J Med Genet 41:778-783 doi:10.1136/jmg.2004.020370
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A novel PHF6 mutation results in enhanced exon skipping and mild Börjeson-Forssman-Lehmann syndrome

  1. D Vallée1,
  2. E Chevrier1,
  3. G E Graham2,
  4. M A Lazzaro1,
  5. P A Lavigne1,
  6. A G Hunter2,
  7. D J Picketts3
  1. 1Molecular Medicine Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada
  2. 2Eastern Ontario Regional Genetics Program, Children’s Hospital of Eastern Ontario, Ottawa
  3. 3Molecular Medicine Program, Ottawa Health Research Institute, and Departments of Medicine, Biochemistry, Microbiology, and Immunology; and the Centre for Neuromuscular Disease, University of Ottawa
  1. Correspondence to:
 Dr David J Picketts
 Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6;

    BFLS is a rare X linked recessive disorder characterised by moderate to severe mental retardation, obesity with gynaecomastia, hypogonadism, and large prominent ears.1 However, a clear diagnosis is often difficult. BFLS may be confused with other obesity related mental retardation syndromes as there can be intrafamilial and interfamilial phenotypic variability and women may also be affected, possibly because of skewed X inactivation. Following the identification of the PHF6 gene (Xq26–27) as the cause of BFLS, Turner et al showed that the phenotype may be milder and broader than originally appreciated.2

    Mutations in the PHF6 gene have been identified in 11 families and they are localised throughout the gene, suggesting a loss of function mechanism.3–5 Primary sequence analysis has suggested that PHF6 encodes a transcriptional regulator based on the presence of two PHD zinc finger domains, a motif common to chromatin remodelling proteins including the ATRX protein. Nonetheless, little is known of the function of the PHF6 protein or how different mutations give rise to the phenotypic variability observed in patients. Clearly, the identification of additional mutations will enhance our understanding of PHF6 function and provide insight into the clinical spectrum of this disorder. Here we describe mutational analysis in two Canadian families, one with classic features of BFLS and another with milder phenotypic features.


    Case reports

    The affected individual from family 1 (fig 1A) was diagnosed at age 19 because of a classical phenotype that was consistent with that described in the most comprehensive clinical review of BFLS patients.6 He is severely intellectually handicapped with psychiatric challenges that include self-injurious behaviour. He has characteristic facial features, a stooped kyphoscoliotic posture, central obesity, marked gynaecomastia, hypogonadism, incomplete virilisation, and anomalies of the hands and feet. In contrast, the two affected half brothers in family 2 (fig 1C) have …