Cerebro-oculo-facio-skeletal syndrome (COFS) is a rare congenital autosomal recessive disorder that impairs development of the brain, head, eyes, limbs, and face. It is caused by defects in the nucleotide excision repair (NER) pathway (Suzumura & Arisaka, 2010 [PMID: 20687508]).
Only 14 cases were recorded between 1974 and 2010 (Suzumura & Arisaka, 2010 [PMID: 20687508]). A documented case after 2010 includes a familial recurrence reported by Sirchia et al. in 2021, with biallelic ERCC5 mutations (Sirchia et al., 2021 [PMID: 33766032]).
In previously reported case series, most patients died by 30 months of age. The main causes of death are failure to thrive due to feeding difficulties and recurrent aspiration pneumonia (Suzumura & Arisaka, 2010 [PMID: 20687508]; Reunert et al., 2021 [PMID: 33369099]).
The prognosis is extremely poor. In most cases, survival does not exceed 30 months. Failure to thrive due to feeding difficulties and recurrent aspiration pneumonia are the main causes of death.
Because COFS involves severe developmental delay, it is difficult for patients to report symptoms. Multisystem abnormalities are evident from birth.
Clinical findings of COFS are broadly divided into ophthalmic, craniofacial, neurological, and musculoskeletal findings.
Ophthalmic Findings
Blepharophimosis: Narrowing of the palpebral fissure.
Microphthalmia: Bilateral ocular hypoplasia.
Congenital cataract: Lens opacity present at birth.
Nystagmus: Involuntary eye movements.
Orbital hypertelorism: Increased distance between the eyes.
Craniofacial
Microcephaly: The head circumference is significantly small.
Micrognathia: Underdevelopment of the lower jaw is observed.
Microstomia and cleft palate: Accompanied by oral morphological abnormalities.
High-arched palate: The palate is high and arched.
Short neck: The neck is shortened.
Neurological findings
Decreased or absent tendon reflexes: Deep tendon reflexes throughout the body are reduced.
Sensorineural hearing loss: Hearing loss due to damage to the inner ear or auditory nerve.
Cognitive developmental disorder: Accompanied by severe developmental delay.
Musculoskeletal system
Arthrogryposis: Multiple joint contractures are present.
Flexion contractures: Particularly prominent in the elbow and knee joints.
Hypotonia: Decreased muscle tone throughout the body.
Syndactyly and rocker-bottom feet: Associated with limb malformations.
Osteoporosis: Reduced bone density is observed.
COFS is caused by mutations in genes of the transcription-coupled nucleotide excision repair (TC-NER) pathway. Defects in the NER pathway lead to accumulation of genetic mutations, manifesting as developmental disorders in multiple organs.
The causative genes are as follows (Suzumura & Arisaka, 2010 [PMID: 20687508]; Laugel et al., 2008 [PMID: 18628313]).
Consanguineous marriage is an important risk factor for COFS. Due to autosomal recessive inheritance, couples who are both carriers have an increased risk of having an affected child.
Microarray analysis and targeted molecular testing for the following NER-related genes are useful for identifying carriers:
COFS is clinically diagnosed based on a combination of the following findings (Laugel et al., 2008 [PMID: 18628313]).
To confirm DNA repair defects in the NER pathway. The following tests are available.
The differential diagnosis of COFS directly determines the treatment strategy. In particular, distinguishing it from Cockayne syndrome is extremely important when deciding on the indication for cataract surgery.
| Disease | Difference from COFS | Cataract surgery |
|---|---|---|
| Cockayne syndrome | Survival approximately 12 years | Beneficial |
| COFS syndrome | Survival approximately 30 months | Usually not performed |
Other differential diagnoses are as follows.
Both COFS and Cockayne syndrome result from defects in the NER pathway, but their clinical courses differ. The survival period for Cockayne syndrome is about 12 years, and cataract surgery is beneficial for improving visual outcomes before the onset of retinal dystrophy. In contrast, the survival period for COFS is about 30 months, and cataract surgery is not typically performed.
There is no curative treatment for COFS. Ophthalmic findings are managed symptomatically according to standard protocols.
In COFS, cataract surgery is usually not performed. Because survival is extremely short, approximately 30 months, the balance of risks and benefits of surgery is difficult to establish. This contrasts with Cockayne syndrome, where survival is about 12 years and cataract surgery is recommended.
The NER pathway is a crucial mechanism for repairing DNA damage caused by ultraviolet light and other factors. In COFS, defects in this pathway lead to accumulation of DNA damage, causing developmental disorders in multiple organs.
Transcription-coupled NER (TC-NER) is a repair mechanism that operates when RNA polymerase II stalls at a DNA damage site during transcription. The causative genes of COFS—CSB, XPD, XPG, and ERCC1—are all components of this pathway.
Mutations in the same group of genes in the TC-NER pathway can lead to different clinical presentations such as COFS, Cockayne syndrome, and xeroderma pigmentosum, depending on the site and type of mutation. COFS is considered the most severe form within the Cockayne spectrum, with developmental impairment progressing from before birth (Laugel et al., 2008 [PMID: 18628313]).
