Börjeson-Forssman-Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families

Abstract

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS.

Fig. 1. Facial phenotype of males and females with BFLS.

Photographs show individual M2 at age 26 years; individual M5 at age 6.5 years; individual M8; individual M9 at age 17 years; individual M10 at age 11 years; individual M11; individual F1 at age 13 years; individual F2 at 16 years of age; individual F3 at age 8 years; individual F5 at age 2 months and 3.5 years; individual F6 at age 9 years; and individual F7 at age 15 years. The dysmorphic facial features in both sexes include deep-set eyes, narrow palpebral fissures, large fleshy ears lobes, and short noses with a bulbous nasal tip. Facial features tend to coarsen with age.

Fig. 2. Skin and dental features of patients with BFLS.

Hypertrophic or keloid scarring on the chest of individual M2 (a), the ears of individual M10 (b,c), chest of individual M9 (d) and chest of individual F2 (e). Individual F2 had large fibromas grow from the nail beds of 8 toes (f, g). Dental examination of individual F2 (h) found a hypoplastic maxilla leading to a prognathic mandible and a range of dental anomalies including hypodontia, small widely spaced and irregularly shaped teeth, double talon cusps, dens invaginatus, and enamel hypoplasia. Teeth were removed due to compound composite odontomas (arrows). Steaky skin hyperpigmentation seen on individuals F1 (i) and F2 (j, k).

Fig. 3. Comparison of PHF6 variants found in affected males and females.

a PHF6 mutation types in families (our series plus literature) grouped by sex of BFLS probands. b Model of PHF6 gene showing location of BFLS associated sequence variants. The domain structure of the PHF6 protein is shown with exons below. The PHD-like domains (orange rectangles) containing zinc fingers are PHD1 (residues 14–132) and PHD2 (residues 209-330). PHF6 contains two nuclear localisation sequences (yellow boxes, residues 13–16 and 129–133) and a nucleolar localisation sequence (yellow box, residues 157–169). Domains positions are based on UniProtKB Q8IWS0. Exon model based on transcript NM_032458. PHF6 variants reported in affected females and males are shown above and below the model respectively. Missense variants are in red text. Large deletions and duplications are not shown. Below the model are plotted allele counts for missense variants from gnomAD (v2.1.1) demonstrating the severe depletion of variation across the PHD2 domain in the general population.