Borjeson-Forssman-Lehman syndrome (BFLS) is a rare X-linked genetic disorder characterized by a range of symptoms including seizures, intellectual disability, obesity, developmental delay, and a distinctive facial appearance. It is caused by mutations in the PHF6 gene located on the X-chromosome, and the clinical symptoms can vary widely within and between families.
In 1962, Börjeson, Forssman, and Lehman first identified BLFS in three males who exhibited significant intellectual disability, developmental delay, obesity, hypogonadism, and hypometabolism. Other physical features, such as narrow palpebral fissures, thickening of facial tissues, large ears, and dwarfism, were also observed. The syndrome was later studied by researchers such as Brun et al. (1974) and Turner et al. (2004), who discovered additional clinical characteristics and confirmed the genetic mutation in the PHF6 gene.
The symptoms of BFLS evolve with age. Newborns may have floppy muscle tone, failure to thrive, small external genitalia, and large ears. Developmental delay typically begins before the first birthday, with varying degrees of mental impairment. Other features may include short stature, truncal obesity, and gynecomastia. The facial appearance becomes more coarse in adolescence and adulthood.
BFLS is primarily manifested in males, but heterozygous females may exhibit milder symptoms and learning difficulties. The disease is caused by mutations in the PHF6 gene, which is involved in transcriptional control. It is inherited in an X-linked recessive manner, but sporadic cases can occur due to de novo mutations.
The exact incidence of BFLS is unclear, but it is considered a rare condition affecting both males and females. Diagnosis is made based on the patient’s clinical history and physical examination, and can be confirmed through genetic testing of the PHF6 gene. Treatment focuses on managing the specific symptoms experienced by each individual, and early developmental intervention is important for optimal outcomes. Special educational services and genetic counseling may be beneficial for affected individuals and their families.
References:
Bellad A, Bandari AK, Pandey A, et al. A Novel Missense Variant in PHF6 Gene Causing Börjeson-Forssman-Lehman Syndrome. Journal of Molecular Neuroscience. 2020;70(9):1403-1409.
Zhang X, Fan Y, Liu X, et al. A Novel Nonsense Mutation of PHF6 in a Female with Extended Phenotypes of Borjeson-Forssman-Lehmann Syndrome. Journal of Clinical Research in Pediatric Endocrinology. 2019;11(4):419-425.
Kasper BS, Dörfler A, Di Donato N, et al. Central nervous system anomalies in two females with Borjeson-Forssman-Lehmann syndrome. Epilepsy & Behavior. 2017;69:104-109.
Jahani-Asl A, Cheng C, Zhang C, et al. Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function. Neurobiology of Disease. 2016;96:227-235.
Gécz J, Turner G, Nelson J, et al. The Börjeson-Forssman-Lehman syndrome (BFLS, MIM #301900). European Journal of Human Genetics. 2006;14(12):1233-1237.
Borjeson-Forssman-Lehmann syndrome. NIH-GARD.
BORJESON-FORSSMAN-LEHMANN SYNDROME; BFLS. OMIM.
Börjeson-Forssman-Lehman Syndrome. National Organization for Rare Disorders.
