular screening for calcium in patients with epileptic seizure. The serum calcium is biomarker of bone metabolism; so, the correlation can be further studied with some more bone metabolism markers in epileptic seizure patients. How to cite this article Sharma S, Fiza B, Tiwari SK, et al. Evaluation of Serum Calcium Levels in Patients with Epileptic Seizure. J Mahatma Gandhi Univ Med Sci Tech 2020;5(2):35–37.

SAT-343 Diagnosis and Management of Pseudohypoparathyroidism Type 1B

Background: Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders characterized by end-organ resistance to PTH. Most subtypes are caused by pathogenic variants or epigenetic alterations in GNAS, which encodes the alpha subunit of the G protein regulating end-organ response to PTH. PHP type 1B (PHP1B) is caused by methylation defects in GNAS and presents with isolated renal PTH resistance. Clinical Case: A 29-year-old gentleman presented with intermittent muscle spasms, perioral and digital paresthesias, fatigue, and anxiety. Family history was notable for similar symptoms in his sister and nephew. Physical examination revealed normal stature, non-dysmorphic facies, and no soft tissue ossifications or skeletal anomalies. Chvostek sign was positive. Laboratory studies showed total calcium 6.0 mg/dL (n 8.6–10.0 mg/dL), phosphorus 6.8 mg/dL (n 2.5–3.5 mg/dL), creatinine 0.8 mg/dL (n 0.8–1.3 mg/dL), albumin 5.0 (n 3.5–5.0 mg/dL), PTH 231 pg/mL (n 15–65 pg/mL), total 25-hydroxyvitamin D 19 mg/mL (n 20–50 ng/mL), and 1,25-dihydroxyvitamin D 45 pg/mL (n 18–64 pg/mL). Additional endocrine testing showed TSH 6.4 mIU/L (n 0.3–4.2 mIU/L), free T4 1.1 ng/dL (n 0.9–1.7 ng/dL), and TPO antibody <0.3 IU/mL (n <9.0 IU/mL). Renal ultrasound was normal. CT head showed diffuse intracranial calcifications. He was diagnosed with PHP1B and started on calcitriol, cholecalciferol, and calcium carbonate. He declined genetic testing. Repeat laboratory studies were improved with total calcium 8.5 mg/dL, phosphorus 3.9 mg/dL, total 25-hydroxyvitamin D 49 mg/mL, PTH 124 pg/mL, and 24-hour urinary calcium 269 mg (n <250 mg). Conclusion: International consensus guidelines for the diagnosis and management of PHP and related disorders were recently published by Mantovani et al. in 2018. Proposed clinical and biochemical major criteria include PTH resistance, ectopic ossifications, early-onset obesity, TSH resistance, and Albright hereditary osteodystrophy (AHO; round facies, short stature, brachydactyly, developmental delay). Unlike PHP type 1A, PHP1B often presents later in life and features of AHO are usually absent, so diagnosis requires a high degree of clinical suspicion. It is recommended that patients with suspected PHP have molecular confirmation with sequencing, methylation, and/or copy number variant analysis of GNAS. Routine monitoring of calcium, phosphorus, and PTH levels and treatment with active vitamin D analogues with or without calcium supplements are advised to maintain normal calcium and phosphorus and PTH <2 times the upper limit of normal. Other recommendations include renal imaging for nephrocalcinosis, eye exam for cataracts, CT head imaging (in patients with neurological findings) for calcifications, regular dental care, and management of comorbid endocrinopathies. A multidisciplinary approach is needed in this complex, heterogeneous group of disorders.

SAT-371 Severe Hypocalcemia Secondary to Pseudohypoparathyroidism

Introduction: Pseudohypoparathyroidism (PHP) is a rare disorder characterized by PTH resistance due to a mutation in the GNAS gene causing decreased cyclic AMP generation. The 5 subtypes of PHP include type 1a, 1b, 1c, 2, and pseudo-PHP with type 1a being the most common. Patients with PHP present with hypocalcemia, hyperphosphatemia, appropriately elevated PTH, and suppressed calcitriol levels. PHP type 1a patients have characteristic features including obesity, short stature, round facies, and shortened metacarpals. PHP patients should be evaluated for other endocrinopathies as mutations in the GNAS gene may result in resistance to other hormones like TSH, GHRH, and gonadotropins.Case Report: This patient is a 25 year old male who presented to clinic for evaluation of hypocalcemia. He denied any personal or family history of calcium disorders, thyroid disease, or parathyroid disease. He admitted to severe fatigue and muscle cramps for over one year leading to a car accident. He was sent to the emergency room and diagnosed with hypocalcemia requiring IV calcium gluconate. He was then seen by his family physician and was found to have elevated intact PTH and low 25-hydroxy vitamin D levels. He was placed on cholecalciferol 5000 international units (IU) daily, ergocalciferol 50,000 IU once weekly, calcium carbonate 500 mg (6 tablets daily), and referred to endocrinology. The physical exam was unremarkable. The laboratory values tested were an intact PTH of 645 pg/mL (10–65 pg/mL), ionized calcium of 4.2 mg/dL (4.6–5.08 mg/dL), magnesium of 2.1 mg/dL (1.5–2.3 mg/dL), 25-OH vitamin D of 31.7 ng/mL (20–100 ng/mL), and creatinine of 0.81 mg/dL (0.7–1.3 mg/dL) four months after starting the above mentioned calcium and vitamin D supplementation. Further testing revealed a phosphorus level of 4.8 mg/dL (2.3–4.7 mg/dL), calcitriol level of 55.8 pg/mL(19.9–79.3 pg/mL), TSH of 10.46 uIU/mL (0.4–4.2 uIU/mL) and free T4 of 1.5 ng/dL (0.8–1.7 ng/dL). His labs were consistent with PHP. Although unknown which PHP subtype, it is likely not type 1a as he lacks its characteristic phenotype. His abnormal thyroid function tests may be secondary to TSH resistance associated with the GNAS gene mutation. He was told to continue the current dose of calcium carbonate but to discontinue ergocalciferol and cholecalciferol. He was placed on calcitriol 0.5 mcg daily. He will have repeat levels of his ionized calcium, calcitriol, TSH, and free T4 in two weeks. If TSH is still above 10 uIU/mL, we will start levothyroxine replacement.Conclusion: Although a rare disorder, clinicians should have a high index of suspicion for PHP to prevent complications of hypocalcemia (tetany, arrhythmias, seizures) and metabolic bone disease from PTH resistance.

MON-920 Pediatric Parathyroid Carcinoma Presenting With Acute Progressive Genu Valgum

BACKGROUND: Parathyroid carcinoma (PC) is exceptionally rare in children and its clinical features are poorly understood. Available reports have identified that very high serum calcium and parathyroid hormone levels would be expected in this disease. Definitive therapy for PC requires en bloc resection of the parathyroid tumor to reduce the risk of disease recurrence. Unfortunately, there are very few treatment options for metastatic PC and patients with recurrent PC have a high risk of mortality related to their disease. Because of the rarity of the condition, there are very limited data including pediatric patients. Case: A previously healthy 13-year-old girl initially presented to primary care with bilateral foot and ankle pain in the context of acute and progressive genu valgum, referred to the orthopedic clinic. Lab evaluation prompted by imaging demonstrated severe hypercalcemia (15.6 mg/dL) and hyperphosphatasia (Alkaline phosphatase 2056 units/L). She was urgently referred to our clinic where we found her to have a firm right sided neck mass within the thyroid. Lab testing at that time confirmed profound hyperparathyroidism (PTH 2970 pg/mL). Neck ultrasound confirmed the presence of a 5.8 cm hypoechoic lesion adjacent to the right lower lobe of the thyroid. The patient received IV fluid resuscitation before undergoing urgent parathyroid surgery. The parathyroid lesion was grossly adherent to the thyroid gland and she received en bloc resection of the tumor and right lobe of the thyroid. Post-operatively, PTH rapidly declined to <3.4 and she developed a prolonged hypocalcemic phase. PTH function improved, but she continued to require high doses of calcium carbonate to address hungry bone syndrome over subsequent weeks. Comprehensive evaluation included testing for genetic mutations, deletions, and duplications in CASR, CDC73, CDKN1B, MEN1 and RET, all of which were negative. Extensive genetic testing of the parathyroid tumor did not identify any specific mutations which have been previously associated with PC. Six months post-operatively, her labs have vastly improved, although she has clinical evidence of PTH resistance and her alkaline phosphatase has not yet normalized. Neck ultrasound, F-18 FDG PET/MRI imaging and Sestamibi scans show no evidence of persistent disease. Conclusions: While parathyroid carcinoma is extremely rare in pediatric patients, the diagnosis must be considered in cases of hypercalcemia with marked elevations in PTH and palpable neck mass. Although rarely described, bone changes related to PC may be dramatic and may result in lasting morbidity - including genu valgum requiring surgical intervention as well as prolonged hungry bone syndrome and metabolic bone disease. Genu valgum is a unique pediatric feature of this disease because this may only evolve in individuals whose physes are open.

SUN-212 PRELIMINARY RESULTS OF SECONDARY HYPERPARATHYROIDISM BY ETELCALCETIDE IN A SPECIAL COHORT OF HOME HEMODIALYSIS PATIENTS

Secondary hyperparathyroidism (SHP) is a major complication in chronic kidney disease (CKD), in particular CKD5 on hemodialysis. It carries both high co-morbidity and mortality. In patients with CKD G5D, the KDIGO guidelines 2017, recommended to maintain the intact PTH levels in the range of approximately 2 to 9 times the upper normal limit for the assay (2C). We are reporting in this study our experience in treating SHP by Etelcalcetide, in a very special cohort of sick, highly co-morbid, bed, and home bound, hemodialysis patients, treated at home with the assistance of a hemodialysis nurse, we called the program as Nurse Assisted Home Hemodialysis (NAHHD). This is a prospective observational three month study. Twenty seven home HD patients, managed by NAHHD program, were included in this study, average age 58.4 (26-87) year, 61.5% female. Etiology of ESRD was DM in 70%, 54% of them have hypertension. Vascular access AVF & AVG 16 (60%), CVC 11(40%). Average comorbidities 9.4 (6-16). Indications for Etelcalcetide were 50% non compliance, 31% PTH resistance, and 19% bad tolerance of Cinacalcet Three month results are illustrated in the table:Tabled 1M0M1M2M3pPTH (pg/ml)1003882877631<0.01Corrected Ca (mmol/l)2.242.142.162.1NSEtelcalcetide Dose (mg/week)141418.416.4NSOne Alpha Vit.D3 Dose (mcg/week)11.1511.3NSThe medication was well tolerated, only two patients had GI side effects (7%), led to holding the drug in one patient, and the other one was managed by re-adjusting the dose. Open table in a new tab The medication was well tolerated, only two patients had GI side effects (7%), led to holding the drug in one patient, and the other one was managed by re-adjusting the dose. This preliminary and short study showed, Etelcalcetide is efficient and well tolerated in this special group of sick, highly co-morbid, bed and home bound home hemodialysis patients. The drug was well tolerated with minimal GI side effects.

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.

MON-259 Transient PTH Resistance and Vitamin D Deficiency in a Newborn with Hypocalcemic Seizure and Bacteremia

Background: Late onset neonatal hypocalcemia is a rare condition defined by a total calcium of <7 mg/dL after 72 hours of life. Etiologies include increased phosphate load, hypoparathyroidism, vitamin D deficiency, hypomagnesemia, and PTH resistance. Hypocalcemia has been reported in the setting of critical illness/sepsis in both adults and children, and in adults with bacteremia. Clinical case: An 18 day old full-term, formula-fed female infant was admitted with hypocalcemic seizures. Four days prior to presentation, she began experiencing brief episodes of altered mentation and rhythmic jerking with associated vomiting and decreased oral intake. She was afebrile and normotensive. She had no dysmorphic features or brachydactyly, and she was otherwise well appearing. Initial labs showed hypocalcemia (total calcium 6.4 mg/dL (9-10.9), ionized calcium 2.8 mg/dL (4.2 - 5.2)) and hyperphosphatemia (phosphorous 9 mg/dL (3.4-5.9). Magnesium and alkaline phosphatase were normal. Bicarbonate was low at 17 mEq/L (22-32) with an anion gap of 16. Lactic acid was mildly elevated at 2.2 mEq/L (0.2-1.9) with a normal pH. BUN was 5 mg/dL with a creatinine of 0.23 mg/dL. She had a witnessed seizure and was given 1 mL/kg of 10% calcium gluconate and initiated on calcium supplementation. In the setting of a total calcium of 6.8 mg/dL and phosphorous of 7.9 mg/dL, PTH was elevated at 143 pg/mL (18-80). The 25-OHD was low at 7.4 ng/mL (>30), and 1,25 OHD was 56 pg/mL (31-87 pg/mL). Urine calcium/creatinine ratio was 0.58. Random urine phosphorous was low at <10 mg/dL. TSH was normal. Initial evaluation included urine, blood, and CSF cultures which revealed Klebsiella pneumoniae bacteremia. Ionized calcium normalized by day 4 of calcium therapy, and over the following two weeks, the calcium dose was slowly reduced. She was also treated with cholecalciferol and low phosphate formula, and completed a 10 day antibiotic course. Maternal labs revealed normocalcemic vitamin D deficiency with a 25-OHD of 9.4 ng/mL. Conclusion: We describe a full-term, formula-fed newborn who presented with seizures due to late onset hypocalcemia in the setting of bacteremia, and severe vitamin D deficiency. Evaluation was consistent with transient PTH resistance, evidenced by hypocalcemia, hyperphosphatemia, low urinary phosphorous, and elevated PTH. Mechanism is likely multifactorial including excess phosphate load from formula intake, dehydration or relative renal insufficiency from bacteremia, and vitamin D deficiency. To our knowledge, this is the first report of a neonate with late onset hypocalcemia due to PTH resistance found to have concomitant bacteremia and severe vitamin D deficiency, and emphasizes the importance of evaluation for sepsis in a neonate presenting with seizure, regardless of etiology.

MON-327 A Case of Parathyroid Carcinoma in a Patient with Late Stage Chronic Kidney Disease

Introduction: Parathyroid carcinoma (PC) is rare, representing 0.3-5% of primary hyperparathyroidism cases. Its pathophysiology is incompletely understood. Established predisposing factors are lacking, with the exception of known genetic mutation and possibly radiotherapy. The rarity of PC and the fact that its clinical and biochemical features overlap benign parathyroid disease make pre-operative diagnosis challenging. Often the diagnosis is made post-operatively through histopathology. It has been hypothesized that chronic kidney disease may predispose to PC, given chronic parathyroid stimulus related to hypocalcemia and hyperphosphatemia. Here we describe an unusual case of parathyroid cancer in a man with long-standing secondary hyperparathyroidism related to stage IV chronic kidney disease. Case report: A 70-year-old man with hypertension and stage IV chronic kidney disease (CKD) presented for treatment ofsuspected tertiary hyperparathyroidism. His intact parathyroid hormone (iPTH) was 384 (8-54 pg/ml) and serum calcium 11.3 (8.6-10.2 mg/dl). He initially opted not to pursue surgery. Five months later, he presented to theemergency department with shortness of breath and new onset of hoarseness. He was diagnosedwith left vocal cord paralysis. Neck ultrasound showed a 1.1 X 1.4 x 1.4 cm hypoechoic nodule posterior and inferior to the lower left thyroid gland with internal color flow, and he was referred to surgery. Pre-operative serumcalcium was 10.1 with iPTH 774. Intra operatively, the mass was adherent to the surrounding musculature, thyroid and esophagus. Biopsy suggested parathyroid cancer. He underwent an en bloc resection of the left lower parathyroid mass, left superior parathyroidectomy, and ipsilateral hemithyroidectomy. Intra-operative iPTH dropped from 747 to 245. Pathology was consistent witha 3 cm parathyroid carcinoma. The posterior margin was focally positive for tumor. PTH remained elevated post-operativelyat 249 with a corrected serum calcium of 8.6. PET CT was without evidence of metabolically active disease,and neck ultrasound was unremarkable.The patientdeclined HRPT2 mutation testing. Conclusion: The vast majority of PC cases present with primary hyperparathyroidism. The first case of PC diagnosed in secondary hyperparathyroidism was published in 1982. Most patients with long-standing CKD develop polyclonal hyperplasia. In some cases, a monoclonal form of nodular growth has been reported. This monoclonal transformation may involve somatic mutations, such as in the tumor suppressor gene WT1. Whether such cases could progress to malignancy is conceivable, although as yet unproven. Biochemical monitoring for PC recurrence in patients with underlying secondary hyperparathyroidism is challenging. PTH levels do not normalize after surgery, and PTH resistance may delay the development of recurrence-associated hypercalcemia.