Clinical Guidance

Pathogenic variants result in two distinct DNA methylation patterns, depending on the location of the variant within ANDP. Class 1 methylation signatures are typically observed in individuals with ADNP pathogenic variants located outside the region between c.2000 (p.667) and c.2340 (p.780). In contrast, class 2 methylation signatures are associated with variants located within this region . A class 2 methylation signature appears to correlate with a generally more severe phenotypic presentation. These individuals were found to experience recurrent infections, gastrointestinal problems (including reflux, constipation, and feeding difficulties) and short stature two to three times more often than individuals with a class 1 signature.

Source: GeneReviews — "ADNP-Related Helsmoortel-Van der Aa Syndrome"

Penetrance

Penetrance is less than 100%. In two families reported to date, probands diagnosed with ADNP-related HVDAS inherited a pathogenic variant from an unaffected parent .

Source: GeneReviews — "ADNP-Related Helsmoortel-Van der Aa Syndrome"

Diagnostic Criteria

No consensus clinical diagnostic criteria for ADNP-related Helsmoortel-Van der Aa syndrome (also referred to as Helsmoortel-Van der Aa syndrome [HVDAS]) have been published.

Suggestive Findings

ADNP-related HVDAS should be considered in individuals with the following clinical and brain MRI findings and family history.

Clinical findings

Source: GeneReviews — "ADNP-Related Helsmoortel-Van der Aa Syndrome"

Differential Diagnosis

ADNP plays a major role in chromatin regulation and neuronal differentiation . SWI/SNF-related intellectual disability disorders (SSRIDDs) or BAFopathies (BRG1/BRM-associated factor) are a group of neurodevelopmental syndromes caused by pathogenic variants in genes encoding components of the SWI/SNF chromatin remodeling complex . These disorders, including Nicolaides-Baraitser syndrome and Coffin-Siris syndrome, share overlapping clinical features with ADNP-related Helsmoortel-Van der Aa syndrome (also referred to as Helsmoortel-Van der Aa syndrome [HVDAS]), making them important considerations in the differential diagnosis . Table 3. SWI/SNF-Related Neurodevelopmental Syndromes (BAFopathies) of Interest in the Differential Diagnosis of ADNP-Related Helsmoortel-Van der Aa Syndrome

Management Guidelines

No clinical practice guidelines for ADNP-related Helsmoortel-Van der Aa syndrome (HVDAS) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADNP-related HVDAS, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

ADNP-Related Helsmoortel-Van der Aa Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Development

| Comprehensive developmental assessment | • Motor, adaptive, cognitive, speech-language eval

• Testing for ASD ID

• Eval for early intervention/ special education

Neurobehavioral/

Psychiatric

| Neuropsychiatric eval if behavioral problems are present | For persons age 12 mos: screen for concerns incl findings suggestive of ASD, anxiety, OCD, aggression, ADHD, /or sleep disturbances

Gastrointestinal/

Feeding

| • Nutrition/ swallowing / feeding team eval

• Referral to gastroenterologist/ENT

| • To incl eval of aspiration risk nutritional status

• Consider eval for gastrostomy tube placement in those w/dysphagia /or aspiration risk.

Vision

| Ophthalmologic exam vision assessment | Referral to ophthalmologist if indicated for electrophysiologic visual perception exam to detect cortical visual impairment in those w/atypical visual function

Source: GeneReviews — "ADNP-Related Helsmoortel-Van der Aa Syndrome"

Therapies Under Investigation

Ketamine treatment has been proposed as a potential therapy for ADNP-related HVDAS. Ketamine is an NMDA receptor agonist with pro-glutamatergic activity, approved for anesthetic purposes and as a therapeutic intervention for treatment-resistant depression. A recent Phase II, open-label trial (NCT04388774) investigated the effects of a single low-dose intravenous ketamine infusion (0.5 mg/kg) in individuals with ADNP-related HVDAS. However, the rationale of ketamine to increase ADNP mRNA levels was not successful as demonstrated by transient peripheral blood transcriptomic responses in children with ADNP-related HVDAS. In addition, ketamine induced immediate and significant changes in gene expression, particularly affecting monocyte-related pathways.

Source: GeneReviews — "ADNP-Related Helsmoortel-Van der Aa Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 6. ADNP-Related Helsmoortel-Van der Aa Syndrome: Recommended Surveillance

Source: GeneReviews — "ADNP-Related Helsmoortel-Van der Aa Syndrome"