History
Cause and symptoms
Genetics
Epidemiology
Diagnosis and treatment
References
Further reading

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Borjeson-Forssman-Lehman syndrome or BFLS is an X-linked genetic disorder encompassing a wide range of symptoms like seizures, intellectual disability, obesity, development delay, and distinctive facial appearance.

It is caused due to mutations in the PHF6 gene located on the X-chromosome. The primary clinical symptoms evolve as people become older, and there is a lot of variance within and between families.

History

Börjeson, Forssman, and Lehman originally identified BLFS in three males with significant intellectual disability, developmental delay, obesity, hypogonadism, and hypometabolism six decades ago.

Narrow palpebral fissures, thickening of subcutaneous tissue of the face, big ears, and dwarfism were also present in the individuals. Three females with moderate mental retardation who may be carriers were also identified.

Borjeson’s observations were expanded upon by Brun et al. (1974). Turner et al. (2004) looked at the clinical characteristics of affected males in nine BFLS families where a mutation in the PHF6 gene had been discovered by Lower et al. (2002).

The affected males' clinical history and physical findings revealed that the phenotypic is milder and more diverse than previously thought and that it evolves with age.

In general, newborns are floppy in the first year, with failure to thrive, large ears, and small external genitalia. They have learning difficulties and moderately small stature as children, with the onset of truncal obesity and gynecomastia. The typically described heavy facial look comes in late adolescence and adulthood.

Some heterozygous females have lesser clinical characteristics, such as tapered fingers and shorter toes. Significant learning impairments were discovered in 20% of the cases, and skewed X inactivation was discovered in 95% of the cases.

According to Turner et al. (2004), the disease may be underdiagnosed in young males and completely ignored in solitary heterozygous females.

Cause and symptoms

BFLS is caused by mutations in the plant homeodomain (PHD)-like finger (PHF6) gene. This mutation is frequently passed down as an X-linked recessive characteristic, meaning that the condition is primarily manifested in males. In the early stages of the development of the central nervous system, PHF6 is extensively expressed. It codes for a plant-homeodomain zinc-finger protein that is highly conserved in vertebrate species. It has been postulated that it plays a role in transcriptional control because of its nuclear localization and interaction with the PAF1 transcriptional elongation complex and the Nucleosome Remodeling and Deacetylation (NuRD) complex.

The primary clinical symptoms of BFLS change as people become older, and a lot of variances are observed within and between families. Pregnancy, childbirth, and birth weight are all common occurrences.

At birth, many newborns have small genitalia and huge ears, and many have generalized hypotonia and poor eating. The earliest signs of developmental delay normally appear before the first birthday, and the degree of mental impairment is mild to severe.

The circumference of the head is normally normal, however, macrocephaly and microcephaly can develop. The lobes of the ears are fleshy and large. Short stature is frequent, however, some people grow to be standard height. Truncal obesity and gynecomastia appear in late childhood and adolescence, respectively.

The genitalia is still rather tiny. The fingers are flexible and tapering. The toes are foreshortened and often flexed, and the feet are broad. In adulthood, the facial features become coarser, with a prominence of the supraorbital ridges and deep-set eyes. Female heterozygotes may experience learning difficulties and exhibit physical characteristics such as shorter toes, thickened, fleshy ear lobes, noticeable supraorbital ridges, and deep-set eyes.

Genetics

Inherited BFLS affects males in an X-linked recessive manner, whereas sporadic BFLS affects females due to de novo mutations.

Mutations in the PHF6 gene, located at Xq26.3, were identified as the genetic etiology of BFLS four decades after it was first described. Following that, a variety of mutations were discovered in BFLS patients, including missense, nonsense, insertions, deletions, and duplications, as well as some recurrent mutations.

Epidemiology

Börjeson-Forssman-Lehmann syndrome is an uncommon illness that affects both males and females equally. Female phenotypic expression is exceedingly varied and would be difficult to anticipate at this time.

The exact incidence of BFLS is unclear, however, it might be underestimated based on the identification of solitary-affected females. In the medical literature, mutations in the PHF6 gene have been described in around 64 unrelated families and numerous isolated individuals (males and a growing number of females).

Diagnosis and treatment

The diagnosis of BFLS is usually made clinically based on the patient's medical history and physical examination, and it can be verified with PHF6 gene sequencing. There is a scarcity of MRI data in patients with BFLS. Enlarged ventricles have been observed in one of the few BFLS cases where MRI data is available in the literature.

The treatment for BFLS is focused on the specific symptoms that each person experiences. Treatment may necessitate the collaboration of a group of professionals.

Early developmental intervention is critical for BFLS-affected children to realize their full potential. Special educational services, along with other medical, social, and occupational services, may be beneficial to affected children. Affected individuals and their families may also benefit from genetic counseling sessions.

References

• Bellad A, Bandari AK, Pandey A, et al. (2020). A Novel Missense Variant in PHF6 Gene Causing Börjeson-Forssman-Lehman Syndrome. Journal of Molecular Neuroscience, 70(9), 1403–1409. doi:10.1007/s12031-020-01560-5
• Zhang X, Fan Y, Liu X, et al. (2019). A Novel Nonsense Mutation of PHF6 in a Female with Extended Phenotypes of Borjeson-Forssman-Lehmann Syndrome. Journal of Clinical Research in Pediatric Endocrinology, 11(4), 419–425. doi: 10.4274/jcrpe.galenos.2019.2018.0220
• Kasper BS, Dörfler A, Di Donato N, et al. (2017). Central nervous system anomalies in two females with Borjeson-Forssman-Lehmann syndrome. Epilepsy & Behavior, 69, 104–109. doi:10.1016/j.yebeh.2017.01.022
• Jahani-Asl A, Cheng C, Zhang C, et al. (2016). Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function. Neurobiology of Disease, 96, 227–235. doi:10.1016/j.nbd.2016.09.011
• Gécz J, Turner G, Nelson J, et al. (2006). The Börjeson-Forssman-Lehman syndrome (BFLS, MIM #301900). European Journal of Human Genetics, 14(12), 1233–1237. doi:10.1038/sj.ejhg.5201639
• Borjeson-Forssman-Lehmann syndrome. [Online] NIH-GARD. Available at: https://rarediseases.info.nih.gov/diseases/936/borjeson-forssman-lehmann-syndrome
• BORJESON-FORSSMAN-LEHMANN SYNDROME; BFLS. [Online] OMIM. Available at: https://www.omim.org/entry/301900
• Börjeson-Forssman-Lehman Syndrome. [Online] National organization for Rare Disorders. Available at: https://rarediseases.org/rare-diseases/borjeson-forssman-lehman-syndrome/

Further Reading

• All Genetic Disorder Content
• What are Genetic Disorders?
• Genetic Disorder Comorbidities
• Multifactorial And Polygenic (Complex) Genetic Disorder
• Single Gene Genetic Disorder