autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome

Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, often called KAT6A syndrome or Arboleda-Tham syndrome, is a neurodevelopmental and multi-system condition caused by pathogenic variants in the KAT6A gene. The gene encodes a protein that helps regulate how other genes are switched on and off during early development, so disruptions can affect the brain, face, heart, and other organs. Symptoms typically begin in infancy, with global developmental delay becoming apparent within the first year of life. The condition affects people of all sexes and is considered very rare, with fewer than one in a million individuals estimated to be affected worldwide. Severity and specific features vary widely between individuals.

Most children present with global developmental delay and intellectual disability, and many have limited or absent spoken language. Neonatal hypotonia and early feeding difficulties are common starting points that prompt medical evaluation. Characteristic facial features often noted by clinicians include a broad nasal tip, thin tented upper lip, highly arched or sparse medial eyebrows, and a long or triangular face. Craniofacial differences may be accompanied by primary microcephaly and low-set ears. Neurological and developmental features extend beyond cognition. Gait imbalance, delayed sitting and walking, and motor stereotypies reflect broader motor involvement, while sleep disturbances can further affect daily functioning. Because the KAT6A protein is active in the developing brain, cognitive and behavioral challenges are integral to the condition and may be unexpected for families focusing on physical signs. The syndrome also involves other body systems. Cardiac anomalies and a narrow, long thorax have been reported, so cardiology follow-up is important. Musculoskeletal findings such as pes planus and limb amyotrophy can influence mobility. Gastrointestinal reflux, frequent infections, and ocular concerns like strabismus, esodeviation, or amblyopia occur in a subset of individuals. Not all people experience every feature, and the range of severity is considerable.

The condition results from pathogenic variants in the KAT6A gene, which provides instructions for a histone acetyltransferase that helps control gene expression during embryonic development. When one copy of KAT6A is altered, its reduced or abnormal function disrupts multiple developmental pathways, leading to the diverse features described above. Inheritance is autosomal dominant, meaning a single altered copy of the gene is sufficient to cause the condition. An affected individual has a 50 percent chance of passing the variant to each child. Some people inherit the variant from an affected parent, while others are the first in their family because the genetic change occurred spontaneously. Even within the same family, the type and severity of symptoms can vary considerably, a phenomenon called variable expressivity. Genetic counseling is recommended for families to discuss testing options and reproductive planning.

Currently, management focuses on supportive care and symptom management tailored to each person’s needs. Early-intervention services, including speech, occupational, and physical therapy, aim to maximize cognitive and motor development. Feeding specialists and nutritionists can address swallowing difficulties and gastroesophageal reflux, while orthopedic or physiotherapy input helps with gait imbalance and pes planus. Cardiac defects, when present, are managed according to standard pediatric cardiology guidelines, and ophthalmologists monitor and treat strabismus or amblyopia. Because multiple organ systems can be affected, long-term care is best coordinated through a multidisciplinary team familiar with complex neurodevelopmental disorders. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Suggested monitoring often includes periodic cardiac imaging, growth and nutrition reviews, developmental assessments, and vision checks. Families should work closely with their healthcare team to determine the surveillance schedule most appropriate for their situation, and genetic counseling offers ongoing support as new information emerges.

Outcomes vary depending on the combination and severity of neurological, cardiac, and other systemic features. Many children make developmental gains over time, especially with access to early therapies and specialized educational support, though independent living in adulthood may require assistance for most. Because the condition is very rare, long-term data are limited and individual experiences differ significantly. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with clinicians who have experience in complex neurodevelopmental syndromes, and genetic counseling can provide guidance for family planning, available resources, and emerging research.