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.

Teaching point: Some genetic syndromes have characteristic features that allow for their diagnosis to be made based on radiological findings.

GNAS variants were recently described in 1% of patients not known to have pseudohypoparathyroidism/inactivating PTH/PTHrP signalling disorder 2 in the UK Genetics of Obesity Study. We describe a new missense GNAS variant, c.791A > C, p.(Asp264Thr), in a family with obesity, hyperphagia and mild PTH resistance. A 6-year-old female (body mass index +4.3 SD score [SDS], height +1.9 SDS) presented with hyperphagia and obesity from age 3 years. She had subtle brachydactyly, macrocephaly, and mildly delayed development. The 12-year-old brother (height +2.1 SDS, body mass index +2.9 SDS) had hyperphagia, obesity, mildly delayed development, and autism. He had subtle brachydactyly, as did the affected mother. We assessed the functional effect of the mutant, measuring cAMP production in cells transfected with wild type and mutant GNAS after ligand stimulation. Cells with the mutant GNAS showed impaired cAMP generation through melanocortin receptor 4, GH releasing hormone receptor, and PTH receptor. These cases demonstrate the clinical heterogeneity of monogenic disease, suggesting a need to test for PHP1A in children with obesity even without classical signs of PHP1A.

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.

BACKGROUND: Pseudohypoparathyroidism (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.
METHODS: We 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.
CONCLUSIONS: This 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.

We encountered a Chinese girl with pseudohypoparathyroidism type 1A (PHP1A) and her mother with pseudopseudohypoparathyroidism (PPHP). Sequencing analysis of GNAS-Gsα revealed a heterozygous c.212+2T>C variant (NM_000516.4) affecting the canonical splice donor site of intron 2 in the girl and her mother. RT-PCR performed on mRNA samples obtained from cycloheximide-treated and cycloheximide-untreated lymphoblastoid cell lines of this girl revealed the utilization of an alternative splice donor site at 33-34 bp from the boundary between exon 2 and intron 2 and the production of an aberrant mRNA with a retention of a 32 bp intronic sequence between exon 2 and exon 3 (p.(Gly72Lysfs*39)), which satisfied the condition for the occurrence of nonsense-mediated mRNA decay, as predicted by SpliceAI. This study revealed the molecular consequences of disruption of the canonical splice donor site and confirmed the clinical utility of SpliceAI.

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.

Pseudohypoparathyroidism is a rare disorder characterized by end-organ resistance to intact parathyroid hormone (PTH) and concomitant laboratory findings of hypocalcemia and hyperphosphatemia. Radiologic evidence of the disease may manifest as a variety of bone abnormalities. This case describes an 11-year-old female with a history of repaired bilateral slipped capital femoral epiphysis who presented with a limited range of motion of the bilateral upper extremities. Laboratory findings were consistent with pseudohypoparathyroidism. Radiographs revealed subchondral resorption of bilateral clavicular heads and multiple ribs and band lucencies of proximal humeral metaphyses, along with vara deformity and inferior subluxation of the humeral heads. This presentation adds to the spectrum of potential radiographic manifestations of pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterised by a non-functioning PTH. Usually, the diagnosis is made following (symptomatic) hypocalcaemia. We describe a case in which epileptic seizures and abnormalities in dental development were the main clinical manifestation of PHP type 1B. This case demonstrates the importance of screening for hypocalcaemia in patients with de novo epileptic seizures. In addition, antiepileptic medications themselves may interfere with calcium-phosphate metabolism, causing or aggravating a hypocalcaemia as well. By correcting the calcium level, a resolution of these symptoms could be obtained.