Characterizing Cerebral Imaging and Electroclinical Features of Five Pseudohypoparathyroidism Cases Presenting with Epileptic Seizures.

Objective: To characterize the cerebral imaging and electroclinical features and investigate their etiological contributions to seizures in pseudoparathyroidism (PHP). Methods: The clinical symptoms, biochemical imaging by magnetic resonance imaging (MRI) and computed tomography (CT) tests, and electroencephalogram (EEG) manifestations of five PHP patients with seizures were retrospectively collected and analyzed. Results: Physical examination showed an average stature in cases 2~4 and short stature in cases 1 and 5. X-ray tests suggested ectopic calcification in four patients. The seizures in four cases were effectively controlled with antiseizure medicines (ASMs). Cerebral CT scans showed extensive brain calcifications in the bilateral basal ganglia (all five cases), cerebellum (cases 1, 3, and 5), thalamus (case 4), and cerebral cortex. Cerebral MRI showed short T1 signals mainly in the basal ganglia. EEG records revealed focal EEG abnormalities, including abnormal slow waves and epileptiform discharges, mainly over the temporal and frontal lobes. The brain areas with focal EEG abnormalities and calcification did not always coincide. Conclusion: The seizures in PHP can be focal to bilateral tonic-clonic. ASMs are effective in epilepsy combined with PHP. Intracranial calcification is not a reliable etiological cause of epilepsy in PHP patients.

Pseudohypoparathyroidism: Focus on Cerebral and Renal Calcifications.

CONTEXT: Pseudohypoparathyroidism (PHP) is a group of disorders characterized by hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) levels as a result of end-organ resistance to PTH. OBJECTIVE: To describe a cohort of 26 patients with PHP followed in a single tertiary center. METHODS: Clinical, biochemical, radiological, and genetic analysis of the GNAS gene in 26 patients recruited since 2002. RESULTS: Ten patients harbored a GNAS mutation, 15 epigenetic abnormalities at the GNAS locus, and 1 did not show genetic or epigenetic abnormalities. According to clinical, biochemical, and genetic features, patients were classified as PHP1A, PHP1B, and pseudopseudohypoparathyroidism. Patients with PHP1A had an earlier diagnosis and more cases with family history, Albright hereditary osteodystrophy (AHO) features, hormonal resistance, and hypertension. Obesity was a common feature. No difference in biochemical values was present among PHP1A and PHP1B. Intracerebral calcification occurred in 72% of patients with no difference among PHP1A and PHP1B subgroups. No significant difference was observed between patients with and without intracerebral calcification for the time-weighted average values of total serum calcium, phosphate, calcium-phosphate product, and PTH fold increase. A borderline association between cerebral calcification and age at the time of diagnosis (P = .04) was found in the whole cohort of patients. No renal calcifications were found in the overall cohort. CONCLUSION: Patients with PHP1A more frequently have AHO features as well as hypertension than patients with PHP1B. Patients with PHP presented a high rate of intracerebral calcification with no significant difference between subgroups. No increased risk of renal calcifications was also found in the entire cohort.

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.

Paroxysmal dyskinesia and epilepsy in pseudohypoparathyroidism.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) and epilepsy share common pathogenic mechanisms but their pathophysiological connections remain unknown. Our study reports an individual with both disorders as a consequence of pseudohypoparathyroidism (PHP). This observation suggests potential shared pathophysiological mechanisms between PKD and epilepsy. METHODS: We report the case of a 15-year-old male with pre-diagnosed PKD and symptomatic epilepsy. We recorded the symptoms and carried out comprehensive biochemical, genetic, imaging, and EEG analyses to examine the characteristics and potentially shared etiology of these conditions. RESULTS: In this case, the patient's PKD and symptomatic epilepsy were secondary to pseudohypoparathyroidism (PHP). The patient had a seven-year history of intermittent, involuntary paroxysmal episodic movements, and a six-year history of a loss of consciousness with convulsions. The electroencephalography results showed that the paroxysmal low and medium amplitude slow waves, isolated sharp waves, and sharp slow-wave release occurred in the right prefrontal temporal cortex. Serum analysis indicated a calcium concentration of 1.91 mmol/L, a phosphorus concentration of 2.68 mmol/L, an alkaline phosphatase concentration of 114 IU/L, and a parathyroid hormone concentration of 109 pg/ml. Computerized tomography and magnetic resonance imaging results showed multiple calcifications in the bilateral frontal and parietal lobe cortex, bilateral thalamus, basal ganglia, and centrum semiovale. Furthermore, GNAS methylation abnormalities were discovered during methylation testing. There was no recurrence of abnormal movements or epileptic seizures, and calcium concentrations returned to healthy levels, following the pharmacological treatment of PHP. CONCLUSION: In this case, PKD and symptomatic epilepsy were caused by PHP. This report underscores the importance of looking for biochemical abnormalities in PKD and symptomatic epilepsy patients. We suggest that all such intractable epilepsy seizure patients should be screened for PHP.

[Pseudohypoparathyroidism: report of two cases of late presentation]. / Pseudohipoparatiroidismo de presentación tardía: reporte de dos casos.

Pseudohypoparathyroidism (PHP) is a group of rare genetic disorders that share organ targeted resistance to the action of parathyroid hormone (PTH) as a common feature. Biochemically, they may present with hypocalcemia, hyperphosphatemia and elevated PTH. Some forms present with a specific phenotype: short stature, round facies, short neck, obesity, brachydactyly and subcutaneous calcifications, called Albrigth's Hereditary Osteodystrophy (AHO). This spectrum of disorders are caused by several alterations in the gene coding for the alpha subunit of the G protein (GNAS): an ubiquitous signaling protein that mediates the action of numerous hormones such as PTH, TSH, gonadotropins, and ACTH, among others. According to their inheritance with maternal or paternal imprinting, they may manifest in a diversity of clinical forms. Although most commonly diagnosed during childhood, PHP may manifest clinically during adolescence or early adulthood. We report two late presenting cases of pseudohypoparathyroidism. A 21-year-old female with biochemical abnormalities characteristic of pseudohypoparathyroidism who was misdiagnosed as epilepsy and a 13-year-old boy with the classic AHO phenotype but without alterations in phospho-calcium metabolism, compatible with pseudopseudohypoparathyrodism.

Pseudohipoparatiroidismo de presentación tardía: reporte de dos casos / Pseudohypoparathyroidism: report of two cases of late presentation

Pseudohypoparathyroidism (PHP) is a group of rare genetic disorders that share organ targeted resistance to the action of parathyroid hormone (PTH) as a common feature. Biochemically, they may present with hypocalcemia, hyperphosphatemia and elevated PTH. Some forms present with a specific phenotype: short stature, round facies, short neck, obesity, brachydactyly and subcutaneous calcifications, called Albrigth's Hereditary Osteodystrophy (AHO). This spectrum of disorders are caused by several alterations in the gene coding for the alpha subunit of the G protein (GNAS): an ubiquitous signaling protein that mediates the action of numerous hormones such as PTH, TSH, gonadotropins, and ACTH, among others. According to their inheritance with maternal or paternal imprinting, they may manifest in a diversity of clinical forms. Although most commonly diagnosed during childhood, PHP may manifest clinically during adolescence or early adulthood. We report two late presenting cases of pseudohypoparathyroidism. A 21-year-old female with biochemical abnormalities characteristic of pseudohypoparathyroidism who was misdiagnosed as epilepsy and a 13-year-old boy with the classic AHO phenotype but without alterations in phospho-calcium metabolism, compatible with pseudopseudohypoparathyrodism.

Bone Status Among Patients With Nonsurgical Hypoparathyroidism, Autosomal Dominant Hypocalcaemia, and Pseudohypoparathyroidism: A Cohort Study.

Nonsurgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP) are both rare diseases, characterized by hypocalcemia. In Ns-HypoPT, PTH levels are low, whereas patients with PHP often have very high levels due to receptor-insensitivity to PTH (PTH-resistance). Accordingly, we hypothesized that indices of bone turnover and bone mineralization/architecture are similar in Ns-HypoPT and PHP despite marked differences in PTH levels. We studied 62 patients with Ns-HypoPT and 31 with PHP as well as a group of age- and sex-matched healthy controls. We found a significantly higher areal BMD (aBMD) by DXA among patients with Ns-HypoPT, both compared with PHP and the background population. Compared with Ns-HypoPT, PHP patients had significantly lower total and trabecular volumetric BMD (vBMD) assessed by quantitative computed tomography (QCT) scans at the spine and hip. High-resolution peripheral quantitative computed tomography (HRpQCT) scans showed a lower trabecular area and vBMD as well as a lower trabecular number at the tibia in PHP compared to Ns-HypoPT and matched controls. In PHP, PTH levels correlated with levels of markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, P1NP), and bone resorption (CTx). In adult males, levels of bone markers were significantly higher in PHP compared with Ns-HypoPT. Levels of procalcitonin and calcitonin were significantly higher in PHP compared with Ns-HypoPT. In conclusion, indices of bone turnover, density, and microarchitecture differ between patients with Ns-HypoPT and PHP. Our data suggest that patients with PHP do not have a complete skeletal resistance to PTH and that the effects of chronically high PTH levels in PHP are mostly confined to the trabecular tissue. © 2017 American Society for Bone and Mineral Research.

Bone Mineral Density and Its Serial Changes Are Associated With PTH Levels in Pseudohypoparathyroidism Type 1B Patients.

Bone responsiveness to serum parathyroid hormone (PTH) in pseudohypoparathyroidism 1B (PHP1B) is controversial. Forty-eight PHP1B patients diagnosed by molecular analysis were recruited from 2000 to 2016 from the Peking Union Medical College Hospital. Fifty-five sex-matched nonsurgical hypoparathyroidism (NS-HP) patients were selected and included for comparison. Basic information, laboratory test, and dual-energy X-ray absorptiometry (DXA) results were collected. Linear regression was performed to identify independent predictors of lumbar spine (LS), femoral neck (FN), and total hip (TH) bone mineral density (BMD) Z-scores in PHP1B patients. BMD and related markers were compared between PHP and NS-HP patients. Longitudinal observation of 10 PHP1B patients was performed. The BMD Z-score for the LS (1.14 ± 1.41) was higher than that for the FN (-0.20 ± 1.00, p < 0.001) and the TH (0.03 ± 1.06, p < 0.001) in PHP1B patients. Despite lower serum calcium levels in untreated patients (1.72 mmol/L in untreated patients versus 2.14 mmol/L in treated patients, p = 0.024), the PTH levels as well as BMD Z-scores were comparable between treated and untreated patients at baseline. PTH was a negative predictor for LS-BMD Z-score (B = -0.004, p = 0.028) for sporadic PHP1B patients, and a similar result was obtained for all the PHP1B patients (B = -0.002, p = 0.053). Z-scores for FN- and LS-BMDs after treatment increased by 0.31 ± 0.10 and 0.58 ± 0.12, respectively, where the increase in LS-BMD correlated with a decrease in PTH (r = -0.72, p = 0.044). All BMD Z-scores were significantly lower in PHP1B patients than in IHP patients for the FN, LS, and TH (-0.20 ± 1.00 versus 1.57 ± 1.07, 1.14 ± 1.41 versus 1.96 ± 1.32, 0.03 ± 1.06 versus 1.67 ± 1.01, respectively, all p < 0.05). Skeletal tissue in PHP1B patients responds to PTH, where heterogenous sensitivities to PTH may exist in different regions of bone. Therefore, it is reasonable to normalize PTH levels when treating PHP1B to avoid negative effects of PTH on bone. © 2017 American Society for Bone and Mineral Research.

Raised intracranial pressure as a result of pansynostosis in a child with Albright's hereditary osteodystrophy.

CASE: The authors describe the case of an 8-year-old boy with pansynostosis in the context of Albright's hereditary osteodystrophy (AHO). This condition had lead to raised intracranial pressure (ICP). The elevated ICP was a consequence of the rigid skull impeding brain growth. Therefore, a decompressive cranioplasty was performed successfully, leaving further space for the growing brain. Affection of the central nervous system has been documented in AHO. However, affection of the skull bones has rarely been described in literature. CONCLUSION: We suggest that craniosynostosis may develop in patients with AHO and other types of pseudohypoparathyroidism (PHP). Furthermore, we suggest regular head circumference-for-age and ophthalmic examination for children with AHO or other types of PHP.

Musculoskeletal manifestations of endocrine disorders.

Endocrine disorders can lead to disturbances in numerous systems within the body, including the musculoskeletal system. Radiological evaluation of these conditions can demonstrate typical appearances of the bones and soft tissues. Knowledge of these patterns can allow the radiologist to suggest a diagnosis that may not be clinically apparent. This review will highlight the typical musculoskeletal findings of acromegaly, hypercortisolism, hyperthyroidism, hypothyroidism, hyperparathyroidism, pseudo- and pseudopseudohypoparathyroidism, and diabetes mellitus. The radiological manifestations of each of these endocrine disorders, along with a brief discussion of the pathophysiology and clinical implications, will be discussed.

Guanine nucleotide-binding protein α subunit hypofunction in children with short stature and disproportionate shortening of the 4th and 5th metacarpals.

BACKGROUND: GNAS encodes the α subunit of the stimulatory G protein (Gsα). Maternal inherited Gsα mutations cause pseudohypoparathyroidism type Ia (PHP-Ia), associated with shortening of the 4th and 5th metacarpals. AIMS: Here we investigated the Gsα pathway in short patients with distinct shortening of the 4th and 5th metacarpals. METHODS: In 571 children with short stature and 4 patients with PHP-Ia metacarpal bone lengths were measured. In identified patients we analysed the Gsα protein function in platelets, performed GNAS sequencing, and epigenetic analysis of four significant differentially methylated regions. RESULTS: In 51 patients (8.9%) shortening of the 4th and 5th metacarpals was more pronounced than their height deficit. No GNAS coding mutations were identified in 20 analysed patients, except in 2 PHP-Ia patients. Gsα activity was reduced in all PHP-Ia patients and in 25% of the analysed patients. No significant methylation changes were identified. CONCLUSIONS: Our findings suggest that patients with short stature and distinct metacarpal bone shortening could be part of the wide variety of PHP/PPHP, therefore it was worthwhile analysing the Gsα protein function and GNAS gene in these patients in order to further elucidate the phenotype and genotype of Gsα dysfunction.

Spectrum of neurological manifestations of idiopathic hypoparathyroidism and pseudohypoparathyroidism.

We describe clinical, biochemical, radiological profile, and treatment outcome in 97 patients with idiopathic hypoparathyroidism seen over a period of 18 years. Of the 97 patients, 78 (80%) had idiopathic hypoparathyroidism and 19 (20%) had pseudohypoparathyroidism. The mean age±standard deviation (SD) at presentation was 28.7±14.1 years. There were 52 males, the mean lag time from first reported symptom to diagnosis was 5.9±5.2 years and the mean (±SD) follow-up was 1.8±0.4 years. The most common presenting manifestation was carpopedal spasm in 68 (70%) patients, followed by paresthesia and seizures in 52 (54%) patients. The mean (±SD) serum calcium and inorganic phosphate concentrations were 6.1±1.5 mg/dl and 6.3±1.5 mg/dl, respectively. The most common imaging abnormality noted was basal ganglia calcification followed by cerebral cortex and cerebellum calcification. More than one-third of patients were on various antiepileptic drugs including phenytoin. In addition to oral calcium and active vitamin D (calcitriol), twenty-six patients (27%) also required hydrochlorothiazide. The important finding in our study was long lag time from the first reported symptom to diagnosis. Phenytoin was the drug in almost one- third of our patients with seizures. Practicing clinicians should have high index of suspicion of diagnosis hypoparathyroidism in the appropriate clinical states to avoid the morbidity associated with hypoparathyroidism. Phenytoin should be avoided in patients with hypoparathyroidism and seizures.

Multilevel myelopathy associated with pseudohypoparathyroidism simulating diffuse skeletal hyperostosis: a case report and literature review.

STUDY DESIGN: A case report and review of previous literature are presented. OBJECTIVE: The objective of this manuscript was to report a case of pseudohypoparathyroidism (PHP) 1a simulating diffuse idiopathic skeletal hyperostosis and resulting in spinal cord compression, and discuss the pathogenesis of this disease. SUMMARY OF BACKGROUND DATA: Spinal cord compression due to PHP is not common, to the authors' knowledge, none of the previous reported cases simulated diffuse idiopathic skeletal hyperostosis. METHODS: The patient's history, clinical examination, imaging findings, and treatment were reported; and the pathogenesis was discussed. RESULTS: Characteristic findings were revealed from imaging studies, a multiplane reconstruction of the computed tomography images, and magnetic resonance imaging. The patient was treated by 2-stage posterior decompression on the basis of the images. A mild improvement was observed after the surgeries and the patient's neurology was not completely restored after 6 months. CONCLUSION: We reported a rare case of skeletal and ligamentous abnormality resulting in spinal cord compression associated with PHP. A multiplane reconstruction of the computed tomography images was very necessary for diagnosis and treatment of this case. The unfavorable neurologic restoration might be due to the severe injury of the spinal cord caused by diffuse ossification of the posterior longitudinal ligament and ligamentum flavum.