ADNP syndrome (ORPHA:404448)
A rare syndromic intellectual disability characterized by global developmental delay, gastrointestinal problems, hypotonia, delayed speech, behavioral and sleep problems, pain insensitivity, seizures, structural brain anomalies, dysmorphic features, visual problems, early tooth eruption and autistic features.
Epidemiology
The point prevalence of ADNP syndrome is approximately 1-2/100,000 individuals. The syndrome represents 0.17% of the autism spectrum disorder cases.
Clinical description
The ADNP syndrome phenotype includes intellectual disability (ID) of various severities, severely delayed speech including oral apraxia, behavioral problems (anxiety, obsessive compulsive disorder, aggressive behavior, temper tantrums, attention deficit hyperactivity disorder), motor development delays of various severities. ADNP patients have higher rates of ID but less severe social affect symptoms and high levels of stereotyped motor behaviors compared to high levels of restricted interests in idiopathic ASD. Other ADNP symptoms may include delayed toilet training, pain insensitivity, sleep problems, seizures, structural brain anomalies, distinct dysmorphic facial features, sensory problems including mostly visual problems, occasional hearing problems, autistic traits and hypotonia or in rare cases, hypertonia. Gastrointestinal problems are most frequently encountered. Congenital heart defects, short stature, skin cell deficiencies and hormonal deficiencies/abnormalities as well as recurrent infections are also apparent. About 80% of the children harboring ADNP mutations show early deciduous dentation.
Etiology
A single de novo ADNP mutation presumably occurs during the formation of the sperm/egg or during early embryonic development. The condition occurs in families with no history of the disease. Most frequent ADNP protein coding mutations include STOP or frameshift-STOP autosomal dominant mutations.
Diagnostic methods
Whole exome sequencing, or specific ADNP gene sequencing for mutation. Early deciduous tooth eruption (almost fully erupted dentition by 1 year of age).
Differential diagnosis
Some similarities are found with Okihiro syndrome plus developmental delay, Angelman syndrome, Rett syndrome, Noonan syndrome, Kleefstra syndrome, Smith-Magenis syndrome, and other Coffin-Siris syndrome related disorders.
Antenatal diagnosis
Prenatal testing and preimplantation genetic diagnosis (PGD) are possible options.
Genetic counseling
The ADNP syndrome is expressed in an autosomal dominant manner. Given that affected individuals were reported to have the disorder as a result of a de novo ADNP pathogenic variant, the risk to other family members is presumed to be low. C-terminal mutations were reported to be inherited, the severity of these mutations (if any) is yet to be explored.
Management and treatment
Routine symptomatic care by primary care professionals is recommended and includes: speech, occupational, and physical therapy, specialized individualized learning programs, treatment of neuropsychiatric features including sleep disorders, behavioral problems, and/or seizures. Nutritional/hormonal support, routine treatment of cardiac, ophthalmologic and auditory findings are also recommended.
Prognosis
With developmental delays, it is expected that children with ADNP syndrome will start walking and talking relatively late. Depending on the precise ADNP mutation, independent walking can be established at 3.5 years of age or later. Speech may be acquired even later. However, in longitudinal observations, progress is noticed over the years. To date, there is only a paucity of adults that are known to have the ADNP syndrome.

                            Last update: 
                            January 2019


                            - Expert reviewer(s): 
                            Pr Illana GOZES  - Pr Frank KOOY