A New Mutation of 5-Alpha-Reductase Type 2 (A62E) in a Large Egyptian Kindred

Hafez, Mona; Mazen, Inas; Ghali, Isis; Sultan, Charles; Lumbroso, Serge

doi:10.1159/000070626

Cited by 18 publications

(11 citation statements)

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“…Differential diagnosis of 5a-reductase deficiency with PAIS is difficult since the clinical signs and biological parameters are similar. In most but not all patients, low plasma DHT levels and an elevated plasma T ⁄ DHT ratio after hCG stimulation testing is observed (Imperato-McGinley et al, 1986;Boudon et al, 1995a,b;Hafez et al, 2003;Mazen et al, 2003a). However, as we reported previously (Boudon et al, 1995a,b;Mazen et al, 2003b), SRD5A2 mutations have been identified in patients with a non-significant increase in plasma T ⁄ DHT.…”

Section: Introductionsupporting

confidence: 68%

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Undervirilization in XY newborns may hide a 5α‐reductase deficiency: report of three new SRD5A2 gene mutations

et al. 2010

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The observation of ambiguous genitalia in the newborn signals a medical, surgical and psychological emergency. The most crucial decision will be the choice of sex assignment. Rapid and precise diagnosis is thus essential. In XY newborns with normal/high plasma testosterone (T), partial androgen insensitivity syndrome (PAIS) is usually the first diagnosis evoked, which implies an androgen receptor (AR) defect. The diagnosis of steroid-5-alpha-reductase deficiency is rarely considered by the paediatrician. We report three new SRD5A2 gene mutations in four newborns from France, Morocco and Turkey. The newborns presented with ambiguous genitalia and normal plasma T values and the initial diagnosis\PAIS. In all four cases, normal sequences of the complete AR gene excluded this diagnosis and raised the hypothesis of 5α-reductase deficiency. The entire coding region (5 exons) of the SRD5A2 gene was assessed by PCR and direct sequencing analysis. For patient 1, we identified a new homozygous 2bp deletion in exon 1 (c.122_123delAG). Patient 2 had a known homozygous mutation, p.G115D, in exon 2. New compound heterozygous mutations in exon 4 (p.A215V) and exon 5 (p.X255Q) were found in patient 3. Patient 4 presented a new substitution in exon 1 (p.S14R) associated with a known polymorphism (p.V89L). Our data confirm our previous experience and clearly demonstrate that a 5-α reductase defect should be considered in all XY newborns with ambiguous genitalia and normal plasma T secretion, whatever their geographic area or ethnic group; moreover, this defect was not linked to specific phenotype. Early molecular diagnosis is indispensable for the crucial decision of the newborn's sex of rearing.

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Section: Introductionsupporting

confidence: 68%

“…, 1993). Various authors have suggested that SRD5A2 gene mutations can be separated into two broad categories, including recurrent mutations, as they have been identified in various ethnic groups or reflect a founder gene effect (Hafez et al. , 2003; Skordis et al.…”

Section: Discussionmentioning

confidence: 99%

Undervirilization in XY newborns may hide a 5α‐reductase deficiency: report of three new SRD5A2 gene mutations

et al. 2010

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“…Mutations in the SRD5A2 gene lead to a reduction in enzymatic activity and DHT production [6], causing defective masculinization in the forms of hypospadia and microphallus [7,8]. To date, more than 50 different mutations have been reported in patients with 5α-reductase type 2 deficiency, and missense and nonsense mutations were frequently reported [4,9,10,11,12,13]. …”

Section: Introductionmentioning

confidence: 99%

A Novel SRD5A2 Mutation with Loss of Function Identified in Chinese Patients with Hypospadias

et al. 2011

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Objective: To investigate the functional change of SRD5A2 gene mutations identified in patients with 5α-reductase type 2 deficiency. Patients and Methods: Three unrelated subjects born with ambiguous genitalia were included. All patients were initially reared as girls, but they gradually exhibited variable degrees of virilization at puberty without breast development, followed by a change of gender role. Sequencing analysis of the SRD5A2 gene was performed and enzymatic activities of 5α-reductase type 2 were assessed. Results: Three compound heterozygous mutations in the SRD5A2 gene were identified: patient 1 with p.G203S/ c.655delT, patient 2 with p.Q6X/p.G203S, and patient 3 with p.G203S/c.755_756insT. Heterozygosity for the p.V89L polymorphism was also found in patients 2 and 3. The c.655delT mutation led to a complete loss of the enzymatic activity, whereas mutants p.G203S and c.755_756insT resulted in a reduction of the enzymatic activities by 60 and 90%, respectively. Conclusion: Two frameshift heterozygous mutations, c.655delT and c.755_756insT, led to a dramatic reduction in 5α-reductase activity, and the latter had not been reported previously. In addition, the heterozygous mutation (p.G203) identified in the 3 patients presumably suggests a founder effect in the Chinese population and may explain the similarity in phenotype among the patients.

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“…The primordial role of 5α-reductase enzyme activity was first demonstrated in animal studies, until a cluster of male pseudohermaphrodite patients, in whom deficient virilisation was attributable to an almost complete lack of this enzyme activity, was described [1, 2]. A number of deletions and point mutations in the SRD5A2 gene, which encodes the 5α-reductase type 2 enzyme [3], had been demonstrated in patients with variable clinical and biochemical phenotypes [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]. This variability may depend on the patient’s age at the time of the study, availability of testicular androgen production studies, of genital skin for enzyme activity determination in fresh tissue or in its cultured fibroblasts and on the effects of the different mutations on protein synthesis and function.…”

Section: Introductionmentioning

confidence: 99%

Clinical, Biochemical and Morphologic Diagnostic Markers in an Infant Male Pseudohermaphrodite Patient with Compound Heterozygous Mutations (G115D/R246W) in SRD5A2 Gene

et al. 2004

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A patient with male pseudohermaphroditism and clinical diagnosis of partial androgen insensitivity in the neonatal period was studied at pubertal age for a molecular diagnosis. Hormone studies were conducted at baseline and under hCG stimulation for testosterone and dihydrotestosterone determinations at 2 months of age. Gonadectomy was performed at 4 months. At the age of 13 years genital skin fibroblasts were studied for androgen binding and 5α-reductase activity and peripheral blood DNA was available for androgen receptor (AR) and 5α-reductase (SRD5A2) gene analysis. Exons 1–8 of AR gene and exons 1–5 of SRD5A2 gene were sequenced. AR gene coding sequences were normal. SRD5A2 gene analysis revealed two heterozygote mutations (G115D and R246W), with the mother carrying the G115D and the father the R246W mutations. The compound heterozygote mutations in SRD5A2 gene explained an extremely low 5α-reductase enzyme activity in genital skin fibroblasts. Revision of hormonal data from the neonatal period revealed an increased testosterone-to-dihydrotestosterone ratio at the end of an hCG stimulation test, which concurred with the molecular diagnosis. Testis morphology at 4 months of age was normal. Clinical and biochemical differential diagnosis between partial androgen insensitivity syndrome and 5α-reductase enzyme deficiency is difficult in the neonatal period and before puberty. Our results show that in our patient the testosterone-to-dihydrotestosterone ratio would have adequately orientated the diagnosis. The two mutations in SRD5A2 gene have been described in patients of different lineages, though not in combination to date. Testis morphology showed that, during early infancy, the 5α-reductase deficiency may not have affected interstitial or tubular development.

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A New Mutation of 5-Alpha-Reductase Type 2 (A62E) in a Large Egyptian Kindred

Cited by 18 publications

References 8 publications

Undervirilization in XY newborns may hide a 5α‐reductase deficiency: report of three new SRD5A2 gene mutations

Undervirilization in XY newborns may hide a 5α‐reductase deficiency: report of three new SRD5A2 gene mutations

A Novel SRD5A2 Mutation with Loss of Function Identified in Chinese Patients with Hypospadias

Clinical, Biochemical and Morphologic Diagnostic Markers in an Infant Male Pseudohermaphrodite Patient with Compound Heterozygous Mutations (G115D/R246W) in SRD5A2 Gene

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