Borjeson-Forssman-Lehmann Syndrome

A number sign (#) is used with this entry because Borjeson-Forssman-Lehmann syndrome is caused by mutation in the PHF6 gene (300414).

Clinical Features

The features of this syndrome, described in a single kindred by Borjeson et al. (1962), are severe mental defect, epilepsy, hypogonadism, hypometabolism, marked obesity, swelling of subcutaneous tissue of face, narrow palpebral fissure, and large but not deformed ears. Three females who might be carriers had moderate mental retardation. Brun et al. (1974) extended the observations of Borjeson et al. (1962). Baar and Galindo (1965) described a single case they thought represented the same entity. Robinson et al. (1983) observed a Saudi Arabian sibship with a severely affected male and a more mildly affected pair of female monozygotic twins. They pointed to a report of cases by Weber et al. (1978) as well as others.

Ardinger et al. (1984) studied 5 affected males in 2 unrelated families. The authors were impressed with a characteristic facial appearance which included prominent superciliary ridges, deep-set eyes, ptosis, and large ears. They could find no reliable means of identifying heterozygotes. The differential diagnosis includes Prader-Willi (176270), Coffin-Lowry (303600), and Bardet-Biedl (209900) syndromes.

Turner et al. (2004) reviewed the clinical features of affected males in 9 families with BFLS in which mutation in the PHF6 gene had been identified (Lower et al., 2002). The clinical history and physical findings in the affected males indicated that the phenotype is milder and more variable than previously described and evolves with age. Generally, in the first year, the babies are floppy, with failure to thrive, big ears, and small external genitalia. As schoolboys, the picture is one of learning problems and moderate short stature, with emerging truncal obesity and gynecomastia. Head circumferences are usually normal, and macrocephaly may be seen. Big ears and small genitalia remain. The toes are short and fingers tapered and malleable. In late adolescence and adult life, the classically described heavy facial appearance emerges. Some heterozygous females showed milder clinical features such as tapering fingers and shortened toes. Significant learning problems were found in 20%, and skewed X inactivation in 95%. Turner et al. (2004) concluded that the syndrome may be underdiagnosed in males in their early years and missed altogether in isolated heterozygous females.

Manifestations in Females

Dereymaeker et al. (1986) described a typical case. The mother had suggestive features, and a first cousin, the daughter of a maternal male (who was himself 'feeble-minded,' but with a normal somatic phenotype), had hyperkyphosis that increased with age, no menarche at age 17, and sudden death at age 17 due probably to epileptic seizures.

Using a methylation-specific PCR assay, Kubota et al. (1999) demonstrated that a woman with typical findings of the BFL syndrome had an extremely skewed X-inactivation pattern. The 32-year-old Japanese woman was the only affected member of her family. She was hypotonic during early infancy and attended a school for the mentally handicapped. She had the first seizure at age 3 and became obese at age 5. Diabetic ketoacidosis crisis occurred at age 31 years. Her height was only 142 cm. She had a 'coarse' face with a narrow forehead, prominent supraorbital ridges, narrow palpebral fissures, ptosis, deep-set eyes, full cheeks, and large ears. Her hands were small with tapering fingers and short fifth fingers.

In all but 1 of the female carriers tested by Lower et al. (2002), the chromosome carrying the mutation in PHF6 (300414; see later) was 100% inactivated. The exception was a woman with roughly 70% skewing, who showed mild clinical features of BFLS, including obesity, large ears, amenorrhea, hypothyroidism, epilepsy, and learning difficulties.

Crawford et al. (2006) reported a 14-year-old girl with BFLS-like symptoms, with psychomotor retardation, IQ of 84 at age 4, and a remarkably shallow forehead, large ears with fleshy earlobes, deep-set eyes with a wide neck and face, broad feet, and hammertoes. Testing of her blood DNA showed a 93% skewed X-inactivation pattern.

Wieczorek et al. (2013) reported 2 females described as having Coffin-Siris syndrome (CSS; 135900) with mutations in the PHF6 gene. The first girl presented with mild to moderate developmental delay, hypertrichosis, coarse facial features, hypoplastic fifth finger- and toenails, and hypoplastic fifth digits. These features fulfilled the diagnostic criteria for CSS; Wieczorek et al. (2013) remarked that more characteristic clinical features of BFLS may not be evident in early childhood. A second girl was found to have a de novo frameshift mutation in PHF6. She had mild intellectual disability, average stature, and hypoplasia of distal phalanges of the fifth digits. Additionally, she had nystagmus, strabismus, and coarse facial features.

Mapping

In a family with presumed BFL syndrome, Mulley et al. (1989) found suggestions of linkage to X DNA markers that would place the locus in the Xq26-q27 region. On the basis of the same study, Turner et al. (1989) reported a maximum lod score of 2.1 at theta = 0.0 with DXS51. The regional localization was thought to be Xq26-q27. The 7 affected males showed mild to moderate intellectual handicap, remarkably long, thick ears, deep-set eyes, small testes, and postpubertal gynecomastia. The affected males and some of the heterozygous females also had tapering fingers and short, widely spaced and flexed toes. Mathews et al. (1989) also found evidence suggesting location of the BFLS locus on distal Xq. They found maximum lod scores of 2.32 with DXS10 and 2.24 with DXS51, both at theta = 0.0. Mathews et al. (1989) combined the 2 sets of data and arrived at a maximum lod score of 4.09. The family studied by Mathews et al. (1989) was one of those reported by Ardinger et al. (1984). The clinical features as demonstrated by the photographs were strikingly similar to those in the family of Turner et al. (1989).

Molecular Genetics

Lower et al. (2002) narrowed the interval of the BFLS locus to roughly 9 Mb containing more than 62 genes. Among these, a novel, widely expressed zinc finger gene, designated PHF6 (300414), had 8 missense and truncation mutations in 7 familial and 2 sporadic cases of BFLS. Transfection studies with PHF6 tagged with green fluorescent protein (GFP) showed diffuse nuclear staining with prominent nucleolar accumulation. Such localization, and the presence of 2 plant homeodomain (PHD)-like zinc fingers, suggested a role for PHF6 in transcription.

Lower et al. (2004) identified a mutation in the PHF6 gene (300414.0001) in affected members of the original BFLS family reported by Borjeson et al. (1962) and in affected members of a previously undescribed BFLS family from Western Australia.

In a 14-year-old girl with BFLS-like symptoms, Crawford et al. (2006) identified heterozygosity for a 1-bp insertion in the PHF6 gene (300414.0010). The authors stated that this was the first report of a clinically diagnosed BFLS female with a confirmed PHF6 mutation. Crawford et al. (2006) also identified mutations in the PHF6 gene in 4 of 24 unrelated males with clinically diagnosed BFLS; 1 was an isolated case with skewed maternal X inactivation, and 3 were familial cases, of which 2 had skewed maternal X inactivation. Crawford et al. (2006) concluded that the success of PHF6 screening in males suspected of having BFLS is markedly increased if there is a positive family history and/or skewed X inactivation is found in the mother.

Gecz et al. (2006) reviewed the clinical features and molecular genetics of BFLS, stating that 19 unrelated mutation-positive cases had been reported, of which 13 were familial and 6 were isolated cases.

Wieczorek et al. (2013) reported 2 females, each with a de novo mutation in the PHF6 gene (e.g., C305F; 300414.0011), who fulfilled diagnostic criteria for Coffin-Siris syndrome (CSS; 135900).

History

Gecz et al. (1999) identified a male infant with BFLS-like features and a duplication, 46,Y,dup(X)(q26q28), inherited from his phenotypically normal mother. FISH using yeast artificial chromosome clones from Xq26 localized the duplication breakpoint to an interval of approximately 400 kb in the Xq26.3 region between DXS155 and DXS294/DXS730. Database searches and analysis of available genomic DNA sequence from the region revealed the presence of the fibroblast growth factor-13 gene (FGF13; 300070) within the duplication breakpoint interval. Northern blot hybridization showed highest expression of FGF13 in brain and skeletal muscle. The FGF13 gene localization and tissue-specific expression pattern suggested that it is a candidate gene for familial cases of BFLS and other syndromal and nonspecific forms of X-linked mental retardation mapping to that region.