Jacobsen syndrome is a rare chromosome disorder that affects multiple aspects of physical and mental development.
Jacobsen syndrome is characterized by a distinctive facial appearance, some degree of mental impairment, and certain types of birth defects, especially of the heart. Other common medical complications include recurrent infections, decreased platelet count, failure to thrive, and slow growth. The syndrome derives its name from a Danish physician, Dr. Petra Jacobsen, who first described an affected child in 1973. It is also known as 11q deletion syndrome or partial 11q monosomy syndrome because a specific region of one copy of chromosome 11 is missing and thus an affected person has one out of a possible two copies of the genes in that region. It is the loss of these genes that leads to the multiple problems found in Jacobsen syndrome.
The loss of genetic material from a specific segment of chromosome 11q, which at least includes the critical region at band 11q24.1, leads to the manifestations of Jacobsen syndrome. There are several ways in which this portion of chromosome 11 can be deleted. In at least two-thirds of Jacobsen syndrome cases there is a partial chromosome 11q deletion (a terminal deletion) that begins at band q23 and extends through the end of the chromosome. The remainder of cases are attributed to the loss of this chromosome 11q genetic material due a deletion within, but not including, the end of the chromosome (an interstitial deletion), or due to a chromosome rearrangement such as an unbalanced chromosome translocation or a ring chromosome.
Most deletions and chromosome rearrangements responsible for Jacobsen syndrome are not familial; they are the result of a new or de novo genetic change that occurred only in the gamete (the egg or sperm) contributed by the mother or father of that individual. Less often, the origin of chromosome deletion or rearrangement is familial. In a minority of cases a parent of an affected child has a folate-sensitive fragile site at chromosome band 11q23.3 that can cause chromosomal breakage and subsequent deletion of chromosome 11q when inherited. Also, there are children who have inherited an unbalanced chromosome translocation from a parent who is a balanced translocation carrier.
Although it is not known how many people have Jacobsen syndrome, estimates are that one person in every 100,000 is affected by the disorder. More females than males have the disorder with 70–75% of cases being females.
Signs and symptoms
Symptoms of Jacobsen syndrome are variable and the prognosis for an affected child depends on the presence of life-threatening birth defects or medical problems. Individuals with Jacobsen syndrome have a distinctive physical appearance. The face is characterized by wide-spaced eyes (hypertelorism), droopy eyelids (ptosis), redundant skin covering the inner eye (epicanthal folds), a broad or flat nasal bridge, a short nose with upturned nostrils, a small chin (micrognathia), low-set ears, and a thin upper lip. As many as 90–95% of affected individuals have a malformation of the skull, trigonocephaly, a defect that results from premature closure of one of the cranial sutures. A small head size (microcephaly) is found in over one-third of cases. Overall, individuals with Jacobsen syndrome are smaller than their peers or siblings. Prenatal growth retardation occurs about 75% of the time. A newborn with Jacobsen syndrome is usually small at birth and continues to have delayed growth and subsequent short stature. Feeding problems that can result in failure to thrive are also common.
Children with Jacobsen syndrome usually have some degree of developmental delay or mental retardation, ranging from mild to severe. Nearly all affected individuals also have decreased muscle tone (hypotonia) or increased muscle tone (hypertonia) as well as fine and gross motor delays. Occasionally, brain abnormalities are present.
Multiple types of physical abnormalities are known to occur in individuals with Jacobsen syndrome. Congenital heart disease is present in about half of affected children and, if severe, can pose a significant health problem. Other common internal abnormalities include pyloric stenosis , undescended testes, inguinal hernia, kidney defects, and urinary tract abnormalities. Craniofacial abnormalities such as strabismus, ptosis, colobomas, a high-arched palate, and external ear anomalies are frequent. Orthopedic problems, mainly joint contractures and abnormalities of the digits (the fingers and toes), have been described in some cases.
In addition to congenital defects, there are a variety of other health problems found in individuals with Jacobsen syndrome. Illnesses including recurrent respiratory infections, sinusitis, and otitis media occur more frequently in children with Jacobsen syndrome. Gastrointestinal problems such as gastroesophageal reflux and chronic constipation may occur. Blood disorders such as thrombocytopenia and pancytopenia are often seen in childhood and may improve with time.
Most individuals with Jacobsen syndrome are diagnosed after birth. The diagnosis is usually made through a blood test called chromosome analysis in an infant or child who has mental retardation and a typical facial appearance. The karyotype will show a deletion or rearrangement of the longer segment, known as the q arm, of one copy of chromosome 11. Jacobsen syndrome can be diagnosed before birth. There have been reports of prenatal diagnosis through amniocentesis after an ultrasound demonstrated one or more fetal abnormalities. Another technique, known as FISH (fluorescent in-situ hybridization), may be used to further define the chromosome 11q deletion breakpoints; this laboratory test is being done on a research basis to identify the disease-causing genes in the Jacobsen syndrome critical region.
Treatment and management
There is no cure for Jacobsen syndrome nor is there a therapy that can replace the missing genes from the deleted segment of chromosome 11. In addition to routine pediatric exams, there are management strategies and treatments that aim to prevent or minimize some of the serious health consequences associated with Jacobsen syndrome.
At the time of diagnosis a series of evaluations should be undertaken in order to appropriately guide medical management. Pediatric specialists in genetics, cardiology, orthopedics, ophthalmology, and neurology should be consulted, especially since some problems can be treated if caught early. Important tests may include a karyotype, a cardiac echocardiogram, a renal sonogram, a platelet count, a blood count, a brain imaging study, hearing and vision screenings, and a dental exam.
A neurodevelopmental evaluation should be initiated in infancy or at the time of diagnosis with implementation of age-appropriate early intervention services such as speech therapy, occupational therapy, and physical therapy. An ear, nose, and throat specialist (ENT) may be needed to treat problems such as otitis media. Craniofacial and neurosurgery consults may be indicated if trigonocephaly or other forms of craniosynostosis are present.
Some children may require a gastroenterology specialist to evaluate problems such as failure to thrive, chronic constipation, and/or severe gastroesophageal reflux, some or all of which may require surgical intervention. Boys with Jacobsen syndrome should be examined for undescended testes, a problem found in half of males and one that often requires surgery.
Approximately 25% of affected children die before two years of age mainly from cardiac defects, a tendency to bleed, or infection. Except for respiratory infections, the remainder of children are generally healthy. Most individuals described here are children or adolescents. Little is known about the course of this syndrome in adulthood, and the life expectancy for those who live beyond age two is unknown.
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Dawn Cardeiro, MS, CGC