Obesity arises from disrupted energy homeostasis, yet the neural mechanisms linking transcriptional regulation to energy expenditure remain unclear. Here, we identify plant homeodomain finger protein 6 (Phf6), a gene mutated in Börjeson-Forssman-Lehmann syndrome (BFLS), as a pivotal regulator of energy balance. Phf6 is enriched in a subset of estrogen receptor 1 (Esr1)-expressing neurons within the hypothalamic medial preoptic area (MPOA). Knockout of Phf6 in the MPOA leads to obesity in a sex-dependent manner by reducing physical activity and energy expenditure, independent of food intake. In female mice, MPOAPhf6 neurons respond to physical activity. Activation and inhibition of MPOAPhf6 neurons increases and decreases physical activity and energy expenditure, respectively. Phf6 sustains the intrinsic excitability of MPOAPhf6 neurons and their responsiveness to estrogen. Circuit mapping identified an MPOAPhf6-VMHvlEsr1 pathway mediating Phf6's effect on metabolism. These findings reveal a neurobiological basis for BFLS-associated obesity and highlight potential therapeutic targets.

Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked neurodevelopmental disorder caused by pathogenic variants in the plant homeodomain finger protein 6 (PHF6) gene. Core features include developmental delay, intellectual disability, dysmorphic craniofacial characteristics, obesity, hypogonadism and digital anomalies. Orofacial clefting has not been recognised as part of the canonical phenotype and is rarely reported in association with BFLS. One cohort study listed cleft lip and/or palate as an uncommon feature without individual case details, and a separate report described a female with a nonsense PHF6 variant and clefting of the hard and soft palate. Here, we describe a BFLS female with a de novo missense PHF6 variant who presented with cleft palate. This case adds to the emerging evidence that clefting, though uncommon, may be a recurrent manifestation. It supports the inclusion of PHF6 in the genetic testing of patients presenting with syndromic orofacial clefting when accompanied by neurodevelopmental delay or dysmorphism.

Börjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked neurodevelopmental disorder caused by pathogenic variants in the plant homeodomain finger protein 6 (PHF6) gene, typically associated with intellectual disability, hypotonia, dysmorphic features, endocrinological abnormalities, epilepsy, and global developmental impairment. Most published literature focuses on genetic and phenotypic characterization, with limited information regarding rehabilitation or long-term functional outcomes. We report the longitudinal follow-up of a male child with genetically confirmed BFLS, monitored from the age of 7 months (December 2021) to the age of 4.5 years (October 2025) at the time of manuscript submission, while receiving multidisciplinary rehabilitation. Interventions included physiotherapy targeting postural control and antigravity activation, occupational therapy addressing sensory regulation and purposeful reaching, speech and feeding therapy providing oral-motor stimulation and saliva management, structured caregiver training, and the prescription of assistive devices such as adaptive seating systems and a standing frame. Despite severe axial hypotonia and global developmental delay, the child achieved gradual but modest gains in head control, brief supported sitting, visually guided reaching, and social engagement. Feeding transitioned from mixed oral intake to percutaneous endoscopic gastrostomy (PEG) dependence for nutritional safety and adequacy, while minimal oral stimulation was maintained. A review of the literature confirms that rehabilitation trajectories in BFLS are rarely described and that no standardized guidelines exist. This case contributes one of the few multi-year functional follow-ups available and highlights that early, sustained, and individualized multidisciplinary rehabilitation can promote incremental improvements in motor function, interaction, even in severe presentations, with meaningful implications for quality of life.

Background: More than 1500 genes are associated with developmental delay and intellectual disability, with variants in many of these genes contributing to a shared phenotype. The discovery of variants of uncertain significance (VUS) found in these genes during genetic testing can lead to ambiguity and further delay in diagnosis and medical management. Phenotyping, additional genetic testing, and functional studies can all add valuable information to help reclassify these variants. Here we demonstrate the clinical utility of epigenetic signatures in prioritizing variants of uncertain significance in genes associated with developmental delay (DD) and intellectual disability (ID). Methods: Genome sequencing was performed in a male with developmental delay. He was found to have VUSs in both PHF6 and DDB1 genes, linked with Börjeson-Forssman-Lehmann syndrome (BFLS) and White-Kernohan syndrome (WHIKERS), respectively. These two disorders share a similar phenotype but have distinct inheritance patterns and molecular pathogenic mechanisms. DNA methylation profiling (DNAm) of whole blood was performed using the clinically validated EpiSign assay. Results: The proband's methylation profile demonstrated a strong correlation with the BFLS methylation signature, supporting the PHF6 variant as a likely cause of his neurodevelopmental disorder. Conclusions: Epigenetic testing for disorders with distinct methylation patterns can provide diagnostic utility when a patient presents with variants of uncertain significance in genes associated with developmental delay. Epigenetic signatures can also guide genetic counselling and family planning.

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability and endocrine disorder caused by pathogenic variants of plant homeodomain finger gene 6 (PHF6). An understanding of the role of PHF6 in vivo in the development of the mammalian nervous system is required to advance our knowledge of how PHF6 mutations cause BFLS. Here, we show that PHF6 protein levels are greatly reduced in cells derived from a subset of patients with BFLS. We report the phenotypic, anatomical, cellular and molecular characterization of the brain in males and females in two mouse models of BFLS, namely loss of Phf6 in the germline and nervous system-specific deletion of Phf6. We show that loss of PHF6 resulted in spontaneous seizures occurring via a neural intrinsic mechanism. Histological and morphological analysis revealed a significant enlargement of the lateral ventricles in adult Phf6-deficient mice, while other brain structures and cortical lamination were normal. Phf6 deficient neural precursor cells showed a reduced capacity for self-renewal and increased differentiation into neurons. Phf6 deficient cortical neurons commenced spontaneous neuronal activity prematurely suggesting precocious neuronal maturation. We show that loss of PHF6 in the foetal cortex and isolated cortical neurons predominantly caused upregulation of genes, including Reln, Nr4a2, Slc12a5, Phip and ZIC family transcription factor genes, involved in neural development and function, providing insight into the molecular effects of loss of PHF6 in the developing brain.