Börjeson-Forssman-Lehmann syndrome

Overview

Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked genetic disorder characterized by intellectual disability, distinctive facial features, obesity, hypogonadism, and other physical and developmental abnormalities. It primarily affects males, although some female carriers may exhibit mild symptoms. First described in 1962, BFLS is now known to be associated with mutations in the PHF6 gene, which plays a key role in early development and gene regulation. The condition is chronic but non-progressive, and management focuses on symptom relief and supportive care.

Causes

BFLS is caused by mutations in the PHF6 gene, located on the X chromosome. This gene encodes a protein involved in regulating gene expression during development, particularly in the brain and gonads. Because BFLS follows an X-linked recessive inheritance pattern, it predominantly affects males. Females, who have two X chromosomes, are typically carriers and may be asymptomatic or have only mild features. In some cases, the mutation arises spontaneously (de novo) without a family history.

Symptoms

The severity of symptoms in BFLS can vary, but common features in affected males include:

• Intellectual disability – typically moderate to severe, with delays in speech and motor skills

• Distinctive facial features – including narrow palpebral fissures, ptosis (drooping eyelids), large ears, and a prominent upper lip

• Obesity – especially in adolescence and adulthood

• Hypogonadism – underdeveloped testes, micropenis, or delayed puberty

• Gynecomastia – development of breast tissue in males

• Short stature or delayed growth

• Seizures – may occur in some individuals

• Behavioral issues – such as hyperactivity, aggression, or social difficulties

• Coarse or sparse scalp hair

• Digital anomalies – including tapering fingers or toe abnormalities

Carrier females may show subtle symptoms, such as learning disabilities, irregular menstruation, or mild facial features.

Diagnosis

Diagnosis of BFLS involves a combination of clinical assessment and genetic testing. Key steps include:

• Physical examination – to identify characteristic facial features, genital abnormalities, and body habitus

• Developmental assessment – evaluating intellectual, speech, and motor delays

• Hormonal testing – to assess for hypogonadism and delayed puberty

• Brain imaging – in some cases to evaluate structural abnormalities or investigate seizures

• Genetic testing – confirming PHF6 mutations through DNA analysis (via whole exome sequencing or targeted gene panels)

• Family genetic studies – especially in families with a history of intellectual disability or related symptoms

Treatment

There is no cure for BFLS. Treatment focuses on managing symptoms and improving the individual’s quality of life through a multidisciplinary approach. Interventions include:

• Early intervention programs – including speech, occupational, and physical therapy to address developmental delays

• Special education services – tailored to individual cognitive abilities and learning needs

• Hormonal therapy – for addressing hypogonadism and delayed puberty, under endocrinologist supervision

• Weight management – through dietary guidance and physical activity to control obesity

• Seizure management – using antiepileptic medications if seizures are present

• Psychological support – including behavioral therapy and counseling for emotional and social challenges

• Regular health monitoring – to screen for complications related to obesity, hormone levels, and learning difficulties

Prognosis

The prognosis for individuals with Börjeson-Forssman-Lehmann syndrome varies depending on the severity of symptoms and the availability of supportive care. While intellectual and developmental impairments are typically lifelong, early intervention and tailored therapies can significantly improve functioning and independence. Life expectancy is generally not severely affected, though secondary issues such as obesity-related health problems or hormonal imbalances should be closely managed. Genetic counseling is recommended for families with a history of BFLS to assess recurrence risks and support informed reproductive decisions.