ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder

ADNP-related multiple congenital anomalies–intellectual disability–autism spectrum disorder is a neurodevelopmental condition that affects many body systems but is especially notable for its impact on learning and behavior. It is caused by pathogenic variants in the ADNP gene, which follows an autosomal dominant inheritance pattern. Signs are usually recognized in infancy or early childhood when developmental milestones are delayed. Precise prevalence figures are not yet established, but only a relatively small number of individuals have been described worldwide. Because recognition of the condition is increasing, more families are receiving a molecular diagnosis and access to tailored support.

The clinical picture is broad and can differ markedly from one person to another. Neurological and developmental features are most prominent, with all affected individuals exhibiting cognitive or intellectual disability, and many showing autistic behaviors such as echolalia, social communication challenges, and heightened anxiety. Early motor milestones are frequently delayed, and low muscle tone can contribute to difficulties with sitting, walking, and fine-motor tasks. Seizures occur in a minority of children and are usually tonic in type. Distinctive facial and dental findings often guide clinicians toward the diagnosis. A prominent forehead, high hairline, wide nasal bridge, anteverted nares, and a long philtrum are common. Rapid or advanced tooth eruption, widely spaced teeth, and a thick lower lip vermilion further characterize the condition. Musculoskeletal issues such as pes planus and joint hypermobility may affect gait and posture. Additional, less consistent findings include short nose, down-slanted palpebral fissures, pineal cysts noted on brain imaging, and episodic behavioral outbursts. Not all individuals experience all features, and severity varies considerably.

The condition results from changes (pathogenic variants) in the ADNP gene. Although the exact role of the ADNP protein is still being clarified, disruption of this gene alters critical pathways involved in early brain development and other organ systems, leading to the diverse features seen in affected individuals. The disorder is inherited in an autosomal dominant manner, meaning a single altered copy of ADNP can cause the condition. Most diagnosed children have the variant for the first time in the family (a de novo event), but an affected parent would have a 50 percent chance of passing the variant to each child. Family members benefit from genetic counseling to discuss these implications and options for future pregnancies.

Currently, management focuses on supportive care and symptom management. Early intervention programs that include speech, occupational, and physical therapy foster developmental progress, while behavioral therapy can help address autism spectrum features and anxiety. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious; this often involves periodic neurological reviews for seizures, dental examinations for tooth crowding or spacing, and orthopedic monitoring for flat feet or joint laxity. Care is typically coordinated by a multidisciplinary team that may include developmental pediatricians, neurologists, dentists, and physical therapists. Families are encouraged to discuss emerging therapies or clinical trial opportunities with their specialists as science evolves.

Severity and symptoms vary widely between individuals, and long-term outcomes depend on the combination of neurological, medical, and behavioral challenges each person faces. Many children make meaningful developmental gains with early, intensive support, although most will need lifelong assistance with daily activities. While the condition appears to be lifelong, major medical complications are not inevitable, and quality of life can improve with tailored therapies and supportive services. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialist teams and genetic counselors to plan for ongoing educational, therapeutic, and medical needs.

Clinical trials are underway exploring new treatment approaches, including potential therapies aimed at modulating ADNP function or alleviating specific neurological symptoms. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.