Guidelines on Hereditary Leukodystrophies
Chromosome 18q deletion syndrome (OMIM#601808)
Disease description: Chromosome 18q deletion syndrome is a chromosomal abnormality caused by the deletion of qter from q21 on the long arm of chromosome 18. The loss of the myelin basic protein (MBP) gene, which is located in the 18q23 deleted region, is responsible for the congenital cerebral leukodystrophy seen in chromosome 18q deletion syndrome. Pathologically, it resembles demyelination. In addition to hearing impairment and cerebral white-matter abnormalities, it also involves other symptoms due to the chromosomal deletion.
Treatment: Mainly symptomatic care and rehabilitation.
1. Overview
Definition
Chromosome 18q deletion syndrome, a chromosomal abnormality caused by the deletion of qter from q21 on the long arm of chromosome 18, was first described in 1964. The loss of MPB, which maps to 18q23 (74.69–74.84 Mb from 18 pter), causes congenital cerebral leukodystrophy due to haploinsufficiency due to deletion. Patients with chromosome 18q deletion syndrome in which the deleted region of 18 qter does not contain MBP do not exhibit congenital cerebral leukodystrophy.
Epidemiology
Over 300 cases have been reported to date. This disease is believed to occur in approximately 1 in 40,000 births with a male/female ratio of 0.71.
Etiology and pathophysiology
Clinical symptoms are caused by haploinsufficiency of the genes deleted from 18q and are severe if the deleted region is large. TCF4, the causative gene of Pitt-Hopkins syndrome, is also located on 18q21.2, so patients' facial features resemble those seen in Pitt-Hopkins. Dysmyelination is a common finding that is believed to be due to MBP haploinsufficiency (Gay et al. 1997). However, the association between dysmyelination and intellectual delay is unclear. There are few clear correlations between symptoms and deleted regions other than MBP, and cases of wide intrafamilial variation in symptoms have been reported. Epilepsy may also be present.
The possibility of demyelination in chromosome 18q deletion syndrome has been raised. As progressive gliosis occurs, the process should perhaps be termed demyelination rather than dysmyelination (Tanaka et al., 2012). Tada & Talanashi (2014) and Tassano et al. (2016) also identified gliosis. MBP haploinsufficiency is correlated with hearing impairment. However, since no actual cases of nonsense mutations or truncating variants of MBP have been reported, whether it is actually directly implicated in myelination is unknown.
Clinical symptoms
Facial features include midfacial hypoplasia, non-prominent philtrum, everted lower lip, and a thin upper lip. The eyes appear deeply set. Congenital heart defects are present in more than 1 in 4 cases. Scoliosis, kyphosis, and other spinal abnormalities also occur. Other skeletal abnormalities include clinodactyly of the 5th finger, club foot, and coxa valga. Hypospadias is present in 25% of boys, while cleft lip and palate occur in approximately 10% of both boys and girls. Sensorineural or mixed hearing loss is present, and a range of ophthalmic abnormalities may also occur. Hypothyroidism is also present. Intellectual delay is usually severe, and a large number of autistic spectrum elements are present in behavior.
Imaging and other investigations
Deletion of the terminal of the long arm from 18q21 is confirmed by the chromosome G-band staining method. However, cerebral white-matter abnormalities are not apparent if the 18qter region sub-telomere region does not include MPB. Microdeletions are confirmed by chromosomal microarray analysis. In either case, it should be confirmed cytogenetically that the region of 18q23 including MPB was lost. Dysmyelination is demonstrated by cranial MRI.
2. Treatment and care
Treatment consists mainly of symptomatic therapies. An early definitive cytogenetic diagnosis is important. During infancy, encourage demand by parents and provide regular medical management. Special-needs rehabilitation is also important. Care should be taken for hearing examinations. If congenital heart defects or cleft lip and palate are also present, their treatment should be prioritized. The possibility of attending school should be considered in light of the environment and the capacity of the affected individual.
3. Diet and nutrition
If cleft lip and palate is also present, measures such as eating training should be considered.
4. Prognosis
An individual’s long-term prognosis depends on the nature of the comorbidities present. Although little accurate information is available, the prognosis for survival is not necessarily poor as long as comorbidities are stable and controlled.
5. Differential diagnosis
Numerous other chromosomal abnormalities. Facial features in particular are easily confused with those of individuals with Down syndrome.
Other dysmyelinating disorders.
6. Recent topics
None in particular.
References (All are evidence level 6.)
- Gay CT, Hardies LJ, Rauch RA, Lancaster JL, Plaetke R, DuPont BR, Cody JD, Cornell JE, Herndon RC, Ghidoni PD, Schiff JM, Kaye CI, Leach RJ, Fox PT. Magnetic resonance imaging demonstrates incomplete myelination in 18q- syndrome: evidence for myelin basic protein haploinsufficiency. Am J Med Genet 1997; 74(4): 422-431.
- Tada H, Takanashi J. MR spectroscopy in 18q(-) syndrome suggesting other than hypomyelination. Brain Dev 2014; 36(1): 57-60.
- Tanaka R, Iwasaki N, Hayashi M, Nakayama J, Ohto T, Takahashi M, Numano T, Homma K, Hamano K, Sumazaki R. Abnormal brain MRI signal in 18q syndrome not due to dysmyelination. Brain Dev 2012; 34: 234-237.
- Tassano E, Severino M, Rosina S, Papa R, Tortora D, Gimelli G, Cuoco C, Picco P. Interstitial de novo 18q22.3q23 deletion: clinical, neuroradiological and molecular characterization of a new case and review of the literature. Mol Cytogenet 2016; 9: 78.
Literature search
PubMed
- “18q deletion” AND “MBP”
19 results - “MBP” AND “leukodystrophy”
15 results
