A severe form of X-linked mental retardation with short stature, obesity, hypogonadism, and large ears.
First described in 1962 in three men by the Swedish physicians Mats Börjeson, Hans Forssmann, and Orla Lehmann.
More than 50 males from approximately 20 families have been described.
It is transmitted as an X-linked recessive trait, thus, predominantly affects males, although heterozygous female carriers may manifest certain, although much more variable features of the disease (suggesting skewed X-inactivation). The mutations affect the PHF6 (plant homeodomain zinc-finger 6 transcription factor) gene, which has been mapped to chromosome Xq26.2 and is involved in DNA-transcription, cell growth, proliferation, and neuronal migration in the cerebral cortex. PHF6 dysfunction in neuronal migration may lead to the formation of white matter heterotopias with neuronal hyperexcitability and thus may play a role in the pathogenesis of intellectual disability and seizures in BFLS. The highest PHF6 gene expression is found during the pre- and postnatal development in the central nervous system (including the anterior pituitary gland) and in the primordial structures of the face. Female carriers are usually not or only mildly affected, but more severe forms have been described (see “Clinical aspects”).
Based on the clinical appearance of characteristic facial appearance, mental retardation, obesity, large ears, seizures, and family history. Confirmation requires genetic molecular testing.
There is a fairly wide intra- and interfamilial variability in the phenotype of BFLS. Affected males can present with mild to severe mental retardation, seizure disorder, large ears, short stature, marked truncal obesity and gynecomastia, hypogonadismus (hypogonadotropic hypogonadism with small penis and [often impalpable] testes and delayed or absent secondary sexual characteristics), and hypometabolism. More recent publications more and more report BFLS patients of normal height, weight and head circumference, and absence of seizures, which most likely reflects the wide phenotypic variability of this disorder. Psychomotor development is typically delayed. Chronologically, infancy is notable for mild hypotonia, failure to thrive, big ears, and hypogonadism. Short stature and obesity become more obvious at school age as are learning and behavioral problems. During adolescence and adult life, the facial features and body habitus become coarser, the big ears and hypogonadism persist and behavioral issues may become more problematic. Facial dysmorphism consists of a round, full or “swollen” face (particularly around the eyes and cheeks due to increased subcutaneous fat tissue), thickened calvaria, large (but normally formed) ears and earlobes, prominent supraorbital ridges, hypotelorism with decreased biparietal skull diameter, large and protruding tongue, deep set and upslanting eyes with narrow palpebral fissures and/or ptosis. Both, micro- and macrocephaly have been described. Nystagmus, decreased vision, corneal changes, abnormal electroretinogram, ...