ADNP Syndrome, Helsmoortel-Van Der Aa Syndrome

ADNP syndrome, also known as Helsmoortel-Van Der Aa syndrome, is a neurodevelopmental genetic disorder caused by changes (mutations) in the ADNP gene. These mutations occur spontaneously in the majority (97%) of reported patients, meaning there has been no family history of the disorder (de novo mutations).

The hallmark features of the syndrome are intellectual disability, global developmental delays, global motor planning delays, and autism spectrum disorder or autistic features. Although ADNP syndrome was only discovered in 2014, it is projected to be one of the most frequent single-gene causes of autism.

The genetic changes that cause ADNP syndrome vary from person to person. The symptoms can also vary and can cause a wide range of medical, developmental, intellectual, and behavioral changes. The most common characteristics found in those with ADNP syndrome are developmental delays (100%), intellectual delays (100%), motor planning delays (96%) of varying degrees, delayed or absent speech (98%), and autism spectrum disorder including autistic features (93%). Autistic features in ADNP syndrome are quite similar and most children display a very happy demeanor similar to Angelman syndrome as infants and toddlers. Feeding and gastrointestinal problems (83%) are also very common. Additional symptoms are low or weak muscle tone in newborns and infants (hypotonia) (78%), neonatal/infant feeding disorders, sensory processing disorder, sleep disorder, high pain threshold, and additional symptoms and behavioral disorders of varying levels of severity.

The disorder can potentially affect multiple systems of the body including the brain, heart, immune system, gastrointestinal system, endocrine system, and musculoskeletal system. The specific signs and symptoms associated with the disorder can vary greatly from one individual to another but the majority of children exhibit distinctive facial features. Many infants (>80%) develop early primary tooth eruption and often have a happy disposition and unprovoked episodes of laughter and smiling. Parents report that approximately 50% of the children develop breathing irregularities (breath-holding episodes) and episodes of developmental regression of speech that are usually regained over time with intensive therapy.

Causes

ADNP syndrome is caused by a change (mutation) in the activity-dependent neuroprotective protein (ADNP) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

Researchers have determined that the ADNP gene produces a protein called activity-dependent neuroprotective protein that helps to regulate as many as 400 other genes in the body. These genes and the proteins they produce are extremely important for the proper development and maturation of the brain and other organs. Collectively, they are involved with almost every system of the body.

ADNP syndrome occurs most frequently as a new (sporadic or de novo) mutation, which means that in most reported patients, the gene mutation has occurred at the time of the formation of the egg or sperm/during embryonic development for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent; however, several hereditary cases have been reported, in most instances when the mutation is at the end of the protein, probably resulting in a very mild presentation of symptoms.

If a person with ADNP syndrome were to have a child, they could pass the altered ADNP gene on to their children through autosomal dominant inheritance. Genetic diseases are determined by the combination of genes for a particular trait that is on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary for the appearance of the disease. The mutated gene encoding a dysfunctional protein can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the mutated gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

Investigators have determined that the ADNP gene is located on the long arm (q) of chromosome 20 (20q12). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 20q12” refers to band 12 on the long arm of chromosome 20. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

ADNP syndrome is caused by mutations in the ADNP gene. The protein produced from this gene helps control the activity (expression) of other genes through a process called chromatin remodeling. Chromatin is the network of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling is one-way gene expression is regulated during development; when DNA is tightly packed, gene expression is lower than when DNA is loosely packed.

Related Disorders

Symptoms of the following disorders can be similar to those of ADNP syndrome. Comparisons may be useful for a differential diagnosis.

Phelan-McDermid syndrome (PMS) is a rare genetic condition caused by a deletion or other structural change of the terminal end of chromosome 22 in the 22q13 region or a disease-causing mutation of the SHANK3 gene. Although the range and severity of symptoms may vary, PMS is generally thought to be characterized by neonatal hypotonia, normal growth, absent to severely delayed speech, moderate to profound developmental delay, and minor dysmorphic features. Heart defects and autistic behaviors are also common in this disorder. (For more information on this disorder, choose “Phelan-McDermid” as your search term in the Rare Disease Database.)

Angelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delays and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although those with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional symptoms may occur including seizures, sleep disorders, and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database.)

Smith-Magenis syndrome (SMS) is a complex developmental disorder that affects multiple organ systems of the body. The disorder is characterized by a pattern of abnormalities that are present at birth (congenital) as well as behavioral and cognitive problems. Common symptoms include distinctive facial features, skeletal malformations, varying degrees of intellectual disability, speech and motor delays, sleep disturbances, and self-injurious or attention-seeking behaviors. The specific symptoms present in each patient can vary dramatically from one individual to another. Approximately 90% of cases are caused when a portion of the chromosome is missing or deleted (monosomic). This deleted portion within chromosome 17p11.2 includes the RAI1 gene, which is believed to play a major role in the development of the disorder. In the remaining cases, there is no deleted material on chromosome 17; these cases are caused by mutations in the RAI1 gene. Other genes within the deleted segment may also play a role in variable features in the syndrome, but it is not fully understood how significant a role they play in the development of SMS. (For more information on this disorder, choose “Smith-Magenis” as your search term in the Rare Disease Database.).

Coffin-Siris syndrome (CSS) is a rare genetic disorder that may be evident at birth. The disorder may be characterized by abnormalities of the head and facial area, resulting in a coarse facial appearance. Craniofacial malformations may include an abnormally small head (microcephaly); a wide nose with a low nasal bridge; a wide mouth with thick, prominent lips; thick eyebrows and eyelashes (hypertrichosis); and sparse scalp hair. In addition, affected infants and children typically have short fifth fingers and toes with underdeveloped (hypoplastic) or absent nails; other malformations of the fingers and toes; and eye abnormalities. Feeding difficulties and frequent respiratory infections during infancy, hypotonia, abnormal looseness (laxity) of the joints, delayed bone age, developmental delays, hearing loss, and intellectual disability may also be present. The specific symptoms and severity can vary among affected individuals. Mutations in five different genes, ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1, have been found to cause CSS. Researchers believe the disease can follow autosomal dominant inheritance in some families but usually appears to be the result of a new gene mutation in the affected child. (For more information on this disorder, choose “Coffin Siris” as your search term in the Rare Disease Database.)

Additional similar rare genetic disorders associated with developmental delays, intellectual disability, seizures, and other symptoms commonly found in individuals with ADNP syndrome include:

Rett syndrome
FOXG1 syndrome
FOXP1 syndrome
Fragile X syndrome
Prader-Willi syndrome
Pitt-Hopkins syndrome
Kleefstra syndrome
MECP2 duplication syndrome
CH2D-related neurodevelopmental disorders
15q duplication syndrome.

Symptoms

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

Diagnosis

A diagnosis of ADNP syndrome may be suspected based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Premature tooth eruption and abnormal tooth development when occurring along with developmental delays or intellectual disabilities and autism symptoms can also lead to a suspicion of ADNP syndrome.

The diagnosis of ADNP syndrome is confirmed by molecular genetic testing that can detect mutations in the ADNP gene. Testing for mutations in the ADNP gene is included in whole-genome sequencing.

Clinical Testing and Workup
Imaging techniques such as magnetic resonance imaging (MRI) may be used to aid in a diagnosis. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain can reveal distinctive changes including atypical white matter lesions, abnormally-wide, fluid-filled cavities called ventricles, and cysts within specific areas of the brain (choroid cysts). These findings alone are not sufficient for a diagnosis of ADNP syndrome.

An echocardiogram is a test that uses reflected sound waves to create images of the heart and can reveal structural heart defects associated with the disorder. An eye doctor will conduct a thorough, extensive eye examination to look for eye abnormalities that may be associated with the disorder.

Treatment

The treatment of ADNP syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, a physician who specializes in the diagnosis and treatment of disorders of the brain, nerves and nervous system in children (pediatric neurologists), neurologists, a physician who specializes in the diagnosis and treatment of disorders of the eye (ophthalmologists), a physician who specializes in the diagnosis and treatment of disorders of the gastrointestinal tract (gastroenterologist), a physician who specializes in the diagnosis and treatment of disorders of the heart in children (pediatric cardiologist), speech pathologist, physical therapist, occupational therapist, psychologist, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well.

Genetic counseling is recommended for affected individuals and their families.

There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with ADNP syndrome.

Infants with ADNP syndrome should be evaluated for feeding issues and treated with standard methods if necessary. Surgery may be necessary to treat certain complications associated with ADNP syndrome including cardiac defects. Eyeglasses or surgery may help with vision and other eye problems. Assistive and augmentative communication devices can help children express thoughts, wants, needs and ideas. Medications may be tried to treat seizures and certain neuropsychiatric conditions including sleep disorders or behavioral problems. Some children with sleep disorders have responded positively to melatonin treatment.

Affected children may benefit from occupational, physical, and speech therapy which should be done frequently due to difficulties in learning and motor planning. Some children require daily year-round therapy. Water and music therapy have also been beneficial for some affected children. ABA therapy has been beneficial for most affected children with autism. Additional medical, social, and/or vocation services including specialized learning programs may be necessary. Behavioral modification therapy may be useful, especially if self-injurious behavior is present.

Recommended Evaluations Following Initial Diagnosis in Individuals with ADNP-Related Disorder

System/Concern	Evaluation	Comment
Development	Comprehensive developmental assessment	To incl: motor, adaptive, cognitive, & speech/language eval; testing for ASD & ID; eval for early intervention / special education
Psychiatric/ Behavioral	Neuropsychiatric eval if behavioral problems are present	For persons age >12 mos: screen for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD.
Gastrointestinal/ Feeding	Gastroenterology / nutrition / feeding team eval	To incl eval of aspiration risk & nutritional status Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Vision	Ophthalmologic exam & vision assessment	Incl electrophysiologic & visual perception exam to detect cortical visual impairment
Musculoskeletal	Orthopedics / physical medicine & rehab / PT / OT eval	To incl assessment of: Gross motor & fine motor skills Joint hypermobility Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Growth	Measurement of growth parameters	To evaluate for growth deficiency, short stature, obesity
Endocrine	Assess for: Thyroid problems; Growth hormone deficiency in those w/short stature.
Cardiac	Echocardiogram
Hearing	Audiology eval; referral to ENT if indicated
Neurologic	Neurologic exam	Consider EEG if seizures a concern. To incl brain MRI to detect brain abnormalities
Urinary tract	Assess for frequent urinary tract infections
Immunology	Assess for recurrent infections
Genetic counseling	By genetics professionals ¹	To inform affected persons & their families re nature, MOI, & implications of ADNP-related disorder in order to facilitate medical & personal decision making
Family support/ resources	Assess: Use of community or online resources such as Parent to Parent; Need for social work involvement for parental support; Need for home nursing referral.

ADNP Syndrome, Helsmoortel-Van Der Aa Syndrome

Causes

Diagnosis

Treatment

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ADNP Syndrome, Helsmoortel-Van Der Aa Syndrome

Causes

Related Disorders

Symptoms

Diagnosis

Treatment

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