De la Chapelle syndrome

De la Chapelle syndrome in short

• A rare disorder of sex development (DSD) occurring in individuals with a 46,XX karyotype, characterized by male external genitalia that may appear typical or atypical, and is commonly associated with testosterone deficiency.

Synonyms of De la Chapelle syndrome

• 46,XX testicular DSD
• XX, male syndrome
• 46,XX testicular disorder of sex development

Inheritance

Autosomal dominant

Age of onset

• Adolescent
• Antenatal
• Neonatal

Epidemiology – how common is De la Chapelle syndrome?

• The estimated prevalence is 1/20,000 males.

What are the symptoms of De la Chapelle syndrome?

Very frequent symptoms

• Ambiguous genitalia
• Decreased testicular size
• Male hypogonadism
• Polycystic ovaries 

Clinical description

• The clinical presentation is highly variable and may include a range of features such as normal to atypical male external genitalia, undescended testes, absence of Müllerian structures, and infertility.
• The presentation largely depends on the presence or absence of the SRY gene (sex-determining region of the Y chromosome).
• In SRY-positive individuals (accounting for 80–90% of cases), the phenotype typically resembles that of otherwise normal males who present after puberty with short stature, normal pubic hair and penile development, but small testes, gynecomastia, and azoospermia-related infertility.
• Undescended testes and hypospadias may also occur. Gender identity and gender role are generally not areas of concern. In contrast, SRY-negative individuals (10–20% of cases) usually present at birth with features such as penoscrotal hypospadias and undescended testes.
• Long-term complications from male hypogonadism may include low libido, erectile dysfunction, reduced secondary sexual characteristics, osteopenia, and depression.

What causes this condition?

• In the majority of cases, the condition results from the translocation of a small fragment of the Y chromosome—containing the SRY gene—onto the X chromosome or another chromosome.
• In SRY-negative individuals, copy number variations involving regulatory genes such as SOX3 and SOX9, as well as a common recurrent variant in the NR5A1 gene, have been identified as potential causes.

Differential diagnosis

The main differential diagnoses are

• 45,X/46,XY mixed gonadal dysgenesis
• 47,XXY Klinefelter syndrome
• 46,XX ovotesticular
• DSD and sex chromosome mosaicisms

NR2F2 gene variants have been described in individuals with a 46,XX testicular / ovotesticular DSD phenotype associated with cardiac defects, some with congenital diaphramatic hernia and blepharophimosis-ptosis-epicanthis inversus.

Rarely, others include

• Palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (caused by biallelic RSPO1 gene variants)
• SERKAL syndrome (recessive WNT4 variants)
• Microphthalmia with linear skin defects (MIDAS) syndrome

How is De la Chapelle syndrome diagnosed?

• Diagnosis is established through a combination of clinical evaluation and laboratory testing. Endocrine studies typically reveal hypergonadotropic hypogonadism, while cytogenetic or molecular analysis, such as SNP array, confirms the presence of a 46,XX karyotype.
• The presence of the SRY gene can be identified using fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) techniques.

Antenatal diagnosis

• If there is a possibility of identifying the underlying genetic cause of De la Chapelle syndrome, then Prenatal testing in pregnancies would be greatly helpful.

Genetic counseling

• Genetic counseling is recommended for affected individuals and their families.
• The risk of recurrence varies based on the underlying genetic alteration.
• SRY-positive cases are typically not inherited, as they are usually associated with infertility.
• In SRY-negative cases, the inheritance pattern depends on the specific genetic cause, if identified.

Management and treatment – how is this condition treated?

• The primary treatment approach involves testosterone replacement therapy to address hormonal imbalances, prevent gynecomastia, and promote the development of male secondary sexual characteristics.
• Hypergonadotropic hypogonadism typically does not manifest until adulthood.
• In some cases, reduction mammoplasty may be appropriate.
• Psychological support should be provided, along with timely referral to assisted reproductive services when needed.

What is the prognosis of De la Chapelle syndrome?

• Effective management of male hypogonadism helps minimize associated complications.
• Most affected individuals are infertile, and the risk of tumor development is considered low.