neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties

This neurodevelopmental disorder presents with a constellation of developmental delays and multisystem abnormalities, along with distinctive craniofacial features such as a prominent forehead. It is caused by pathogenic variants in the DPH5 gene, which affect the normal function of the diphthamide synthesis pathway. Affected individuals typically exhibit global developmental delay, absent speech, feeding difficulties, and short stature from early childhood. Precise prevalence estimates are not well established, and not all individuals experience every symptom, with severity varying considerably.

The clinical picture is dominated by profound neurodevelopmental delay that affects cognitive and communication skills, including absent speech and profound intellectual disability. Characteristic findings include short stature, a prominent forehead (which may appear broad or narrow in different aspects), and feeding difficulties that are consistently observed. Additional features in many individuals include hypotonia, sparse eyebrows, and epicanthal folds, while a subset may present with seizures, cerebral palsy, and even cardiac complications such as aortic aneurysm or pericardial effusion. Not all individuals experience every feature, and the severity and combination of symptoms can vary considerably.

This condition is caused by pathogenic variants in the DPH5 gene, which is integral to the diphthamide synthesis pathway and thus important for proper protein function. It is inherited in an autosomal dominant manner, meaning that a single altered copy of the gene is sufficient to cause the disorder. Consequently, an affected individual has a 50% chance of passing the genetic change to each child, although variable expressivity means that the clinical presentation can differ even among family members. Genetic counseling is recommended to help families understand these implications and explore reproductive options.

Currently, management focuses on supportive care and symptom management, as there are no specific foundational or targeted therapies approved for this condition. Treatment is tailored to the individual and typically involves a multidisciplinary team to address neurodevelopmental, feeding, and other multisystem challenges. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Patients and families are encouraged to discuss treatment options with their healthcare team, and genetic counseling is recommended for further guidance.

Outcomes vary widely among affected individuals, and the overall course is influenced by the severity of developmental and multisystem involvement. With current standards of care, many individuals experience periods of stabilization following early developmental challenges, though the disorder remains lifelong and its impact may change with age. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists experienced in managing this condition and to seek genetic counseling for ongoing support and guidance.