Wilson–Turner syndrome

Rare X-linked genetic disorder with intellectual disability and obesity

Wilson–Turner syndrome
Synonyms	Mental retardation X-linked syndromic 6 (MRXS6), Mental retardation X-linked with gynecomastia and obesity
Pronounce	N/A
Specialty	N/A
Symptoms	Intellectual disability, obesity, gynecomastia, hypogonadism, dysmorphic facial features
Complications	Psychological distress, obesity-related complications, social and developmental issues
Onset	Childhood
Duration	Lifelong
Types	None identified
Causes	Mutation in the HDAC8 gene on chromosome Xq13.1
Risks	Family history (X-linked inheritance pattern)
Diagnosis	Clinical evaluation, molecular genetic testing
Differential diagnosis	Prader–Willi syndrome, Börjeson–Forssman–Lehmann syndrome, Fragile X syndrome, Cornelia de Lange syndrome
Prevention	None
Treatment	Supportive management including hormone replacement, diet and exercise, speech therapy, educational support
Medication	Hormone replacement therapy, antiestrogens, aromatase inhibitors (experimental)
Prognosis	Variable; intellectual disability lifelong, physical symptoms manageable
Frequency	Very rare (fewer than 1 per million)
Deaths	Not specifically reported

X chromosome, location of the HDAC8 gene mutation

Wilson–Turner syndrome (WTS) is a rare, X-linked genetic disorder characterized primarily by intellectual disability, obesity, hypogonadism, and gynecomastia. Due to its association with the X chromosome, males tend to exhibit more severe manifestations than females. Females often have milder symptoms or may only be carriers with minimal clinical presentation.

History

Wilson–Turner syndrome was first identified in 1991 through the study of a family exhibiting intellectual disabilities, obesity, hypogonadism, and gynecomastia in multiple generations. Initially thought related to Prader–Willi syndrome, WTS was eventually recognized as a distinct clinical entity due to its unique genetic inheritance pattern (X-linked recessive) and distinct physical features. Since its first identification, fewer than 20 confirmed cases have been reported.

Signs and symptoms

Wilson–Turner syndrome has several characteristic clinical features:

• Intellectual disability – Typically mild to moderate impairment, associated with delayed speech and language development.
• Obesity – Truncal obesity, with significant fat accumulation around the abdomen starting from childhood, becoming prominent during adolescence.
• Hypogonadism – Reduced function of the testes in males resulting in reduced testosterone production, delayed or absent puberty, underdeveloped secondary sexual characteristics, sparse body hair, and small testes.
• Gynecomastia – Enlargement of male breast tissue due to hormonal imbalance, evident during puberty.
• Facial dysmorphisms – Includes a small head circumference, high forehead, prominent ears, flattened nasal bridge, thick eyebrows, and occasionally a high palate.
• Skeletal anomalies – Small hands and feet, tapered fingers, and occasionally flat feet (pes planus).

Females carrying the genetic mutation may display mild intellectual disabilities and subtle physical features, or no symptoms at all.

Causes

Wilson–Turner syndrome results from mutations in the HDAC8 gene located on chromosome Xq13.1. This gene encodes an enzyme known as histone deacetylase 8, essential in regulating gene expression during normal development. Mutations in HDAC8 disrupt developmental processes, particularly impacting brain development, endocrine function, and metabolism, leading to the clinical features seen in WTS.

Pathophysiology

Histone deacetylase 8 (HDAC8) influences gene expression by modifying histones and regulating genetic transcription. In Wilson–Turner syndrome, the mutated HDAC8 enzyme fails to function normally, disrupting normal developmental patterns. This disruption manifests primarily in the nervous and endocrine systems, affecting cognitive function, hormonal regulation, and fat metabolism. The hormonal disturbances cause elevated estrogen relative to androgens, resulting in gynecomastia and hypogonadism.

Diagnosis

Diagnostic techniques

Diagnosis is based on clinical evaluation and characteristic symptoms, supported by genetic testing. Molecular genetic analysis identifies the specific HDAC8 gene mutation to confirm the diagnosis.

Diagnostic criteria

A clinical diagnosis of Wilson–Turner syndrome is considered when males present with intellectual disability, obesity, hypogonadism, gynecomastia, and characteristic facial and skeletal features. Females, who typically have mild manifestations, are diagnosed primarily through family history and genetic testing for carrier status.

Family and medical history

Due to its X-linked inheritance, thorough family history evaluation is crucial. Pedigrees reveal an X-linked recessive inheritance pattern, typically affecting males more severely than females, who often serve as asymptomatic or mildly symptomatic carriers.

Screening

Females from affected families can undergo genetic testing, such as X chromosome inactivation analysis, to identify asymptomatic carriers. Genetic counseling is recommended for families with a known mutation in HDAC8 to discuss inheritance risks and reproductive options.

Treatment and management

There is currently no cure for Wilson–Turner syndrome. Management is symptomatic and supportive, aimed at improving quality of life and managing complications:

• Obesity management – Dietary modification, nutritional counseling, regular physical exercise.
• Hormone therapy – Testosterone replacement therapy for hypogonadism.
• Gynecomastia treatment – Weight reduction, and in severe cases, surgical correction (mammaplasty). Antiestrogen therapy and aromatase inhibitors are under investigation.
• Educational and behavioral support – Special education programs, speech therapy, occupational therapy, psychological counseling.

Prognosis

Wilson–Turner syndrome varies widely in its severity. Intellectual disabilities persist throughout life, but physical symptoms such as obesity and gynecomastia can often be effectively managed. Life expectancy is not typically reduced, provided obesity and associated complications are appropriately managed.

Epidemiology

Wilson–Turner syndrome is exceedingly rare, occurring in fewer than one per million individuals globally. It affects all ethnic groups and demographics equally, with only a few documented families studied extensively.

== Recent research == Recent studies of affected families suggest variability in the physical presentation, highlighting a broader spectrum of clinical features than originally recognized. Research continues to explore the biochemical and genetic pathways involving HDAC8 and its impact on endocrine and neurological development. Studies are also examining novel therapies targeting HDAC activity and gene expression, which may hold potential for improved treatments in the future.

Gallery

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  Gynecomastia, characteristic breast enlargement in males

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  Truncal obesity, central accumulation of body fat

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  Flat feet (pes planus), common in Wilson–Turner syndrome

See also

• Prader–Willi syndrome
• Fragile X syndrome
• Börjeson–Forssman–Lehmann syndrome
• Bardet–Biedl syndrome
• Cornelia de Lange syndrome

External links

• Genetic and Rare Diseases Information Center (GARD)
• National Organization for Rare Disorders (NORD)
• Orphanet

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