8q21.11 Microdeletion Syndrome

8q21.11 microdeletion syndrome encompasses heterozygous overlapping microdeletions on chromosome 8q21.11 resulting in intellectual disability, facial dysmorphism comprising a round face, ptosis, short philtrum, Cupid's bow and prominent low-set ears, nasal speech and mild finger and toe anomalies.

Epidemiology

The prevalence is unknown but 8q21.11 microdeletion syndrome is rare. To date, 13 cases, of which 5 from the same family, have been clinically and molecularly characterized without a notable gender discrepancy.

Clinical description

Very frequent facial anomalies in patients with 8q21.11 microdeletions include a round face with full cheeks, ptosis, short philtrum, small mouth with downturned corners and a Cupid's bow of the upper lip, low-set and prominent ears and nasal speech. Mild to moderate intellectual disability is present in all affected individuals. Mild finger and toe anomalies such as camptodactyly, syndactyly of the 3rd and 4th fingers, and broadening of the first rays are relatively common. Most also suffer from hypotonia. Other features comprise a high forehead, short palpebral fissures, wide nasal bridge, underdeveloped alae, micrognathia, short neck, hearing loss and ophthalmic manifestations including strabismus, sclerocornea and microphthalmia.

Etiology

The syndrome is caused by a heterozygous deletion at chromosome region 8q21.11, reported in the majority of patients. The constant microdeletion overlap region contains the ZFHX4 gene, a microRNA gene of unknown function, as well as a pseudogene and in 7 cases heterozygous deletions of PEX2 were noted. Microdeletions appear de novo or are inherited from affected parents in an autosomal dominant manner.

Diagnostic methods

Diagnosis is based on clinical manifestations leading to cytogenetic analysis. The 8q21.11 microdeletion can be detected using a range of molecular techniques including array based comparative genomic hybridization (array CGH) and fluorescence in situ hybridization (FISH).

Differential diagnosis

Differential diagnosis includes Schilbach-Rott syndrome, auriculo-condylar (question mark ear) syndrome, Frydman syndrome, Kabuki syndrome (see these terms). The syndrome also bares resemblance with distal 22q11.2 microdeletion syndrome and 10p13 microdeletion syndrome. The entity should not be confused with the 8q22.1 microdeletion (see this term) found in patients with Nablus mask-like facial syndrome.

Antenatal diagnosis

Antenatal diagnosis of 8q21.11 microdeletion is possible by amniocentesis or chorionic villus sampling and cytogenetic analysis. Preimplantation genetic diagnosis should be available for at risk couples.

Genetic counseling

Cytogenetic testing and genetic counseling should be offered to parents of affected individuals, informing them of the 50% risk of recurrence. Although the 8q21.11 microdeletion occurs sporadically, most deletions appearing de novo, a small number of patients have been inherited from affected parents.

Management and treatment

Management involves assessment, developmental therapies and a regular follow-up by a primary care physician and if required by appropriate specialists. Affected children almost invariably need special education. Early diagnosis and access to therapies with attention to speech and language, motor development and cognition are recommended.

Prognosis

Prognosis depends on clinical features. Adult affected individuals, despite their learning difficulties specifically regarding abstract thinking and planning ahead, function normally in everyday life. Fertility and life expectancy does not seem to be reduced.