Clinical characteristics.

ADNP-related Helsmoortel-Van der Aa syndrome (also referred to as Helsmoortel-Van der Aa syndrome [HVDAS]) is characterized by hypotonia, speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features (prominent forehead, high anterior hairline, wide and depressed nasal bridge, and short nose with full, upturned nasal tip). Features of autism spectrum disorder are common (stereotypic behavior, impaired social interaction). Other common findings include additional behavioral problems, sleep disturbance, structural brain abnormalities, feeding issues, gastrointestinal problems, visual dysfunction (hypermetropia, strabismus, cortical visual impairment), musculoskeletal anomalies, recurrent infections, endocrine issues including short stature and thyroid and/or growth hormone deficiencies, cardiac anomalies, hearing loss, seizures, and urinary tract anomalies.

Diagnosis/testing.

The diagnosis of ADNP-related HVDAS is established by identification of a heterozygous ADNP pathogenic variant by molecular genetic testing.

Management.

Treatment of manifestations: Treatment is symptomatic and can include: speech, occupational, and physical therapy; specialized learning programs depending on individual needs; treatment of neuropsychiatric features; nutritional support as needed; standard treatment of gastrointestinal, ophthalmologic, and musculoskeletal issues, recurrent infections, endocrine and cardiac findings, hearing loss, seizures, and urinary tract anomalies; family and social support.

Surveillance: At each visit monitor developmental progress, educational needs, behavioral issues, occupational and physical therapy needs, growth and nutrition, gastrointestinal issues, infection frequency, endocrine issues, seizures, urinary tract infections, and family needs; annual vision and hearing assessment.

Genetic counseling.

ADNP-related HVDAS is an autosomal dominant disorder. Most probands whose parents have undergone molecular genetic testing have the disorder as the result of a de novo ADNP pathogenic variant. In two families reported to date, probands diagnosed with ADNP-related HVDAS inherited a pathogenic variant from an unaffected parent. Once the ADNP pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

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

Clinical findings

• Speech and motor delay
• Mild-to-severe intellectual disability
• Autism spectrum disorder, additional behavioral problems, and sleep disturbance
• Characteristic facial appearance including prominent forehead, high anterior hairline, downslanted palpebral fissures, prominent eyelashes, ear malformations, wide and depressed nasal bridge, short nose with full, upturned nasal tip, long philtrum, thin vermilion of the upper lip, pointed chin, and widely spaced teeth (See Figure 1.)
• Feeding difficulties and gastrointestinal problems (e.g., gastroesophageal reflux disease, lack of satiation, frequent vomiting, constipation)
• Vision issues (e.g., strabismus, cortical visual impairment, hypermetropia) and various ophthalmologic defects
• Musculoskeletal anomalies (e.g., hand and foot anomalies, joint laxity, scoliosis, hip problems, pectus deformities, skull deformities)
• Other features including recurrent infections, endocrine manifestations, cardiac and kidney anomalies, hearing loss, and seizures

Figure 1.

Facial features of individuals with ADNP pathogenic variants. Frontal and lateral views. Note the prominent forehead with high anterior hairline, wide and depressed nasal bridge, and short nose with full, upturned nasal tip Reproduced with permission (more...)

Brain MRI findings include atypical white matter lesions, wide ventricles, corpus callosum underdevelopment, cerebral atrophy, cortical dysplasia, and choroid cysts. Note that these findings are not sufficiently distinct to specifically suggest the diagnosis of ADNP-related HVDAS.

Family history. Because ADNP-related HVDAS is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of ADNP-related HVDAS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in ADNP identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics (AMCG) / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous ADNP variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with exome sequencing / genome sequencing [Manickam et al 2021, van der Sanden et al 2023]. Other options include use of chromosomal microarray analysis (CMA) or a multigene panel. Single-gene testing (sequence analysis of ADNP, followed by gene-targeted deletion/duplication analysis) may be indicated in individuals with the distinctive findings described in Suggestive Findings.

• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to a multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability whereas some multigene panels may not. Genome sequencing is recommended if exome sequencing fails to identify an ADNP pathogenic variant. Genome sequencing identified an intragenic inversion in ADNP that was not detected on exome sequencing [Georget et al 2023, D'Incal et al 2024a]. ACMG and the American Academy of Pediatrics recommend exome/genome sequencing as first- or second-tier diagnostic testing for children with developmental delay, intellectual disability, and/or multiple congenital anomalies [Manickam et al 2021, Rodan et al 2025].
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• CMA uses oligonucleotide or SNP array to detect genome-wide large deletions/duplications (including ADNP) that cannot be detected by sequence analysis.
• A multigene panel that includes ADNP and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Single-gene testing. Sequence analysis of ADNP can be performed to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

Epigenetic signature analysis / methylation array. Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample could be used to clarify the diagnosis in individuals with clinical findings of ADNP-related HVDAS and (1) an ADNP variant of uncertain clinical significance or (2) if molecular genetic testing did not establish a diagnosis (see Table 1). For an introduction to epigenetic signature analysis click here.

ADNP pathogenic variants may result in two distinct episignatures. Individuals with an ADNP pathogenic variant located outside the region between c.2000 (p.667) and c.2340 (p.780) have an overall hypomethylated CpG pattern; individuals with an ADNP pathogenic variant located within that interval have an overall hypermethylated CpG pattern [Bend et al 2019, Breen et al 2020].

Clinical Description

ADNP-related Helsmoortel-Van der Aa syndrome (HVDAS) is characterized by hypotonia, speech and motor delay, intellectual disability, neurobehavioral manifestations, characteristic facial features, feeding issues, gastrointestinal problems, visual dysfunction, musculoskeletal anomalies, recurrent infections, endocrine issues, cardiac anomalies, hearing loss, seizures, and urinary tract anomalies. The following clinical description is based on a published report of a large cohort of 78 individuals in whom a pathogenic variant in ADNP was identified [Van Dijck et al 2019]. Note: To date, the oldest individual known to the authors is age 69 years [L Harutyunyan, RF Kooy, CP D'Incal, & A Van Dijck, personal communication; information provided by patient organization].

Development. Infants often have hypotonia. Developmental milestones are delayed: the average age to sit independently is 13 months, and the average walking age is 2.5 years. Speech impairment is common, with expressive language ranging from no words to sentences. Bladder training is delayed in 81% of affected individuals.

All affected individuals have mild-to-severe intellectual disability.

Neurobehavioral/psychiatric manifestations. Autism spectrum disorder (ASD), characterized by stereotypic behavior and impaired social interaction, is reported in 93% of children with ADNP-related HVDAS. Children have a strong sensory interest (sensory processing disorder). A high pain threshold is common.

Additional behavior problems may include anxiety, obsessive-compulsive disorder, aggressive behavior, temper tantrums, attention-deficient/hyperactivity disorder, and sleep problems.

Characteristic facial features include a prominent forehead, high anterior hairline, ptosis, downslanted palpebral fissures, prominent eyelashes, wide and depressed nasal bridge, short nose with full, upturned nasal tip, a long philtrum, thin vermilion of the upper lip, widely spaced teeth, pointed chin, and ear abnormalities including small, low-set ears and protruding cup-shaped ears.

Gastrointestinal/feeding. Feeding difficulties and gastrointestinal problems are common, including decreased sucking or chewing, swallowing problems, gastroesophageal reflux disease, lack of satiation, frequent vomiting, respiratory aspirations, and constipation. Some individuals required a gastrostomy tube.

Vision issues. More than half of affected individuals have visual problems, most commonly hypermetropia or strabismus. Forty-one percent have cortical visual impairment. Ophthalmologic defects are diverse: ectropion, coloboma, congenital cataracts, nystagmus, everted or notched eyelid, or mild ptosis.

Hand abnormalities are present, including clinodactyly and/or small fifth fingers, polydactyly, fetal fingertip pads, prominent interphalangeal joints and distal phalanges, a single transverse palmar crease, and nail anomalies.

Foot abnormalities include toe malformations, flat feet, and sandal gap.

Additional muscular skeletal features include joint laxity (38%), scoliosis, hip problems, pectus deformities (22%) such as pectus excavatum, pectus carinatum, or narrow thorax, or skull deformity (14%) including plagiocephaly, trigonocephaly, or brachycephaly. Metopic craniosynostosis was reported in two individuals.

Recurrent infections. Half of affected children (51%) have recurrent infections, including upper respiratory and urinary tract infections.

Endocrine manifestations include thyroid hormone abnormalities (15%, mainly hypothyroidism) and/or growth hormone deficiency. Some have signs of early pubertal development.

Growth. Birth weight, length, and occipitofrontal circumference are within the normal range. Several develop truncal obesity (8%). Twenty-three percent of affected individuals have short stature (height more than two standard deviations below the mean in individuals reported with age range of 2-23 years). Growth hormone deficiency is present in 11%.

Cardiac anomalies. Atrial septal defect is the most common (16%). Less frequent cardiac defects include patent ductus arteriosus, patent foramen ovale, mitral valve prolapse, ventricular septal defect, and other cardiovascular malformations.

Ear and hearing issues. Ear problems are reported in 32% of affected individuals. Hearing loss is present in 12% of individuals and is identified during early childhood. The majority of individuals with ear problems suffer from a narrow auditory canal (88%) and frequent otitis media (86%). Seventy-three percent of these individuals have pressure equalization tubes.

Seizures. Some children have seizures including absence seizures, focal seizures with reduced awareness, and epilepsy with continuous spike and waves during slow-wave sleep.

Brain imaging. Brain MRI revealed the following: underdevelopment of the frontal lobes with simplified gyral pattern of the cortex and occasional hypoplasia of the bulbus olfactorius and chiasma opticum; a thin and/or short, underdeveloped corpus callosum and inferior vermis hypoplasia; abnormal, often asymmetric opercularization of the sylvian fissure with sometimes abnormal overlying cortex; dilatation of the lateral ventricles, mostly in the frontal areas; and dilated perivascular spaces in the cerebral white matter.

Urinary tract anomalies include narrow ureters or bilateral vesicoureteral reflux.

Obstructive sleep apnea is reported in 7% of affected individuals.

Other. Submucous cleft palate was reported in one individual.

Genotype-Phenotype Correlations

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 [Bend et al 2019, Breen et al 2020].

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. Neurodevelopmental problems are more common in individuals with a class 1 signature [Dingemans et al 2023].

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 [Van Dijck et al 2019].

Prevalence

The prevalence of pathogenic variants in ADNP is estimated at 0.17% of individuals with ASD (95% binomial confidence interval: 0.083%-0.32%). It is one of the most commonly known single-gene causes of ASD [Helsmoortel et al 2014].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADNP-related HVDAS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment is symptomatic; no specific therapy is available. Routine medical care by a pediatrician or primary care physician is recommended.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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. These alterations involve the upregulation of immune and inflammatory processes and the downregulation of RNA processing and metabolic functions. Notably, these gene expression changes were transient, returning to baseline within 24 hours to one week post infusion. These findings enhance our understanding of ketamine's molecular impact and may inform future therapeutic strategies for ADNP-related HVDAS [Buxbaum Grice et al 2024].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

ADNP-related Helsmoortel-Van der Aa syndrome (also referred to as Helsmoortel-Van der Aa syndrome [HVDAS]) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with ADNP-related HVDAS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo ADNP pathogenic variant.
• In two families reported to date, probands diagnosed with ADNP-related HVDAS inherited a pathogenic variant from an unaffected parent [Van Dijck et al 2019].
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo constitutional or postzygotic pathogenic variant [Mohiuddin et al 2022, D'Incal et al 2023].
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for an ADNP pathogenic variant may theoretically be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Sib recurrence of ADNP-related HVDAS has not been reported to date.
• If the ADNP 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 possibility of parental gonadal mosaicism [Rahbari et al 2016]. Parental mosaicism has not been reported to date.
• If the parents have not been tested for the ADNP pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for ADNP-related HVDAS because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband. Individuals with ADNP-related HVDAS are not known to reproduce.

Other family members

• The risk to other family members depends on the genetic status of the proband's parents: if a parent has the ADNP pathogenic variant, the parent's family members may be at risk.
• Given that most probands with ADNP-related HVDAS reported to date have the disorder as a result of a de novo ADNP pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of an affected individual.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the ADNP pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Prenatal imaging (ultrasound and MRI). Intrauterine growth restriction (IUGR), proportionate microcephaly, abnormal skull shape, cranial abnormalities, and white matter changes were identified in a fetus subsequently found to have an ADNP pathogenic variant on genomic testing [Rosenblum et al 2023]. Although short stature is frequently observed postnatally, IUGR and proportionate microcephaly not commonly associated with ADNP-related HVDAS and prenatal anomalies are rarely reported. Most diagnoses are established after birth.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ADNP contains six exons, the last three of which are translated. The protein, activity-dependent neuroprotector homeobox protein (ADNP), contains nine zinc fingers and several other functional domains, including the NAP motif, an eight-amino-acid neuroprotectant peptide (NAPVSIPQ) together with a bipartite nuclear localization signal (NLS), a DNA-binding homeobox domain, and an HP1-binding motif.

ADNP is a vasoactive intestinal peptide (VIP)-responsive gene. VIP, a neuroprotective peptide, is active during embryonic development, in particular during the time of neuronal tube closure. It protects damaged nerve cells from cell death by inducing glia-derived, survival-promoting substances [Helsmoortel et al 2014].

ADNP pathogenic variants cause ADNP-related Helsmoortel-Van der Aa syndrome (HVDAS) by disturbing several important biological processes that are critical for normal brain development and function. One of the central processes involves defects in chromatin remodeling, leading to widespread abnormalities in DNA methylation across the genome. These epigenetic changes affect genes critical for cytoskeletal organization, synaptic transmission, nervous system development, calcium binding, and WNT signaling pathways. This leads to defective neurogenesis and contributes to some of the characteristic clinical features, such as motor problems and learning difficulties. In addition, ADNP pathogenic variants affect the autophagy pathway, indicating impaired cellular homeostasis, which can contribute both to neurodevelopmental abnormalities. Overall, pathogenic variants in ADNP lead to problems in brain wiring, nerve communication, and cellular maintenance, which together result in the combination of intellectual disability, autism spectrum disorder, and other medical issues observed in children with ADNP-related HVDAS [D'Incal et al 2023, D'Incal et al 2024c].

Mechanism of disease causation. The mechanism of disease causation is not yet fully understood. ADNP-related HVDAS is caused by de novo pathogenic variants in ADNP. Most ADNP pathogenic variants are nonsense or frameshift variants in the last coding exon, exon 6, that lead to predicted protein truncation and have been demonstrated to escape nonsense-mediated decay [Helsmoortel et al 2014, Van Dijck et al 2019]. It is likely that most individuals produce some abnormal protein. Although mutated protein was undetectable in affected individuals, the possibility of a toxic gain-of-function effect cannot be ruled out [Vandeweyer et al 2014, Ganaiem et al 2022, Karmon et al 2022, D'Incal et al 2024b]. A splice acceptor site pathogenic variant in one individual resulted in the absence of a truncated protein, indicating haploinsufficiency as the molecular mechanism underlying the variant [D'Incal et al 2024a].

Author Notes

The Medical Genetics of the Faculty of Pharmaceutical, Biomedical, and Veterinary Sciences of the University of Antwerp research group's mission is to identify genetic causes of cognitive disorders and study the molecular defects in order to eventually develop rational therapy.

Dr Anke Van Dijck (eb.neprewtnau@kcjidnav.ekna) is actively involved in clinical research regarding individuals with ADNP-related Helsmoortel-Van der Aa syndrome (HVDAS). Dr Van Dijck would be happy to communicate with persons who have any questions regarding diagnosis of ADNP-related HVDAS or other considerations.

Contact Dr Van Dijck to inquire about review of ADNP variants of uncertain significance.

Acknowledgments

We thank the families with individuals affected by an ADNP pathogenic variant who are participating in our research programs.

Author History

Claudio Peter D'Incal, PhD (2025-present)
Lusine Harutyunyan (2025-present)
Céline Helsmoortel, MSc; University of Antwerp (2016-2021)
R Frank Kooy, PhD (2016-present)
Anke Van Dijck, MD, PhD (2016-present)
Geert Vandeweyer, PhD (2016-2025)

Revision History

• 21 August 2025 (sw) Comprehensive update posted live
• 15 April 2021 (sw) Comprehensive update posted live
• 7 April 2016 (bp) Review posted live
• 18 December 2015 (avd) Original submission

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