DYRK1A-related intellectual disability syndrome (ORPHA:464306)
A rare genetic syndromic intellectual disability characterized by microcephaly, global developmental delay, mild to severe intellectual disability, impairment of speech, feeding problems, behavior problems (often autism spectrum disorder) and dysmorphic facial features (such as prominent ears, deep-set eyes, a short nose with a broad nasal tip, and retrognathia with a broad chin). Other, more variable manifestations include seizures, short stature, ocular anomalies, cardiac anomalies, urogenital anomalies and musculoskeletal defects.
Epidemiology
DYRK1A-related intellectual disability syndrome (DYRK1A syndrome) accounts for 0.1%-0.5% of individuals with intellectual disability and/or autism.
Clinical description
Developmental delay is observed at a young age and, usually, mild to severe intellectual disability later in life. An apparent speech/language delay is typical with understanding seemingly greater than verbal expression. Neonatal feeding problems (reflux, suck or swallowing problems) may occur and may persist into adulthood, warranting tube feeding in some individuals. Low weight and a slender build are common in later in life. Children have delayed motor development but most children learn to walk, sometimes with a broader gait. The motor skills may be hampered by hypertonia and, later in life the, occurrence of contractures. Many individuals have autism spectrum disorder and other behavior disorders (anxiety, hyperactivity or sleeping problems) are possible. Febrile seizures may develop during infancy and epilepsy may ensue thereafter. Eye abnormalities mainly include strabismus, astigmatism, and hypermetropia; other ocular anomalies have also been reported. More variable anomalies include cardiac defects (septal defects, hypoplastic left heart, valve abnormalities, aortic stenosis, and patent ductus arteriosus), urogenital anomalies (undescended testes, hypoplastic scrotum, shawl scrotum, micropenis, hypospadias, inguinal hernia, frequent urinary infections, vesicoureteral reflux, and unilateral renal agenesis) and, less frequently, dental anomalies. Most children have overlapping physical characteristics such as short stature, microcephaly, prominent ears, deep-set eyes, a short nose with a broad nasal tip, and retrognathia with a broad chin. Brain imaging may be indicative of global cerebral underdevelopment or hypomyelination.
Etiology
DYRK1A syndrome can be caused by a single nucleotide variant in the DYRK1A gene (21q22.13) or due to a chromosome 22q22.13 (micro)deletion including the DYRK1A gene.
Diagnostic methods
The disorder may be suspected on clinical presentation and diagnosed with molecular genetic testing. Chromosomal microarray analysis may detect chromosome 21q22.13 deletions including DYRK1A. Pathogenic DYRK1A single nucleotide variants may be detected by sequencing of the DYRK1A gene (most often by a multigene panel using whole exome sequencing or genome sequencing).
Differential diagnosis
There is a broad differential diagnosis including syndromes with primary microcephaly and absence/delay of speech development.
Antenatal diagnosis
Signs and symptoms of DYRK1A syndrome may be visible during the third trimester of pregnancy showing urogenital anomalies, cardiac anomalies and/or microcephaly. However, the absence of ultrasound anomalies does not exclude this disorder. Genetic antenatal testing is not applicable as mutations occur de novo.
Genetic counseling
To date, all reported cases, whose parents have undergone genetic testing, have occurred de novo suggesting a low recurrence risk (<1% due to risk of germline mosaicism). Penetrance is likely to be 100%. The course of the syndrome is similar in males and females.
Management and treatment
Regular follow-up is recommended by a pediatrician or a doctor specialized in the care for people with an intellectual disability, preferably in consultation with other specialties in a multidisciplinary setting. These may include a speech therapist, rehabilitation doctor, physiotherapist, occupational therapist and/or dietician. In case of epilepsy, the referral to a neurologist is required. After diagnosis, cardiac evaluation and periodical ophthalmological check-ups are required. In case of behavioral problems, a (child) psychiatrist can be involved in the treatment.
Prognosis
Based on current data, life expectancy is not limited in affected individuals as several adults have been reported. Data on possible progression of behavior abnormalities or neurologic findings are still limited.

                            Last update: 
                            April 2021


                            - Expert reviewer(s): 
                            Dr B.M.W. [Bregje] VAN BON | ITHACA*


                                * European Reference Network