NORD gratefully acknowledges Janette DiMonda, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program, Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, and Deborah A. Bruns, PhD, Professor, Special Education Program, Department of Counseling, Quantitative Methods and Special Education, Southern Illinois University Carbondale, for assistance in the preparation of this report.
Mosaic trisomy 9 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 typical chromosomal pair. Mosaic Trisomy 9 may be caused by errors during the division of a parent's egg or sperm or during the division of body tissue cells (somatic cells) early in the development of the fetus.
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 restriction or IUGR); structural malformations of the heart that are present at birth (congenital heart defects); and/or distinctive differences in the shape 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 ears. The syndrome may also be characterized by musculoskeletal, genital, kidney (renal), and/or additional physical anomalies. Intellectual disability is common and varies in severity.
As noted above, mosaic trisomy 9 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 cells in the body with an extra chromosome 9 (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 full trisomy 9 syndrome. According to investigators, in such patients, characteristic clinical features and affected organs 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 due to the percentage of cells with an extra chromosome 9.
Mosaic trisomy 9 is commonly characterized by growth deficiency beginning before birth, failure to grow and gain weight at the expected rate (failure to thrive) during infancy, and low muscle tone (hypotonia). Some infants and children with mosaic trisomy 9 have feeding difficulties after birth and may require a feeding tube. In addition, many affected individuals have severe intellectual disability and severe delays in gaining skills relating to mental and physical activities. However, there have also been some reports in which individuals with the disorder have normal – typical psychomotor development or are only mildly developmentally delayed. Children that do have developmental or intellectual disabilities have not been shown to lose skills over time, or regress. Recent reports indicate that affected individuals possess strengths in language and communication development (particularly receptive speech, or their ability to understand language expressed to them) as well as social-emotional development.
Persons with mosaic trisomy 9 have specific differences in their facial features and the shape of their skull. Many affected infants have a small head size (microcephaly); a sloping forehead with narrow temples; a broad nose with a bulbous tip and “slit-like” nostrils; and/or a small jaw (micrognathia). Additional characteristic features may include 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, unusually-shaped ears; and/or a short neck. Various eye (ocular) anomalies may also be present, such as short, upwardly slanting eyelid folds (palpebral fissures); deeply set eyes; reduction in the size of the eyes (microphthalmia); clouded corneas, and/or other ocular defects that can lead to vision problems. Some affected infants may also have a groove in the upper lip (cleft lip); incomplete closure of the palate (cleft palate); outgrowths of skin and cartilage on or before the ears (preauricular tags); and/or other craniofacial differences. Some individuals have been reported to have hearing loss that required ear tubes or hearing aids
Previous studies have estimated that approximately 65% of affected individuals have congenital heart defects, however more recent studies report lower numbers. The most common defects include an abnormal opening in the partition (septum) that separates the two lower or upper chambers (ventricles or atria) of the heart, called ventricular septal defects (VSDs) or atrial septal defects (ASDs). Other heart defects include patent ductus arteriosus (PDA) and/or other associated defects that allow some oxygen-rich blood to recirculate through the lungs and potentially lead to rising blood pressure in the lungs (pulmonary hypertension). Some individuals with mosaic trisomy 9 will have more than one heart defect. Descriptions of heart defects is available here: http://www.heart.org/HEARTORG/Conditions/CongenitalHeartDefects/AboutCongenitalHeartDefects/Common-Types-of-Heart-Defects_UCM_307017_Article.jsp#.WrpRCDZK0dV
In individuals with cardiac defects, associated symptoms and concerns may vary depending upon the size, nature, and/or combination of heart malformations present and other factors including age and respiratory function. Some individuals may show no apparent symptoms (asymptomatic), while others may develop difficulties in feeding, poor growth, difficult or labored breathing (dyspnea), profuse sweating, an impaired ability of the heart to pump blood efficiently to the lungs and other parts of the body (heart failure), and/or other problems. In severe cases, congenital heart disease may lead to potentially life-threatening complications.
Individuals with mosaic trisomy 9 may also experience respiratory issues including central and/or obstructive apnea. There are instances of short as well as long term need for oxygen (via nasal canula) and placement of a tracheotomy to assist with the airway. A sleep study is often utilized to identify specific respiratory needs. A bronchoscopy or similar procedure may be needed to determine anatomical anomalies affecting respiration. Nebulizer treatments may be needed as well as deep suctioning to assist with mucus build-up affecting breathing. It is critical to include a pulmonologist on the medical team if these concerns persist especially when one or more cardiac defect is also present.
Mosaic trisomy 9 is also often characterized by various problems with the muscles and bones. These frequently include congenital dislocation of the hips (developmental dysplasia of the hip); atypical position and/or limited function of other joints, such as the elbows, knees, and/or fingers and toes (digits); atypical curvature of the spine; and/or other complications. Additional differences 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 (single transverse palmar crease). Other skeletal differences have also been reported in association with the disorder including a narrow chest, rib defects, additional shape differences of certain bones of the spine (vertebral anomalies), and/or other problems.
Affected males may also have genital complications including undescended testes (cryptorchidism); a small penis (micropenis); and/or atypical placement of the urinary opening (hypospadias), such as on the underside of the penis. Kidney (renal) complications may also be present in both males and females, 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 problems.
In some cases, mosaic trisomy 9 may also be associated with brain anomalies such as hydrocephalus, Dandy-Walker malformation, and/or other features. Hydrocephalus involves excess cerebrospinal fluid (CSF) on the brain, resulting in increased pressure on the skull 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, worsening – reduction in 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 – already defined in this paragraph, with increased prominence of the back region of the head (occiput), and/or additional associated anomalies. A minority of affected individuals have agenesis of the corpus callosum, or partial or complete absence (agenesis) of an area of the brain that connects the two cerebral hemispheres. Agenesis of the corpus callosum can range in severity and may result in seizures and/or developmental delays.
In some instances, additional physical features have been reported in association with mosaic trisomy 9. Such abnormalities have included clouding of the cornea of the eye, the presence of cysts on the eyeballs (epibulbar dermoids); underdevelopment of the lungs (pulmonary hypoplasia); diaphragmatic hernia; gastroesophageal reflux; and/or other features.
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 backflow (reflux) of stomach acid into the esophagus, causing inflammation of and possible damage to the esophageal lining.
In individuals with mosaic trisomy 9, the entire 9th chromosome appears three times (trisomy) rather than twice in some cells of the body (mosaicism). Chromosomes are found in the nucleus, or central part, 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 chromosomally distinct. In individuals with mosaic trisomy 9, there is trisomy (three copies) of chromosome 9 in a percentage of cells, while other cells have a typical chromosomal makeup with two copies. The additional chromosome causes the symptoms and physical findings (phenotype) that are seen in 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). The percentage of mosaicism can fluctuate depending on where the sample is drawn (cheek swab versus blood for example) and the age of the individual.
Mosaic trisomy 9 appears to result from errors of chromosomal separation (nondisjunction) during meiosis, which is the division of reproductive cells (sperm or eggs) in the parents. It has also been shown to occur 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. 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 the genetic material is in a different order but is in the correct quantity, it is usually harmless to the carrier. However, such a chromosomal rearrangement may result in a child with unbalanced genetic material.
Chromosome studies and genetic counseling are typically recommended for parents with an affected child. These can help confirm or exclude the presence of a pericentric inversion or other chromosomal rearrangement involving chromosome 9 in one of the parents. In addition, knowing the chromosome structure of the parents can inform them of their risk to have another affected child.
Mosaic trisomy 9 appears to affect males and females of all ethnicities in relatively equal numbers. Since the disorder was originally described in 1973 (Haslam RH), over 55 cases have been reported in the medical literature.
In some cases, the diagnosis of mosaic trisomy 9 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 problems. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed. CVS involves the removal of tissue samples from a portion of the placenta, the organ that supplies the developing fetus with nutrients and blood. Fetal blood samples may be obtained with a needle guided via ultrasound into a blood vessel in the umbilical cord, the structure that connects the fetus to the placenta. 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. This is because test samples may not be representative of the entire cell population of the fetus. Different tissue types (such as brain, kidney, or skin cells) are composed of varying proportions of cells with the extra chromosome. Therefore, sampling from one tissue type (such as blood) may not accurately reflect the distribution of atypical and typical cell lines throughout the fetus. In addition, there have been cases reported in the medical literature in which prenatal testing detected mosaicism, but the infant was born with typical chromosomes on postnatal testing. It may be necessary to use multiple testing methods and to collect samples from various tissue sites in order to detect low-level mosaicism.
Mosaic trisomy 9 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 require various studies, including advanced imaging techniques to help detect and/or characterize certain anomalies that may be associated with the disorder (e.g., craniofacial differences, skeletal anomalies, brain anomalies, etc.). A thorough cardiac evaluation may be advised to detect any heart defects 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 mosaic trisomy 9 is directed toward the specific symptoms that are apparent in each individual. Such treatment requires the coordinated efforts of a team of medical professionals such as pediatricians; surgeons; heart specialists (cardiologists); physicians who diagnose and treat problems 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 specific medications, surgical intervention, and/or other measures may be required. For those with hydrocephalus, disease management may include administration of specific 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 complications associated with the disorder. The specific surgical procedures performed will depend upon the nature and severity of the anatomical differences, 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, occupational therapy, speech therapy, feeding therapy, and/or other medical, social, and/or vocational services.
Genetic counseling is recommended for families of affected children. Other treatment for this disorder is symptomatic and supportive.
The Tracking Rare Incidence Syndromes (TRIS) project is designed to raise awareness and provide support for families and professionals involved in the care of children and adults with rare trisomy conditions. The TRIS project seeks to increase the knowledge base on rare incidence trisomy conditions, and to make this information available to families and interested educational, medical and therapeutic professionals. For more information, contact:
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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For more information about clinical trials conducted in Europe, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., intellectual disability, craniofacial differences, congenital heart defects, etc.].)
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