ADNP Syndrome, Helsmoortel-Van Der Aa Syndrome

Although researchers have established a clear syndromic presentation with characteristic or “core” symptoms associated with pathogenic variants in the ADNP gene, much about the disorder is not fully understood. Several factors have impeded the identification of a complete picture of the associated symptoms and prognosis?; these include the small number of identified children, the lack of large clinical studies, a lack of understanding of moderating effects of genetic background, and the presence of additional gene variants, or environmental contributions. Therefore, it is important to note that every child is unique and that affected individuals may not have all of the symptoms discussed below.

Many infants (78%) present with hypotonia and, thus, can appear abnormally “floppy.” Cerebral imaging shows structural brain abnormalities in slightly over half of the patient population (56%). Other neurological problems may exist. Individuals with ADNP syndrome may develop seizures (16%). Many parents report absent seizures as infants along with breath-holding episodes. Reported brain abnormalities include wide ventricles (29%), cerebral atrophy? (18%), delayed myelination (9%), and white matter lesions (8%). Approximately 50% of children with ADNP syndrome have had one or more episodes of developmental regression of speech.

Hypotonia and oral movement problems such as oral motor apraxia and oral motor dyspraxia (oral motor dysfunction) are often seen together in children with ADNP syndrome. This contributes to causing the majority of infants to experience feeding difficulties (83%). Poor sucking or chewing ability may occur in infancy. Swallowing problems may also be seen and there can be a risk of food or drink ending up in the lungs (aspiration). Some children who have difficulties with feeding may benefit from thickened liquids and some may require a feeding tube for nutrition.

Missed milestones such as delays in sitting and holding up one’s head are seen in infancy and children have mild to severe global developmental delays. Walking independently is often delayed until a few years later in childhood and children may have an unusual manner of walking (abnormal gait). Most children experience mild to moderate global motor planning delays. As they age, they will exhibit mild to severe intellectual disability. There are often delays in developing speech. Some children may not be able to speak, while others speak a few words or in short sentences. Apraxia or other oral motor disorders specifically affecting the tongue appear to cause the most difficulty in the majority of non-verbal children.

Children with ADNP syndrome in their younger years tend to be easily amused and have a happy demeanor similar to Angleman syndrome. This often delays the diagnosis? of behavior disorders such as autism even when the child displays many autistic features early in life. Sleep disorders can also occur, including sleep apnea, frequent waking throughout the night as well as early waking. There may be bladder training delays.

The majority of affected children may meet the criteria for autism spectrum disorder and may exhibit poor social interaction and mild to severe repetitive (stereotypic) behaviors such as repetitive speech, rocking back and forth, hand flapping, hand-clapping, rubbing fingers, or snapping fingers (93%). The majority of children with ADNP syndrome seek direct “adult” interaction. Specifically, at a very young age, they appear to enjoy direct social interactions with adults and often smile, laugh, and make eye contact. This is atypical for autism but it is very typical for ADNP syndrome. This often delays the autism diagnosis? even when the child displays many autistic features at a young age.

Sensory sensitivities, interests, and aversions (resulting in both seeking and avoiding sensory stimuli) are often seen (67%), with oral sensory seeking behaviors most prevalent. Because of this, children tend to lick their hands or other objects often, chew on non-edible items, gag, and put objects in their mouths. They often have an obsession with music and water play. They also tend to place tablets and other lit objects or devices directly in front of their eyes for stimulation.

In addition to autism and sensory sensitivities and aversions, children may have a variety of behavioral issues including attention deficit hyperactivity disorder, obsessive-compulsive disorder, temper tantrums and aggression, mood disorders, and anxiety.

Children with ADNP syndrome often have a high pain? threshold (64%). Many parents report that their child does not seem to feel pain, some reporting fractures with no sign of uncomfortableness or distress. Low perception of pain in conjunction with communication issues can make it difficult for parents to know when their child has pain or an injury.

Gastrointestinal symptoms are common. Affected individuals can develop a backflow of stomach acids into the esophagus (gastroesophageal reflux). This has been reported as mild to severe. Some children require the placement of a feeding tube due to severe feeding problems. Episodes of chronic? constipation? and diarrhea? are seen in almost all children with ADNP syndrome. Other symptoms include cyclic vomiting?, delayed digestion, and irritable or inflammatory bowel conditions.
Some children as they grow past the toddler years have an abnormally increased appetite and have difficulties feeling full (hyperphagia), similar to Prader Willi syndrome. This can lead to excessive weight gain. Some children also develop an abnormally increased desire to drink water.

Some affected individuals may have congenital? heart defects (38%). Ventricle or atrial septal defect is a common heart defect in ADNP syndrome. Additional congenital heart defects that have been reported in ADNP syndrome include enlargement of the main artery that supplies oxygen-rich blood to the body (aorta), the abnormal location of the aortic arch on the right side of the body instead of the left (right aortic arch), an abnormally rapid heart rate (tachycardia?), and mitral valve prolapse. Affected individuals may also have an abnormal opening between the main artery of the lungs (pulmonary artery) and the aorta (patent ductus arteriosus), narrowing (stenosis?) of blood vessels of the pulmonary artery system (peripheral pulmonary artery stenosis), or tetralogy of Fallot, a specific combination of heart defects.

Affected individuals have distinctive facial features including a prominent forehead, high hairline, droopy eyelids (ptosis), thin upper lip, broad nasal bridge, malformed ears, and eyes that are farther apart than normal (hypertelorism), and crossed eyes (strabismus). Affected individuals may see objects that are farther away clearer than they see objects that are close up (farsightedness or hypermetropia). Cortical vision impairment has also been reported in multiple affected children.

Some infants experience early eruption of their baby (deciduous or primary) teeth, showing a full set of baby teeth by the first birthday, including molars. To date, this has not been reported in any other known syndrome making it potentially unique to ADNP syndrome. The teeth may be abnormally small, jagged, and discolored. Because of early tooth eruption, some children develop tooth decay as toddlers due to the decrease in enamel.

Some affected individuals have underdeveloped (hypoplastic) fingernails and toenails, extra fingers or toes (polydactyly), and abnormally small pinkies that are fixed or ‘locked’ in a bent position (clinodactyly). Certain joints of fingers may be abnormally prominent.

Additional symptoms include abnormally loose (lax) joints that have a larger range of motion than normal (hyperlaxity), abnormal sideways curvature of the spine (scoliosis), and recurrent infections, especially upper respiratory and urinary tract. These recurrent infections may indicate an underlying problem with the immune system. Some children exhibit growth delays and will be shorter than expected for their age and gender (short stature). Some children have tended to develop truncal obesity, in which the trunk of the body is affected as opposed to the arms and legs. There have also been reports that some children have difficulty regulating their body temperature and many have cold feet and hands. Parents also report that children spike fevers extremely fast.

Clinical findings

• Severe speech and motor delay
• Mild-to-severe intellectual disability
• Autism spectrum disorder, additional behavioral problems, and sleep disturbance
• Characteristic facial appearance includes a prominent forehead, high anterior hairline, down slanted 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.
• Feeding difficulties and gastrointestinal problems (e.g., gastroesophageal reflux disease, lack of satiation, frequent vomiting?, constipation?)
• Vison issues (e.g., strabismus, cortical visual impairment, hypermetropia) and various ophthalmologic defects
• Musculoskeletal anomalies (e.g., joint laxity, hand and foot anomalies, pectus deformities, plagiocephaly)
• Other features: endocrine manifestations, cardiac and renal? anomalies, hearing loss, seizures, recurrent infections