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.

Identification of a novel GNAS mutation in a family with pseudohypoparathyroidism type 1A.

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. CASE PRESENTATION: 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.

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.

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.

Parathyroid Hormone Resistance: An Uncommon Cause of Hypocalcaemia in an Adult Ghanaian Female.

BACKGROUND AND OBJECTIVE: Parathyroid hormone (PTH) resistance, the main biochemical feature of a rare group of disorders known as Pseudohypoparathyroidism (PHP) is an uncommon cause of hypocalcaemia. In addition to the biochemical abnormalities, some individuals with PHP may have features of Albright Hereditary Osteodystrophy (AHO). Being a rare disorder with a significant level of variation and overlap in its clinical presentation, diagnosis of PHP may be challenging in some clinical settings. This case report highlights the diagnosis of this rare disorder. CASE REPORT: A 20-year-old Ghanaian female who had been involved in a road traffic accident (RTA) was referred to the endocrine clinic after a computer tomography (CT) scan of her head revealed an incidental finding of multiple basal ganglia calcifications. Investigations revealed hypocalcaemia, hyperphosphatemia, and elevated intact PTH in the presence of normal levels of 25-hydroxyvitamin D and magnesium, and a normal kidney function. She also had phenotypic features of AHO. Findings suggested a diagnosis of PHP, however, the type could not be identified due to the unavailability of further testing. CONCLUSION: This report of a Ghanaian female with PTH resistance and features of AHO diagnosed at the age of 20 years, is expected to add to the existing literature and assist in increasing the level of awareness and facilitate the diagnosis of this disorder in our setting.

CONTEXTE ET OBJECTIF: La résistance à l'hormone parathyroïdienne (PTH), principale caractéristique biochimique d'un groupe rare de troubles connus sous le nom de pseudohypoparathyroïdie (PHP), est une cause rare d'hypocalcémie. En plus des anomalies biochimiques, certaines personnes atteintes de PHP peuvent présenter des caractéristiques d'ostéodystrophie héréditaire d'Albright (AHO). Étant un trouble rare avec un niveau significatif de variation et de chevauchement dans sa présentation clinique, le diagnostic de PHP peut être difficile dans certains contextes cliniques. Ce rapport de cas met en lumière le diagnostic de cette maladie rare. RAPPORT DE CAS: Une femme ghanéenne de 20 ans qui avait été impliquée dans un accident de la circulation routière (RTA) a été référée à la clinique endocrinienne après qu'une tomodensitométrie (TDM) de sa tête a révélé la découverte fortuite de multiples calcifications des ganglions de la base. Les examens ont révélé une hypocalcémie, une hyperphosphatémie et une PTH intacte élevée en présence de taux normaux de 25 hydroxyvitamine D et de magnésium et d'une fonction rénale normale. Elle avait également des caractéristiques phénotypiques d'AHO. La découverte a suggéré un diagnostic de PHP, mais le type n'a pas pu être identifié en raison de l'indisponibilité de tests supplémentaires. CONCLUSION: Ce rapport d'une femme ghanéenne présentant une résistance à la PTH et des caractéristiques d'AHO diagnostiquée à l'âge de 20 ans, devrait s'ajouter à la littérature existante et aider à accroître le niveau de sensibilisation et à faciliter le diagnostic de ce trouble dans notre contexte. Mots-clés: Hypocalcémie, Hormone parathyroïdienne, Ghana.

A novel GNAS variant presents with disorders of GNAS inactivation and cardiomyopathy.

The GNAS gene (OMIM#139320), located on chromosome 20q13.2, encodes for the alpha-subunit of the stimulatory signaling protein, Gsα protein. GNAS variants with inactivating properties are associated with Albright's hereditary osteodystrophy (AHO) and when maternally inherited, pseudohypoparathyroidism 1a (OMIM#103580), which includes multiple hormone resistance. In this clinical report we describe a novel GNAS variant, c.159A>G, p.K53N, in an individual with features consistent with AHO and pseudohypoparathyroidism 1a and its segregation through multiple maternal relatives, including two genotype positive maternal first cousins who also display features classic for AHO. The proband developed unique features including cardiomyopathy which required a heart transplant at 5 years old and immune dysregulation resulting in multisystem organ failure and ultimately, death at the age of 18 years. Additional investigations exploring alternative explanations for the proband's presentation were pursued including whole genome sequencing which was negative. We postulate that the atypical features seen in the proband may have resulted from dysregulated Gsα signaling in cardiac tissue. Future studies are needed to explore the properties of the K53N GNAS variant and this proposed mechanism.

Clinical and genetic analysis of pseudohypoparathyroidism complicated by hypokalemia: a case report and review of the literature.

BACKGROUND: Pseudohypoparathyroidism (PHP) encompasses a highly heterogenous group of disorders, characterized by parathyroid hormone (PTH) resistance caused by mutations in the GNAS gene or other upstream targets. Here, we investigate the characteristics of a female patient diagnosed with PHP complicated with hypokalemia, and her family members. CASE PRESENTATION AND GENE ANALYSIS: A 27-year-old female patient occasionally exhibited asymptomatic hypocalcemia and hypokalemia during her pregnancy 1 year ago. Seven months after delivery, she experienced tetany and dysphonia with diarrhea. Tetany symptoms were relieved after intravenous calcium gluconate supplementation and she was then transferred to our Hospital. Laboratory assessments of the patient revealed hypokalemia, hypocalcemia and hyperphosphatemia despite elevated PTH levels. CT scanning of the brain revealed globus pallidus calcification. Possible mutations in GNAS and hypokalemia related genes were identified using WES, exon copies of STX16 were analized by MLPA and the methylation status of GNAS in three differential methylated regions (DMRs) was analyzed by methylation-specific polymerase chain reaction, followed by confirmation with gene sequencing. The patient was clinically diagnosed with PHP-1b. Loss of methylation in the A/B region and hypermethylation in the NESP55 region were detected. No other mutations in GNAS or hypokalemia related genes and no deletions of STX16 exons were detected. A negative family history and abnormal DMRs in GNAS led to a diagnosis of sporadic PHP-1b of the patient. CONCLUSIONS: Hypokalemia is a rare disorder associated with PHP-1b. Analysis of genetic and epigenetic mutations can aid in the diagnosis and accurate subtyping of PHP.

Evaluating the variety of GNAS inactivation disorders and their clinical manifestations in 11 Chinese children.

BACKGROUND: The GNAS gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of GNAS inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis. METHODS: We enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations. RESULTS: Among these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright's hereditary osteodystrophy (AHO) phenotype. GNAS abnormalities were detected in all 11 patients, including nine cases with GNAS gene variations and two cases with GNAS methylation defects. These GNAS variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > A, were found to be novel. This data was then used to assign a GNAS subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH. CONCLUSIONS: Evaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of GNAS mutations significantly. In addition, our results suggest that when GNAS gene sequencing is negative, GNAS methylation study should be performed. Early genetic detection is required for the differential diagnosis of GNAS disorders and is critical to the clinician's ability to distinguish between heterotopic ossification in the POH and AHO phenotype.

Fahr´s Syndrome; Pseudohypoparathyroidism Type Ib Masquerading as Epileptic Seizures.

Hypocalcaemia of various origin can be manifested by paresthesia, muscle cramps, muscle weakness, syncope, convulsions and even severe psychomotor retardation. Such symptoms can be initially considered as signs of epilepsy. We present a 12- year old boy with partial seizures and basal ganglia calcifications, initially diagnosed as having Fahr´s disease and epilepsy, where severe hypocalcaemia, due to genetically confirmed pseudohypoparathyroidism type Ib was the underlying cause. Excellent clinical improvement was observed after calcium and vitamin D therapy. The basal ganglia calcifications were secondary due to chronic hypocalcaemia, therefore the appropriate diagnosis was pseudohypoparathyroidism type Ib with Fahr´s syndrome, but not Fahr´s disease. In conclusion, the serum evaluation of minerals, especially calcium and phosphate, should be performed in all patients with convulsions, cramps and psychomotor retardation. This is essential in arriving at a proper diagnosis and early initiation of appropriate treatment.

Fourteen-year follow-up of a child with acroscyphodysplasia with emphasis on the need for multidisciplinary management: a case report.

BACKGROUND: Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes. CASE PRESENTATION: The patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability. DISCUSSION AND CONCLUSIONS: Key challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.

Management of pseudohypoparathyroidism.

PURPOSE OF REVIEW: This review is timely given the 2018 publication of the first international Consensus Statement for the diagnosis and management of pseudohypoparathyroidism (PHP) and related disorders. The purpose of this review is to provide the knowledge needed to recognize and manage PHP1A, pseudopseudohypoparathyroidism (PPHP) and PHP1B - the most common of the subtypes - with an overview of the entire spectrum and to provide a concise summary of management for clinical use. This review will draw from recent literature as well as personal experience in evaluating hundreds of children and adults with PHP. RECENT FINDINGS: Progress is continually being made in understanding the mechanisms underlying the PHP spectrum. Every year, through clinical and laboratory studies, the phenotypes are elucidated in more detail, as are clinical issues such as short stature, brachydactyly, subcutaneous ossifications, cognitive/behavioural impairments, obesity and metabolic disturbances. Headed by a European PHP consortium, experts worldwide published the first international Consensus that provides detailed guidance in a systematic manner and will lead to exponential progress in understanding and managing these disorders. SUMMARY: As more knowledge is gained from clinical and laboratory investigations, the mechanisms underlying the abnormalities associated with PHP are being uncovered as are improvements in management.

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.

Language delay and developmental catch-up would be a clinical feature of pseudohypoparathyroidism type 1A during childhood.

Pseudohypoparathyroidism type 1A (PHP1A) is characterized by resistance to multiple hormones, the Albright Hereditary Osteodystrophy phenotype, obesity, and developmental delay. Developmental delay usually appears prior to hypocalcemia due to parathyroid hormone resistance and could be a clinically important feature for early diagnosis of PHP1A. To date, however, the details have not been documented. With regard to developmental delays, we conducted a multicenter retrospective study of 22 PHP1A patients from 18 families who were diagnosed clinically or genetically from 2005 to 2015. For quantitative analysis of their development, we calculated the ratios of the milestone ages of the patients to those in normal reference data. The ratio of the ages with respect to speech development, i.e., speaking a first meaningful word (median: 1.67), was significantly higher than that for gross motor development, walking unassisted (median: 1.34). The ratio of age at stringing a two-word sentence (median: 1.32) was significantly lower than that of saying a first word (median: 1.84). Ten out of 11 (91%) patients exhibited two or three of the following clinical phenotypes: developmental delay, obesity, and hyperthyrotropinemia. These results suggest two possible clinical features of developmental delays in PHP1A patients: developmental delay is more obvious in speech acquisition than in gross motor skills, and speech delays could be attenuated during later childhood. Further, the presence of multiple of three clinical symptoms could be an important indicator to differentiate the diagnosis of PHP1A during early childhood.

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.

What to consider when pseudohypoparathyroidism is ruled out: iPPSD and differential diagnosis.

BACKGROUND: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright's hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. METHODS: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. RESULTS: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. CONCLUSIONS: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes.

Cognitive and behavioral phenotype of children with pseudohypoparathyroidism type 1A.

Pseudohypoparathyroidism 1A (PHP1A) is a rare, genetic disorder. Most patients with PHP1A have cognitive impairment but this has not been systematically studied. We hypothesized that children with PHP1A would have lower intelligent quotient (IQ) scores than controls. To evaluate cognition and behavior, we prospectively enrolled children with PHP1A, one unaffected sibling (when available) and controls matched on BMI/age/gender/race. Evaluations included cognitive and executive function testing. Parents completed questionnaires on behavior and executive function. We enrolled 16 patients with PHP1A, 8 unaffected siblings, and 15 controls. Results are presented as mean (SD). The PHP1A group had a composite IQ of 85.9 (17.2); 25% had a composite IQ < -2 SD. The PHP1A group had significantly lower IQs than matched controls (composite IQ -17.3, 95%CI -28.1 to -6.5, p < 0.01) and unaffected siblings (composite IQ -21.5, 95%CI -33.9 to -9.1, p < 0.01). Special education services were utilized for 93% of the patients with PHP1A. Deficits were observed in executive function and parents reported delayed adaptive behavior skills and increased rates of attention deficit hyperactivity disorder. In conclusion, children with PHP1A have lower intelligence quotient scores, poorer executive function, delayed adaptive behavior skills, and increased behavior problems.

Severe Hypocalcemia and Extreme Elevation of Serum Creatinkinase in a 16-Year Old Boy with Pseudohypoparathyroidism Type Ib.

Calcium is essential for proper muscular function and metabolism. Myopathy with high creatinkinase activity can be a rare manifestation of hypocalcemia of various origin, such as vitamin D deficiency, hypoparathyroidism, pseudohypoparathyroidism (PHP). 16-year old previously healthy boy was admitted to intensive care unit with convulsions lasting for three minutes and a transient loss of consciousness. Laboratory results revealed severe hypocalcemia (total S-Ca < 1.0 mmol/L; normal 2.2-2.6 mmol/L), hyperphosphatemia (S-P 2.8 mmol/L; normal 0.6-1.6 mmol/L). Serum creatinkinase (S-CK) activity was 32 µkat/L (normal 0.57-2.45 µkat/L). Other basic biochemical parameters including creatinine, troponin, alkaline phosphatase were within normal values. Calcemia was gradually corrected within two weeks by intravenously and orally administered calcium and by cholecalciferol. S-CK reached a maximum of 222 µkat/L on day 4 and dropped to 7.2 µkat/L on day 14. Boy had no myalgias, neither clinical signs of myopathy. Echocardiography was normal with normal myocardial contractility, without any signs of calcification. The serum level of parathyroid hormone (S-PTH) was high (12 pmol/L; normal 0.7-5.5 pmol/L), fully compatible with the diagnosis of PHP. Molecular analysis revealed pseudohypoparathyroidism type Ib (PHPIb).In conclusion, manifest tetany and even mild myopathy with very high S-CK can occur in hypocalcemic patients and usually resolves after normalization of hypocalcemia.

Painful subcutaneous nodules on the thigh.

Osteoma cutis is the presence of bone within the dermis or subcutaneous tissue. This condition may occur sporadically or secondary to other dermatologic or genetic conditions. We present a 12-year-old girl with pseudohypoparathyroidism type-Ia who developed osteoma cutis on the right thigh.