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A rare genetic disorder caused by deletions in the long arm of chromosome 11 (11q) and mainly characterized by craniofacial dysmorphism, congenital heart disease, intellectual disability, Paris Trousseau bleeding disorder, structural kidney defects and immunodeficiency.
ORPHA:2308Classification level: Disorder
Whilst prevalence of Jacobsen syndrome is unknown, the birth prevalence has been suggested at 1/50,000-100,000 in the United States, with a female/male ratio of 2:1.
Jacobsen syndrome is contiguous gene disorder, characterized by craniofacial dysmorphism (skull deformities, hypertelorism, ptosis, coloboma, downslanting palpebral fissures, epicanthal folds, a broad nasal bridge, short nose, V-shaped mouth, and small, low-set and posteriorly rotated ears), craniosynostosis, eye abnormalities, congenital heart disease, intellectual disability, behavioral problems including ADHD and autism, seizures, Paris-Trousseau bleeding disorder, structural kidney defects and other urogenital anomalies including undescended testes in males, chronic constipation, pyloric stenosis, and immunodeficiency.
The syndrome is caused by deletion of one copy of the long arm of chromosome 11 (11q). Most of the deletions are terminal, i.e. extending to the end of the chromosome. The deletion size ranges from ~7 to ~16Mb, with the proximal breakpoint within or telomeric to subband 11q23.3 and the deletion usually extending to the telomere. Interstitial deletions in this region and terminal deletions less than 7Mb can cause a ''partial Jacobsen syndrome'' phenotype. In a minority of cases the breakpoint is at the FRA11B fragile site. There are a few reported cases of mosaicism for the deletion, which may lessen the severity of the clinical phenotype.
Diagnosis is based on clinical findings and confirmed by array comparative genomic hybridization, and/or FISH.
Differential diagnoses may include the Turner and Noonan syndromes, as well as acquired thrombocytopenia due to sepsis.
Prenatal diagnosis of 11q deletion is possible through array comparative genomic hybridization analysis of genomic DNA from amniocytes or chorionic villus samples. Deletions can also potentially be detected by non-invasive prenatal testing from a maternal blood sample, although the reliability of this test for Jacobsen syndrome is unknown.
About 90% of cases are de novo. The remainder are inherited from an affected parent, either from one carrying a balanced translocation (giving rise to an unbalanced translocation in the offspring) or from a parent carrying a terminal 11q deletion. Genetic counseling is not possible.
Management and treatment
Management is multi-disciplinary and requires evaluation by a pediatrician, pediatric cardiologist, neurologist, hematologist, allergy/immunologist, endocrinologist and ophthalmologist. Additional subspecialty evaluations might include neurosurgery, urology, and nephrology. Follow-up with subspecialists varies between individuals, depending on need. Most individuals with JS have intellectual disability (ranging from mild learning disabilities to severe intellectual disability) and behavioral problems, requiring care by a pediatrician specializing in behavioral/developmental disabilities. Psychological and psychiatric care may also be warranted. Cardiac malformations can be severe and require heart surgery in the neonatal period. Newborns with Jacobsen syndrome may also have feeding difficulties requiring tube feeding. Special attention should be devoted to hematological problems.
Historically, the most common causes of death in people with JS have been from congenital heart disease, bleeding and immunodeficiency. Early diagnosis of the syndrome can lead to lifesaving interventions including the need for prophylactic platelet transfusions at times of risk to prevent bleeding, prophylactic antibiotic or IVIG infusions to prevent life-threatening infections, early medical or surgical intervention for complex congenital heart defects, and brain imaging to identify potential life-threatening brain aneurysms. Intellectual disability can range from mild to severe. For patients who survive the neonatal period and infancy, the life expectancy remains unknown.
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