A Single Nucleotide Variant in the Promoter Region of 17β-HSD Type 5 Gene Influences External Genitalia Virilization in Females with 21-Hydroxylase Deficiency

Abstract Background Steroid 21-hydroxylase deficiency is an autosomal recessive disorder, present in 90–95% of all cases with congenital adrenal hyperplasia (CAH). The classical simple virilizing (SV) form of the disease causes virilization of the external genitalia in newborn females and pseudo-precocious puberty in both sexes, due to reactive androgen overproduction. Case presentation We describe a 3.5-year-old girl presenting with pubarche, P2 according to Tanner, advanced bone age of 6 years and 10 months, and high serum levels of 17-hydroxyprogesterone (17-OHP). Molecular analysis of the nine most common pseudogene-derived CYP21A2 point mutations was performed in the patient and her family members using the polymerase chain reaction/amplification-created restriction site (PCR/ACRS) method. We detected the P30L/I172N genotype in the patient. She had inherited a mild P30L mutation from her mother and a severe I172N mutation from her father. Conclusions Although the CAH phenotype is determined by the allele that produces most of the enzyme activity and the mild non-classical (NC) phenotype should be expected, the mild P30L known to be more virilizing probably induced the classical SV phenotype in our patient. A continuous regimen of hydrocortisone at a recommended dose failed to decrease the 17-OHP sufficiently. Careful tapering of the dose did not help, and her pubic hair advanced to P3 according to Tanner. Individually tailored treatment is warranted in this patient.

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Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency*

Endocrine Reviews ◽

10.1210/edrv.21.3.0398 ◽

2000 ◽

Vol 21 (3) ◽

pp. 245-291 ◽

Cited By ~ 9

Author(s):

Perrin C. White ◽

Phyllis W. Speiser

Keyword(s):

Congenital Adrenal Hyperplasia ◽

External Genitalia ◽

Clinical Severity ◽

Sodium Balance ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Gene Encoding ◽

Salt Wasting ◽

Direct Mutation ◽

21 Hydroxylase Deficiency

Abstract More than 90% of cases of congenital adrenal hyperplasia (CAH, the inherited inability to synthesize cortisol) are caused by 21-hydroxylase deficiency. Females with severe, classic 21-hydroxylase deficiency are exposed to excess androgens prenatally and are born with virilized external genitalia. Most patients cannot synthesize sufficient aldosterone to maintain sodium balance and may develop potentially fatal “salt wasting” crises if not treated. The disease is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombinations between CYP21 and the closely linked CYP21P pseudogene. Approximately 20% are gene deletions due to unequal crossing over during meiosis, whereas the remainder are gene conversions—transfers to CYP21 of deleterious mutations normally present in CYP21P. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disease in patients carrying it. Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females to minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before salt wasting crises develop, reducing mortality from this condition. Glucocorticoid and mineralocorticoid replacement are the mainstays of treatment, but more rational dosing and additional therapies are being developed.

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A neglected case of treatable genetic disorder

Indian Journal of Pharmaceutical and Biological Research ◽

10.30750/ijpbr.4.4.1 ◽

2016 ◽

Vol 4 (04) ◽

pp. 01-03

Author(s):

C. Rekha ◽

R. Paramaguru ◽

Vimala Sarojini ◽

Dinisha Einstien ◽

A. Prathiba

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Genetic Disorder ◽

External Genitalia ◽

Female Child ◽

Ambiguous Genitalia ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Adrenal Hormones ◽

Stage 4 ◽

21 Hydroxylase Deficiency

Congenital adrenal hyperplasia(CAH) is a autosomal recessive genetic disorder involving adrenal hormones resulting in excessive production of androgens and hence their effects. Here we report a case of CAH which was diagnosed very late but was treated successfully. 12 years old female child came to us with ambiguous genitalia. Examination showed praders stage 4 external genitalia. Evaluated further and confirmed as a case of classic type of simple virilising congenital adrenal hyperplasia due to 21 hydroxylase deficiency. She was successfully treated with steroids and surgical correction was also done. Now child has also attained menarche and on follow up at our pediatric out patient department.

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A Greek girl with 11β-hydroxylase deficiency due to compound heterozygosity for two novel mutations in CYP11B1 gene

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-15-0074 ◽

2015 ◽

Vol 2015 ◽

Author(s):

Chrisanthi Marakaki ◽

Anna Papadopoulou ◽

Olga Karapanou ◽

Dimitrios T Papadimitriou ◽

Kleanthis Kleanthous ◽

...

Keyword(s):

External Genitalia ◽

Bone Age ◽

Compound Heterozygous ◽

List Type ◽

Novel Mutations ◽

Acth Stimulation ◽

Adrenal Androgen ◽

Hydroxylase Deficiency ◽

Adrenal Androgens ◽

21 Hydroxylase Deficiency

Summary 11β-hydroxylase deficiency (11β-OHD), an autosomal recessive inherited disorder, accounts for 5–8% of congenital adrenal hyperplasia. In Greece, no cases of 11β-OHD have been described so far. The patient presented at the age of 13 months with mild virilization of external genitalia and pubic hair development since the age of 3 months. Hormonal profile showed elevated 11-deoxycortisol, adrenal androgens and ACTH levels. ACTH stimulation test was compatible with 11β-OHD. DNA of the proband and her parents was isolated and genotyped for CYP11B1 gene coding cytochrome P450c11. The girl was found to be compound heterozygous for two CYP11B1 novel mutations, p.Ala386Glu (exon 7), inherited from the father and p.Leu471Argin (exon 9) from the mother. Hydrocortisone supplementation therapy was initiated. Four years after presentation she remains normotensive, her growth pattern is normal and the bone age remains advanced despite adequate suppression of adrenal androgens. Learning points 11β-hydroxylase (CYP11B1) deficiency (11OHD; OMIM +202010) is the second most common cause of CAH accounting for approximately 5–8% of cases with an incidence of 1:100 000–1:200 000 live births in non-consanguineous populations. Two CYP11B1 inactivating novel mutations, p.Ala386Glu and p.Leu471Arg are reported Regarding newborn females, in utero androgen excess results in ambiguous genitalia, whereas in the male newborn diagnosis may go undetected. In infancy and childhood adrenal androgen overproduction results in peripheral precocious puberty in boys and various degrees of virilization in girls. Accumulation of 11-deoxycorticosterone and its metabolites causes hypertension in about two thirds of patients. Diagnosis lies upon elevated 11-deoxycortisol and DOC plus upstream precursors, such as 17α-hydroxyprogesterone and Δ4-androstenedione. The established treatment of steroid 11β-OHD is similar to that of steroid 21-hydroxylase deficiency and consists of glucocorticoid administration in order to reduce ACTH-driven DOC overproduction resulting in hypertension remission and improvement of the virilization symptoms.

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The degree of external genitalia virilization in girls with 21-hydroxylase deficiency appears to be influenced by the CAG repeats in the androgen receptor gene

Clinical Endocrinology ◽

10.1111/j.1365-2265.2007.03023.x ◽

2007 ◽

Vol 0 (0) ◽

pp. 070907132242006-???

Author(s):

Rosana O. Rocha ◽

Ana Elisa C. Billerbeck ◽

Emília M. Pinto ◽

Karla F. S. Melo ◽

Chin J. Lin ◽

...

Keyword(s):

Androgen Receptor ◽

Receptor Gene ◽

External Genitalia ◽

Androgen Receptor Gene ◽

Cag Repeats ◽

Hydroxylase Deficiency ◽

21 Hydroxylase Deficiency

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So, and if it is not congenital adrenal hyperplasia? Addressing an undiagnosed case of genital ambiguity

10.21203/rs.3.rs-869034/v1 ◽

2021 ◽

Author(s):

Reinaldo Luna de Omena Filho ◽

Reginaldo José Petroli ◽

Fernanda Caroline Soardi ◽

Débora de Paula Michelatto ◽

Taís Nitsch Mazzola ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Treatment Options ◽

External Genitalia ◽

Autosomal Recessive Disorder ◽

Missense Variant ◽

Ambiguous Genitalia ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Genital Ambiguity ◽

21 Hydroxylase Deficiency

Abstract The Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency is the most common cause of genital ambiguity in persons with XX sexual chromosomes. Genital ambiguity among persons with XY sexual chromosomes comprises diverse and rare etiologies. The deficiency of 17-beta-hydroxysteroid dehydrogenase type 3 enzyme (HSD17B3) is a rare autosomal recessive disorder due to functionally altered variants of the HSD17B3 gene. In this disorder/difference of sex development, the conversion of androstenedione into testosterone is impaired. The appearance of external genitalia of 46,XY individuals varies from typically male to almost female. We report on a child presenting severe ambiguous genitalia. Due to access constraints, specialized care did not start until the child was 10 months old. Parents are consanguineous and were born in an area of high isonymy that is a cluster for rare recessive diseases. A new homozygous missense variant c.785G > T was found in exon 10 of the HSD17B3 gene. Researchers-clinicians and researchers-researchers collaborative efforts to elucidate the genetic basis of this disease were critical since this etiologic investigation is not available through the public health system. This case exemplifies the families’ pilgrimage in cases of genital ambiguity due to a rare genetic condition. Recognizing the etiology was the baseline to provide information on prognosis and treatment options, and to shelter family and child doubts and hopes in order to better support their decisions.

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Disorders of Sex Development of Adrenal Origin

Frontiers in Endocrinology ◽

10.3389/fendo.2021.770782 ◽

2021 ◽

Vol 12 ◽

Author(s):

Gabriela P. Finkielstain ◽

Ana Vieites ◽

Ignacio Bergadá ◽

Rodolfo A. Rey

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Disorders Of Sex Development ◽

External Genitalia ◽

Special Focus ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Trophic Effect ◽

Salt Wasting ◽

Sex Development ◽

21 Hydroxylase Deficiency

Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.

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