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Estimated prevalence at birth has been reported to be 1/147,000 in the Netherlands; the prevalence may be higher elsewhere, especially in populations with high consanguinity.

The clinical presentation is variable. Atypical external genitalia with variable phallic size and posterior labioscrotal fusion are often noticed at birth. Patients with typical female-appearing external genitalia may present with inguinal hernia in childhood. Although some patients, with less severe enzyme defiency, are assigned males at birth, affected individuals are often assigned females at birth. However, at puberty, a portion of these patients develop signs of unusual androgenization (phallic enlargement, male secondary sexual characteristics) as the result of increased testosterone (due to conversion of androstenedione by 17-beta-hydroxysteroid dehydrogenase isoenzymes). Testes can be abdominal, inguinal, or in the labioscrotal folds. The internal urogenital tract is developed to a variable extent, and Müllerian structures are absent. All affected individuals are infertile.

The condition is caused by mutations in the HSD17B3 gene (9q22) encoding an enzyme expressed predominantly in the testes that converts androstenedione to testosterone. The variable clinical phenotype may be related to partial activity of the enzyme or activity of isoenzymes.

Hormonal evaluation demonstrates increased androstenedione and low testosterone levels, with an elevated androstenedione/testosterone ratio. The Sertoli cell markers, serum AMH and inhibin B, are usually in the typical age-related reference range for males. Before puberty, an hCG (human chorionic gonadotropin) stimulation test is often necessary for diagnosis, since basal levels may be uninformative. Therefore, recent consensus statements recommend the molecular genetic analysis of the HSD17B3 gene as a primary diagnostic approach.

The differential diagnosis includes disorders of androgen synthesis such as 5-alpha-reductase 2 deficiency, complete and partial androgen insensitivity syndromes and partial gonadal dysgenesis (caused by NR5A1 mutations for example).

Prenatal diagnosis is available for the kindred of affected patients if causal pathogenic variants have been identified. Atypical fetal genitalia may be seen on prenatal ultrasound.

The condition follows an autosomal recessive inheritance pattern. Parents of an affected individual should be informed that there is a 25% of chance of having an affected child at each pregnancy.

If diagnosed at birth, gender assignment should be discussed openly with the family and an evaluation should be done at a DSD center. Any genital surgery demands a thorough assessment and is restricted in several countries in childhood. Early gonadectomy is unnecessary. Depending on gender identity development, some adolescents may demand a gender change whereas others may request treatment to prevent pubertal androgenization and to induce female puberty.

Life expectancy and overall morbidity (other than related to untreated hormone deficiency) are not altered. The impact on genital development, puberty and adult sexual functioning is usually severe and may require endocrine and/or surgical treatment, as well as psychological counseling.