Terminal deletion of 1p36.

Mental retardation affects 2–3% of the population, and although its cause is often unknown, chromosome abnormalities account for about 20% of cases. One such abnormality is deletion of the most distal (telomeric) band of the short arm of chromosome 1. The prevalence of this deletion (1p36) is estimated to be 1 in 5000, making it the most common terminal deletion. In 1997, a large group of patients with this deletion was studied. The researchers noted that the individuals had distinct facial features and an identifiable set of clinical symptoms. This information allows experienced doctors to recognise the syndrome. However, tests are also needed to confirm the diagnosis. Improved techniques in cytogenetics, such as fluorescence-in-situ hybridisation (FISH), have helped to identify submicroscopic or difficult to visualise chromosome deletions at the cytogenetic level. The 1p36 band, for example, does not show up very clearly with cytogenetic banding techniques and, in the past, about half of our patients had apparently normal chromosome analyses. After identification of a 1p36 deletion in a child, both parents should receive genetic counselling and be tested with FISH probes to identify parental chromosome rearrangements. A parental translocation greatly increases the chances of having another child with a 1p36 deletion. Fortunately, few parents (about 6%) carry translocations because deletions seen in children are usually sporadic (not inherited). As well as distinct facial features (figure), most patients with a 1p36 deletion have mental retardation, and delayed growth. By doing systematic clinical investigations, we have found other medical problems in patients, such as hearing loss, seizures, hypothyroidism, heart defects, and orofacial clefting abnormalities. Most of these problems can be treated, but when left untreated can lead to further difficulties. Thus, doctors need to recognise the clinical problems early in the patient’s life, to provide maximum benefit of treatment. Clinicians, other caregivers, and parents should be made aware of potential medical problems associated with deletion of 1p36, so that they can monitor and treat difficulties as they arise. Disorders, such as hypothyroidism and hearing loss, have standard treatments. Recognition of developmental delay and other developmental issues, allows for early therapeutic intervention. However, treatment is not the same as cure. Most clinical manifestations arising as a result of deletion of 1p36 are probably caused by the absence of one copy of a dose-sensitive gene. Dosesensitive genes need two functional copies, one on each chromosome, if they are to work properly. Unfortunately, it is not possible to replace missing genes or chromosome segments at present. Unlike other common deletion syndromes, patients with a chromosome 1p36 deletion have different sized pieces of chromosome missing. Individual patients, therefore, might be missing different genes, resulting in phenotype variability. Interestingly, the severity of associated disorders varies, whereas physical features are remarkably similar in patients. The degree of mental retardation and the ability to acquire complex speech is somewhat, but not exclusively, dependent on deletion size. Thus, in general, those patients with larger deletions have more severe mental retardation than those with smaller missing segments. The parental origins of deletions have also been investigated. Most deletions affect the chromosome inherited from the mother (68%). However, there does not seem to be any clinical difference between children with deletions derived from either parental chromosome. It is noteworthy though, that individuals with deletions on their paternally inherited chromosome tend to have larger deletions than those with maternally derived deletions. The underlying mechanisms that cause chromosomes to break in this syndrome are unknown. By comparison of a patient’s phenotype with their genotype, researchers can start to define a region in which to search for candidate genes for specific features. For example, grouping patients based on whether or not they have hearing loss, and comparing the size of their deletions, might identify a gene for hearing loss. Searching for single genes on 1p36 that cause specific phenotypes has implications for individuals without deletion of 1p36 and only one feature of the syndrome. Now armed with information about which genes cause specific features, scientists can begin to develop new therapeutic strategies. These will not only benefit individuals with 1p36 deletions, but would also help those with mutations in single genes on 1p36. Child with monosomy 1p36 Note the small pointed chin, short palpebral fissures, epicanthal folds, deep-set eyes, and flat nasal bridge.