Mosaic trisomy 8 (ORPHA:96061)
A rare autosomal anomaly defined by the presence of three copies of chromosome 8 in some cells of the body, and clinically characterized by facial dysmorphism, typically deep palmar and plantar creases, mild intellectual deficit and joint, urinary, cardiac and skeletal anomalies.
Epidemiology
Historically, the birth prevalence was estimated between 1/25,000-50,000 but supporting epidemiological studies are lacking. Males are more frequently affected than females (sex-ratio 4:1).
Clinical description
Facial dysmorphic features are mild and include elongation of the skull (scaphocephaly), prominent forehead, hypertelorism, deeply set eyes (50%), bulbous upturned nose (60%), micrognathia (with everted lower lips), large dysplastic ears with prominent anthelices and large lobules. Additional features include: agenesis of the corpus callosum, highly arched or cleft palate (8%), short and broad neck, tall stature, elongated narrow chest, shoulders and pelvis. Urinary (hydronephrosis, ureteral reflux), and cardiac and large vessels abnormalities are frequent (40% and 25% respectively). Camptodactyly (70%), arthrogryposis of the joints (aggravating with time), deep palmar (in infants) and plantar furrows (75%), absent or hypoplastic patellae, vertebral malformations (65%: segmentation anomalies, costal anomalies, scoliosis), epilepsy, as well as corneal opacity and strabismus are also commonly observed. Most individuals present a mild-to-moderate intellectual disability (IQ between 50 and 75), with some patients having normal intelligence. Usually speech is more delayed than other developmental domains. There is no correlation between the percentage of trisomic cells and the severity of the intellectual disability.
Etiology
Mosaic trisomy 8 is the result of a post-zygotic event (error in chromosome segregation during mitosis in a fetus having a normal karyotype or due to spontaneous correction of trisomy 8). Complete trisomy 8 is due to an error in chromosome segregation during meiosis and often results in miscarriage during the first trimester. When, exceptionally, the fetus survives, it presents the same phenotype as mosaic trisomy. Patients with isochromosome 8p (tetrasomy of the short arm (p) of chromosome 8) have the same phenotype as patients with trisomy 8p.
Diagnostic methods
Diagnosis is based on karyotype analysis or on detection of copy number variation by microarray or whole exome sequencing. In the latter case confirmation by karyotyping is recommended.
Differential diagnosis
Differential diagnosis includes non-specific syndromic intellectual disability.
Antenatal diagnosis
Prenatal ultrasound abnormalities (hydronephrosis, corpus callosum agenesis and increased nuchal fold) are occasionally observed. On the other hand, when mosaic trisomy 8 is detected without ultrasound abnormalities, this should be interpreted with care since confined placental mosaicism frequently occurs. Prenatal diagnosis should be considered in cases where one of the parents has a mosaic trisomy 8.
Genetic counseling
The origin of the mosaic trisomy 8 is either post-zygotic non-disjunction, i.e. a mitotic error in the fetus, or meiotic non-disjunction resulting in a full trisomy 8 karyotype with subsequently trisomy rescue by mitotic loss of a chromosome 8. Almost all cases occur sporadically, but genetic counseling should be offered to parents and the individuals themselves.
Management and treatment
Management requires a multidisciplinary approach. In some cases, cardiac surgery may be proposed.
Prognosis
Mosaic trisomy 8 seems to predispose to Wilms tumors, myelodysplasias and myeloid leukemia. Some mosaic trisomy 8 patients have had children. In absence of serious malformations, life expectancy is normal.

                            Last update: 
                            July 2021


                            - Expert reviewer(s): 
                            Pr C.M.A. [Conny] VAN RAVENSWAAIJ-ARTS | ITHACA*


                                * European Reference Network