STX16 exon 5-7 deletion in a patient with pseudohypoparathyroidism type 1B.

OBJECTIVES: Pseudohypoparathyroidism (PHP) comprises a cluster of heterogeneous diseases characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone (PTH) resistance. PHP type 1B (PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16. STX16 exon 2-6 deletion is commonly observed in autosomal dominant (AD)-PHP1B, while sporadic PHP1B commonly results from methylation abnormalities of maternal differentially methylated regions and remains unclear at the molecular level. CASE PRESENTATION: A 39-year-old male patient with PHP1B, who had his first seizure at 15 years of age, presented to our hospital. The methylation-specific multiplex ligation-dependent probe amplification results showed a half-reduced copy number of STX16 exon 5-7 and loss of methylation at GNAS exon A/B. His mother also had a half-reduced copy number of STX16 exon 5-7 but with normal methylation of GNAS. His father has a normal copy number of STX16 and normal methylation of GNAS. CONCLUSIONS: For the recognition and early diagnosis of this kind of disease, here we report the clinical symptoms, auxiliary examinations, genetic testing characteristics, and treatment of the patient.

Pseudohypoparathyroidism type 1B with involuntary movements: a case report and literature review.

Pseudohypoparathyroidism (PHP) is a rare disorder characterized by convulsions, tetany, and sensory abnormalities caused by hypocalcemia due to parathyroid hormone (PTH) resistance. Only few patients present with involuntary movements. We report the case of a 7-yr-old girl with PHP and involuntary movements triggered by running. Initially, she was suspected of having paroxysmal kinesigenic dyskinesia and was treated with carbamazepine (CBZ). Involuntary movements were reduced. However, 2 months post-treatment, she experienced convulsions during a fever. Blood tests and brain computed tomography revealed hypocalcemia, hyperphosphatemia, elevated intact PTH, and calcifications in the frontal cortex and basal ganglia. The patient showed no features of Albright's hereditary osteodystrophy. The involuntary movements disappeared after the discontinuation of CBZ and initiation of calcium and active vitamin D preparations. Methylation-specific multiplex ligation-dependent probe amplification for the GNAS region and microsatellite analysis of chromosome 20 led to the diagnosis of PHP1B caused by epimutation. In 15 reported cases, with or without intracranial calcification, PHP-associated involuntary movements disappeared or became less severe with treatment for hypocalcemia; in eight of 11 cases, they were triggered by exercise or movement. PHP-associated hypocalcemia can trigger exercise-induced involuntary movements owing to lowered serum ionized calcium levels. In such patients, early blood tests are vital for the differential diagnosis of PHP.

Induced pluripotent stem cells derived renal tubular cells from a patient with pseudohypoparathyroidism and its response to parathyroid hormone stimulation.

INTRODUCTION: Creating induced pluripotent stem cells (iPSCs) from somatic cells of patients with genetic diseases offers a pathway to generate disease-specific iPSCs carrying genetic markers. Differentiating these iPSCs into renal tubular cells can aid in understanding the pathophysiology of rare inherited renal tubular diseases through cellular experiments. MATERIALS AND METHODS: Two Japanese patients with Pseudohypoparathyroidism (PHP), a 49-year-old woman and a 71-year-old man, were studied. iPSC-derived tubular cells were established from their peripheral blood mononuclear cells (PBMCs). We examined changes in intracellular and extracellular cyclic adenosine monophosphate (cAMP) levels in these cells in response to parathyroid hormone (PTH) stimulation. RESULTS: Renal tubular cells, differentiated from iPSCs of a healthy control (648A1), showed a PTH-dependent increase in both intracellular and extracellular cAMP levels. However, the renal tubular cells derived from the PHP patients' iPSCs showed inconsistent changes in cAMP levels upon PTH exposure. CONCLUSION: We successfully created disease-specific iPSCs from PHP patients' PBMCs, differentiated them into tubular cells, and replicated the distinctive response of the disease to PTH in vitro. This approach could enhance our understanding of the pathophysiology of inherited renal tubular diseases and contribute to developing effective treatments.

High prevalence of hypercalcitoninemia in a large cohort of adult and paediatric patients with PTH resistance syndromes.

BACKGROUND: Pseudohypoparathyroidism (PHP) refers to a group of rare hereditary disorders associated with resistance to parathormone (PTH) and other hormones now termed inactivating PTH/PTHrP disorders (iPPSD). Hypercalcitoninemia has been seldom reported in small series. Our aim was to investigate the characteristics of hypercalcitoninemia in paediatric and adult patients with PHP/iPPSD. METHODS: We retrospectively collected data from two cohorts from two European Endocrinology tertiary centers: the paediatric cohort comprised 88 children with available calcitonin (CT) measurements; the adult cohort included 43 individuals with simultaneous CT and PTH measurements. RESULTS: In the paediatric cohort 65.9% had hypercalcitoninemia (median CT 15 ng/L); in the adult cohort 53.5% (mean CT 21.6 ng/L). There was no difference between CT in paediatric and adult population; we observed stable CT levels over a median follow-up of 134.5 months in adults. Notably, no correlations were detected between CT and PTH levels. Other etiologies of hypercalcitoninemia were excluded, adult patients underwent regular thyroid ultrasound (US) to screen for medullary thyroid cancer (MTC). We performed 20 calcium stimulation tests in adult patients. While there was a significant difference in basal and peak CT between our patients, healthy subjects and subjects with MTC, there was no difference with patients with C-cell hyperplasia. CONCLUSIONS: This study underscores the common occurrence of hypercalcitoninemia in both paediatric and adult PHP/iPPSD patients, in particular with subtypes iPPSD2-iPPSD3. Furthermore, these patients show an hyperresponsiveness to calcium stimulation test falling between healthy subjects and patients with MTC. These findings contribute into the understanding of CT dynamics in the context of PHP/iPPSD.

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.

The Diagnosis of Albright's Osteodystrophy in a Case With Respiratory Failure.

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.

A novel GNAS-Gsα splice donor site variant in a girl with pseudohypoparathyroidism type 1A and her mother with pseudopseudohypoparathyroidism.

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.

Medulloblastoma in a child with osteoma cutis - a rare association due to loss of GNAS expression.

OBJECTIVES: Inactivating GNAS mutations result in varied phenotypes depending on parental origin. Maternally inherited mutations typically lead to hormone resistance and Albright's hereditary osteodystrophy (AHO), characterised by short stature, round facies, brachydactyly and subcutaneous ossifications. Paternal inheritance presents with features of AHO or ectopic ossification without hormone resistance. This report describes the case of a child with osteoma cutis and medulloblastoma. The objective of this report is to highlight the emerging association between inactivating germline GNAS mutations and medulloblastoma, aiming to shed light on its implications for tumor biology and promote future development of targeted surveillance strategies to improve outcomes in paediatric patients with these mutations. CASE PRESENTATION: A 12-month-old boy presented with multiple plaque-like skin lesions. Biopsy confirmed osteoma cutis, prompting genetic testing which confirmed a heterozygous inactivating GNAS mutation. At 2.5 years of age, he developed neurological symptoms and was diagnosed with a desmoplastic nodular medulloblastoma, SHH molecular group, confirmed by MRI and histology. Further analysis indicated a biallelic loss of GNAS in the tumor. CONCLUSIONS: This case provides important insights into the role of GNAS as a tumor suppressor and the emerging association between inactivating GNAS variants and the development of medulloblastoma. The case underscores the importance of careful neurological assessment and ongoing vigilance in children with known inactivating GNAS variants or associated phenotypes. Further work to establish genotype-phenotype correlations is needed to inform optimal management of these patients.

Vara Deformity and Subluxed Humeral Heads: An Unusual Sign in Pseudohypoparathyroidism.

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.

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

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

Diagnosis and approach of pseudohypoparathyroidism type 1A and related disorders during long term follow-up: a case report.

OBJECTIVES: 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. CASE PRESENTATION: 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.

Interpreting epigenetic causes of recurrent hypokalemia and seizures: Gitelman syndrome co-exist with pseudohypoparathyroidism type 1B.

We describe a unique case of 27-year-old male with Gitelman syndrome (GS) co-exist with pseudohypoparathyroidism type 1B (PHP1B). The patient presented with a 5-year history of seizures, tetany, and numbness of the extremities. Further examinations showed recurrent hypokalemia, inappropriate kaliuresis, hypocalcemia, hyperphosphatemia, and elevated PTH levels. A novel variant of autosomal recessive GS (p.Val287Met SLC12A3) and a novel 492.3Kb deletion containing the whole of STX16, were discovered by a whole-exome sequencing. Following the diagnosis, calcitriol, calcium, and potassium supplements were started. Hematuria calcium and phosphorus levels, as well as blood potassium levels, have recovered and remained within normal ranges after 3 years of follow-up. Our findings have important consequences for supporting the idea that heterozygosity for variants have effects on the patients' clinical performance with autosomal recessive inheritance disorders. Further study is need for the putative effects of the variant. Likewise, further investigation with regards to the gene-gene interaction relations between GS and other electrolyte imbalance disorders is warranted.

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

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

Recurrent transient severe hypocalcaemia in two siblings with type 1 Bartter syndrome.

Type 1 Bartter syndrome causes hypokalaemia and metabolic alkalosis owing to mutation in the SLC12A1 gene. Meanwhile, hypocalcaemia is rare in Bartter syndrome, except in type 5 Bartter syndrome. Herein, we describe two siblings with type 1 Bartter syndrome with recurrent transient severe hypocalcaemia. They each visited our hospital several times with chief complaints of numbness in the limbs, shortness of breath and tetany after stresses such as exercise or fever. Severe hypocalcaemia was also observed with a serum calcium level of approximately 6.0 mg/dL at each visit. The clinical symptoms and abnormalities in laboratory findings quickly improved with rest and intravenous treatment. In a steady state, no severe hypocalcaemia was evident, but serum intact parathyroid hormone (PTH) levels were high. In recent years, a large-scale study has revealed that type 1 and type 2 Bartter syndrome have high PTH values. In addition, there are reports that these patients develop hypocalcaemia due to PTH resistance. Therefore, our patient was also in a PTH-resistant state, and hypocalcaemia was thought to be exacerbated by physical stress. It is not well known that Bartter syndrome patients other than those with type 5 suffer from hypocalcaemia. And hypocalcaemia was not detected in normal examinations under steady-state conditions. Therefore, in patients with type 1 and type 2 Bartter syndrome, severe hypocalcaemia may occur, but may go unnoticed. When following up these patients, the attending physician must keep in mind that such patients are in a PTH-resistant state and that physical stress can cause severe hypocalcaemia.

Intrafamilial phenotypic heterogeneity in siblings with pseudohypoparathyroidism 1B due to maternal STX16 deletion.

OBJECTIVES: Pseudohypoparathyroidism (PHP1B) is most commonly caused by epigenetic defects resulting in loss of methylation at the GNAS locus, although deletions of STX16 leading to GNAS methylation abnormalities have been previously reported. The phenotype of this disorder is variable and can include hormonal resistances and severe infantile obesity with hyperphagia. A possible time relationship between the onset of obesity and endocrinopathies has been previously reported but remains unclear. Understanding of the condition's natural history is limited, partly due to a scarcity of literature, especially in children. CASE PRESENTATION: We report three siblings with autosomal dominant PHP1B caused by a deletion in STX16 who presented with early childhood onset PTH-resistance with normocalcemia with a progressive nature, accompanied by TSH-resistance and severe infantile obesity with hyperphagia in some, not all of the affected individuals. CONCLUSIONS: PHP1B from a STX16 deletion displays intrafamilial phenotypic variation. It is a novel cause of severe infantile obesity, which is not typically included in commercially available gene panels but must be considered in the genetic work-up. Finally, it does not seem to have a clear time relationship between the onset of obesity and hormonal resistance.

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.

Pseudohypoparathyroidism: complex disease variants with unfortunate names.

Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. Thus, pseudohypoparathyroidism type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1-13 resulting in characteristic abnormalities referred to as Albright's hereditary osteodystrophy (AHO) that are associated with resistance to several agonist ligands, particularly to parathyroid hormone (PTH), thereby leading to hypocalcemia and hyperphosphatemia. GNAS mutations involving the paternal Gsα exons also cause most of these AHO features, but without evidence for hormonal resistance, hence the term pseudopseudohypoparathyroidism (PPHP). Autosomal dominant pseudohypoparathyroidism type Ib (PHP1B) due to maternal GNAS or STX16 mutations (deletions, duplications, insertions, and inversions) is associated with epigenetic changes at one or several differentially methylated regions (DMRs) within GNAS. Unlike the inactivating Gsα mutations that cause PHP1A and PPHP, hormonal resistance is caused in all PHP1B variants by impaired Gsα expression due to loss of methylation at GNAS exon A/B, which can be associated in some familial cases with epigenetic changes at the other maternal GNAS DMRs. The genetic defect(s) responsible for sporadic PHP1B, the most frequent variant of this disorder, remain(s) unknown for the majority of patients. However, characteristic epigenetic GNAS changes can be readily detected that include a gain of methylation at the neuroendocrine secretory protein (NESP) DMR. Multiple genetic or epigenetic GNAS abnormalities can thus impair Gsα function or expression, consequently leading to inadequate cAMP-dependent signaling events downstream of various Gsα-coupled receptors.

Fahr Syndrome Secondary to Pseudohypoparathyroidism.

Fahr syndrome is a rare neurologic disorder, usually affecting young and middle-aged adults, that can present with symptoms ranging from extrapyramidal to neuropsychiatric abnormalities. Pseudohypoparathyroidism (PHP), characterized by parathyroid hormone (PTH)-resistance or PTH-unresponsiveness at target organs, is associated with Fahr syndrome and typically presents with hypocalcemia. The following case presents a 39-year-old-woman with PHP complicated by symptomatic hypocalcemia, hypokalemia, and movement disturbances, who had computed tomography imaging showing basal ganglia calcifications consistent with Fahr syndrome. She initially presented with headache and was hospitalized for hypertensive emergency and severe hypocalcemia. Examination, including the neurologic examination, was unrevealing aside from hypertension and central adiposity. Laboratory tests were consistent with PHP, showing hypocalcemia with elevated PTH, and negative for hyperaldosteronism. Management of hypocalcemia consisted of intravenous calcium infusion, oral calcium carbonate, oral vitamin D3, and oral calcitriol. Patients with severe hypocalcemia and elevated PTH who present with new neurological symptoms despite normal general neurologic examination may warrant consideration for brain imaging to evaluate for Fahr syndrome. Further investigations are necessary to determine the prevalence of Fahr syndrome and hypokalemia in patients with PHP, explore if these findings are significantly associated with PHP-1b subtype, and ultimately inform potential new screening pathways for these patients.

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

OBJECTIVE: Pseudohypoparathyroidism type 1B (PHP1B) caused by methylation defects of differentially methylated regions (DMRs) on the GNAS locus can be categorized into groups according to etiologies and methylation defect patterns of the DMRs. The aim of this study was to clarify the clinical characteristics of each group. DESIGN: Comprehensive molecular analyses consisting of methylation, copy number, and microsatellite analyses. METHODS: Eighty-four patients with PHP1B were included in this study. We classified them into 5 groups, namely, autosomal dominant inheritance-PHP1B (Group 1, G1), sporadic-PHP1B (G2), and atypical-PHP1B (G3-G5), based on the methylation defect patterns in 4 DMRs on the GNAS locus and etiologies and evaluated the clinical findings in each group and compared them among the groups. RESULTS: G2 had the youngest age and the highest serum intact parathyroid hormone levels among the 5 groups at the time of diagnosis. The most common symptoms at the time of diagnosis were tetany in G1, and seizures or loss of consciousness in G2. Albright's hereditary osteodystrophy and PHP-suggestive features were most frequently observed in the G2 proband. Nine patients had neurodevelopmental disorders (NDs) consisting of mild to borderline intellectual disability and/or developmental delay. There were no significant correlations between the average methylation ratios of 7 CpG sites in the GNAS-A/B:TSS-DMR and hormonal and biochemical findings. CONCLUSION: This study revealed the differences in some clinical characteristics, particularly clinical features, and ages at the time of diagnosis between G2 and other groups and detailed NDs observed in some patients with PHP1B.

C-Cell Hyperplasia and Cystic Papillary Thyroid Carcinoma in a Patient with Type 1B Pseudohypoparathyroidism and Hypercalcitoninaemia: Case Report and Review of the Literature.

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.