PACS1 Neurodevelopmental Disorder

Clinical characteristics: PACS1 neurodevelopmental disorder (PACS1-NDD) is characterized by mild-to-severe neurodevelopmental delays. Language skills are more severely affected than motor skills. Hypotonia is reported in about a third of individuals and is noted to improve over time. Approximately 60% of individuals are ambulatory. Feeding difficulty is common, with 25% requiring gastrostomy tube to maintain appropriate caloric intake. Other common features include constipation, seizures, behavioral issues, congenital heart anomalies, short stature, and microcephaly. Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth. To date approximately 35 individuals with PACS1-NDD have been reported.

Diagnosis/testing: The diagnosis of PACS1-NDD is established in a proband with a heterozygous pathogenic variant in PACS1 identified by molecular genetic testing.

Management: Treatment: Standard treatment for feeding issues, constipation, seizures, behavioral issues, cardiac anomalies, vision issues, and renal anomalies.

Surveillance: Monitor for growth and nutrition issues, constipation, seizures, and behavioral issues. Monitor closure of septal defects as per cardiologist; monitor renal function if renal malformation is present as per nephrologist.

Agents/circumstances to avoid: Known seizure triggers.

Genetic counseling: PACS1-NDD is an autosomal dominant disorder. All individuals reported to date have the disorder as the result of a de novo pathogenic variant. If the PACS1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.