Oculofaciocardiodental syndrome

Associate Editor in Chief: Berna Zorkun DMD [mailto:bernazorkun@gmail.com]

Synonyms and related keywords: MCOPS2 or Microphthalmia, cataracts, radiculomegaly, and septal heart defects or Microphthalmia, syndromic 2, Oculo-facio-cardio-dental syndrome, OFCD syndrome

Overview
Oculofaciocardiodental syndrome is a condition that affects the development of the eyes (oculo-), facial features (facio-), heart (cardio-) and teeth (dental). This condition occurs only in females.

The eye abnormalities associated with oculofaciocardiodental syndrome can affect one or both eyes. Many people with this condition are born with eyeballs that are abnormally small (microphthalmia). Other eye problems can include clouding of the lens (cataract) and a higher risk of glaucoma, an eye disease that increases the pressure in the eye. These abnormalities can lead to vision loss or blindness.

People with oculofaciocardiodental syndrome often have a long, narrow face with distinctive facial features, including deep-set eyes and a broad nasal tip that is divided by a cleft. Some affected people have an opening in the roof of the mouth called a cleft palate.

Heart defects are another common feature of oculofaciocardiodental syndrome. Babies with this condition may be born with a hole between two chambers of the heart (an atrial or ventricular septal defect) or a leak in one of the valves that controls blood flow through the heart (mitral valve prolapse).

Teeth with very large roots (radiculomegaly) are characteristic of oculofaciocardiodental syndrome. Additional dental abnormalities can include delayed loss of primary (baby) teeth, missing or abnormally small teeth, misaligned teeth, and defective tooth enamel.

Incidence
Oculofaciocardiodental syndrome is very rare; the incidence is estimated to be less than 1 in 1 million people.

Genetics
Mutations in the BCOR gene cause oculofaciocardiodental syndrome. The BCOR gene provides instructions for making a protein called the BCL6 co-repressor. This protein helps regulate the activity of other genes. Little is known about the protein's function, although it appears to play an important role in early embryonic development. Several mutations in the BCOR gene have been found in people with oculofaciocardiodental syndrome. These mutations prevent the production of any functional protein from the altered gene, which disrupts the normal development of the eyes and several other organs and tissues before birth.

Historical Aspect of Oculofaciocardiodental Syndrome

 * 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.

Mapping

 * 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 (MCOPS4; 301590). 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)

Molecular Genetics

 * 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 (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.

Diagnosis
Diagnosis of oculofaciocardiodental syndrome is hard for medical specialists and the syndrome is often unrecognized.

Cardiac Abnormalities

 * Ventricular septal defect
 * Atrial septal defect
 * Mild cardiomegaly
 * Atrial hypertrophy
 * Ventricular hypertrophy
 * Benign peripheral pulmonic stenosis
 * Mitral valve prolapse

Dental Abnormalities
The specific dental findings (visible on a panoramic radiograph of the jaws) can be easily diagnosed by an orthodontist or a dentist.


 * Radiculomegaly: The most consistent and pathognomic dental finding of oculofaciocardiodental syndrome is radiculomegaly (extremely long roots), particularly of the canines and occasionally of other teeth including premolars and incisors.
 * Slow and delayed dental eruption: The dental eruption in both the deciduous and the permanent dentition is consistently slow and delayed.
 * Oligodontia
 * Fused teeth
 * Supernumerary teeth
 * Malformed permanent teeth
 * Enamel defects
 * Root dilacerations
 * Malposition
 * Malocclusion

Facial Abnormalities

 * Long narrow face
 * High nasal bridge
 * Broad nasal tip with separated nasal cartilages
 * Laterally curved and thick eyebrows
 * Long philtrum
 * Clefts of the hard / soft palate

Ocular Abnormalities

 * Bilateral congenital cataracts
 * Microphthalmia
 * Regressive vision impairment
 * Secondary glaucoma
 * Ptosis
 * Exotropia: Exotropia is very common.

Others

 * Syndactyly of the second and third toes
 * Hammer-type flexion of the second and fourth toes
 * Radio-ulnar synostosis
 * Vertebral and rib anomalies
 * Intestinal malrotation
 * Hearing impairment
 * Mental and psychomotor retardation

Inheritance
This condition is inherited in an X-linked dominant pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. Some cells produce a normal amount of BCL6 co-repressor protein and other cells produce none. The resulting overall reduction in the amount of this protein leads to the signs and symptoms of OFCD syndrome.

In males (who have only one X chromosome), mutations result in a total loss of the BCL6 co-repressor protein. A lack of this protein appears to be lethal very early in development, so no males are born with OFCD syndrome.

Management
Management of oculofaciocardiodental syndrome requires appropriate cardiac, ophthalmic and dental care.

Source

 * Genetics Home Reference
 * National Center for Biotechnology Information