Pseudohypoparathyroidism (PHP) is a group of disorders characterized by end-organ resistance to parathyroid hormone (PTH), resulting in high serum PTH, low calcium, and high phosphate levels. Among its 5 subtypes, PHP type 1a is the most common and leads to hereditary osteodystrophy, marked by short stature, short metacarpals, and electrolyte abnormalities such as hyperphosphatemia and hypocalcemia, which can cause tetany and seizures. Rarely, PHP patients can experience pathological fractures of long bones. This report discusses a 22-year-old female with PHP who presented with myoclonic seizures and bilateral hip fractures. Initial symptoms included fits, flank pain, and later, leg weakness. Diagnosis was based on clinical history, elevated serum PTH, low calcium, high phosphate, bilateral cataracts, hypothyroidism, basal ganglia calcification, and family history. Treatment began with IV calcium, followed by alfacalcidol, oral calcium, and antibiotics, leading to symptom remission. Hip fractures were managed with a POP cast and later closed reduction. The patient was discharged with calcium and 1,25 dihydroxy Vitamin D supplementation and scheduled for regular follow-up.

Pseudohypoparathyroidism (PHP) type 1a (PHP 1a) is a rare hereditary disorder characterized by target organ resistance to hormonal signaling and the Albright hereditary osteodystrophy (AHO) phenotype, which features round facial features, short fingers, subcutaneous calcifications, short stature, obesity, and intellectual disability. Progressive osseous heteroplasia (POH) is another rare disorder characterized by heterotopic ossification (HO) that progressively affects skin, subcutaneous tissues, and deep skeletal muscle. PHP 1a is inherited maternally due to a GNAS mutation, while pure POH is inherited paternally. This case study presented a Chinese boy with congenital hypothyroidism, tonic-clonic seizures, hypoparathyroidism, AHO, POH, and joint fixation deformity. Sequencing analysis of GNAS-Gsα revealed a heterozygous C.432+2T>C(P.?) variant (NM_000516.7) affecting the canonical splice donor site of intron 5 in the boy and his mother, indicating maternal inheritance of a GNAS mutation. The patient was diagnosed with POH overlap syndrome (POH/PHP 1a). Following calcium and calcitriol supplementation, he experienced a reduction in seizures, and surgery was performed to correct the joint fixation deformity caused by HO. This case report provided valuable insights into the genotype-phenotype correlations of POH overlap syndrome and underscored the significance of genetic testing in diagnosing rare diseases.

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.

Albright\'s hereditary osteodystrophy is a rare hereditary disease due to a mutation of the complex guanine nucleotide-binding protein, alpha-stimulating activity polypeptide. This condition is commonly associated with type 1A and 1C pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism due to resistance of parathyroid hormone. Patients present with specific characteristics such as brachydactyly, short stature, round facies, subcutaneous ossifications, developmental delay, and obesity, associated with hypocalcemia and hyperphosphatemia. This case presents a 55-year-old woman with short stature and neurocognitive impairment, who was admitted to the emergency department with acute decompensated heart and respiratory failure. On admission, hypocalcemia and hyperphosphatemia were noted, which in combination with the patient\'s clinical history led to an etiological investigation. This case stresses the importance of not only treating the acute disease but also looking at the patient and their clinical and analytical features to diagnose this disease and prevent its complications.

OBJECTIVE: Pseudohypoparathyroidism type 1A (PHP1A) encompasses the association of resistance to multiple hormones, features of Albright hereditary osteodystrophy and decreased Gsα activity. Little is known about the early signs of PHP1A, with a delay in diagnosis. We report two PHP1A cases and their clinical and biochemical findings during a 20-year follow-up.
METHODS: Clinical suspicion was based on obesity, TSH resistance and ectopic ossifications which appeared several months before PTH resistance, at almost 3 years of age. Treatment with levothyroxine, calcitriol and calcium was required in both patients. DNA sequencing of GNAS gene detected a heterozygous pathogenic variant within exon 7 (c.569_570delAT) in patient one and a deletion from XLAS to GNAS-exon 5 on the maternal allele in patient 2. In patient 1, ectopic ossifications that required surgical excision were found. Noticeably, patient 2 displayed adult short stature, intracranial calcifications and psychomotor delay. In terms of weight, despite early diagnosis of obesity, dietary measures were established successfully in both cases.
CONCLUSIONS: GNAS mutations should be considered in patients with obesity, ectopic ossifications and TSH resistance presented in early infancy. These cases emphasize the highly heterogeneous clinical picture PHP1A patients may present, especially in terms of final height and cognitive impairment.

Hypercalcitoninaemia has been described in patients with pseudohypoparathyroidism (PHP) type 1A and 1B. Elevated calcitonin levels are thought to result from impaired Gsα receptor signaling, leading to multiple hormone resistance. Evidence on the risk of medullary thyroid carcinoma (MTC) or C-cell hyperplasia in PHP patients with hypercalcitoninaemia is lacking. A 43-year-old Caucasian man was referred to our endocrinology clinic for chronic hypocalcemia associated with elevated serum parathormone levels and a single cystic thyroid nodule. The patient did not show skeletal deformities, and screening for concomitant hormone resistances was negative, except for the presence of elevated serum calcitonin levels. The workup led to a molecular diagnosis of sporadic PHP1B. Fine needle aspiration of the thyroid nodule was not diagnostic. The calcium stimulation test yielded an abnormal calcitonin response. Given the scarcity of data on the risk of thyroid malignancy in PHP and calcium stimulation test results, total thyroidectomy was performed. Histological examination revealed cystic papillary thyroid cancer in a background of diffuse C-cell hyperplasia. To our knowledge, we are the first to describe a rare form of thyroid cancer combined with C-cell hyperplasia in a patient with PHP and hypercalcitoninaemia. In the present case, a mere receptor resistance might not fully explain the elevated calcitonin levels, suggesting that hypercalcitoninaemia should be carefully evaluated in PHP patients, especially in the case of concomitant thyroid nodules. Further studies on larger cohorts are needed to elucidate this topic.

We report a 15-year-old Chinese girl who presented with intermittent seizure episodes and had been misdiagnosed as having idiopathic epilepsy 5 years previously. Laboratory testing revealed hypocalcemia, hyperphosphatemia, and a high parathyroid hormone (PTH) concentration. She was subsequently shown to have pseudohypoparathyroidism type Ib (PHPIb) based on the results of methylation analysis of the GNAS gene, which showed a loss of methylation of the differentially methylated regions (DMR) of GNAS-AS1, GNAS-XL, and GNAS-A/B; and a gain of methylation of the DMR of the GNAS-NESP55 region. We adjusted the patient\'s medication by prescribing calcium and calcitriol supplements, and gradually reduced the doses of antiepileptic drugs, until they had been completely discontinued. As a result, the patient did not experience any further seizures or epileptiform symptoms; and had normal plasma calcium, phosphorus, and 25-hydroxyvitamin D concentrations and 24-hour urinary calcium excretion. In addition, her PTH concentration gradually normalized over 12 months, and no urinary stones were found on ultrasonographic examination. In conclusion, the clinical presentation of PHP is complex, and the condition is often misdiagnosed. The diagnosis and follow-up of the present patient have provide valuable insights that should contribute to informed clinical decision-making and the implementation of appropriate treatment strategies.

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PTH resistance is characterized by hypocalcemia and hyperphosphatemia in the presence of elevated PTH concentrations, resulting in pseudohypoparathyroidism, which is subdivided into different types according to its different pathogenesis and phenotype. PTH receptor is the alpha subunit of stimulatory G protein (Gsα)-coupled receptor. Pathogenic variants of GNAS gene, encoding for Gsα, lead to reduced Gsα function and PTH resistance. We report a patient with PHP type 1a, with no documented evidence of hypocalcemia, presenting with AHO phenotype and multihormone resistance to PTH, TSH, and GnRH. Her genetic testing showed a novel heterozygous pathogenic variants, a c.934T > G change in exon 11 in adenylate cyclase stimulatory G protein that has not been reported in the literature so far.

Pseudohypoparathyroidism is a terminology used to describe a group of metabolic disorders characterized by parathyroid hormone resistance. Patients with pseudohypoparathyroidism have hypocalcemia, hyperphosphatemia, and elevated serum parathyroid hormone. This methylation defect leads to signaling abnormalities in the parathyroid hormone and parathyroid hormone-related peptide receptor. We present a 40-year-old African American male who was referred to our endocrinology clinic for hypocalcemia. On physical examination, his body mass index was 34.3 kg/m2 and he was found to have a round face, and several subcutaneous nodules on his scalp, hands, and legs. Laboratory findings revealed hypocalcemia, hyperphosphatemia, and elevated levels of intact parathyroid hormone and thyroid stimulating hormone (TSH). His hand X-ray showed brachydactyly of all metacarpal bones, and soft tissue calcifications. Brain CT indicated dense calcifications in the subcortical region, bilateral basal ganglia, bilateral thalami, bilateral cerebellum and vermis, and soft tissue calcifications in the scalp. The \"inactivating parathyroid hormone/parathyroid hormone-related peptide signaling disorder\" diagnostic approach suggested by the Euro pseudohypoparathyroidism network was applied to the patient, who was diagnosed with parathyroid hormone signaling disorder. Compared to the old pseudohypoparathyroidism classification and the 2018 Pseudohypoparathyroidism International Consensus Statement Report, the inactivating parathyroid hormone/parathyroid hormone-related peptide signaling disorder cluster classification appears to be more flexible, and easier to use. It also accommodates future inclusion of genetic mutations associated with hormonal signaling disorders. Adoption of the inactivating parathyroid hormone/parathyroid hormone-related peptide signaling disorder classification remains limited, and further larger studies are needed to compare the three approaches.