Börjeson-Forssman-Lehmann Syndrome (PHF6)

X-linked neurodevelopmental disorder caused by loss of function of PHF6, with a male phenotype of intellectual disability, truncal obesity, hypogonadism, gynaecomastia and large ears, variable expression in female carriers from affected families, and a de novo female phenotype overlapping with Coffin-Siris syndrome; the article also distinguishes the somatic role of PHF6 in leukaemias and covers the differential diagnosis with X-linked intellectual disability, Siderius type (PHF8).

Literature and regulatory information updated: 18 October 2026.

0. Reference Summary Table

1. Introduction

1.1. Original description and clinical delineation

In 1961, at the Second International Congress on Mental Deficiency in Vienna, and in 1962, in Acta Medica Scandinavica, Mats Börjeson, Hans Forssman and Olof Lehmann described in a Swedish family a syndrome that was "X-linked, recessively transmitted, and characterised by severe mental deficiency, epilepsy and endocrine disorder" [26, 27]. The three affected males, two maternal half-brothers and a maternal half-uncle, had severe ID, epilepsy, hypogonadism, hypometabolism, marked obesity, swelling of the subcutaneous tissue of the face, narrow palpebral fissures and large but normally shaped ears; three women in the family, possible carriers, had moderate ID [1, 20]. Brun, Börjeson and Forssman published the neuropathological study of the family in 1974, and Baar and Galindo described in 1965 an isolated case that they considered to be the same entity [1, 27].

Subsequent reports broadened the phenotype and introduced affected females. In 1978, Weber and colleagues identified, in a 28-year-old man with the classic picture, primary hypogonadism as the underlying endocrine abnormality, rather than the hypopituitarism suggested by earlier reports, and in 1983 Robinson and colleagues reported a sibship from Saudi Arabia with a severely affected male and monozygotic twin girls with milder expression (short stature, hypotonia, cognitive impairment, coarse face with prominent supraorbital ridges and large ears), with clinical, radiographic, electroencephalographic and endocrine data [28, 29]. In 1984, Ardinger and colleagues studied five males from two families, emphasised the facies with prominent supraorbital ridges, deep-set eyes, ptosis and large ears, found no reliable way to identify heterozygotes, and proposed Prader-Willi, Coffin-Lowry and Bardet-Biedl syndromes as differential diagnoses [1, 30]. In 1986, Dereymaeker and colleagues described a proband with severe ID, seizures, a round face with a large tongue, large ears, relative microcephaly, short stature with hyperkyphosis and a short neck, with similar features in the mother and in a maternal cousin, and discussed X-linked dominant or autosomal dominant inheritance with variable expression and penetrance [1, 31].

1.2. Mapping and gene identification

In 1989, Turner and colleagues obtained a maximum lod score of 2.1 (θ = 0) with DXS51 in a family with seven affected males, and Mathews and colleagues obtained values of 2.32 with DXS10 and 2.24 with DXS51 in one of the Ardinger families; combining the two data sets gave a lod score of 4.09 and placed the locus at Xq26–q27 [1, 32]. In 1999, a dup(X)(q26q28) duplication in an infant with features resembling the syndrome made FGF13 a candidate gene, a hypothesis superseded by the identification of PHF6 [1]. In 2002, Lower and colleagues, in Adelaide, narrowed the interval to about 9 Mb containing more than 62 genes and identified in PHF6 eight different variants (missense and truncating) in seven families and two sporadic cases; the GFP-tagged protein (green fluorescent protein) showed diffuse nuclear distribution with nucleolar accumulation [7, 33]. In 2004, the same team showed that the original Swedish family carried NM_001015877.2:c.1024C>T p.(Arg342*) (designated 1024C>T, R342X, in the article), a recurrent variant [34].

1.3. Phenotypic expansion and the female phenotype

The series of nine families with a confirmed variant published by Turner and colleagues in 2004 showed that the male phenotype is milder and more variable than in the original description and evolves with age, and that 20% of heterozygous females have significant learning difficulties [18]. In the same year, Visootsak and colleagues described ten males from two families without microcephaly, seizures or short stature, with a more favourable behavioural profile than males with Prader-Willi syndrome or Klinefelter variants [35]. In 2006, Crawford and colleagues described the first female with a clinical diagnosis of BFLS and a confirmed de novo variant, and Gécz and colleagues published a review of 19 unrelated cases [36, 37]. Between 2011 and 2014, Berland, Zweier and Di Donato defined the phenotype of females with de novo variants or deletions, which overlaps with Coffin-Siris syndrome (CSS) in early childhood [38–41]. The series of Gerber (2022; 11 females) and Jain (2023; 19 individuals from 15 families in the United Kingdom) quantified the differences between the sexes and proposed recommendations for evaluation and follow-up [13, 16].

1.4. Nomenclature and entities within scope

OMIM records the entity as BFLS (#301900), with the synonyms MRXSBFL and Börjeson syndrome; Orphanet uses ORPHA:127 and the name «Síndrome Borjeson-Forssman-Lehmann» in the Portuguese version [1–3]. Smith's Recognizable Patterns classifies BFLS among the disorders of chromatin remodelling with abnormal brain development [27]. Three germline presentations of the same gene are distinguished in this article: (a) hemizygous males, as a rule with variants inherited from carrier mothers, who constitute the classic form; (b) heterozygous females from families with affected males, who are asymptomatic or have mild features; and (c) females with de novo PHF6 variants or deletions, with a distinct phenotype that includes the CSS-like picture [13, 16]. The French national protocol considers that de novo females with "non-syndromic ID, without signs suggestive of BFLS" appear to represent a different entity, whereas Zweier, Gerber and Jain include the de novo female phenotype within the BFLS spectrum [13, 16, 20, 40]. Somatic PHF6 variants in T-cell acute lymphoblastic leukaemia (T-ALL) and in myeloid neoplasms are a distinct biological reality, with no demonstrated germline predisposition [16, 42]. X-linked ID, Siderius type, caused by PHF8, shares the PHD (plant homeodomain) domain and X-linked inheritance and is treated as a differential diagnosis in section 6.

2. Molecular Genetics and Pathophysiology

2.1. The PHF6 gene and its protein

PHF6 lies at Xq26.2, spans about 55 kb of the genome (GRCh38 X:134,373,284–134,428,792) and has 11 exons; the 1095 bp open reading frame encodes a protein of 365 amino acids and about 41 kDa [7, 8, 42]. The gene produces two splice variants (PHF6a and PHF6b) that differ by the presence of a 330 bp sequence which constitutes intron 10 in the shorter form [7]. The protein has two PHD-like domains with imperfect, extended zinc fingers, PHD1 (residues 14–132) and PHD2 (residues 209–330, according to UniProtKB Q8IWS0), two nuclear localisation signals (residues 13–16 and 129–133) and one nucleolar localisation signal (residues 157–169) [13, 16]. PHF6 is conserved in vertebrates and intolerant of loss of function in gnomAD (pLI = 1) [16]. In the 12.5-day mouse embryo, expression is highest in the developing central nervous system; after birth it is ubiquitous, with high or moderate levels in the thymus, gonads, thyroid, spleen, adipose tissue and skin, and the protein is expressed in all haematopoietic subpopulations [7, 16, 42]. Phf6 expression is particularly strong in the central nervous system, the adenohypophysis, the facial primordia and the limb buds, which relates to the organs affected in the syndrome [43].

The MANE Select designation corresponds to transcript NM_001015877.2 (ENST00000370803.8); the clinical BFLS literature (Jain 2023, Gerber 2022, Ramsey 2025) uses NM_032458.2 or NM_032458.3, and Zhang 2019 uses NM_001015877 [8, 13, 16, 44, 45]. For the variants checked in ClinVar and Ensembl, c. and p. numbering is identical between NM_001015877.2 and NM_032458.3; transcript NM_032335.3 has numbering shifted by three nucleotides (c.729G>A corresponds there to c.732G>A p.Met244Ile), so a report should always state the transcript and its version [10, 11].

2.2. Molecular function

PHF6 is a chromatin-associated nucleolar protein that acts as an epigenetic transcriptional regulator of neurogenesis and haematopoiesis; it associates with ribosomal RNA promoters and suppresses their transcription, and it has no enzymatic activity or measurable metabolite, which explains the absence of a biochemical biomarker [3, 16]. In the mouse cortex, PHF6 is required for neuronal migration: it associates physically with the PAF1 transcription elongation complex and promotes migration through this pathway; it also interacts with the NuRD complex and with the nucleolar regulator UBF, and its messenger RNA is a target of miR-128 [46]. RNA interference knockdown in the mouse cortex produces white matter band heterotopias with neuronal hyperexcitability, a proposed mechanism for the ID and seizures [16, 46]. In differentiated human SK-N-BE(2) neuronal cells, CRISPR/Cas9 knockout dysregulates chromatin, transcription, axon and neuron genes and reduces proliferation, neurite outgrowth and migration [47].

Studies in animal models have added three pathways. In the developing cortex, PHF6 binds near neurogenesis genes and directly promotes the expression of ephrin receptors (EphR-A); patient mutations increase the self-renewal of embryonic neural stem cells, and forced EphR-A expression corrects the defect [48]. Phf6 deletion reduces the expression of growth hormone-releasing hormone (GHRH) in the brain, of growth hormone (GH) in the pituitary and of insulin-like growth factor 1 (IGF1) in the liver, and deletion restricted to the nervous system reproduces the deficit, indicating a neuroendocrine contribution to short stature [49]. In 2026, Phf6 deletion in Esr1+ neurons of the medial preoptic area caused sex-dependent obesity through reduced physical activity and energy expenditure, independently of food intake, providing a preclinical neurobiological basis for the obesity of the syndrome [50]. A September 2026 preprint, not peer reviewed, proposes TCF4 as an effector of PHF6 in neural stem cells, with improvement of behavioural deficits in BFLS mice after restoration of TCF4 [51]. In leukaemic cells, PHF6 forms a chromatin complex with PHIP (the gene for Chung-Jansen syndrome) that represses a network of stemness genes [52].

2.3. Inheritance, X inactivation and functional mosaicism

BFLS is X-linked. Hemizygous males are affected; no source describes an unaffected hemizygous male, and the French protocol states that all carrier boys will be affected, with variable expressivity [20, 35]. Heterozygous females from families with affected males are mostly asymptomatic or mildly affected, and females with de novo variants have a moderate to severe phenotype [13, 16]. Skewed X inactivation in blood is frequent in all three groups: Lower and colleagues found the variant-bearing chromosome 100% inactivated in all carriers tested except one, who had about 70% skewing and mild features (obesity, large ears, amenorrhoea, hypothyroidism, epilepsy and learning difficulties) [1]. Turner 2004 reports skewing in 95% of heterozygous females, Gerber 2022 in 23/29 (79.3%) carriers from recessive families and in 22/22 (100%) affected females, and Zhang 2019 in 38 of 43 females with a variant, of whom only 18 were affected [13, 18, 45].

The degree of skewing in blood does not predict severity. Zweier 2013 found skewing in lymphocytes with a random pattern in fibroblasts, suggesting functional mosaicism in solid tissues, including the brain [39]. In two de novo females, preferential inactivation of the mutated allele was demonstrated in blood, and in three transmissions from a mildly affected or asymptomatic mother to a more severely affected daughter the blood pattern was similar in both generations (for example, 91.4% in the mother and 97.2% in the daughter) [13]. Streaky hyperpigmentation following the lines of Blaschko, present in about half of de novo females and absent in asymptomatic carriers, is the visible cutaneous expression of this functional mosaicism [13, 53]. Gerber and colleagues conclude that female manifestation results from the interaction between X inactivation, functional mosaicism and the location, nature and severity of the variant; Jain and the French protocol likewise found no useful correlation between the blood pattern and symptoms [13, 16, 20].

2.4. Variant spectrum and sex differences

ClinVar lists 585 entries for PHF6 (207 pathogenic, 27 likely pathogenic, 128 of uncertain significance (VUS), 9 with conflicting interpretations and 122 benign or likely benign) [10]. In the Jain 2023 compilation, which combines the authors' own series and the literature, males mainly have missense variants or small in-frame deletions (59%, 16/27 families), distributed across the gene and both PHD domains; truncating variants (n = 7) and start-loss variants (n = 4) in males are confined to exons 2 and 10, the first and last coding exons, suggesting alternative initiation or escape from nonsense-mediated decay (NMD) with a partially functional protein [16]. No male had a multi-exon or whole-gene CNV [16]. Among affected females, 32% (12/37) had large de novo deletions or duplications, 46% (17/37) nonsense or frameshift variants distributed across the gene and 22% (8/37) missense variants clustered in the PHD2 domain, which is highly constrained in gnomAD [16]. Up to 2023, no pathogenic variant had been described both in an affected male and de novo in an affected female [16].

The variant NM_001015877.2:c.1024C>T p.(Arg342*), in exon 10 and at a CpG dinucleotide, has been observed at least five times, including in the original Swedish family and in a family from Western Australia; it is recurrent through independent mutation, not a founder variant [16, 34, 54]. No founder variants have been described. The following table brings together the variants of clinical or historical significance described in the sources, normalised to the MANE transcript; rows without a ClinVar identifier keep the authors' notation.

The 206 kb deletion of exons 6–10 in F2 of Jain 2023 also includes the adjacent gene HPRT1, and the 342 kb deletion in F5 includes the whole of PHF6; both arose de novo in females [16]. Intragenic duplications of exons 4–5 have been described in females with a typical phenotype and malformation of cortical development [39, 62]. The GeneReviews resource on epigenetic signatures refers to "biallelic" PHF6 variants in people with CSS features; no primary source consulted describes biallelic variants in an X-linked gene with hemizygous males and heterozygous females, and the wording is not reproduced as clinical data [15].

2.5. The hypothesis of male lethality of complete loss of function

Smith's Recognizable Patterns considers that de novo variants with complete loss of function, described in females, would be "presumably lethal" in males [27]. Berland 2011 hypothesised that large PHF6 deletions are incompatible with male fetal survival, and Jain 2023 notes that no male has a multi-exon CNV and that male truncating variants are concentrated in the terminal exons [16, 38]. In the International Mouse Phenotyping Consortium, the Phf6 knockout was classified as homozygous lethal, owing to the absence of homozygous animals in at least 28 litters before weaning, and Kurzer cites the lethality of germline deletion in male mice [7, 42, 63]. The data pointing the other way are equally direct: p.(Arg342*) causes near-complete loss of the protein in viable males; start-loss variants occur in males who reach adulthood; McRae's models studied viable male Phf6−/Y mice, a discrepancy with the consortium data that the sources do not explain; and R342X mice are born in Mendelian proportions, with hydrocephalus and high perinatal mortality only on the C57BL/6J background [13, 16, 49, 55, 56, 64]. The formulation compatible with these sources is that no males with deletion of the whole gene have been described and that non-viability of complete loss of function in males is an unproven hypothesis [3, 16].

2.6. Genotype–phenotype correlations, penetrance and expressivity

The most robust correlation is between sex, origin and variant type: inherited variants in males probably leave residual activity (hypomorphic or with a lesser effect on stability), whereas de novo variants in females tend to abolish the protein [16, 47]. The analogy proposed by Jain is that of IKBKG, with incontinentia pigmenti in females and hypohidrotic ectodermal dysplasia with immunodeficiency in males [16]. In males, PHD1 missense variants with a strong destabilising effect occur only in recessive families, and in PHD2 the "female" missense variants are more deleterious than the "male" ones; Gerber proposes that PHD1 is less critical than PHD2 [13]. PHF6 levels are markedly reduced with the missense variants p.(Cys45Tyr) and p.(Cys99Phe), but normal or increased with the in-frame deletions p.(Asp333del) and p.(Glu337del) (published protein designations, with no c. notation in the source), showing that protein stability does not account for the whole mechanism [44, 64]. The c.139-8A>G variant increases in-frame skipping of exon 3 and is associated with a mild phenotype, possibly owing to partial function of the protein lacking this exon [7, 57].

Penetrance in males is complete in the sources consulted, with expressivity ranging from mild to severe ID within and between families (Visootsak 2004: family A with mild to moderate ID, family B more severe) [20, 35]. In carriers, Zhang 2019 estimates a "penetrance" of about 44% (21/48) in the literature, and Gerber 2022 finds learning difficulties in 6/32 (18.8%) carriers from recessive families [13, 45]. Post-zygotic mosaicism is associated with a milder phenotype: the second female of Di Donato 2014 had a mosaic deletion and a very mild phenotype [13, 41].

2.7. Allelic disorders and the somatic role of PHF6

No germline allelic disorders distinct from BFLS are known. The somatic role of PHF6 differs in origin and consequences [42]. In 2010, Van Vlierberghe and colleagues identified inactivating mutations and somatic deletions of PHF6 in 16% (14/89) of paediatric and 38% (16/42) of adult primary T-ALL samples, almost all from male patients and associated with aberrant expression of TLX1 and TLX3; mutated cell lines completely lost the protein, and PHF6 was defined as an X-linked tumour suppressor [7, 65]. Later series report inactivating mutations in 5–16% of children and 19–40% of adults with T-ALL, about 25% of adults with T-lymphoblastic lymphoma, up to 25% (3/12) of early T-cell precursor ALL and copy number alterations in 13–14% of paediatric T-ALL; 67–84.6% of PHF6-mutated cases also have a NOTCH1 mutation [42]. In the T lineage, PHF6 inactivation is an early event that requires cooperating lesions; PHF6 is a direct target of NOTCH1 [42, 54].

In myeloid neoplasms, PHF6 mutations are later events, sometimes in parallel clones, with co-mutations in RUNX1, U2AF1, SMC1A, ZRSR2, EZH2 and ASXL1, and mutually exclusive with SF3B1 [42]. Van Vlierberghe found them in 10/353 adult AML cases, seven times more frequent in males; in Kurzer's compilation, the frequency is about 2–3% in acute myeloid leukaemia (AML), 15% in AML with inv(3)/t(3;3), 2% (6/318) in paediatric AML, about 3% in myelodysplastic syndromes (MDS) and 23% in mixed-phenotype acute leukaemias [42, 66]. Kubota 2024 described sex-specific co-mutations (RUNX1 and U2AF1 in males; ASXL1 and X deletions in females), a physical PHF6–RUNX1 interaction at active enhancers and a negative prognostic impact, especially with RUNX1 [67]. In familial platelet disorder with predisposition to myeloid malignancy due to germline RUNX1 variants, acquired PHF6 mutations have been implicated in progression to MDS or AML [42, 68]. PHF6 is included in the myeloid and lymphoid panels recommended by the ESMO (European Society for Medical Oncology) handbook of oncological genomics [69]. A PHF6 variant on a tumour panel is somatic unless shown to be germline and does not imply the syndrome; conversely, p.(Gly10Argfs*), p.(Arg274*) and p.(Arg342*) have been described both as germline in BFLS and as somatic in leukaemias [3, 16].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and natural history

Clinical knowledge rests on family descriptions, small series and literature compilations, without prospective natural history studies. The main cohorts are: the series of nine Australian, British, Dutch and American families of Turner 2004; the ten males from two American families of Visootsak 2004; the 19 individuals from 15 UK families (mostly from the Deciphering Developmental Disorders, DDD, study) of Jain 2023, with 11 males aged 2 to 34 years and 8 females aged 8 to 26 years; the 11 de novo females (10 months to 36 years) of Gerber 2022, from centres in Germany, Switzerland, Norway, Spain, Belgium, the USA and New Zealand; and the Gerber 2022 aggregate of 27 affected females, 62 males and 63 carriers from recessive families [13, 16, 18, 35]. The French protocol (PNDS (French National Diagnosis and Care Protocol)) compiles percentages from Gécz 2006, Turner 1989 and 2004, Carter 2009 and de Winter 2009 without denominators [20]. No source separates the natural history from treated disease; the data describe patients receiving variable symptomatic care.

The male course is that of a phenotype that becomes complete with age. In the first year, hypotonia, feeding difficulties, poor weight gain, large ears and small external genitalia predominate; at school age, learning difficulties, moderate short stature, truncal obesity and gynaecomastia appear, with tapering, soft fingers and short toes; the classically described heavy, coarse facies is complete only in late adolescence and adulthood [1, 18]. For this reason the clinical diagnosis is often missed in young boys and in isolated heterozygous females [18]. Pregnancy, delivery and birth measurements are usually normal; in the Jain series there were few gestational complications, one male and one female were born preterm, birth weight was normal and there was no intrauterine growth restriction [16, 20]. In the Swedish description, walking began at 4–6 years and speech was limited to a few sentences, two of the patients died of bronchopneumonia at 20 and 44 years, and life expectancy was presumed to be normal [27].

3.2. Male phenotype

Neurodevelopment and behaviour. All males have motor delay and ID, ranging from mild to severe [13, 16]. The original description and Smith's Recognizable Patterns give IQ values between 10 and 40, but the molecularly confirmed series show mild to moderate ID in a proportion of patients, and OMIM summarises the male phenotype as mild to moderate ID [1, 27, 35]. The PNDS itself describes the ID as "moderate to severe" in one section and "mild to moderate" in another [20]. Neonatal hypotonia occurs in 85% and can be severe, independent walking is achieved at a mean age of 2 years and 10 months (between 1 year 11 months and 4 years in the Gerber aggregate), and spoken language is generally present but limited; no adult is fully independent [13, 20]. In the Jain series, speech was limited or delayed in 18/19 and there were behavioural problems in 13/19 (6 males and 7 females): autistic traits, food seeking or hyperphagia, and challenging or aggressive behaviour [16]. The PNDS reports behavioural disorders in 90%, with attention-deficit/hyperactivity disorder (ADHD) in childhood, impulsivity and aggressiveness in adolescence and the possibility of bipolar disorder or psychotic disorder in adulthood; it describes few eating disorders despite the obesity [20]. Visootsak 2004 compared the ten males with 10 patients with Prader-Willi syndrome and 23 with Klinefelter variants (48,XXYY, 48,XXXY and 49,XXXXY) using the CBCL, Vineland and Reiss scales: daily living and social skills were stronger than communication skills, and males with BFLS had fewer internalising and externalising symptoms and were more sociable [35]. De Winter 2009 described four Dutch males with generally friendly but sometimes challenging behaviour, with externalising and sensation-seeking traits, and marked hypersexual behaviour in three patients from one family, not observed in the others [43].

Growth and obesity. Height is below the mean in 9/10 of Jain's males and below −2 standard deviations (SD) in 4/10; the PNDS reports short stature below −2 SD in 30%, usually not below −3 SD [16, 20]. Carter 2009 described males with normal to tall stature, and Jain's M12 measured +1.7 SD at 10 years [16, 70]. Truncal obesity is cardinal: 44/48 (91.7%) in the Gerber aggregate, 7/8 in the Jain series and 77% from adolescence onwards in the PNDS [13, 16, 20]. Smith's Recognizable Patterns describes moderate obesity beginning in adolescence that may decrease later [27].

Head circumference. Microcephaly was part of the classic description, the Oxford Desk Reference groups BFLS among the XLID (X-linked ID) disorders with microcephaly [71], and the appendix of Smith's Recognizable Patterns lists it as frequent, although the text of the same book describes a usually normal head circumference [27, 72]; however, the molecularly confirmed series show a usually normal head circumference, with possible macrocephaly [18, 70]. In the Gerber aggregate, males with available data had 5 microcephalies, 25 normal head circumferences and 6 macrocephalies (n = 36), and the PNDS gives 17% microcephaly and 22% macrocephaly; in the Jain series there was one microcephaly (M7, −2.5 SD, with de novo p.(Arg342*)) and one macrocephaly [13, 16, 20]. Microcephaly is therefore a minority finding and not discriminating.

Face and extremities. The facies includes prominent supraorbital ridges, deep-set eyes (enophthalmos), narrow, upslanting palpebral fissures, ptosis, hypertelorism, a thin upper lip and long ears with fleshy lobes, 7.5 to 9 cm long but normally shaped; the features coarsen with age, with a bulbous nose and swelling of the facial subcutaneous tissue [1, 16, 27]. The characteristic face was present in 47/47 published males [13]. Digital anomalies affect 92% of males in the Jain data set and 16/16 in the Gerber data set: short, tapering, soft fingers (68.8%), fifth-finger clinodactyly, broad feet with short toes (brachydactyly of the toes 54.5%) and a gap between the first and second toes (sandal gap, 59.1%) [13, 16]. Smith's Recognizable Patterns describes a thick calvarium, a narrow cervical spinal canal, mild scoliosis, kyphosis, Scheuermann-like vertebral changes, metaphyseal widening and hypoplastic middle and distal phalanges [27]. The PNDS reports scoliosis in 40% and joint hyperlaxity in 20% [20].

Genitalia and puberty. A small penis and testes, cryptorchidism and delayed secondary sexual characteristics define male hypogonadism, present in 44/45 (97.8%) published males and in 93% in the PNDS, with cryptorchidism in 50% and absence of pubic hair in 75% in adolescence [13, 20]. Post-pubertal gynaecomastia is distinctive in older males (5 males aged 10 to 34 years in the Jain series) [16]. In the Jain series, hypogonadism or small genitalia were recorded in only 4/9 males, which the authors attribute to the young age of the patients [16].

3.3. Carriers from families with affected males

The phenotype of heterozygous females ranges from asymptomatic to identical to the male phenotype [20, 27]. Turner 2004 found mild features in some (tapering fingers, short toes) and significant learning difficulties in 20% [18]. In the Gerber aggregate, 6/32 (18.8%) carriers had learning difficulties, 16/23 (69.6%) a subtle male-type face, 8/21 (38.1%) finger anomalies, 9/21 (42.8%) toe anomalies, 4/19 (21.1%) obesity and 1/15 (6.7%) oligomenorrhoea; linear hyperpigmentation and dental anomalies were not described [13]. The PNDS gives ID in about 14% of carriers and learning difficulties in 45%, with morphological signs in 50% and obesity in 19% [20]. Smith's Recognizable Patterns describes a range of performance from mild to moderate ID (IQ 56–70) to above-average intelligence [27]. OMIM mentions hypothyroidism in heterozygous females with a male-like phenotype [1].

Two historical female cases show full expression in a heterozygote. Kubota 1999 described a 32-year-old Japanese woman, the only affected member of her family, with hypotonia in early infancy, special schooling, a first seizure at 3 years, obesity from the age of 5, diabetic ketoacidosis at 31 years, a height of 142 cm, a coarse face with a narrow forehead, prominent supraorbital ridges, narrow palpebral fissures, ptosis, deep-set eyes, full cheeks and large ears, small hands with tapering fingers and short fifth fingers, and extremely skewed X inactivation on methylation-specific polymerase chain reaction (PCR) [1, 73]. In the Dereymaeker 1986 family, a first cousin, the daughter of a male relative on the maternal side with ID and a normal somatic phenotype, had progressive hyperkyphosis, absence of menarche at 17 years and sudden death at 17 years, probably during a seizure [1, 31].

3.4. Females with de novo variants and overlap with Coffin-Siris syndrome

The de novo female phenotype is recognisable and differs from the male one [39, 40]. Zweier 2013 described seven females with variable ID, sparse hair, a characteristic face, hypoplastic nails, brachydactyly, clinodactyly mainly of the fourth and fifth fingers, dental anomalies and linear hyperpigmentation [39]. The face includes bitemporal narrowing, supraorbital ridges, high or arched eyebrows, synophrys, a high nasal bridge, a short nose with a bulbous tip and long ears with prominent lobes [13, 40, 41]. In adolescents and adults the phenotype overlaps with the male one without being identical; in younger girls the overlap with CSS (ID, sparse hair, hypoplastic nails) is marked [40]. Two girls with a clinical diagnosis of CSS in early childhood had PHF6 variants (one with de novo c.914G>T p.(Cys305Phe), hypertrichosis, a coarse face and hypoplasia of the nails and phalanges of the fifth finger; the other with a de novo frameshift, mild ID, average stature, nystagmus and strabismus), and most patients acquired features closer to BFLS with age [1, 14, 60]. The CSS GeneReviews entry regards PHF6 as a rare cause, and the two syndromes are still considered distinct entities [14].

In Gerber's aggregate of 27 females, 23/26 had de novo variants, 24/27 (88.9%) ID, 23/25 (92%) the typical female face, 24/25 (96%) finger anomalies (clinodactyly 64%, brachydactyly 52%, tapering fingers 28%, hypoplastic nails 32%), 21/23 (91.3%) toe anomalies (syndactyly 43.5%, hypoplastic nails 30.4%), 17/25 (68%) linear hyperpigmentation, 18/20 (90%) dental anomalies, 10/10 oligomenorrhoea or amenorrhoea and only 5/25 (20%) obesity [13]. Height was normal in 17, short in 2 and tall in 4, and head circumference was normal in 14, with 4 microcephalies and 2 macrocephalies [13]. In Gerber's own series, ID was mild to moderate in 7/10 and severe or profound in 3/10, walking was achieved between 10 months and not at all by 7 years, and two patients had no speech at 7 and 15 years [13]. In the Jain series, 6/7 females had obesity or a body mass index (BMI) above +2 SD, height ranged from −2.7 SD to +1.8 SD, and 5 females had syndactyly of the toes and hypoplastic or dysplastic nails [16]. Crawford 2006 described a 14-year-old girl with an IQ of 84 at 4 years, a low forehead, large ears with fleshy lobes, deep-set eyes, broad feet and hammer toes, and 93% skewing of X inactivation [1, 36]. Di Donato 2014 described two females with overlapping Xq26.2 deletions of 100 kb and 270 kb, one of them mosaic with a very mild phenotype, both with occasional major malformations [41].

The differences between the sexes are summarised in the following table, with the denominators from the sources.

Source: table 1 of Gerber 2022 and table 2 of Jain 2023; NR, not reported; NA, not applicable [13, 16]. The figure for camptodactyly or hammer toes in females (6/23) is given by Gerber as 43.5%, but 6/23 corresponds to 26.1% [13].

3.5. Endocrine system

Male hypogonadism was initially considered hypogonadotropic owing to pituitary dysfunction, but Weber 1978 described primary hypogonadism and there are reports of males with low testosterone and raised gonadotropins, and of abnormal testicular tissue; both central and gonadal forms are possible [20, 28, 45]. In the Zhang 2019 review, testosterone was reduced in 12/15 males, gonadotropins below the reference range in 8/23 patients and oestradiol reduced in 2/4 females, there was hypothyroidism in 6/15 and genital anomalies in 27/46 (59%) [45]. The PNDS reports hypothyroidism in 8% of adults, central or peripheral [20]. Birrell 2003 described two brothers with p.(Lys8*) and multiple pituitary hormone deficiency of GH, thyrotropin (TSH), corticotropin (ACTH) and gonadotropins, confirmed biochemically and radiologically, with optic nerve hypoplasia; Dattani described in these brothers hypoplasia of the adenohypophysis and absence of the stalk and neurohypophysis [59, 74]. The PNDS mentions neonatal hypoglycaemia in two newborns and two cases of panhypopituitarism [20]. Five patients with GH deficiency had been published by 2019, two of them with multiple pituitary hormone deficiency [45]. In the Jain series, two males had GH deficiency (M2 and M8; M2 with an IGF-1 of 5.2 nmol/L against a normal range of 11.5–34.6 nmol/L, hypoglycaemia at 7 years and a small posterior pituitary), M1 required testosterone for delayed puberty, three females had primary amenorrhoea and one (F1) had hypogonadotropic hypogonadism with absent ovaries and a rudimentary uterus [16]. In de novo females, the frequent oligomenorrhoea may reflect hypogonadism, but only one published female had confirmed hypogonadotropic hypogonadism up to 2022 [13].

3.6. Nervous system

Epilepsy was part of the original description but is inconstant in modern series: 12% in the PNDS, non-specific and usually not drug-resistant; 2/9 males and 1/8 females in the Jain series (in one male possibly due to recurrent hypoglycaemia); 5/23 females in the literature [16, 20, 26]. Gerber concludes that neither structural brain anomalies nor epilepsy appear to be frequent in either sex [13]. By contrast, Jain's F1 had drug-resistant frontal lobe epilepsy with cortical dysplasia, and the Portuguese case of Silva 2026 had seizures from three weeks of life, which the authors describe as "common" in the syndrome [16, 61]. Smith's Recognizable Patterns describes an electroencephalogram (EEG) with a very poor alpha rhythm and central nervous system anomalies attributed to disturbed neuronal migration [27]. On magnetic resonance imaging (MRI), 10/15 published females and 3/5 in the Jain series had anomalies: periventricular hyperintensity, hypoplasia of the corpus callosum, cavum septi pellucidi, enlarged ventricles and, in two females with intragenic duplications of exons 4–5, simplified gyration and temporal and peri-insular subcortical band heterotopia with adult-onset epilepsy [13, 16, 62]. In males, mild hypoplasia of the corpus callosum, delayed or reduced myelination and, in one brother, posterior atrophy of the corpus callosum with an abnormal pituitary have been described [16]. Polyneuropathy has been described in a carrier mother, her affected sons and a brother, and Jain's F3 had distal motor axonal neuropathy of the lower limbs [16, 20].

3.7. Eyes, hearing, skin, teeth and other organs

Ocular anomalies were present in 8/9 males and 7/8 females in the Jain series: refractive errors (6 males, 5 females), strabismus (2 males, 5 females) and nystagmus (2 males); retinal dystrophy, retinal depigmentation with maculopathy and optic disc dysplasia occur mainly in females [13, 16]. The PNDS gives refractive errors in 19%, and Smith's Recognizable Patterns describes nystagmus, ptosis and poor vision with retinal and optic nerve anomalies [20, 27]. Recurrent otitis media or conductive hearing loss affected 9 of Jain's patients and mild sensorineural hearing loss 2; the PNDS reports sensorineural deafness in about 6%, with onset from childhood to adulthood [16, 20].

In the skin, streaky and whorled hyperpigmentation following the lines of Blaschko is distinctive of de novo females (at least 6/8 in the Jain series), may fade with age and has been interpreted as a reflection of lyonisation [16, 53]. Garcia-Melendo 2021 described a 6-year-old Spanish girl with linear hyperpigmentation in the axillae and groins, ID, dysplastic teeth and nails and a mosaic splice variant [75]. Hypertrophic scars or keloids occurred in 4 of Jain's patients (3 males, 1 female), including substantial keloids after otoplasty, and F2 developed from the age of 9 painful bluish fibromas of the nail beds of eight toes, recurring after surgery, similar to those of terminal osseous dysplasia with pigmentary defects [16]. Hypopigmented macules, café-au-lait spots, multiple naevi and sparse or fine hair in 4 females and 2 males have also been described [16]. Dental anomalies (hypodontia, enamel defects, small or widely spaced teeth, large incisors with long roots, talon cusps, dens invaginatus, odontomas) are frequent in females (18/20 in the literature, 6/8 in the Jain series) and rare in males [13, 16].

Congenital anomalies in the Jain series include umbilical hernia (1 male, 4 females), clubfoot (2 females) and structural renal anomalies (2 males, 1 female, including horseshoe kidney and pelvic kidney); Zhang 2019 also described a horseshoe kidney [16, 45]. The PNDS, by contrast, states that no congenital malformation has been reported apart from one case of cleft lip and palate [20]. Cleft palate was described in one female in Gerber 2022 and, in February 2026, in a female with a de novo missense variant, whose authors propose including PHF6 in the investigation of syndromic orofacial clefts with developmental delay or dysmorphism [13, 76]. The PNDS mentions dilated cardiomyopathy as exceptional [20]. Obstructive sleep apnoea occurred in two of Jain's females (one treated with continuous positive airway pressure, the other with tonsillectomy and adenoidectomy) and hypoventilation in the Portuguese case [16, 61].

3.8. Neoplasms in patients with BFLS

Up to 2023, only three neoplasms had been described in patients with BFLS: T-ALL in a boy with germline c.1024C>T p.(Arg342*), diagnosed at 7 years, Hodgkin lymphoma in a man (attributed by Jain to the Carter 2009 series) and a Wilms tumour at 3 years in Jain's female F8 [16, 54]. Chao and colleagues suggested, on the basis of one case, that BFLS "may represent" a predisposition syndrome; the leukaemic cells were not available for somatic study [54]. Kurzer reports that, up to 2021, PHF6 mutations had been identified only in haematological neoplasms and that only one patient with BFLS had T-ALL [42]. Germline predisposition to leukaemia has not been demonstrated, and the oncological risk is uncertain owing to lack of data [3, 16].

4. Clinical Recognition and Red Flags

4.1. When to suspect, by age

No sign is specific, and the PNDS requires molecular confirmation [20]. More and more patients are diagnosed by genome-wide sequencing without prior suspicion; a clinical diagnosis is more likely when the combination of signs is sought according to age [18, 20].

In a young girl with a CSS picture and in a woman with linear pigmentation, BFLS should be considered before accepting a diagnosis of CSS without molecular confirmation or of incontinentia pigmenti; in three of Jain's females the pigmentation led to testing of IKBKG [16, 40].

4.2. Red flags and emergency signs

The situations requiring immediate assessment arise mainly from the hypothalamic-pituitary axis and from feeding. Neonatal or childhood hypoglycaemia, especially with micropenis or bilateral cryptorchidism, should prompt investigation for anterior pituitary deficiency (GH, ACTH) from birth [20, 59]. Severe feeding difficulties with a risk of aspiration, hypoventilation and obstructive sleep apnoea led to gastrostomy and to an indication for non-invasive ventilation in the Portuguese case [16, 61]. Drug-resistant seizures, especially in females with malformation of cortical development, require specialist neurology [16, 62]. Recurrent respiratory infections are relevant: two patients in the original family died of bronchopneumonia, and Jain's M1 died at 26 years of Haemophilus influenzae pneumonia with suspected common variable immunodeficiency, whose investigation remained incomplete [16, 27]. Lymphadenopathy with hyperleucocytosis led to the diagnosis of T-ALL in Chao's boy [54].

4.3. Newborn screening

There is no newborn screening for BFLS, nor any biochemical marker that would allow it [3]. The sensorineural hearing loss of one boy in the Jain series was detected by newborn hearing screening, which is universal and not specific [16].

5. Diagnosis: Criteria, Testing and Algorithms

5.1. Criteria and definition of the diagnosis

There are no formal clinical criteria. The PNDS defines clinical criteria for suspicion in boys (mild to severe ID; hypogonadism with small testes, micropenis and sparse pubic hair; post-pubertal gynaecomastia; truncal obesity; a face with large fleshy ear lobes, enophthalmos and a prominent supraorbital rim) and other features of variable frequency (epilepsy, sensorineural deficits, behavioural disorders) [20]. The diagnosis is confirmed by identification of a pathogenic (class V) or likely pathogenic (class IV) PHF6 variant, hemizygous in a male or heterozygous in a female [20].

5.2. Baseline clinical evaluation

For ID with apparently X-linked inheritance, the Oxford Desk Reference proposes: a pedigree of at least three generations in the maternal line; distinction between syndromic and non-syndromic forms; comparison with known syndromes; awareness that unbalanced chromosomal rearrangements can mimic X linkage in small families; and FMR1 testing in all boys with ID [71]. Baseline biochemical tests (electrolytes, uric acid, liver function tests, full blood count, creatine kinase and urine metabolic screen; free T3 for SLC16A2; urine creatine/creatinine ratio for SLC6A8) serve to exclude other causes, not to confirm BFLS [71]. GeneGuidance suggests assessment of the hypothalamic-pituitary-gonadal axis, thyroid function and metabolic status, growth monitoring, neuropsychological and language assessment, an EEG if seizures are suspected and dysmorphological examination of the hands, feet, nails and teeth; in at-risk heterozygous females, a careful search for tapering fingers, short toes, nail hypoplasia and linear hyperpigmentation [3].

5.3. Molecular tests in order

In an evidence-based guideline from 2021, the ACMG (American College of Medical Genetics and Genomics) recommends exome or genome sequencing as a first- or second-tier test in patients with congenital anomalies before 1 year of age or with developmental delay or ID before 18 years of age [19]. The 2025 clinical report of the American Academy of Pediatrics (AAP) recommends a phenotype-directed test when the phenotype suggests a specific condition and, in other cases, a genome-agnostic approach [77]. The PNDS makes this specific for BFLS: Sanger sequencing or a small panel when clinical suspicion is strong; a large panel, exome or genome when there is no suspicion; and chromosomal microarray (CMA) for deletion of the whole gene, which it considers very rare [20]. In the Gerber series, targeted PHF6 testing (Sanger and MLPA, multiplex ligation-dependent probe amplification) was performed on clinical suspicion in 4/11 females, showing that the female phenotype is recognisable [13]. Because females have deletions and duplications in about one third of cases, CNV analysis (CMA, MLPA or CNV calling from the exome or genome) is mandatory when sequencing is negative [16, 38, 41].

5.4. Test sensitivity and yield

There are no studies of the clinical sensitivity of tests for BFLS. The table in the CSS GeneReviews chapter indicates that 100% of the PHF6 variants known in that syndrome were detected by sequencing and that the proportion detected by targeted deletion/duplication analysis is unknown; this figure describes the type of published variants, not the probability that a test will detect the disease in a patient [14]. Lower 2002 found no PHF6 variants in four sporadic cases with a presumptive diagnosis [7]. Crawford 2006 screened 25 patients with clinical suspicion (24 males and 1 female) and found variants in 5, four of the 24 males; one of these was an isolated case with skewed maternal X inactivation, and three were familial, two of them with maternal skewing [1, 36]. This is the yield in a cohort selected by phenotype, not a sensitivity, and it shows that the yield increased when there was a family history or maternal skewing; the PNDS now considers the X-inactivation study useless in practice [20, 36].

5.5. DNA methylation signature

BFLS has been part of the EpiSign classifier since version 3 [21]. GeneReviews refers to a distinct episignature in affected males, absent in affected heterozygous females [15]. Vos 2024 built an episignature combined with Chung-Jansen (PHIP) and White-Kernohan (WHIKERS, DDB1) syndromes, with 213 probes, from 14 BFLS discovery samples, all from males; of the 10 test samples, all but two did not match the episignature, and none of the four females with pathogenic or likely pathogenic missense variants was positive [21]. A negative episignature does not exclude BFLS, especially in a female, and a positive combined episignature requires analysis of PHIP, PHF6 and DDB1 [21]. Ramsey 2025 used EpiSign v5 in a boy with maternal c.763_765del p.(Thr255del) and a de novo DDB1 VUS: the profile was more consistent with BFLS, and the authors applied the PS3 criterion of the ACMG and the Association for Molecular Pathology (ACMG/AMP) to reclassify the variant as likely pathogenic, without excluding concomitant WHIKERS [44]. In a series of 298 patients from Rotterdam, the episignature was positive in 18% (10/55) of the VUS tested, 91% (10/11) of likely pathogenic variants and 89% (8/9) of pathogenic variants, figures for all the disorders combined and not for BFLS [79]. Long-read sequencing detects episignatures and allows haplotype-based assessment of X inactivation, as a proof of concept [80]. The sensitivity and specificity of the BFLS episignature alone were not found in the sources consulted.

5.6. Variant interpretation and report content

The report should state the gene, the transcript with its version (NM_001015877.2, MANE Select; if the laboratory uses NM_032458.3, the equivalence), the HGVS c. and p. nomenclature, the genomic coordinate with the genome build, the zygosity (hemizygous or heterozygous), the ACMG/AMP class with the criteria applied, and the origin when known [10, 16]. Discrepancies between laboratories and ClinVar are frequent: c.1014_1016del p.(Glu338del) is pathogenic in the Jain series on the basis of segregation in five males from two families and a VUS in ClinVar with a single submitter; c.732G>C p.(Leu244Phe) is likely pathogenic in Jain and a VUS in ClinVar [10, 16]. The tools for resolving a VUS are segregation in males of the maternal line, confirmation of de novo origin in a female with a compatible phenotype, the episignature in a male, location in a PHD domain with predicted destabilisation (VIPUR) and RNA studies for splice variants [13, 44, 57]. The p.(Asp353His) variant of M6 was excluded from the Jain series as a VUS [16]. For PHF8, Sobering 2022 kept five missense variants in four families without an alternative explanation as VUS [17].

5.7. Practical algorithm

5.8. Prenatal and preimplantation diagnosis

When the familial variant is known, prenatal diagnosis is performed by chorionic villus sampling or amniocentesis, and preimplantation genetic testing (PGT) is possible if the mother is a carrier [20]. Without a defined variant, fetal sexing by cell-free fetal DNA, chorionic villi or amniocentesis requires robust evidence of X linkage and does not distinguish affected from unaffected male fetuses; linkage analysis is risky given the heterogeneity of XLID [71]. The family of M2 in the Jain series used fetal sexing before the molecular diagnosis was known [16]. Prenatal ultrasound shows no specific signs; a female with deletion of the whole gene (Jain's F5) had increased nuchal translucency and hydrops at birth [16]. Counselling aspects are covered in section 8.

6. Differential Diagnosis

6.1. Comparison table

6.2. Main differentials in males

Prader-Willi syndrome is the most frequently cited differential because of the combination of neonatal hypotonia, feeding difficulties, obesity, hypogonadism and short stature [20, 81]. In BFLS, ID is as a rule more severe, there is nystagmus and a distinctive facies with prominent supraorbital ridges, ptosis and deep-set eyes, and hyperphagia is less constant [20, 81]. The behavioural profile of Visootsak 2004 also separates them: males with BFLS had less maladaptive behaviour than patients with Prader-Willi syndrome of the same age [35]. Several patients in the Jain series had undergone Prader-Willi testing before diagnosis [16]. Coffin-Lowry syndrome shares soft hands with tapering fingers, kyphoscoliosis and prominent ears; BFLS is distinguished by marked hypogonadism, gynaecomastia and obesity [82]. The PNDS adds Bardet-Biedl, Summit, Carpenter, Wilson-Turner, Cohen, Noonan and Klinefelter syndromes to the list [20]. The table of syndromic XLID in the Oxford Desk Reference (adapted from Raymond 2006) guides the choice: small genitalia with hypogonadism point to BFLS or CUL4B, tapering fingers to Coffin-Lowry, a coarse facies with thick lips to Coffin-Lowry, Atkin-Flaitz or mucopolysaccharidosis II, and macro-orchidism to fragile X [71]. The Oxford Desk Reference describes free T3 in Allan-Herndon-Dudley syndrome as low in the text and raised in its table 2.20; the correct value is raised [71].

6.3. Main differentials in females

In a young girl, the overlap with CSS is the main pitfall: two girls with PHF6 variants met the clinical criteria for CSS and only later acquired the BFLS face [14, 60]. The features favouring BFLS are Blaschkoid linear hyperpigmentation, syndactyly of the toes, dental anomalies, bitemporal narrowing with synophrys and primary amenorrhoea [13, 40]. Nicolaides-Baraitser syndrome, Cornelia de Lange syndrome and Mabry syndrome (PIGV, with raised alkaline phosphatase) are additional differentials of the same phenotype [78, 83]. The streaky pigmentation led to consideration of incontinentia pigmenti and to IKBKG testing in three of Jain's females; Jain notes that the ectodermal changes of females with BFLS (skin, hair, teeth, brain and retina) resemble other X-linked dominant disorders, and that grey matter heterotopia may be an expression of functional mosaicism, as in X-linked cortical malformations [16]. Jain's F2, with recurrent digital fibromas, led to consideration of terminal osseous dysplasia with pigmentary defects, and the prominent supraorbital ridges with hearing loss of the girl reported by Berland 2011 suggested a filaminopathy; FLNA was normal in both cases [16, 38]. The overlap of episignatures with Chung-Jansen and WHIKERS, with no positive episignature in females with BFLS, limits methylation as a tool for the female differential diagnosis [21].

6.4. X-linked intellectual disability, Siderius type (PHF8)

Genetics and mechanism. PHF8 (Xp11.22; MANE NM_015107.3) encodes a histone lysine demethylase of 1024 amino acids, dependent on Fe²⁺, 2-oxoglutarate and oxygen, with an N-terminal PHD domain that reads H3K4me3 and a Jumonji C (JmjC) catalytic domain that removes H3K9me1/me2 and H4K20me1, which are repressive marks; it therefore acts as a transcriptional activator, required for cell-cycle progression, ribosomal DNA transcription and neurodevelopment [6, 17]. Loenarz 2010 showed that the p.(Phe279Ser) variant renders the enzyme catalytically inactive and proposed that oxygen dependence explains an association between maternal hypoxia and facial clefts [4, 86]. ClinGen assigned PHF8 a haploinsufficiency score of 3 (sufficient evidence) and a triplosensitivity score of 0, so deletions that include it are a valid mechanism [6].

History and variants. Siderius 1999 described in the Netherlands a family with three males (the proband, a maternal uncle and a maternal cousin) with mild to borderline ID, a long face and a broad nasal tip; two had cleft lip and palate and one had preaxial polydactyly and cryptorchidism; linkage to DXS441 gave a lod score of 2.78 (θ = 0) in the Xp11.3–q21.3 interval [4, 87]. Laumonnier 2005 identified in this family the deletion NM_015107.3:c.943_946+8del, which affects the splice donor of intron 8 with a frameshift p.(Thr315Leufs25) according to the authors (ClinVar 10797), and a nonsense variant in a second family [12, 17, 88]. Abidi 2007 described NM_015107.3:c.529A>T p.(Lys177) (ClinVar 10799) de novo in a male with ID, microcephaly and cleft lip and palate, with a truncated protein lacking JmjC [4, 12, 89]. Koivisto 2007 sequenced PHF8 in 18 patients with cleft lip or palate and ID of unknown cause, selected from 7712 patients operated on since 1950 at the cleft centre of Helsinki University Hospital, and identified two Finnish brothers with mild ID, mild dysmorphism and cleft lip (unilateral in one, bilateral in the other) and palate, carrying NM_015107.3:c.836T>C p.(Phe279Ser) in the JmjC domain (ClinVar 10800), absent from about 300 X chromosomes of blood donors; the original article, Loenarz 2010 and table 1 of Sobering 2022 write "c.836C>T", which is incompatible with the ClinVar reference allele T and with the TTC→TCC change required for Phe→Ser [12, 17, 86, 90]. Qiao 2008 described, in a CNV screen by array comparative genomic hybridisation in patients with ASD, two brothers with autistic disorder, ID, cleft lip and palate and dysmorphism, with a microdeletion of about 470 kb at Xp11.22 removing PHF8, FAM120C and WNK3, inherited from their unaffected mother, who had 100% skewing of X inactivation against the chromosome carrying the deletion; the deletion was not found in 481 X chromosomes from patients with ASD (319 males and 81 females) or in 282 control X chromosomes (90 males and 96 females) [4, 91]. An Xp11.22 duplication that includes PHF8 is classified as pathogenic in ClinVar (ID 979619) [12].

Phenotype. The Oxford Desk Reference includes PHF8, together with PQBP1, among the XLID genes to consider in the presence of cleft lip and palate [71]. Before 2022, eight individuals had been published in five articles; in the original family, only two of the three males had a cleft, and in another family three of four males had ID with a cleft and the fourth had mild ID without a cleft [17, 89]. Sobering 2022 brought together 16 males from 11 families with predicted loss of function (9 Western European, 3 Moroccan, 2 Indian, 1 Afro-Caribbean), with 5 frameshift, 3 splice, 2 nonsense variants and 1 deletion, eight inherited from unaffected mothers and three de novo [4, 17]. All had developmental and speech delay; ID was absent in two (one with dyscalculia, the other with mild learning difficulties) and in the rest was borderline or mild in 5, moderate in 4 and severe in 5 [17]. Cleft lip or palate was present in only 3/16, and Sobering attributes the earlier frequency (6/8) to selection bias, because a cleft had been a screening criterion in four of the first reports [17]. Other findings were hypertelorism (11), retrognathia (10), a long face (8, more evident with age), microcephaly (6), macrocephaly (2), seizures (5), ASD (7), ADHD (7), aggressiveness (5), feeding difficulties in infancy (10/16, including gastrostomy) and MRI abnormalities in 5 of 6 studied (periventricular hyperintensity, polymicrogyria in monozygotic twins, posterior fossa hypoplasia and a thin corpus callosum); walking was achieved at a mean of 20 ± 7 months [17]. Of the mothers, 10 were unaffected carriers, and X inactivation was completely skewed in two of the three tested [17].

Diagnosis and distinction from BFLS. The diagnosis is purely molecular, by panel, exome or genome with CNV analysis [6]. Unlike BFLS, no recognisable episignature was observed in blood in nine males with PHF8-XLID, and the cardinal features of BFLS (truncal obesity, gynaecomastia, hypogonadism, fleshy ear lobes) are not part of the 2022 series [17]. The p.(Ser969del) variant (published protein designation) is common in gnomAD, including in hemizygotes, and is not pathogenic [17]. The five individuals from four families with PHF8 missense variants inherited from unaffected mothers remained classified as VUS, and GeneGuidance recommends not upgrading them without new evidence [6, 17]. Management includes the full cleft pathway (feeding, surgery on the usual schedule, audiology, speech and velopharyngeal therapy, orthodontics), screening for and treatment of ASD and ADHD, early intervention, ophthalmology and examination of the palate, including for submucous cleft and bifid uvula; testing of the mother is recommended [6]. Preclinical data from 2026 in neural stem cells and in the mouse link PHF8 to chromatin accessibility at the promoters of metabolic genes and to serine biosynthesis, with no diagnostic application [6].

7. Treatment and Risk Management Strategies

7.1. Principles and organisation of care

There is no disease-modifying treatment and no medicine with an approved indication for BFLS; care is symptomatic, multidisciplinary and long-term [3, 20]. The only specific guideline is the French PNDS (French National Diagnosis and Care Protocol), produced in 2021 by the Reference Centre for Intellectual Disabilities of Rare Causes (CRDI, AP-HP Pitié-Salpêtrière) and the DéfiScience network using the methodology of the Haute Autorité de Santé (HAS), published by HAS but not validated by it; it is an expert consensus without grades of recommendation [20]. On the basis of 19 patients and the literature, Jain 2023 proposed tables for initial evaluation and prevention of complications, without numerical intervals [16]. The PNDS recommends that the diagnosis be communicated in a dedicated consultation, promptly, because of the risk to the maternal line, ideally with both parents, with psychological support, contact details of the patient organisation and a letter to the corresponding doctors [20]. Follow-up is coordinated by a reference or competence centre in liaison with the paediatrician or general practitioner [20].

7.2. Neurodevelopment, motor function and rehabilitation

Hypotonia warrants early physiotherapy and psychomotor therapy, assessment in physical and rehabilitation medicine (PRM) for equipment (moulded seating, orthoses) and speech therapy; the PNDS recommends weekly speech therapy and physiotherapy or psychomotor therapy sessions and regular neuropsychological assessments to guide educational and vocational planning [20]. Jain recommends regular assessment by a developmental paediatrician with occupational, physical and speech therapy as required [16]. GeneGuidance adds an individualised education programme with attention to communication, which is the weakest domain relative to daily living and social skills [3, 35]. The Portuguese case of Silva 2026, at the severe end of the spectrum, received physiotherapy 2–3 times a week, weekly occupational therapy and speech therapy 1–2 times a week, in sessions of 30–45 minutes, with parent training, adapted seating and a standing frame for bone health and hip alignment; the authors note the absence of standardised rehabilitation guidelines for BFLS and propose standardised measures such as the PEDI and the GMFM [61]. Adapted physical activity is recommended to prevent weight gain and promote social integration [20].

7.3. Behaviour and mental health

The PNDS recommends psychological or psychiatric assessment for ADHD and behavioural disorders, with non-specific treatments, and annual follow-up by child and adolescent psychiatry or adult psychiatry [20]. There are no trials of psychotropic drugs in BFLS. De Winter 2009 described a Dutch man with mild to moderate ID, exhibitionism since adolescence despite hypogonadism and impulsive aggressiveness, treated with libido inhibitors, clomipramine, pipamperone, haloperidol and alprazolam and admitted for psychosis with regression and self-harm; the report documents the possible severity, not a course of action [43]. Jain's M2, with aggressive behaviour and skin picking to the point of bleeding, was followed by adult psychiatry [16].

7.4. Feeding, nutrition and obesity

Feeding difficulties in infancy require oral-motor therapy and, in severe cases, a nasogastric tube; the PNDS states that they improve with age, usually without the need for gastrostomy, and proposes follow-up by paediatric gastroenterology every 6 months in early childhood [20]. The Portuguese case required percutaneous endoscopic gastrostomy in April 2022, in the first year of life, because of the risk of aspiration and insufficient intake, which shows that the PNDS statement does not apply to severe forms [61]. Weight and BMI should be monitored annually from childhood to detect early adiposity rebound, a rapid rise in BMI or crossing of the International Obesity Task Force (IOTF) thresholds of IOTF 25 (overweight) and IOTF 30 (obesity), throughout life [20]. A balanced, supervised diet adapted to cognitive ability (with easy-read materials) and coordinated with carers in the places where the person lives, together with physical activity, is the cornerstone; Jain recommends early referral to a dietitian when there is food seeking or hyperphagia [16, 20]. The PNDS proposes a dietitian if BMI exceeds 25 kg/m² and a specialist obesity centre if it exceeds 35 kg/m²; in the presence of obesity, annual screening for complications (diabetes, dyslipidaemia, liver disease, obstructive sleep apnoea syndrome, alveolar hypoventilation, pain and orthopaedic problems) [20]. Bariatric surgery should only be considered after assessment in a centre for syndromic obesity, according to the generic French PNDS on obesity of rare causes [20]. No anti-obesity drug has been studied in BFLS; setmelanotide is in a trial in Chung-Jansen syndrome (NCT04963231), but BFLS is not included [21].

7.5. Endocrinology

Anterior pituitary deficiency. The PNDS recommends looking for anterior pituitary deficiency from birth in the presence of hypoglycaemia, micropenis or bilateral cryptorchidism, with assessment in paediatric endocrinology [20]. The two brothers of Birrell 2003 had GH, TSH, ACTH and gonadotropin deficiencies [59]. ACTH deficiency confers a risk of adrenal insufficiency; no source consulted publishes a recommendation for glucocorticoid cover, and assessment of the corticotropic axis before surgery in a patient with multiple pituitary hormone deficiency is a clinical inference from these cases [20, 59].

Hypogonadism and puberty. The PNDS recommends systematic assessment for hypogonadism, referral to paediatric endocrinology at birth if there is micropenis or bilateral cryptorchidism and again at around 12 years, and hormone supplementation "to be discussed according to age and the usual protocols", without a dose [20]. Jain recommends an endocrinology consultation for all adolescents with BFLS and measurement of pituitary and sex hormones [16]. Before starting testosterone, the US label requires confirmation of hypogonadism with a morning serum testosterone below normal on at least two separate days [92]; the Portuguese summary of product characteristics (SmPC) for testosterone enantate (Testoviron Depot®) requires clinical and biochemical confirmation of the deficiency and measurement of serum testosterone before initiation and at the end of the injection interval during treatment [93]. The two jurisdictions diverge on delayed puberty: the US label allows testosterone enantate to stimulate puberty in selected boys with delayed puberty, with hand and wrist radiographs every 6 months, whereas the Portuguese SmPC indicates it only for male hypogonadism and states that it is not indicated in children and adolescents, so that in Portugal pubertal induction with this medicine is off-label use [92, 93]. A left wrist radiograph for bone age helps decide the timing of treatment for delayed puberty [20]. Jain's M1 received testosterone supplementation for delayed puberty, with no dose described [16]. Persistent cryptorchidism requires paediatric surgical assessment from 2 years of age, and clinical, possibly ultrasound, surveillance of the testes from adolescence is recommended because of the risk of cancer [20]. Persistent gynaecomastia in adolescence may require surgery [20]. Bone mineral density should be monitored if there is hypogonadism [20]. In females, primary amenorrhoea warrants an endocrinology consultation and, from adolescence, a gynaecology consultation; Jain's F1, with hypogonadotropic hypogonadism, was treated with estriol gel, with no dose described [16, 20].

Short stature and growth hormone. With height below −2 SD, the PNDS recommends paediatric endocrinology to exclude GH deficiency and other treatable causes, and Jain proposes a consultation to consider GH [16, 20]. BFLS is not a labelled indication for somatropin; its use is supported only by documented GH deficiency [94]. The evidence in BFLS consists of case reports: Jain's M2 received GH until the age of 15 with poor adherence and no response, Birrell's brothers had multiple pituitary hormone deficiency, and the girl of Zhang 2019 started 0.036 mg/kg/day and developed lower-limb oedema at 3 weeks, leading to discontinuation [16, 45, 59]. This dose corresponds to 0.252 mg/kg/week, slightly above the range of the US Genotropin® label for paediatric GH deficiency (0.16–0.24 mg/kg/week) and the upper limit of the European SmPCs (European Medicines Agency, EMA, and INFARMED) for Omnitrope® and Genotropin® (0.025–0.035 mg/kg/day, or 0.7–1.0 mg/m²/day), although these state that higher doses have been used [94–96]; the US label states that fluid retention (oedema, arthralgia, carpal tunnel syndrome) may be frequent and requires dose reduction [45, 94]. Zhang and colleagues advise caution with GH in BFLS, citing the oedema and the association of PHF6 with leukaemia; the second reason is the authors' opinion, with no data on GH-associated risk [45]. The European SmPCs for Omnitrope® and Genotropin® record cases of leukaemia in a small number of patients with GH deficiency, some treated with somatropin, with no evidence of increased incidence in patients without predisposing factors; none of the labels consulted mentions BFLS, and germline predisposition to haematological neoplasms in BFLS has not been demonstrated [42, 95, 96]. The same SmPCs require monitoring of thyroid function and warn that central adrenal insufficiency may be unmasked when somatropin is started, which matters in patients with multiple pituitary hormone deficiency such as Birrell's brothers [59, 95].

Thyroid and metabolism. Thyroid dysfunction should be sought as a matter of principle, because the signs are subtle, and treated as in the general population; the PNDS proposes thyroid function tests in the presence of weight gain, mood changes or decreased activity [20]. If there is obesity, the tests include fasting glucose, glycated haemoglobin, total cholesterol, HDL cholesterol, triglycerides and transaminases; the diabetic ketoacidosis of Kubota's patient at 31 years illustrates the importance of screening for diabetes [1, 20, 73].

7.6. Epilepsy and neurology

Epilepsy is treated in a non-specific way; no antiepileptic drug is known to be specific to BFLS [20]. EEG and brain MRI are indicated if there are seizures, and Jain adds MRI in the presence of focal signs and referral to a neurologist experienced in epilepsy [16, 20]. Most of the seizures described are controllable: Jain's M5 had partial seizures at 2 years controlled with one antiepileptic drug, and F1, with cortical dysplasia, had nocturnal epilepsy resistant to four antiepileptic drugs at 6 years, with 9 months seizure-free after a change at 7 years [16]. In a patient with hypoglycaemic episodes, these should be excluded as the cause of seizures [16].

7.7. Sensory organs, skin, teeth, orthopaedics and sleep

A complete ophthalmological examination, with fundoscopy and visual acuity, and an ear, nose and throat assessment with audiometry (and evoked potentials if necessary) form part of the initial evaluation; Jain recommends considering dilated fundoscopy in females, glasses for refractive errors, strabismus or ptosis surgery when required, hearing aids and otorhinolaryngology for chronic otitis media [16, 20]. For hypertrophic scars and keloids, Jain recommends avoiding cosmetic surgery and skin injuries such as piercings and caring for the wound after any surgery, since M10 developed substantial keloids after otoplasty [16]. Dental assessment is annual, with an orthopantomogram if cooperation allows, especially in females with dental anomalies [16, 20]. Scoliosis and joint hyperlaxity require annual assessment by orthopaedics or PRM, with decisions on orthoses, surgery and physiotherapy; radiographs are directed at scoliosis and Perthes disease [20]. Obstructive sleep apnoea and hypoventilation should be sought in obese and severely affected patients: two of Jain's females required continuous positive airway pressure or adenotonsillectomy, and the Portuguese case had an indication for nocturnal non-invasive ventilation, abandoned because of intolerance [16, 20, 61]. Renal ultrasound is proposed by Jain to detect structural renal or genitourinary anomalies [16].

7.8. Drugs with described or plausible use in BFLS

Testosterone enantate and somatropin are used in BFLS within their general indications (confirmed hypogonadism, documented GH deficiency), and not for a syndrome-specific indication [20, 94]. Testosterone medicines for male hypogonadism are not on the EMA centralised register and are authorised through national or decentralised procedures; in Portugal, testosterone enantate (Testoviron Depot®), a combination of testosterone esters (Sustenon®), testosterone undecanoate (Nebido®) and two testosterone gels (Testogel®, Testavan®) are marketed [93]. Somatropin has a centralised authorisation for Omnitrope® and a national authorisation for Genotropin®, with the same indications and posology text in both SmPCs [95, 96].

7.9. Comparative regulatory status

7.10. Available therapeutic evidence

There are no therapeutic trials in BFLS. A ClinicalTrials.gov search on 18 October 2026 (terms PHF6, Börjeson and Börjeson-Forssman-Lehmann) returned three records, none therapeutic; the only one listing BFLS is the CoRDS observational registry of Sanford Research, which is recruiting [25]. None of the setmelanotide studies includes BFLS [21]. The table brings together the existing intervention evidence, all of it descriptive.

None of these data allows efficacy to be estimated: they are isolated cases, without a comparison group, with heterogeneous doses and adherence, and the functional outcome of the Portuguese case reflects the patient's severity and cannot be compared with that of other reports. The absence of trials on ClinicalTrials.gov does not prove that no studies exist in other registries; the EU clinical trials register was not consulted.

7.11. Developments in the past 12 months

None of these results has clinical application in germline BFLS. Ramsey 2025 and Smits 2025, from July and August 2025, lie at the edge of the window and are diagnostic studies [44, 79].

7.12. Agents to avoid, pregnancy, perioperative care and transition

No drugs are specifically contraindicated in BFLS in the sources consulted. The precautions derive from the phenotype: testosterone has gynaecomastia and fluid retention among its adverse effects, and somatropin fluid retention [92, 94]. The sources consulted contain no data on pregnancy in affected women or carriers beyond documentation of fertility in mildly affected women (one woman with oligomenorrhoea had a daughter) and of mother-to-daughter transmissions [13, 45]. No man with BFLS has been reported to have had children [20]. The sources consulted include no anaesthetic recommendations for BFLS. The features with perioperative implications that have been described are obesity, obstructive sleep apnoea and hypoventilation, multiple pituitary hormone deficiency with ACTH deficiency, the narrow cervical spinal canal described in Smith's Recognizable Patterns, the tendency to keloids and, exceptionally, dilated cardiomyopathy [16, 20, 27, 59, 61]. Transition to adult services should be prepared in late adolescence to avoid breaks in care; in adults, the PNDS proposes a specialist consultation every 2–3 years, adapted to needs [20].

7.13. Guidelines and divergences between sources

The sources diverge on five points. First, the PNDS states that no congenital malformations have been reported apart from one cleft lip and palate, whereas Jain describes umbilical hernias, clubfoot and renal anomalies, and Gerber and Dutta describe cleft palate in females [13, 16, 20, 76]. Second, the PNDS considers gastrostomy usually unnecessary, and the Portuguese case required it [20, 61]. Third, the PNDS describes the ID as "moderate to severe" and, in another section, "mild to moderate" [20]. Fourth, the PNDS treats the "non-syndromic" de novo female phenotype as a possible separate entity, whereas Jain and Gerber include it within the spectrum of the syndrome [13, 16, 20]. Fifth, epilepsy occurs in 12% in the PNDS and is infrequent in modern series, contrary to the original description and to the opinion of the authors of the Portuguese case [16, 20, 61]. The PNDS gives follow-up intervals and Jain does not; Jain's recommendations on keloids, renal ultrasound and dilated fundoscopy in females are not in the PNDS and are complementary [16, 20].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

De novo origin is the rule in affected females (23/26 in the Gerber aggregate) and the exception in males (1/56) [13]. In the Jain series, 10 males inherited the variant from carrier mothers, and M12's mother herself had a de novo variant, showing that a carrier can be the first case in the family [16]. Crawford 2006 showed that the de novo variant of the 14-year-old girl arose on the paternal chromosome, and Gerber found no mosaicism by Sanger sequencing in the blood of the mother in family 2; the empirical risk of germline mosaicism is not quantified in the sources consulted [13, 36].

8.2. Carrier testing and cascade testing

Testing the mother is the first step after diagnosis in a male or a female [16, 20]. At-risk women in the maternal line (sisters, maternal aunts and maternal cousins) should be informed and tested for the familial variant; in France, the law places on the patient a duty to inform relatives [20]. Ramsey recommended testing of the sister, who had a 50% probability of being a carrier, and of maternal relatives [44]. The X-inactivation study is not suitable for identifying carriers: the Oxford Desk Reference considers it usable only with near-complete skewing (>95%) consistent across all obligate carriers in a large family, and the PNDS considers it useless in practice [20, 71]. Identified carriers should be examined rather than assumed to be unaffected, because about one in five has significant learning difficulties [3, 18].

8.3. Prenatal and preimplantation diagnosis

Prenatal diagnosis is performed by chorionic villus sampling or amniocentesis after an opinion from the multidisciplinary prenatal diagnosis centre, and PGT is possible when the mother is a carrier [20]. Fetal sexing alone does not distinguish an affected from an unaffected male fetus [71]. In a female carrier fetus, the prognosis cannot be predicted: neither the type of inheritance (familial) nor the X-inactivation pattern allows severity to be anticipated [13, 20]. Ultrasound findings are not specific; the increased nuchal translucency and hydrops of Jain's F5 and the reduced fetal movements of M12 are isolated observations [16].

8.4. Counselling of minors and content of the consultation

The genetic counselling consultation should be conducted by a clinical geneticist or genetic counsellor, provide information on inheritance and its implications, and support medical and personal decisions [16]. The main purpose of testing minor girls at risk of being carriers is future reproductive information; the sources consulted give no specific guidance on the age of testing in BFLS, and the general rules for carrier testing in minors apply. The consultation should address the variability in females, the possibility that a mildly affected mother may have a more severely affected daughter, the absence of a demonstrated oncological risk and the need for a new consultation in each pregnancy [13, 16, 20]. The Oxford Desk Reference recommends storing DNA, with consent, a practice reinforced by the Jain series, in which M1's variant was confirmed in DNA stored after his death [16, 71].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

There is no population estimate of the prevalence or incidence of BFLS. Orphanet places it in the prevalence class <1/1,000,000 and records about 50 described cases; the PNDS states that the incidence is unknown [2, 20]. The available figures are counts of published cases, which grow with sequencing and are not equivalent to rates.

The true frequency is probably underestimated because of the evolution of the phenotype with age, underdiagnosis in young boys and in isolated heterozygous females, and the female overlap with CSS [18, 40]. The proportion of male ID attributable to BFLS has not been measured; the Oxford Desk Reference states that XLID could account for about 10% of ID if the entire male excess (20–40%) were due to X-linked genes, a hypothesis not proven in clinical surveys [71]. For ID, Siderius type, the Orphanet count (two families) is out of date compared with the 11 families of 2022 [5, 17].

The frequency of somatic alterations measures something else: the proportion of neoplasms with altered PHF6, 16% (14/89) in paediatric and 38% (16/42) in adult T-ALL in the founding series, and about 2–3% in AML [42, 65]. These values say nothing about the frequency of the syndrome.

9.2. Geography, ancestry and founder populations

The published families come from Australia (Lower 2002, Turner 2004), Canada (Vallée 2004, Carter 2009), the USA (Lower 2002, Visootsak 2004, Ramsey 2025, Dutta 2026), Saudi Arabia (Robinson 1983), Japan (Kubota 1999), China (Zhang 2019), Sweden (original family), the United Kingdom (Birrell 2003, Jain 2023), Germany, Switzerland, Norway, Spain and Belgium (Gerber 2022), Denmark (Ernst 2015), the Netherlands (Lower 2002, de Winter 2009), Spain (Garcia-Melendo 2021), France (Di Donato 2014) and Portugal (Silva 2026) [13, 16, 18, 29, 33–35, 41, 43–45, 56, 57, 59, 61, 70, 73, 75, 76]. Zhang 2019 presented their patient as the first molecularly confirmed Asian case, all previous ones being of European ancestry; the Japanese woman of Kubota 1999 was described before the gene was identified, with a clinical diagnosis only [1, 45, 73]. In the USA, the data come from isolated families and the Visootsak series (Emory); in Europe, from the UK series (DDD study) and the Gerber aggregate [13, 16, 35]. There are no founder variants; p.(Arg342*) is recurrent through mutation at a CpG site [16, 54].

In Portugal, the published case is that of Silva 2026, from Guimarães (Unidade Local de Saúde do Alto Ave), with the de novo variant c.729G>A p.(Met243Ile) [61]. The sources consulted include no data from Brazil; this does not demonstrate the absence of published cases. For ID, Siderius type, the 2022 series included Western European, Moroccan, Indian and Afro-Caribbean patients [17].

9.3. Special populations

Heterozygous females are a population in their own right, to be examined and followed rather than considered unaffected [3]. Adults have psychiatric, metabolic and independence needs that require planned transition; no adult is fully independent [20].

9.4. Reference networks and patient organisations

ERN ITHACA (European Reference Network on rare congenital malformations and rare intellectual disability) has no guideline of its own and lists five reference articles (Carter 2009, Di Donato 2014, Jahani-Asl 2016, Visootsak 2004 and de Winter 2009) [22]. In France, the CRDI and AnDDI-Rares reference centres, the DéfiScience network and the Xtraordinaire association of families with X-linked ID are the resources indicated by the PNDS, alongside Orphanet, the Alliance Maladies Rares and Eurordis [20, 23]. In the USA, BFLS Incorporated is a patient organisation that aims to raise awareness of the syndrome and to raise funds for research, listed by Global Genes [24]. The CoRDS registry of Sanford Research includes BFLS [25]. In the United Kingdom, the Oxford Desk Reference lists the generic ID organisations Mencap and ENABLE [71].

10. Illustrative Clinical Case

10.1. Girl with a variant inherited from an unaffected mother and growth hormone deficiency (Zhang 2019)

A girl aged 9 years and 1 month was seen in the genetic endocrinology clinic of the Shanghai Children's Medical Center for ID and short stature [45]. She measured 123 cm (−2 SD), with a height age of 7 years, weighed 23 kg (−1.3 SD) and had a BMI of 15.2 (25th–50th centile); her mid-parental target height was 156 cm (−0.85 SD) [45]. She had been born post-term by caesarean section, weighing 4.25 kg and measuring 50 cm; severe developmental delay was noted in early childhood, she walked independently at 3 years and said a few simple words at 5 [45]. On examination she had a coarse face, sparse hair, a narrow forehead, ptosis, deep-set eyes, a broad nasal tip, a short nose, malformed teeth and large ears, tapering fingers with curved fifth fingers, flat feet with the fourth toe shorter than the fifth, and extensive hyperpigmentation, mainly of the lower limbs; she was at Tanner stage B1 P1 [45]. Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC6878345/figure/f1/) shows, at 9 years, the face (panels A and B), the dental anomalies (C), the hand with short, curved fifth fingers (D), the foot with short fourth toes (E) and the result of methylation-specific PCR (F) [45].

Thyroid and liver function were normal, but the patient had complete GH deficiency; bone age was 7 years and 10 months [45]. Ultrasound showed a horseshoe kidney, and brain MRI showed periventricular leucomalacia and a pituitary that appeared thinner than that of girls of the same age, without formal measurement [45]. The karyotype was 46,XX and the chromosomal microarray was normal. Before the molecular diagnosis, she started recombinant somatropin at 0.036 mg/kg/day; after three weeks she developed oedema of both lower limbs and treatment was stopped [45]. Exome sequencing identified the heterozygous variant c.673C>T p.(Arg225*) in NM_001015877 (the MANE transcript), inherited from her mother, who had no apparent signs according to the family but was not formally assessed; ClinVar classifies it as pathogenic (ID 488410) [10, 45]. Methylation-specific PCR showed highly skewed X inactivation in the patient (98:2) and in her mother (95:5) [45].

The case illustrates three points of this article: the X-inactivation pattern in blood does not distinguish a mother without signs from an affected daughter; an inherited truncating variant can cause a full female phenotype; and GH deficiency is part of the endocrine spectrum [13, 45]. The somatropin dose used corresponds to 0.252 mg/kg/week, slightly above the labelled range for paediatric GH deficiency, and treatment was started before the diagnosis; the authors advise caution with GH in BFLS, which does not correspond to a PNDS recommendation, since the PNDS proposes excluding GH deficiency if height is below −2 SD [20, 45, 94].

10.2. Portuguese boy with a de novo variant and a severe phenotype (Silva 2026)

A boy followed in Physical and Rehabilitation Medicine at the Unidade Local de Saúde do Alto Ave, in Guimarães, was born at 39 weeks and 4 days weighing 2465 g (small for gestational age), measuring 49 cm and with a head circumference of 34 cm [61]. He had respiratory distress, axial hypotonia, feeding difficulties and seizures from three weeks of life, with a 1.5-month admission to neonatal intensive care in 2021; MRI showed a thin corpus callosum and a simplified gyral pattern, and the EEG frequent epileptiform discharges, treated with antiepileptic drugs not named in the article [61]. The de novo variant c.729G>A p.(Met243Ile) was identified and classified as likely pathogenic; the article does not state the transcript, but the variant was validated on the MANE transcript NM_001015877.2 (GRCh38 g.134413966G>A, exon 7, in the PHD2 domain) [11, 61]. At 7 months he had severe axial hypotonia without head control, limited eye contact, oromotor inefficiency, a coarse face, large low-set ears and suspected bilateral ptosis [61]. He started a programme of physiotherapy, occupational therapy and speech therapy with parent training; in April 2022 a gastrostomy was placed because of the risk of aspiration and insufficient intake, and a sleep study showed raised transcutaneous carbon dioxide (median 52 mmHg), with an indication for nocturnal non-invasive ventilation, abandoned because of intolerance [61]. At 4.5 years he could sit for about one second with anterior hand support, had no independent mobility, was dependent on the gastrostomy, and had intentional vocalisations and a consistent social smile; the seizures improved with optimised treatment [61]. The article has no clinical figures. It is a case at the severe end of the spectrum, in a male with a de novo variant, and the gastrostomy departs from the PNDS expectation that feeding difficulties improve without it [20, 61].

10.3. Reference figures

Figure 1 of Jain 2023 shows the facial phenotype of males and females in the series, including M2 at 26 years (https://pmc.ncbi.nlm.nih.gov/articles/PMC10689765/figure/Fig1/); Figure 2 shows the keloids, digital fibromas and dental changes of F2 and the hyperpigmentation of F1 and F2 (https://pmc.ncbi.nlm.nih.gov/articles/PMC10689765/figure/Fig2/); Figure 3 represents the variants by sex and domain (https://pmc.ncbi.nlm.nih.gov/articles/PMC10689765/figure/Fig3/) [16]. Figure 1 of Gerber 2022 documents the de novo female phenotype (https://pmc.ncbi.nlm.nih.gov/articles/PMC9543785/figure/cge14173-fig-0001/) [13].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

There are no survival studies. Smith's Recognizable Patterns presumes a normal life expectancy, and the published males reach adulthood, with ages up to 62 years in the Gerber aggregate [3, 13, 27]. The deaths described were due to respiratory infection (two patients in the original family, from bronchopneumonia, at 20 and 44 years; Jain's M1, from H. influenzae pneumonia, at 26 years) and, in a woman from the Dereymaeker family, sudden death at 17 years, probably during a seizure [1, 16, 27, 31]. The functional prognosis is dominated by ID: no adult is fully independent, schooling is adapted after preschool, and expressivity ranges from mild ID to the complete dependence of the Portuguese case [20, 43, 61]. The comorbidities that determine adult morbidity are obesity and its complications, hypogonadism with skeletal risk, psychiatric disorders, seizures in the forms with cortical malformation, and painful skin lesions (Jain's F2, with ulcerated fibromas that limited walking at 26 years) [16, 20]. Behaviour tends to be more favourable than in comparable syndromes, with relatively preserved social skills [35, 43].

The oncological risk is uncertain: three neoplasms in about one hundred published patients do not allow a risk to be estimated or its absence to be asserted [16]. Jain and the PNDS do not recommend specific oncological surveillance; Ramsey mentions a "potential" haematological risk with surveillance, without a protocol, which is the authors' opinion [16, 20, 44]. The testicular surveillance from adolescence recommended by the PNDS concerns cryptorchidism, not a tumour risk specific to PHF6 [20]. In somatic AML with mutated PHF6, the series of Kubota 2024 and Wang 2026 associate the mutation with shorter survival, especially with RUNX1, but this prognosis refers to sporadic leukaemias [67, 98].

11.2. Initial evaluation after diagnosis

11.3. Surveillance

The PNDS describes these schedules as indicative, to be adapted to complications, and accompanies them with the recommendation of physical activity and integration into community life [20]. Jain does not give numerical intervals; his recommendations (endocrinology for all adolescents, a dietitian if there is hyperphagia, skin care) have been incorporated into the corresponding rows [16].

12. Summary and Concluding Remarks

Börjeson-Forssman-Lehmann syndrome is an X-linked neurodevelopmental disorder caused by loss of function of PHF6, a chromatin regulator with two PHD domains, located at Xq26.2 and expressed in the developing brain, the adenohypophysis and the haematopoietic system [7, 16]. In males, almost always with missense variants, in-frame deletions or truncating variants of the terminal exons inherited from carrier mothers, the phenotype becomes complete with age: hypotonia and feeding difficulties in infancy, learning difficulties and moderate short stature in childhood, and truncal obesity, hypogonadism, gynaecomastia and a heavy facies in adolescence and adulthood [16, 18]. Microcephaly and epilepsy, emphasised in the original description, are minority findings in the molecularly confirmed series [13, 20]. Carriers from affected families are mostly asymptomatic or mildly affected, with learning difficulties in about one in five, and females with de novo variants or deletions have a distinct phenotype, with ID, sparse hair, hypoplastic nails, digital and dental anomalies, Blaschkoid hyperpigmentation and amenorrhoea, which in early childhood is confused with Coffin-Siris syndrome [13, 40]. Skewed X inactivation in blood is frequent in all females and has no diagnostic or prognostic value [13, 20].

The diagnosis is molecular: exome or genome as first tier, or a panel including PHF6, always with CNV analysis in females, in whom deletions and duplications account for about one third of variants [16, 19]. The DNA methylation episignature helps to reclassify variants of uncertain significance in males, but was negative in all females tested [21, 44]. Care follows the 2021 French PNDS (French National Diagnosis and Care Protocol) and the Jain 2023 recommendations: endocrine assessment from birth and at peripuberty, annual BMI monitoring, treatment of hypogonadism and of documented GH deficiency within their general indications, early rehabilitation, skin care to prevent keloids, and annual ophthalmological, hearing, dental and orthopaedic follow-up [16, 20]. There is no specific treatment and there are no clinical trials; recent developments are preclinical (PHF6 pathways in the medial preoptic area, in the pituitary and via TCF4) or case reports, including the first Portuguese case [50, 51, 61].

PHF6 is also a tumour suppressor with frequent somatic alterations in T-ALL and less frequent ones in myeloid neoplasms, but germline predisposition has not been demonstrated: only three neoplasms have been described in patients with the syndrome, and no source recommends oncological surveillance [16, 42]. X-linked ID, Siderius type, caused by PHF8, is the differential diagnosis with the same type of domain and inheritance, distinguished by a long face, hypertelorism, retrognathia and orofacial clefting in a minority, without the endocrine picture of BFLS [17]. Counselling centres on testing the mother and the women of the maternal line, on the 50% risk per pregnancy for a carrier and on the impossibility of predicting severity in a carrier daughter [13, 20].

13. References

1. Online Mendelian Inheritance in Man (OMIM). #301900 Borjeson-Forssman-Lehmann syndrome; BFLS [Internet]. Baltimore (MD): Johns Hopkins University; last edited 1 Mar 2021; accessed 18 Oct 2026. https://www.omim.org/entry/301900
2. Orphanet. Borjeson-Forssman-Lehmann syndrome. ORPHA:127. https://www.orpha.net/en/disease/detail/127
3. GeneGuidance. PHF6 — gene and condition record (Borjeson-Forssman-Lehmann syndrome). Version of 26 Sep 2026.
4. Online Mendelian Inheritance in Man (OMIM). #300263 Intellectual developmental disorder, X-linked, syndromic, Siderius type; MRXSSD [Internet]. Baltimore (MD): Johns Hopkins University; last edited 24 Aug 2023; accessed 18 Oct 2026. https://www.omim.org/entry/300263
5. Orphanet. X-linked intellectual disability, Siderius type. ORPHA:85287. https://www.orpha.net/en/disease/detail/85287
6. GeneGuidance. PHF8 — gene and condition record (X-linked intellectual disability, Siderius type). Version of 26 Sep 2026.
7. Online Mendelian Inheritance in Man (OMIM). *300414 PHD finger protein 6; PHF6 [Internet]. Baltimore (MD): Johns Hopkins University; last edited 22 Aug 2024; accessed 18 Oct 2026. https://www.omim.org/entry/300414
8. Ensembl. PHF6 ENSG00000156531; MANE Select ENST00000370803.8 / NM_001015877.2 [Internet]. Accessed 18 Oct 2026. https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000156531
9. Ensembl. PHF8 ENSG00000172943; MANE Select ENST00000338154.11 / NM_015107.3 [Internet]. Accessed 18 Oct 2026. https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000172943
10. National Center for Biotechnology Information. ClinVar — PHF6 [gene] (585 records). https://www.ncbi.nlm.nih.gov/clinvar/?term=PHF6[gene]
11. VariantValidator. Validation of NM_001015877.2:c.729G>A (PHF6, MANE Select) on GRCh38 and GRCh37, version 4.0.1.dev7 (vvdb_2025_3) [Internet]. Manchester: University of Manchester; accessed 18 Oct 2026; independent confirmation in Ensembl VEP on the same date. https://variantvalidator.org/
12. National Center for Biotechnology Information. ClinVar — PHF8 [gene] (574 records). https://www.ncbi.nlm.nih.gov/clinvar/?term=PHF8[gene]
13. Gerber CB, Fliedner A, Bartsch O, Berland S, Dewenter M, Haug M, et al. Further characterization of Borjeson-Forssman-Lehmann syndrome in females due to de novo variants in PHF6. Clin Genet. 2022;102(3):182-190. doi:10.1111/cge.14173. PMID: 35662002; PMCID: PMC9543785.
14. Vergano SS, Santen G, Wieczorek D, Matsumoto N. Coffin-Siris Syndrome. 2013 Apr 4 [updated 2025 May 15]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. https://www.ncbi.nlm.nih.gov/books/NBK131811/
15. Wallace SE, Mirzaa GM, Bean LJH. Resources for Genetics Professionals — Epigenetic Signature Analysis. 2019 Dec 5 [revised 2022 Jun 30]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. https://www.ncbi.nlm.nih.gov/books/NBK550348/
16. Jain V, Foo SH, Chooi S, Moss C, Goodwin R, Berland S, et al. Börjeson-Forssman-Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families. Eur J Hum Genet. 2023;31(12):1421-1429. doi:10.1038/s41431-023-01447-0. PMID: 37704779; PMCID: PMC10689765.
17. Sobering AK, Bryant LM, Li D, McGaughran J, Maystadt I, Moortgat S, et al. Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology. HGG Adv. 2022;3(3):100102. doi:10.1016/j.xhgg.2022.100102. PMID: 35469323; PMCID: PMC9034099.
18. Turner G, Lower KM, White SM, Delatycki M, Lampe AK, Wright M, et al. The clinical picture of the Börjeson-Forssman-Lehmann syndrome in males and heterozygous females with PHF6 mutations. Clin Genet. 2004;65(3):226-232. doi:10.1111/j.0009-9163.2004.00215.x. PMID: 14756673.
19. Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(11):2029-2037. doi:10.1038/s41436-021-01242-6. PMID: 34211152.
20. Centre de Référence Déficiences Intellectuelles de causes rares; Marey I, Héron D, coord. Protocole National de Diagnostic et de Soins (PNDS): Syndrome Borjeson Forssman Lehmann. Paris: Filière DéfiScience/HAS; 2021 Sep [synthèse médecin traitant: 2021 Nov]. Available from: https://www.has-sante.fr/jcms/p_3300863/fr/syndrome-borjeson-forssman-lehmann (text: https://www.has-sante.fr/upload/docs/application/pdf/2021-11/borjeson_forssman_lehman-final.pdf; supporting argument: https://www.has-sante.fr/upload/docs/application/pdf/2021-11/argumentaire_pnds_borjeson_forssman_lehman_final.pdf).
21. Vos N, Haghshenas S, van der Laan L, Russel PKM, Rooney K, Levy MA, et al. The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes. Hum Genet. 2024;143(6):761-773. doi:10.1007/s00439-024-02679-w. PMID: 38787418; PMCID: PMC11186873.
22. ERN ITHACA. Guidelines Literature — Borjeson-Forssman-Lehmann (list of articles: Carter 2009, Di Donato 2014, Jahani-Asl 2016, Visootsak 2004, de Winter 2009). https://ern-ithaca.eu/guidelines-literature/
23. Xtraordinaire — association française de familles de patients avec déficiences intellectuelles liées au chromosome X. https://www.xtraordinaire.org/
24. Global Genes. Borjeson-Forssman-Lehmann syndrome — Advocacy organizations (BFLS Incorporated) [Internet]. Washington (DC): Global Genes; accessed 18 Oct 2026. https://globalgenes.org/disorder/borjeson-forssman-lehmann-syndrome/
25. Sanford Research. Rare Disease Patient Registry & Natural History Study — Coordination of Rare Diseases at Sanford (CoRDS). ClinicalTrials.gov NCT01793168. https://clinicaltrials.gov/study/NCT01793168
26. Börjeson M, Forssman H, Lehmann O. An X-linked, recessively inherited syndrome characterized by grave mental deficiency, epilepsy, and endocrine disorder. Acta Med Scand. 1962;171:13-21. doi:10.1111/j.0954-6820.1962.tb04162.x. PMID: 13871358.
27. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 820–821 (Börjeson-Forssman-Lehmann Syndrome).
28. Weber FT, Frias JL, Julius RL, Felman AH. Primary hypogonadism in the Borjeson-Forssman-Lehmann syndrome. J Med Genet. 1978;15(1):63-6. doi:10.1136/jmg.15.1.63. PMID: 564968; PMCID: PMC1012825.
29. Robinson LK, Jones KL, Culler F, Nyhan WL, Sakati N, Jones KL. The Börjeson-Forssman-Lehmann syndrome. Am J Med Genet. 1983;15(3):457-468. doi:10.1002/ajmg.1320150311. PMID: 6683929.
30. Ardinger HH, Hanson JW, Zellweger HU. Borjeson-Forssman-Lehmann syndrome: further delineation in five cases. Am J Med Genet. 1984;19(4):653-64. doi:10.1002/ajmg.1320190405. PMID: 6517094.
31. Dereymaeker AM, Fryns JP, Hoefnagels M, Heremans G, Marien J, van den Berghe H. The Borjeson-Forssman-Lehmann syndrome: a family study. Clin Genet. 1986;29(4):317-20. PMID: 3720009. https://pubmed.ncbi.nlm.nih.gov/3720009/
32. Turner G, Gedeon A, Mulley J, Sutherland G, Rae J, Power K, Arthur I. Borjeson-Forssman-Lehmann syndrome: clinical manifestations and gene localization to Xq26-27. Am J Med Genet. 1989;34(4):463-9. doi:10.1002/ajmg.1320340402. PMID: 2624253.
33. Lower KM, Turner G, Kerr BA, Mathews KD, Shaw MA, Gedeon AK, et al. Mutations in PHF6 are associated with Börjeson-Forssman-Lehmann syndrome. Nat Genet. 2002;32(4):661-665. doi:10.1038/ng1040. PMID: 12415272.
34. Lower KM, Solders G, Bondeson ML, Nelson J, Brun A, Crawford J, et al. 1024C>T (R342X) is a recurrent PHF6 mutation also found in the original Börjeson-Forssman-Lehmann syndrome family. Eur J Hum Genet. 2004;12(10):787-789. doi:10.1038/sj.ejhg.5201228. PMID: 15241480.
35. Visootsak J, Rosner B, Dykens E, Schwartz C, Hahn K, White SM, et al. Clinical and behavioral features of patients with Borjeson-Forssman-Lehmann syndrome with mutations in PHF6. J Pediatr. 2004;145(6):819-825. doi:10.1016/j.jpeds.2004.07.041. PMID: 15580208.
36. Crawford J, Lower KM, Hennekam RC, Van Esch H, Mégarbané A, Lynch SA, et al. Mutation screening in Borjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient. J Med Genet. 2006;43(3):238-243. doi:10.1136/jmg.2005.033084. PMID: 15994862; PMCID: PMC2563250.
37. Gécz J, Turner G, Nelson J, Partington M. The Börjeson-Forssman-Lehman syndrome (BFLS, MIM #301900). Eur J Hum Genet. 2006;14(12):1233-1237. doi:10.1038/sj.ejhg.5201639. PMID: 16912705.
38. Berland S, Alme K, Brendehaug A, Houge G, Hovland R. PHF6 Deletions May Cause Borjeson-Forssman-Lehmann Syndrome in Females. Mol Syndromol. 2011;1(6):294-300. doi:10.1159/000330111. PMID: 22190899; PMCID: PMC3214959.
39. Zweier C, Kraus C, Brueton L, Cole T, Degenhardt F, Engels H, et al. A new face of Borjeson-Forssman-Lehmann syndrome? De novo mutations in PHF6 in seven females with a distinct phenotype. J Med Genet. 2013;50(12):838-847. doi:10.1136/jmedgenet-2013-101918. PMID: 24092917.
40. Zweier C, Rittinger O, Bader I, Berland S, Cole T, Degenhardt F, et al. Females with de novo aberrations in PHF6: clinical overlap of Borjeson-Forssman-Lehmann with Coffin-Siris syndrome. Am J Med Genet C Semin Med Genet. 2014;166C(3):290-301. doi:10.1002/ajmg.c.31408. PMID: 25099957.
41. Di Donato N, Isidor B, Lopez Cazaux S, Le Caignec C, Klink B, Kraus C, et al. Distinct phenotype of PHF6 deletions in females. Eur J Med Genet. 2014;57(2-3):85-89. doi:10.1016/j.ejmg.2013.12.003. PMID: 24380767.
42. Kurzer JH, Weinberg OK. PHF6 Mutations in Hematologic Malignancies. Front Oncol. 2021;11:704471. doi:10.3389/fonc.2021.704471. PMID: 34381727; PMCID: PMC8350393.
43. de Winter CF, van Dijk F, Stolker JJ, Hennekam RC. Behavioural phenotype in Börjeson-Forssman-Lehmann syndrome. J Intellect Disabil Res. 2009;53(4):319-328. doi:10.1111/j.1365-2788.2009.01156.x. PMID: 19187102.
44. Ramsey K, Prakash S, Kerkhof J, Sadikovic B, White S, Naymik M, et al. Integration of Genome and Epigenetic Testing in the Diagnostic Evaluation of Developmental Delay: Differentiating Börjeson-Forssman-Lehmann (BFLS) and White-Kernohan (WHIKERS) Syndromes. Genes (Basel). 2025;16(8):933. doi:10.3390/genes16080933. PMID: 40869981; PMCID: PMC12385824.
45. Zhang X, Fan Y, Liu X, Zhu MA, Sun Y, Yan H, et al. A Novel Nonsense Mutation of PHF6 in a Female with Extended Phenotypes of Borjeson-Forssman-Lehmann Syndrome. J Clin Res Pediatr Endocrinol. 2019;11(4):419-425. doi:10.4274/jcrpe.galenos.2019.2018.0220. PMID: 30630810; PMCID: PMC6878345.
46. Jahani-Asl A, Cheng C, Zhang C, Bonni A. Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function. Neurobiol Dis. 2016;96:227-235. doi:10.1016/j.nbd.2016.09.011. PMID: 27633282; PMCID: PMC5102843.
47. Fliedner A, Gregor A, Ferrazzi F, Ekici AB, Sticht H, Zweier C. Loss of PHF6 leads to aberrant development of human neuron-like cells. Sci Rep. 2020;10(1):19030. doi:10.1038/s41598-020-75999-2. PMID: 33149206; PMCID: PMC7642390.
48. Rasool D, Burban A, Sharanek A, Madrigal A, Hu J, Yan K, et al. PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS. EMBO Rep. 2024;25(3):1256-1281. doi:10.1038/s44319-024-00082-0. PMID: 38429579; PMCID: PMC10933485.
49. McRae HM, Eccles S, Whitehead L, Alexander WS, Gécz J, Thomas T, Voss AK. Downregulation of the GHRH/GH/IGF1 axis in a mouse model of Börjeson-Forssman-Lehman syndrome. Development. 2020;147(21):dev187021. doi:10.1242/dev.187021. PMID: 32994169.
50. Wang J, Liu B, Wu X, Sun J, Wang Y, He L, et al. Regulation of physical activity and energy expenditure through Phf6 in the medial preoptic area. Nat Commun. 2026;17(1):4468. doi:10.1038/s41467-026-70962-7. PMID: 41876547; PMCID: PMC13187260.
51. Nateghi B, Li Y, Qu D, Rasool D, Madrigal A, Najafabadi HS, et al. TCF4 Mediates PHF6 Transcriptional Regulation of Neural Stem Cells in the Developing Brain, a Mechanism Disrupted in Börjeson-Forssman-Lehmann Syndrome (BFLS) [preprint]. bioRxiv. 2026 Sep 16. doi:10.64898/2026.09.12.750495.
52. Pawar AS, Somers P, Alex A, Grana J, Feist VK, George SS, et al. Leukemia mutated proteins PHF6 and PHIP form a chromatin complex that represses acute myeloid leukemia stemness. Genes Dev. 2025;39(19-20):1219-1240. doi:10.1101/gad.352602.125. PMID: 40721297; PMCID: PMC12340699.
53. Happle R. An unusual linear hypermelanosis reflecting lyonization in women with Börjeson-Forssman-Lehmann syndrome. J Eur Acad Dermatol Venereol. 2016;30(2):323-324. doi:10.1111/jdv.12717. PMID: 25209262.
54. Chao MM, Todd MA, Kontny U, Neas K, Sullivan MJ, Hunter AG, et al. T-cell acute lymphoblastic leukemia in association with Börjeson-Forssman-Lehmann syndrome due to a mutation in PHF6. Pediatr Blood Cancer. 2010;55(4):722-724. doi:10.1002/pbc.22574. PMID: 20806366; PMCID: PMC2933084.
55. Ahmed R, Sarwar S, Hu J, Cardin V, Qiu LR, Zapata G, et al. Transgenic mice with an R342X mutation in Phf6 display clinical features of Börjeson-Forssman-Lehmann Syndrome. Hum Mol Genet. 2021;30(7):575-594. doi:10.1093/hmg/ddab081. PMID: 33772537; PMCID: PMC8120135.
56. Ernst A, Le VQ, Højland AT, Pedersen IS, Sørensen TH, Bjerregaard LL, et al. The PHF6 Mutation c.1A>G; pM1V Causes Börjeson-Forsman-Lehmann Syndrome in a Family with Four Affected Young Boys. Mol Syndromol. 2015;6(4):181-186. doi:10.1159/000441047. PMID: 26648834; PMCID: PMC4662274.
57. Vallée D, Chevrier E, Graham GE, Lazzaro MA, Lavigne PA, Hunter AG, Picketts DJ. A novel PHF6 mutation results in enhanced exon skipping and mild Börjeson-Forssman-Lehmann syndrome. J Med Genet. 2004;41(10):778-783. doi:10.1136/jmg.2004.020370. PMID: 15466013; PMCID: PMC1735599.
58. Cheng C, Deng PY, Ikeuchi Y, Yuede C, Li D, Rensing N, et al. Characterization of a Mouse Model of Börjeson-Forssman-Lehmann Syndrome. Cell Rep. 2018;25(6):1404-1414.e6. doi:10.1016/j.celrep.2018.10.043. PMID: 30403997; PMCID: PMC6261530.
59. Birrell G, Lampe A, Richmond S, Bruce SN, Gécz J, Lower K, et al. Borjeson-Forssman-Lehmann syndrome and multiple pituitary hormone deficiency. J Pediatr Endocrinol Metab. 2003;16(9):1295-1300. doi:10.1515/jpem.2003.16.9.1295. PMID: 14714754.
60. Wieczorek D, Bögershausen N, Beleggia F, Steiner-Haldenstätt S, Pohl E, Li Y, et al. A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling. Hum Mol Genet. 2013;22(25):5121-35. doi:10.1093/hmg/ddt366. PMID: 23906836.
61. Silva MF, Machado Sousa V, Santos RS, Pimenta JP, Reis Costa H. Börjeson-Forssman-Lehmann Syndrome in a Pediatric Patient: A Four-Year Longitudinal Case Report Focused on Functional Evolution and Rehabilitation. Cureus. 2026;18(1):e101421. doi:10.7759/cureus.101421. PMID: 41694865; PMCID: PMC12895377.
62. Kasper BS, Dörfler A, Di Donato N, Kasper EM, Wieczorek D, Hoyer J, Zweier C. Central nervous system anomalies in two females with Borjeson-Forssman-Lehmann syndrome. Epilepsy Behav. 2017;69:104-109. doi:10.1016/j.yebeh.2017.01.022. PMID: 28237832.
63. Dickinson ME, Flenniken AM, Ji X, Teboul L, Wong MD, White JK, et al. High-throughput discovery of novel developmental phenotypes. Nature. 2016;537(7621):508-14. Erratum in: Nature. 2017;551(7680):398. doi:10.1038/nature19356. PMID: 27626380; PMCID: PMC5295821.
64. McRae HM, Leong MPY, Bergamasco MI, Garnham AL, Hu Y, Corbett MA, et al. Loss of PHF6 causes spontaneous seizures, enlarged brain ventricles and altered transcription in the cortex of a mouse model of the Börjeson-Forssman-Lehmann intellectual disability syndrome. PLoS Genet. 2024;20(10):e1011428. doi:10.1371/journal.pgen.1011428. PMID: 39405291; PMCID: PMC11478892.
65. Van Vlierberghe P, Palomero T, Khiabanian H, Van der Meulen J, Castillo M, Van Roy N, et al. PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat Genet. 2010;42(4):338-342. doi:10.1038/ng.542. PMID: 20228800; PMCID: PMC2847364.
66. Van Vlierberghe P, Patel J, Abdel-Wahab O, Lobry C, Hedvat CV, Balbin M, et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia. 2011;25(1):130-134. doi:10.1038/leu.2010.247. PMID: 21030981; PMCID: PMC3878659.
67. Kubota Y, Gu X, Terkawi L, Bodo J, Przychodzen BP, Awada H, et al. Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting. Nat Commun. 2024;15(1):1832. doi:10.1038/s41467-024-46134-w. PMID: 38418452; PMCID: PMC10901781.
68. Deuitch N, Broadbridge E, Cunningham L, Liu P. RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies. 2021 Mar 4. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. https://www.ncbi.nlm.nih.gov/books/NBK568319/
69. Hörst K, Kühn C, Haferlach T. Genomics in Haematological Malignancies. In: ESMO Handbook — Cancer Genomics. Lugano: ESMO Press. p. 115–116.
70. Carter MT, Picketts DJ, Hunter AG, Graham GE. Further clinical delineation of the Börjeson-Forssman-Lehmann syndrome in patients with PHF6 mutations. Am J Med Genet A. 2009;149A(2):246-250. doi:10.1002/ajmg.a.32624. PMID: 19161141.
71. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 194–197 (Intellectual disability with apparent X-linked inheritance).
72. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Appendix: Pattern of Malformation Differential Diagnosis by Anomalies. p. 999–1056.
73. Kubota T, Oga S, Ohashi H, Iwamoto Y, Fukushima Y. Borjeson-Forssman-Lehmann syndrome in a woman with skewed X-chromosome inactivation. Am J Med Genet. 1999;87(3):258-61. PMID: 10564881. https://pubmed.ncbi.nlm.nih.gov/10564881/
74. Dattani MT. Borjeson-Forssman-Lehmann syndrome: a novel pituitary phenotype due to mutation in a novel gene. J Pediatr Endocrinol Metab. 2003;16(9):1207-1209. doi:10.1515/jpem.2003.16.9.1207. PMID: 14714741.
75. Garcia-Melendo C, Roé E, Rodríguez-Santiago B, Amat-Samaranch V, Cubiró X, Puig L, Boronat S. A case report of PHF6 mosaicism: Beyond the classic Börjeson-Forssman-Lehmann syndrome. Pediatr Dermatol. 2021;38(4):919-925. doi:10.1111/pde.14636. PMID: 34041787.
76. Dutta D, Garg R. Orofacial clefting in PHF6-related Börjeson-Forssman-Lehmann syndrome. BMJ Case Rep. 2026;19(2):e270011. doi:10.1136/bcr-2025-270011. PMID: 41741118.
77. Rodan LH, Stoler J, Chen E, Geleske T; Council on Genetics. Genetic Evaluation of the Child With Intellectual Disability or Global Developmental Delay: Clinical Report. Pediatrics. 2025;156(1):e2025072219. doi:10.1542/peds.2025-072219. PMID: 40545261.
78. Vergano SA, van der Sluijs PJ, Santen G. ARID1B-Related Disorder. 2019 May 23. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. https://www.ncbi.nlm.nih.gov/books/NBK541502/
79. Smits DJ, Debuy C, Brooks AS, Schot R, Ferraro F, Rots D, et al. Clinical utility of DNA-methylation signatures in routine diagnostics for neurodevelopmental disorders. Eur J Hum Genet. 2025;33(10):1281-1289. doi:10.1038/s41431-025-01919-5. PMID: 40730689; PMCID: PMC12480637.
80. Geysens M, Huremagic B, Souche E, Breckpot J, Devriendt K, Peeters H, et al. Clinical evaluation of long-read sequencing-based episignature detection in developmental disorders. Genome Med. 2025;17(1):1. doi:10.1186/s13073-024-01419-z. PMID: 39789644; PMCID: PMC11721592.
81. Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi Syndrome. 1998 Oct 6 [updated 2023 Mar 9]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. https://www.ncbi.nlm.nih.gov/books/NBK1330/
82. Rogers RC, Abidi FE. RPS6KA3-Related Intellectual Disability. 2002 Jul 16 [updated 2023 Mar 16]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. https://www.ncbi.nlm.nih.gov/books/NBK1346/
83. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 816–817 (Coffin-Siris Syndrome).
84. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 652–653 (Chromosomal mosaicism postnatal — hypomelanosis of Ito).
85. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 278–279 (Patchy pigmented skin lesions).
86. Loenarz C, Ge W, Coleman ML, Rose NR, Cooper CDO, Klose RJ, et al. PHF8, a gene associated with cleft lip/palate and mental retardation, encodes for an Nepsilon-dimethyl lysine demethylase. Hum Mol Genet. 2010;19(2):217-22. doi:10.1093/hmg/ddp480. PMID: 19843542; PMCID: PMC4673897.
87. Siderius LE, Hamel BC, van Bokhoven H, de Jager F, van den Helm B, Kremer H, et al. X-linked mental retardation associated with cleft lip/palate maps to Xp11.3-q21.3. Am J Med Genet. 1999;85(3):216-220. PMID: 10398231.
88. Laumonnier F, Holbert S, Ronce N, Faravelli F, Lenzner S, Schwartz CE, et al. Mutations in PHF8 are associated with X linked mental retardation and cleft lip/cleft palate. J Med Genet. 2005;42(10):780-786. doi:10.1136/jmg.2004.029439. PMID: 16199551; PMCID: PMC1735927.
89. Abidi F, Miano M, Murray J, Schwartz C. A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate. Clin Genet. 2007;72(1):19-22. doi:10.1111/j.1399-0004.2007.00817.x. PMID: 17594395; PMCID: PMC2570350.
90. Koivisto AM, Ala-Mello S, Lemmelä S, Komu HA, Rautio J, Järvelä I. Screening of mutations in the PHF8 gene and identification of a novel mutation in a Finnish family with XLMR and cleft lip/cleft palate. Clin Genet. 2007;72(2):145-9. doi:10.1111/j.1399-0004.2007.00836.x. PMID: 17661819.
91. Qiao Y, Liu X, Harvard C, Hildebrand MJ, Rajcan-Separovic E, Holden JJA, Lewis MES. Autism-associated familial microdeletion of Xp11.22. Clin Genet. 2008;74(2):134-44. doi:10.1111/j.1399-0004.2008.01028.x. PMID: 18498374.
92. Hikma Pharmaceuticals USA Inc. Testosterone Enanthate Injection, USP [prescribing information]. ANDA091120. DailyMed set ID e89d6458-428c-4256-97a3-f1fa851293c1; revised 2026-05-08. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e89d6458-428c-4256-97a3-f1fa851293c1
93. INFARMED. Testoviron Depot 250 mg/ml solução injetável (testosterone enantate; registration no. 888822; first authorised 26 March 1980) — summary of product characteristics. Infomed. https://extranet.infarmed.pt/INFOMED-fo/. Accessed 18 October 2026.
94. Pfizer Laboratories Div Pfizer Inc. GENOTROPIN (somatropin) for injection [prescribing information]. BLA020280. DailyMed set ID ffebf88b-d257-4542-9808-74d9b7167765; revised 2026-08-04. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffebf88b-d257-4542-9808-74d9b7167765
95. European Medicines Agency. Omnitrope (somatropin) — summary of product characteristics (Annex I of the EPAR; EMEA/H/C/000607; marketing authorisation holder Sandoz GmbH; first authorised 12 April 2006; product information updated 5 August 2025). https://www.ema.europa.eu/en/medicines/human/EPAR/omnitrope. Accessed 18 October 2026.
96. INFARMED. Genotropin 5,3 mg/1 ml e 12 mg/1 ml pó e solvente para solução injetável (somatropin; Laboratórios Pfizer, Lda.) — summary of product characteristics. Infomed. https://extranet.infarmed.pt/INFOMED-fo/. Accessed 18 October 2026.
97. Liu B, Wang J, Wu X, Gan L, Sun J, Wang G, et al. Regulation of stress susceptibility by chromatin-binding protein PHF6 in the pituitary intermediate lobe. Mol Psychiatry. 2026;31(3):1665-1680. doi:10.1038/s41380-025-03300-w. PMID: 41053436; PMCID: PMC12916324.
98. Wang D, Pan H, Wang Y, Xu H, Liu L, Xu Y, Tong H. Clinical Characteristics, Gene Mutation Profiles and Prognosis of Patients With Acute Myeloid Leukemia Carrying PHF6 Mutations. Cancer Med. 2026;15(5):e71902. doi:10.1002/cam4.71902. PMID: 42087483; PMCID: PMC13144755.