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17-beta-HSD deficiency
This deficiency can lead to underdeveloped external male genitals at birth, and individuals often experience virilisation (development of male secondary sexual characteristics) during puberty. It is an inherited condition caused by changes in the HSD17B3 gene.
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Overview
17-beta-HSD deficiency is a rare inherited condition that disrupts the body's ability to produce specific male sex hormones, known as androgens, effectively. Specifically, it affects the conversion of a less active androgen, androstenedione, into a more potent androgen, testosterone. This conversion is crucial for the development of male characteristics both before birth and during puberty [PMID:33671239].
The condition predominantly affects individuals who are genetically male (meaning they have XY chromosomes). Due to reduced testosterone production during foetal development, external male genitalia may not develop fully. This can lead to a variety of presentations at birth, ranging from female-like external genitalia to ambiguous genitalia, where it is not clear if the baby is male or female. Despite the external appearance, internal male reproductive organs, such as testes, are typically present [PMID:24606775].
Symptoms & clinical features
The symptoms of 17-beta-HSD deficiency primarily affect individuals with XY chromosomes. At birth, the most common symptom is the presence of ambiguous external genitalia or external genitalia that appear female. This happens because the foetal testes produce a normal amount of androstenedione but cannot convert it effectively into testosterone, which is required for the development of typical male external genitalia [PMID:33671239].
During puberty, affected individuals often experience virilisation. This means they develop secondary male sexual characteristics, such as an enlarged penis (if present), increased muscle mass, a deepened voice, and the development of pubic and axillary hair. This occurs because the accumulating androstenedione can be converted into testosterone by other enzymes in the body, particularly in peripheral tissues, which become more active at puberty. This can lead to a spontaneous masculinisation during adolescence, regardless of earlier sex assignment [PMID:24606775]. Puberty can be affected by the timing of diagnosis and medical management.
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Affected organs
The primary organs affected in 17-beta-HSD deficiency are the reproductive organs, specifically the testes and external genitalia. In individuals with XY chromosomes, the testes are typically present and functional in terms of producing other hormones, but the crucial conversion of androstenedione to testosterone is impaired within these glands. The external genitalia are directly affected by the reduced testosterone levels during foetal development, leading to their atypical development.
While the deficiency directly impacts sex hormone production, it does not typically cause problems in other organ systems. The internal reproductive structures, such as the Wolffian ducts, which develop into the epididymis, vas deferens, and seminal vesicles, usually form correctly due to normal anti-Müllerian hormone (AMH) production by the testes.
Risks & severity
The severity of 17-beta-HSD deficiency can vary, influencing the degree of atypical genital development at birth and the extent of virilisation at puberty. Some individuals may have external genitalia that are mostly female in appearance, while others may have more ambiguous features. The condition is associated with a lifelong impact on sexual development and identity, especially if not diagnosed early. There are no known direct risks to general health or life expectancy associated with this condition itself, beyond complexities related to sexual development and potential gender identity issues.
As the condition is rare, the exact prevalence in the UK is not well established. The age of onset for noticeable symptoms is typically at birth, with the presentation of ambiguous or female-appearing external genitalia in individuals with XY chromosomes. A second phase of symptom presentation, virilisation, generally occurs during puberty, usually between 10 and 14 years of age, when the body attempts to compensate for the enzyme deficiency.
Genetic causes
17-beta-HSD deficiency is caused by pathogenic variants in the HSD17B3 gene. This gene provides instructions for making an enzyme called hydroxysteroid 17-beta dehydrogenase 3. This enzyme plays a crucial role in the biosynthesis of sex hormones, particularly in the testes.
Specifically, the HSD17B3 enzyme is responsible for converting androstenedione, a precursor androgen, into testosterone, the primary male sex hormone. When there are pathogenic changes in the HSD17B3 gene, the enzyme either does not work correctly or is not produced in sufficient amounts. This leads to a build-up of androstenedione and a significant reduction in testosterone production within the testes [PMID:24606775]. The lack of testosterone during critical developmental stages results in the characteristic features of 17-beta-HSD deficiency.
- HSD17B3 hydroxysteroid 17-beta dehydrogenase 3
Inheritance pattern
17-beta-HSD deficiency follows an autosomal recessive inheritance pattern. This means that an individual must inherit two altered copies of the HSD17B3 gene-one from each parent-to develop the condition.
Someone who inherits only one altered copy of the HSD17B3 gene is called a 'carrier'. Carriers typically do not show any symptoms of the condition because their single working copy of the gene is sufficient. If two carriers have children together, there is a 25% chance with each pregnancy that their child will inherit two altered copies and thus be affected by the condition, a 50% chance the child will be a carrier, and a 25% chance the child will inherit two working copies of the gene and will not be affected or be a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of 17-beta-HSD deficiency is typically made based on clinical presentation, especially ambiguous genitalia at birth in an individual with XY chromosomes, combined with specific hormone test results. Blood tests usually show high levels of androstenedione and significantly lower levels of testosterone, particularly after stimulation tests designed to assess hormone production [PMID:33671239]. Levels of Follice-Stimulating Hormone (FSH) and Luteinising Hormone (LH) may also be elevated.
Confirmation of the diagnosis involves genetic testing to identify pathogenic variants in the HSD17B3 gene. In the UK, such genetic testing is typically accessed through the NHS Genomic Medicine Service (GMS). Referral for genetic testing would usually come from a paediatric endocrinologist or a clinical genetics specialist, often after initial endocrine investigations. The relevant R-codes for testing related to disorders of sex development would be used to guide the diagnostic pathway.
Management & lifestyle
Individuals with 17-beta-HSD deficiency require lifelong management coordinated by a multi-disciplinary team, including endocrinologists, urologists, psychologists, and genetic counsellors. The initial management decision often involves gender assignment, which requires careful consideration, particularly given the potential for spontaneous virilisation at puberty [PMID:24606775]. Discussions with families should address the long-term implications of various choices.
If raised as female, puberty may involve surgical intervention to address virilising effects and hormone replacement therapy (oestrogen) to induce female secondary sexual characteristics. If raised as male, testosterone therapy may be initiated to promote male pubertal development. Genetic counselling is vital for affected individuals and their families to understand the condition, its inheritance, and reproductive options. Regular follow-up appointments with specialist teams are essential to monitor hormone levels and address any physical or psychological needs as the individual develops.
UK care pathway
In the UK, individuals suspected of having conditions like 17-beta-HSD deficiency would typically enter the NHS Genomic Medicine Service (GMS) pathway. Initial assessment often involves paediatricians or endocrinologists who would then refer to a clinical genetics service or specialist endocrine teams. Genetic testing is available through the GMS; specific R-codes would be used for molecular genetic analysis of genes associated with disorders of sex development. Genetic counsellors play a key role in explaining the genetic diagnosis, inheritance patterns, and providing support and information to families.
Frequently asked questions
What does 'autosomal recessive' mean for my family?
Autosomal recessive means that both biological parents must be carriers of a change in the HSD17B3 gene for a child to inherit 17-beta-HSD deficiency. If you are a carrier, you have one working copy and one altered copy of the gene, but typically show no symptoms. With each pregnancy, if both parents are carriers, there is a 1 in 4 chance the child will be affected.
Can 17-beta-HSD deficiency affect individuals with XX chromosomes?
No, 17-beta-HSD deficiency specifically impacts the production of testosterone, which is critical for male sexual development. Therefore, it primarily affects individuals with XY chromosomes. Individuals with XX chromosomes are not typically affected by this condition.
What kind of medical specialists will be involved in my child's care?
Your child's care will likely involve a team of specialists. This typically includes a paediatric endocrinologist (hormone specialist), a urologist, a clinical geneticist, and a genetic counsellor. They will work together to manage the condition and provide support.
Is there a cure for 17-beta-HSD deficiency?
There isn't a 'cure' in the sense of correcting the genetic change. However, the condition is manageable through hormone therapy and, sometimes, surgical interventions. These treatments aim to align an individual's physical characteristics with their gender identity and support healthy development, but they do not alter the underlying genetic cause.
Will my child be able to have children when they are older?
Fertility can be complex for individuals with 17-beta-HSD deficiency and often requires individual assessment. While their testes are typically present, sperm production may be affected due to the hormonal imbalance. This is a topic that can be discussed in more detail with their endocrinologist and fertility specialists as they get older.
References
- Andersson S, Moghrabi N. Physiology and molecular genetics of 17 beta-hydroxysteroid dehydrogenases. Steroids. 1997. PMID: 9029729
- Zhu YS, Katz MD, Imperato-McGinley J. Natural potent androgens: lessons from human genetic models. Bailliere's clinical endocrinology and metabolism. 1998. PMID: 9890063
- Gross DJ, Landau H, Kohn G. Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency: gender reassignment in early infancy. Acta endocrinologica. 1986. PMID: 3017038
- Andersson S. Molecular genetics of androgenic 17 beta-hydroxysteroid dehydrogenases. The Journal of steroid biochemistry and molecular biology. 1995. PMID: 8547178
- Rösler A, Bélanger A, Labrie F. Mechanisms of androgen production in male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency. The Journal of clinical endocrinology and metabolism. 1992. PMID: 1325474
- Wilson SC, Hodgins MB, Scott JS. Incomplete masculinization due to a deficiency of 17 beta-hydroxysteroid dehydrogenase: comparison of prepubertal and peripubertal siblings. Clinical endocrinology. 1987. PMID: 2820622
- Luu-The V, Labrie C, Simard J. Structure of two in tandem human 17 beta-hydroxysteroid dehydrogenase genes. Molecular endocrinology (Baltimore, Md.). 1990. PMID: 2330005
- Rösler A, Kohn G. Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase deficiency: studies on the natural history of the defect and effect of androgens on gender role. Journal of steroid biochemistry. 1983. PMID: 6310248