What is the management and treatment approach for Arboleda Tham syndrome?

Arboleda-Tham Syndrome: Management and Treatment Approach

Arboleda-Tham syndrome (ARTHS) requires early multidisciplinary intervention focused on developmental support, feeding management, and monitoring for associated complications, as there is no disease-modifying therapy available. 1, 2, 3

Diagnostic Confirmation

• Establish genetic diagnosis through whole exome sequencing (WES) or clinical exome sequencing (CES) when clinical features suggest ARTHS, including global developmental delay, hypotonia, feeding difficulties, and characteristic facial dysmorphism 3, 4, 5
• Look for specific pathogenic variants in the KAT6A gene, which cause autosomal dominant inheritance patterns (typically de novo mutations) 1, 2, 4
• Consider DNA methylation episignature testing as an emerging biomarker for diagnostic confirmation 4

Early Intervention (Birth to First Year)

Immediate Neonatal Management

• Address respiratory compromise at birth, as neonates may present with asphyxia, involuntary breathing, and weak crying requiring immediate support 2
• Initiate feeding support early for oro-intestinal problems and feeding difficulties, which are nearly universal in ARTHS 2, 3, 5
• Monitor for hypotonia and weak muscle tone affecting limbs and reflexes from birth 2

Neurological Support

• Administer mouse nerve growth factor for brain neuroprotection in the early postnatal period 2
• Implement early physical rehabilitation including tactile stimulation, back massage, passive limb movements, and audio-visual stimulation 2

Ongoing Multidisciplinary Management

Developmental and Rehabilitation Services

• Provide intensive physical therapy to address persistent hypotonia and motor delays 2, 3
• Implement speech and language therapy for expressive language delays, which emerge as a prominent feature during development 5
• Ensure occupational therapy for feeding difficulties and fine motor skill development 3, 4

Monitoring for Associated Complications

Cardiac surveillance: Screen for congenital heart defects with echocardiography, as cardiac anomalies are common 3, 5

Gastrointestinal assessment: Monitor for bowel obstruction, megacolon, and intestinal malrotation, which represent severe manifestations requiring surgical intervention 4

Ophthalmologic evaluation: Screen for ocular anomalies that may be present 3

Auditory assessment: Perform automatic auditory brainstem response testing to evaluate hearing 3

Genitourinary examination: Check for cryptorchidism and inguinal hernias, with surgical correction (testis reduction and orchiopexy) planned around 1 year of age when present 3

Nutritional Management

• Provide aggressive nutritional intervention to address feeding difficulties and support growth, as failure to thrive is common 2, 3
• Consider gastrostomy tube placement in severe cases of feeding dysfunction 4

Prenatal and Genetic Counseling Considerations

• Recognize that prenatal diagnosis is rare due to nonspecific findings, though severe cases may show fetal hepatic calcification on ultrasound 1
• Offer genetic counseling to families emphasizing the typically de novo nature of mutations and low recurrence risk for future pregnancies 2, 3, 4
• Discuss the extreme phenotypic variability, ranging from severe presentations with prenatal findings to milder postnatal presentations 1, 4

Critical Pitfalls to Avoid

• Do not delay WES/CES in patients with unexplained developmental delay and dysmorphism, as early genetic diagnosis prevents unnecessary invasive testing and guides appropriate management 3, 5
• Avoid attributing all symptoms to a single alternative diagnosis when multiple systems are involved—the constellation of hypotonia, feeding difficulties, developmental delay, and dysmorphism should trigger consideration of ARTHS 4, 5
• Do not overlook surgical needs for gastrointestinal complications, which can be life-threatening if unrecognized 4

Long-Term Follow-Up

• Maintain serial developmental assessments to document progression of delays and adjust therapeutic interventions 2, 5
• Continue monitoring for emergence of additional features over time, as the phenotype evolves with age 4
• Coordinate care through a single medical home to ensure comprehensive management across multiple subspecialties 3, 4