Handbook of Genetic Counseling/1p36 Deletion Syndrome-2

1p36 Deletion Syndrome Introduction Mental retardation affects 2-3% of the population and chromosome abnormalities account for about 20% of cases Improved techniques in cytogenetics (FISH) have helped to identify submicroscopic deletions at the cytogenetic level Syndrome is characterized by distinct facial features, mental retardation, and delayed growth This condition is likely a contiguous gene deletion syndrome There is no uniform region of deletion but rather a spectrum of different deletion sizes with a common minimal region of deletion overlap Genotype/phenotype comparisons can help researchers to start to define a region in which to search for candidate genes for specific features Etiology of 1p36 deletion syndrome (monosomy 1p36) Caused by deletion of the most distal (telomeric) light band of the short arm of chromosome 1 Most clinical manifestations are probably caused by the absence of one copy of a dose-sensitive gene Patients with a 1p36 deletion have different sized pieces of the chromosome missing and may result in phenotype variability Mechanism causing chromosome breakage is unknown Severity of associated disorders varies, but the physical features are very similar Degree of MR and ability to acquire complex speech is somewhat dependent on deletion size Most deletions affect the chromosome inherited from the mother (68%), but there doesn't seem to be differences in the clinical manifestations based on whether the deletion is on the paternal or maternal chromosome. Those with paternally derived deletions tend to have larger deletions than those with maternally derived deletions Prevalence Prevalence of this deletion is estimated to be 1 in 10,000 to as high as 1 in 5,000 (making it the most common terminal deletion) Most cases result from sporadic deletions and are not inherited 1p36 deletion syndrome is usually diagnosed through recognition of the symptoms and characteristics as well as lab testing. This is done using high-resolution chromosome analysis or FISH with a chromosome 1-specific subtelomeric probe. The deletion often doesn't show up clearly with standard cytogenetic banding techniques. Characteristics Children with 1p36 deletion syndrome are all unique individuals, but do have some common characteristics. Distinct facial features including: Large anterior fontanel (~100% of patients) Small and pointed chin (~80%) Flat nasal bridge (~65%) Clinodactyly and/or short fifth finger (~64%) Low-set ears, ear asymmetry (~59%) Thickened ear helices (~53%) Small head Deep-set eyes (~50%) Most patients have mental retardation Most patients have delayed growth (~85%) and/or difficulty gaining weight Some have difficulty with sucking and swallowing while others may not grow well even though they eat well. Some older children may become obese. Most young children with 1p36 deletion syndrome have delayed development. They sit up, walk and talk later than typical children. Speech is severely affected with many patients learning only a few words Other medical problems: Hypotony (which may explain delayed motor skills) (seen in ~92%) Hearing loss (~56%) Seizures (~72%) KCNAB2 is a voltage-gated K+ channel beta-subunit gene that has been localized to 1p36 and thought to be associated with the epilepsy phenotype of 1p36 Eye/vision problems (~75%) Hypothyroidism Increased risk for neuroblastoma Heart defects (which have included cardiomyopathy, ductus arteriosus, tetralogy of Fallot, VSD) Orofacial clefting abnormalities SKI, a proto-oncogene located at distal 1p36.3 has been found to be deleted in a number of patients tested and may contribute to facial clefting seen in this syndrome SKI overexpression has suggested that the gene is involved in neural tube development and muscle differentiations. Recurrence Risk for next pregnancy The majority of patients with 1p36 deletion syndrome are isolated cases resulting from a de novo deletion. There have been reports of patients with 1p36 deletion syndrome whose parents have a balanced translocation. Parents should be tested for chromosomal rearrangements because about 6% of parents with an affected child have a balanced translocation Translocation increases the chances of having another child with a 1p36 deletion. If no translocation is found the chances of having another child with a 1p36 deletion are very small Prenatal Diagnosis In 1999 a case was reported in which a 1p36 deletion in a fetus was detected when an amniocentesis was performed due to detection of multiple malformations on ultrasound Another case was picked up prenatally because of the presence of elevated maternal serum alpha-fetoprotein (no abnormal sign seen on ultrasound) Another was diagnosed prenatally because the mother was known to have a balanced translocation between the short arms of chromosome 1 and 20 that was picked up after their first child had inherited an unbalanced product. (no abnormal sign seen on ultrasound) Medical Treatment Seizures can usually be controlled with medication Medical interventions and feeding therapy may be needed to manage feeding issues Early Intervention for developmental delay Surgery may be necessary to correct heart defects, cleft lip, cleft palate if present Physical examinations should involve palpating the abdomen for lumps which might be neuroblastomas There are no clear indications on whether they should continue to be followed by a cardiologist or whether the cardiomyopathy is limited to a congenital form. Psychosocial Issues Initially parents may experience denial about how severe the developmental delay and mental retardation will be Blaming of self or partner may occur Stress of having a child with developmental delays and mental retardation Stress associated with having a child with serious medical problems especially if they have heart malformations or seizures Time commitment involved with early intervention services (OT, PT, speech therapy) Patient Resources 1p36 Deletion Syndrome Chromosome Deletion Outreach MUMS References Colmenares, C., et al. Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski -/- mice. Nature Genetics 30(1), 106-109, Jan 2002. Faivre, L. et al. Prenatal Detection of a 1p36 Deletion in a Fetus with Multiple Malformations and a Review of the Literature. Prenatal Diagnosis. 19:49-53, 1999. Heilstedt, H.A. et al. Loss of the Potassium Channel B-subunit gene, KCNAB2, Is Associated with Epilepsy in Patients with 1p36 Deletion Syndrome. Epilepsia. 42(9): 1103-1111, 2001. Shaffer, L.G. and Heilstedt, H.A. Terminal Deletion of 1p36. The Lancet Supplement 358: 89, 2001. Shapira, Stuart, et al. Chromosome 1p36 Deletions: The Clinical Phenotype and Molecular Characterization of a Common Newly Delineated Syndrome. American Journal of Human Genetics 61: 642-650, 1997. Slavotinek, Anne, Lisa G. Shaffer, Stuart K Sharpira. Monosomy 1p36. Journal of Medical Genetics 36: 657-663, 1999. Notes The information for this outline was last updated in June of 2002.