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Objectives Hypomagnesemia 1, intestinal (HOMG1) is characterized by neurological symptoms that occur due to hypocalcemia and hypomagnesemia and caused by mutations in the TRPM6. Most of the identified variants in TRPM6 lead to premature termination: nonsense, frameshift, deletion, and splice site mutations. Case presentation Herein, we report a 1.5 month-old case who presented with convulsion due to hypocalcemia and hypomagnesemia in the early infancy. Sequencing of TRPM6 revealed a novel homozygous synonymous variant [c.2538G > A (p.Thr846Thr)] in the last codon of exon 19, which is most likely to affect the splicing. We report a novel homozygous synonymous variant in the TRPM6 leading to HOMG1, expanding the mutational spectrum. Conclusions Synonymous mutations that were previously considered as harmless should be evaluated at the nucleotide level, keeping in mind that they may affect splicing and cause to the disease.

Vitamin D metabolism represents a well-integrated, hormonally regulated endocrine unit interlinking calcium and phosphate metabolism. Pathophysiologic processes disturbing vitamin D metabolism comprise classic defects of vitamin D activation and action presenting as different forms of vitamin D-dependent rickets as well as disorders with increased vitamin D activity. The latter may result in hypercalcemia, hypercalciuria, and renal calcifications. Acquired and hereditary disorders causing hypervitaminosis D are discussed, including vitamin D intoxication, granulomatous disease, and idiopathic infantile hypercalcemia that may be caused by either a defective vitamin D degradation or by a primary defect in phosphate conservation.

Cystinosis is an autosomal recessive storage disease due to impaired transport of cystine out of lysosomes. Since the accumulation of intracellular cystine affects all organs and tissues, the management of cystinosis requires a specialized multidisciplinary team consisting of pediatricians, nephrologists, nutritionists, ophthalmologists, endocrinologists, neurologists' geneticists, and orthopedic surgeons. Treatment with cysteamine can delay or prevent most clinical manifestations of cystinosis, except the renal Fanconi syndrome. Virtually all individuals with classical, nephropathic cystinosis suffer from cystinosis metabolic bone disease (CMBD), related to the renal Fanconi syndrome in infancy and progressive chronic kidney disease (CKD) later in life. Manifestations of CMBD include hypophosphatemic rickets in infancy, and renal osteodystrophy associated with CKD resulting in bone deformities, osteomalacia, osteoporosis, fractures, and short stature. Assessment of CMBD involves monitoring growth, leg deformities, blood levels of phosphate, electrolytes, bicarbonate, calcium, and alkaline phosphatase, periodically obtaining bone radiographs, determining levels of critical hormones and vitamins, such as thyroid hormone, parathyroid hormone, 25(OH) vitamin D, and testosterone in males, and surveillance for nonrenal complications of cystinosis such as myopathy. Treatment includes replacement of urinary losses, cystine depletion with oral cysteamine, vitamin D, hormone replacement, physical therapy, and corrective orthopedic surgery. The recommendations in this article came from an expert meeting on CMBD that took place in Salzburg, Austria, in December 2016. ispartof: JOURNAL OF INHERITED METABOLIC DISEASE vol:42 issue:5 pages:1019-1029 ispartof: location:United States status: published

BackgroundOver the last decaces, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, ±20% of all tubulopathy patients remain without genetic diagnosis. Here, we explore a large multicentric patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia and dilated cardiomyopathy (DCM).MethodsWhole exome and genome sequencings were performed with various subsequent functional analyses of identified RRAGD variants in vitro.ResultsIn 8 children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt-wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients additionally suffered from DCM requiring heart transplantation in 3 of them. An additional dominant variant in RRAGD was simultaneously identified in eight members of a large family with a similar renal phenotype. RRAGD encodes GTPase RagD mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron include the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro,ConclusionsOur findings establish a novel disease phenotype combining kidney tubulopathy and cardiomyopathy (KICA) caused by an activation of mTOR signaling suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.SIGNIFICANCE STATEMENTHere, we report on heterozygous variants in RRAGD in patients with profound hypomagnesemia, renal salt wasting, nephrocalcinosis, and dilated cardiomyopathy. The identified RagD variants induce a constitutive activation of mTOR signaling in vitro. These findings not only establish a novel monogenic disorder of the kidney tubule, but demonstrate the essential role of mTOR signaling for distal tubular electrolyte handling and cardiac function.

Síndrome de Bartter; Hipokalièmia heretada; Tubulopatia perdedora de sal Síndrome de Bartter; Hipopotasemia hereditaria; Tubulopatía perdedora de sal Bartter syndrome; Inherited hypokalemia; Salt-losing tubulopathy Bartter syndrome is a rare inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism with hypokalemic and hypochloremic metabolic alkalosis and low to normal blood pressure. The primary pathogenic mechanism is defective salt reabsorption predominantly in the thick ascending limb of the loop of Henle. There is significant variability in the clinical expression of the disease, which is genetically heterogenous with 5 different genes described to date. Despite considerable phenotypic overlap, correlations of specific clinical characteristics with the underlying molecular defects have been demonstrated, generating gene-specific phenotypes. As with many other rare disease conditions, there is a paucity of clinical studies that could guide diagnosis and therapeutic interventions. In this expert consensus document, the authors have summarized the currently available knowledge and propose clinical indicators to assess and improve quality of care.

Mutations in the KCNA1 gene encoding the voltage-gated potassium (K+) channel Kv1.1 have been linked to rare neurological syndromes, episodic ataxia type 1 (EA1) and myokymia. In 2009, a KCNA1 mutation was identified in a large family with autosomal dominant hypomagnesemia. Despite efforts in establishing a genotype-phenotype correlation for the wide variety of symptoms in EA1, little is known on the serum magnesium (Mg2+) levels in these patients. In the present study, we describe a new de novo KCNA1 mutation in a Polish patient with tetany and hypomagnesemia. Electrophysiological and biochemical analyses were performed to determine the pathogenicity of the mutation. A female patient presented with low serum Mg2+ levels, renal Mg2+ wasting, muscle cramps, and tetanic episodes. Whole exome sequencing identified a p.Leu328Val mutation in KCNA1 encoding the Kv1.1 K+ channel. Electrophysiological examinations demonstrated that the p.Leu328Val mutation caused a dominant-negative loss of function of the encoded Kv1.1 channel. Cell surface biotinylation showed normal plasma membrane expression. Taken together, this is the second report linking KCNA1 with hypomagnesemia, thereby emphasizing the need for further evaluation of the clinical phenotypes observed in patients carrying KCNA1 mutations.

CYP24A1 mutations are now accepted as a cause of idiopathic infantile hypercalcemia (IIH). A rapid liquid-chromatography tandem mass spectrometry (LC-MS/MS)-based blood test enabling measurement of the 25-OH-D3 :24,25-(OH)2 D3 ratio (R) can identify IIH patients on the basis of reduced C24-hydroxylation of 25-OH-D3 by CYP24A1 in vivo. Although values of this ratio are significantly elevated in IIH, somewhat surprisingly, serum 24,25-(OH)2 D3 remains detectable. The current study explores possible explanations for this including: residual CYP24A1 enzyme activity in individuals with certain CYP24A1 genotypes, expression of alternative C24-hydroxylases, and the possibility of isobaric contamination of the 24,25-(OH)2 D3 peak on LC-MS/MS. We employed an extended 20-min run time on LC-MS/MS to study serum vitamin D metabolites in patients with IIH due to mutations of CYP24A1 or SLC34A1; in unaffected heterozygotes and dialysis patients; in patients with vitamin D deficiency; as well as in normal subjects exhibiting a broad range of 25-OH-D levels. We identified 25,26-(OH)2 D3 as a contaminant of the 24,25-(OH)2 D3 peak. In normals, the concentration of 24,25-(OH)2 D3 greatly exceeds 25,26-(OH)2 D3 ; however, 25,26-(OH)2 D3 becomes more significant in IIH with CYP24A1 mutations and in dialysis patients, where 24,25-(OH)2 D3 levels are low when CYP24A1 function is compromised. Mean R in 30 IIH-CYP24A1 patients was 700 (range, 166 to 2168; cutoff = 140) as compared with 31 in 163 controls. Furthermore, patients possessing CYP24A1 L409S alleles exhibited higher 24,25-(OH)2 D3 levels and lower R (mean R = 268; n = 8) than patients with other mutations. We conclude that a chromatographic approach which resolves 24,25-(OH)2 D3 from 25,26-(OH)2 D3 produces a more accurate R that can be used to differentiate pathological states where CYP24A1 activity is altered. The origin of the residual serum 24,25-(OH)2 D3 in IIH patients appears to be multifactorial. © 2017 American Society for Bone and Mineral Research.

Over the last decades, a growing spectrum of monogenic disorders of human magnesium homeostasis has been clinically characterized, and genetic studies in affected individuals have identified important molecular components of cellular and epithelial magnesium transport. Here, we describe three infants who are from non-consanguineous families and who presented with a disease phenotype consisting of generalized seizures in infancy, severe hypomagnesemia, and renal magnesium wasting. Seizures persisted despite magnesium supplementation and were associated with significant intellectual disability. Whole-exome sequencing and conventional Sanger sequencing identified heterozygous de novo mutations in the catalytic Na(+), K(+)-ATPase α1 subunit (ATP1A1). Functional characterization of mutant Na(+), K(+)-ATPase α1 subunits in heterologous expression systems revealed not only a loss of Na(+), K(+)-ATPase function but also abnormal cation permeabilities, which led to membrane depolarization and possibly aggravated the effect of the loss of physiological pump activity. These findings underline the indispensable role of the α1 isoform of the Na(+), K(+)-ATPase for renal-tubular magnesium handling and cellular ion homeostasis, as well as maintenance of physiologic neuronal activity.

The term Idiopathic infantile hypercalcemia (IIH) was first introduced almost 70 years ago when symptomatic hypercalcemia developed in children after receiving high doses of vitamin D for the prevention of rickets. The underlying pathophysiology remained unknown until recessive mutations in CYP24A1 encoding Vitamin D3-24-hydroxylase were discovered. The defect in vitamin D degradation leads to an accumulation of active 1,25(OH)2D3 with subsequent hypercalcemia. Enhanced renal calcium excretions lead to hypercalciuria and nephrocalcinosis. Meanwhile, the phenotypic spectrum associated with CYP24A1 mutations has significantly broadened. Patients may present at all age groups with symptoms originating from increased serum calcium levels as well as from increased urinary calcium excretions, i.e. kidney stones. Possible long term sequelae comprise chronic renal failure as well as cardiovascular disease. Here, we present a family with two affected siblings with differing clinical presentation as an example for the phenotypic variability of CYP24A1 defects., Highlights • CYP24A1 mutations result in increased vitamin D sensitivity. • Associated phenotypes range from infantile hypercalcemia to kidney stone disease. • Potential long-term sequelae include chronic renal failure. • Future research needs to focus on potential treatments to limit vitamin D activation.

Hypercalcemia in infancy is a rare event, however, when present, it requires a targeted diagnostic work-up and therapy. Underlying etiologies comprise inborn defects in calcium, phosphate, and bone metabolism. Critical components for differential diagnosis are the determination of parathyroid hormone and vitamin D metabolites. Idiopathic infantile hypercalcemia was first recognized when symptomatic hypercalcemia developed in children after receiving high doses of vitamin D for the prevention of rickets in Great Britain in the 1950s. The exact pathophysiology remained unknown until recessive mutations in CYP24A1 encoding 25 hydroxyvitamin D 3 -24-hydroxylase were discovered. The defect in vitamin D degradation leads to an accumulation of active 1,25-dihydroxyvitamin D 3 with subsequent hypercalcemia. Enhanced renal calcium excretion causes hypercalciuria and nephrocalcinosis. Meanwhile, the phenotypic spectrum associated with CYP24A1 mutations has significantly broadened. Moreover, defects in renal phosphate handling have been discovered resulting in similar disease patterns. This chapter will review the recent developments in our understanding of inborn errors of vitamin D metabolism resulting in an augmented action of vitamin D and discuss critical diagnostic and therapeutic aspects in the care of patients.

Background/Aims: Hypercalcemia can result in nephrocalcinosis/nephrolithiasis and may lead to renal failure. Idiopathic infantile hypercalcemia is caused by mutations of the CYP24A1 gene, which regulates vitamin D activity. Classically infants present with hypercalcemia. Recently, a number of individuals have been reported with late onset clinical manifestation or late diagnosis in adulthood. All these patients are believed to show hypercalciuria. Methods: We report a 24 year old patient of healthy consanguine parents. Genetic analysis was performed by Sanger sequencing of the CYP24A1 gene in the index patient and targeted exon 2 analysis of all other family members. Results: The patient was hospitalized with severe malaise during an acute EBV-infection. He showed hypercalcemia > 3mmol/l and acute, hypovolemic renal failure with profound nephrocalcinosis, but no hypercalciuria. Genetic workup revealed a homozygous loss-of-function mutation p.E143del in the CYP24A1 gene. His clinically asymptomatic brother showed nephrocalcinosis of lesser degree. Repeatedly, low parathyroid hormone levels were detected in both brothers. Conclusion: This family displays the highly variable phenotype of CYP24A1 biallelic mutation carriers. CYP24A1 associated disease is an important differential diagnosis for the workup and counseling of infants as well as adults with hypercalcemia since a proper genetic diagnosis may result in therapeutic consequences.

International audience; Vitamin D metabolism involves 3 highly specific cytochrome P450 (CYP) enzymes (25-hydroxylase, 1α-hydroxylase, and 24-hydroxylase) involved in the activation of vitamin D3 to the hormonal form, 1,25-(OH)2D3, and the inactivation of 1,25-(OH)2D3 to biliary excretory products. Mutations of the activating enzymes CYP2R1 and CYP27B1 cause lack of normal 1,25-(OH)2D3 synthesis and result in rickets whereas mutations of the inactivating enzyme CYP24A1 cause build-up of excess 1,25-(OH)2D3 and result in hypercalcemia, nephrolithiasis, and nephrocalcinosis. This article reviews the literature for 3 clinical conditions. Symptoms, diagnosis, treatment, and management of vitamin D-dependent rickets and idiopathic infantile hypercalcemia are discussed.

Background and objectives Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. Design, setting, participants, & measurements We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years. Results In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. Conclusions Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.

Salt-losing tubulopathies with secondary hyperaldosteronism (SLT) comprise a set of well-defined inherited tubular disorders. Two segments along the distal nephron are primarily involved in the pathogenesis of SLTs: the thick ascending limb of Henle's loop, and the distal convoluted tubule (DCT). The functions of these pre- and postmacula densa segments are quite distinct, and this has a major impact on the clinical presentation of loop and DCT disorders - the Bartter- and Gitelman-like syndromes. Defects in the water-impermeable thick ascending limb, with its greater salt reabsorption capacity, lead to major salt and water losses similar to the effect of loop diuretics. In contrast, defects in the DCT, with its minor capacity of salt reabsorption and its crucial role in fine-tuning of urinary calcium and magnesium excretion, provoke more chronic solute imbalances similar to the effects of chronic treatment with thiazides. The most severe disorder is a combination of a loop and DCT disorder similar to the enhanced diuretic effect of a co-medication of loop diuretics with thiazides. Besides salt and water supplementation, prostaglandin E2-synthase inhibition is the most effective therapeutic option in polyuric loop disorders (e.g., pure furosemide and mixed furosemide-amiloride type), especially in preterm infants with severe volume depletion. In DCT disorders (e.g., pure thiazide and mixed thiazide-furosemide type), renin-angiotensin-aldosterone system (RAAS) blockers might be indicated after salt, potassium, and magnesium supplementation are deemed insufficient. It appears that in most patients with SLT, a combination of solute supplementation with some drug treatment (e.g., indomethacin) is needed for a lifetime.

Item does not contain fulltext BACKGROUND: Vitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. METHODS: We used a candidate-gene approach in a cohort of familial cases of typical idiopathic infantile hypercalcemia with suspected autosomal recessive inheritance. Identified mutations in the vitamin D-metabolizing enzyme CYP24A1 were evaluated with the use of a mammalian expression system. RESULTS: Sequence analysis of CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D(3) degradation, revealed recessive mutations in six affected children. In addition, CYP24A1 mutations were identified in a second cohort of infants in whom severe hypercalcemia had developed after bolus prophylaxis with vitamin D. Functional characterization revealed a complete loss of function in all CYP24A1 mutations. CONCLUSIONS: The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants.

Background Three pregnancies with male offspring in one family were complicated by severe polyhydramnios and prematurity. One fetus died; the other two had transient massive salt-wasting and polyuria reminiscent of antenatal Bartter's syndrome. Methods To uncover the molecular cause of this possibly X-linked disease, we performed whole-exome sequencing of DNA from two members of the index family and targeted gene analysis of other members of this family and of six additional families with affected male fetuses. We also evaluated a series of women with idiopathic polyhydramnios who were pregnant with male fetuses. We performed immunohistochemical analysis, knockdown and overexpression experiments, and protein-protein interaction studies. Results We identified a mutation in MAGED2 in each of the 13 infants in our analysis who had transient antenatal Bartter's syndrome. MAGED2 encodes melanoma-associated antigen D2 (MAGE-D2) and maps to the X chromosome. We also identified two different MAGED2 mutations in two families with idiopathic polyhydramnios. Four patients died perinatally, and 11 survived. The initial presentation was more severe than in known types of antenatal Bartter's syndrome, as reflected by an earlier onset of polyhydramnios and labor. All symptoms disappeared spontaneously during follow-up in the infants who survived. We showed that MAGE-D2 affects the expression and function of the sodium chloride cotransporters NKCC2 and NCC (key components of salt reabsorption in the distal renal tubule), possibly through adenylate cyclase and cyclic AMP signaling and a cytoplasmic heat-shock protein. Conclusions We found that MAGED2 mutations caused X-linked polyhydramnios with prematurity and a severe but transient form of antenatal Bartter's syndrome. MAGE-D2 is essential for fetal renal salt reabsorption, amniotic fluid homeostasis, and the maintenance of pregnancy. (Funded by the University of Groningen and others.).

Magnesium plays an essential role in many biochemical and physiological processes. Homeostasis of magnesium is tightly regulated and depends on the balance between intestinal absorption and renal excretion. During the last decades, various hereditary disorders of magnesium handling have been clinically characterized and genetic studies in affected individuals have led to the identification of some molecular components of cellular magnesium transport. In addition to these hereditary forms of magnesium deficiency, recent studies have revealed a high prevalence of latent hypomagnesemia in the general population. This finding is of special interest in view of the association between hypomagnesemia and common chronic diseases such as diabetes, coronary heart disease, hypertension, and asthma. However, valuable methods for the diagnosis of body and tissue magnesium deficiency are still lacking. This review focuses on clinical and genetic aspects of hereditary disorders of magnesium homeostasis. We will review primary defects of epithelial magnesium transport, disorders associated with defects in Ca(2+)/ Mg(2+) sensing, as well as diseases characterized by renal salt wasting and hypokalemic alkalosis, with special emphasis on disturbed magnesium homeostasis.

The kidney plays a key role in the maintenance of normal magnesium balance. The distal tubule of the kidney, namely the thick ascending limb of the loop of Henle and the distal convoluted tubule, is crucial for the regulation of serum magnesium levels and body magnesium content. The identification of molecular defects related to rare inherited magnesium losing disorders has contributed greatly to a better understanding of the process of renal magnesium handling. Since the number of genetic defects related to magnesium metabolism is still increasing, it might be expected that our knowledge on magnesium physiology will further improve. This knowledge will hopefully lead to therapeutic strategies that enable specific therapies for patients suffering from the symptoms and possible sequelae of chronic magnesium depletion.

Hypercalcemia (3.0 mmol/l), elevated parathyroid hormone concentrations (PTH, C-assay, 49 pg/ml), and hypercalciuria (10.0 mmol/24 h) were found in 1983 in a 31-year-old male, who at that time presented with kidney stones and moderate nephrocalcinosis. Given the combination of high serum calcium along with elevated PTH, primary hyperparathyroidism was diagnosed, and the patient underwent partial parathyroidectomy in 1984 (histology not available). Despite this surgical intervention and the ensuing drop in serum calcium, over the following years repeated episodes of hypercalcemia occurred, severe nephrocalcinosis developed (Figure 1), and renal function deteriorated to chronic kidney disease (CKD) stage 4. Serum calcium was again elevated and PTH inadequately non-suppressed and in the normal range in 2005 (Table 1). Furthermore, serum 1.25-vitamin D was in the high-normal range. An extended and thorough workup did not reveal the cause of the patient’s hypercalcemia. Given the absence of a therapeutic success under cinacalcet and other calcium-lowering drugs (loop diuretics, bisphosphonates), total parathyroidectomy was finally performed in 2006 (Table 1). At that time, the histological analysis revealed normal parathyroid tissue. Interestingly, after cessation of calcitriol, which had been given for the prevention of hungry-bone syndrome after the second parathyroidectomy, and the concomitant start of a self-chosen low calcium diet from 2006 on, the patient has remained normocalcemic and his kidney function stable.

Hereditary hypomagnesemia with secondary hypocalcemia (HSH) is a rare condi-tion caused by mutations in the Transient Receptor Potential Melastatin 6 (TRMP6) gene. Patients usually present during early infancy with symptomatic hypocalcemia; however, intracranial calcification has not been previously reported in HSH. We report on a three-month-old Saudi girl who presented with hypocalcemic convulsions and was initially treated as nutritional rickets. However, further biochemical analysis of blood and urine were suggestive of HSH. This diagnosis was confirmed by mutation analysis, which identified a novel homozygous frame shift mutation (ins 2999T) of the TRMP6 gene. A computed tomography brain scan, done around the time of diagnosis, identified bilateral basal ganglia calcification (BGC). Her serum calcium and the BGC improved with magnesium replacement. BGC can be added as a new feature of HSH and the case highlights the importance of measuring serum Mg in patients with hypocalcemic convulsions, particularly in children of consanguineous parents.

We report on a male infant presenting at 4 months of age with failure to thrive, dehydration, hypotonia, lethargy, and vomiting. Laboratory and imaging tests revealed severe hypercalcemia (5.8 mmol/l), suppressed parathyroid hormone (0.41 pmol/l), hypercalciuria (8.0 mmol/mmol creatinine), elevated 25-hydroxyvitamin D3 (over 600 nmol/l), and nephrocalcinosis. These symptoms are characteristic of idiopathic infantile hypercalcemia (IIH, MIM 143880). Conservative therapy (parenteral rehydration, diuretics, corticosteroids, bisphosphonates, and vitamin D prophylaxis withdrawal) was not able to improve the symptoms and laboratory values, and acute hemodiafiltration was necessary to normalize hypercalcemia. Clinical symptoms resolved rapidly after normalization of serum calcium levels. Molecular genetic testing revealed a homozygous mutation (R396W) in the CYP24A1 gene (MIM 126065) encoding 25-hydroxyvitamin D3 24-hydroxylase, which is the key enzyme responsible for 1,25-dihydroxyvitamin D3 degradation. The CYP24A1 gene mutation leads to the increased sensitivity of the patients to even prophylactic doses of vitamin D and to the development of severe symptomatic hypercalcemia in patients with IIH. Conclusion: Our patient is only the thirteenth patient with IIH caused by mutation in the CYP24A1 gene and the first one needing acute hemodiafiltration for severe symptomatic hypercalcemic crisis. In all patients with suspected IIH the DNA analysis for CYP24A1 gene mutations should be performed regardless of the type of vitamin D supplementation and serum levels of vitamin D.

BACKGROUND Recent identification and characterization of novel renal Mg(2+) transporters and ion channels have greatly increased our understanding of the normal physiology of renal magnesium handling. METHODS The present study deals with the clinical and molecular characterization of eight Turkish children (median age 10.6 years, range 3-16.2 years, five boys and three girls) with primary hypomagnesaemia from six families. RESULTS All patients initially presented with tetany and convulsions. Laboratory evaluation yielded severely low serum magnesium levels and low serum calcium levels in all patients. While six patients exhibited inadequately low parathyroid hormone levels, the two remaining patients showed hyperparathyroidism, hypercalciuria and nephrocalcinosis. Genetic studies revealed familial hypomagnesaemia with secondary hypocalcaemia (HSH) due to a TRPM6 mutation in six patients and familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) due to a CLDN16 mutation in one patient. CONCLUSIONS Among recently identified magnesium-wasting disorders, HSH and FHHNC represent two major entities also in the Turkish population. Besides clinical course and laboratory diagnosis of hypomagnesaemia, the detection of renal calcium wasting and parathyroid function are crucial to differentiate between these most prevalent forms of hereditary magnesium deficiency. While TRPM6 mutations underlying HSH almost uniformly lead to a complete loss of function of the TRPM6 protein, the severity of FHHNC phenotype depends on the residual function of the mutated claudin-16 protein.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive renal tubular disorder that typically presents with disturbances in magnesium and calcium homeostasis, recurrent urinary tract infections, and polyuria and/or polydipsia. Patients with FHHNC have high risk of the development of chronic kidney disease and end-stage renal disease in early adolescence. Multiple distinct mutations in the CLDN16 gene, which encodes a tight junction protein, have been found responsible for this disorder. In addition, mutations in another member of the claudin family, CLDN19, were identified in a subset of patients with FHHNC with visual impairment. The claudins belong to the family of tight junction proteins that define the intercellular space between adjacent endo- and epithelial cells. Claudins are especially important for the regulation of paracellular ion permeability. We describe a Brazilian family with 2 affected siblings presenting with the typical FHHNC phenotype with ocular anomalies. The clinical diagnosis of FHHNC was confirmed using mutational analysis of the CLDN19 gene, which showed 2 compound heterozygous mutations. In the context of the case vignette, we summarize the clinical presentation, diagnostic criteria, and therapeutic options for patients with FHHNC. We also review recent advances in understanding the electrophysiologic function of claudin-16 and -19 in the thick ascending limb of the loop of Henle and implications for ion homeostasis in the human body.

UNLABELLED Activating calcium sensor receptor (CaSR) mutations often present with hypocalcemia and hypomagnesemia. Severe hypocalcemia with this mutation has been reported but severe hypomagnesemia has not been well described. AIM To identify the cause of severe hypocalcemia and hypomagnesemia in a young child, and explore the efficacy of continuous subcutaneous magnesium therapy as a safer alternative to intravenous magnesium. PATIENT A 2-8/12 year-old female with severe hypocalcemia and hypomagnesemia of unknown etiology. METHODS Genetic analysis was performed on the proband and both parents. The proband was treated with human parathyroid hormone (teriparatide) and a continuous infusion of subcutaneous magnesium sulfate initially using a Deltec insulin pump and subsequently a Curlin infusion pump. RESULTS The patient has a known de novo mutation in the CASR gene (A843E). She could not be adequately managed with enteral and intravenous electrolyte replacement even after adding teriparatide. She responded well to adjunctive therapy with continuous subcutaneous magnesium. CONCLUSIONS Severe hypomagnesemia can be part of the phenotype of activating CaSR mutations. Subcutaneous magnesium should be considered in patients with difficult to control hypomagnesemia.

Mutations in genes encoding chloride transporters cause Bartter's syndrome. An antenatal form associated with salt wasting and deafness has been observed in persons with mutations in BSND, the gene...