Weintrob N, Brautbar C, Pertzelan A, Josefsberg Z, Dickerman Z, Kauschansky A, Lilos P, Peled D, Phillip M, Israel S
Institute for Endocrinology and Diabetes, Schneider Children's Medical Center of Israel, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Eur J Endocrinol. 2000 Sep;143(3):397-403. doi: 10.1530/eje.0.1430397.
To evaluate whether genotype differences can explain the clinical variability of non-classical steroid 21-hydroxylase deficiency (NC21-OHD) and to determine if genotype is related to ethnic origin.
Genotyping for mutations in the steroid 21-hydroxylase (CYP21) gene was performed in 45 unrelated Israeli Jewish patients (nine males) with NC21-OHD (60min 17-hydroxyprogesterone (17-OHP), 45-386nmol/l) who were referred for evaluation of postnatal virilization or true precocious/early puberty. Eleven siblings diagnosed through family screening were genotyped as well.
Patients were divided by genotype into three groups: (A) homozygous or compound heterozygous for the mild mutations (V281L or P30L) (n=29; eight males); (B) compound heterozygous for one mild and one severe mutation (Q318X, I2 splice, I172N) (n=12; no males); (C) mild mutation detected on one allele only (n=4; one male; peak 17-OHP 58-151nmol/l). We then related the genotype to the ethnic origin, clinical phenotype and hormone level. Since group C was very small, comparisons were made between groups A and B only.
At diagnosis, group B tended to be younger (5. 8+/-3.0 vs 8.1+/-4.3 years, P=0.09), had greater height SDS adjusted for mid-parental height SDS (1.6+/-1.1 vs 0.7+/-1.4, P=0.034), tended to have more advanced bone age SDS (2.9+/-1.5 vs 1.7+/-2.1, P=0.10) and had a higher peak 17-OHP level in response to ACTH stimulation (226+/-92 vs 126+/-62nmol/l, P<0.01). Group B also had pubarche and gonadarche at an earlier age (5.1+/-2.4 vs 7.4+/-2.2 years, P<0.01 and 7.4+/-1.8 vs 9.9+/-1.4 years, P<0.001, respectively) and a higher rate of precocious puberty (50 vs 17%, P=0.04). Stepwise logistic regression analysis (excluding males) yielded age at gonadarche as the most significant variable differentiating the two groups, with a positive predictive value of 86% for a cut-off of 7.5 years.
The findings suggest that genotype might explain some of the variability in the phenotypic expression of NC21-OHD. Compound heterozygotes for one mild and one severe mutation have a higher peak 17-OHP associated with pubarche and gonadarche at an earlier age and more frequent precocious puberty. Hence, the severity of the enzymatic defect might determine the timing and pattern of puberty.
评估基因型差异是否能解释非经典型类固醇21-羟化酶缺乏症（NC21-OHD）的临床变异性，并确定基因型是否与种族起源相关。
对45例无亲缘关系的以色列犹太患者（9例男性）进行类固醇21-羟化酶（CYP21）基因突变基因分型，这些患者患有NC21-OHD（60分钟17-羟孕酮（17-OHP），45 - 386nmol/L），因产后男性化或真性性早熟/青春期提前前来评估。通过家族筛查确诊的11名同胞也进行了基因分型。
患者按基因型分为三组：（A）轻度突变（V281L或P30L）的纯合子或复合杂合子（n = 29；8例男性）；（B）一个轻度和一个重度突变（Q318X、I2剪接、I172N）的复合杂合子（n = 12；无男性）；（C）仅在一个等位基因上检测到轻度突变（n = 4；1例男性；峰值17-OHP 58 - 151nmol/L）。然后将基因型与种族起源、临床表型和激素水平相关联。由于C组非常小，仅在A组和B组之间进行比较。
诊断时，B组往往年龄更小（5.8±3.0岁对8.1±4.3岁，P = 0.09），根据父母身高标准差调整后的身高标准差更高（1.6±1.1对0.7±1.4，P = 0.034），骨龄标准差往往更超前（2.9±1.5对1.7±2.1，P = 0.10），对促肾上腺皮质激素刺激的峰值17-OHP水平更高（226±92对126±62nmol/L，P<0.01）。B组青春期阴毛发育和性腺发育也更早（分别为5.1±2.4岁对7.4±2.2岁，P<0.01和7.4±1.8岁对9.9±1.4岁，P<0.001），性早熟发生率更高（50%对17%，P = 0.04）。逐步逻辑回归分析（不包括男性）得出性腺发育年龄是区分两组的最显著变量，以7.5岁为临界值时阳性预测值为86%。
研究结果表明基因型可能解释NC21-OHD表型表达的一些变异性。一个轻度和一个重度突变的复合杂合子具有更高的峰值17-OHP，与更早的青春期阴毛发育和性腺发育以及更频繁的性早熟相关。因此，酶缺陷的严重程度可能决定青春期的时间和模式。
