cerebrooculofacioskeletal syndrome 1

Cerebrooculofacioskeletal syndrome 1 (COFS 1) is a very rare, multisystem condition that primarily affects the brain, eyes, facial development, and skeleton. It results from harmful changes in the ERCC6 gene, which is involved in repairing damage to DNA. Signs usually become apparent before or shortly after birth and progress through infancy. Because only scattered cases have been described, the precise number of affected individuals worldwide is not well established. Both males and females can be affected and the disorder follows an autosomal recessive inheritance pattern, meaning it appears when a child receives two altered copies of the ERCC6 gene, one from each parent.

COFS 1 has a broad range of clinical features, and not all individuals experience every symptom. Severity and symptoms vary widely between individuals. Neurological and developmental features: All affected babies show profound global developmental delay and axial hypotonia, and many go on to experience progressive neurologic deterioration and seizures. Microcephaly (a small head size) is another consistent finding, reflecting abnormal brain growth. Gliosis, ventriculomegaly, and CNS demyelination reported on brain imaging further illustrate central nervous system involvement. Eye findings: Microphthalmia (small eyes), deeply set eyes, and episodes of excessive pupil constriction (miosis) are common. These ocular changes can impair vision and may help clinicians recognize the condition early. Growth and skeletal manifestations: Infants are typically small for gestational age and may have failure to thrive despite aggressive nutritional support. Joint stiffness or flexion contractures can limit movement. Facial and skeletal differences such as micrognathia (small lower jaw) and delayed eruption of teeth are often noted. Endocrine and metabolic issues: Some children develop insulin resistance or metabolic acidosis, underlining the need for close metabolic monitoring. Other systemic features: Recurrent pneumonia is frequent, likely related to weak respiratory muscles and swallowing difficulties. Cryptorchidism is reported in boys, and dehydration can occur during illnesses. Not all individuals experience all features, and the timing of symptom onset can differ. Regular assessment across organ systems helps capture emerging problems early.

COFS 1 is caused by pathogenic variants in the ERCC6 gene. The ERCC6 protein plays a key role in nucleotide excision repair, one of the body’s main pathways for correcting damage to DNA. When both copies of ERCC6 are altered, cells—especially those in the developing brain, eyes, and skeletal system—accumulate DNA damage that disrupts normal growth and function. The condition is inherited in an autosomal recessive pattern. Parents who each carry one non-working ERCC6 copy usually have no symptoms but have a 25 percent chance with each pregnancy of having an affected child, a 50 percent chance of having a carrier child, and a 25 percent chance of having a child who has two working copies. Because the gene change must be present in both parents, COFS 1 is more likely to appear in families where parents share a common ancestor. Genetic counseling can help relatives understand carrier testing options and family-planning considerations.

Currently, management focuses on supportive care and symptom management. Care typically involves a multidisciplinary team that may include neurologists, ophthalmologists, pulmonologists, orthopedic surgeons, nutrition specialists, and physical and occupational therapists. Acute and ongoing care: Feeding support, such as high-calorie formulas or gastrostomy tube placement, can address failure to thrive. Physical therapy helps preserve joint mobility and manage hypotonia, while orthotic devices may mitigate flexion contractures. Prompt treatment of respiratory infections and proactive airway clearance techniques are critical because recurrent pneumonia is common. Surveillance and monitoring: Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Suggested monitoring includes periodic brain imaging to track structural changes, ophthalmologic exams to evaluate vision, respiratory assessments to gauge airway health, and metabolic panels to watch for acidosis or insulin resistance. Because COFS 1 is genetic, families often benefit from meeting with a genetic counselor to discuss inheritance, carrier testing, and reproductive options. Patients should discuss treatment options with their healthcare team to determine which therapies may be appropriate for their specific situation.

COFS 1 is generally considered a severe disorder that begins in infancy and can progress quickly, especially in the nervous system. Many children face significant challenges with growth, breathing, and nutrition. Outcomes vary depending on the specific symptoms present, the timing of diagnosis, and access to intensive supportive care. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialized centers familiar with complex neurodevelopmental conditions, participate in disease registries when available, and seek genetic counseling to clarify inheritance and future planning.