Non-Classical 21-Hydroxylase Deficiency: Analysis of a Mutant Gene in a Uyghur Family and Literature Review.

OBJECTIVE: The gene mutation and clinical characteristics of a patient with non-classical 21-hydroxylase deficiency and his family were analyzed. METHODS: A patient was diagnosed with non-classical 21-hydroxylase deficiency in the Department of Endocrinology of People's Hospital of Xinjiang Uygur Autonomous Region in December 2016. The clinical data and related gene-sequencing results were analyzed. The detected mutations were verified in nine members of the family. RESULTS: Gene-sequencing results revealed that the proband and the other three members of the family (proband, proband's mother's younger brother and the proband's mother's younger brother's younger daughter, and proband's second elder sister) shared the following mutations: Ile173Asn, Ile237Asn, Val238Glu, Met240Lys, Val282Leu, Leu308Phefs*6, Gln319Ter, Arg357Trp, and Arg484Profs. The Val282Leu mutation was heterozygous in the proband's mother's younger brother's younger daughter, but homozygous in the other three individuals. The father of the proband, the elder brother of the father of the proband, the third younger brother of the father of the proband, and the elder sister of the proband all carried only the Val282Leu mutation. CONCLUSION: Val282Leu is the gene responsible for non-classical 21-hydroxylase deficiency. Screening for this gene in the offspring of patients with non-classical 21-hydroxylase deficiency may help to identify cases early.

Non-classical 21-hydroxylase deficiency of a pedigree and related literature review / 中华内分泌代谢杂志

The clinical data of a patient with non-classical 21-hydroxylase deficiency ( 21-OHD) were retrospectively analyzed. The CYP21A2 gene analysis was performed on the patient and his family members by PCR-DNA direct sequencing. It was found that the proband had a heterozygous mutation [ point mutation:p.Ile173Asn, p. ( Ile237Asn, Val238Glu, Met240Lys ), p. Val282Leu, p. Gln319Ter, p. Arg357Trp, insertion mutation: p.Leu308Phefs?6, deletion/insert mutation: p. Arg484Profs]. Among the members of the family, the patient's eldest sister and three paternal members all carried the p.Val282Leu heterozygous mutation, and the patient's second sister and two maternal members carried the same p. Val282Leu homozygous mutation and other compound heterozygous mutations just as the proband. The proband presented a non-classical phenotype with ultimately normal height and fertility. It is suggested that the potential phenotype of the disease is related to the residual activity of its allele, and there exists a good genotype-phenotype correlation.

Classic and non-classic 21-hydroxylase deficiency can be discriminated from P450 oxidoreductase deficiency in Japanese infants by urinary steroid metabolites.

We previously reported a two-step biochemical diagnosis to discriminate classic 21-hydroxylase deficiency (C21OHD) from P450 oxidoreductase deficiency (PORD) by using urinary steroid metabolites: the pregnanetriolone/tetrahydrocortisone ratio (Ptl / the cortisol metabolites 5α- and 5ß-tetrahydrocortisone (sum of these metabolites termed THEs), and 11ß-hydroxyandrosterone (11OHAn). The objective of this study was to investigate whether both C21OHD and non-classic 21OHD (C+NC21OHD) could be biochemically differentiated from PORD. We recruited 55 infants with C21OHD, 8 with NC21OHD, 16 with PORD, 57 with transient hyper-17α-hydroxyprogesteronemia (TH17OHP), and 2,473 controls. All infants were Japanese with ages between 0-180 d. In addition to Ptl, THEs, and 11OHAn, we measured urinary tetrahydroaldosterone (THAldo) and pregnenediol (PD5). The first step: by Ptl with the age-specific cutoffs 0.06 mg/g creatinine (0-10 d of age) and 0.3 mg/g creatinine (11-180 d of age), we were able to differentiate C+NC21OHD and PORD from TH17OHP and controls (0-10 d of age: 0.065-31 vs. < 0.001-0.052, 11-180 d of age: 0.40-42 vs. < 0.001-0.086) with 100% sensitivity and specificity. The second step: by the 11OHAn/THAldo or 11OHAn/PD5 ratio with a cutoff of 0.80 or 1.0, we were able to discriminate between C+NC21OHD and PORD (1.0-720 vs. 0.021-0.61 or 1.8-160 vs. 0.005-0.32, respectively) with 100% sensitivity and specificity. Ptl, 11OHAn/THAldo, and 11OHAn/PD5 could differentiate between C+NC21OHD and PORD in Japanese infants.

Screening non-classical 21-hydroxylase gene deficiency from patients diagnosed as polycystic ovary syndrome by gene assay / 解放军医学杂志

Objective To screen non-classical 21-hydroxylase deficiency (NC-21OHD) from patients diagnosed as polycystic ovary syndrome (PCOS) by gene assay. Methods Ninety-eight patients with PCOS were enrolled according to 2003 Rotterdam criteria from Department of Endocrinology, Tangdu Hospital of Fourth Military Medical University, and they were divided into three groups according to the modified Ferriman-Gallway (mF-G) score as follows: group A with score 0-2; group B with score 3-5, and group C with score ≥6. Meanwhile, 30 healthy subjects from the Medical Center of the Hospital were recruited as control group. Peripheral blood of all subjects were collected for extracting DNA, the CYP21A2 gene were amplified by 5 pairs of specific primers, and then the PCR products were sequenced by Shanghai Sangon Co. The subjects would accept test for serum cortisol and adrenocorticotropic hormone (ACTH) at 8:00am if their CYP21A2 was proved to be abnormal. Results Thirty subjects of control group had no any defects in CYP21A2, but 5 of 98 patients with PCOS were proved to be deficient in CYP21A2, and the genotypes were V281L/920-921insT (P1), V281L/I230M (P2), V281L/Normal (P3, P4, P5), respectively, and all of them were heterozygous mutations. The incidences of NC-21OHD in group C and B were 28.6% and 3.3%, respectively. Genotype P1 had been identified to belong to NC-21OHD, which was consistent with its clinical phenotype. All genotypes P3, P4 and P5 belonged to carriers. But for P2, since I230M hadn't been reported in literature, the patient with V281L/I230M couldn't be classified now. Serum biochemical results showed that only in P1 the cortisol was close to the normal lower level, and ACTH was close to the normal upper limit of the reported level in the literature, and the remainders were all normal. Conclusions Although PCOS and NC-21OHD are very similar in clinical manifestations, they are different completely in the pathogenesis and treatment. So it is necessary to accurately screen NC-21OHD out from the patients diagnosed as PCOS, especially from those with polytrichosis and mF-G ≥6, in order to avoid wrong diagnosis.