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Disorders of isolated mineralocorticoid deficiency, which cause potentially life-threatening salt-wasting crisis early in life, have been associated with gene variants of aldosterone biosynthesis or resistance; however, in some patients no such variants are found. WNT/β-catenin signaling is crucial for differentiation and maintenance of the aldosterone-producing adrenal zona glomerulosa (zG). Herein, we describe a highly consanguineous family with multiple perinatal deaths and infants presenting at birth with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Whole exome sequencing revealed a homozygous splice variant in the R-SPONDIN receptor LGR4 gene (c.618-1G>C) regulating WNT signaling. The resulting transcripts affected protein function and stability and resulted in loss of Wnt/β-catenin signaling in vitro. The impact of LGR4 inactivation was analyzed by adrenal cortex-specific ablation of Lgr4, using Lgr4fl/fl mice mated with Sf1:Cre mice. Inactivation of Lgr4 within the adrenal cortex in the mouse model caused decreased WNT signaling, aberrant zonation with deficient zG, and reduced aldosterone production. Thus, human LGR4 mutations establish a direct link between LGR4 inactivation and decreased canonical WNT signaling, which results in abnormal zG differentiation and endocrine function. Therefore, variants in WNT signaling and its regulators should systematically be considered in familial hyperreninemic hypoaldosteronism.

Background RMND1 is a nuclear gene needed for proper function of mitochondria. A pathogenic gene will cause multiple oxidative phosphorylation defects. A renal phenotype consisting of hyponatremia, hyperkalemia, and acidosis is frequently reported, previously considered to be due to aldosterone insensitivity. Methods Clinical features and pathophysiology of three patients will be reported. DNA of these patients was subjected to exome screening. Results In the first family, one pathogenic heterozygous and one highly probable heterozygous mutation were detected. In the second family, a homozygous pathogenic mutation was present. The electrolyte disbalance was not due to aldosterone insensitivity but to low plasma aldosterone concentration, a consequence of low plasma renin activity. This disbalance can be treated. In all three patients, the kidney function declined. In the first family, both children suffered from an unexplained arterial thrombosis with dire consequences. Conclusions Hyporeninemic hypoaldosteronism is the mechanism causing the electrolyte disbalance reported in patients with RMND1 mutations, and can be treated.

Background X-linked Adrenal Hypoplasia Congenita (AHC) is a rare cause of primary adrenal insufficiency due to mutations in the NR0B1 gene, causing a loss of function of the nuclear receptor protein DAX-1 . Adrenal insufficiency usually appears in the first 2 months of life, but can sometimes emerge during childhood. Hypogonadotropic Hypogonadism is often associated later in life and patients may develop azoospermia. We describe an unusual onset of AHC started with isolated hypoaldosteronism as first and only sign of the disease. Case presentation A 18-days-old newborn presented with failure to thrive and feeding difficulties. Blood tests showed severe hyponatremia, hyperkalemia and hypochloremia. Renin was found over the measurable range and aldosterone was low whereas cortisol level was normal with a slightly increased ACTH. In the suspicion of Primary Hypoaldosteronism, correction of plasmatic electrolytes and replacement therapy with Fludrocortisone were promptly started. The subsequent evidence of low plasmatic and urinary cortisol and increased ACTH required the start of Hydrocortisone replacement therapy and it defined a clinical picture of adrenal insufficiency. Genetic analysis demonstrated a novel mutation in the DAX-1 gene leading to the diagnosis of AHC. Conclusions AHC onset may involve the aldosterone production itself, miming an isolated defect of aldosterone synthesis. NR0B1/DAX-1 mutations should be considered in male infants presenting with isolated hypoaldosteronism as first sign of adrenal insufficiency.

Corticosterone methyloxidase deficiency type 2 is an autosomal recessive disorder presenting with salt loss and failure to thrive in early childhood and is caused by inactivating mutations of the gene. Herein, we describe four Turkish patients from two families who had clinical and hormonal features compatible with corticosterone methyloxidase deficiency and all had inherited novel variants. All of the patients presented with vomiting, failure to thrive and severe dehydration, except one patient with only failure to thrive. Biochemical studies showed hyponatremia, hyperkalemia and acidosis. All patients had normal cortisol response to adrenocorticotropic hormone stimulation test and had elevated plasma renin activity with low aldosterone levels. Three patients from the same family were found to harbor a novel homozygous variant c.1175T>C (p.Leu392Pro) and a known homozygous variant c.788T>A (p.Ile263Asn) in the gene. The fourth patient had a novel homozygous variant c.666_667delCT (p.Phe223ProfsTer35) in the gene which caused a frame shift, forming a stop codon. Corticosterone methyloxidase deficiency should be considered as a differential diagnosis in patients presenting with hyponatremia, hyperkalemia and growth retardation, and it should not be forgotten that this condition is life-threatening if untreated. Genetic analyses are helpful in diagnosis of the patients and their relatives. Family screening is important for an early diagnosis and treatment. In our cases, previously unreported novel variants were identified which are likely to be associated with the disease.

Isolated aldosterone synthase deficiency may result in life-threatening salt-wasting and failure to thrive. The condition involves hyperkalemia accompanying hyponatremia. Two types of aldosterone synthase deficiency may be observed depending on hormone levels: corticosterone methyl oxidase type 1 (CMO 1) and CMO 2. Herein, we describe a Turkish infant patient with aldosterone synthase deficiency who presented with failure to thrive and salt wasting but with normal potassium levels. Urinary steroid characteristics were compatible with CMO I deficiency. Diagnosis of aldosterone synthase deficiency was confirmed by mutational analysis of the CYP11B2 gene which identified the patient as homozygous for two mutations: c.788T>A (p.Ile263Asn) and c.1157T>C (p.Val386Ala). Family genetic study revealed that the mother was heterozygous for c.788T>A and homozygous for c.1157T>C and the father was heterozygous for both c.788T>A and c.1157T>C. To the best of our knowledge, this is only the second Turkish case with a confirmed molecular basis of type 1 aldosterone synthase deficiency. This case is also significant in showing that spot urinary steroid analysis can assist with the diagnosis and that hyperkalemia is not necessarily part of the disease.

Aldosterone synthase (P450c11AS) deficiency is a rare autosomal recessive disorder, presenting with severe salt-losing in early infancy. It is caused by inactivating mutations of the CYP11B2 gene. Here, we describe three unrelated Asian patients who have clinical and hormonal features compatible with aldosterone synthase deficiency and identify their CYP11B2 mutations. Patient 1 was a Thai female infant. Patient 2 was an Indian boy, and patient 3 was a Thai male infant. All subjects presented at the age of 1–2 months with diarrhea, failure to thrive, and severe dehydration. Their plasma electrolytes showed hyponatremia, hyperkalemia, and acidosis. All patients had normal cortisol response and had elevated plasma renin activity with low aldosterone levels. The entire coding regions of the CYP11B2 gene were amplified by polymerase chain reaction and sequenced. Patient 1 was homozygous for a previously described mutation, p.T318M. Patient 2 was homozygous for a novel c.666delC mutation inherited from both parents resulting in p.223F>Sfsx295. No CYP11B2 mutation was detected in patient 3. Conclusions: We report the first CYP11B2 defects in Southeast Asian families responsible for aldosterone synthase deficiency and identified a novel CYP11B2 mutation. However, the affected gene(s) responsible for primary hypoaldosteronism other than CYP11B2 remain to be determined.

Isolated aldosterone biosynthesis defect causing congenital hyperreninemic hypoaldosteronism with otherwise normal adrenal function usually results from aldosterone synthase deficiency. Patients present with manifestations of mineralocorticoid deficiency during the first weeks of life. The largest numbers of cases have been described in Iranian Jews, who carried concomitantly two homozygous missense mutations (R181W and V386A). In a few cases with presumed aldosterone synthase deficiency no mutations in CYP11B2 gene have been identified. We describe a molecular and endocrine evaluation of seven cases of congenital hyperreninemic hypoaldosteronism in Israel. Two of the six Jewish patients are of Iranian origin. The parents of five other patients originated from Yemen, Syria and Morocco. One patient is a Muslim-Arab. CYP11B2's exons, exon-intron boundaries and promoter region were sequenced by multiple PCR amplifications. Gene size determination was performed either by long-range PCR or by Southern blot analysis. Only two patients (Iranian Jews) carried a known homozygous R181W, V386A mutations, other two were compound heterozygotes for either the R181W or V386A and one additional novel amino acid substitution (A319V or D335G), and one patient was found to be a carrier of the two novel variations (A319V and D335G). We could not find a molecular defect in 2 patients: one was a carrier of the D335G mutation and the other had no detectable molecular change in the coding and promoter regions. The genetic and molecular basis of congenital hyperreninemic hypoaldosteronism is more heterogeneous than previously described. The significance of amino acid substitutions identified in this study remains to be determined.

To clarify the underlying molecular mechanism of corticosterone methyl oxidase type II (CMO II) deficiency, Japanese patients newly diagnosed with CMO II deficiency were investigated. We analyzed the patients' genomic DNA sequence on all 9 exons of the CYP11B2 gene. In addition, restriction fragment length polymorphism (RFLP) analysis and expression studies were performed. The analysis showed that the patients homozygously retained a missense mutation, Gumacr;GC[435Gly]-->Aumacr;GC[Ser], in the CYP11B2 gene. Expression studies indicated that the steroid 18-hydroxylase/oxidase activities of the mutant enzyme were substantially reduced. These results support the hypothesis that this mutation causes CMO II deficiency in the patients, and are in accordance with our theory that the partial loss of P-450(C18) activities causes CMO II deficiency.

Two boys presenting with infection-triggered, life-threatening salt-loss and hyperkalaemia were published in 1991 in the European Journal of Pediatrics. In both boys, the diagnosis of corticosterone methyl oxidase (CMO) deficiency type II has been established on the basis of determinations of plasma and urinary steroids. We had the opportunity to perform a molecular genetic study in one of the two boys. This boy had an elevated plasma 18-hydroxycorticosterone/aldosterone ratio which is pathognomonic for CMO deficiency type II. Sequence analysis of the CYP11B2 gene revealed a homozygous single base exchange in codon 185 of CYP11B2 causing an amino acid substitution Thr185Ile. A Thr185Ile mutation in the CYP11B2 gene was found in a patient with CMO deficiency type II. This mutation may change the secondary structure of the enzyme leading to its decreased activity.