Dyrk1a-Related Intellectual Disability Syndrome

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2021-01-18
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Summary

Clinical characteristics.

DYRK1A-related intellectual disability syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder including anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies. The majority of affected individuals function in the moderate to severe range of intellectual disability; however, a few individuals with mild intellectual disability have been reported. About half of affected individuals develop epilepsy including atonic attacks, absences, and generalized myoclonic seizures. About half of affected individuals develop scoliosis, kyphosis, and/or pectus excavatum. About one third have short stature. Rarely, endocrine problems and dental, ophthalmologic, and/or cardiac anomalies are reported.

Diagnosis/testing.

The diagnosis of DYRK1A-related intellectual disability syndrome is established in a proband by identification of a heterozygous pathogenic variant in DYRK1A.

Management.

Treatment of manifestations: Educational programs to address the specific needs identified; speech therapy directed at improving communication skills; occupational therapy for feeding problems; physical therapy for hypertonic musculature and gait disturbances. Routine treatment of epilepsy under the care of a neurologist. Standard treatment for sleep disturbances, and other medical issues (e.g., orthopedic, endocrine, dental, cardiac, and ophthalmologic involvement).

Surveillance: Monitoring and guidance as needed for educational and behavior problems, complications of hypertonic musculature (e.g., scoliosis, gait disturbances). Regular lifelong attention to nutritional status, dental hygiene, heart (if a congenital anomaly is present), eyes, and vision.

Genetic counseling.

DYRK1A-related intellectual disability syndrome is inherited in an autosomal dominant manner. To date all affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a de novo DYRK1A pathogenic variant. When the DYRK1A pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs appears to be very low but is presumed to be greater than that of the general population because of the possibility of germline mosaicism. Prenatal testing for pregnancies presumed to be at increased risk for DYRK1A-related intellectual disability syndrome is possible.

Diagnosis

No formal clinical criteria exist for DYRK1A-related intellectual disability syndrome.

Suggestive Findings

DYRK1A-related intellectual disability syndrome should be suspected in individuals with the following:

  • Intellectual disability and/or autism spectrum disorders
    AND
  • Microcephaly (often present at birth or early infancy)
    AND
  • Two or more of the following features
    • Typical facial gestalt:
      • During infancy and childhood facial features include prominent ears, deeply set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin.
      • In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [van Bon et al 2016].
    • Neonatal feeding problems that may persist
    • Seizures
    • Hypertonia
    • Abnormal gait
    • Foot anomalies: mild cutaneous syndactyly of toes 2, 3, 4; hallux valgus; and short fifth toe

Establishing the Diagnosis

The diagnosis of DYRK1A-related intellectual disability syndrome is established in a proband by identification of a heterozygous pathogenic variant in DYRK1A (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of DYRK1A is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. Note: Two individuals with a de novo apparently balanced translocation with a breakpoint within DYRK1A have been reported [Møller et al 2008].
  • A multigene panel that includes DYRK1A and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes DYRK1A) fails to confirm a diagnosis in an individual with features of DYRK1A-related intellectual disability syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in DYRK1A-Related Intellectual Disability Syndrome

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
DYRK1ASequence analysis 331/33 4
Gene-targeted deletion/duplication analysis 52/33 6, 7
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Courcet et al [2012], O'Roak et al [2012], Redin et al [2014], Bronicki et al [2015], Deciphering Developmental Disorders Study Group [2015], Ji et al [2015], Ruaud et al [2015], van Bon et al [2016]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

These two intragenic deletions were reported by [van Bon et al 2011, Courcet et al 2012].

7.

Individuals reported to have larger deletions that include more genes in the 21q22 region have phenotypic features that overlap those of the DYRK1A-related intellectual disability syndrome described in this GeneReview [Oegema et al 2010, Valetto et al 2012].

Clinical Characteristics

Clinical Description

DYRK1A-related intellectual disability syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder including anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies [van Bon et al 2016].

Intellectual disability. The majority of affected individuals function in the moderate to severe range of intellectual disability; however, a few individuals with mild intellectual disability have been reported.

Several individuals show speech impairment with a lack of speech or the use of one to two word utterances only. In general, expressive language is more severely affected than receptive language.

Although some individuals achieve independent walking at the upper age limit of normal, the majority achieve walking after age two to three years. Motor development is often impaired by gait disturbances and hypertonia.

Behavioral phenotype. Autism spectrum disorders, stereotypies, anxious behavior, and sleep disturbances (difficulty falling asleep and awakening at night) have been observed [van Bon et al 2016].

Microcephaly, intrauterine growth restriction, and/or oligohydramnios may be noted prenatally. Low birth weight (<-2 SD) and microcephaly (<-2 SD) are frequently observed [Courcet et al 2012, Deciphering Developmental Disorders Study Group 2015, Ruaud et al 2015, van Bon et al 2016].

Facial gestalt. During infancy and childhood facial features include prominent ears, deeply set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [van Bon et al 2016].

Feeding problems due to gastrointestinal reflux and difficulties with suck and swallowing occur in the majority of infants. Feeding problems may persist during childhood and adulthood, warranting tube feeding in some affected individuals [van Bon et al 2016].

Seizures. Febrile seizures during infancy are common. About 50% of affected individuals develop epilepsy including atonic attacks, absences, and generalized myoclonic seizures [Courcet et al 2012, Bronicki et al 2015, Ji et al 2015, van Bon et al 2016].

Hypertonia. Generalized hypertonia may already be noted during the first months of life.

Gait disturbances. The majority are described as having a broad-based/ataxic gait [Ji et al 2015, van Bon et al 2016]. A stiff gait (possibly related to generalized hypertonia) has also been reported [Ji et al 2015].

Foot anomalies. A combination of mild cutaneous syndactyly of toes 2-4, hallux valgus, and a short fifth toe has been noted in several individuals [van Bon et al 2016].

Other

In about half of affected individuals scoliosis, kyphosis, and/or pectus excavatum has been reported.

Short stature (<-2 SD) is present in about one third of individuals. Onset may occur prior to birth or later in childhood [Bronicki et al 2015, Ji et al 2015, van Bon et al 2016].

Although no major structural brain anomalies have been reported, brain imaging may reveal enlarged ventricles, myelination delay, brain atrophy, and/or hypoplasia of the corpus callosum.

Endocrine problems (hypothyroidism, premature thelarche, and low growth hormone levels) have been reported in a few individuals [Ji et al 2015].

Dental anomalies, including widely spaced teeth, extreme calculus (hardened dental plaque), and supernumerary teeth have also been reported.

In a small number of individuals the following congenital defects have been observed:

  • Heart: aortic valve insufficiency, pulmonary valve abnormality, aortic stenosis and ventricular septal defect
  • Eye: astigmatism, hypermetropia, early cataract, iris coloboma and retinal detachment

Other anomalies (each reported in 1 individual only) include [van Bon et al 2011, Courcet et al 2012, Redin et al 2014, Deciphering Developmental Disorders Study Group 2015, Ji et al 2015, Ruaud et al 2015, van Bon et al 2016]:

  • Cleft of the soft palate
  • Breast aplasia
  • Micropenis
  • Sacral dimple
  • Inguinal hernia
  • Polydactyly
  • Tibial osteochondrosis
  • Hearing loss

Genotype-Phenotype Correlations

To date the number of published cases is insufficient to determine whether there is a true genotype-phenotype correlation based on the type of DYRK1A truncation.

Penetrance

Penetrance is likely to be 100% in individuals with a de novo pathogenic variant. Haploinsufficiency of DYRK1A has not been observed in control populations. Expressivity is similar in males and females [van Bon et al 2016].

Prevalence

In the following three studies, DYRK1A-related intellectual disability syndrome accounted for 0.1%-0.5% of individuals with intellectual disability and/or autism.

  • In 1,133 children with developmental disorders, six individuals with a DYRK1A pathogenic variant were identified [Deciphering Developmental Disorders Study Group 2015].
  • In 7,162 individuals with developmental delay and/or autism spectrum disorder, eight individuals with a DYRK1A pathogenic variant were identified [O'Roak et al 2012, van Bon et al 2016].
  • In 105 individuals with intellectual disability and at least two of the following – microcephaly, ataxic gait, and seizures – one individual with a DYRK1A pathogenic variant was identified [Courcet et al 2012].

Differential Diagnosis

Developmental delay, neonatal feeding problems, and microcephaly, the most frequent findings in the DYRK1A-related intellectual disability syndrome, have an extensive differential diagnosis.

Diagnoses that may be considered in individuals with findings suggestive of DYRK1A-related intellectual disability syndrome include:

  • Primary autosomal recessive microcephalies, a heterogeneous set of disorders. Onset of microcephaly before birth and short stature are common. In DYRK1A-related intellectual disability syndrome, microcephaly often develops before birth or in the first months after birth and intrauterine growth restriction is variable. The occurrence of additional findings should distinguish this syndrome from other disorders in which primary microcephaly occurs. (See ASPM Primary Microcephaly.)
  • Angelman syndrome. Microcephaly, seizures, and absence of speech are common in Angelman syndrome; however, the microcephaly in DYRK1A-related intellectual disability syndrome appears more severe than in Angelman syndrome [Courcet et al 2012]. In addition, in DYRK1A-related intellectual disability syndrome the EEG does not have a specific pattern like that observed in Angelman syndrome [Courcet et al 2012], and the facial gestalt and behavior differ.
  • MECP2 related disorders. Overlapping features may include speech impairment, epilepsy, microcephaly, growth retardation, stereotypic behavior, and feeding difficulties. Developmental regression is observed in classic Rett syndrome, but not in DYRK1A-related intellectual disability syndrome.
  • Mowat-Wilson syndrome (MWS). Similar to individuals with DYRK1A-related intellectual disability syndrome, individuals with MWS may present with moderate to severe intellectual disability, severe speech impairment, growth retardation with microcephaly, and seizures. MWS is more likely to be associated with a variety of malformations including Hirschsprung disease and genitourinary anomalies, which are not typically observed in DYRK1A-related intellectual disability syndrome.
  • Pitt-Hopkins syndrome. Features observed in both disorders include a similar level of intellectual disability, lack of speech, and seizures. Microcephaly may develop postnatally in Pitt-Hopkins syndrome. Episodic hyperventilation and/or breath-holding are not features of DYRK1A-related intellectual disability syndrome.
  • MBD5 haploinsufficiency syndrome may result in intellectual disability with severe language impairment, autism spectrum disorder, and seizures. Microcephaly is mainly noted in individuals with MBD5 haploinsufficiency due to larger 2q23.1 deletions including nearby genes.

See Mental retardation, autosomal dominant – OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of the disease and needs in an individual diagnosed with DYRK1A-related intellectual disability syndrome, the following evaluations are recommended:

  • Multidisciplinary developmental evaluation including speech/language evaluation focused on nonverbal language ability and related educational and teaching strategies
  • Sleep history and sleep evaluation if necessary
  • Feeding assessment in infants and young children to detect gastroesophageal reflux or suck/swallowing problems
  • Neurologic evaluation including brain imaging studies and EEG in individuals with microcephaly and/or seizures
  • Musculoskeletal examination for signs of hypertonia and spine curvature anomalies; orthopedic referral if needed
  • Physical therapy evaluation regarding interventions needed to achieve optimal ambulation
  • The following baseline evaluations:
    • Endocrine
    • Dental
    • Cardiac (for possible heart anomalies including valve, aorta and septal defects)
    • Ophthalmology
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment includes the following:

  • Ongoing routine medical care by a pediatrician or other primary care physician
  • Educational programs to address the specific needs identified; speech therapy directed at improving communication skills; introduction of sign language and augmentative communication aids such as picture cards, communication boards and/or computer touch screens as early as possible
  • Therapeutic management of sleep disturbances if necessary
  • Early intervention with occupational therapy for feeding problems; consideration of tube feeding for severe persisting feeding problems
  • Epilepsy treatment in accordance with standard practice under care of a neurologist
  • Early intervention with physical therapy for hypertonic musculature and gait disturbances. A wheeled walker may be useful for children with serious gait disturbances.
  • Standard treatment for orthopedic, endocrine, dental, cardiac, ophthalmologic, and other medical issues

Surveillance

The following are appropriate:

  • Monitoring and guidance as needed for educational and behavior problems
  • Regular lifelong dietary evaluation to assure optimal nutritional status
  • Monitoring for complications of hypertonic musculature such as scoliosis and the development of a stiff gait
  • Regular lifelong evaluations of the following:
    • Teeth: frequency determined by a dentist, based on the dental condition
    • Heart: based on the type of congenital anomaly. If no congenital cardiac anomaly is present, ongoing cardiac surveillance is not needed.
    • Eyes

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.