craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 is a very rare inherited condition that affects multiple body systems, particularly the facial and skeletal structures as well as cognitive development. It is caused by pathogenic variations in the TMCO1 gene. This autosomal recessive disorder typically presents in early childhood, with characteristic facial features and skeletal abnormalities that prompt further evaluation. Given its rarity, it affects fewer than 1 in 1,000,000 individuals, and outcomes vary widely between affected individuals.

The clinical presentation is marked by a consistent pattern of distinctive facial features and skeletal anomalies. Virtually all affected individuals display features such as highly arched and thick eyebrows, long eyelashes, a wide nasal bridge with anteverted nares, low-set ears, a flat face, and a short nose. In addition, there is a high prevalence of brachycephaly, low anterior and posterior hairlines, synophrys, high palate, and microdontia affecting primary teeth. Musculoskeletal involvement is evident with gait disturbances, pes planus, pectus excavatum, and Sprengel anomaly, while feeding difficulties and hypotonia are also universally observed. Not all individuals experience every finding, and severity can vary considerably.

This condition results from variations in the TMCO1 gene, which plays a role in cellular processes that are essential for normal craniofacial and skeletal development as well as cognitive function. It is inherited in an autosomal recessive manner, meaning that an affected individual must inherit two copies of the pathogenic variant, one from each parent. This condition is more common when parents share a common ancestor, since both parents are more likely to carry the same rare variant, leading to a 25% chance of recurrence in each pregnancy. Genetic counseling is recommended for families to understand these implications and to discuss testing options.

Currently, management focuses on supportive care and symptomatic treatment since there are no specific FDA-approved or foundational therapies for this condition. Treatment is tailored to the individual and typically involves a multidisciplinary team that may include pediatricians, neurologists, orthopedists, and other specialists as needed. Long-term management includes regular surveillance to detect complications early, along with interventions such as physical and occupational therapy, nutritional support, and strategies to address feeding difficulties. Patients should discuss treatment options with their healthcare team to determine the most appropriate interventions, and genetic counseling is recommended to help families navigate inheritance and family planning.

The long-term outlook for individuals with craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 is variable, and the severity of symptoms can range widely. With current standards of care, many individuals are able to manage their symptoms and experience an improved quality of life, although challenges related to feeding, motor skills, and cognitive development may persist. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with genetic counselors and specialists familiar with this condition, as these professionals can offer guidance regarding ongoing management and future planning.