Oculofaciocardiodental Syndrome and BCOR-Related Disorders

Allelic class of the BCOR gene (BCL6 corepressor, Xp11.4): oculofaciocardiodental syndrome (OFCD) in females heterozygous for null alleles, with X-linked dominant transmission and presumed male lethality, and severe male microphthalmia syndrome (BCOR-related “Lenz”), X-linked recessive, caused by hypomorphic alleles, together with the more recently described male and ocular phenotypes.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

The BCOR gene gives rise to two clinical presentations that depend on sex and on variant type: in females, variants that abolish the function of one allele (nonsense, frameshift, splicing and partial or whole-gene deletions) cause oculofaciocardiodental syndrome (OFCD), whereas in hemizygous males alleles with residual function, above all the missense variant p.(Pro85Leu), cause a severe syndromic microphthalmia historically included in Lenz syndrome [1–3]. OMIM groups the two presentations under a single entry, “syndromic microphthalmia 2” (MCOPS2), with X-linked dominant inheritance, and Orphanet keeps OFCD (ORPHA:2712) separate from Lenz-type microphthalmia (ORPHA:568), an entry it shares with the NAA10 gene [4–6]. In 2019, Ragge and colleagues proposed the designation “BCOR-related X-linked syndrome”, specifying sex, and the abandonment of the generic Lenz eponym for males with severe microphthalmia without a molecular diagnosis [3]. The NAA10-related form of Lenz (MCOPS1) is included here only as a differential diagnosis.

1. Introduction

1.1 From canine radiculomegaly to oculofaciocardiodental syndrome

The history of the syndrome began in dentistry. In 1990, Marashi and Gorlin drew attention to radiculomegaly, that is, an increase in the length and calibre of a tooth root, above all of the canine, and asked whether its association with congenital cataract constituted a syndrome; they observed that radiculomegaly of isolated teeth was rare, that the canine was the tooth most often affected and that detailed case reports were lacking [20]. Two years later, the same authors confirmed the association, and Smith's Recognizable Patterns of Human Malformation dates the delineation of the malformation pattern to 1992 [13, 21]. Orphanet preserves this early phase in the historical entry “canine teeth radiculomegaly–congenital cataract”, with the synonym Marashi-Gorlin syndrome [7]. The first description of a giant canine associated with congenital cataract is attributed to Hayward, in 1980 (“cuspid gigantism”), according to OMIM and the review by Batkova and colleagues [10, 15]. In parallel, Wilkie and colleagues described in 1993 a woman with a long, narrow face, congenital cataract, microphthalmia, persistent primary teeth, radiculomegaly and atrial septal defect, whose daughter had a similar picture with mild delay, and proposed a new syndrome with autosomal dominant inheritance; Aalfs and colleagues reported in 1996 two unrelated adult women of normal intelligence with cataract, radiculomegaly, septal defects, moderate hearing loss and 2–3 syndactyly, one of them with a transverse vaginal septum [10].

In 1996, Gorlin, Marashi and Obwegeser proposed the name oculo-facio-cardio-dental and defined four components: ocular (congenital cataract and microphthalmia, or secondary glaucoma), facial (long, narrow face, high nasal bridge, pointed nose with the alar cartilages separated at the tip, cleft palate or submucous cleft), cardiac (atrial septal defect, ventricular septal defect or redundant mitral valve) and dental (canine radiculomegaly, delayed dentition, oligodontia, persistent primary teeth and variable root length) [22]. They added sensorineural hearing loss, septate vagina and syndactyly of the second and third toes as less frequent findings, and suggested X-linked dominant inheritance lethal in males, at a time when the syndrome had been described in seven females from two generations and in no males [10, 22]. In 1999, Schulze and colleagues reviewed the nine cases published up to then and added three, with dental fusion and supernumerary permanent upper teeth, and in 2003 Hedera and Gorski documented skewed X inactivation in an affected mother and daughter, which strengthened the hypothesis of X-linked dominant inheritance with male lethality [10].

1.2 Molecular discovery and relationship with Lenz microphthalmia

In 1955, Widukind Lenz described a pedigree with X-linked recessive microphthalmia and multiple malformations; for decades, the eponym was applied to males with syndromic microphthalmia, even without a family history [8, 23]. Linkage analysis separated two loci: MAA (microphthalmia with associated anomalies), at Xq27–q28, and MAA2, at Xp11.4–p21.2 [1]. In 2002, Ng and colleagues excluded the Xq27–q28 region in an African American family with six males affected by microphthalmia or clinical anophthalmia, microcephaly, intellectual disability, large ears, renal aplasia, cryptorchidism and hypospadias, and found linkage to a 10 cM interval at Xp21.2–p11.4 (maximum lod score 2.46), designated ANOP2; the interval was later narrowed to about 5 Mb [10]. In 2004, Ng and colleagues identified the substitution c.254C>T, p.(Pro85Leu), in the BCOR gene in the affected males of the family used to define the MAA2 locus, originally described by Hoefnagel in 1963 and by Ogunye in 1975 [1, 4]. Because of the clinical overlap, the same authors sequenced BCOR in seven families with OFCD and found in each one different frameshift, deletion or nonsense variants, which showed that the two syndromes were allelic and resulted from distinct classes of variants [1].

In 2005, Horn and colleagues described three new patients with OFCD (two small deletions and a submicroscopic deletion of about 60 kb spanning at least exons 2 to 15) and found no BCOR variants in eight patients with a clinical diagnosis of Lenz syndrome, concluding that BCOR was the OFCD gene but not the main gene for Lenz syndrome [24]. In 2009, Hilton and colleagues assembled the largest single clinical cohort (35 females with a variant, 31 of them new), described somatic mosaicism for the first time and confirmed the rarity of BCOR in males with microphthalmia [2]. The MAA locus would later turn out to correspond to the NAA10 gene (MCOPS1) [8].

1.3 Current nomenclature and classifications

OMIM describes the disease in a single phenotype entry, “microphthalmia, syndromic 2” (MCOPS2, #300166), linked to gene *300485 and with X-linked dominant inheritance, with the alternative titles OFCD syndrome and “microphthalmia, cataracts, radiculomegaly and cardiac septal defects”, and the former designations ANOP2 and MAA2 [4, 10]. OMIM also notes that the term “anophthalmia” is used improperly in the literature: true anophthalmia, demonstrable only histologically, is rare and accompanied by major brain defects, and most published cases correspond to extreme microphthalmia or clinical anophthalmia [10]. GeneReviews explained that MCOPS2 had been redesignated OFCD because of the higher frequency of loss-of-function variants in females, retaining p.(Pro85Leu) as the cause of Lenz syndrome in males [8]. Orphanet classifies OFCD (ORPHA:2712) as a malformation syndrome, with X-linked dominant inheritance and neonatal or childhood onset, and Lenz-type microphthalmia (ORPHA:568) as an X-linked recessive form allelic to OFCD and to Ogden syndrome [5, 6, 12]. The International Classification of Diseases assigns OFCD the codes Q87.8 (ICD-10) and LD21.0 (ICD-11), and Lenz microphthalmia the code Q11.2 (ICD-10) [12].

In 2019, after reviewing 95 cases from 66 families, Ragge and colleagues proposed the designation “BCOR-related X-linked syndrome”, with specification of sex, for three reasons: OFCD is broader than the four components of its name, the male syndrome does not always include microphthalmia or intellectual disability, and the term Lenz describes a pedigree rather than a genetic entity [3]. Since then, other less well-established phenotypes have been associated with BCOR: practically isolated dominant congenital nuclear cataract, early X-linked retinal degeneration due to missense variants and X-linked recessive partial epilepsy [25–27]. The somatic role of BCOR in tumours is distinct and does not carry over to a constitutional result [12].

1.4 Definition of the entities covered

OFCD is defined as the association, in a female, of congenital or early-onset cataract with dental anomalies (radiculomegaly, delayed or persistent dentition, hypodontia, dental fusion) and a variable number of other ocular, facial, cardiac and skeletal findings, confirmed by a loss-of-function variant in BCOR [2, 3]. Male BCOR-related syndrome is defined by the presence of a hemizygous allele with residual function (in most cases p.(Pro85Leu)) in a male with microphthalmia or anophthalmia and extraocular anomalies, with the recent extension to males without major ocular anomalies [3]. Neither entity has published formal clinical criteria; the diagnosis is molecular [12].

2. Molecular Genetics and Pathophysiology

2.1 The gene and the protein

BCOR is located at Xp11.4 (GRCh38 X:40 051 246–40 177 277), spans about 55 kb and has 15 exons [4, 8]. Huynh and colleagues cloned it in 2000 from a screen for proteins interacting with the POZ domain of BCL6, a zinc-finger transcriptional repressor required for germinal centre formation; the deduced protein had 1721 amino acids and three C-terminal ankyrin repeats, and a short isoform (BCOR-S, 1004 amino acids) shared the first 999 residues without the ankyrin repeats, according to OMIM [4]. The full-length form, but not the short one, acts as a corepressor when tethered to the promoter and potentiates repression by BCL6; both associate with class I and II histone deacetylases, and the interaction of BCL6 with BCOR precludes simultaneous binding of SMRT or NCOR [4]. The MANE Select transcript is NM_001123385.2, which encodes an isoform of 1755 amino acids (NP_001116857.1); GeneReviews and the European clinical utility gene card used NM_017745.5 (isoform of 1721 amino acids) [8, 9, 16]. Variant numbering in the first exons is identical in the two transcripts: NM_001123385.2:c.254C>T and NM_017745.5:c.254C>T correspond to the same genomic nucleotide, NC_000023.11:g.40075092G>A (GRCh38), and both give p.(Pro85Leu) [9].

BCOR is a core component of Polycomb repressive complex 1.1 (PRC1.1, a non-canonical form of PRC1): its C-terminal regions bind the ubiquitin-like fold domains of PCGF1 and PCGF3, and it is recruited to promoters by sequence-specific factors such as BCL6 and MLLT3 [4, 12, 28]. Expression is ubiquitous, with intermediate levels in adult liver, kidney, spinal cord and brain [4]. The Clinical Genome Resource (ClinGen) classifies BCOR haploinsufficiency with a score of 3 (sufficient evidence) and triplosensitivity with a score of 0 [12].

2.2 Mechanism: two allele types, two diseases

Ng and colleagues showed that both the p.(Pro85Leu) protein and an OFCD mutant protein still bind BCL6 and effectively repress transcription in in vitro assays, so the diseases result from loss of other BCOR functions, such as the interaction with partners other than BCL6 [1]. In females with OFCD, the variants are predicted to truncate the protein or remove part of the gene: in the review of 85 cases, 48% were frameshift, 33% nonsense, 7% affected splicing and 12% were partial or whole-gene deletions [3]. In the first study, all the variants in the seven OFCD families predicted premature termination codons [10]. Truncated transcripts were not detected in patients, which is consistent with nonsense-mediated messenger RNA decay (NMD) [2, 8]. In all the females studied, X inactivation was strongly skewed in favour of the normal allele (90–100% in informative cases), indicating that cells expressing the null allele are at a selective disadvantage, at least in haematological lineages; patients are functional mosaics, and tissues in which the lack of BCOR is tolerated express the mutated allele [2, 3].

In males, hemizygosity for a null allele is presumably lethal: no liveborn male with a non-mosaic truncating variant had been described up to 2019, and mothers transmitting OFCD report recurrent miscarriages (one mother had eight) [3]. The mouse model confirms the lethality: Bcor hemizygosity in the whole male embryo causes embryonic death by day E9.5, and heterozygous females, with mosaic expression, have reduced postnatal viability and OFCD-like defects [29]. In 2022, a male fetus with the hemizygous frameshift variant c.251dupT, inherited from a mother with OFCD features, was described; it was still alive at 26 weeks of gestation, when the pregnancy was terminated because of ultrasound anomalies [30]. Liveborn males with BCOR-related disease have alleles with residual function: missense variants in seven families and a splicing variant in another; carrier mothers do not manifest disease and have skewed X inactivation (100% and 96:4 in one family) [3].

2.3 Pathophysiology by tissue

Radiculomegaly has the most extensively studied molecular basis. Mesenchymal stem cells from a patient with OFCD showed increased osteo-dentinogenic potential; the transcription factor AP-2α (encoded by TFAP2A) is a target repressed by BCOR, its abnormal activation mediates the increase in dentinogenesis, and loss of BCOR increases H3K4 and H3K36 histone methylation, reactivating silenced genes [31]. In periodontal ligament cells from a patient with c.3668delC, the factors NFIB, DLX5 and ZFPM2 were overexpressed; normal BCOR is recruited with BCL6 to the ZFPM2 promoter, whereas the mutant is not, and reduction of ZFPM2 decreases proliferation and alkaline phosphatase, a marker of odontoblasts and cementoblasts [32]. In the same cells, the UPF1 protein, central to NMD, binds exon 9 of the mutated transcript, and its reduction increases BCOR transcription and alters BMP2 expression [33].

The cardiac and laterality defects are linked to the left–right pathway. Hilton and colleagues identified patients with dextrocardia, asplenia and intestinal malrotation and showed, in Xenopus tropicalis, that reducing Bcor on the left side of the embryo reverses cardiac orientation and disorganises the gut, decreasing Pitx2c expression, whereas the ocular defects (microphthalmia, coloboma) showed no side bias [34]. In Xenopus, the BCL6/BCOR complex blocks Notch-dependent activity and protects Pitx2 expression in the left lateral mesoderm; the repressor ESR1, downstream of Notch, recruits HDAC1 to the left-side Pitx2 enhancer and prevents p300 recruitment [35]. The 2009 authors consider that septal defects, which are very frequent, may be the most common manifestation of abnormal lateral specification, and that facial clefting and septate nasal cartilage may result from midline defects linked to the same pathway [2].

The conditional mouse model of Hamline and colleagues localised the defects: loss of Bcor in the neural crest caused cleft palate (secondary to a mandibular defect, not to a palatal one), short mandible and tympanic bone, ectopic salivary glands and abnormal tongue musculature; loss in the hindlimb lateral mesoderm caused 2/3 syndactyly; loss in Isl1-expressing cardiac lineages caused persistent truncus arteriosus, ventricular septal defect and fetal death; and loss in extraembryonic lineages caused placental defects and mid-gestation death [29]. Overexpression of isoform A was also lethal, which indicates dosage sensitivity in both directions in the mouse [29]. In zebrafish, knockdown of the orthologue disrupts development of the eye, skeleton and central nervous system [1].

In the retina, BCOR interacts with the transcription factors CRX and OTX2 and reduces activation of photoreceptor gene promoters; it shares their genome-wide binding profile, and human missense variants increase OTX2 repression and cause degeneration when expressed in the mouse retina [26].

2.4 Variant spectrum and nomenclature

The table lists the variants mentioned in the article, in the notation of the publications; those verified in VariantValidator are indicated.

Variants published before 2019 often use the notation without parentheses and the NM_017745.5 transcript; Ragge and colleagues renamed all published variants on NM_001123385.1 and checked them in Mutalyzer [3]. OMIM records that the Oberoi article uses two numberings for the same deletion (2613delC and 1315delC) [4]. The NM_001123385.1 and NM_001123385.2 notations give the same c. numbering for the variants in this article. In ClinVar, p.(Pro85Leu) is classified as pathogenic with criteria from a single submitter [36].

2.5 Genotype–phenotype correlation, penetrance and expressivity

The strongest correlation is that of allele type with sex: null alleles in the heterozygous state produce OFCD in females; hypomorphic alleles in the hemizygous state produce the male syndrome, with asymptomatic carriers [2, 3]. Within OFCD, penetrance is complete for non-mosaic truncating variants: all non-mosaic cases manifested congenital or early cataract, and all sporadic cases with tested parents (35%) had a de novo variant [3]. Expressivity is variable within families: in a three-generation Croatian family (grandmother, mother and monozygotic twins) with p.(Arg1480*), heart disease and cataract were more severe in successive generations [39]. Factors modulating severity include the degree of skewing of X inactivation, somatic mosaicism and the coexistence of other variants: a patient with mosaic biallelic variants had severe anterior segment dysgenesis, cataract and retinal involvement [2, 40].

Contiguous deletions may add phenotypes. A de novo deletion of about 2.3 Mb at Xp11.4 removed BCOR and OTC, the gene for ornithine transcarbamylase deficiency, in a girl with mild OFCD [41]. A Korean family had, in addition to the c.888delG variant, duplications at Xp22.2–p22.13 that included NHS, the gene for Nance-Horan syndrome [42]. A de novo deletion of exons 7–15 was accompanied by a 162 kb deletion at 2p15 (including OTX1) in an infant with pontocerebellar hypoplasia [3]. Multilocus pathogenic variation has also been described: an adolescent girl with OFCD had a paternal pathogenic MYLK variant, associated with thoracic aortic aneurysm and dissection [43], and a girl had both Duchenne muscular dystrophy (maternal deletion of exons 30–43 of DMD, with completely skewed X inactivation) and OFCD due to a de novo frameshift variant [44].

2.6 BCOR in tumours: a distinct somatic role

BCOR is altered somatically in tumours in three ways. In-frame internal tandem duplications of the last exon cause overexpression and define clear cell sarcoma of the kidney, primitive myxoid mesenchymal tumour of infancy and high-grade neuroepithelial tumour of the central nervous system with BCOR alteration [12]. Fusions, above all BCOR::CCNB3 (24 of 594 sarcomas without an EWSR1/ETS translocation in one series), BCOR::MAML3 and ZC3H7B::BCOR, define undifferentiated round cell sarcoma, ossifying fibromyxoid tumour and high-grade endometrial stromal sarcoma [4, 12, 45]. Somatic truncating variants occur in myeloid neoplasms, and BCOR is part of the myeloid panels recommended by the European Society for Medical Oncology (ESMO) handbook [12, 46]. These mechanisms are not equivalent to one another, and the effect depends on cell type and developmental stage [28]. No BCOR germline tumour predisposition syndrome has been established, although a child with OFCD and T-cell lymphoma and three patients with OFCD and insulinoma, one of them without genetic confirmation, have been described (see section 3) [3, 12, 17].

3. Clinical Spectrum and Manifestations by System

3.1 Data sources and what they measure

Frequency data for OFCD come from case series and literature reviews, not from population studies. The cohort of Hilton and colleagues (2009) brought together 35 females with a pathogenic BCOR variant, recruited by centres in the United Kingdom, France, Switzerland, Belgium, Japan and the United States; one of them, a mosaic, was asymptomatic, and the frequencies refer to the 34 symptomatic patients, with denominators that change according to whether or not each domain was recorded [2]. The review by Ragge and colleagues (2019) brought together 85 females from 58 published families, including 15 new cases from British, French and Spanish cohorts and from the DDD study (Deciphering Developmental Disorders) [3]. These series have ascertainment bias: they favour patients with a complete phenotype and predate the widespread use of exome sequencing, and Redwood and colleagues showed, in a single Manchester institution, 10 patients from 5 families in two years, with more variable forms identified through congenital cataract testing [14]. The table summarises Hilton's data, which give denominators for each trait.

Source: Hilton and colleagues, 2009, Table 3 [2]. GeneReviews gives radioulnar synostosis as “7/35”; the primary source gives 7 of 28 patients with the skeletal phenotype recorded [2, 8].

In the review of 85 cases, only 41% had anomalies in all four categories that give the syndrome its name; toe anomalies were present in 82%, radioulnar synostosis in 13%, vertebral anomalies in 10%, heart disease in 63%, mild developmental delay in about 10% and hearing loss in 9%, and only four cases had no dental anomalies [3]. In the supplementary data of that review, tabulated by Yamashita and colleagues, cataract was present in 82/83, microphthalmia in 56/83, skeletal anomalies in 36/67, cardiac anomalies in 51/61, dental anomalies in 68/72, and development was normal in 10/16 of the cases with information [47]. In the Manchester series, cataract was present in 10/10, microphthalmia in 3/10, skeletal anomalies in 4/10, cardiac anomalies in 5/10, dental anomalies in 6/10, and development was normal in 9/10 [14, 47]. Smith's Recognizable Patterns gives mild intellectual disability in 15–20% and hearing loss in about 15% [13].

3.2 Eye

Congenital cataract is the most constant finding and often the first: it was present in all patients in the 2009 cohort and in all non-mosaic cases in the 2019 review [2, 3]. It is usually bilateral but may be unilateral, and it was detected on prenatal ultrasound at 22 and 32 weeks of gestation in two cases [3, 14, 15]. The morphology described includes posterior lenticonus with posterior cortical opacity and cataract associated with persistent fetal vasculature; in a series from Israel and Palestine, BCOR variants were found in two of three families with this type of cataract [48, 49]. Microphthalmia, when present, is less severe than in the male syndrome and is associated with microcornea and a shallow anterior chamber [2, 8].

Secondary glaucoma is the ocular complication with the greatest impact. In a Portuguese series from the Centro Hospitalar Universitário de São João (Porto), three women with cataract diagnosed in the first days of life and operated on between 6 and 16 weeks all developed ocular hypertension and glaucoma requiring surgery in childhood (trabeculectomy, Ahmed valve implant, cyclophotocoagulation) [50]. In the Ragge review, several cases had chronic bilateral glaucoma with acute crises, pupillary block glaucoma after surgery, retinal detachment at 12 years and loss of light perception in one eye [3]. Two North American cases with aphakia developed intraocular pressures of 37 and 36 mmHg at 3.5 years, and both had multiple lesions of congenital hypertrophy of the retinal pigment epithelium [51]. An adolescent girl with bilateral microcornea had persistent secondary glaucoma requiring multiple interventions [43]. Less frequent ocular findings include ptosis, nystagmus, coloboma, lens dislocation, optic disc dysplasia, iris synechiae and phthisis bulbi [2, 13].

3.3 Face and oral cavity

The most specific facial trait is septate nasal cartilage, with a broad or bifid nasal tip, present in 25 of 26 patients with the facial phenotype recorded [2]. The face is long and narrow, the nasal bridge high, the eyes may be deep-set and the eyebrows arched [2, 3, 13]. Clefts include cleft palate, submucous cleft and bifid uvula (31% in the 2009 cohort), with cleft lip described in isolated cases [2, 15]. Craniosynostosis, temporal hypertrichosis and midface hypoplasia have also been reported, as well as unilateral coronal synostosis in a Japanese girl [47, 52].

3.4 Teeth

The dental phenotype is the most specific feature of the syndrome. Radiculomegaly, or root gigantism, mainly affects the permanent canines, whose roots continue to grow until they approach the orbit or the lower border of the mandible, and less often the incisors and premolars [15, 53]. It was present in 20 of 22 patients with permanent dentition assessed; in the remaining two, radiographs were lacking [2]. An affected canine measured 38.0 mm on cone-beam computed tomography, corresponding to +14.8 standard deviations, and 29-year follow-up showed that the root continues to grow for months or years, with calcified dental papillae beneath open apices and stone-like pulp calcifications [54]. A 2018 review found 67 cases of radiculomegaly and 92 of OFCD in the English-language literature, and only one previous confirmed case of non-syndromic, non-familial radiculomegaly [53]. A Danish preprint from 2026, not yet peer reviewed, with a literature review and two new cases, found radiculomegaly already in the primary dentition in all cases with data, with the lower canine most affected [55].

Other dental anomalies include delayed eruption and exfoliation of the primary dentition, persistent primary teeth that may have to be extracted to allow eruption of the permanent ones, unerupted teeth, hypodontia or oligodontia, fused or duplicated teeth, root dilaceration, talon cusps and a single central incisor [2, 3, 13, 15, 39]. In the two Czech families, all five females (3 to 49 years) had dental changes, radiculomegaly appeared in the three with permanent dentition, two had agenesis of permanent teeth and two had malocclusion; a 13-year-old child had dental delay of about three years and had undergone multiple extractions under general anaesthesia at 4 years because of caries [15]. A 26-year-old Portuguese woman had multiple missing teeth, radiculomegaly of incisors, canines and premolars, a gummy smile, a 9 mm deep bite and a Class II malocclusion on a Class III skeletal base [56].

3.5 Heart and laterality

Congenital heart disease was present in 74% of patients with a cardiac assessment, and 85% of these had a septal defect, mainly atrial septal defect [2]. In the 2019 review, the frequency was 63% [3]. Patent ductus arteriosus, mitral valve regurgitation or prolapse, pentalogy of Fallot, double outlet right ventricle, left ventricular non-compaction, pulmonary hypertension and Wolff-Parkinson-White syndrome have also been described [2, 3, 47, 51]. Laterality defects (dextrocardia, asplenia, intestinal malrotation) are rare, but Hilton and colleagues recommend looking for them [2, 34]. A septal defect may go unnoticed until adulthood: a 21-year-old French woman had a large, asymptomatic atrial septal defect detected only after the genetic diagnosis, and underwent surgery [57].

3.6 Skeleton and limbs

Toe anomalies are the most frequent outside the four classic domains: cutaneous syndactyly of the second and third toes and hammer toes, present in 93% of patients with a skeletal assessment [2]. Radioulnar synostosis, with limited supination, was present in 25% of these patients and is considered a BCOR marker common to both syndromes [2]. Broad or long halluces, camptodactyly, clinodactyly, brachydactyly, mesoaxial polysyndactyly, scoliosis, lordosis, vertebral fusion, joint hypermobility and clubfoot also occur [3, 13, 48].

3.7 Nervous system, hearing and development

Most women with OFCD have normal intelligence; intellectual disability, usually mild, was recorded in 18% in the 2009 cohort and in about 10% in the 2019 review [2, 3]. Motor delay may partly reflect the visual deficit: a Japanese girl walked at 2 years and 6 months and had a developmental quotient of 60 [47]. Hearing loss (conductive or sensorineural) occurred in 15% and 9% in the two series, and only 2 of the 9 cases with hearing loss in the review had cleft palate, which argues against an exclusively otological cause [2, 3]. Cerebral atrophy, ventriculomegaly, calcification of the choroid plexus and falx, lipoma of the corpus callosum, arachnoid cyst, pontocerebellar hypoplasia (in a patient with a second deletion), hypotonia, hyporeflexia and neuropathy have been described [3, 13].

3.8 Other systems

Severe feeding problems with recurrent vomiting in early infancy and gastro-oesophageal reflux are frequent [2, 13, 15]. Vesicoureteral reflux, septate vagina, recurrent urinary tract infections and late bladder control have been described [2, 3, 22]. In the endocrine domain, one patient had growth hormone deficiency treated from the age of 3, and the 2019 review suggests pituitary hypoplasia as an additional trait [3]. Infantile haemangiomas appear to be frequent: one case with haemangiomas on the forehead and neck, two North American cases with a haemangioma of the forehead or scalp (one of them initially diagnosed as PHACE syndrome) and a boy with a temporal haemangioma [3, 51]. Other findings include thyroglossal duct cyst, thyroid lipoma, primary lymphoedema of the lower limbs and bronchial asthma [3, 15].

3.9 Tumours

The association with tumours has not been quantified. A girl with OFCD (de novo variant p.(Gln404Alafs*35)) had stage III T-cell lymphoma at 12 months, in remission after two years of chemotherapy, and the authors called for multicentre follow-up studies to measure tumour incidence [3]. Three patients with OFCD and insulinoma have been published: one case with a clinical diagnosis, without genetic testing, with recurrent insulinoma; one case with the c.2014_2015del variant and multiple synchronous insulinomas; and a Japanese woman with a deletion of exons 7–15 and multiple metachronous insulinomas over more than six years [17]. The authors of this last case do not recommend systematic screening for insulinoma, but rather attention to symptoms of hypoglycaemia [17].

3.10 Mosaicism and mild forms

Somatic mosaicism explains part of the variability. In the 2009 cohort, two monozygotic twins with classic OFCD had a mosaic deletion of exons 4–15 (about half of the metaphases), and the asymptomatic mother of a girl with OFCD, with a normal orthopantomogram, was mosaic for a deletion of exons 13–14 [2]. In the 2019 review, a mother with about 20% mutated alleles in blood had cataract, microphthalmia and agenesis of the lateral incisors [3]. At the mild end, a woman recorded as having isolated bilateral cataract with unilateral microphthalmia had, on questioning, extraction of many primary teeth in adolescence and 2–3 syndactyly, and a three-generation British family had dominant congenital nuclear cataract with a minimal systemic phenotype [2, 25]. A woman with cataract attributed to maternal rubella had radiculomegaly and was the transmitter of her daughter's variant [3].

3.11 Male BCOR-related syndrome

The male syndrome is rare: up to 2019, 10 males from 8 families had been published [3]. The p.(Pro85Leu) variant has been described in the original African American family, in a European boy, in two Japanese families and in two men from the 2019 series, indicating a pan-ethnic distribution [3, 8]. In the original family, six affected males shared the variant, with a lod score of 2.46 [4]. The 7-year-old European boy in the 2009 cohort had bilateral microphthalmia, a narrow forehead, simple ears, atrial septal defect, partial syndactyly of several fingers, fifth-finger clinodactyly, right radioulnar synostosis, mild intellectual disability and hypospadias [2, 4]. In the Japanese family, the first son, with syndromic clinical anophthalmia, died of heart disease at 6 months; the carrier mother later had a healthy son, a miscarriage at 8 weeks and an ectopic pregnancy, and in the fifth pregnancy the 15-week ultrasound showed underdeveloped eyes with unopened palpebral fissures, the fetal karyotype was 46,XY, the variant was confirmed in fetal DNA and the pregnancy was terminated at 19 weeks, with clinical anophthalmia, a depressed nasal bridge and simple ears on examination [4, 10]. Horn and colleagues noted that the picture in the original African American family was not fully consistent with Lenz syndrome and might be specific to that family [10].

Ragge and colleagues summarised the traits of males with p.(Pro85Leu): bilateral microphthalmia or anophthalmia, microcephaly, hypoplasia of the corpus callosum, mild to severe developmental delay, radioulnar synostosis, simple ears, cardiac anomalies, partial syndactyly of the fingers, clinodactyly and hypospadias, without dental anomalies [3]. In the review of the 10 males, ocular, craniofacial, cardiac and skeletal anomalies were present in most, developmental delay in half and genitourinary anomalies in 40% [3]. The two new men with p.(Pro85Leu) showed the breadth of the picture: a 21-year-old man, with the variant inherited from his healthy mother, had severe bilateral microphthalmia without light perception, autism spectrum disorder, absent speech at 9 years, cryptorchidism, vesicoureteral reflux operated on at 7 years, severe scoliosis operated on, hypotonia and short stature; a 27-year-old man, also with maternal inheritance, had bilateral anophthalmia, bilateral renal dysplasia with moderate chronic kidney disease and vesicoureteral reflux, but normal development and high verbal and musical abilities [3]. Thus, the p.(Pro85Leu) variant does not imply intellectual disability in all male carriers [3].

Compared with the NAA10-related form of Lenz syndrome (splicing variant c.471+2T>A), the BCOR-related form lacks the manifestations described in males with NAA10 variants: greater cognitive impairment, digestive symptoms, 2–3 cutaneous syndactyly with short terminal phalanges, and progressive scoliosis and neuropathic muscle degeneration [8]. Female carriers of p.(Pro85Leu) have no features of OFCD or Lenz syndrome [3, 8]. The frequency of BCOR in males with microphthalmia is low: the variant was found in 1 of 21 males with a putative diagnosis of Lenz syndrome (20 without a family history) and in less than 1% of males with severe microphthalmia in the British and French series [2, 3]. Horn and colleagues found no variants in eight patients with the same diagnosis [24]. A young adult with a diagnosis of BCOR-related Lenz syndrome and immunohaematological abnormalities underwent decompressive craniectomy after an accidental fall [58].

3.12 Emerging male and ocular phenotypes

Ragge and colleagues described two half-brothers with the p.(Ser1603Arg) variant, inherited from their asymptomatic mother and absent in the two unaffected brothers, with severe developmental delay, hypotonia, atrial septal defect, posterior cleft palate, camptodactyly, capillary malformations or haemangioma, arachnoid cyst and bilateral posterior embryotoxon, without cataract or microphthalmia, and with early neonatal diabetes mentioned in the discussion [3]. They also described a boy with the splicing variant c.4741+1G>A with megalophthalmos, myopia of −17 dioptres, posterior embryotoxon, ventricular and atrial septal defects, patent ductus arteriosus, persistent left superior vena cava, left ventricular non-compaction, cryptorchidism, grade 4–5 vesicoureteral reflux, epilepsy from the first year and severe delay [3]. These cases suggest that BCOR should be considered in males with syndromic intellectual disability even without microphthalmia [3].

A 7-month-old Chinese boy with congenital glaucoma, complex heart disease, dextrocardia and white matter hypoplasia had the de novo missense variant p.(Arg540Gln), whose causality the authors themselves did not establish [3, 38]. In a Chinese cohort of 323 patients with partial epilepsy without an acquired cause studied by trio exome sequencing, seven had hemizygous missense variants in BCOR; all became seizure-free, two had mild delay and one had cortical dysplasia, and the frequency of these variants was higher than in controls and in the gnomAD database, so the authors propose BCOR as a candidate gene for X-linked recessive partial epilepsy [27]. In five families without cancer, BCOR missense variants caused severe, early-onset X-linked retinal degeneration [26]. These three phenotypes have limited evidence (one case, one cohort or a few families) and are not part of the OMIM or Orphanet definitions [4, 5].

A Chinese boy with congenital cataract, atrial and ventricular septal defects, dental changes and right radioulnar synostosis had a 14 bp deletion, c.4724_4737del, described as heterozygous; his mother, with cataract and dental changes, had the same variant in about 3.4% of leucocytes, detected only by ultra-deep sequencing [59]. The published abstract does not explain the mechanism that allowed the boy to survive.

3.13 Natural history and treated disease

OFCD is a congenital disease that is non-progressive in the malformative sense, but with complications that evolve throughout life. In the first year, cataract, eye surgery, heart disease, cleft palate and feeding difficulties predominate; in childhood, secondary glaucoma, amblyopia and changes in the primary dentition; in adolescence and adulthood, radiculomegaly, malocclusion, tooth loss and chronic glaucoma [13, 15, 50, 54]. Almost all published information describes treated disease (cataract operated on in the first weeks or months, corrected heart defects), so the sources consulted do not allow the untreated natural history to be described or survival or life expectancy to be calculated. Women with OFCD have been described at 45–49 years, mothers of patients, and one woman referred at 49 years was followed for more than six years [15, 17].

4. Clinical Recognition and Warning Signs

4.1 When to suspect, by age

In the prenatal period, suspicion arises in the presence of fetal cataract (detected at 22 and 32 weeks in published cases), microphthalmia, cleft palate, septal defect or toe syndactyly, especially if the mother has congenital cataract or dental changes [3, 15, 30]. In a male fetus, the 24-week ultrasound showed a right nasal alar cleft, duodenal obstruction, cleft palate, ventricular septal defect and toe syndactyly [30].

In female newborns and infants, the warning sign is congenital cataract, unilateral or bilateral, especially when accompanied by microphthalmia or microcornea, septal heart disease, cleft palate, a broad or bifid nasal tip, 2–3 syndactyly or hammer toes [2, 12]. Ragge and colleagues recommend that females with early-onset cataract be examined for extraocular features and tested for BCOR if any are present, bearing in mind that purely ocular forms exist [3]. Feeding difficulties with vomiting and reflux are frequent at this stage [2, 13].

In childhood and adolescence, suspicion often comes from dentistry: delayed eruption and exfoliation, persistent primary teeth, agenesis, fused teeth and, after eruption of the permanent teeth, disproportionately long canine roots on the orthopantomogram [15, 53]. Batkova and colleagues recommend testing all patients with congenital cataract and dental changes, even without a family history, and considering the syndrome when radiculomegaly is found [15]. In a boy with severe microphthalmia or anophthalmia, suspicion of BCOR-related disease increases when development is relatively preserved and there are long, slender fingers, large ears, heart disease or vesicoureteral reflux [3].

In adults, OFCD may be recognised late in a mother or grandmother with cataract operated on in childhood, tooth loss or dental anomalies and recurrent miscarriages, sometimes after the diagnosis of a descendant; a previous diagnosis of cataract due to maternal rubella does not exclude the syndrome [3, 15]. The presence of radioulnar synostosis, in a male or a female, is a clinical marker of BCOR [2].

4.2 Warning signs and urgent situations

The table lists the situations that require targeted or urgent assessment.

The relationship with ornithine transcarbamylase deficiency was described in a single girl with a 2.3 Mb deletion, whose abstract does not mention hyperammonaemia; the proposed action derives from the function of the OTC gene included in the deletion [41].

4.3 Newborn screening

There is no biochemical or genetic newborn screening for OFCD. The sources consulted do not address neonatal eye screening; the review by Bell and colleagues stresses that early surgery and close ophthalmological follow-up are what allow visual potential to be optimised and amblyopia to be prevented, which makes detection of cataract in the first weeks decisive [60].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Clinical criteria

There are no validated formal diagnostic criteria for OFCD or for the male syndrome, and there is no confirmatory biochemical or functional test; the diagnosis rests on the identification of a pathogenic BCOR variant in a compatible clinical picture [12]. The classic criteria used in the literature are congenital cataract, microphthalmia and radiculomegaly, to which Hilton and colleagues added systematic searching for skeletal defects (above all radioulnar synostosis) and for cardiac and laterality defects [2]. The combination of congenital cataract with dental anomalies is described as pathognomonic [3]. Radiculomegaly is the most distinctive single sign: the three women with OFCD features but without radiculomegaly in the 2009 cohort had no BCOR variant, and a review cited in a 2024 report gives it a positive predictive value of 88.23% and a sensitivity of 75.94% for OFCD [2, 57].

5.2 Clinical assessment and non-molecular investigations

The assessment of a patient with suspected disease includes slit-lamp ophthalmological examination and dilated fundoscopy, axial length biometry, intraocular pressure measurement, echocardiography (septal defects, mitral valve, situs), orthopantomography or cone-beam computed tomography for the tooth roots, and skeletal radiographs (forearms, spine, feet) [12, 54, 57]. Microphthalmia is defined by an axial length at least 2 standard deviations below the mean for age: the most widely accepted limit is less than 21 mm in adults and 19 mm at 1 year, and microcornea by a horizontal diameter of less than 9 mm in the newborn and 10 mm from 2 years onwards [16]. The Lenz GeneReviews used different values: normal neonatal axial length close to 17 mm, microphthalmia below the 5th centile for age and, in adults, less than 18.5 mm (mean 23.8 mm), whereas the review of the MAC spectrum placed the lower 2.5% limit in adults at about 21.0 mm [8, 11]. Magnetic resonance imaging of the brain and orbits is indicated in severe microphthalmia and clinical anophthalmia, to assess the globe, optic nerve, chiasm and associated brain anomalies [8, 16].

5.3 Molecular strategy

The first-line test is a multigene panel for congenital cataract or ocular developmental malformations, or exome sequencing with analysis of ocular genes, always with copy number variant analysis [16, 60]. The European clinical utility gene card for syndromic microphthalmia (EuroGentest and the European Society of Human Genetics, 2020) includes BCOR in the microphthalmia, anophthalmia and coloboma subpanel of the “oculome” panel and draws attention to GC-rich genes (SIX3, PITX3, SHH) poorly covered by standard exome kits; it recommends CNV testing by array comparative genomic hybridisation (aCGH) or multiplex ligation-dependent probe amplification (MLPA), confirmation of variants on a fresh DNA extraction and segregation analysis [16]. In bilateral congenital cataract, the molecular diagnostic yield of panels is between 50% and 90%, and genome sequencing may add up to about 40% according to one cited estimate [60]. In a series from Israel and Palestine, the cause was identified in 18 of 22 families (81.8%) with bilateral paediatric cataract [49].

In males with severe microphthalmia or anophthalmia, the panel should include SOX2, BCOR and NAA10, because the male BCOR-related syndrome overlaps with SOX2 anophthalmia syndrome [3, 8]. The Lenz GeneReviews proposed targeted testing for c.254C>T, followed by sequencing and deletion analysis; with the current availability of panels and exomes, this sequential approach has lost relevance, and the proportion of cases explained by the variant is not known [8]. If the panel or exome is negative in a suggestive picture, reanalysis of the data with CNV analysis or genome sequencing are options; the review of the MAC spectrum recommended reassessing undiagnosed patients after two years [11, 16].

5.4 Limitations of testing

Sequencing of exons and flanking introns does not detect deletions of one or more exons, which account for 12% of OFCD variants; a Japanese woman had an initial result with only a variant of uncertain significance (p.Val89Ile), and only reanalysis with read-depth CNV calling revealed the deletion of exons 7–15 [3, 17]. Mosaicism is the second limitation: it has been documented in monozygotic twins, in an asymptomatic mother and in a mother with 20% mutated alleles, and Redwood and colleagues described patients whose variant was detectable only in tissues other than blood, such as buccal cells [2, 3, 14]. A mother with cataract and dental anomalies had the variant in about 3.4% of leucocytes, below the usual detection threshold, identified only by ultra-deep sequencing (10,000×) and quantitative PCR [59]. Consequently, a negative blood result in a patient with a convincing picture should be followed by testing of a second tissue [12, 14]. In families with parents negative in blood and saliva, recurrence in sisters indicates germline mosaicism [61].

Tests also have interpretive limitations. Missense variants in BCOR in males require caution: in the 2009 cohort, two rare variants found in patients with laterality defects (p.Arg763Leu and p.Lys1325Arg) appeared in controls of the same origin and were considered polymorphisms [2]. Somatic BCOR variants found in tumours (internal duplications, fusions, truncating variants in myeloid neoplasms) are not equivalent to a constitutional variant and are not interpreted in the same way [12]. The clinical sensitivity of panels for OFCD has not been published; the frequency with which variants are detected in a series is not the clinical sensitivity of the test.

5.5 Report content

The molecular report should state the gene, the transcript with version (the MANE transcript is NM_001123385.2), the HGVS nomenclature at complementary DNA and protein level, the genomic coordinate with the reference genome version, the zygosity (heterozygous, hemizygous or mosaic, with the estimated allele fraction), the tissue analysed, the classification according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria and the criteria applied [9, 15]. In the Czech cases, the de novo frameshift variants were classified as pathogenic using the criteria PVS1 (null variant in a gene with a loss-of-function mechanism), PS2 (de novo with confirmed maternity and paternity), PM2 (absent from population databases), PP1 (cosegregation) and PP4 (specific phenotype) [15]. A variant of uncertain significance should be reassessed with the phenotype (radiculomegaly, radioulnar synostosis), segregation analysis, CNV analysis and, where relevant, the X-inactivation pattern, which is strongly skewed in carriers of pathogenic alleles [2, 3, 17].

5.6 Diagnostic algorithm

5.7 Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal diagnosis is performed by chorionic villus sampling at 10–12 weeks or amniocentesis after 14 weeks, and preimplantation genetic testing is possible [8, 16]. Transvaginal ultrasound can measure the orbits from 12 weeks, comparing them with ocular growth curves, but most ocular malformations are detected only after 22 weeks and the sensitivity is not known; three-dimensional ultrasound and fetal magnetic resonance imaging are complementary [11, 16]. Non-invasive prenatal diagnosis using cell-free fetal DNA was not available for microphthalmia in 2020 [16]. Without a known familial variant, a fetus with anomalies may be studied by exome sequencing on amniotic fluid, as in the male fetus with c.251dupT, whose karyotype and microarray were normal [30].

6. Differential Diagnosis

6.1 Comparative table

6.2 Main differentials

The closest differential of OFCD is Nance-Horan syndrome, which shares congenital cataract and dental anomalies and is also X-linked with mildly affected female carriers. Kondo and colleagues, faced with a family with a BCOR variant and a duplication that included NHS, considered that the bilateral 2–3 syndactyly and the septal defects, characteristic of OFCD, indicated BCOR as the main determinant of the phenotype [42]. Radiculomegaly is not part of the Nance-Horan picture described in the sources consulted [2].

In a woman with isolated congenital cataract, the differential includes the dozens of congenital cataract genes (crystallins, connexins, membrane proteins, transcription factors), metabolic causes (galactosaemia, in which diet may stabilise the cataract), congenital infections and trisomy 21 [60]. A unilateral cataract does not exclude OFCD [12, 14]. The presence of any dental anomaly, 2–3 syndactyly, septal heart disease or radioulnar synostosis increases the probability of BCOR [2, 15].

In a male with syndromic microphthalmia, the main alternatives are SOX2, NAA10, OTX2, STRA6 and chromosomal causes (trisomy 13, 3q26 and 14q22 deletions) [3, 16, 63]. The male BCOR-related syndrome is distinguished from the SOX2-related form by a lower frequency of developmental delay and by the presence of long fingers, large ears, heart disease and vesicoureteral reflux [3]. The differential with the NAA10-related form rests on the neuromuscular progression and digestive symptoms of the latter; radioulnar synostosis points to BCOR [2, 8]. NAA10-related disorders include Ogden syndrome and Lenz microphthalmia.

Cases with segmental infantile haemangioma may be confused with PHACE syndrome: a 10-year-old girl with a parietal haemangioma and an aberrant right subclavian artery had a provisional diagnosis of PHACE before the ocular resemblance to another patient led to BCOR testing [51]. Congenital cataract and dental anomalies are not part of the PHACE criteria [51].

6.3 The phenotypic series of syndromic microphthalmias

OMIM groups the syndromic microphthalmias in a numbered series, which serves as a map for the genetic differential: MCOPS1 (NAA10, Xq28), MCOPS2 (BCOR, Xp11), MCOPS3 (SOX2, 3q26), MCOPS5 (OTX2, 14q22), MCOPS6 (BMP4, 14q22), MCOPS7 (HCCS, Xp22), MCOPS9 (STRA6, 15q24), MCOPS11 (VAX1, 10q25), MCOPS12 (RARB, 3p24), MCOPS13 (HMGB3, Xq28), MCOPS14 (MAB21L2, 4q31), MCOPS15 (TENM3, 4q) and MCOPS16 (RAX, 18q21), as well as MCOPS8 (mapped to 6q21) and MCOPS10 (with progressive cerebral atrophy) [62]. The former MCOPS4 has been recognised as the same entity as MCOPS1 [62]. Among the X-linked forms (MCOPS1, MCOPS2, MCOPS7 and MCOPS13), OFCD and MLS are those that typically affect heterozygous females, and only OFCD combines constant congenital cataract and radiculomegaly [2, 62, 63].

7. Treatments and Risk Management Strategies

7.1 Principles and evidence base

There is no treatment targeting the BCOR defect, nor any guideline or consensus specific to OFCD or to the male syndrome; management is symptomatic and multidisciplinary and derives from case series (Ng 2004, Hilton 2009, Redwood 2020, Ragge 2019) and from general recommendations for congenital cataract and microphthalmia [12, 16, 60]. The GeneReviews chapters on Lenz microphthalmia and on the microphthalmia–anophthalmia–coloboma (MAC) spectrum have been withdrawn and serve only as historical references; the recommendations from them used in this article are those not contradicted by current sources, identified as coming from those chapters [8, 11]. The team includes paediatric ophthalmology with experience in glaucoma, orthoptics, paediatric cardiology, medical genetics, paediatric dentistry, orthodontics and oral and maxillofacial surgery, cleft palate surgery, otorhinolaryngology and audiology, developmental paediatrics and visual impairment support services [12, 15, 60].

7.2 Eye: cataract, aphakia and amblyopia

The congenital cataract of OFCD is treated like other visually significant congenital cataracts. The review by Bell and colleagues recommends extraction at 6 weeks of age in unilateral cataract and between 6 and 8 weeks in bilateral cataract, with anterior and posterior capsulotomy and anterior vitrectomy [60]. In the 5-year follow-up studies cited by the same review, intraocular lens implantation before 2 years gave visual acuity similar to contact lens correction, did not protect against postoperative glaucoma and increased the need for reoperations, so it is recommended that children be left aphakic, especially those operated on before 6 months [60]. Earlier surgery is associated with better vision but a higher risk of glaucoma, and later surgery with more strabismus [60]. In partial cataracts, pharmacological mydriasis may increase the light reaching the retina [60]. After surgery, optical correction of aphakia (high-power spectacles or contact lenses), occlusion to treat amblyopia and orthoptic follow-up are ongoing; one girl with OFCD reached acuities of 0.7 and 0.2 logMAR at 4 years after occlusion, and another needed +20 dioptres in both eyes [3].

In the published patients with OFCD, cataract surgery was performed between 5 weeks and 4 years of age, and secondary membranes requiring further surgery in the following months were frequent [3, 15, 50, 51]. In the Portuguese series, all surgeries (between 6 and 16 weeks) were uneventful, but all three patients developed glaucoma [50].

7.3 Eye: secondary glaucoma and other complications

Secondary glaucoma is frequent and early in operated OFCD: 12% in the 2009 cohort and all three patients in the Portuguese series, with onset in childhood [2, 50]. The Portuguese authors consider that the BCOR disorder may predispose to a more aggressive and earlier glaucoma than usual after congenital cataract surgery, almost always requiring surgery in childhood [50]. Treatment begins with topical ocular hypotensive agents (in one patient, timolol 0.5% from 3.5 years) and progresses to trabeculectomy, Ahmed valve implantation and cyclophotocoagulation [50, 51]. Pupillary block glaucoma has been described after surgery [3]. Retinal detachment (1/34 in the 2009 cohort and one case at 12 years in the 2019 review) and phthisis bulbi are the most severe end-stage complications [2, 3].

Microphthalmic eyes with residual vision have a shallow anterior chamber and a risk of angle-closure glaucoma. The Lenz GeneReviews recommended using mydriatics and drugs with a mydriatic effect (antihistamines, decongestants, tricyclic antidepressants) only in liaison with the ophthalmologist [8]. The same source described high hypermetropia (+7 to +11 dioptres) in eyes with mild microphthalmia, requiring early refractive correction [8].

7.4 Severe microphthalmia and anophthalmia

In severe microphthalmia or anophthalmia, more typical of the male syndrome, the aim is orbital growth and facial appearance. The ocularist can begin, shortly after birth, expansion of the palpebral fissures, conjunctival fornix and orbit with conformers of increasing size; conformers may fail to expand the orbit horizontally and cause an hourglass deformity [11]. The oculoplastic surgeon decides on surgical intervention after 6 months, when orbital growth can be assessed, and before the orbital dimensions become fixed; options include fixed-size orbital implants, expandable implants (silicone balloon, hydrophilic polymers) and dermis-fat grafts, which can grow [11]. In a non-seeing eye, appearance can be addressed with cosmetic shells or contact lenses [16]. In unilateral disease, the healthy eye should be protected [11]. Children with low vision benefit from early intervention with physiotherapy and occupational therapy, visual aids and adapted education, and from referral to services for people with visual impairment [8, 16].

7.5 Heart

All patients should have an echocardiogram at diagnosis, even if asymptomatic, because a large atrial septal defect may remain silent until adulthood [2, 57]. Some septal defects closed spontaneously in the published patients; the others are treated as in the general population (surgical closure of an atrial septal defect at 3 and 4 years, and in a 21-year-old woman) [3, 57]. Screening for laterality defects (situs, spleen, intestinal rotation) is recommended [2]. Before eye or dental surgery under general anaesthesia, an up-to-date cardiovascular assessment is needed: in an adolescent girl with OFCD and a pathogenic MYLK variant, preoperative imaging revealed progressive dilatation of the ascending aorta, and glaucoma surgery was postponed because of the anaesthetic risk [43]. This case also shows that secondary findings from an exome can change perioperative management [43].

7.6 Teeth and occlusion

Dental management begins in the primary dentition: intensive caries prevention, monitoring of eruption and decisions on the extraction of persistent primary teeth that prevent eruption of the permanent ones [3, 13, 15]. The permanent dentition is affected in all cases and in most requires orthodontic treatment [13]. Radiculomegaly complicates orthodontic treatment, endodontics and extractions [12, 15]. In a Japanese patient followed for 29 years, orthodontic treatment (2 years and 9 months) was planned on the basis of serial radiographs, and the authors advocate extending surveillance until root growth has ended [54]. In the Portuguese patient from Coimbra, the team used light orthodontic forces to minimise the risk of ankylosis, a LeFort I maxillary osteotomy with 5 mm impaction, bilateral sagittal split osteotomy of the mandible and a 6 mm vertical reduction genioplasty, and rehabilitation with implants; one of the three implants was lost to peri-implantitis one year later, and the result was stable 4 years and 6 months after the end of treatment, which lasted about five years [56]. The Czech authors consider that radiculomegaly does not contraindicate implants, with bone augmentation when needed, and described an implant without complications at 10 years [15]. These reports describe individual management, not validated protocols; the 2018 review found only 10 reports with details of dental treatment [53].

7.7 Cleft palate, hearing, feeding and development

Cleft palate or submucous cleft is treated according to the usual protocols, with speech assessment [12]. Hearing should be assessed at diagnosis and during childhood, because hearing loss affects 9–15% of patients and is not explained by the cleft alone [2, 3]. Feeding difficulties and gastro-oesophageal reflux in early infancy are treated as in the general population, and poor weight gain was recorded in two of the five Czech patients [13, 15]. Developmental assessment should take account of the effect of visual impairment, and early intervention applies to cases with delay [8, 47]. In males with autism spectrum disorder or intellectual disability, support follows usual practice [3].

7.8 Endocrinology and tumours

Growth hormone deficiency has been described and treated in one patient, and pituitary hypoplasia is a possible feature; the brain magnetic resonance imaging performed in severe microphthalmia allows the pituitary to be assessed, and the clinical utility gene card mentions referral to endocrinology when there are midline or pituitary anomalies [3, 16]. In the patient with metachronous insulinomas, initial medical treatment with diazoxide controlled blood glucose at the cost of peripheral oedema and hypertrichosis; functional localisation by selective arterial calcium stimulation guided laparoscopic enucleation of one functioning lesion and, six years later, robotic enucleation of two lesions with spleen-preserving distal pancreatectomy, with normoglycaemia without drugs [17]. This approach preserved pancreatic endocrine function, and the authors warn of the risk of metachronous recurrence after limited resections [17]. There is no recommendation for systematic tumour screening; the 2019 review calls for long-term follow-up studies to measure tumour incidence [3, 17]. In patients with a deletion that includes OTC, the possibility of ornithine transcarbamylase deficiency should be considered [41].

7.9 Drugs

No medicinal product is indicated for OFCD or for the male BCOR-related syndrome. The drugs used (ocular hypotensive agents, mydriatics, diazoxide for insulinoma-related hypoglycaemia) are those in routine use for the respective indications, without doses specific to this disease in the sources consulted [12, 17, 51].

7.10 Ongoing trials and studies

A search of ClinicalTrials.gov on 29 October 2026, using the terms BCOR and oculofaciocardiodental, found no therapeutic trials in the constitutional disease; the studies involving BCOR concern tumours with somatic alterations (sarcomas with BCOR internal tandem duplication or BCOR::CCNB3 fusion, registries of rare brain tumours, CAR-T cell therapies with BCOR knock-out) [64]. The only relevant study is observational.

The registration of this study cites previous work in which about 10% of probands with congenital cataract and variants in BCOR, CWC27, IFIH1, NHS or PAX6 had dental anomalies [64]. In the absence of trials, there are no comparative efficacy data; the approaches described come from case reports, subject to publication bias, and should not be read as results comparable with one another.

7.11 Developments in the last 12 months

Between November 2025 and October 2026, the publications identified are of low level of evidence (case reports, reviews and a preprint), with no regulatory developments. In 2026, the third case of insulinoma in OFCD was published, the first with metachronous recurrence proven by repeated functional localisation and with a deletion of exons 7–15 initially undetected (case report) [17]. Also in 2026, a report showed how a concomitant pathogenic MYLK variant, identified by trio exome sequencing, led to postponement of glaucoma surgery because of aortic dilatation (case report) [43]. A 2026 review summarised the biology of BCOR in PRC1.1 and the differences between somatic alterations (narrative review) [28]. A Danish preprint from February 2026, not yet peer reviewed, describes radiculomegaly already in the primary dentition [55]. In 2025, low-level maternal mosaicism (about 3.4%) detected only by ultra-deep sequencing was described (case report) [59]. The NCT06950619 registration was updated in November 2025 (observational study, no results) [64]. No trials, marketing authorisation applications or regulatory opinions were identified.

7.12 Special situations

In the pregnancy of a woman with OFCD, the risk of transmission is 50% per pregnancy, with presumed loss of affected male fetuses; pregnancies carry a risk of miscarriage, and one mother with OFCD had eight miscarriages [3]. The sources consulted do not describe obstetric complications specific to OFCD beyond this; corrected or residual heart disease should be assessed before pregnancy. In the perioperative setting, an up-to-date cardiovascular assessment, the airway (cleft palate, mandible) and the management of patients with low vision should be planned; the Coimbra patient underwent bimaxillary orthognathic surgery with no perioperative complications described [43, 56]. In the transition to adulthood, surveillance of glaucoma, heart disease and dentition continues, and reproductive counselling should be offered to young women with OFCD and to female carriers of the male alleles [8, 50].

8. Reproductive Options and Family Counselling

8.1 OFCD: X-linked dominant inheritance with male lethality

OFCD is transmitted from mother to daughter, and male fetuses that inherit the null allele are presumably lost during pregnancy [3, 13]. An affected woman has, in each pregnancy, a 50% probability of transmitting the variant: daughters who inherit it will have OFCD, with variable expressivity, and sons who inherit it do not, in principle, survive to term [3, 29]. In practice, this translates into recurrent miscarriages (up to eight in one mother) and a pattern of births in which affected daughters and non-carrier sons predominate; the sources consulted do not quantify the sex ratio among live births [3]. The case of a hemizygous male fetus still alive at 26 weeks shows that the loss may be late [30]. Penetrance is complete in non-mosaic carriers, so a daughter with the variant will have manifestations, although sometimes only ocular or dental ones [3, 25].

About three quarters of OFCD cases are sporadic or of unknown origin, and in all sporadic cases with parents tested the variant was de novo [3]. The recurrence risk for the parents of a child with a de novo variant is not negligible because of mosaicism. Two Indian sisters had the same nonsense variant, absent from the blood and saliva of their phenotypically normal parents, which indicates germline mosaicism in one of the parents, possibly the father, since male gonadal mosaicism is compatible with survival [61]. Mothers with somatic mosaicism may be asymptomatic or have mild manifestations and transmit the variant in the non-mosaic state to their daughters [2, 3]. According to Yamashita and colleagues, Redwood and colleagues suggested that the risk of maternal mosaicism is higher in OFCD than in other genetic diseases, and Yamashita and colleagues themselves applied recurrence counselling even in a de novo case [47].

8.2 Male syndrome: X-linked recessive inheritance

In the male BCOR-related syndrome, the father of an affected boy is not a carrier, and a mother with more than one affected son is an obligate carrier [8]. In the published families, the mothers were healthy carriers with skewed X inactivation, and all cases were inherited at the time of the GeneReviews [3, 8]. A carrier mother has a 50% probability of transmitting the variant in each pregnancy: sons who inherit it will be affected and daughters will be carriers, in principle asymptomatic [8]. If the variant is not detected in the blood of the mother of an isolated case, the risk to siblings is low but higher than in the general population, because of the possibility of germline mosaicism [8]. Most affected men do not have children; those who reproduce transmit the variant to all their daughters (carriers) and to none of their sons [8]. Maternal aunts and their female descendants may be carriers [8]. In one family, a maternal aunt had terminated a pregnancy of a male fetus with severe malformations without genetic testing [3].

8.3 Cascade testing and female carriers

Testing of at-risk women requires prior identification of the familial variant [8]. In OFCD, assessment of the mother should include ophthalmological examination, dental examination with orthopantomography and cardiac examination, because mild and mosaic forms may go unnoticed, and blood testing may not detect low-level mosaicism [2, 59]. Study of X inactivation may support interpretation, but Smith's Recognizable Patterns notes that skewing is not constant in carriers of Lenz microphthalmia in general; in BCOR carriers, skewing was constant in the published series [2, 3, 23]. DNA banking of the patient is recommended, given that techniques and knowledge evolve [8, 11].

8.4 Prenatal and preimplantation diagnosis

Once the familial variant is known, prenatal diagnosis by chorionic villus sampling (10–12 weeks) or amniocentesis (after 14 weeks) and preimplantation genetic testing are possible [8, 16]. In the pregnancy of a mother with OFCD, prenatal diagnosis has a particular feature: a male fetus with the variant may survive into the second trimester, and the decision should be discussed before pregnancy [30]. Targeted ultrasound can detect fetal cataract (at 22 and 32 weeks in described cases), cleft palate, septal defect, syndactyly and, in the male syndrome, underdeveloped eyes (unopened palpebral fissures at 15 weeks in one case); the Lenz GeneReviews proposed ultrasound at 18 weeks to assess the kidneys [3, 8, 15, 30]. When ultrasound detects an ocular anomaly in a pregnancy without known risk, investigation includes microarray and sequencing of SOX2 or of a panel [11].

8.5 Counselling

The recommended time to discuss risk, carrier status and reproductive options is before pregnancy, and counselling should be offered to affected or at-risk young adults [8]. Testing of asymptomatic minor girls for carrier status of the male form has no immediate medical benefit and is not discussed in the sources consulted; in OFCD, the affected child has clinical manifestations and the test is diagnostic. Explanation of variable expressivity, of the possibility of very mild forms in mothers and of recurrence through mosaicism are the central points of counselling [3, 59, 61].

9. Special Considerations: Population Diversity and Epidemiology

9.1 What is known about frequency

There is no population estimate of the prevalence or incidence of OFCD; Orphanet classifies the prevalence as unknown, with worldwide distribution [5, 12]. The available counts are counts of published cases, not prevalences: 64 cases in 2009, 85 females from 58 families and 10 males from 8 families in 2019, 92 cases of OFCD in a 2018 review of the English-language literature, and more than 60 cases according to Smith's Recognizable Patterns (2022) [2, 3, 13, 53]. Batkova and colleagues report fewer than 100 pathogenic variants described worldwide in 2024 [15]. These counts underestimate the true frequency: Redwood and colleagues identified 10 patients from 5 families in a single institution in two years and concluded that OFCD is more frequent than previously thought among women with congenital cataract, including unilateral cataract [14]. The male syndrome is much rarer: BCOR explained less than 1% of males with severe microphthalmia in a British and French series, and 1 of 21 males with a clinical diagnosis of Lenz syndrome [2, 3].

For context, microphthalmia has a prevalence of 2 to 23 per 100,000 births (41 per 100,000 pregnancies in an Israeli study that included late fetal forms), accounts for 3–11% of blind children and is syndromic in 60–80% of cases (31% in a Japanese series) [16]. A 16-year Scottish study gave a minimum birth prevalence of 14 per 100,000 for microphthalmia and 3 per 100,000 for anophthalmia [63]. Congenital or infantile cataract affects 20,000 to 40,000 newborns per year worldwide, and about 15% of cases have systemic manifestations [60]. BCOR appears in the review of the MAC spectrum among the genes responsible for more than 1% of cases [11]. These figures refer to the malformations in general, not to OFCD.

9.2 Geographical and population distribution

Published OFCD cases are distributed across several regions, without a founder effect: Europe (United Kingdom, France, Belgium, Switzerland, Germany, Italy, Spain, Croatia, Czechia, Denmark, Portugal), the United States, Japan, China, Korea, India and Israel [2, 3, 15, 24, 30, 39, 41, 42, 47, 49–51, 55, 61]. Each family usually has a private variant, and only c.2926C>T, p.(Arg976*), has been described in several families [2, 8]. The male variant p.(Pro85Leu) has been found in an African American family, in European families and in two Japanese families, which is compatible with recurrent mutation rather than a founder [3, 8]. The sources consulted do not describe phenotypic differences between populations.

In Portugal, two reports have been published: a series of three women followed at the Centro Hospitalar Universitário de São João, in Porto, with severe glaucoma after congenital cataract surgery and confirmed variants (an insertion, an Xp21.2–p11.4 microdeletion and a 2 bp deletion) [50]; and a 26-year-old woman treated in Coimbra, with a clinical diagnosis and no molecular testing, whose dental and orthognathic rehabilitation is described in the article [56]. The legends of Figures 1 to 3 of the OFCD chapter of Smith's Recognizable Patterns (a 26-year-old woman, with the same list of missing teeth) match those of this Coimbra case [13, 56]. The sources consulted do not include cases from Brazil; one of the family series (Croatian) was published in a Brazilian journal [39]. The lack of data in the sources consulted does not mean an absence of cases in these countries.

9.3 Special populations

In children with low vision, motor development and sleep regulation may be delayed because of the lack of visual stimulation, and the Lenz GeneReviews mentioned sleep–wake cycle disturbances in boys without light perception [8]. In pregnant women with OFCD, the loss of male fetuses and the risk of transmission require prior counselling (section 8) [3]. In adults, the late complications described are chronic glaucoma, tooth loss requiring rehabilitation and, rarely, neuroendocrine tumours [15, 17, 50].

9.4 European networks and patient associations

The European Reference Network for Rare Eye Diseases (ERN-EYE) brings together paediatric ophthalmology centres and provides online training on rare paediatric eye diseases and a group of patient representatives (ePAG) [18]. ERN CRANIO covers four disease groups (craniosynostosis and craniofacial anomalies, cleft lip and palate, orodental anomalies and ear, nose and throat disorders), relevant to the facial and dental phenotype [19]. ERN ITHACA covers malformation syndromes and intellectual disability. The International Children's Anophthalmia and Microphthalmia Network (ICAN), in the United States, and Microphthalmia, Anophthalmia and Coloboma Support (MACS), in the United Kingdom, support families of children with microphthalmia and anophthalmia [8, 63, 65]. The sources consulted do not identify a patient association specific to OFCD in Portugal or Brazil.

10. Illustrative Clinical Case

10.1 Two generations of a Czech family with OFCD

Batkova and colleagues, from Motol University Hospital in Prague, published in 2024 the dental follow-up of five females from two Czech families with molecularly confirmed OFCD [15]. In family 1, the proband was a 45-year-old woman when she underwent exome sequencing; she had bilateral congenital cataract operated on at 4 years, strabismus and bilateral secondary glaucoma, a broad nasal root and nasal tip with septate nasal cartilage and, at 49 years, periodontitis with mobile teeth stabilised by splints, an implant in place of the lower left first molar, agenesis of the upper right lateral incisor and the lower right second premolar, a conical crown of the upper left lateral incisor and radiculomegaly of seven teeth, including all four canines [15]. She also had primary lymphoedema of the lower limbs and bronchial asthma, and the implant was free of complications ten years after placement [15]. The exome identified the heterozygous variant NM_001123385.2:c.2382del, p.(Lys795ArgfsTer12), absent in the parents (maternity and paternity confirmed), classified as pathogenic [9, 15]. The pedigree and the segregation of the variants in the two families are shown in Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC11494979/figure/Fig1/), and the proband's orthopantomogram, with the radiculomegaly and the implant, in Figure 2 (https://pmc.ncbi.nlm.nih.gov/articles/PMC11494979/figure/Fig2/) [15].

Her daughter, 13 years old at the time of examination, had inherited the variant. She had bilateral congenital cataract operated on at 3 months in the left eye and at 3.5 months in the right, followed by microphthalmia, secondary glaucoma, amblyopia and left ptosis, with corneal opacity after surgery [15]. She was born with cleft lip and palate, and had a long, narrow face with asymmetry, deep-set eyes, epicanthic folds, thick arched eyebrows, a long philtrum and anteverted dysplastic ears, as well as atrial septal defect, patent ductus arteriosus, syndactyly of the second and third toes of the right foot with a hammer toe, mild bilateral conductive hearing loss, bronchial asthma and poor weight gain; intelligence was normal [15]. At 4 years she underwent multiple extractions of primary teeth under general anaesthesia because of destruction by caries. At 13 years, her dental age corresponded to about 10 years, seven permanent teeth had not yet erupted, there was agenesis of four teeth (including the lower central incisors) and the orthopantomogram showed radiculomegaly of six teeth (upper central incisors, canines and lower lateral incisors) with widely open apices and incomplete roots; she wore a removable expansion appliance and a partial lower fixed appliance [15]. Figure 3 of the article shows the intraoral photographs, the cleft palate and the orthopantomogram (https://pmc.ncbi.nlm.nih.gov/articles/PMC11494979/figure/Fig3/) [15].

In family 2, the de novo variant NM_001123385.2:c.3914dup, p.(Gln1306AlafsTer20), was identified in a 33-year-old mother with bilateral congenital cataract, radiculomegaly of eight teeth and talon cusps, without heart disease, and in her two daughters: a 5-year-old with cataract operated on at 2 and 3 months, secondary glaucoma, atrial septal defect, gastro-oesophageal reflux and delayed primary eruption; and a 3-year-old with cataract detected on the 32-week ultrasound and operated on at 1.5 months, right microphthalmia, cleft palate, atrial septal defect, reflux, poor weight gain and Class III malocclusion [9, 15]. None of the five patients had intellectual disability [15].

10.2 What the case teaches

The case brings together the most constant features of OFCD (congenital cataract in all patients, dental changes in all, radiculomegaly in all those with permanent dentition) and the variability of the others (heart disease in three of five, cleft palate in two, no skeletal anomalies in family 2) [15]. It shows the evolution by age: in the young child, radiculomegaly cannot yet be assessed on the orthopantomogram, and the diagnosis depends on the cataract, the heart disease and the family history; in the adolescent, delayed eruption and long roots with open apices already point to the diagnosis [15]. It also shows the importance of secondary glaucoma after cataract surgery, present in three of the five patients, and the time that may elapse before molecular diagnosis in a woman with the full picture, tested at 45 years after several decades of ophthalmological and dental care [15]. The dental approaches described (extractions under general anaesthesia, expansion appliances, implant with bone augmentation) are individual decisions of one team and not a validated protocol [15, 53].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

The sources consulted do not include survival or life expectancy studies in OFCD; there are patients described between 45 and 49 years of age and women who were mothers of patients [3, 15, 17]. The functional prognosis depends mainly on vision. Cataract is present in practically all patients, microphthalmia or microcornea in 82% and secondary glaucoma in 12% in the 2009 cohort, but in all patients in the Portuguese series, requiring surgery in childhood [2, 50]. The visual acuities described range from useful values with correction (0.2 logMAR in one eye at 4 years) to blindness in one eye due to glaucoma or retinal detachment [3]. Intellectual development is normal in about 80–90% of patients [2, 3]. The permanent dentition is always affected, and orthodontic, surgical and prosthetic treatment may extend over years, with stable medium-term results in the published reports [13, 54, 56]. Early death has been described mainly in males with heart disease (a Japanese infant with p.(Pro85Leu) died at 6 months) [4, 8]. In the male syndrome, the visual prognosis is poor in severe microphthalmia and anophthalmia, and development ranges from severe disability to normal intelligence [3].

11.2 Initial assessment after diagnosis

After diagnosis, the assessment includes a full ophthalmological examination (intraocular pressure, biometry, fundus), echocardiography with assessment of situs, dental examination and orthopantomography when age allows, hearing assessment, forearm radiography if supination is limited, developmental assessment and a genetics clinic appointment with testing of the mother [2, 3, 12]. In boys with severe microphthalmia, magnetic resonance imaging of the orbits and brain (globe size, corpus callosum, pituitary), visual evoked potentials, renal ultrasound, sleep assessment if there are complaints and genitourinary assessment are added [8, 16].

11.3 Surveillance table

The sources consulted do not publish a surveillance protocol specific to OFCD; the table brings together the existing recommendations and indicates when the interval depends on the specialist.

11.4 Long-term follow-up and transition

Follow-up is lifelong and coordinated between ophthalmology, cardiology, dentistry and genetics. The Lenz GeneReviews recommended lifelong case management to facilitate access to social services and to technical aids for visual impairment [8]. The 2019 review recommends multicentre follow-up studies to determine tumour incidence, given the description of a T-cell lymphoma in childhood and the role of BCOR as a tumour suppressor gene in T lymphocytes in the mouse [3]. In the transition to adulthood, surveillance of glaucoma and dentition continues, and reproductive counselling is one of the main objectives (section 8) [8, 50].

12. Summary and Final Considerations

BCOR-related disorders form an X-linked allelic class in which variant type and sex determine the phenotype. In females, loss of function of one allele causes oculofaciocardiodental syndrome, described from 1990 onwards by Marashi and Gorlin through the association of canine radiculomegaly with congenital cataract and linked to BCOR in 2004 [1, 20, 22]. Congenital cataract, present in practically all patients, and dental anomalies, with radiculomegaly as the most specific sign, are the core of the diagnosis; septate nasal cartilage, cardiac septal defects (74% of the patients assessed), 2–3 syndactyly and hammer toes, and radioulnar synostosis complete the picture, which includes all four components of the name in only 41% of cases [2, 3]. In males, null alleles are presumably lethal, and alleles with residual function, above all p.(Pro85Leu), cause a syndromic microphthalmia or anophthalmia formerly attributed to Lenz syndrome, with more recent phenotypes without microphthalmia [1, 3].

Diagnosis is molecular and has two practical limitations: deletions of one or more exons, which require CNV analysis, and mosaicism, which may make blood testing negative and justifies testing of a second tissue [2, 14, 17]. Germline and somatic mosaicism make the recurrence risk non-negligible even when the parents test negative [59, 61]. There is no targeted treatment and there are no trials; management is multidisciplinary and centred on early cataract surgery, detection and treatment of secondary glaucoma, which is frequent and early, echocardiography at diagnosis, dentistry and orthodontics throughout root growth, and reproductive counselling [15, 50, 57, 60]. Open questions include the true frequency of OFCD among congenital cataracts, the existence of a tumour risk (lymphoma, insulinoma) and the significance of the emerging phenotypes due to missense variants: retinal, epileptic and male intellectual disability [3, 14, 17, 26, 27].

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