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A rare, genetic, syndromic intellectual disability disorder characterized by craniofacial features, global developmental delay, intellectual disability and variable neurobehavioral abnormalities (autism spectrum disorder, aggressiveness, and self-injury). Additional features include vision abnormalities and variable sensorineural hearing loss, as well as short stature, hypotonia and gastrointestinal manifestations (e.g. poor feeding, gastroesophageal reflux, constipation).
ORPHA:468678Classification level: Disorder
- Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal dominant
- Age of onset: Neonatal, Infancy, Antenatal
- ICD-10: -
- OMIM: 616364
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
About 50 patients have been reported in the literature to date. Some researchers estimate that this syndrome may account for up to 1/700 cases of intellectual disability associated or not with autism spectrum disorder.
Presentation may be with neonatal hypotonia or developmental delay during infancy. The main features observed in these patients are developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities (including autism spectrum disorder). Most individuals have been described with mild to moderate ID; but the spectrum ranges from low-normal intelligence to severe ID. Some mild cerebral malformations can be found. Common craniofacial characteristics include microcephaly, high and broad forehead, midface hypoplasia or retrusion, tented or triangular mouth with downturned corners of the mouth, a broad nasal root and flat nasal bridge. Additional features may include hypotonia, seizures, sleep apnea, sensorineural hearing impairment, visual defects (strabismus, refraction errors), tendency to be overweight, short stature and gastrointestinal difficulties.
The disorder is caused by heterozygous pathogenic variants in POGZ. POGZ gene mutations are thought to impair the ability of the POGZ protein to bind to chromatin.
Diagnosis is usually made by gene panels or exome/genome sequencing in the absence of distinctive features.
The differential diagnosis includes numerous syndromes with developmental disorders as a feature.
Prenatal diagnosis can be considered in cases with an affected parent with a 50% recurrence risk, and in couples with a de novo mutation in a first child for a 1% recurrence risk limited to the risk of germline mosaicism.
The disorder usually occurs sporadically due to de novo mutations in POGZ. The pattern of inheritance is autosomal dominant. Genetic counseling should be offered to affected individuals informing them of that there is a 50% risk of transmission to offspring, at each pregnancy. In couples with a de novo mutation in a first child, the recurrence risk is 1% due to the possibility of germline mosaicism.
Management and treatment
Following the initial diagnosis, a comprehensive physical and neurologic examination, genetics consultation, and developmental/behavioral evaluation should be completed if they have not already been done. Careful neuropsychological evaluation should include intellectual quotient with or without verbal working memory, speed of treatment, attention, divided attention, planning and cognitive flexibility, theory of mind, communication, and executive function. Autism evaluation can be proposed in patients with suspicion of autism spectrum disorder. Follow-up of children by a developmental pediatrician, neurologist, or psychiatrist is required in order to propose appropriate therapies (e.g. physical therapy, occupational therapy, speech therapy, behavioral therapy) and individualized education plans. Methylphenidate can be proposed in patients with attention deficit disorders.
There is currently no data on life expectancy but there is no known complication that could lead to early death. The quality of life and functional consequences are variable, and are highly dependent of the severity of neuropsychological problems and the timing of therapeutic management and education plans. Some individuals are able to live independently whilst others will require significant support.
- Clinical genetics review
- English (2021)