Case report: Familial hypoparathyroidism with elevated parathyroid hormone due to an inactivating PTH mutation.

Introduction: So far, only 11 PTH mutations have been described as causes of familial isolated hypoparathyroidism (FIH). In this report, we describe a family with FIH but with significant elevation of functionally inactive PTH due to a PTH mutation. We also show a positive therapeutic outcome of recombinant human PTH (teriparatide) therapy in one of the siblings who was not well controlled on large doses of calcitriol and calcium replacement therapy. Case description: The proband is a 34-year-old woman who has a history of chronic severe hypocalcemia (HypoCa) since birth. She and her three brothers (33-year-old male twins, and a 21-year-old male) were diagnosed with pseudohypoparathyroidism type 1b (PHPT 1b) based on the presence of chronic HypoCa (serum Ca 1.6-1.85 mmol/l) since birth associated with significantly elevated plasma PTH levels in the range of 310-564 pg/dl (normal range 10-65) and absence of signs of Albright hereditary osteodystrophy. Molecular studies: WES showed no pathogenic, likely pathogenic or variants of unknown significance in any known calcium-associated genetic disorder but a bi-allelic variant in the PTH itself ((NM_000315.4:c.128G>A, p.Gly43Glu). This was confirmed by Sanger sequencing in the patient and her affected brothers. Management: Because the patient's HypoCa was not controlled on large doses of calcitriol and calcium carbonate, a trial of teriparatide 20 mcg SC daily was started and resulted in normalization of calcium, decline in PTH levels and significant improvement in her general wellbeing. Conclusion: High PTH in the presence of congenital hypocalcemia is not always due to receptor or post-receptor defect and can be due to a biologically inactive mutated PTH. In such cases, treatment with teriparatide may result in stabilization of biochemical profile and improvement in quality of life.

Pseudohypoparathyroidism during pregnancy and the postpartum period: A case series of five patients.

Objectives: Pseudohypoparathyroidism (PHP) is a rare disease, especially when combined with pregnancy. We aimed to explore the changes in serum calcium/parathyroid hormone (PTH) level and medical treatment in a case series of PHP during pregnancy and the postpartum period. Methods: A total of five PHP patients with six pregnancies were enrolled. The classification of PHP was based on (epi)genetic analysis. Clinical characteristics, biochemical indices, and treatment strategies before, during, and after pregnancy were retrospectively collected. Results: All patients received calcium and vitamin D agents with nearly normal serum calcium before pregnancy except patient 2 who was found hypocalcemic during gestation. All patients chose Cesarean section, and one suffered preterm delivery due to oligoamnios. The neonatal birth weight ranged from 2,250 to 4,300 g, and all neonates were free of hypocalcemia-related symptoms. The change in calcium metabolism was inconsistent including stable, improved, or worsened during pregnancy. Serum PTH level remained low in the first two trimesters in patients with stable and improved conditions while increased in the last two trimesters in patients with a worsened condition. Serum calcium changed inconsistently while PTH increased consistently during lactation. For patients who did not breastfeed, calcium homeostasis improved after delivery. Conclusion: Calcium homeostasis and medicine dosage changed differently in PHP patients during pregnancy and lactation. However, most patients had good pregnancy outcomes. Serum PTH levels might predict changes in calcium metabolism during pregnancy.

Intralesional sodium thiosulfate treatment of calcinosis cutis in pseudopseudohypoparathyroidism.

Pseudopseudohypoparathyroidism is an imprinted GNAS spectrum disorder that induces the phenotype of Albright's hereditary osteodystrophy. This phenotype often involves the formation of calcinosis cutis: firm, painful cutaneous eruptions, which are classically difficult to treat. Intralesional sodium thiosulfate has been reported successfully in various cases of calcinosis cutis; however, these reports describe patients with autoimmune or idiopathic calcinosis. This case details the clinical improvement and resolution of calcinosis cutis lesions utilizing intralesional sodium thiosulfate in an adolescent patient with pseudopseudohypoparathyroidism.

Molecular genetic analysis and growth hormone response in patients with syndromic short stature.

BACKGROUND: Syndromic short stature is a genetic and phenotypic heterogeneous disorder with multiple causes. This study aims to identify genetic causes in patients with syndromic short stature of unknown cause and evaluate the efficacy of the growth hormone response. METHODS: Trio-whole-exome sequencing was applied to identify pathogenic gene mutations in seven patents with short stature, multiple malformations, and/or intellectual disability. Whole-genome low-coverage sequencing was also performed to identify copy number variants in three patients with concurrent intellectual disability. Recombinant human growth hormone was administered to improve height in patients with an identified cause of syndromic short stature. RESULTS: Of the seven patients, three pathogenic/likely pathogenic gene mutations, including one FGFR3 mutation (c.1620C>A p.N540K), one novel GNAS mutation (c.2288C>T p.A763V), and one novel TRPS1 mutation (c.2527_c.2528dupTA p.S843fsX72), were identified in three patients. No copy number variants were identified in the three patients with concurrent intellectual disability. The proband with an FGFR3 mutation, a female 4 and 3/12 years of age, was diagnosed with hypochondroplasia. Long-acting growth hormone improved her height from 85.8 cm [- 5.05 standard deviation (SD)] to 100.4 cm (- 4.02 SD), and her increased height SD score (SDS) was 1.03 after 25 months of treatment. The proband with a GNAS mutation, a female 12 and 9/12 years of age, was diagnosed with pseudohypoparathyroidism Ia. After 14 months of treatment with short-acting growth hormone, her height improved from 139.3 cm (- 2.69 SD) to 145.0 cm (- 2.36 SD), and her increased height SDS was 0.33. CONCLUSIONS: Trio-whole-exome sequencing was an important approach to confirm genetic disorders in patients with syndromic short stature of unknown etiology. Short-term growth hormone was effective in improving height in patients with hypochondroplasia and pseudohypoparathyroidism Ia.

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.

Ossifying epulis in pseudohypo-parathyroidism: a case-based therapeutic approach.

BACKGROUND: The term Pseudohypoparathiroidism indicates a group of rare conditions characterised by end-organ resistance to the action of parathyroid hormone (PTH). Ossifying epulis (OE) is a exophytic gingival lesion characterised by spontaneous bone formation beneath the mucosa, which may affect children and adults: the exophytic, calcified outgrowths can occur in any bone and generally have favorable prognosis. Drug therapy may normalise calcium serum levels, but not completely avoid the occurrence of peripheral ossifying epulis. CASE REPORT: We report a representative case of a peripheral ossifying epulis in the mouth of a patient following a drug treatment protocol for her pseudohypoparathyroidism and to optimise serum markers. An 11-year-old girl was referred to our department, showing a bulky neoformation on the gingival margin of 0.6 mm diameter with sharp margins. The mass was completely excised. Histological analysis revealed distinctive features of a chronic and acute inflammatory microenvironment with plasma cells (positivity for CD38, MUM1, Lambda and Kappa chains) and bone tissue fragments with remodeling aspects referable to flogistic osteolysis. The biopsy result leads to hypothese a change in the patient's drug therapy. Multidisciplinary screening and individualised pharmacological treatment are strongly recommended in the clinical practice in order to improve the therapeutic results.

[A rare type of severe obesity in children and adolescents].

A four-year-old girl was referred to a paediatric department with low height, obesity and hypothyroidism. Her paraclinical tests were characteristic with elevated P-parathyroid hormone concentration, hypothyroidism, growth hormone deficiency, abnormal phenotype with brachydactyly, tooth problems and mental retardation, which led to a suspicion of Albright's hereditary osteodystrophy (AHO). The diagnosis was verified by molecular genetic testing. Less than 1% of children with obesity have an endocrine disorder, and AHO is one of them.

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.

Hypocalcemic Cardiomyopathy and Pseudohypoparathyroidism Due to Severe Vitamin D Deficiency.

Hypocalcemic cardiomyopathy is a rare entity. We describe a patient with severe heart failure, decreased ejection fraction and global hypokinesia documented on echocardiogram, associated with severe hypocalcemia, very low vitamin D status, increased QT intervals, increased BNP (serum brain natriuretic peptide) levels and CPK (creatine phosphokinase) levels. All these defects reversed on treatment with vitamin D and calcium within a few days without any specific cardiac intervention.

Pseudohypoparathyroidism type 1B caused by methylation changes at the GNAS complex locus.

Pseudohypoparathyroidism type 1B (PHP1B) consists of a heterogeneous group of disorders characterised by resistance to parathyroid hormone (PTH). There are several different PHP1B subtypes that are all associated with methylation changes at GNAS. These epigenetic changes are caused by maternal deletions in GNAS or STX16, by paternal uniparental isodisomy of chromosome 20q (patUPD20q) or by undefined genetic mutations. The GNAS methylation changes are ultimately responsible for resistance to PTH signalling in the proximal renal tubules. However, there is no PTH resistance in the distal renal tubules nor in bone cells; consequently, patients with PHP1B have reduced urinary calcium excretion and can readily mobilise calcium (and phosphate) from the skeleton. We report a case of a sporadic PHP1B patient with broad GNAS methylation changes that were presumably caused by an unknown genetic mutation outside the GNAS locus. PTH resistance was preceded by several years by autoimmune negative hypothyroidism. Treatment consisted of calcium substitution and calcitriol.

Cinacalcet as adjunctive therapy in pseudohypoparathyroidism type 1b.

BACKGROUND: In patients with pseudohypoparathyroidism type 1b (PHP1b) due to a tissue-specific imprinting defect in the G-protein α-subunit, skeletal disorders can arise from the bones being sensitive to parathyroid hormone (PTH) while the kidneys remain resistant to this hormone. CASE-DIAGNOSIS/TREATMENT: We report a 4.8-year-old girl with PHP1b who presented with an abnormal gait, severe skeletal changes and elevated levels of serum PTH (2844 pg/ml), phosphate (7.2 mg/dl) and bone turnover markers. Traditional treatment with calcium and calcitriol failed to suppress PTH secretion, which was still elevated at 2877 pg/ml after 14 months of therapy, nor did it correct the other clinical, biochemical and radiographic abnormalities. The addition of cinacalcet to the treatment regimen over the subsequent 32 months resulted in normalization of serum PTH (58 ng/ml), phosphate (4.9 mg/dl) and bone turnover markers, and resolution of the radiographic changes, with no adverse effects noted. CONCLUSIONS: Due to its ease of administration, we recommend the addition of cinacalcet into the armamentarium of medications available to treat children with PHP1b.

Prolonged spontaneous normocalcaemia in pseudohypoparathyroidism from resorption of soft tissue calcium deposits: a cautionary tale.

A 42-year-old man diagnosed with pseudohypoparathyroidism and Albright's hereditary osteodystrophy as an infant was lost to follow-up and remained, unmonitored, on calcitriol and calcium for over 20 years. He presented after having an ST-elevation myocardial infarction. In addition to coronary artery calcifications, he was found to have diffuse subcutaneous and joint calcifications. His calcium, phosphate and parathyroid hormone (PTH) levels were normal, and given the lack of prior documentation in the diagnosis he was instructed to discontinue calcitriol and calcium until further investigations were completed. Despite stopping the medication, his serum calcium remained normal for over 1 year. It was not until 18 months later, when his soft tissue calcium stores were depleted, that he finally developed symptomatic hypocalcaemia and an elevated PTH. This case not only emphasises the importance of long-term follow-up for patients with pseudohypoparathyroidism, but also highlights the potential complications of long-term, unmonitored, calcitriol use.

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.

Secondary bilateral striopallidodentate calcinosis associated with generalized pustular psoriasis (Von Zumbusch).

Bilateral striopallidodentate calcinosis (BSPDC) mentioned in the literature as Fahr's disease (a misnomer), is characterized by symmetrical and bilateral intracerebral calcifications located in the basal ganglia with or without deposits in the dentate nucleus, thalamus, and white matter. This entity is usually asymptomatic but may be manifested by neurological symptoms. Idiopathic BSPDC can occur either as sporadic or autosomal dominant familial forms. Secondary presentations of BSPDC are associated with infections, neoplastic diseases, toxicological or traumatic factors, and metabolic disorders. We describe a case of generalized pustular psoriasis associated with secondary BSPDC owing to pseudohypoparathyroidism. Laboratory tests revealed hypocalcemia, hyperphosphatemia, and a normal serum level of parathormone. The correction of the phosphorus-calcium metabolism disorder produced clinical improvement.

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.

Coexistence of glucocorticoid resistance and pseudohypoparathyroidism / Coexistencia de la resistencia a glucocorticoides y el pseudohipoparatiroidismo

We report for the first time the case of a young man who developed both glucocorticoid resistance and resistance to parathyroid hormone. Treatment with high doses of dexamethasone together with administration of calcium and calcitriol resulted in a significant improvement in the patient's condition. In this paper, we discuss in detail diagnostic and treatment strategies used on the patient and the impact on the course and outcome of both disorders. We associate the development of both these disorders with a possible inherited defect in the signal pathways common to glucocorticoid and parathyroid hormone receptors.

Por primera vez se reporta el caso de un joven que desarrolló resistencia a glucocorticoides y resistencia a la hormona paratiroidea. El tratamiento con altas dosis de dexametasona, junto con la administración de calcio y calcitriol, trajo como resultado una mejoría significativa de la condición del paciente. En este papel, se analiza en detalle el diagnóstico así como las estrategias de tratamiento del paciente, y su impacto en el curso y resultado de ambos trastornos. Se concluye que el desarrollo de ambos trastornos se halla asociado a un posible defecto hereditario en las vías de transducción de señales comunes a los receptores de las hormonas glucocorticoides y las hormonas paratiroideas.