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What is Cerebro-Oculo-Facio-Skeletal Syndrome?

Cause and Symptoms
Case Reports
Diagnosis and Treatment
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Cerebro-oculo-facio-skeletal syndrome or COFS is a rare neurodegenerative disease with an autosomal recessive pattern of inheritance. A pediatric genetic disorder involving the brain and spinal cord, COFS includes facial dysmorphism, microcephaly, and congenital cataracts as characteristic features.

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COFS is a condition that is diagnosed at birth and was first described by Pena and Shokeir. The cause of the condition is often unknown. However, few genes responsible for the condition have been reported. The majority of children with this disease do not live past the age of five. Treatment is based on an individual’s symptoms and includes supportive care.


Microcephaly, hypotonia, arthrogryposis, ocular abnormalities, drooping upper lip, micrognathia, flared nipples, kyphoscoliosis, and osteoporosis were noted in ten cases in three families reported by Pena and Shokeir in 1974.

In 1974, Preus and Fraser recorded a single event in the offspring of Italian parents of the first cousin. Pena and Shokeir had sibling parents in one of their affected siblings (2 affected out of 6 children). COFS syndrome was first diagnosed in a black American newborn by Surana et al. in 1978.

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Cause and Symptoms

The cause of the disease is unknown in many patients. In some circumstances, the condition can be caused by mutations in one or more undiscovered genes. Some cases of COFS syndrome have been associated with mutations in the ERCC1, ERCC2, ERCC5, and ERCC6 genes. These genes provide instructions on how to make proteins that help repair damaged DNA.

DNA damage is not quickly repaired if one of these genes is changed. Damaged DNA therefore accumulates, resulting in impaired cell functions and eventual cell death. It is still unclear how mutations in these genes cause the indications and symptoms of COFS syndrome.

COFS is characterized by craniofacial and skeletal abnormalities, as well as drastically decreased muscle tone and reflex dysfunction. Large, low-set ears, small eyes, microcephaly, micrognathia, clenched fists, and flared nipples are all possible symptoms.

There have also been reports of vision abnormalities, involuntary eye movements and impaired cognitive development, which may be mild or severe. Infections of the lungs are common. Some patients may also experience cutaneous photosensitivity, hypogonadism, seizures, peripheral neuropathy, and optic atrophy.

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There is no known exact prevalence of the syndrome in the population, but according to the orphan database, COFS has a prevalence of less than 1/1,000,000.

Read next: What is Jackson-Weiss syndrome?

Case Reports

In 2020, Quyen et al. documented the morphological and microscopic phenotypes of three fetuses from two families with ERCC5/XPG probable pathogenic mutations, as well as reviewed five previously reported fetal cases.

The fetuses had thymic hyperplasia, splenomegaly, and increased hematopoiesis, in addition to the usual features of COFS. The three fetuses showed microencephaly, which is characterized by delayed gyri development and normal microscopic anatomy at the supratentorial level. At the infratentorial level, microscopic abnormalities resembling pontocerebellar hypoplasia were found.

Finally, when intrauterine growth retardation is associated with microcephaly, artrogryposis, and ocular defects in fetuses, the COFS syndrome should be evaluated. More research is needed to better understand how XPG works during human development.

Sirchia et al. described in 2021 a case of recurrence of COFS3 syndrome in the same family with similar diagnostic features. The parents were in good health, young (under 30 years old) and from different countries. As a result, consanguinity was excluded. There were no birth defects or recurrent diseases in their families. The COFS syndrome remained undetected in the first case, but prenatal observations of artrogryposis and cataracts led to a genetic study targeting COFS-related genes (ERCC5, ERCC6, and FKTN genes) in the second case. The fetus was determined to be compound heterozygous for two separate ERCC5 mutations, confirming the clinical suspicion of COFS syndrome.

The association between microphthalmia and/or cataracts and arthrogryposis appears to be unique to COFS disease and has only been reported in a few other conditions. In the genomic era, molecular diagnosis is possible, and estimating the risk of recurrence in the family is critical.

The researchers conducted a literature search on putative causal genes of prenatal cataract and arthrogryposis and presented a flowchart to aid in differential diagnosis and genetic testing if these symptoms are found. The flowchart represents a process for guiding differential diagnosis based on prenatal evidence. The main syndromes, important tests and specific genes are all covered. In order to diagnose and determine the likelihood of recurrence in future pregnancies, the couple should be offered targeted molecular testing.

Diagnosis and Treatment

COFS syndrome is often diagnosed at birth in children. Because the fetus moves very little and some problems are caused by lack of movement, ultrasound technology can detect COFS fetuses at an early stage of pregnancy.

During the neonatal phase, infants with COFS syndrome usually require oxygen supplementation for respiratory distress. Feeding problems require tube feeding. Most newborns die at the age of 4-5 years due to chronic respiratory infections, which cause severe stunted growth and developmental delays.

Treatment is based on an individual’s symptoms and includes supportive care. The condition often requires tube feeding. Because COFS is a genetic condition, genetic counseling is available and can help families better understand the situation.

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Further Reading

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