Partial monosomy 11q, also known as Jacobsen syndrome, is a rare chromosomal disorder in which a portion of chromosome 11 is missing or deleted 11q monosomy. The range and severity of symptoms varies, depending in part on the exact location and size of the missing material. Symptoms commonly associated with partial monosomy 11q include abnormally slow growth before and after birth (prenatal and postnatal growth retardation), and/or moderate to severe delays in the acquisition of skills requiring the coordination of mental and muscular activity (psychomotor retardation). In rare cases, individuals may have normal/borderline intelligence while in most cases children have mild to severe intellectual disability. Characteristic physical abnormalities may include malformations of the head and face (craniofacial), abnormalities of the eyes, hands, feet, bleeding due to platelet abnormalities, and/or defects of the heart that are present at birth (congenital). The exact cause of partial monosomy 11q is not fully understood.
Symptoms and physical characteristics associated with partial monosomy 11q vary greatly depending on the exact size and gene content of the deleted material on chromosome 11. No specific feature has been seen in every individual case, so it is important to note that affected children will not have all of the symptoms discussed below.
Many individuals with partial monosomy 11q may reach an adult height that is well below average (short stature). Some children with partial monosomy 11q have low levels of a growth hormone known as insulin growth factor-1 (IGF-1).
Affected infants and children may also experience delays in reaching developmental milestones (psychomotor developmental delay). In rare cases, intelligence may be normal or borderline; in most cases mild to moderate intellectual disability may occur. Affected infants may also have severe speech impairment. The degree of speech impairment and intellectual disability are usually associated with the size of the deletion. Individuals with smaller deleted segments are more likely to have borderline normal intelligence and less severe symptoms overall.
A specific finding associated with partial monosomy 11q is thrombocytopenia, a condition characterized by reduced levels of platelets. Platelets are tiny, specialized blood cells that help prevent bleeding by forming clots. When a blood vessel is injured, platelets travel to the site of injury and clump together to form a clot that stops bleeding. Infants with partial monosomy 11q may have low levels of platelets causes them to bruise easily and bleed excessively. They may be at risk of internal bleeding. As affected individuals age, platelet numbers increase, but many individuals still bruise easily and experience prolonged bleeding episodes suggesting that the platelets may not function properly.
The bleeding abnormalities associated with partial monosomy 11q are extremely similar to Paris-Trousseau syndrome (PTS), a bleeding disorder also associated with deleted material on chromosome 11q. Some researchers believe these disorders are actually one disorder; some believe PTS is a variant of partial monosomy 11q; and others believe that they are similar, yet distinct, disorders.
Many infants with partial monosomy 11q exhibit distinctive facial features including skull deformities (macrocrania or abnormal skull shape defined craniosynostosis), high prominent forehead, facial asymmetry, broad nasal bridge; short nose; nostrils that are flared forward (anteverted nares); thin upper lips; down-turned mouth; small lower jaw (micrognathia); low-set and malformed (dysplastic) ears. Some individuals may develop dental abnormalities. Abnormalities affecting the eyes are also common, including that are widely spaced apart (hypertelorism), crossed eyes (strabismus), dropping of the upper eyelids (ptosis), and the presence of tiny folds of skin on either side of the nose that may partially cover the eyes’ inner corners near the nose (epicanthal folds).
Infants with partial monosomy 11q may also have abnormalities of the hands and feet. Such malformations may include minor webbing of the fingers (skin syndactyly); thin fingers; abnormal curving of the pinky so that is bent toward the ring finger (clinodactyly); the presence of a single, deep crease across the palms of the hands (simian crease); big and long allux with short toes; an abnormally twisted position of feet (talipes equinovarus or clubfoot). In addition, in many cases, certain joints may become fixed or stuck in a bent position (contractures). A contracture occurs when thickening and shortening of tissue such as muscle fibers causes deformity and restricts movements of affected areas, especially the joints.
More than half of individuals with partial monosomy 11q show heart abnormalities that are present at birth (congenital heart defects). The most common congenital heart defects associated with partial monosomy 11q are ventricular septal defects (VSDs) and left-sided obstructive lesions. The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The aorta, the main vessel of arterial circulation, carries blood from the left ventricle and away from the heart.
Ventricular septal defects (VSDs) can occur in any portion of the ventricular septum. The size and location of the defect determine the severity of the symptoms. Small ventricular septal defects may close without treatment (spontaneously) or become less significant as the child matures and grows. Moderately-sized defects may affect the ability of the heart to pump blood efficiently to the lungs and the rest of the body (congestive cardiac failure). Symptoms associated with cardiac failure may include an abnormally rapid rate of breathing (tachypnea), wheezing, unusually fast heartbeat (tachycardia), and/or failure to grow at the expected rate (failure to thrive). Large ventricular septal defects can cause life-threatening complications during infancy. Persistent elevation of the pressure within the artery that carries blood away from the heart and to the lungs (pulmonary artery) can cause permanent damage to the lungs.
Left-sided obstructive lesions are defects that prevent the adequate blood flow from the heart. Such defects that have been associated with partial monosomy 11q include narrowing of aorta (aortic coartation); narrowing of the valve that connects the left ventricle to the aorta (aortic valve stenosis); narrowing of the valve of that connects the lower and upper left chamber of the heart (mitral valve stenosis); and hypoplastic left heart syndrome, a group of closely-related defects characterized by underdevelopment (hypoplasia) of the left side of the heart and associated structures.
Additional heart defects that have been reported in some individuals with partial monosomy 11q include double outlet right ventricle, in which both the pulmonary artery and aorta connect to the right ventricle (the aorta normally connects to the left ventricle); transposition of the great arteries, in which the two large (great) arteries arises from the wrong area of the heart – aorta arises from the right ventricle and the pulmonary arises from the left ventricle; aberrant right subclavian artery, in which one of the main arteries supplying blood to the upper arms and legs arises from the wrong area of the heart; and atrioventricular septal canal defects, in which the partitions (septa) and valves separating the right and left chambers of the heart are improperly developed.
Individuals with partial monosomy 11q frequently have infections such as middle ear infections (otitis media) and inflammation of the sinuses (sinusitis), although deficit of cellular or humoral immunity with low IgM and IgA has been reported only occasionally.
Additional findings have been associated with partial monosomy 11q. These finding affect less than half of affected individuals. In some cases, the fibrous joints (metopic sutures) between the two sides of the bone in the forehead (frontal bone) may close prematurely (craniosynostosis). As a result, the head may have an unusual “triangular-shaped” appearance with an abnormally prominent forehead (trigonocephaly).
Additional findings affecting the eyes may occur including absence of some tissue from the colored portion of the eye (iris coloboma), giving the eye a “keyhole” appearance and improper developed of the nerve-rich membrane lining the eyes (retina). The retina converts visual images into nerves, which are then relayed to the brain. In some individuals with partial monosomy 11q a condition called tortuosity of the retinal vessels may occur. In this condition, the tiny vessels that supply blood to the retina may be twisted and malformed.
Some individuals with partial monosomy 11q experience some degree of hearing impairment. Eczema, a skin condition in which individuals develop an inflamed, scaly, red rash that is often itchy, may also occur.
Some individuals may develop gastrointestinal problems including feeding difficulties, chronic constipation, abnormal narrowing (stenosis) of the band of muscle fibers (pyloric sphincter) at the junction between the stomach and small intestine (pyloric stenosis), resulting in obstruction of the normal flow of stomach contents into the small intestine. Pyloric stenosis can cause affected individuals to vomit forcefully and may result in dehydration.
In some cases, affected infants may also have abnormalities of the genital and urinary (genitourinary) systems. For example, females may have an abnormal passage between the bladder and the vagina (vescicovaginal fistula). In affected males, the urinary opening (meatus) may appear on the underside of the penis (hypospadias); the testes may fail to descend into the scrotum (cryptorchidism); and/or portions of the large intestine may protrude through an abnormal opening in muscles of the groin (inguinal hernia).
In rare cases, some infants with partial monosomy 11q may also exhibit kidney (renal) abnormalities such as a horseshoe kidney (abnormally shaped kidneys) and duplicate kidney and/or a duplicate ureter, the small, thin tube that connects the kidneys to the bladder. The ureters drain urine through the muscular contractions. Most individuals have two ureters (one connected to each kidney). A duplicate ureter is an extra ureter that may or may not be associated with any symptoms depending upon their exact location, whether they are malformed and whether they hinder the flow of urine.
Partial monosomy 11q is a rare disorder in which a portion of the long (q) of chromosome 11 is missing (deleted). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The range and severity of symptoms associated with this disorder depend in part upon the exact length and location of the deleted portion of chromosome 11q. In general, if less of the chromosome is missing, there may be fewer symptoms; if more of the chromosome is deleted, there may be more symptoms. In individuals with partial monosomy 11q, the deleted portion of 11q tends to begin within band 11q23 (breakpoint) and extend toward the end or “terminal” portion of chromosome 11q (qter). The symptoms of partial monosomy 11q result from the genes that are normally present on the missing portion of chromosome 11. Researchers have suggested that the region consistently missing in individuals with the disorder is band q24.1 (11q24.1) suggesting that the absence of this specific area is critical to developing the disorder.
The exact cause of the chromosomal alteration in partial monosomy 11q is not fully understood. The medical literature has indicated that most documented cases appear to be due to a spontaneous (de novo) genetic change (mutation) that occurs for unknown reasons (sporadic). Less frequently deletion 11q is the result of an error during very early embryonic development due to a chromosomal balanced translocation in one of the parents. A translocation is balanced if pieces of two or more chromosomes break off and trade places, creating an altered but balanced set of chromosomes. If a chromosomal rearrangement is balanced, it is usually harmless to the carrier. However, they may be associated with a higher risk of abnormal chromosomal development in the carrier’s offspring. In this cases the clinical features of children may be influenced by additional imbalances of other chromosomes than 11. Chromosomal testing can determine whether a parent has a balanced translocation.
More recently, however, researchers have speculated that inheritance of a rare, fragile site or sites on the long arm of chromosome 11 may play a role in causing the disorder in some cases. Such a fragile site (or “folate-sensitive fragile site”), designated “FRA11B”, has been linked to band 11q23.3. Inheritance of FRA11B and subsequent breakage at this site during early embryonic development may give rise to the disorder in some individuals. Reports have indicated that the mothers of some affected individuals have been carriers for FRA11B and that FRA11B has been the deletion breakpoint. In addition, based upon evidence that the 11q breakpoint is sometimes beyond (i.e., telomeric to) FRA11B, some researchers suggest that there may be other fragile sites within or below11q23.3 in addition to FRA11B. In reported cases with breakpoints telomeric to FRA11B, the deleted chromosome has been paternal in origin, indicating that the tendency for a certain breakpoint may differ based upon the parental origin of the deleted chromosome.
Some researchers believe the FLI1 gene on the long arm of chromosome 11 plays a role in the development the bleeding complications (Paris-Trousseau syndrome) associated with partial monosomy 11q. The extra function and role of this gene is unknown. More research is necessary to identify the specific genes (and their functions) associated with the symptoms of partial monosomy 11q.
In most cases, individuals have an altered chromosome 11q in every cell of the body. However, in some cases, affected individuals have a mix of cells with an altered chromosome 11q and some with normal chromosomes 11.This is termed mosaicism and is generally associated with less severe symptoms.
Partial monosomy 11q is an extremely rare chromosomal disorder that is apparent at birth. The disorder was initially described in the medical literature in 1973. Since that time, more than 200 cases have been described in the medical literature. According to some sources, more females are affected than males. The prevalence has been estimated at 1/100,000 births.
Partial monosomy 11q may be diagnosed based upon a thorough clinical evaluation, the identification of characteristic physical findings and chromosomal studies that demonstrate missing (deleted) material on chromosome 11q. Chromosomes can be obtained from a blood sample. These chromosomes are stained so that they can be viewed more easily and are then examined under a microscope where the missing segment of chromosome 11q can be detected (high resolution karyotype). To determine the precise breakpoint on 11q, more a sensitive test may be necessary such as: fluorescent in situ hybridization (FISH), a diagnostic test in which probes marked by a specific color of fluorescent dye attach to a specific chromosome allowing researchers to better view that specific region of a chromosome; m-array comparative genomic hybridization (CGH) a method in which a normal DNA is mixed to patient's DNA in order to analyse gains (duplications) or losses (deletions) of chromosomal regions. M-array CGH allows a better defining of breakpoints in 11q deletion but it cannot detect balanced rearrangements (such as balanced translocation that sometimes can be diagnosed in one parent of the affected child.).
The diagnosis of certain specific abnormalities that may occur in association with partial monosomy 11q may be confirmed by specialized imaging studies and/or additional tests. For example, congenital heart defects may be confirmed by a thorough clinical examination and specialized tests that allow physicians to evaluate the structure and function of the heart. These tests may include X-ray studies, electrocardiogram (EKG), echocardiogram, and cardiac catheterization. X-ray studies may reveal abnormal enlargement of the heart (cardiomegaly) or malformation of other heart structures. An EKG, which records the heart's electrical impulses, may reveal abnormal electrical patterns. During an echocardiogram, ultrasonic waves are directed toward the heart, enabling physicians to study cardiac function and motion. During cardiac catheterization, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. This procedure allows physicians to determine the rate of blood flow through the heart, measure the pressure within the heart, and/or thoroughly identify anatomical abnormalities.
In some cases, the diagnosis of partial monosomy 11q may be determined before birth (prenatally) by specialized tests such as ultrasound, amniocentesis, and/or chorionic villus sampling (CVS). Ultrasound studies may reveal characteristic findings that suggest a chromosomal disorder or other developmental abnormalities in the fetus. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, a tissue sample is removed from a portion of the placenta. Chromosomal studies performed on this fluid or tissue sample may show a partial monosomy of chromosome 11q.
The treatment of partial monosomy 11q is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, ear, nose and throat specialists, dental specialists, speech pathologists, specialists who assess and treat eye problems (ophthalmogists), specialists who assess and treat disorders affecting the hormones and glands (endocrinologists), specialists who assess and treat disorders of the skeleton (orthopedists), and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.
Physicians must regularly monitor affected individuals who tend to exhibit low platelet counts (thrombocytopenia) to ensure proper preventive measures and early, prompt treatment. In some cases, affected individuals may be treated with platelet transfusion or desmopression acetate a drug that helps the blood clot. Blood or Platelet transfusion may be necessary before or during surgeries.
In some cases, treatment may include surgical repair of certain malformations. For example, surgery may be performed to correct certain craniofacial, ocular, skeletal, cardiac, genitourinary, renal, and/or other malformations that may be associated with this disorder. The surgical procedures performed will depend upon the severity of the anatomical abnormalities and their associated symptoms.
For example, in affected children with craniosynostosis and trigonocephaly, surgery may be performed to help correct the premature closure of bones in the skull. In addition, certain congenital heart abnormalities occurring in association with Partial monosomy 11q (e.g., ventricular septals defects) may be corrected surgically. Complications of certain congenital heart defects (e.g., rapid heartbeat [tachycardia], fluid accumulation, etc.) may be treated with a variety of drugs such as those that may help prevent or correct abnormal heart rhythms (antiarrhythmics) and/or medications that help to eliminate excessive fluid from the body (diuretics).
In addition, nutritional considerations may be important in infants with VSDs, ASDs, and/or certain other congenital heart defects. Respiratory infections should be treated vigorously and early. Because of the risk of bacterial infection of the lining of the heart (endocarditis) and the heart valves, individuals with VSDs, ASDs, and/or certain other heart defects may be given antibiotic drugs before any surgical procedure, including dental procedures such as tooth extractions.
In affected children with eye abnormalities (e.g., iris colobomas, strabismus, etc.), surgery and/or other measures may be used to help treat and/or correct such malformations. Corrective glasses, contact lenses, surgery, and/or other measures may also be used to help improve visual problems associated with such ocular abnormalities.
In some cases, abnormalities involving the joints, tendons, muscles, and bones (orthopedic), such as flexion contractures, clubfeet, and/or other abnormalities of the hands and/or feet may be treated by orthopedic techniques, potentially in combination with surgery. Again, the procedures used will depend upon the severity and location of the abnormalities and their associated symptoms. Physical therapy may also be prescribed to help improve coordination of certain movements (mobility).
Early intervention is important in ensuring that children with partial monosomy 11q reach their highest potential. Services that may be beneficial may include special remedial education and other medical, social, and/or vocational services. A team approach may be helpful and should include special remedial education, speech therapy, and other medical, social, or vocational services. Genetic counseling may be of benefit for affected individuals and their families.
Some individuals with partial monosomy 11q have low levels of a specific growth hormone (IGF-1). It is unknown whether treatment with growth hormone replacement therapy would be of benefit for these individuals. More research is necessary to determine the effectiveness and safety of such therapy in these specific cases of partial monosomy 11q.
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Contact for additional information about chromosome 11, partial monosomy 11q:
Prof. Teresa Mattina
Direttore Scuola Specializzazione Genetica Medica
Centro di Riferimento Regionale
Diagnosi e Cura delle Malattie Genetiche
Via S. Sofia,78 ed.4
tel/fax +39 095 378 2450
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