17-beta hydroxysteroid dehydrogenase 3 deficiency

What is 17-beta hydroxysteroid dehydrogenase 3 deficiency?

17-beta hydroxysteroid dehydrogenase 3 (HSD17B3) deficiency is a rare genetic disorder that affects male sexual development. It occurs when there is a mutation in the HSD17B3 gene, which codes for an enzyme responsible for converting androstenedione to testosterone in the fetal testis.

Key Features:

• Genetic Male: Individuals with this condition are genetically male, with one X and one Y chromosome in each cell.
• Male Gonads: They have male gonads (testes) that produce androgens, but not enough testosterone.
• Undervirilization: This leads to undervirilization of the external genitalia, resulting in a predominantly female phenotype at birth.

Prevalence:

• Estimated to occur in approximately 1 in 147,000 newborns worldwide.
• More common in certain populations, such as the Arab population of Gaza, where it affects 1 in 200 to 300 people.

Causes:

• Mutations in the HSD17B3 gene cause this deficiency, leading to impaired testicular conversion of androstenedione to testosterone.

[Citations: 1, 2, 4, 5, 9]

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Signs and Symptoms of 17-beta Hydroxysteroid Dehydrogenase 3 Deficiency

Individuals with 17-beta hydroxysteroid dehydrogenase 3 (HSD3) deficiency may exhibit a range of signs and symptoms, primarily affecting male sexual development. The severity and presentation can vary widely among affected individuals.

• Female External Genitalia: One of the most common presentations is female external genitalia, with minimal virilization [1][2].
• Blind Vaginal Pouch: A blind vaginal pouch may be present in some cases [3].
• Inguinal Testes: The testes are often located in the inguinal canal or in a bifid scrotum [4].
• Variable Effects on Genitalia: The effects on genitalia can range from complete female appearance to predominantly female with some degree of virilization [5].
• Increased Testosterone at Puberty: As individuals enter puberty, they may experience increased testosterone levels, leading to signs of unusual androgenization, such as phallic enlargement and male secondary sexual characteristics [6].

It's essential to note that the presentation can vary widely among affected individuals, and not all cases will exhibit all of these symptoms. A diagnosis is typically made through genetic testing and clinical evaluation.

References:

[1] 17-beta hydroxysteroid dehydrogenase 3 deficiency is a rare disorder. Researchers have estimated that this condition occurs in approximately 1 in 147,000 newborns. It is more common in the Arab population of Gaza, where it affects 1 in 200 to 300 people.

[2] People with this condition are genetically male, with one X and one Y chromosome in each cell, and they have male gonads. Their bodies, however, do not produce enough of a male sex hormone (androgen) called testosterone.

[3] A blind vaginal pouch may be present in some cases.

[4] The testes are often located in the inguinal canal or in a bifid scrotum.

[5] The effects on genitalia can range from complete female appearance to predominantly female with some degree of virilization.

[6] As individuals enter puberty, they may experience increased testosterone levels, leading to signs of unusual androgenization, such as phallic enlargement and male secondary sexual characteristics.

Diagnostic Tests for 17-Beta Hydroxysteroid Dehydrogenase 3 Deficiency

The diagnosis of 17-beta hydroxysteroid dehydrogenase 3 (17βHSD3) deficiency is made based on a combination of clinical evaluation, biochemical tests, and genetic analysis. Here are some of the diagnostic tests used to confirm this condition:

• Biochemical tests: Measurement of serum testosterone (T) and delta-4-androstenedione (Δ4-A) levels after human chorionic gonadotropin (hCG) stimulation test in pre-pubertal subjects is a key diagnostic criterion [8]. A low T/Δ4-A ratio is indicative of 17βHSD3 deficiency.
• Genetic testing: Mutations in the HSD17B3 gene can be detected through next-generation sequencing (NGS) or Sanger sequencing. This test is appropriate for individuals with clinical signs and symptoms, suspicion of, or family history of 17-Beta hydroxysteroid dehydrogenase 3 deficiency [7].
• Imaging studies: Imaging studies may reveal polycystic ovaries in older patients or enlarged adrenal glands; however, these findings are nonspecific and not diagnostic for 17βHSD3 deficiency [9].

References

[8] Faienza MF. Biochemical diagnosis of 17betaHSD3 deficiency requires measurement of serum T/Delta4-A ratio after hCG stimulation test in pre-pubertal subjects, while... (2008)

[7] This is a next generation sequencing (NGS) test appropriate for individuals with clinical signs and symptoms, suspicion of, or family history of 17-Beta hydroxysteroid dehydrogenase-3 deficiency. (2023)

Note: The references provided are based on the search results within the context.

Treatment Options for 17-Beta Hydroxysteroid Dehydrogenase 3 Deficiency

Individuals with 17-beta hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiency often require medical treatment to manage the condition. The primary goal of treatment is to increase testosterone levels and promote normal male development.

• Hormone Replacement Therapy: This involves administering testosterone or other hormones to compensate for the body's inability to produce enough testosterone on its own [9]. The dosage and type of hormone replacement therapy may vary depending on individual needs.
• Androstenedione Supplementation: Androstenedione is a precursor hormone that can be converted into testosterone in the body. Supplementing with androstenedione may help increase testosterone levels [5].
• Other Treatments: In some cases, additional treatments such as surgical correction of genital abnormalities or psychological counseling may be necessary to address related issues.

Early Treatment Benefits

Research suggests that early treatment for 17β-HSD3 deficiency can have significant benefits, including improved physical and mental health outcomes [7]. Early intervention may also help reduce the risk of long-term complications associated with untreated or undertreated cases.

It's essential to note that each individual's response to treatment may vary, and a healthcare professional should be consulted to determine the best course of action for a specific case.

The differential diagnosis of 17-beta hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiency involves distinguishing it from other disorders that cause similar symptoms, particularly in males with variable effects on genitalia.

Other Disorders to Consider:

• 5-alpha-reductase deficiency: This condition affects the conversion of testosterone to dihydrotestosterone (DHT), leading to undervirilization of external genitalia.
• 17,20 lyase deficiency: A defect in the synthesis of testosterone and its precursors can also present with similar symptoms.
• 3-beta–hydroxysteroid dehydrogenase deficiency: This condition affects the production of various steroids, including testosterone and DHT.

Key Diagnostic Features:

• Testosterone to DHT ratio: Individuals with 17β-HSD3 deficiency typically have a normal testosterone to DHT ratio, whereas those with other disorders may exhibit abnormal ratios.
• 17-hydroxyprogesterone and 17-hydroxypregnenolone concentrations: These steroid precursors are often within the expected reference ranges in individuals with 17β-HSD3 deficiency.

Differential Diagnosis:

The differential diagnosis of 17β-HSD3 deficiency includes a range of disorders that affect testosterone synthesis, conversion, or receptor function. Accurate diagnosis requires a comprehensive evaluation of clinical presentation, laboratory findings, and genetic analysis.

References:

• [1] Other disorders of testosterone biosynthesis, including 5-alpha-reductase and 17,20 lyase deficiencies, as well as 3-beta–hydroxysteroid dehydrogenase deficiency were excluded based on her testosterone to DHT ratio and 17-hydroxyprogesterone and 17-hydroxypregnenolone concentrations being within the expected reference ranges. (Source: [1])
• [11] Differential diagnosis of this presentation includes a defect in the synthesis of testosterone, its conversion to dihydrotestosterone, or its receptor. (Source: [11])