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 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.

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.

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.

A typical 22q11.2 deletion syndrome and pseudohypoparathyroidism: A CARE compliant case report.

RATIONALE: It is rare to find 22q11.2 deletion syndrome with pseudohypoparathyroidism in children. Furthermore, the phenotypic spectrum of this disorder varies widely. PATIENT CONCERNS: A patient was diagnosed with pseudohypoparathyroidism at age 14 years because of convulsions, hypocalcemia, hyperphosphatemia, normal parathyroid hormone levels, and basal ganglia calcifications. Thereafter, the child presented with symptoms of nephrotic syndrome; subsequently, he was diagnosed with nephrotic syndrome at the local hospital. DIAGNOSIS: At our hospital, multiplex ligation-dependent probe amplification confirmed that the patient had 22q11.2 deletion syndrome. INTERVENTIONS: The patient continued to be treated with calcium supplements. OUTCOMES: Seizure activity and proteinuria ceased. LESSONS: Signs of this syndrome include delayed speech development due to velofacial dysfunction, recurrent croup attacks during early childhood due to latent hypocalcemia, and mild dysmorphic features. The findings of this patient indicated that 22q11.2 deletion syndrome may include a wide spectrum of clinical findings and that this diagnosis needs to be considered for all patients presenting with hypocalcemia, regardless of age.

Renal Tubular Dysfunction Fully Accounts for Plasma Biochemical Abnormalities in Type 1A Pseudohypoparathyroidism.

Context: Type 1A pseudohypoparathyroidism (PHP-1A) is characterized by target organ resistance to PTH. Patients can present with various dysmorphic features; however, renal failure has not been classically described. Case Description: A female patient came to our attention at the age of 7 years with characteristic signs of PTH resistance (i.e., hypocalcemia, hyperphosphatemia, and high serum PTH levels). She also presented with hypothyroidism, early-onset obesity, short metacarpal bones, and multiple subcutaneous ossifications, leading to a clinical diagnosis of pseudohypoparathyroidism. In addition to her genetic condition, she had bilateral renal hypodysplasia that was slowly progressing to end-stage kidney disease. She received a kidney transplant at the age of 16 years and, after transplantation, experienced rapidly normalized calcium, phosphate, and PTH levels, allowing f withdrawal of vitamin D supplementation. Conclusions: To the best of our knowledge, ours is the first report of a patient with PHP-1A undergoing kidney transplantation. Normalization of biochemical parameters after the procedure demonstrated that renal tubular resistance to PTH is sufficient to explain the calcium/phosphate abnormalities observed in PHP-1A.

Pseudohypoparathyroidism with basal ganglia calcification: A case report of rare cause of reversible parkinsonism.

RATIONALE: Parkinsonism can be secondary to many internal diseases, in some certain conditions, it seems that the clinical manifestations of parkinsonism presenting reversible. We report a case of patient with parkinsonism secondary to pseudohypoparathyroidism, who improved markedly after the supplement of serum calcium. PATIENT CONCERNS AND DIAGNOSES: A 52-year-old woman with acute parkinsonism was diagnosed as pseudohypoparathyroidism after the conducting of brain computed tomography, laboratory examinations, and gene detection. The son of the patient was also examined and was diagnosed as pseudohypoparathyroidism, who had ever complained of the history of epilepsy. The clinical manifestations of parkinsonism of the patient was reevaluated after the supplement of serum calcium according to the diagnosis. INTERVENTIONS AND OUTCOMES: The brain computed tomography revealed the basal ganglia calcification of the patient, accompanying by serum hypocalcemia and hyperphosphatemia. Loss of function mutation also confirmed the diagnosis. Five days after the therapy targeting at correction of serum hypocalcemia, the patient improved greatly in dyskinesia. LESSONS: This study reported a patient presenting as acute reversible parkinsonism, who was finally diagnosed as pseudohypoparathyroidism. It indicated us that secondary parkinsonism should be carefully differentiated for its dramatic treatment effect. And the family history of seizures might be an indicator for the consideration of pseudohypoparathyroidism.

Iatrogenic acute pancreatitis due to hypercalcemia in a child with pseudohypoparathyroidism.

Pancreatitis due to hypercalcemia is very rare in children, and its pathogenetic role is still debated. The following report describes a case of acute pancreatitis secondary to hypercalcemia in a 6-year-old boy with pseudohypoparathyroidism treated with calcium and vitamin D. Pseudohypoparathyroidism is characterized by parathormone (PTH) resistance, high PTH levels and hypocalcemia which need to be corrected with calcium and vitamin D supplementation. The patient was admitted for severe abdominal pain and vomiting associated with high plasma amylase, lipase and calcium levels. Hypercalcemia due to vitamin D and calcium overtreatment was probably responsible for the acute pancreatitis in this case. High serum calcium levels seem to sensitize patients to pancreatitis, even if the mechanism through which it happens is not completely understood. Moreover, the importance of concomitant predisposing factors, either acquired or especially genetic, needs to be further defined. Even though a rare occurance in childhood, hypercalcemia should be considered as a cause of pancreatitis and it should be examined together with the other etiologies that may contribute to the development of this disease.

Congestive heart failure: an unusual presentation of pseudohypoparathyroidism.

We report on an infant presenting with acute cardiogenic shock. She was eventually diagnosed with pseudohypoparathyroidism, which is a heterogeneous group of disorders characterized by severe hypocalcemia, hyperphosphatemia, and increased parathyroid hormone. The patient responded dramatically to calcium and vitamin D supplementation; left ventricular systolic function was normalized within days of treatment. Although the diagnosis of pseudohypoparathyroidism is rare, this case is a reminder of the importance of obtaining calcium levels in patients presenting in acute cardiogenic shock.

Pseudohypoparathyroidism presenting with ventricular arrhythmia: a case report.

Pseudohypoparathyroidism (PHP) is a rare disorder characterized by varying degrees of unresponsiveness to parathyroid hormone. Patients usually present with hypocalcemia-induced seizures or tetany, whereas no case of hypocalcemia-induced cardiac arrhythmia in PHP has been described to date. In this paper, we report the case of a male adolescent with PHP type 1a who presented with hypocalcemia-induced ventricular extrasystoles (bigeminy, trigeminy) and mild corrected QT interval prolongation. The patient had brachydactyly and his second fingers and toes were longer than the others, a finding consistent with PHP. Laboratory tests detected hypomagnesemia, as well as elevated levels of creatine kinase and lactate dehydrogenase. Ventricular arrhythmia and abnormal laboratory tests improved with calcium supplementation and vitamin D treatment. The findings in this patient suggest that hypomagnesemia may make patients with PHP more susceptible to hypocalcemia and may thus prompt a state of hypocalcemia-induced arrhythmia or other cardiac complications.

Spinal-cord compression related to pseudohypoparathyroidism.

We report a 24-year-old male with pseudohypoparathyroidism and a 6-month history of sensory disturbance in both legs which was associated with difficulty in walking. His physical signs included a short stature, a thick neck, short fourth metacarpals and metatarsals, a spastic paraparesis and sphincteric disturbance. His serum electrolytes included low serum calcium and high serum phosphorus levels. CT reconstruction showed compression of the spinal cord in association with ossified ligamentum flavum at the C2-7 and T9-10 levels. These findings were confirmed by MRI scans.

Transient pseudohypoparathyroidism as a cause of late-onset hypocalcemia in neonates and infants.

BACKGROUND/PURPOSE: Transient pseudohypoparathyroidism is a rare cause of late-onset hypocalcemia in neonates and infants. The purpose of this study was to investigate the clinical presentation and natural course of transient pseudohypoparathyroidism in neonates and infants. METHODS: From 1995 to 2006, 21 patients under 3 months of age were admitted to our department because of late-onset neonatal hypocalcemia. Among these, five were noted to have transient hypocalcemia, hyperphosphatemia and elevated serum parathyroid hormone levels. Their clinical data, biochemical findings and natural course were thoroughly analyzed. RESULTS: All five patients were boys with increased neuromuscular irritability as their initial clinical manifestation. Initial biochemical data showed calcium 1.5 +/- 0.16 mmol/L, phosphorus 9.6 +/- 1.5 mg/dL, intact parathyroid hormone 182 +/- 93 pg/mL and tubular reabsorption of phosphorus 94.8 +/- 3.7%. Two of the patients had magnesium deficiency. After reduction of phosphorus intake and supplementation with calcium and/or magnesium as indicated, the biochemical derangements resolved in 28 +/- 3 days. CONCLUSION: Neuromuscular irritability is usually the initial clinical presentation of transient pseudohypoparathyroidism. Aside from delayed renal maturation, pseudohypoparathyroidism is also caused by magnesium deficiency. Such a disturbance usually resolves before 3 months of age.

Neonatal pseudohypoparathyroidism.

The case of a neonate is presented who had early onset seizure associated with hypocalcemia, hyperphosphatemia, and raised parathyroid hormone. The infant did not have any stigmata of pseudohypoparathyroidism. The hypocalcemia was initially resistant to calcium therapy, but responded to vitamin D analog therapy. The diagnosis of 'neonatal pseudohypoparathyroidism' was entertained; the infant remained stable and seizure-free with normal serum biochemistry during 3 months of follow-up.

Psedohypoparathyroidism in newborn - a rare presentation.

A 7-day-old male baby was referred with history of persistent multifocal convulsions from second day of life. He was found to have hypocalcemia, hyperphosphatemia, normal serum magnesium and normal renal function tests. Serum parathormone was found to be elevated. Baby was diagnosed as case of pseudohypoparathyroidism and was treated with calcium supplementation and calcitriol. At 9 months he was asymptomatic on treatment, with normal serum calcium and phosphorus.

Pseudohypoparathyroidism and Graves'disease: a rare combination of two endocrinological diseases.

We report a 26-year-old woman presented at the day of admission in the I.C.U. with increased perspiration, plethora and distinct tetany of both legs. Particularly unusual was an exophthalmus on both sides, a rectal temperature of 38.3 degrees Celsius and a blood pressure of high level (180/110 mmHg). Laboratory findings were a low serum calcium concentration of 2.86 mval/l, a hyperphosphataemia (5.0 mg/dl), free thyroxine of 31.7 pmol/l, TSH basal of < 0.01 U/ml and positive MAK and TRAK. Serum parathormone concentration was excessively high: 766 ng/l (12-72). Ultrasound of the thyroid gland revealed a normal size with a volume of 10.4 ml; the echosonic state was not typical for Graves' disease. The initial treatment consisted of high dose thiamazole and hydrocortisone intravenous, calciumcarbonate and propranolol per os. After acute situation the treatment continued with thyreostatics, calcitriol and calciumcarbonate. The symptoms at the day of admission (tetany) disappeared within 2 days; only local paraesthesia of fingers persisted longer. Normalization of thyroid parameters was reached after 11 days; the serum calcium concentration persisted on an increasing but still lower level than standard (3.8 mval/l). During substitution parathormone decreased to 443 ng/l. What is unusual about this case is the combined appearance of autoimmunethyreoiditis (Graves' disease) and pseudohypoparathyroidism.

Seudohipoparatiroidismo tipo Ia de presentación pediátrica / Pseudohypoparathyroidism type Ia presenting during childhood

El seudohipoparatiroidismo tipo la es una enfermedad infrecuente, de presentación familiar, caracterizada por resistencia renal a la acción de la parathormona, resultado de una actividad defectuosa de la proteína Gs, reguladora de la síntesis del AMPe. Se asocia con anomalías fenotípicas y con defectos en otras hormonas. Describimos un caso pediátrico de presentación esporádica asociado a hipotiroidismo, en el que la presencia de una calcificación en el talón izquierdo a los 4 años de edad fue la clave para orientar el diagnóstico. Se comenta la evolución y la respuesta al tratamiento (AU)