Neonatal salt‐wasting and 11 β‐hydroxylase deficiency in a child carrying a homozygous deletion hybrid <i>CYP11B2</i> (aldosterone synthase)–<i>CYP11B1</i> (11 β‐hydroxylase)

Ezquieta, Begoña; Luzuriaga, Cristina

doi:10.1111/j.1399-0004.2004.00291.x

Cited by 17 publications

(7 citation statements)

References 40 publications

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“…ASD is a rare, autosomal recessive disease, and cases have been identified in the Iranian Jewish, European and North American populations. It has also been reported in Asian populations, including Thai, Japanese, and Indian individuals (8,14,15). However, to the best of our knowledge, only one Chinese patient with ASD has been reported with a heterozygous missense mutation (c.977C>A) and a heterozygous small deletion mutation (c.523_525delAAG) of the CYP11B2 gene (17).…”

Section: Discussionmentioning

confidence: 88%

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Novel mutations in the CYP11B2 gene causing aldosterone synthase deficiency

Niu

Ding

et al. 2016

Molecular Medicine Reports

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Aldosterone synthase deficiency (ASD) is a rare, autosomal recessive inherited disease. Mutations in the CYP11B2 gene are responsible for the occurrence of ASD, and the clinical manifestations of ASD vary with age. Affected infants may develop symptoms of mineralocorticoid deficiency, including clinical presentation with frequent vomiting, a variable degree of hyponatremia, hyperkalemia, and metabolic acidosis combined with poor growth, which are easily confused with several other endocrine genopathies, including pseudohypoaldosteronism type 1 and congenital adrenal hyperplasia. In the present study, whole exome sequencing (WES) was used to screen for causal variants in the genome of a Chinese pediatric patient with confusing endocrine disorder symptoms. Clinical symptoms of frequent vomiting, hyponatremia and hyperkalemia were selected as the filtering indices to analyze the WES data. Clinically relevant variants were subsequently verified using Sanger sequencing. Minigene construct analysis was used to assess the consequence of a splicing variant in the CYP11B2 gene. The compound heterozygous mutations, c.1009C>T and c.240‑1G>A, in the CYP11B2 gene were identified and confirmed, and represented novel variants. Sequence analysis results revealed that the c.1009C>T mutation at codon 337 of exon 6 was a nonsense mutation, which led to early termination of the protein translation process. In addition, further investigation of the splicing pattern in a minigene construct showed that the c.240‑1G>A mutation led to the preservation of intron 1, with the 3'‑splice site disappearing during transcriptional processing of the mRNA. Using molecular genetic assessments, the patient was finally diagnosed with ASD. Therefore, the present study identified two novel CYP11B2 gene mutations in a Chinese patient with ASD, indicating exome sequencing as an effective diagnostic tool for rare endocrine-metabolic diseases.

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Section: Discussionmentioning

confidence: 88%

“…Affected individuals are often characterized by an increased 18OHB/aldosterone ratio (2,(11)(12)(13)(14). The predominant method of treatment for patients with ASD is mineralocorticoid and sodium supplementation (15).…”

Section: Discussionmentioning

confidence: 99%

Novel mutations in the CYP11B2 gene causing aldosterone synthase deficiency

Niu

Ding

et al. 2016

Molecular Medicine Reports

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“…Hence, during acute illness with electrolyte imbalance, adequate dietary sodium intake and mineralocorticoid treatment may be required [44,45]. Few cases with mineralocorticoid deficiency have been described in untreated patients with classic 11βOHD and patients on glucocorticoid replacement with one case of documented homozygous deletion hybrid (CYP11B2-CYP11B1) [10,43,46].…”

Section: Electrolyte Regulationmentioning

confidence: 97%

Clinical perspectives in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

2016

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Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is a rare autosomal recessive genetic disorder. It is caused by reduced or absent activity of 11β-hydroxylase (CYP11B1) enzyme and the resultant defects in adrenal steroidogenesis. The most common clinical features of 11 beta-hydroxylase deficiency are ambiguous genitalia, accelerated skeletal maturation and resultant short stature, peripheral precocious puberty and hyporeninemic hypokalemic hypertension. The biochemical diagnosis is based on raised serum 11-deoxycortisol and 11-deoxycorticosterone levels together with increased adrenal androgens. More than 100 mutations in CYP11B1 gene have been reported to date. The level of in-vivo activity of CYP11B1 relates to the degree of severity of 11 beta-hydroxylase deficiency. Clinical management of 11 beta-hydroxylase deficiency can pose a challenge to maintain adequate glucocorticoid dosing to suppress adrenal androgen excess while avoiding glucocorticoid-induced side effects. The long-term outcomes of clinical and surgical management are not well studied. This review article aims to collate the current available data about 11 beta-hydroxylase deficiency and its management.

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“…Neonatal salt-wasting can be seen with this mutation. [66] Complications of longstanding, uncontrolled hypertension, including cardiomyopathy, retinal vein occlusion, and blindness have been reported in 11β-OHD patients. Malignant hypertension with cerbrovascular accidents have also been reported.…”

Section: (Beta)-hydroxylase Deficiencymentioning

confidence: 99%

Mineralocorticoid hypertension

Gupta

2011

Indian J Endocr Metab

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Hypertension affects about 10 – 25% of the population and is an important risk factor for cardiovascular and renal disease. The renin-angiotensin system is frequently implicated in the pathophysiology of hypertension, be it primary or secondary. The prevalence of primary aldosteronism increases with the severity of hypertension, from 2% in patients with grade 1 hypertension to 20% among resistant hypertensives. Mineralcorticoid hypertension includes a spectrum of disorders ranging from renin-producing pathologies (renin-secreting tumors, malignant hypertension, coarctation of aorta), aldosterone-producing pathologies (primary aldosteronism – Conns syndrome, familial hyperaldosteronism 1, 2, and 3), non-aldosterone mineralocorticoid producing pathologies (apparent mineralocorticoid excess syndrome, Liddle syndrome, deoxycorticosterone-secreting tumors, ectopic adrenocorticotropic hormones (ACTH) syndrome, congenitalvadrenal hyperplasia), and drugs with mineraocorticoid activity (locorice, carbenoxole therapy) to glucocorticoid receptor resistance syndromes. Clinical presentation includes hypertension with varying severity, hypokalemia, and alkalosis. Ratio of plasma aldosterone concentraion to plasma renin activity remains the best screening tool. Bilateral adrenal venous sampling is the best diagnostic test coupled with a CT scan. Treatment is either surgical (adrenelectomy) for unilateral adrenal disease versus medical therapy for idiopathic, ambiguous, or bilateral disease. Medical therapy focuses on blood pressure control and correction of hypokalemia using a combination of anti-hypertensives (calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers) and potassium-raising therapies (mineralcorticoid receptor antagonist or potassium sparing diuretics). Direct aldosterone synthetase antagonists represent a promising future therapy.

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Neonatal salt‐wasting and 11 β‐hydroxylase deficiency in a child carrying a homozygous deletion hybrid CYP11B2 (aldosterone synthase)–CYP11B1 (11 β‐hydroxylase)

Cited by 17 publications

References 40 publications

Novel mutations in the CYP11B2 gene causing aldosterone synthase deficiency

Novel mutations in the CYP11B2 gene causing aldosterone synthase deficiency

Clinical perspectives in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Mineralocorticoid hypertension

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