What are the other Names for this Condition? (Also known as/Synonyms)

• BFLS (Borjeson-Forssman-Lehmann Syndrome)
• Intellectual Disability-Epilepsy-Endocrine Disorders Syndrome
• Mental Deficiency, Epilepsy, and Endocrine Disorders

What is Borjeson-Forssman-Lehmann Syndrome? (Definition/Background Information)

• Borjeson-Forssman-Lehmann Syndrome (BFLS) is an extremely rare X-linked syndrome that is characterized by obesity (including truncal obesity), epileptic seizures, intellectual delays, abnormal facial features, reduction or absence of sex organs, tapered fingers, and short toes
• Thus, it is also known as Intellectual Deficiency-Epilepsy-Endocrine Disorders Syndrome. The signs and symptoms can vary from one individual to another and may be mild or severe. Complications of the disorder may include abnormal spinal curvature and Perthes disease
• Borjeson-Forssman-Lehmann Syndrome is caused by a mutation (permanent change) in the PHF6 gene located on the X chromosome. Usually, the mutation is transmitted as an X-linked recessive trait, meaning that the disorder is primarily manifested in males
• The disorder is typically incurable, although the signs and symptoms may be treated adequately. The prognosis of Borjeson-Forssman-Lehmann Syndrome depends on its severity and the range of presentations noted

Who gets Borjeson-Forssman-Lehmann Syndrome? (Age and Sex Distribution)

• Borjeson-Forssman-Lehmann Syndrome (BFLS) is a rare congenital disorder that can be expressed in both males and females to a variable extent. However, the condition is typically more severe in males than females
• BFLS is a very uncommon disorder. It has been only reported in approximately 40 unrelated families and individual patients
• In mild cases, there is a high chance of misdiagnosis of the disorder in males; it may be altogether missed in females too
• The disorder is present at birth (meaning the signs and symptoms may be noted at or immediately following the birth of the child)

What are the Risk Factors for Borjeson-Forssman-Lehmann Syndrome? (Predisposing Factors)

• A positive family history is an important risk factor, since Borjeson-Forssman-Lehmann Syndrome can be inherited
• No other specific risk factors have been identified for the condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Borjeson-Forssman-Lehmann Syndrome? (Etiology)

The cause of Borjeson-Forssman-Lehmann Syndrome (BFLS) is due to mutation(s) involving the PHF6 gene (also known as the PHD finger protein 6 gene). The mutation is inherited as an X-linked recessive trait; therefore, the disorder typically affects males.

• The protein that PHF6 encodes for has many functions including prevention of cancer in certain blood cells (such as T-lymphocytes, which are important factors of the immune system)
• X-linked syndromes, such as BFLS, are caused by gene mutations on the X-chromosome and are typically noted in males. Males only have one X chromosome (that they receive from their mother); and if that chromosome has the defective gene, the disorder is manifested in them
• The expression of the mutation in females is due to X-inactivation in about 95% of cases. Females have two X chromosomes, one from each parent. X-inactivation (or X-lyonization) is when one of those X-chromosomes is inactivated (silenced). If a carrier female has the mutated gene, there is a possibility that the X-chromosome on which it is present will be silenced. However, if the other X-chromosome is silenced, then the disease will phenotypically (observable characteristic or trait) vary from case to case
• If a female has the defective gene, they are carriers of the syndrome. Carriers often do not display signs and symptoms of the disease as there are 2 X-chromosomes and only one carries the mutated gene. However, female carriers can also manifest the disease while having only 1 PHF6 gene mutated due to X-lyonization

A male cannot pass a mutated X-chromosome to his children, but all his daughters would be carriers.

What are the Signs and Symptoms of Borjeson-Forssman-Lehmann Syndrome?

The signs and symptoms of Borjeson-Forssman-Lehmann Syndrome (BFLS) vary in severity from no clinical presentation to fully affected individuals. Most cases in male are characterized by the following signs and symptoms:

• Mental retardation
• Hypotonia, also known as floppy baby syndrome, from reduced muscle tone and muscle strength
• Microcephaly, where the infant’s head is significantly smaller than other children of the same age group
• Mild (truncal) obesity
• Gynecomastia: Enlargement of the male breast gland due to imbalance between estrogen and testosterone hormones
• Cryptorchidism: Absence of one or both testes from the scrotum; it is the most common male sexual development abnormality
• Short stature
• Tapering fingers and shortened toes
• Epileptic seizures

Females who carry the mutated PHF6 gene for BFLS are much less affected and develop only some of the signs and symptoms. These generally include:

• Intellectual disability
• Dental irregularities
• Skin hyperpigmentation
• Underdeveloped nails

Although there is overlap with BFLS that affects males, there may be other features present. Individuals may also have:

• Characteristic (abnormal) facial features such as:
  • Large ear lobes
  • Deep-set eyes
  • Ptosis (drooping of the upper eyelid)
  • Nystagmus (involuntary eye movement)
  • Hyperopia (farsightedness)
  • Prominent supraorbital ridges (thick ridges above the eyes)
  • Thickened connective tissue of face (gives the face a coarse appearance)
• Hypogonadism: Reduction or absence of hormone secretion from the gonads (ovaries or testes)
• Skeletal abnormalities such as scoliosis or kyphosis (abnormal curvature of the spine)
• Hypoplasia - incomplete or underdevelopment of a tissue or organ

In the first year, the babies present a floppy appearance, with characteristic big ears and small external genitalia. As young children, they have learning disabilities, short stature, truncal obesity, gynecomastia, and short toes and tapered fingers. In late adolescence, the characteristic facial features are more prominently visible.

How is Borjeson-Forssman-Lehmann Syndrome Diagnosed?

A diagnosis of Borjeson-Forssman-Lehmann Syndrome may be suspected by the healthcare provider based on the characteristic appearance and range of signs and symptoms. The suspicion may be reinforced, if there are other boys or men having the disorder, within the affected family. 

• Complete physical examination and evaluation of family medical history
• Assessment of the presenting signs and symptoms
• Hearing and vision assessment
• A definitive diagnosis may be made via a genetic test which can be used to also test the severity of the syndrome
• Other diagnostic tests include:
  • Magnetic resonance imaging (MRI) scans of the affected region; MRI uses radio waves and a magnetic field to create detailed images of the organs and tissues
  • Electroencephalography, in order to evaluate the electrical activity of the brain
  • Electroneuronography: It is a non-invasive test to evaluate the integrity of the peripheral nerves
• Differential diagnosis: It is also important to distinguish Borjeson-Forssman-Lehmann Syndrome from other conditions such as the following:
  • Bardet-Biedl syndrome
  • Chudley-Lowry syndrome
  • Coffin-Lowry syndrome
  • Coffin-Siris syndrome
  • Klinefelter syndrome
  • Prader-Willi syndrome
  • Wilson-Turner syndrome

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Borjeson-Forssman-Lehmann Syndrome?

The following complications of Borjeson-Forssman-Lehmann Syndrome may be noted:

• Severe emotional stress for the parents and caregivers
• Hearing impairment
• Vision loss
• Perthes disease: Childhood hip disorder with disruption of blood flow to the femoral head (ball of the femur); due to lack of blood supply, the bone dies and growing stops
• Spinal abnormalities that may cause standing and walking difficulties
• Seizures increasing the risk for falls
• Severe intellectual deficiency
• Infertility
• Overall reduced quality of life

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Borjeson-Forssman-Lehmann Syndrome Treated?

There is no cure for Borjeson-Forssman-Lehmann Syndrome (BFLS) since it is a genetic condition; however, there are medications and surgery to treat the symptoms. The treatment measures may involve:

• Use of hearing aids, if required
• Use of vision aids, as needed
• Seizure control medications
• Employing suitable learning strategies
• Physiotherapy for stiff muscles, including incorporating daily exercise regimen
• Surgical correction of physical defects, as assessed by a healthcare expert
• Psychotherapy and behavior modification

Regular medical screening at periodic intervals with tests and physical examinations are necessary and highly recommended.

How can Borjeson-Forssman-Lehmann Syndrome be Prevented?

Currently, there are no specific methods or guidelines to prevent Borjeson-Forssman-Lehmann Syndrome (BFLS) since it is a genetic condition.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as BFLS

What is the Prognosis of Borjeson-Forssman-Lehmann Syndrome? (Outcomes/Resolutions)

• Although children affected with Borjeson-Forssman-Lehmann Syndrome have developmental delays, many learn to walk between the ages of 4 and 6
• In some individuals, the signs and symptoms decrease in severity over time
• Children with mild conditions (usually from small duplications) are generally able to cope well via appropriate treatment and adaptive behaviors as they get older

Additional and Relevant Useful Information for Borjeson-Forssman-Lehmann Syndrome:

• The PHF6 gene acts as tumour suppressor gene, and although it is unlikely to cause cancer on its own, it can contribute to cancer development if a mutation is present

PHF6 mutation in combination with other mutations can lead to cancers such as T-cell acute lymphoblastic leukaemia (T-ALL) or acute myelogenous leukemia (AML). However, such individuals do not present with Borjeson-Forssman-Lehmann Syndrome