NORD gratefully acknowledges 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.
Trisomy 9p is a rare chromosomal syndrome in which a portion of the 9th chromosome appears three times (trisomy) rather than twice in cells of the body. 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.
In trisomy 9p, the trisomy (or duplicated material) may involve a portion of the short arm (9p), the entire short arm, or the short arm and a portion of the long arm (9q) of chromosome 9. Evidence suggests that, in many cases, associated symptoms and findings may be relatively similar among affected infants despite differing lengths of the trisomic (duplicated) segment of 9p. However, in those with larger trisomies (e.g., extending to middle or end [distal] regions of 9q), additional features may also be present that appear to correlate with the extent of the duplication. Additionally, certain individuals with duplications of specific areas of chromosome 9p have not developed any symptoms or only very mild or subtle symptoms.
Children with trisomy 9p are affected by delays in reaching developmental milestones including crawling or walking (developmental delays), growth deficiency, and distinctive malformations of the skull and facial (craniofacial) region. As children grow older, intellectual disability may become apparent.
In some instances, additional physical abnormalities may also be present, such as other skeletal defects and/or structural malformations of the heart that are present at birth (congenital heart defects). In some cases, the trisomy appears to result from a balanced chromosomal rearrangement in one of the parents; in others, it is thought to arise from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically).
The chromosomal abnormality was originally reported in the medical literature in1970. Trisomy 9p was first proposed as a distinct syndrome with characteristic symptoms and findings in 1975.
The specific symptoms of trisomy 9p can vary greatly from one person to another due, in part, to the specific length of the duplicated material on chromosome 9p.
Trisomy 9p is often characterized by low muscle tone (hypotonia) as well as growth deficiency and delayed bone maturation, which means that the rate of growth and development of the bones is slower than in individuals with 46 chromosomes. Hypotonia can affect infants, most often related to difficulty feeding, resulting in the failure to gain weight and grow at the expected rate (failure to thrive). In general, growth deficiency primarily begins after birth (postnatally). Some infants may also experience oropharyngeal dysphagia, in which there is difficulty emptying food or drink from the back of the throat at the back of the mouth (oropharynx) into the esophagus. However, reports indicate that, in those with larger trisomic segments (e.g., through bands 9q22 or 9q32), growth deficiency may begin before birth (intrauterine growth retardation). Microcephaly, a condition indicates that the head circumference is smaller than would be expected based upon an infant’s age and gender, is also apparent in infancy.
In many cases, trisomy 9p is also associated with varying degrees of intellectual disability, ranging from moderate to severe, and delays in the acquisition of skills requiring the coordination of mental and physical activities (developmental coordination disorder). According to reports in the medical literature, language development appears to be most severely delayed. Learning disabilities, ranging from mild to severe, also occur. Intellectual and learning issues go hand in hand. Intellectual and learning disabilities represent a broad range, especially when the children with partial trisomy 9p are considered as well. The gap with typically developing peers will often widen with age.
Many infants and children with trisomy 9p also have a characteristic facial appearance. Most individuals with this condition present with a short and broad head (brachycephaly); a wide mouth with downturned corners; a prominent, relatively bulbous nose; large, low-set, “cup-shaped” ears; and/or a short vertical groove in the center of the upper lip (philtrum). Characteristic eye abnormalities may also be present, such as deeply set, widely spaced eyes; downwardly slanting eyelid folds (palpebral fissures); vertical skin folds that may cover the eyes’ inner corners (epicanthal folds); and/or abnormal deviation of one eye in relation to the other (strabismus). Some affected infants may also have a short, webbed neck; a highly arched roof of the mouth (palate); and/or widely spaced nipples. Teeth may erupt later than expected and may emerge crooked. In addition, in those with larger trisomic segments, additional craniofacial features may include a small jaw (micrognathia), incomplete closure (clefting) of the roof of the mouth (cleft palate), and/or an abnormal groove or gap in the upper lip (cleft lip).
Many individuals with trisomy 9p may also have various anomalies of the hands and feet. These may include decreased length of specific bones of the fingers and toes (phalanges) and within the hands (metacarpals) and feet (metatarsals); short fingers and toes (digits) with small nails; and/or the pinkies may be fixed or ‘locked’ in a bent position (clinodactyly). The syndrome may also be associated with unusual, distinctive skin ridge patterns of the fingers and hands (abnormal dermatoglyphics), including a single flexion crease on the fifth fingers and a reduced total finger ridge count. Less often, a single crease across the palms may also be present.
In some cases, trisomy 9p may be associated with skeletal defects including delayed closure of the “soft spots” (fontanels) and the fibrous joints (cranial sutures) between certain? bones of the skull; a deformity in which the foot is twisted out of shape or position (clubfoot); and/or abnormal front-to-back or side-to-side curvature of the spine (kyphoscoliosis) that may develop during the second decade of life. Less commonly, partial webbing (syndactyly) of certain fingers and toes and dislocation of the hips at birth have been noted.
Approximately five to 25% of children with may also have congenital heart defects, particularly an abnormal opening in the partition (septum) that separates the two lower chambers (ventricles) of the heart (ventricular septal defects [VSDs]). In those with cardiac defects, associated symptoms and findings may vary, depending upon the size, nature, and/or combination of heart malformations present. For example, in some cases, such as those with small, isolated VSDs, no symptoms may be apparent (asymptomatic). However, in other instances, such as children with larger VSDs and/or other cardiac defects, associated symptoms and findings may include difficulties feeding, shortness of breath, profuse sweating, irritability, fatigue, bluish discoloration of the skin and/or mucous membranes (cyanosis. In severe cases, congenital heart disease may lead to potentially life-threatening complications. Surgery may be necessary to remedy heart defects along with follow-up care and monitoring.
In some instances, additional physical abnormalities have been reported. These have included genital malformations in affected males, such as undescended testes (cryptorchidism) and/or abnormal placement of the urinary opening (hypospadias); kidney (renal) malformations; protrusion of part of the intestine and the fold of fatty membrane in front of the intestine (omentum) through a defect in the abdominal wall at the navel (umbilical hernia); and/or hydrocephalus, in which blockage of the normal flow of spinal fluid leads to excessive amounts of cerebrospinal (CSF) fluid accumulating in and around the brain. This leads to abnormally high pressure within the skull and swelling of the head, and can result in neurological impairment. CSF is the watery protective fluid that circulates through the cavities (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 upon the age at symptom onset and other factors, associated symptoms may include sudden episodes of uncontrolled electrical activity in the brain (seizures), irritability, vomiting, headache, loss of coordination, deteriorating mental functioning, and/or other findings.
Some individuals may also develop a brain malformation known as Dandy-Walker malformation (DWM). DWM occurs during embryonic development of the cerebellum and 4th ventricle. The cerebellum is an area at the back of the brain that helps coordinate movement, and, to a lesser extent, may be involved with some cognitive and behavioral functions. The 4th ventricle is a space around the cerebellum that channels fluid from inside to around the outside of the brain. DWM is characterized by improper development (e.g. small size and abnormal position) of the middle part of the cerebellum known as the cerebellar vermis, cystic enlargement of the 4th ventricle and enlargement of the base of the skull (posterior fossa). DWM may be associated with hydrocephalus. (For more information on this condition, Search for “DWM’ in the Rare Disease Database.)
Affected children may be below average height for their age (short stature). In some cases, affected children have been diagnosed with growth hormone deficiency.
In many cases, the trisomy appears to result from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons (sporadically). In such de novo cases, the parents of the affected child usually have normal chromosomes and a relatively low risk of having another child with the chromosomal abnormality.
In approximately 50% of cases, trisomy 9p may be due to a balanced chromosomal rearrangement in one of the parents. In most cases, the parental rearrangement is described as a “balanced translocation.” Translocations occur when portions of a chromosome break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. However, no genetic material is gained or lost, only rearranged. 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. Such children may inherit an unaltered set of chromosomes, the same balanced translocation as the parent, or an unbalanced translocation, in which a chromosome has extra (trisomic) or missing (monosomic) genetic material.
Rare cases have also been reported in which the parental chromosomal rearrangement has been an inversion. An inversion is characterized by breakage of a chromosome in two places and reunion of the segment in reverse order from the original arrangement.
Chromosomal analysis and genetic counseling are typically recommended for parents of an affected child to help confirm or exclude the presence of a balanced translocation or other chromosomal rearrangement involving chromosome 9 in one of the parents.
Specific Breakpoints and a “Critical Region”
In individuals with trisomy 9p, all or a portion of the short arm (p) of chromosome 9 (9p) appears three times (trisomy) rather than twice in the cells of the body. In addition, in some cases, a portion of the long arm of chromosome 9 (9q) may also be trisomic (duplicated). In extremely rare cases, individuals with a trisomic portion of 9p may also have a deleted or missing (monosomic) portion.
Evidence indicates that, in many cases, clinical features may be relatively similar among affected individuals despite differing lengths of the duplicated segment of 9p. According to some researchers, such findings suggest that certain characteristic abnormalities associated with the syndrome may result from trisomy of the end (distal) portion of 9p. (“Distal” indicates away or farthest from a particular point of reference, meaning the chromosome’s centromere. The distal region of 9p is sometimes referred to as “9p2” and includes bands 9p21 through 9p24, the latter of which is the end or “terminal” band of 9p [also known as “9pter”].) However, in individuals with larger trisomies, such as those that extend through bands 9p22, additional clinical findings may also be present that appear to correlate with the extent of the duplication.
Generally, according to investigators, trisomies involving part or all of 9p and, in some cases, extending to 9q11-13 may be characterized by intellectual disability and distinctive craniofacial malformations already described. However, in addition to such features, intrauterine growth retardation, congenital heart defects, other skeletal abnormalities (e.g., congenital hip dislocation), and additional craniofacial malformations (e.g., micrognathia, cleft lip and cleft palate) are more common with trisomies extending to or including band 9p21.3-p24. Researchers believe that 9p22 is a “critical” region responsible for most of the classic symptoms of trisomy 9p. However, there are individuals reported in the medical literature who have duplications involving this region and exhibit only mild symptoms. More research is necessary to determine the specific correlation between the duplicated segment of 9p and the associated symptoms and whether additional factors such as modifier genes play a role in the development of specific symptoms in each individual case. twice in the cells of the body. In addition, in some cases, a portion of the long arm of chromosome 9 (9q) may also be trisomic (duplicated). In extremely rare cases, individuals with a trisomic portion of 9p may also have a deleted or missing (monosomic) portion.
In observed cases, trisomy 9p has appeared to affect females approximately twice as frequently as males. As of 2013, more than 150 cases have been reported in the medical literature since the disorder was first described in 1970. Trisomy 9p is the fourth most common type of trisomy after trisomy 21 (Down syndrome), trisomy 18 (Edwards’s syndrome) and trisomy 13 (Patau syndrome).
In some cases, the diagnosis of trisomy 9p may be suggested before birth (prenatally) by specialized tests such as ultrasound, amniocentesis, and/or chorionic villus sampling (CVS). During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing 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. Chromosomal studies performed on such fluid or tissue samples may reveal trisomy of part or all of the short arm of chromosome 9 (9p) and, in some cases, a portion of the long arm (9q).
Trisomy 9p may also be diagnosed and/or confirmed after birth (postnatally) by a thorough clinical evaluation, identification of characteristic physical findings, chromosomal analysis, and other specialized tests. Chromosomes can be obtained from a blood sample.
Clinical Testing and Workup
There are different tests that can be performed on sample tissue for chromosomal analysis. Chromosomes obtained from sample tissue are stained so that they can be viewed more easily and are then examined under a microscope where the duplicated segment of chromosome 9p can be detected (high resolution karyotype). To determine the precise breakpoint on 9p, a more 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 analyze gains (duplications) or losses (deletions) of chromosomal regions. M-array CGH allows for improved definition of breakpoint(s) in trisomy 9p, but it cannot detect balanced rearrangements (such as balanced translocation that sometimes can be diagnosed in one parent of the affected child).
In some cases, diagnostic evaluation may include enzyme tests to detect elevated activity of the galactose-1-phosphate uridyltransferase (GALT) enzyme or the nucleoside triphosphate adenylatekinase (AK3) enzyme, both of which are known to be regulated by genes on the short arm of chromosome 9. In addition, in those diagnosed with trisomy 9p, various specialized tests may be performed to help detect and/or characterize certain abnormalities (e.g., certain skeletal malformations, congenital heart defects, etc.) that may be associated with the syndrome.
The treatment of trisomy 9p is directed toward the specific symptoms and physical findings that are displayed in each individual. Such treatment may require the coordinated efforts of a team of medical professionals, such as pediatricians; surgeons; physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists); physicians who specialize in heart abnormalities (cardiologists); neurologists; and/or other healthcare professionals. Genetic counseling is recommended for families with children affected by this condition. Psychosocial support for the entire family may be needed as well.
Early intervention services during infancy and toddlerhood (before the age of three) are important in ensuring that affected children reach their potential. Early speech therapy for children who experience severe communication and language problems is extremely important. Special services that may be beneficial during childhood include special education, physical therapy, occupational therapy, speech therapy and/or other medical, and social services. In the US, an Individualized Family Support Plan (IFSP) may be developed to guide the early intervention process for infants and toddlers with disabilities. An Individualized Education Program (IEP) may be developed to assist children in school if special services are required, or a Section 504 plan which can ensure that the child receives access to an equal education through accommodations in their learning environment. Vocational and habilitation services are often necessary during adulthood.
Additional treatment for this disorder is symptomatic. For example, for congenital heart defects, treatment with medication, surgical intervention (palliative and/or corrective), and/or other measures may be required. In addition, in some cases, physicians may recommend surgical repair or correction of characteristic craniofacial malformations, skeletal abnormalities, genital defects, hernias, renal anomalies, 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. In addition, growth hormone deficiency has been successfully treated with supplemental growth hormone.
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:
Tracking Rare Incidence Syndromes (TRIS) project
Phone: (618) 453-2311
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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
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Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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