Alternative titles; symbols
SNOMEDCT: 699300009; ORPHA: 2712, 568; DO: 0111809;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.4 | Microphthalmia, syndromic 2 | 300166 | X-linked dominant | 3 | BCOR | 300485 |
A number sign (#) is used with this entry because syndromic microphthalmia-2 (MCOPS2) is caused by mutation in the BCL6 corepressor gene (BCOR; 300485) on chromosome Xp11.
The term 'anophthalmia' has been misused in the medical literature. True or primary anophthalmia is rarely compatible with life; in such cases, the primary optic vesicle has stopped developing and the abnormal development involves major defects in the brain as well (Francois, 1961). The diagnosis can only be made histologically (Reddy et al., 2003; Morini et al., 2005; Smartt et al., 2005), but this is rarely done. In most published cases, the term 'anophthalmia' is used as a synonym for the more appropriate terms 'extreme microphthalmia' or 'clinical anophthalmia.'
Wilkie et al. (1993) described an average height woman with a long narrow face, congenital cataract, microphthalmia, persistent primary teeth, dental radiculomegaly, and atrial septal defect (ASD). Her mental development was normal. Her daughter, who had mild delay in physical and mental development, also had cataract, microphthalmia, ventricular heart defect (VSD), and ASD. Wilkie et al. (1993) proposed that these cases represented a distinct syndrome with autosomal dominant inheritance. Aalfs et al. (1996) reported 2 unrelated women with normal intelligence, congenital cataracts, long narrow face with short nose, broad nasal tip and long philtrum, ASD (with VSD in one of them), persistent primary teeth, oligodontia, and dental radiculomegaly. Both women had moderate hearing deficit and syndactyly of the second and third toes. One woman had transverse vaginal septum. The other woman had cleft palate and lens dislocation; her mother had cataract, but no other defects. Aalfs et al. (1996) suggested that their patients might be further examples of the syndrome described by Wilkie et al. (1993).
Obwegeser and Gorlin (1997), who referred to this condition as the oculofaciocardiodental (OFCD) syndrome, stated that Hayward (1980) was probably the first to report the association of congenital cataracts and radiculomegaly of the canine teeth. Marashi and Gorlin (1990, 1992) reported additional examples.
Gorlin et al. (1996) reviewed all reported cases and concluded that the OFCD syndrome consists of (1) eye anomalies (congenital cataract, microphthalmia, or secondary glaucoma); (2) facial abnormalities (long narrow face, high nasal bridge, pointed nose with cartilages separated at the tip, cleft palate, or submucous cleft palate); (3) cardiac anomalies (atrial septal defect, ventricular septal defect, or floppy mitral valve); and (4) dental abnormalities (canine radiculomegaly, delayed dentition, oligodontia, persistent primary teeth, or variable root length). They suggested that inheritance might be X-linked dominant, lethal in the male. The syndrome had been observed in 2 generations and in 7 females but not in males.
Schulze et al. (1999) reviewed the 9 previously reported cases of OFCD syndrome and reported 3 additional female patients. In addition to the known features of the syndrome, fusion of teeth and hyperdontia of permanent upper teeth were seen. Structural and morphologic dental changes were also noted.
Ng et al. (2002) studied an African American family, previously reported by Hoefnagel et al. (1963) and Ogunye et al. (1975), with 6 affected males exhibiting microphthalmia or clinical anophthalmia associated with the variable features of microcephaly, mental retardation, large posteriorly rotated and anteverted ears, renal aplasia, cryptorchidism, and hypospadias, in an X-linked recessive inheritance pattern consistent with Lenz microphthalmia syndrome (MCOPS1; 309800).
Hedera and Gorski (2003) described another instance of mother-daughter OFCD transmission. In addition to the clinical features typically seen in OFCD, the affected daughter exhibited several other congenital anomalies including intestinal malrotation and hypoplastic thumbs. The typical features in both were congenital cataracts, microphthalmia, characteristic dental anomalies, and facial dysmorphism. Favoring X-linked dominant inheritance was the finding of a skewed X-chromosome inactivation in both mother and daughter. Similar patterns of nonrandom lyonization have been documented in other X-linked diseases with male hemizygote lethality such as incontinentia pigmenti (308300) and focal dermal hypoplasia (305600).
Oberoi et al. (2005) reported 2 new cases of the OFCD syndrome characterized by cataracts, microphthalmia, facial anomalies, cleft palate, cardiac septal defects, and canine radiculomegaly. The first patient was a 17-year-old female in whom bilateral cataracts were noted at birth and an atrial septal defect was repaired at age 4 years. She had a long thin face with a prominent nasal bridge and short nasal tip. She had notched alae with a midline crease in the nasal tip, submucous cleft palate, and a single maxillary central incisor. Some primary teeth were retained at the age of 17 years, and eruption pattern was asymmetric, with delayed eruption of the primary teeth. The second patient reported by Oberoi et al. (2005) was found to have bilateral cataracts and a cardiac murmur at birth. She had limited pronation of her left arm secondary to radial-ulnar synostosis. At the age of 9 years, she had a long, narrow face and microphthalmia with ptosis and deep-set eyes with blepharophimosis. The nasal root was narrow with a bulbous and bifid nasal tip. There was delayed eruption of the maxillary permanent central and lateral incisors. The patient had a deletion in the BCOR gene confirmed by molecular analysis.
Hilton et al. (2009) studied 34 female patients from 20 families with features of OFCD and heterozygous mutations in the BCOR gene. All 34 patients had congenital cataract, and microphthalmia and/or microcornea were present in 28 (82%). Twenty-five (96%) of 26 patients for whom a facial phenotype was observed had septate nasal cartilage, and 8 (31%) had palatal abnormalities, including cleft palate, high-arched palate, and bifid uvula. Of 27 patients who underwent cardiac evaluation, 20 (74%) had an abnormality, which involved a septal defect in 17 (85%) of them. Both primary and secondary dental data were available in 22 patients, all of whom exhibited various dental anomalies associated with OFCD, including delayed or persistent primary dentition with multiple unerupted teeth, radiculomegaly, and absent, duplicated, or fused teeth. Hilton et al. (2009) noted that radiculomegaly, a unique and cardinal feature of OFCD, was present in 20 (91%) of the 22 patients; dental x-rays were unavailable in the remaining 2. Skeletal anomalies were observed in 28 (97%) of 29 patients examined, with 2-3 toe syndactyly in 16 (57%) and hammertoes in 15 (54%). Radioulnar synostosis was detected in 7 patients (25%), with limited supination reported in another 2. Hearing loss, both conductive and sensorineural, was present in 5 (15%) of 34 patients. In addition, 3 (9%) of the patients had feeding difficulties, repeated vomiting, and reflux, which Hilton et al. (2009) noted might represent part of a laterality phenotype.
Initial linkage analysis performed by Ng et al. (2002) in the African American family originally reported by Hoefnagel et al. (1963) and Ogunye et al. (1975) excluded the region in Xq27-q28 that had been reported as a candidate region for Lenz microphthalmia syndrome (MCOPS1; 309800) and clinical anophthalmos, ankyloblepharon, and mental retardation (see 309800). An X-chromosome scan revealed linkage to a 10-cM region between markers DXS228 and DXS992 in Xp21.2-p11.4, with a maximum lod score of 2.46 at DXS993. Ng et al. (2002) designated this locus ANOP2. Using sequence-tagged site mapping to exclude regions of Xp deleted in males without microphthalmia, Ng et al. (2004) narrowed the critical region to approximately 5 Mb.
Ng et al. (2004) sequenced 11 candidate genes in members of the African American family originally reported by Hoefnagel et al. (1963) and Ogunye et al. (1975) and identified a missense mutation in the BCOR gene (P85L; 300485.0001) that cosegregated with the disease phenotype. The authors did not identify any mutations in BCOR in males from 2 previously reported families with Lenz microphthalmia syndrome. Because of phenotypic overlap between the microphthalmia syndrome of the African American family and OFCD, Ng et al. (2004) sequenced the BCOR gene in 10 affected females from 7 OFCD families and found different mutations in each of the 7 families (see, e.g., 300485.0002-300485.0005), all of which predicted premature stop codons.
Horn et al. (2005) identified deletions in the BCOR gene (300485.0006-300485.0008) in 3 unrelated patients with OFCD, 1 of whom had been reported by Schulze et al. (1999). The authors did not identify mutations in the BCOR gene in 3 patients with Lenz microphthalmia syndrome or in 5 patients with a phenotype similar to that disorder. Horn et al. (2005) noted that the clinical features of the affected individuals in the African American family described by Ng et al. (2004) were not completely consistent with Lenz microphthalmia syndrome, and suggested that this might represent a unique phenotype exclusive to this family.
Oberoi et al. (2005) identified a 1-bp deletion (300485.0009) in the BCOR gene in a female patient with OFCD.
Hilton et al. (2009) analyzed the BCOR gene in 34 female OFCD patients from 20 families, including 4 previously reported patients (McGovern et al., 2006; Hilton et al., 2007), and identified heterozygous mutations in all of them (see, e.g., 300485.0003). In 2 of the families, there were also individuals who were mosaic for the mutation in BCOR: in the first family, the 2 mosaic patients exhibited the cardinal features associated with OFCD syndrome (300485.0010), whereas the mosaic individual from the second family (300845.0011) was asymptomatic. In addition, a boy who had been diagnosed with Lenz microphthalmia syndrome was found to have the known P85L mutation in the BCOR gene; among his features was radioulnar synostosis, which the authors noted had not previously been reported in Lenz patients but was strongly associated with OFCD. Hilton et al. (2009) analyzed the BCOR gene in a panel of 96 patients with isolated microphthalmia, coloboma, and/or mental retardation, and identified heterozygosity for a 5-bp deletion (300485.0012) in a female patient with bilateral congenital cataract and unilateral microphthalmia; her mother was reported to have a similar phenotype. Further investigation revealed that the proband had had numerous primary teeth removed in the teenage years and also exhibited syndactyly of the second and third toes, suggesting a mild OFCD phenotype.
Suzumori et al. (2013) studied a Japanese family in which the first pregnancy resulted in a male infant with syndromic clinical anophthalmia who died of cardiac defects at 6 months of age; he was found to have the P85L mutation in the BCOR gene, for which his mother was a heterozygous carrier. The woman's second pregnancy resulted in a normal boy, whereas a third pregnancy ended in miscarriage at 8 weeks' gestation. A fourth pregnancy was ectopic, for which laparoscopic surgery was performed. In the woman's fifth pregnancy, ultrasound at 15 weeks showed underdevelopment of both fetal eyes with unopened palpebral fissures; fetal karyotyping showed normal 46,XY G-banding, and analysis of fetal DNA revealed the P85L mutation in BCOR. The pregnancy was terminated at 19 weeks. Autopsy was declined, but examination confirmed clinical anophthalmia and showed depressed nasal bridge and simple ears.
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