Bouchoucha Nadia, Samara-Boustani Dinane, Pandey Amit V, Bony-Trifunovic Helene, Hofer Gaby, Aigrain Yves, Polak Michel, Flück Christa E
Pediatric Endocrinology and Diabetology, University Children's Hospital, Bern, Switzerland; Department of Clinical Research, University of Bern, Bern, Switzerland.
Pediatric Endocrinology, Gynecology and Diabetology, Hôpital Universitaire Necker Enfants Malades, Centre des maladies endocriniennes rares de la croissance et des pathologies gynecologiques rares, IMAGINE affiliate, Université Paris Descartes, Paris, France.
Mol Cell Endocrinol. 2014 Jun 5;390(1-2):8-17. doi: 10.1016/j.mce.2014.03.008. Epub 2014 Apr 4.
P450 aromatase (CYP19A1) is essential for the biosynthesis of estrogens from androgen precursors. Mutations in the coding region of CYP19A1 lead to autosomal recessive aromatase deficiency. To date over 20 subjects have been reported with aromatase deficiency which may manifest during fetal life with maternal virilization and virilization of the external genitalia of a female fetus due to low aromatase activity in the steroid metabolizing fetal-placental unit and thus high androgen levels. During infancy, girls often have ovarian cysts and thereafter fail to enter puberty showing signs of variable degree of androgen excess. Moreover, impact on growth, skeletal maturation and other metabolic parameters is seen in both sexes.
We found a novel homozygous CYP19A1 mutation in a 46,XX girl who was born at term to consanguineous parents. Although the mother did not virilize during pregnancy, the baby was found to have a complex genital anomaly at birth (enlarged genital tubercle, fusion of labioscrotal folds) with elevated androgens at birth, normalizing thereafter. Presence of 46,XX karyotype and female internal genital organs (uterus, vagina) together with biochemical findings and follow-up showing regression of clitoral hypertrophy, as well as elevated FSH suggested aromatase deficiency. Interestingly, her older brother presented with mild hypospadias and bilateral cryptorchidism and was found to carry the same homozygous CYP19A1 mutation. To confirm the clinical diagnosis, genetic, functional and computational studies were performed.
Genetic analysis revealed a homozygous R192H mutation in the CYP19A1 gene. This novel mutation was characterized for its enzymatic activity (Km, Vmax) in a cell model and found to have markedly reduced catalytic activity when compared to wild-type aromatase; thus explaining the phenotype. Computational studies suggest that R192H disrupts the substrate access channel in CYP19A1 that may affect binding of substrates and exit of catalytic products.
R192H is a novel CYP19A1 mutation which causes a severe phenotype of aromatase deficiency in a 46,XX newborn and maybe hypospadias and cryptorchidism in a 46,XY, but no maternal androgen excess during pregnancy.
细胞色素P450芳香化酶（CYP19A1）对于雄激素前体生物合成雌激素至关重要。CYP19A1编码区的突变会导致常染色体隐性芳香化酶缺乏症。迄今为止，已报道20余例芳香化酶缺乏症患者，其可能在胎儿期表现为母体男性化以及女性胎儿外生殖器男性化，这是由于类固醇代谢胎儿 - 胎盘单位中芳香化酶活性低，从而雄激素水平高所致。在婴儿期，女孩常出现卵巢囊肿，之后无法进入青春期，表现出不同程度雄激素过多的迹象。此外，在两性中均可见对生长、骨骼成熟和其他代谢参数的影响。
我们在一名足月出生、父母为近亲的46,XX女孩中发现了一种新的纯合CYP19A1突变。尽管母亲在孕期未出现男性化，但婴儿出生时被发现有复杂的生殖器异常（生殖器结节增大、阴唇阴囊褶融合），出生时雄激素水平升高，之后恢复正常。46,XX核型以及女性内生殖器（子宫、阴道）的存在，连同生化检查结果和随访显示阴蒂肥大消退以及促卵泡生成素升高，提示芳香化酶缺乏症。有趣的是，她的哥哥患有轻度尿道下裂和双侧隐睾症，并且被发现携带相同的纯合CYP19A1突变。为了确诊临床诊断，进行了基因、功能和计算研究。
基因分析揭示了CYP19A1基因中的一个纯合R192H突变。在细胞模型中对这个新突变的酶活性（Km、Vmax）进行了表征，发现与野生型芳香化酶相比，其催化活性明显降低；从而解释了该表型。计算研究表明，R192H破坏了CYP19A1中的底物进入通道，这可能会影响底物的结合和催化产物的排出。
R192H是一种新的CYP19A1突变，它在一名46,XX新生儿中导致了严重的芳香化酶缺乏症表型，在46,XY个体中可能导致尿道下裂和隐睾症，但孕期母亲无雄激素过多情况。
