cerebrooculofacioskeletal syndrome 2

Cerebrooculofacioskeletal syndrome 2 (COFS2) is a very rare, multisystem genetic condition that affects growth, brain development, vision, hearing, connective tissue, and skeletal formation from before birth. It is caused by pathogenic variants in the ERCC2 gene, which encodes a protein essential for repairing DNA damage. Babies are typically small for gestational age and show signs of the condition in the newborn period. Because only a small number of affected individuals have been reported, precise prevalence figures are not available, but the condition is considered extremely uncommon worldwide. Severity and symptoms vary widely between individuals.

Clinical features usually appear before or shortly after birth. Prenatal ultrasound or delivery findings often include intrauterine growth restriction, microcephaly, cataracts, and joint contractures such as camptodactyly or rocker-bottom feet. Newborns may have distinctive facial features including deeply set eyes, a prominent or convex nasal bridge, micrognathia, and sparse scalp hair. Neurological involvement is a hallmark. Global developmental delay is universally reported, and many infants have profound cognitive and motor impairment that becomes apparent within the first months of life. Hearing impairment is common, further affecting communication. Because ERCC2 is expressed in brain tissue, neurological and cognitive manifestations are integral parts of the disorder rather than secondary findings. Supportive therapies such as physical, occupational, and early communication interventions can make a meaningful difference in daily function even when milestones are significantly delayed. Ocular problems are prominent. Congenital cataracts, microphthalmia, and progressive lens opacity contribute to severe visual impairment if not addressed promptly. Cutaneous photosensitivity reflects the underlying DNA repair defect and may lead to easy sunburn or skin irritation. Skeletal and connective-tissue complications include kyphoscoliosis, joint stiffness, and growth delay. Genital differences such as micropenis or a small scrotum have been reported in affected males. Not all individuals experience every feature, and the extent of organ involvement can differ considerably, underscoring the need for individualized care and monitoring.

COFS2 results from inheriting two non-working copies of the ERCC2 gene, one from each parent. ERCC2 encodes a component of the nucleotide excision repair pathway that removes DNA damage caused by ultraviolet light and certain chemicals. When the pathway is disrupted, cells throughout the body—especially in the brain, eyes, skin, and developing skeleton—accumulate DNA lesions that impair normal growth and function. The condition follows an autosomal recessive inheritance pattern, meaning that parents, who usually have no symptoms, each carry one altered copy of ERCC2. With each pregnancy, carrier parents face a 25 percent chance of having an affected child. Because COFS2 is extremely rare, it tends to appear more often in families where parents share a common ancestor, increasing the likelihood that both carry the same rare variant. Genetic counseling can help families understand carrier status, recurrence risks, and options for future pregnancies.

Currently, management focuses on supportive care and symptom management tailored to each individual, and typically involves a multidisciplinary team of specialists. Early cataract surgery may improve visual potential, while low-vision services support development in children with persistent impairment. Hearing aids or other assistive devices can address sensorineural hearing loss. Physical and occupational therapy aim to maintain joint mobility, address kyphoscoliosis, and foster motor skills. Because the skin is photosensitive, strict sun protection is recommended. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Ongoing monitoring often includes ophthalmologic examinations, spinal assessments, growth tracking, and developmental evaluations. Families should discuss specific surveillance schedules with their care team and update them as new concerns arise. Genetic counseling is recommended for affected families to review inheritance, testing for relatives, and reproductive options.

COFS2 is generally associated with significant medical challenges beginning in infancy, and many children require lifelong supportive services. The course can include progressive orthopedic complications and worsening visual or hearing impairment, yet the degree of neurological function and overall health differs from child to child. Outcomes depend on factors such as the severity of developmental delays, respiratory or feeding difficulties, and access to specialized care. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists familiar with complex neurodevelopmental and skeletal disorders, and participation in longitudinal registries may further clarify long-term expectations.