Isolated 17,20-lyase Deficiency

Isolated 17,20-desmolase deficiency is a rare endocrine and autosomal recessive genetic disorder characterized by a complete or partial loss of 17,20-lyase activity, leading to impaired production of androgen and estrogen sex steroids.

This condition results in pseudohermaphroditism (partially or fully underdeveloped genitalia) in males, considered a form of intersex, and in both sexes as a reduced or absent puberty/lack of development of secondary sexual characteristics, leading to a somewhat childlike appearance in adulthood if untreated.

Unlike combined 17α-hydroxylase/17,20-lyase deficiency, isolated 17,20-lyase deficiency does not affect glucocorticoid production or mineralocorticoid levels, and therefore, does not cause adrenal hyperplasia or hypertension.

Symptoms and Signs

The symptoms of isolated 17,20-lyase deficiency in males include pseudohermaphroditism (i.e., feminized, ambiguous, or mildly underdeveloped (e.g., micropenis, perineal hypospadias, and/or cryptorchidism (undescended testes)) external genitalia), female gender identity, and in non-complete cases of deficiency where partial virilization occurs, gynecomastia up to Tanner stage V (due to low androgen levels, resulting in a lack of suppression of estrogen); in females, amenorrhoea or, in cases of only partial deficiency, merely irregular menses, and enlarged-

cystic ovaries (due to excessive stimulation by high levels of gonadotropins); and in both sexes, hypergonadotropic hypogonadism (hypogonadism despite high levels of gonadotropins), delayed, impaired, or fully absent adrenarche and puberty with an associated reduction in or complete lack of development of secondary sexual characteristics (sexual infantilism), impaired fertility or complete sterility, tall stature (due to delayed epiphyseal closure), eunuchoid skeletal proportions, delayed or absent bone maturation, and osteoporosis.

Cause

Isolated 17,20-lyase deficiency is a rare disorder caused by genetic mutations in the CYP17A1 gene, without affecting 17α-hydroxylase. This condition is rare, with only a few confirmed cases due to mutations in the CYP17A1 gene.

Observed physiological abnormalities include significantly elevated serum levels of progestogens such as progesterone and 17α-hydroxyprogesterone (due to upregulation of precursor availability for androgen and estrogen synthesis), very low or absent peripheral concentrations of androgens such as dehydroepiandrosterone (DHEA), androstenedione, and testosterone and estrogens such as estradiol (due to the lack of 17,20-lyase activity, essential for their production), and high serum concentrations of gonadotropins, follicle-stimulating-

hormone (FSH) and luteinizing hormone (LH) (due to a lack of negative feedback because of the absence of sex hormones).

Diagnosis

The diagnosis of Isolated 17,20-lyase deficiency typically involves several steps, including clinical evaluation, biochemical testing, and genetic analysis. Here are the key components of the diagnostic process:

1. Clinical Evaluation

Assessing the patient's symptoms, family history, and any previous medical issues. - Physical Examination: Looking for signs of adrenal insufficiency or abnormal sexual development.

2. Biochemical Testing

Measuring serum levels of steroid hormones, particularly: - Dehydroepiandrosterone (DHEA) - Androstenedione - Cortisol - ACTH Stimulation Test: Evaluating adrenal response to adrenocorticotropic hormone (ACTH) to assess adrenal function.

3. Genetic Testing

Molecular Analysis: Identifying mutations in the CYP17A1 gene, which encodes the 17,20-lyase enzyme. This can confirm the diagnosis.

4. Imaging Studies

In some cases, imaging studies such as ultrasound or MRI may be performed to evaluate adrenal gland morphology.

5. Differential Diagnosis

It is essential to rule out other causes of adrenal insufficiency or disorders of sexual development.

6. Consultation with Specialists

Referral to an endocrinologist for specialized evaluation and management may be necessary. By combining these approaches, healthcare providers can accurately diagnose Isolated 17,20-lyase deficiency and develop an appropriate treatment plan.

Treatment

Males and females may undergo hormone replacement therapy (i.e., with androgens and estrogens, respectively), leading to normal sexual development and alleviating most symptoms. For 46,XY (genetically male) individuals who are phenotypically female and/or identify as female, estrogen treatment is recommended.

In 46,XY females, removal of undescended testes should be performed to prevent malignant degeneration, while in 46,XY males, surgical correction of the genitals is generally necessary, and if needed, an orchidopexy (relocation of undescended testes to the scrotum) may be performed. For genetic females with ovarian cysts, GnRH analogues may be used to manage high FSH and LH levels if unresponsive to estrogens.