Marshall-Smith syndrome

Marshall-Smith syndrome is a rare genetic disorder characterized by tall stature and advanced bone age at birth, in addition to distinctive facial and skeletal features. It is caused by pathogenic variants in the NFIX gene and typically occurs sporadically in an autosomal dominant pattern. Affected individuals present early in life with developmental delays and characteristic dysmorphic features. Although very rare, affecting fewer than 1 in 1 million people, our understanding of the condition continues to evolve with modern diagnostic approaches.

Individuals with Marshall-Smith syndrome often exhibit intellectual disability, proptosis, and global developmental delay along with distinctive facial features such as a high forehead, prominence of the premaxilla, and retrognathia. Early clinical presentation may include decreased body weight and delayed speech and language development. As the condition evolves, additional features may be observed in some affected individuals, including hypertrichosis, midface retrusion, blue sclerae, and airway obstruction, as well as other findings like broad forehead, hallux valgus, sparse hair, anteverted nares, hydrocephalus, short nose, cholesteatoma, stridor, recurrent aspiration pneumonia, gingival overgrowth, wormian bones, and hearing impairment. Not all individuals experience all features, and severity varies considerably.

Marshall-Smith syndrome is caused by pathogenic variants in the NFIX gene, which plays an important role in the development of both the skeletal system and the brain. The condition typically arises sporadically in an autosomal dominant manner, meaning that the genetic change is usually new and not inherited from a parent. This implies that there is generally no family history, although an affected individual can pass the variant on to their children. Genetic counseling is recommended to help families understand the inheritance pattern and discuss family planning options.

Currently, management of Marshall-Smith syndrome focuses on supportive care and symptom management rather than on treatments specifically approved for the condition. A multidisciplinary team is important to address a range of needs, and interventions such as physical, occupational, and speech therapies help support the individual’s development. Regular surveillance is an essential part of long-term care, aiding in the early detection of potential complications. Patients should discuss treatment options with their healthcare team to determine the most appropriate supportive strategies, and genetic counseling is advised to help families understand their options.

The outlook for individuals with Marshall-Smith syndrome is variable, with outcomes depending on the severity of symptoms and access to specialized care. Many individuals benefit from early intervention and coordinated supportive management, although challenges such as developmental delay and systemic complications may persist. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists familiar with the condition, and genetic counseling can provide valuable guidance for understanding inheritance and planning for the future.