A Novel Nonsense Mutation of PHF6 in a Female with Extended Phenotypes of Borjeson-Forssman-Lehmann Syndrome

Abstract

Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked disease caused by PHF6 mutations. Classic BFLS has been associated with intellectual disability (ID), developmental delay (DD), obesity, epilepsy, typical facial features and anomalies of fingers and toes. Endocrinological phenotypes and outcome of treatment in this condition remain to be delineated. Here we report a patient who exhibited complete growth hormone deficiency who responded to hormonal treatment but with adverse effects. Horseshoe kidney was present in this patient, which is also atypical in BFLS. A heterozygous nonsense mutation c.673C>T (p.R225X) of PHF6 gene was identified in the patient, inherited from her unaffected mother. Both the patient and her mother showed highly skewed X-inactivation. We reviewed the phenotypes of all reported BFLS cases, and summarized their endocrine presentations. This first report of an Asian patient with BFLS further delineated the genetic and phenotypic spectrum of the syndrome. The adverse effect experienced by the patient suggests caution in the use of growth hormone treatment in this condition.

Keywords: Borjeson-Forssman-Lehmann syndrome; PHF6; X-inactivation; growth hormone deficiency; rhGH treatment; hypogonadism.

Figure 1

A, B, C, D, E, F) Pictures of our patient at age 9 years. A, B) Facial characteristics, C) Dental abnormalities, D, E) Hand and foot of the patient. The fifth fingers are short and curved, and the fourth toes are short. F) Results of the methylation-specific polymerase chain reaction assay. The inactivated X-chromosome sequence was amplified by the M-primer, the activated X-chromosome sequence was amplified by the U-primer. The result indicated a highly skewed X-inactivation in the patient (98:2) and in her mother (95:5)