Jacobsen Syndrome (JS) is a rare congenital condition. It is classified as a contiguous gene disorder, meaning the symptoms result from the loss of multiple adjacent genes on a chromosome. JS has an estimated prevalence of about one in every 100,000 newborns. The severity of the condition varies widely, but it is often associated with serious medical and developmental complications.
Genetic Basis: The Chromosome 11 Deletion
The underlying cause of Jacobsen Syndrome is the loss of a segment of genetic material from one copy of chromosome 11. The deletion occurs on the long arm, designated as the ‘q’ arm. This loss is known as a terminal deletion because it involves the end portion of the chromosome arm, extending to the tip.
The size of the deleted segment varies considerably, generally ranging from 7 million to 16 million DNA base pairs. The deletion begins at a breakpoint, usually located within or distal to the subband 11q23.3. The extent of this missing region determines the number of lost genes, which can range from approximately 170 to over 340.
The resulting clinical picture, or phenotype, is directly correlated with the size of the deletion. Individuals with larger deletions tend to experience more severe symptoms. The loss of genetic material results in partial monosomy, meaning only one copy of these genes remains instead of the usual two.
A specific subband, 11q24.1, is considered a critical region necessary for the full expression of the JS phenotype. The loss of two particular genes within this region is linked to prominent symptoms. The FLI1 gene is responsible for hematological issues, while the ETS1 gene is associated with the congenital heart defects often seen in the syndrome.
Clinical Outcomes of the Deletion
The loss of multiple genes in the 11q region leads to a wide spectrum of health problems, including hematological, craniofacial, and neurodevelopmental issues.
Hematological Issues
Nearly all individuals with Jacobsen Syndrome (over 90 percent) experience Paris-Trousseau syndrome, a bleeding disorder. This condition is characterized by thrombocytopenia (a persistently low platelet count) and a functional defect in the remaining platelets. This combination results in a lifelong risk of abnormal bleeding and easy bruising.
Craniofacial Features
The syndrome is characterized by distinctive craniofacial features. These include trigonocephaly, a skull abnormality that gives the forehead a pointed appearance. Other common traits are widely spaced eyes (hypertelorism), droopy eyelids, a broad nasal bridge, and small, low-set, and posteriorly rotated ears.
Cardiac and Developmental Issues
Congenital heart defects occur in more than half of all cases. These malformations can be severe and life-threatening, often requiring early medical intervention or surgery. The severity of these heart issues is a primary factor influencing the overall prognosis, as many infants die within the first two years due to cardiac complications.
Developmental delays are a near-universal characteristic, affecting approximately 97 percent of individuals. These delays involve motor skills (such as sitting and walking) and speech development. Cognitive impairment is also present, ranging from mild to severe intellectual disability. Behavioral challenges are common, including symptoms consistent with Attention-Deficit/Hyperactivity Disorder (ADHD) and features of autism spectrum disorder.
Understanding Inheritance and Translocations
The deletion that causes Jacobsen Syndrome arises in two primary ways, most of which are non-inherited events.
De Novo Mutations
In about 85 to 90 percent of reported cases, the deletion is de novo, meaning it is a spontaneous, new mutation. This error occurs randomly either during the formation of the parent’s reproductive cells or in the very early stages of the embryo’s development. When the deletion is de novo, neither parent carries the abnormality, and the recurrence risk for future children is low.
Inherited Translocations
A smaller proportion of cases (10 to 15 percent) are inherited from a parent who carries a balanced translocation. A translocation is a rearrangement where a segment of a chromosome breaks off and reattaches to a different chromosome.
The parent with a balanced translocation is usually healthy because no genetic material has been lost or gained. However, during the formation of reproductive cells, this rearranged chromosome pair may segregate incorrectly, leading to the offspring inheriting an unbalanced translocation.
An unbalanced translocation results in the child having the terminal deletion on chromosome 11, often alongside extra genetic material from the other chromosome involved in the parent’s original translocation. This inherited scenario carries a higher risk for future pregnancies than the de novo mutation.
Confirming the Diagnosis
Diagnosis of Jacobsen Syndrome is confirmed through specific genetic testing, often initiated based on characteristic facial features and the presence of thrombocytopenia.
Karyotyping
The earliest method used is karyotyping, which involves examining an image of the chromosomes under a microscope. Karyotyping can visualize the missing segment on the long arm of chromosome 11.
Fluorescence In Situ Hybridization (FISH)
FISH is utilized for more precise confirmation. This technique uses fluorescently labeled probes designed to bind specifically to the missing region of chromosome 11, allowing for clear visualization of the deletion and confirming its location.
Chromosomal Microarray (CMA)
The most detailed diagnostic tool is Chromosomal Microarray (CMA), also known as array comparative genomic hybridization (aCGH). CMA scans the entire genome to accurately measure the exact size of the deleted segment and precisely map the breakpoints. This detail is important for correlating the extent of gene loss with the severity of clinical features.