Leydig cell hypoplasia

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Leydig cell hypoplasia is a condition that affects male sexual development. It is characterized by underdevelopment (hypoplasia) of Leydig cells in the testes. Leydig cells secrete male sex hormones (androgens) that are important for normal male sexual development before birth and during puberty.

In Leydig cell hypoplasia, affected individuals with a typical male chromosomal pattern (46,XY) may have a range of genital abnormalities. Affected males may have a small penis (micropenis), the opening of the urethra on the underside of the penis (hypospadias), or a scrotum divided into two lobes (bifid scrotum). Because of these abnormalities, the external genitalia may not look clearly male or clearly female.

In more severe cases of Leydig cell hypoplasia, people with a typical male chromosomal pattern (46,XY) have female external genitalia. They have small testes that are undescended, which means they are abnormally located in the pelvis, abdomen, or groin. People with this form of the disorder do not develop secondary sex characteristics, such as increased body hair, at puberty. Some researchers refer to this form of Leydig cell hypoplasia as type 1 and designate less severe cases as type 2.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the LHCGR gene cause Leydig cell hypoplasia. The LHCGR gene provides instructions for making a protein called the luteinizing hormone/chorionic gonadotropin receptor. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function.

The protein produced from the LHCGR gene acts as a receptor for two ligands: luteinizing hormone and a similar hormone called chorionic gonadotropin. The receptor allows the body to respond appropriately to these hormones. In males, chorionic gonadotropin stimulates the development of cells in the testes called Leydig cells, and luteinizing hormone triggers these cells to produce androgens. Androgens, including testosterone, are the hormones that control male sexual development and reproduction. In females, luteinizing hormone triggers the release of egg cells from the ovary (ovulation). Chorionic gonadotropin is produced during pregnancy and helps maintain conditions necessary for the pregnancy to continue.

The LHCGR gene mutations that cause Leydig cell hypoplasia disrupt luteinizing hormone/chorionic gonadotropin receptor function, impeding the body's ability to react to these hormones. In males, the mutations result in poorly developed or absent Leydig cells and impaired production of testosterone. A lack of testosterone interferes with the development of male reproductive organs before birth and the changes that appear at puberty. Mutations that prevent the production of any functional receptor protein cause the more severe features of Leydig cell hypoplasia, and mutations that allow some receptor protein function cause milder signs and symptoms.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Only people who have mutations in both copies of the LHCGR gene and are genetically male (with one X and one Y chromosome in each cell) have the characteristic signs of Leydig cell hypoplasia. Although people who are genetically female (with two X chromosomes in each cell) may inherit mutations in both copies of the LHCGR gene, they do not have Leydig cell hypoplasia because they do not have Leydig cells. They have normal female genitalia and normal breast and pubic hair development, but they may begin menstruation later than usual (after age 16) and have irregular menstrual periods. LHCGR gene mutations in females also prevent ovulation, leading to inability to have children (infertility).

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Leydig cell hypoplasia is a rare disorder; its prevalence is unknown.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal external genitalia · Very frequent (99-80%)

A structural anomaly of the external genitalia.

Abnormal internal genitalia · Very frequent (99-80%)

An anomaly of the adnexa, uterus, and vagina (in female) or seminal tract and prostate (in male).

Absence of secondary sex characteristics · Very frequent (99-80%)

No secondary sexual characteristics are present at puberty.

Ambiguous genitalia · Very frequent (99-80%)

A genital phenotype that is not clearly assignable to a single gender. Ambiguous genitalia can be evaluated using the Prader scale: Prader 0: Normal female external genitalia. Prader 1: Female external genitalia with clitoromegaly. Prader 2: Clitoromegaly with partial labial fusion forming a funnel-shaped urogenital sinus. Prader 3: Increased phallic enlargement. Complete labioscrotal fusion forming a urogenital sinus with a single opening. Prader 4: Complete scrotal fusion with urogenital opening at the base or on the shaft of the phallus. Prader 5: Normal male external genitalia. The diagnosis of ambiguous genitalia is made for Prader 1-4.

Aplasia of the uterus · Very frequent (99-80%)

A congenital defect characterized by absence of the uterus. Aplasia refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue.

Breast aplasia · Very frequent (99-80%)

Failure to develop and congenital absence of the breast.

Cryptorchidism · Very frequent (99-80%)

Testis in inguinal canal. That is, absence of one or both testes from the scrotum owing to failure of the testis or testes to descend through the inguinal canal to the scrotum.

Delayed skeletal maturation · Very frequent (99-80%)

A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.

Other findings in the same source

From: Orphanet

Additional reported features include Female hypogonadism (Very frequent (99-80%)); Hyoplasia of the Leydig cells (Very frequent (99-80%)); Hypergonadotropic hypogonadism (Very frequent (99-80%)); Hypospadias (Very frequent (99-80%)); Increased circulating gonadotropin level (Very frequent (99-80%)); Male hypogonadism (Very frequent (99-80%)); Male pseudohermaphroditism (Very frequent (99-80%)); Micropenis (Very frequent (99-80%)); Phenotypic abnormality (Very frequent (99-80%)); Decreased serum testosterone concentration (Very frequent (99-80%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Leydig cell hypoplasia is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Leydig cell hypoplasia. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.