Search for a rare disease
Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked obesity syndrome characterized by intellectual deficit, truncal obesity, characteristic facial features, hypogonadism, tapered fingers and short toes.
The prevalence is unknown. Approximately 50 patients have been reported, from 24 families and sporadic cases.
BFLS is found mainly in boys, but several mild to moderately symptomatic females have been reported within known families, and as isolated cases. There is a wide variability in manifestations. At birth, large ears and small genitalia are occasionally evident. The head circumference is variable and hypotonia, leading to poor feeding, is seen in all infants. Developmental delay is often noted before the age of one. In late childhood, truncal obesity is apparent. Fingers are malleable and tapered and feet are usually broad with flexed, short toes. Most have short stature but some are of normal height. In adolescence, gynecomastia develops and genitalia usually remain small. Characteristic coarse facial features also appear in adolescence and include deep-set eyes, narrow forehead, supraorbital ridges, ptosis and large, fleshy earlobes, all of which become more pronounced in adulthood. Intellectual disability can range from mild to severe and is not progressive. Patients are usually sociable and friendly but some experience anxiety, depression and challenging or hypersexual behavior. Less common findings reported include acute precursor T-cell acute lymphoblastic leukemia, Legg-Calvé-Perthes disease (LCPD), cleft lip/palate (see these terms), hypopituitarism, hearing impairment, epilepsy and mild to generalized polyneuropathy. Females are mainly asymptomatic but in rare cases can exhibit learning problems along with some of the physical features seen in males.
BFLS is caused by mutations in the PHF6 gene, located on Xq26, encoding PHF6, a protein involved in cell growth and proliferation. In general, mutations that result in loss or reduction of PHF6 expression result in more severe clinical symptoms. Loss-of-function mutations and skewed X-inactivation are thought to explain the rare occurrence of symptomatic females. Although most cases are inherited within families, several isolated cases have been reported, where the etiology is unknown.
BFLS is suspected on clinical examination when the characteristic symptoms are present. A family history showing X-linked recessive inheritance as well as skewed X-chromosome inactivation in obligate female carriers is a strong additional indicator of BFLS. PHF6 mutation screening can confirm a diagnosis.
Differential diagnoses include Coffin-Lowry, Klinefelter, Prader-Willi, Bardet-Biedl, or Wilson-Turner syndromes (see these terms).
When a PHF6 mutation is known to exist in a parent, antenatal diagnosis is possible.
Inheritance is X-linked and genetic counseling is possible to explain X-linkage to families and identify carrier females. Very few patients with BFLS reproduce, but asymptomatic female carriers can pass on the mutation to their children.
Management and treatment
There is no cure for BFLS. Treatment and management is symptomatic. Special education is started early and followed throughout adolescence and adulthood. A healthy diet is recommended. Adults require variable degrees of supervision which may include institutionalization in severe cases. Testosterone replacement therapy and/or a bilateral mastectomy may be considered for the treatment of gynecomastia. If seizures are present, antiepileptic drugs are prescribed. Symptomatic treatment for LCPD and hearing impairment is available. A social network is important as BFLS patients benefit from strong social relationships.
BFLS is not life threatening but due to the intellectual disability encountered, quality of life is limited and life-long supervision is often necessary.
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