Cutaneous Calcified Mass of Foot in Pseudohypoparathyoidism: Case Report.

Soft tissue calcifications frequently appear on imaging studies, representing a prevalent but non-specific discovery, varying from a local reaction without clear cause to suggesting an underlying systemic condition. Because calcifications like these can arise from various causes, an accurate differential diagnosis is crucial. Differential diagnosis entails a methodical assessment of the patient, encompassing clinical presentation, medical history, radiological and pathological findings, and other pertinent factors. Through scrutiny of the patient's medical and trauma history, we can refine potential causes of calcification to vascular, metabolic, autoimmune, neoplastic, or traumatic origins. Furthermore, routine laboratory assessments, including serum levels of calcium, phosphorus, ionized calcium, vitamin D metabolites, and parathyroid hormone (PTH), aid in identifying metabolic etiologies. We describe a rare occurrence of osteoma cutis in a 15-year-old female patient with a history of pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO). The patient presented with a painful mass on the lateral side of her left foot. The diagnosis was based on medical history, laboratory tests, and imaging, leading to an excisional biopsy and complete pain relief post-surgery. Understanding such rare occurrences and related conditions is crucial for accurate diagnosis and management.

Multiple brown tumors: a bone complication due to long-term untreated pseudohypoparathyroidism.

Bone lytic lesions are a possible complication of pseudohypoparathyroidism type 1B, in undertreated adult patients. Whole body [18F] F-fluorocholine PET/CT is a useful imaging tool to assess brown tumor progression in this context. We describe the case of a 33-year-old woman, referred for the diagnostic evaluation of lytic bone lesions of the lower limbs, in the context of asymptomatic pseudohypoparathyroidism. She had been treated with alfacalcidol and calcium during her childhood. Treatment was discontinued at the age of 18 years old because of the lack of symptoms. A femur biopsy revealed a lesion rich in giant cells, without malignancy, consistent with a brown tumor. Laboratory tests showed a parathyroid level at 1387 pg/ml (14-50). Whole-body Fluorocholine PET/CT revealed hypermetabolism of bone lesions. The final diagnosis was brown tumors related to hyperparathyroidism complicating an untreated pseudohypoparathyroidism. Genetic testing confirmed PHP type 1B. Pseudohypoparathyroidism with radiographic evidence of hyperparathyroid bone disease, is a very rare condition due to parathyroid hormone resistance in target organs, i.e., kidney resistance, but with conserved bone cell sensitivity. It has been reported in only a few cases of pseudohypoparathyroidism type Ib. Long-term vitamin D treatment was required to correct bone hyperparathyroidism. With this rationale, the patient was treated with calcium, alfacalcidol, and cholecalciferol. One-year follow-up showed complete resolution of pain, improvement in serum calcium, and regression of bone lesions on [18F]F-fluorocholine PET/CT. This case illustrates the usefulness of [18F]F-fluorocholine PET/CT for the imaging of brown tumors in pseudohypoparathyroidism type 1B, and emphasizes the importance of calcium and vitamin D treatment in adult patients, to avoid the deleterious effects of high parathyroid hormone on skeletal integrity.

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.

Pseudohypoparathyroidism-A Rare Cause of Seizures in a Young Male.

INTRODUCTION: Symptomatic hypocalcemia has a variety of underlying etiologies,with hypoparathyroidism and vitamin D deficiency being the most common. However,rarer etiologies such as pseudohypoparathyroidism, as is present in the current case, should not be overlooked. Pseudohypoparathyroidism (PHP) is a heterogeneous group of disorders characterized by parathyroid hormone (PTH) resistance. The diagnosis of this rare genetic condition is often delayed,due to its myriad presentations,leading to an initially inappropriate approach and therapy. MATERIALS: A 19-year-old male,K/C/O seizure disorder since 18 years,presented to ER in generalized convulsive status epilepticus since 2 hours.Developmentally he had poor growth spurt. No h/o trauma, fever, vomiting, headache. Patient continued to have seizures occasionally despite being compliant to Tab Sodium Valproate 250mg BD.O/E: Patient was drowsy but arousable. He had short stature.Height-35 kg, Weight-136 cm and BMI 18.92 kg/m2.Bilateral cataractous lens+. Examination of limbs revealed brachydactyly of the fingers and fourth toes. Chvostek and Trousseau signs were positive. Knuckle knuckle Dimple Dimple Sign+ Result: ECG showed showed prolonged QT interval. Blood investigations showed Serum calcium-5.8, Serum phosphorus-8.7, iPTH-193, TSH-15.4. MRI brain revealed diffuse bilateral calcifications of basal ganglia. Given the clinical,radiographic and laboratory findings, diagnoses of PHP type Ia with primary hypothyroidism was made.Patient was admitted to wards,hypocalcemia corrected with intravenous and oral calcium and vitamin D.Discharged on 50 ug levothyroxine, oral calcium, vitamin D3 oral solution weekly. The patient is being followed up at half monthly intervals and has remained seizure free since discharge. CONCLUSION: PHP type Ia (GNAS gene mutation) is the most common form of PHP and associated with Albright's hereditary osteodystrophy (AHO), resistance to multiple hormones. This case stresses the pivotal role of a complete biochemical investigation of the calcium phosphate metabolism in every References Melmed S, Koenig R, Rosen C, Auchus R, Goldfine A. Williams textbook of endocrinology: South Asia edition, 2 vol set-E-book. Elsevier India; 2020 Jun 30. Mantovani G, Bastepe M, Monk D, De Sanctis L, Thiele S, Ahmed SF, Bufo R, Choplin T, De Filippo G, Devernois G, Eggermann T. Recommendations for diagnosis and treatment of pseudohypoparathyroidism and related disorders: an updated practical tool for physicians and patients. Hormone research in paediatrics. 2020;93(3):182-96.

Variable Bone Phenotypes in Patients with Pseudohypoparathyroidism.

PURPOSE OF REVIEW: Pseudohypoparathyroidism (PHP) is a disorder caused by mutations and/or epigenetic changes at the complex GNAS locus. It is characterized by hypocalcemia, hyperphosphatemia, and an elevated parathyroid hormone concentration secondary to the resistance of target tissues to the biological actions of parathyroid hormone. PHP is divided into several subtypes with different yet overlapping phenotypes. Research on the bone status in patients with PHP is sparse and has yielded inconsistent results. This review was performed to summarize the current knowledge on the bone phenotypes and possible mechanisms of PHP. RECENT FINDINGS: Patients with PHP exhibit highly variable bone phenotypes and increased concentrations of bone turnover markers. Long-standing elevation of the parathyroid hormone concentration may lead to hyperparathyroid bone diseases, including rickets and osteitis fibrosa. Compared with normal controls, patients with PHP may exhibit similar, increased, or decreased bone mineral density. Higher bone mineral density has been found in patients with PHP type 1A than in normal controls, whereas decreased bone mass, osteosclerosis, and osteitis fibrosa cystica have been reported in patients with PHP type 1B, indicating more variable bone phenotypes in PHP type 1B. Bone tissues show partial sensitivity to parathyroid hormone in patients with PHP, leading to heterogeneous reactions to parathyroid hormone in different individuals and even in different regions of bone tissues in the same individual. Regions rich in cancellous bone are more sensitive and show more obvious improvement after therapy. Active vitamin D and calcium can significantly improve abnormal bone metabolism in patients with PHP.

Neonatal and Early Infancy Features of Patients With Inactivating PTH/PTHrP Signaling Disorders/Pseudohypoparathyroidism.

BACKGROUND: Pseudohypoparathyroidism (PHP) and related disorders newly referred to as inactivating PTH/PTHrP signaling disorders (iPPSD) are rare endocrine diseases. Many clinical features including obesity, neurocognitive impairment, brachydactyly, short stature, parathyroid hormone (PTH) resistance, and resistance to other hormones such as thyroid-stimulating hormone (TSH) have been well described, yet they refer mainly to the full development of the disease during late childhood and adulthood. OBJECTIVE: A significant delay in diagnosis has been reported; therefore, our objective is to increase awareness on neonatal and early infancy presentation of the diseases. To do so, we analyzed a large cohort of iPPSD/PHP patients. METHODS: We included 136 patients diagnosed with iPPSD/PHP. We retrospectively collected data on birth and investigated the rate of neonatal complications occurring in each iPPSD/PHP category within the first month of life. RESULTS: Overall 36% of patients presented at least one neonatal complication, far more than the general population; when considering only the patients with iPPSD2/PHP1A, it reached 47% of the patients. Neonatal hypoglycemia and transient respiratory distress appeared significantly frequent in this latter group, ie, 10.5% and 18.4%, respectively. The presence of neonatal features was associated with earlier resistance to TSH (P < 0.001) and with the development of neurocognitive impairment (P = 0.02) or constipation (P = 0.04) later in life. CONCLUSION: Our findings suggest that iPPSD/PHP and especially iPPSD2/PHP1A newborns require specific care at birth because of an increased risk of neonatal complications. These complications may predict a more severe course of the disease; however, they are unspecific which likely explains the diagnostic delay.

Fahr's Disease and Hypoparathyroidism - A Missing Link.

Fahr's disease is an idiopathic basal ganglia calcification with autosomal dominant inheritance. Prior to diagnosing Fahr's disease based on computed tomography (CT) and/or magnetic resonance imaging (MRI) of the brain, one should rule out hypoparathyroidism (HP), and pseudohypoparathyroidism (PHP). Treatments of these conditions are entirely different. HP- and PHP-related hypocalcemia requires calcium, calcitriol, and vitamin D therapy in a long run to avoid recurrent seizures whereas Fahr's disease is treated with an antiepileptic alone.

Intralesional sodium thiosulfate treatment of calcinosis cutis in pseudopseudohypoparathyroidism.

Pseudopseudohypoparathyroidism is an imprinted GNAS spectrum disorder that induces the phenotype of Albright's hereditary osteodystrophy. This phenotype often involves the formation of calcinosis cutis: firm, painful cutaneous eruptions, which are classically difficult to treat. Intralesional sodium thiosulfate has been reported successfully in various cases of calcinosis cutis; however, these reports describe patients with autoimmune or idiopathic calcinosis. This case details the clinical improvement and resolution of calcinosis cutis lesions utilizing intralesional sodium thiosulfate in an adolescent patient with pseudopseudohypoparathyroidism.

Coexistence of dyschondrosteosis associated to SHOX deficiency, pseudohypoparathyroidism 1B, and chronic autoimmune thyroiditis: a case report.

We present an unusual case of SHOX deficiency associated with Léri-Weill dyschondrosteosis (LWD), Hashimoto's thyroiditis and pseudohypoparathyroidism 1B in a young woman. To our knowledge, this is the first ever report of these disorders coexisting. At the age of nine years, the proband was diagnosed of hypothyroidism due to Hashimoto's thyroiditis, and developed biochemical abnormalities consistent with hyperphosphatemia, mild hypocalcemia and elevated parathyroid hormone without any clinical symptoms except short stature. Replacement therapy with levothyroxine, calcium and alphacalcidol was initiated. The diagnosis of pseudohypoparathyroidism 1B was confirmed at the age of 17.5 years with the demonstration of methylation alteration at the GNAS locus. At the age of 16 years, 3.5 years after her menarche, she presented clear features of LWD. A large deletion of the SHOX gene was confirmed. Family genetic tests were not doable since she was adopted. We discuss the diagnostic challenges of these coexisting rare endocrinopathies.

A novel GNAS mutation in pseudohypoparathyroidism type 1a in a Chinese man presented with recurrent seizure: a case report.

BACKGROUND: Pseudohypoparathyroidism is a rare genetic disease characterized by hypocalcaemia and hyperphosphataemia due to the defect to the guanine nucleotide-binding protein alpha subunit (GNAS) gene. Patients with pseudoparathyroidism type 1a and 1c could manifest Albright's hereditary osteodystrophy and multiple hormone resistance including gonadotropin and thyroid stimulating hormone. CASE PRESENTATION: Here we report a Chinese man who presented with fatigue, recurrent seizure and Albright's hereditary osteodystrophy. His genetic study revealed a heterozygote mutation in the GNAS gene [NM_000516.4(GNAS): c2787_2788del (p.Val930AspfsTer12)]. After calcium and calcitriol supplement, his seizures achieved partially remission. CONCLUSIONS: We report a case of PHP1a or 1c with a novel frameshift mutation in GNAS gene in a patient presenting with AHO, as well as TSH and partial gonadotropin resistance. This mutation in this case has not been reported in literature and adds to the spectrum of genetic mutations related to PHP.

A patient with extensive cerebral calcification due to pseudohypoparathyroidism: a case report.

BACKGROUND: Pseudohypoparathyroidism(PHP) is a heterogeneous group of disorders due to impaired activation of c AMP dependant pathways following binding of parathyroid hormone (PTH) to its receptor. In PHP end organ resistance to PTH results in hypocalcaemia, hyperphosphataemia and high PTH levels. CASE PRESENTATION: A 59 year old male presented with a history of progressive impairment of speech and unsteadiness of gait for 1 week and acute onset altered behavior for 1 day and one episode of generalized seizure. His muscle power was grade four according to MRC (medical research council) scale in all limbs and Chovstek's and Trousseau's signs were positive. Urgent non contrast computed tomography scan of the brain revealed extensive bilateral cerebral and cerebellar calcifications. A markedly low ionized calcium level of 0.5 mmol/l, an elevated phosphate level of 9.5 mg/dl (reference range: 2.7-4.5 mg/dl) and an elevated intact PTH of 76.3 pg/l were noted. His renal functions were normal. His hypocalcemia was accentuated by the presence of hypomagnesaemia. His 25 hydroxy vitamin D level was only marginally low which could not account for severe hypocalcaemia. A diagnosis of pseudohypoparathyroidism without phenotypic defects, was made due to hypocalcaemia and increased parathyroid hormone levels with cerebral calcifications. The patient was treated initially with parenteral calcium which was later converted to oral calcium supplements. His coexisting Vitamin D deficiency was corrected with 1αcholecalciferol escalating doses. His hypomagnesaemia was corrected with magnesium sulphate parenteral infusions initially and later with oral preparations. With treatment there was a significant clinical and biochemical response. CONCLUSION: Pseudohypoparathyroidism can present for the first time in elderly resulting in extensive cerebral calcifications. Identification and early correction of the deficit will result in both symptomatic and biochemical response.

Presentation of pseudohypoparathyroidism and pseudopseudohypoparathyroidism with skin lesions: Case reports and review.

We report three cases of patients with pseudohypoparathyroidism or pseudopseudohypoparathyroidism. These diseases are considered GNAS inactivating mutation syndromes that are characterized by a diversity of alterations among which a particular phenotype and specific endocrine or ossification abnormalities may be found. These patients may present with hard cutaneous nodules, which can represent osteoma cutis. The presence of these lesions in pediatric patients should prompt the dermatologist's consideration of this group of diseases when reaching a diagnosis. A multidisciplinary team of pediatricians, endocrinologists, geneticists, and dermatologists should carefully evaluate these patients.

Dental anomalies and orthodontic characteristics in patients with pseudohypoparathyroidism.

BACKGROUND: Pseudohypoparathyroidism (PHP) is a rare and inherited disease caused by mutations in the GNAS-gene or upstream of the GNAS complex locus. It is characterized by end-organ resistance to PTH, resulting in hypocalcemia and hyperphosphatemia. We aimed to investigate the dental anomalies according to tooth types and the orthodontic characteristics of patients with PHP. METHODS: Using a cross-sectional design, 29 patients (23 females) with PHP, living in Denmark, were included, and their clinical intraoral photos and radiographs were examined. RESULTS: Pulp calcification was found in 76% of the patients. Blunting of root apex was present in 55% and shortening of root in 48% of the examined patients. Blunting and shortening of roots were seen more often in premolars than in other tooth types (pboth < 0.01). Crowding of lower anterior teeth was frequently observed (36%) as well as diastema in the upper arch (25%), midline diastema (18%), and Class III malocclusion (11%). CONCLUSION: In the present study population, the teeth were frequently affected by pulp calcification and/or deviation of the root morphology. Blunting and shortening of root(s) were more often seen in premolars than in other tooth types. Class III malocclusion was relatively prevalent. It is important to pay attention to dental anomalies and occlusion in order to provide adequate care for patients with PHP.

Ossifying epulis in pseudohypo-parathyroidism: a case-based therapeutic approach.

BACKGROUND: The term Pseudohypoparathiroidism indicates a group of rare conditions characterised by end-organ resistance to the action of parathyroid hormone (PTH). Ossifying epulis (OE) is a exophytic gingival lesion characterised by spontaneous bone formation beneath the mucosa, which may affect children and adults: the exophytic, calcified outgrowths can occur in any bone and generally have favorable prognosis. Drug therapy may normalise calcium serum levels, but not completely avoid the occurrence of peripheral ossifying epulis. CASE REPORT: We report a representative case of a peripheral ossifying epulis in the mouth of a patient following a drug treatment protocol for her pseudohypoparathyroidism and to optimise serum markers. An 11-year-old girl was referred to our department, showing a bulky neoformation on the gingival margin of 0.6 mm diameter with sharp margins. The mass was completely excised. Histological analysis revealed distinctive features of a chronic and acute inflammatory microenvironment with plasma cells (positivity for CD38, MUM1, Lambda and Kappa chains) and bone tissue fragments with remodeling aspects referable to flogistic osteolysis. The biopsy result leads to hypothese a change in the patient's drug therapy. Multidisciplinary screening and individualised pharmacological treatment are strongly recommended in the clinical practice in order to improve the therapeutic results.

Glucose Homeostasis and Energy Balance in Children With Pseudohypoparathyroidism.

Context: Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterized by early-onset obesity and multihormone resistance. To treat abnormal weight gain and prevent complications such as diabetes, we must understand energy balance and glucose homeostasis in PHP types 1A and 1B. Objective: The aim of this study was to evaluate food intake, energy expenditure, and glucose homeostasis in children with PHP. Design: Assessments included resting energy expenditure (REE), physical activity, food intake, sucrose preference, questionnaires, endocrine status, and auxological status. All patients underwent an oral glucose tolerance test (OGTT). Setting: Vanderbilt University Medical Center. Patients: We assessed 16 children with PHP1A, three with PHP1B, and 15 healthy controls. Main Outcome Measures: Food intake during an ad lib buffet meal and glucose at five time points during OGTT. Results: PHP1A and control groups were well matched. Participants with PHP1A had significantly lower REE without concomitant change in food intake or physical activity. At baseline, participants with PHP1A had significantly lower fasting glucose and insulin resistance. During OGTT, participants with PHP1A had significantly delayed peak glucose and a slower rate of glucose decline despite similar oral glucose insulin sensitivity. Participants with PHP1A had 0.46% lower HbA1c levels than controls from a clinic database after adjustment for OGTT 2-hour glucose. The PHP1B group was similar to the PHP1A group. Conclusions: In contrast to other monogenic obesity syndromes, our results support reduced energy expenditure, not severe hyperphagia, as the primary cause of abnormal weight gain in PHP. Patients with PHP are at high risk for dysglycemia without reduced insulin sensitivity.

Prevalence of Nephrocalcinosis in Pseudohypoparathyroidism: Is Screening Necessary?

The prevalence of nephrocalcinosis in persons with pseudohypoparathyroidism has not been systematically examined. We conducted a retrospective study of renal imaging and biochemical results in 19 patients with pseudohypoparathyroidism with 49 imaging assessments. No cases of nephrocalcinosis were identified. Routine screening for nephrocalcinosis in pseudohypoparathyroidism may not be necessary.

Obstructive Sleep Apnea and Otolaryngologic Manifestations in Children with Pseudohypoparathyroidism.

BACKGROUND/AIMS: Pseudohypoparathyroidism (PHP) is a rare, genetic disorder. Patients with PHP may have increased prevalence of obstructive sleep apnea (OSA) but this has not been prospectively studied. METHODS: We enrolled children aged 6-18 years with PHP and matched controls. Evaluation included physical examination, medical history, and polysomnography. RESULTS: Fifteen children with PHP type 1A (PHP1A) and 15 controls completed the study. Both groups were obese (BMI 32.2 ± 8.7 vs. 31.7± 6.5). The majority of PHP1A patients required tympanostomy tubes (86.7%) and adenotonsillectomy (73.3%). The primary outcome, i.e., the obstructive disturbance index, was significantly higher in PHP1A children versus controls (1.8 ± 2.3 vs. 0.6 ± 0.5, p = 0.045). Children with PHP1A were more likely to have OSA compared with controls (60.0 vs. 13.3%, p = 0.008). Three siblings with PHP type 1B (PHP1B) were also studied (BMI 25.9 ± 9.0). None had a history of adenotonsillectomy, one had tympanostomy tubes. The obstructive disturbance index (2.0 ± 2.3) was similar to that of children with PHP1A. Two (66.7%) PHP1B participants had OSA. CONCLUSION: Children with PHP1A are at an increased risk for OSA compared with similarly obese peers. They also have higher rates of otitis media and adenotonsillar hypertrophy. Screening for OSA should be considered in all patients with PHP1A and possibly PHP1B though more research is needed.