Börjeson–Forssman–Lehmann Syndrome: A Case Series with Emphasis on Endocrine Manifestations

Background: Börjeson–Forssman–Lehmann syndrome (BFLS; OMIM 301900; ORPHA 127) is a rare X-linked neurodevelopmental disorder caused by pathogenic variants in the PHF6 gene. The aim of this case series was to describe the clinical and endocrine phenotype of two genetically confirmed patients with BFLS and to highlight phenotypic variability relevant to diagnosis and long-term clinical management. Methods: We conducted a case series of two patients with genetically confirmed BFLS who were managed at a pediatric endocrinology center. Clinical data were collected from medical records, including perinatal and developmental history, growth parameters, endocrine assessments, systemic manifestations, genetic findings, treatment, and follow-up. Genetic diagnosis was established using next-generation sequencing-based whole-exome sequencing. Results: Both patients presented with global developmental delay, intellectual disability, short stature, and characteristic dysmorphic features. Endocrine abnormalities included hypothyroidism and growth impairment in both patients. Patient 1 additionally presented with central obesity, delayed skeletal maturation, hypogonadotropic hypogonadism, delayed puberty, and vitamin D insufficiency requiring treatment. Whole-exome sequencing identified pathogenic PHF6 variants in both patients. Patient 1 also had a history of Wilms tumor, representing a previously unreported finding in association with BFLS. Conclusions: These cases illustrate the substantial phenotypic variability of BFLS and emphasize the importance of regular endocrine surveillance, particularly assessment of growth, thyroid function, and pubertal development. The coexistence of BFLS and Wilms tumor represents a novel observation; however, a causal relationship cannot be established from a single case and requires further investigation.