Chromosome 9, Trisomy Mosaic, also known as Trisomy 9 Mosaicism syndrome, is a rare chromosomal disorder in which the entire 9th chromosome appears three times (trisomy) rather than twice in some cells of the body. The term "mosaic" indicates that some cells contain the extra chromosome 9, while others have the normal chromosomal pair.
Associated symptoms and findings may vary greatly in range and severity, depending on the percentage of cells with the extra chromosome. However, common features include growth deficiency before birth (intrauterine growth retardation); mental retardation; structural malformations of the heart that are present at birth (congenital heart defects); and/or distinctive abnormalities of the skull and facial (craniofacial) region, such as a sloping forehead, a bulbous nose, short eyelid folds (palpebral fissures), deeply set eyes, and/or low-set, malformed ears. The syndrome may also be characterized by musculoskeletal, genital, kidney (renal), and/or additional physical abnormalities. Chromosome 9, Trisomy Mosaic may be caused by errors during the division of a parent's reproductive cells (meiosis) or during the division of body tissue cells (somatic cells) early in the development of the embryo (mitosis).
As noted above, Chromosome 9, Trisomy Mosaic is characterized by an extra 9th chromosome (trisomy 9) in some cells of the body (mosaicism). The range and severity of associated features may be variable, depending on the percentage of trisomic cells. In addition, rare cases have also been reported in which all body cells have appeared to be trisomic for all of chromosome 9; such “nonmosaic” cases are sometimes referred to as Trisomy 9 or Complete Trisomy 9 syndrome. According to investigators, in such patients, characteristic clinical features do not substantially differ from those seen with Trisomy 9 Mosaicism; however, symptoms and findings associated with the latter may tend to be less severe in some cases (e.g., due to percentage of mosaicism).
Chromosome 9, Trisomy Mosaic is commonly characterized by growth deficiency beginning before birth (prenatal onset), failure to grow and gain weight at the expected rate (failure to thrive) during infancy, and low muscle tone (hypotonia). In addition, many affected individuals have severe mental retardation and severe delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation). However, there have also been some reports in which individuals with the disorder have normal psychomotor development or are only mildly developmentally delayed.
Chromosome 9, Trisomy Mosaic is also often associated with characteristic malformations of the skull and facial (craniofacial) region. Many affected infants have an abnormally small head (microcephaly); a sloping forehead with narrow temples; a broad nose with a bulbous tip and “slitlike” nostrils; and/or a small jaw (micrognathia). Additional characteristic features may include abnormal wideness of the “soft spots” (fontanels) and the fibrous joints (i.e., cranial sutures) between certain bones of the skull; a prominent upper lip covering a receding lower lip; a highly arched roof of the mouth (palate); low-set, misshapen ears; and/or a short neck. Various eye (ocular) abnormalities may also be present, such as short, upwardly slanting eyelid folds (palpebral fissures); deeply set eyes; abnormal reduction in the size of the eyes (microphthalmia); and/or other ocular defects. Some affected infants may also have an abnormal groove in the upper lip (cleft lip); incomplete closure (clefting) of the palate; abnormal outgrowths of skin and cartilage on or before the ears (preauricular tags); and/or other craniofacial abnormalities.
Approximately two-thirds of affected individuals also have congenital heart defects. Such defects may include an abnormal opening in the partition (septum) that separates the two lower or upper chambers (ventricles or atria) of the heart (ventricular or atrial septal defects), patent ductus arteriosus (PDA), and/or other associated defects, allowing some oxygen-rich blood to recirculate through the lungs and potentially leading to rising blood pressure in the lungs (pulmonary hypertension). In PDA, the channel that is present between the pulmonary artery and the aorta during fetal development fails to close after birth. (The pulmonary artery carries oxygen-depleted blood from the right ventricle to the lungs, where the exchange of oxygen and carbon dioxide occurs. The aorta, which is the major artery of the body, arises from the left ventricle and supplies oxygen-rich blood to most arteries.)
In individuals with cardiac defects, associated symptoms and findings may vary, depending upon the size, nature, and/or combination of heart malformations present and other factors. Some individuals may show no apparent symptoms (asymptomatic), while others may develop difficulties feeding, poor growth, difficult or labored breathing (dyspnea), profuse sweating, irritability, an impaired ability of the heart to pump blood efficiently to the lungs and the rest of the body (heart failure), and/or other abnormalities. In severe cases, congenital heart disease may lead to potentially life-threatening complications.
Chromosome 9, Trisomy Mosaic is also often characterized by various musculoskeletal abnormalities. These frequently include congenital dislocation of the hips; abnormal position and/or limited function of other joints, such as those of the elbows, knees, and/or fingers and toes (digits); abnormal curvature of the spine; and/or other defects. Additional abnormalities of the hands and feet may also be present, such as underdevelopment (hypoplasia) of certain bones of the digits (phalanges); hypoplasia of the nails; and/or a single crease across the palms (simian crease). Other skeletal malformations have also been reported in association with the disorder, including a narrow chest, rib defects, additional malformations of certain bones of the spine (vertebral anomalies), and/or other abnormalities.
Affected males may also have genital abnormalities, including undescended testes (cryptorchidism); a small penis (micropenis); and/or abnormal placement of the urinary opening (hypospadias), such as on the underside of the penis. Kidney (renal) abnormalities may also be present, including renal cysts; swelling (distension) of the kidneys with urine (hydronephrosis) due to narrowing or blockage of the tubes (i.e., ureters) that carry urine from the kidneys into the bladder; and/or other renal defects.
In some cases, Chromosome 9, Trisomy Mosaic may also be associated with certain abnormalities of the brain, such as hydrocephalus, Dandy-Walker malformation, and/or other features. Hydrocephalus is characterized by obstructed flow or impaired absorption of cerebrospinal fluid (CSF), resulting in abnormal accumulation of CSF in the skull, usually under increased pressure, and widening of cavities (ventricles) of the brain. CSF is the watery protective fluid that circulates through the four ventricles of the brain, the canal containing the spinal cord (spinal canal), and the space between layers of the protective membranes (meninges) surrounding the brain and spinal cord (i.e., subarachnoid space). Depending on the age at symptom onset and other factors, associated symptoms may include rapid enlargement of the head, sudden episodes of uncontrolled electrical activity in the brain (seizures), feeding difficulties, vomiting, irritability, headache, loss of coordination, deteriorating mental functioning, and/or other findings. In severe cases, potentially life-threatening complications may result. In those with Dandy-Walker malformation, cystic malformation of the fourth ventricle of the brain may lead to hydrocephalus, a rapid increase in head size, abnormal prominence of the back region of the head (occiput), and/or additional associated abnormalities.
In some instances, additional physical features have been reported in association with Chromosome 9, Trisomy Mosaic. Such abnormalities have included clouding of the dome-shaped, normally transparent region forming the front of the eyeball (corneal opacities); the presence of cysts on the eyeballs (epibulbar dermoids); underdevelopment of the lungs (pulmonary hypoplasia); diaphragmatic hernia; gastroesophageal reflux; and/or other abnormalities. In those with a diaphragmatic hernia, there is protrusion of abdominal structures into the chest cavity through an abnormal opening in the diaphragm. Gastroesophageal reflux is characterized by abnormal backflow (reflux) of stomach acid into the esophagus, causing inflammation of and possible damage to the esophageal lining.
In individuals with Chromosome 9, Trisomy Mosaic, the entire 9th chromosome appears three times (trisomy) rather than twice in some cells of the body (mosaicism). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p,” a long arm identified by the letter “q,” and a narrowed region at which the two arms are joined (centromere). Chromosomes are further subdivided into bands that are numbered outward from the centromere. For example, the short arm of chromosome 9 includes bands 9p11 to 9p24, and the long arm includes bands 9q11 to 9q34.
The same chromosomal makeup is usually present in all body cells. However, those with a mosaicism have two or more cell lines that are karyotypically distinct. In individuals with Chromosome 9, Trisomy Mosaic, there is trisomy (duplication) of chromosome 9 in a percentage of cells, while other cells have a normal chromosomal makeup. The additional chromosome is responsible for the symptoms and physical findings that characterize the disorder. Individuals with a low percentage of affected cells (low mosaicism) may have fewer, less severe symptoms than those with a high percentage of affected cells (high mosaicism).
Chromosome 9, Trisomy Mosaic appears to result from errors of chromosomal separation (nondisjunction) during the division of reproductive cells in one of the parents (meiosis) or during cellular division after fertilization (mitosis). There have been some reports in which the disorder has appeared to occur due to a balanced chromosomal rearrangement known as a “pericentric inversion” in one of the parents; in such cases, affected individuals have had the variant chromosome 9 in duplicate within trisomic cells. A pericentric inversion is characterized by breakage of a chromosome in two places including the centromere and reunion of the segment in the reverse order. If a chromosomal rearrangement is balanced, meaning that it consists of an altered but balanced set of chromosomes, it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring.
Chromosomal analysis and genetic counseling are typically recommended for parents of an affected child to help confirm or exclude the presence of a pericentric inversion or other chromosomal rearrangement involving chromosome 9 in one of the parents.
Chromosome 9, Trisomy Mosaic appears to affect males and females in relatively equal numbers. Since the disorder was originally described in 1973 (Haslam RH), over 30 cases have been reported in the medical literature.
In some cases, the diagnosis of Chromosome 9, Trisomy Mosaic may be suggested before birth (prenatally) by ultrasound and various specialized tests that enable analysis of fluid or tissue samples extracted from the fetus or the uterus (e.g., amniocentesis, chorionic villus sampling [CVS], and/or fetal blood sampling). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing certain characteristic findings that suggest a chromosomal disorder or other developmental abnormalities. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Fetal blood samples may be obtained with a needle guided via ultrasound into a blood vessel in the umbilical cord. Chromosomal studies performed on such fluid or tissue samples may reveal Trisomy 9 Mosaicism. Experts indicate that the nature of mosaicism may complicate prenatal diagnosis for this chromosomal disorder, as test samples may not be representative of the entire cell population of the fetus and may not accurately reflect the distribution of abnormal and normal cell lines. In addition, there have been cases reported in the medical literature in which prenatal testing detected mosaicism, but the infant was born with normal chromosomes.
Chromosome 9, Trisomy Mosaic may be diagnosed and/or confirmed after birth (postnatally) by a thorough clinical evaluation, identification of characteristic physical findings, chromosomal analysis, and other specialized tests. In addition, diagnostic evaluation may include various studies, including advanced imaging techniques, to help detect and/or characterize certain abnormalities that may be associated with the disorder (e.g., particular craniofacial defects, other skeletal malformations, brain abnormalities, etc.). In addition, a thorough cardiac evaluation may be advised to detect any heart abnormalities that may be present. Such evaluation may include a thorough clinical examination; evaluation of heart and lung sounds with a stethoscope; x-ray studies; tests that record the electrical activities of the heart muscle (electrocardiography [EKG]); a technique in which sound waves are directed toward the heart, enabling evaluations of cardiac motion and structure (echocardiogram); or other measures.
The treatment of Chromosome 9, Trisomy Mosaic is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; heart specialists (cardiologists); physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); neurologists; and/or other health care professionals.
In affected individuals with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be required. For those with hydrocephalus, disease management may include administration of particular medications to help reduce the rate of cerebrospinal fluid (CSF) production, shunting, or other measures. (Shunts are specialized devices that drain excess CSF away from the brain to another part of the body for absorption into the bloodstream.. In addition, in some cases, physicians may recommend surgical repair or correction of other craniofacial, musculoskeletal, genital, and/or other malformations associated with the disorder. The specific surgical procedures performed will depend upon the nature and severity of the anatomical abnormalities, their associated symptoms, and other factors.
Early intervention services may also be important in ensuring that affected children reach their potential. Special services that may be beneficial include special remedial education, physical therapy, and/or other medical, social, and/or vocational services. Genetic counseling will also be of benefit for families of affected children. Other treatment for this disorder is symptomatic and supportive.
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