scholarly journals Molecular genetic verification of isolated mineralocorticoid deficiency due to aldosterone synthase deficiency

2009 ◽  
Vol 55 (1) ◽  
pp. 28-30
Author(s):  
N Yu Kalinchenko ◽  
N A Zubkova ◽  
A N Tyulpakov
Keyword(s):  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Autosomal Recessive Disorder ◽  
Adrenal Hyperplasia ◽  
Genetic Studies ◽  
Aldosterone Synthase ◽  
Salt Wasting ◽  
History Of ◽  
17 Hydroxyprogesterone ◽  
Aldosterone Synthase Deficiency

Isolated mineralocorticoid deficiency is a rare hereditary autosomal recessive disorder that is characterized by salt wasting and that has the severest manifestations in infants. This paper is the first in the Russian literature to describe cases of isolated aldosterone deficiency. In both cases, the patients were monitored and treated for misdiagnosed congenital adrenal hyperplasia; however, the permanently low level of 17-hydroxyprogesterone could put in doubt the diagnosis and suspect isolated mineralocorticoid deficiency, by keeping in mind a history of salt wasting. By using the presented cases as an example, the authors give an algorithm for the examination and differential diagnosis of this condition and other diseases that have the similar clinical picture. Aldosterone synthase deficiency in patients was verified by molecular genetic studies - there were mutations in the CYP112 gene.

Molecular Analysis of the CYP11B2 Gene in 62 Patients with Hypoaldosteronism Due to Aldosterone Synthase Deficiency

2020 ◽  
Vol 106 (1) ◽  
pp. e182-e191
Author(s):  
Christina Merakou ◽  
Irene Fylaktou ◽  
Amalia Sertedaki ◽  
Maria Dracopoulou ◽  
Antonis Voutetakis ◽  
...  
Keyword(s):  
Gene Sequencing ◽  
Failure To Thrive ◽  
In Silico Analysis ◽  
Autosomal Recessive Disorder ◽  
Molecular Study ◽  
Aldosterone Synthase ◽  
Salt Wasting ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Aldosterone Synthase Deficiency

Abstract Context Isolated congenital hypoaldosteronism presents in early infancy with symptoms including vomiting, severe dehydration, salt wasting, and failure to thrive. The main causes of this rare autosomal recessive disorder is pathogenic variants of the CYP11B2 gene leading to aldosterone synthase deficiency. Objective To investigate the presence of CYP11B2 pathogenic variants in a cohort of patients with a clinical, biochemical, and hormonal profile suggestive of aldosterone synthase deficiency. Design Clinical and molecular study. Setting Tertiary academic Children’s Hospital, Center for Rare Pediatric Endocrine Diseases. Patients and Methods Sixty-two patients (56 unrelated patients and 6 siblings), with hypoaldosteronism and their parents, underwent CYP11B2 gene sequencing after its selective amplification against the highly homologous CYP11B1 gene. In silico analysis of the identified novel variants was carried out to evaluate protein stability and potential pathogenicity. Results CYP11B2 gene sequencing revealed that 62 patients carried a total of 12 different pathogenic CYP11B2 gene variants, 6 of which are novel. Importantly, 96% of the 56 patients carried the previously reported p.T185I variant either in homozygosity or in compound heterozygosity with another variant. The 6 novel variants detected were: p.M1I, p.V129M, p.R141Q, p.A165T, p.R448C, and the donor splice site variant of intron 8, c.1398 + 1G > A. Conclusion Molecular diagnosis was achieved in 62 patients with aldosterone synthase deficiency, the largest cohort thus far reported. Six novel genetic variants were identified as possibly pathogenic, extending the spectrum of reported molecular defects of the CYP11B2 gene.

scholarly journals Identification of a Large Deletion, Spanning Exons 4 to 11 of the Human Factor XIIIA Gene, in a Factor XIII-Deficient Family

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 149-153 ◽  
Author(s):  
Rashida Anwar ◽  
Krzysztof J.A. Miloszewski ◽  
Alexander F. Markham
Keyword(s):  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Point Mutations ◽  
Autosomal Recessive Disorder ◽  
Large Deletion ◽  
Factor Xiiia ◽  
Paternal Allele ◽  
Bleeding Tendency ◽  
Genetic Studies ◽  
Polymerase Chain

Inherited deficiency of factor XIIIA subunit (FXIIIA) is an autosomal recessive disorder that is characterized by a life-long bleeding tendency and complications in wound healing. Molecular genetic studies have shown the deficiency can be due to small sequence changes within the FXIIIA gene, such as point mutations or microdeletions. On molecular analysis of the FXIIIA gene in an FXIII-deficient patient, of United Kingdom origin, we identified a putative homozygous missense mutation, Arg408Gln. However, the father of this patient is homozygous normal for arginine at codon 408. Having proved paternity in this pedigree by microsatellite analysis, we examined the FXIIIA RNA of the patient by reverse transcriptase-polymerase chain reaction and found the paternal allele to lack exons 4 through 11 inclusive. Hence, a huge deletion extending from intron 3 to intron 11 and the Arg408Gln mutation are jointly responsible for FXIIIA deficiency in this family. This is the first finding of such a large deletion in the FXIIIA gene.

scholarly journals Congenital Adrenal Hyperplasia with Salt Wasting Crisis: A Case Report

2020 ◽  
Vol 58 (221) ◽  
Author(s):  
Deependra Mandal ◽  
Deepa Khanal ◽  
Rajan Phuyal ◽  
Uttara Adhikari
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Elevated Level ◽  
Autosomal Recessive ◽  
Oral Prednisolone ◽  
Severe Form ◽  
Adrenal Hyperplasia ◽  
Autosomal Recessive Disorders ◽  
Salt Wasting ◽  
17 Hydroxyprogesterone ◽  
Recessive Disorders

Congenital Adrenal Hyperplasia is a group of autosomal recessive disorders due to deficienciesof enzymes involved in steroidogenesis. The most common form is a 21-hydroxylase deficiencywhich can be classical or non-classical. The severe form also called Classical Congenital AdrenalHyperplasia is usually detected after birth to infant period. If Congenital Adrenal Hyperplasia is notdiagnosed and treated early, neonates are susceptible to sudden death in the early weeks of life. Wereport a case of thirty-five days male with a salt-wasting variant of congenital adrenal hyperplasia.The diagnosis was based on an elevated level of 17-hydroxyprogesterone. He was managed and lifelong oral Prednisolone and Fludrocortisone were prescribed.

scholarly journals Refining Hormonal Diagnosis of Type II 3β-Hydroxysteroid Dehydrogenase Deficiency in Patients with Premature Pubarche and Hirsutism Based on HSD3B2 Genotyping

2005 ◽  
Vol 90 (3) ◽  
pp. 1287-1293 ◽  
Author(s):  
Livia M. Mermejo ◽  
Lucila L. K. Elias ◽  
S. Marui ◽  
Ayrton C. Moreira ◽  
Berenice B. Mendonca ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Matched Control ◽  
Autosomal Recessive Disorder ◽  
Hydroxysteroid Dehydrogenase ◽  
Ambiguous Genitalia ◽  
Pubic Hair ◽  
Salt Wasting ◽  
17 Hydroxyprogesterone ◽  
The Relationship ◽  
Premature Pubarche

Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3βHSD), a rare autosomal recessive disorder that affects both sexes, has a heterogeneous clinical presentation ranging from the severe salt-wasting to the non-salt-wasting forms and results from mutations in the HSD3B2 gene. The hormonal criteria for diagnosing the mild variant of 3βHSD deficiency have been controversial because the initial studies were not based on genetic evidence. We investigated the relationship between the hormonal phenotype and HSD3B2 genotype in 22 patients with clinical and/or biochemical features suggestive of 3βHSD2 deficiency, including nine female children with premature pubarche, 12 hirsute females, and one boy with salt-wasting and ambiguous genitalia. Serum 17-hydroxypregnenolone (Δ5-17P), cortisol (F), 17-hydroxyprogesterone, dehydroepiandrosterone, and androstenedione levels were determined by RIA and were compared with Tanner pubic hair stage-matched control groups. The genomic DNA was extracted, and the entire HSD3B2 gene was amplified by PCR followed by automatic sequencing. Besides two different mutations previously observed in three patients (T259M and G129R/P222Q mutations), we observed the P222Q mutation in the male patient with salt-wasting form of 3βHSD2 deficiency. Basal and ACTH-stimulated Δ5-17P levels (nanomoles per liter) ranged from 4–41 (−0.2 to 14 sd) and 36–97 (3.5–15.5 sd), respectively, in patients without mutation in HSD3B2 and from 69–153 (25–57 sd) and 201–351 (36–65 sd), respectively, in patients with mutation in HSD3B2. Basal and ACTH-stimulated Δ5-17P to F ratios ranged from 11–159 (0.5–25 sd) and 42–122 (2.4–11.3 sd), respectively, in patients without mutation in HSD3B2 and from 181-1700 (29–282 sd) and 487-1523 (52–167 sd), respectively, in patients with mutation in HSD3B2. The hormone findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3βHSD2 deficiency in children with premature pubarche: ACTH-stimulated Δ5-17P and Δ5-17P to F ratios at or greater than 201 and 487 nmol/liter, respectively, equivalent to or greater than 36 and 52 sd above matched control mean. Basal and ACTH-stimulated Δ5-17P and Δ5-17P to F ratios in all genotype-proven patients in childhood were unequivocally higher than the levels of either genotype-normal patients. All the other parameters overlapped between the patients with and without mutations in the HSD3B2 gene. In conclusion, genotyping more patients in the present study, we confirm that patients with mutations in the HSD3B2 gene have extremely elevated basal and ACTH-stimulated Δ5-17P levels and Δ5-17P to F ratios. Therefore, these data refine the hormonal criteria proposed to predict more accurately 3βHSD2 deficiency.

scholarly journals Identification of a Large Deletion, Spanning Exons 4 to 11 of the Human Factor XIIIA Gene, in a Factor XIII-Deficient Family

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 149-153 ◽  
Author(s):  
Rashida Anwar ◽  
Krzysztof J.A. Miloszewski ◽  
Alexander F. Markham
Keyword(s):  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Point Mutations ◽  
Autosomal Recessive Disorder ◽  
Large Deletion ◽  
Factor Xiiia ◽  
Paternal Allele ◽  
Bleeding Tendency ◽  
Genetic Studies ◽  
Polymerase Chain

Abstract Inherited deficiency of factor XIIIA subunit (FXIIIA) is an autosomal recessive disorder that is characterized by a life-long bleeding tendency and complications in wound healing. Molecular genetic studies have shown the deficiency can be due to small sequence changes within the FXIIIA gene, such as point mutations or microdeletions. On molecular analysis of the FXIIIA gene in an FXIII-deficient patient, of United Kingdom origin, we identified a putative homozygous missense mutation, Arg408Gln. However, the father of this patient is homozygous normal for arginine at codon 408. Having proved paternity in this pedigree by microsatellite analysis, we examined the FXIIIA RNA of the patient by reverse transcriptase-polymerase chain reaction and found the paternal allele to lack exons 4 through 11 inclusive. Hence, a huge deletion extending from intron 3 to intron 11 and the Arg408Gln mutation are jointly responsible for FXIIIA deficiency in this family. This is the first finding of such a large deletion in the FXIIIA gene.

scholarly journals Late-diagnosed salt-wasting congenital adrenal hyperplasia in adult patient

2018 ◽  
Vol 64 (2) ◽  
pp. 105-110
Author(s):  
Liudmila Ya. Rozhinskaya ◽  
Natalia Yu. Kalinchenko ◽  
Zhanna E. Belaya ◽  
Tatiana S. Zenkova ◽  
Alexander S. Lutsenko ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Molecular Genetic ◽  
Gas Chromatography Mass Spectrometry ◽  
Adrenal Hyperplasia ◽  
Molecular Genetic Study ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Adrenal Cortical Adenoma ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

We describe a unique case of diagnosing salt-wasting congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency in a 32-year-old male patient. Before establishing the diagnosis, the main patient complaint was infertility. In childhood, the patient suffered from developmental delay, often illness, overconsumption of salt, and often vomiting; he stopped growing at the age of 12 years. In the adolescent period, his physical condition improved. Later, the patient got married, but was infertile. Plasma steroid profiling by gas chromatography-mass spectrometry (GC-MS) revealed markedly increased levels of 17-hydroxyprogesterone and 21-deoxycortisol and a decreased cortisol level, which enabled the diagnosis of CAH and 21-hydroxylase deficiency. The diagnosis was confirmed by a molecular genetic study that detected a CYP21 gene mutation — l2 splice in the homo(hemi)zygotic state, which was characteristic of the salt-wasting form of CAH. Also, the patient had secondary adrenal cortical adenoma caused by prolonged ACTH hyperstimulation and secondary hypogonadism associated with excessive production of adrenal androgens, which led to elevated levels of estrogens inhibiting production of LH and FSH. Treatment of the patient with glucocorticoids and mineralocorticoids and then with androgens improved his clinical condition and hormonal parameters.

scholarly journals Late consequences of classic congenital adrenal hyperplasia and its long-term poor control in men (case report and literature review)

2020 ◽  
Vol 16 (4) ◽  
pp. 90-102 ◽  
Author(s):  
Boris M. Shifman ◽  
Larisa K. Dzeranova ◽  
Ekaterina A. Pigarova ◽  
Anatoly N. Tiulpakov ◽  
Natalia S. Fedorova
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Autosomal Recessive Disorder ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Glucocorticoid Treatment ◽  
Salt Wasting ◽  
Adult Age ◽  
Chronic Disorder ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of the adrenal cortex characterized by impairment of cortisol biosynthesis (with possible impairment of aldosterone biosynthesis) and excessive pituitary ACTH release, which promotes oversecretion of intact pathways products: 17-hydroxyprogesterone (17OHP), progesterone, and adrenal androgens androstendione and testosterone. 21-hydroxylase deficiency, being the most common cause of congenital adrenal hyperplasia is a chronic disorder, that requires life-long glucocorticoid treatment, that aims both to replace cortisol and prevent ACTH-driven androgen excess. Nevertheless, reaching the optimal glucocorticoid dose is challenging because currently available glucocorticoid formulations cannot replicate the physiological circadian rhythm of cortisol secretion. The difficulties in striking the balance between uneffective normalizing of ACTH-level and excess glucocorticoid exposure leads to different abnormalities, that starts to develop at first months of life and progress, frequently gaining especial clinical meaning in adult age. In the present clinical case we introduce 35 years old male patient with salt-wasting form of 21-hydroxylase deficiency, which had either complications considered to progress due to insufficient glucocorticoid therapy, and some metabolic abnormalities, associated with supraphysiological doses of glucocorticoids.

scholarly journals Monozygotic twins discordant for congenital adrenal hyperplasia due to mosaicism

2020 ◽  
Vol 182 (2) ◽  
pp. K7-K13 ◽  
Author(s):  
Michelle L Kluge ◽  
Evan Graber ◽  
Kathryn Foley ◽  
Lynnette V Hansen ◽  
Heidi L Sellers ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Cell Line ◽  
Gene Deletion ◽  
Molecular Genetic ◽  
Monozygotic Twins ◽  
Adrenal Hyperplasia ◽  
Differential Distribution ◽  
Salt Wasting ◽  
Show Evidence ◽  
17 Hydroxyprogesterone

Introduction Genotype-phenotype discordance occurs occasionally in congenital adrenal hyperplasia (CAH). Its causes are largely unknown. We describe a case of monochorionic, diamniotic twins with discordant clinical presentations of CAH, and show evidence for this being due to mosaicism resulting from a postzygotic full gene deletion of CYP21A2 prior to twinning. Case description A 7-day-old 36-week gestation female infant (Twin A) presented to the emergency department with elevated 17-hydroxyprogesterone (17-OHP). Her identical twin (Twin B) had normal 17-OHP on newborn screening. Both twins showed signs of virilization, more pronounced in Twin B. Molecular genetic testing of both twins and their parents showed a WT paternally-inherited CYP21A2 and a maternally-inherited copy containing the c.293-13C>G mutation. Both twins were also found to have a 5′-CYP21A1P/CYP21A2-3′ hybrid (product of the common 30-kb deletion), derived from the deletion of the paternally-inherited CYP21A2. Neither mother nor father carried the deletion. Conclusions The genetic findings are consistent with mosaicism for two CYP21A2 cell lines in both twins. The first cell line is expected, based on parental results, while the second line is due to a postzygotic full gene deletion of the paternally-inherited WT CYP21A2. The resultant genotype, compound heterozygosity for c.293-13C>G and a CYP21A2 full gene deletion, is consistent with a salt-wasting CAH phenotype. Differential distribution of the second cell line between the twins is most likely the cause for their discrepant phenotypes. We believe this is the first report of somatic CYP21A2 mosaicism, and represents a novel cause for discrepant CAH phenotypes in monozygotic twins.

Molecular genetic diagnostics of Bardet-Biedl syndrome with an MPS-panel

2021 ◽  
pp. 26-35
Author(s):  
М.Д. Орлова ◽  
П. Гундорова ◽  
А.В. Поляков
Keyword(s):  
Autosomal Recessive ◽  
Molecular Genetic ◽  
Autosomal Recessive Disorder ◽  
Genetic Diagnostics ◽  
Bardet Biedl Syndrome ◽  
Pathogenic Variants ◽  
Development Delay ◽  
Molecular Genetic Diagnostics ◽  
First Time

Синдром Барде-Бидля - аутосомно-рецессивное заболевание, характеризующееся ожирением, пигментной дегенерацией сетчатки, полидактилией, задержкой психоречевого развития и структурными повреждениями почек. В работе представлены результаты применения МПС-панели, включающей кодирующие последовательности и прилегающие интронные области 21 гена, ассоциированного с синдромом Барде-Бидля. Впервые была проведена молекулярно-генетическая диагностика в группе из сорока российских пациентов с синдромом Барде-Бидля из неродственных семей. В результате исследования удалось подтвердить диагноз молекулярно-генетическим методом у 40% пациентов (n=16). В генах BBS1, BBS7 и BBS10 встретились повторяющиеся варианты. Частота встречаемости патогенных и вероятно патогенных вариантов в генах BBS1 и BBS10 у российских пациентов соответствует зарубежным данным. Варианты в гене BBS7 встретились у пяти человек, у четырех из них был обнаружен патогенный вариант c.1967_1968delTAinsC, не встречающийся в других популяциях. Результаты, представленные в статье, показывают значительный вклад в заболеваемость синдромом Барде-Бидля в российской популяции патогенных вариантов в гене BBS7. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by obesity, retinitis pigmentosa, polydactyly, development delay, and structural kidney defects. This study shows the results of using an MPS panel that includes coding sequences and intronic areas of 21 genes associated with Bardet-Biedl syndrome. For the first time molecular genetic testing has been provided for the group of 40 Russian patiens with Bardet-Biedl syndrome from unrelated families. As a result of the testing, diagnoses were confirmed for 40% of the patients (n=16). The genes BBS1, BBS7, BBS10 had recurrent variants. The frequency of pathogenic and likely pathogenic variants in the genes BBS1 and BBS10 among Russian patients matches the research data in other countries. Variants in the BBS7 gene were found for five people, four of them had a pathogenic variant c.1967_1968delTAinsC, which is not present among other populations. Results provided in this article show the significant role of pathogenic variants in the BBS7 gene in patients with Bardet-Biedl syndrome in Russian population.

Abetalipoproteinemia Presenting as Severe Vitamin K Deficiency

PEDIATRICS ◽  
1980 ◽  
Vol 65 (1) ◽  
pp. 161-163
Author(s):  
Fernan M. Caballero ◽  
George R. Buchanan
Keyword(s):  
Vitamin K ◽  
Autosomal Recessive ◽  
Neonatal Period ◽  
Chronic Diarrhea ◽  
Autosomal Recessive Disorder ◽  
Vitamin K Deficiency ◽  
History Of ◽  
K Deficiency ◽  
First Time ◽  
To Receive

Vitamin K deficiency has occasionally been observed in infants after the immediate neonatal period when one or more of the following features is present: diet consisting entirely of breast milk, failure to receive prophylactic vitamin K shortly after birth, therapy with broad-spectrum antibiotics, or chronic diarrhea accompanying malabsorption due to cystic fibrosis or to various acquired causes.1-7 In this report we describe for the first time an infant with the uncommon autosomal recessive disorder abetalipoproteinemia whose major presenting manifestation in early infancy was hemorrhage due to vitamin K deficiency. CASE REPORT A 6-week-old baby was brought in for evaluation because of a two- to three-week history of easy bruising.

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