PHF6 – Borjeson-Forssman-Lehmann Syndrome

Borjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked recessive neurodevelopmental disorder caused by pathogenic variants in PHF6, characterized by intellectual disability, truncal obesity, characteristic facial gestalt, endocrine anomalies and skeletal features in affected males, with sporadic de novo presentations in females due to skewed X-inactivation (PMID:22190899).

Genetic evidence for PHF6 involvement includes truncating and missense variants identified in 26 unrelated probands across >13 families (PMID:15580208; PMID:35662002). Case reports describe a de novo c.673C>T (p.Arg225Ter) variant in a female with growth hormone deficiency, horseshoe kidney and skewed X-inactivation inherited from an unaffected mother (PMID:30630810). A 15-kb deletion of PHF6 exons was identified de novo in another female with intellectual disability, abnormal dentition and skin pigmentation (PMID:22190899).

Segregation analysis includes two affected brothers with a Lys8Ter mutation exhibiting combined pituitary hormone deficiency and optic nerve hypoplasia (PMID:14714754), supporting co-segregation in familial BFLS. Ten male patients from two families carrying missense variants (e.g., c.134G>A (p.Cys45Tyr)) demonstrate a consistent BFLS phenotype of coarse facial features, gynecomastia and obesity (PMID:15580208).

Functional assays in patient-derived cells and models reveal that PHF6 loss perturbs neuronal development: CRISPR/Cas9 knockout in SK-N-BE(2) cells impairs neurite outgrowth, migration and transcriptional deregulation of chromatin regulators (PMID:33149206). A transgenic mouse harboring the recurrent c.1024C>T (p.Arg342Ter) mutation recapitulates intellectual disability, hydrocephaly, pituitary hypoplasia and behavioral deficits (PMID:33772537).

No conflicting evidence for PHF6–BFLS association has been reported. The weight of genetic, segregation and experimental data supports a Strong gene-disease association.

Key Take-home: PHF6 mutations cause X-linked BFLS through loss of function, with clear diagnostic utility in both males and females via gene sequencing and copy-number analysis.

References

• Molecular syndromology • 2011 • PHF6 Deletions May Cause Borjeson-Forssman-Lehmann Syndrome in Females. PMID:22190899
• Journal of clinical research in pediatric endocrinology • 2019 • A Novel Nonsense Mutation of PHF6 in a Female with Extended Phenotypes of Borjeson-Forssman-Lehmann Syndrome PMID:30630810
• Journal of pediatric endocrinology & metabolism • 2003 • Borjeson-Forssman-Lehmann syndrome and multiple pituitary hormone deficiency. PMID:14714754
• The Journal of pediatrics • 2004 • Clinical and behavioral features of patients with Borjeson-Forssman-Lehmann syndrome with mutations in PHF6. PMID:15580208
• Scientific reports • 2020 • Loss of PHF6 leads to aberrant development of human neuron-like cells. PMID:33149206
• Human molecular genetics • 2021 • Transgenic mice with an R342X mutation in Phf6 display clinical features of Börjeson-Forssman-Lehmann Syndrome PMID:33772537
• Clinical genetics • 2022 • Further characterization of Borjeson-Forssman-Lehmann syndrome in females due to de novo variants in PHF6. PMID:35662002

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