ADNP syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

ADNP syndrome is a condition that causes a wide variety of signs and symptoms. Its hallmark features are intellectual disability and autism spectrum disorder, which is characterized by impaired communication and social interaction. Affected individuals also have distinctive facial features and abnormalities of multiple body systems.

Individuals with ADNP syndrome have mild to severe intellectual disability and delayed development of speech and motor skills such as sitting and walking. Some affected individuals are never able to speak. People with this disorder exhibit characteristics typical of autism spectrum disorder, including repetitive behaviors and difficulty with social interactions. ADNP syndrome is also associated with mood disorders or behavioral problems, such as anxiety, temper tantrums, attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder, or sleep problems.

Many people with ADNP syndrome have distinctive facial features, which most commonly include a prominent forehead, a high hairline, outside corners of the eyes that point upward or downward (upslanting or downslanting palpebral fissures), droopy eyelids (ptosis), a broad nasal bridge, and a thin upper lip. These individuals may also have unusually shaped ears or hand and finger abnormalities. Eye and vision abnormalities, such as eyes that do not point in the same direction (strabismus) and farsightedness (hyperopia), also occur in ADNP syndrome. Some people with this condition have early appearance (eruption) of primary (baby) teeth.

Some people with ADNP syndrome have weak muscle tone (hypotonia) and feeding difficulties in infancy. They may also have digestive system problems, such as backflow of stomach acids into the esophagus (gastroesophageal reflux), vomiting, and constipation. Other features that occur in ADNP syndrome include obesity, seizures, and heart abnormalities.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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.

By regulating gene expression, the ADNP protein is involved in many aspects of growth and development. It is particularly important for regulation of genes involved in normal brain development, and it likely controls the activity of genes that direct the development and function of other body systems.

Although it is unclear how mutations in the ADNP gene affect ADNP protein function, researchers suggest that the mutations result in abnormal chromatin remodeling. Disturbance of this process alters the activity of many genes and disrupts development or function of several of the body's tissues and organs, including the brain. These changes likely explain the intellectual disability, autism spectrum disorder, and other diverse signs and symptoms of ADNP syndrome.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

ADNP syndrome is not inherited. It results from new (de novo) mutations in the ADNP gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. The condition occurs in people with no history of the disorder in their family.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The prevalence of ADNP syndrome is unknown. It is estimated to account for 0.17 percent of all cases of autism spectrum disorder, making it one of the most common genetic causes of this condition.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormality of speech or vocalization · Very frequent (99-80%)

An abnormality in the sound (volume) or cadence (rate) of speech.

Autistic behavior · Very frequent (99-80%)

Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.

Delayed speech and language development · Very frequent (99-80%)

A degree of language development that is significantly below the norm for a child of a specified age.

Global developmental delay · Very frequent (99-80%)

A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.

Reduced social responsiveness · Very frequent (99-80%)

A reduced ability to participate in the back-and-forth flow of social interaction appropriate to culture and developmental level, which is normally characterized by an influence of the behavior of one person on the behavior of another person. This results in difficulty interacting with others through emotional, physical, or verbal communication.

Urinary incontinence · Very frequent (99-80%)

Loss of the ability to control the urinary bladder leading to involuntary urination.

Abnormal temper tantrums · Frequent (79-30%)

Temper tantrums are brief episodes of extreme, unpleasant, and sometimes aggressive behaviors in response to frustration or anger, which are a normal part of development in toddlers. Temper tantrums that occur more frequently in a given time and/or are more severe in symptomatology and/or longer in duration and/or inappropriate for the given age compared to a temper tantrum that naturally occurs as a part of the developmental process are classified as abnormal temper tantrums.

Abnormality of brain morphology · Frequent (79-30%)

A structural abnormality of the brain, which has as its parts the forebrain, midbrain, and hindbrain.

Other findings in the same source

From: Orphanet

Additional reported features include Abnormality of finger (Frequent (79-30%)); Anxiety (Frequent (79-30%)); Attention deficit hyperactivity disorder (Frequent (79-30%)); Chronic constipation (Frequent (79-30%)); Compulsive behaviors (Frequent (79-30%)); Floppy infant (Frequent (79-30%)); Gastroesophageal reflux (Frequent (79-30%)); Joint hypermobility (Frequent (79-30%)); Moderate global developmental delay (Frequent (79-30%)); Polyphagia (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing ADNP syndrome is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for ADNP syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.