Borjeson-Forssman-Lehmann syndrome (BFLS)

What is Borjeson-Forssman-Lehmann syndrome (BFLS)?

This rare disease is a genetic condition which, due to the way it is inherited, affects mainly males.

There are 40 recorded cases to date but this number is believed to be higher.

The main symptoms of the syndrome include unique facial features, and intellectual disability.

This syndrome is also known as:
Borjeson Syndrome; Borj Mental Retardation, Epilepsy, And Endocrine Disorders Mental Retardation, X-linked, Syndromic, Borjeson-forssman-lehmann Type; Mrxsbfl

What gene changes cause Borjeson-Forssman-Lehmann syndrome (BFLS)?

Changes to the PHF gene on the X chromosome are responsible for the syndrome. As an x-linked recessive condition, it affects mainly males.

However females have been recorded as presenting with some of the features of the condition, although in general they are just carriers.

Syndromes inherited in an X-linked recessive pattern generally only affect males. Males only have one X chromosome, and so one copy of a gene mutation on it causes the syndrome. Females, with two X chromosomes, only one of which will be mutated, are not likely to be affected.

What are the main symptoms of Borjeson-Forssman-Lehmann syndrome (BFLS)?

The symptoms may vary widely between individuals, and even within individuals from the same family. There is some evidence to suggest that in some individuals symptoms may become milder with age.

Unique facial features of the syndrome include a coarse face, droopy eyelids, deep set eyes, large and fleshy earlobes. Issues with the optic nerve and connective tissue may cause cataracts and farsightedness in adults with the condition.

Other symptoms of the syndrome include intellectual disability and developmental delay.

Obesity, seizures and the failure of the testes and ovaries to produce hormones are also symptoms. This in turn leads to a short stature.

Possible clinical traits/features:
X-linked recessive inheritance, Abnormal hair quantity, Widely spaced toes, Scheuermann-like vertebral changes, Macrocephaly, Microcephaly, Truncal obesity, Scoliosis, Thickened calvaria, Ptosis, Thick eyebrow, Shortening of all distal phalanges of the fingers, Hypoplasia of penis, Short toe, Hypoplasia of the prostate, Visual impairment, Hearing impairment, Short stature, Kyphosis, Cognitive impairment, Gynecomastia, Blepharophimosis, Skeletal muscle atrophy, Abnormality of the hip bone, Cataract, Broad foot, Camptodactyly of toe, Cervical spinal canal stenosis, Oral cleft, Joint hypermobility, Macrotia, Intellectual disability, severe, Micropenis, Tapered finger, Muscular hypotonia, Delayed puberty, Shortening of all middle phalanges of the fingers, Deeply set eye, EEG abnormality, Cryptorchidism, Coarse facial features, Large earlobe, Peripheral neuropathy, Prominent supraorbital ridges, Scrotal hypoplasia, Seizure, Nystagmus, Obesity

How does someone get tested for Borjeson-Forssman-Lehmann syndrome (BFLS)?

The initial testing for Borjeson-Forssman-Lehmann syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Borjeson-Forssman-Lehmann syndrome (BFLS)

The most important clinical features are mental retardation in a hypotonic, obese male, sometimes with microcephaly (but note the family reported by Turner et al., 1989), a coarse facial appearance which could be confused with Coffin-Lowry syndrome, prominent supraorbital ridges with deep set eyes, and large ears. Both the penis and the testes are small and secondary sexual characteristics are delayed. The boys are of small stature (but see below - Carter et al., 2009) and usually have a delayed bone age. Nearly all have bilateral ptosis and other ophthalmic signs which include nystagmus in the majority, but also occasional cataracts and even one case of hypoplasia of the optic nerve. Radiologically, the proximal femoral and humeral heads might be small and scoliosis occurs in some. An axonal peropheral neuropathy was reported by Lower et al., (2004) in a number of members of the original family. Two brothers (with a mutation) reported by Birrell had multiple pituitary hormone deficiency (TSH, GH, ACTH).
Kubota et al., (1999) reported a female with features of the condition. A skewed X-inactivation pattern was demonstrated. Crawford et al., (2006), also reported a female (with a PHF6 mutation). Skewed inactivation was present. See also the female reported by Berland et al., (2010), also with a PHF6 mutation,
Stevanovic et al., (1993) demonstrated deletion of the SOX3 gene, a gene related to the SRY male-determining gene, in a patient with haemophilia B and features of Borjeson-Forssman-Lehmann syndrome. Mathews et al., (1989) have localised the gene to Xq26-q27. Lower et al., (2002) demonstrated mutations in the PHF6 gene. This codes for a zinc finger transcription factor gene.
Twenty five males, all with PHF6 mutations, were reported by Turner et al., (2004). They suggest that the phenotype might be milder and more variable than first thought. In the first year of life males are floppy, fail to thrive, have big ears and small genitalia. Later they have learning difficulties, are short, and tend to be obese and have small genitalia.The head circumference is usually normal and even macrocephaly might be seen. The toes are short and the fingers are tapered and malleable. By this stage the heavy facial appearance might be seen. Four males (2 brothers and their 2 cousins were reported by Ernst et al., (2015).. All 4 had a weak suck in infancy, no language, hypogonadism, tapering of fingers, big ears with fleshy lobes, broad feet and short toes, and a sandal gap.
The original Borjeson-Forssman-Lehmann family has now been shown to have a PHF6 mutation (Lower et al., 2004). A mother and her 2 sons were described by Carter et al., (2009) - the males were of normal stature, had hypogonadism and had normal to large head sizes. All had mutations.
Kasper et al. (2017) described central nervous system anomalies in two female patients with Borjeson-Forssman-Lehmann syndrome and de novo frameshift mutations in the PHF6 gene. Clinical features included severe intellectual disability, seizures, impaired speech development, distinct facial appearance, hypodontia, finger deformities, short toes, oligomenorrhea and linear skin hyperpigmentation. Brain MRI showed symmetrical, band-like aggregations of cortex-isointense structures in temporoinsular distribution extending to temporooccipital and parietal lobes bilaterally.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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