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Last updated:
11/6/2023
Years published: 1996, 1997, 2001, 2015, 2018, 2023
NORD gratefully acknowledges Deborah A. Bruns, PhD, Professor, Special Education Program, School of 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 and 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 patients, associated symptoms and findings may be relatively similar among affected infants despite differing lengths of the duplicated segment. However, in those with larger areas with the additional copy (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. Conversely, some individuals with duplications of specific areas of chromosome 9p display mild or subtle symptoms – is this referring to phenotypic characteristics and/or possible medical issues.
Children with trisomy 9p often have delays in reaching developmental milestones including crawling and walking, growth deficiency and distinctive differences of the skull and facial (craniofacial) region. As children grow older, intellectual disability may become apparent in difficulties learning to read and write and other academic tasks. Special education services are often needed. In some patients, additional physical characteristics may also be present, such as other skeletal differences and/or structural malformations of the heart that are present at birth (congenital).
The chromosomal abnormality was originally reported in the medical literature in1970 by Rethore. Trisomy 9p was first proposed as a distinct syndrome in 1975.
The specific symptoms of trisomy 9p can vary greatly from one individual to another due, in part, to the specific length of the duplicated or deleted material related to the p arm.
Trisomy 9p is characterized by low muscle tone (hypotonia) as well as growth deficiency and delayed bone maturation (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 less weight gain and overall growth at the expected rate (failure to thrive). Some infants may also experience oropharyngeal dysphagia, in which there is difficulty emptying food or drink from the mouth or throat (oropharynx) into the esophagus. Reports indicate that, in individuals with larger trisomic segments (e.g., through bands 9q22 or 9q32), growth deficiency may begin before birth. In general, growth deficiency primarily begins after birth.
In many patients, trisomy 9p is also associated with varying degrees of intellectual disability, ranging from mild to severe, and delays in the acquisition of skills requiring coordination of neurological and physical processes. According to reports in the medical literature, language development may be delayed. Learning disabilities, ranging from mild to severe, may also occur. Intellectual and learning disabilities represent a broad range, especially when the children with conditions such as partial trisomy 9p are considered as well. The gap between patients with trisomy 9p and typically developing peers may widen with age.
Individuals with trisomy 9p also have a characteristic facial appearance 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 differences 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 deviation of one eye in relation to the other (strabismus). Some individuals may also have a short, webbed neck. 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), highly arched roof of the mouth (palate), 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 differences 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 patients, trisomy 9p may be associated with skeletal differences including delayed closure of the “soft spots” (fontanels) and the fibrous joints (cranial sutures) between bones of the skull, clubfoot, and/or curvature of the spine (kyphosis, scoliosis) that may develop during the second decade of life. Additional conditions which may be present are partial webbing (syndactyly) of two or more fingers and toes and dislocation of the hips at birth or later in development have been noted.
Approximately five to 25% of individuals with a trisomy 9p variant 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]). Associated symptoms and findings depend on the size, type and/or combination of heart defects present. For example, with small, isolated VSDs, no symptoms may be apparent (asymptomatic). However, in other instances, such as individuals with larger VSDs and/or other cardiac defects, there may also be 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 patients, additional physical abnormalities have been reported. Individuals may have widely spaced nipples, 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), and/or a defect in the abdominal wall at the navel (umbilical hernia).
There is also the possibility of hydrocephalus, in which blockage of the flow of spinal fluid leads to excessive amounts of cerebrospinal (CSF) fluid accumulating in and around the brain which can lead to high pressure and swelling within the skull. 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 (subarachnoid space). Depending upon the age at onset and other factors, associated symptoms may include uncontrolled electrical activity in the brain (seizures), irritability, vomiting, headaches, loss of coordination and changes in neurological functioning.
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 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 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 also be associated with hydrocephalus. (For more information on this condition, Search for “DWM’ in the Rare Disease Database.)
Many individuals with a trisomy 9p variant may be below average height for their age (short stature). Some patients have been diagnosed with growth hormone deficiency. Some individuals have been successfully treated with supplemental growth hormones but the use of growth hormones to assist growth is a controversial topic.
In many patients, the trisomy appears to result from spontaneous (de novo) errors very early in embryonic development that occur for unknown reasons. In such 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 patients, trisomy 9p may be due to a balanced chromosomal rearrangement in one of the parents. Translocations occur when portions of a chromosome break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. No genetic material is gained or lost; it is rearranged. If a chromosomal rearrangement is balanced, 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 for the carrier’s offspring who 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 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 patients, a portion of the long arm of chromosome 9 (9q) may also have three copies. 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 patients, 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 characteristics 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”].)
Generally, trisomies involving part or all of 9p and, in some cases, extending to 9q11-13 may be characterized by intellectual disability and distinctive craniofacial features already described. However, in addition to such features, intrauterine growth delay, congenital heart defects or other skeletal abnormalities (e.g., congenital hip dislocation), and additional craniofacial differences (e.g., micrognathia, cleft lip and cleft palate) are more common with three copies 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 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 play a role in the development of specific symptoms in each affected person.
Based on documented cases, trisomy 9p has appeared to affect females approximately twice as frequently as males. As of 2023, at least 225 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. In addition, during an amniocentesis, a sample of amniotic fluid (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. Chromosome testing can be done on 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 easily viewed 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 normal DNA is mixed with an individual’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 such as skeletal malformations and congenital heart defects that are associated with the syndrome.
Treatment
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; specialists 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 also recommended. Psychosocial support may be recommended or needed as well.
Early intervention services before the age of three are important in ensuring that affected children reach their potential. Early speech therapy for children who experience communication and language delays is extremely important. After the third birthday, school-based services include special education, physical therapy, occupational therapy, speech therapy and/or social services. In the US, an Individualized Family Support Plan (IFSP) is developed to guide the early intervention process for infants and toddlers. An Individualized Education Program (IEP) is developed to assist school-age children, or a Section 504 plan is written to ensure access to an equal education through accommodations in their learning environment. Vocational and habilitation services are often necessary during adulthood.
Additional treatment is symptomatic. For example, for congenital heart defects, treatment with medication, and/or surgery may be required. For some patients, physicians may recommend surgery for characteristic craniofacial malformations, skeletal abnormalities, genital abnormalities, hernias, renal anomalies and/or other malformations associated with the disorder. The specific surgical procedures performed will depend upon the nature and severity of each malformation, associated symptoms, and other individual factors. Information sharing with families is key to decision making to encourage optimal outcomes.
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 – delete phone number
Email: tris@siu.edu
Website: https://tris.siu.edu/
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
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
TEXTBOOKS
Jones KL, Jones MC, del Campo Casanelles. Eds. Smith’s Recognizable Patterns of Human Malformation. 8th ed. Elsevier Saunders, Philadelphia, PA; 2021.
Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Gorlin’s Syndromes of the Head and Neck. 5th ed. Oxford University Press, New York, NY; 2010.
Kardon N. Chromosome 9, Trisomy 9p (Multiple Variants). NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:84-85.
JOURNAL ARTICLES
Tkemaladze T, Bregvadze K, Papiashvili N, Gagua S, Abzianidze E. A de novo chromosome 9p duplication in a female child with short stature and developmental delay. SAGE Open Med Case Rep. 2023;11:2050313X231160883. Published 2023 Mar 21. doi:10.1177/2050313X231160883
Cammarata-Scalisi F. Trisomy 9p. A brief clinical, diagnostic and therapeutic description. Trisomía 9p. Una breve descripción clínica, diagnóstica y terapéutica. Arch Argent Pediatr. 2019;117(5):e473-e476. doi:10.5546/aap.2019.eng.e473
Spazzapan P, Arnaud E, Baujat G, et al. Clinical and neuroradiological features of the 9p deletion syndrome. Childs Nerv Syst. 2016;32(2):327-335. doi:10.1007/s00381-015-2957-2
Martín-De Saro MD, Valdés-Miranda JM, Plaza-Benhumea L, et al. Characterization of a Complex Chromosomal Rearrangement Involving a de novo Duplication of 9p and 9q and a Deletion of 9q. Cytogenet Genome Res. 2015;147(2-3):124-129. doi:10.1159/000444138
Samanta D, Ramakrishnaiah R. Novel brain magnetic resonance imaging finding in a patient with trisomy 9p syndrome. Acta Neurol Belg. 2015;115(3):431-432. doi:10.1007/s13760-014-0410-z
Guilherme RS, Meloni VA, Perez AB, et al. Duplication 9p and their implication to phenotype. BMC Med Genet. 2014;15:142. Published 2014 Dec 20. doi:10.1186/s12881-014-0142-1
Kowalczyk M, Tomaszewska A, Podbiol-Polenta A, et al. Another rare case of a child with de novo terminal 9p deletion and co-existing interstitial 9p duplication: clinical findings and molecular cytogenetic study by array-CGH. Cytogenet Genome Res. 2013;139:9-16. https://www.ncbi.nlm.nih.gov/pubmed/22965227
Bouhjar IB, Hannachi H, Zerelli SM, et al. Array-CGH study of partial trisomy 9p without mental retardation. Am J Med Genet A. 2011;155A:1735-1739. https://www.ncbi.nlm.nih.gov/pubmed/21626676
Chen CP, Lin SP, Su YN, et al. Self-injurious behavior associated with trisomy 9p (9p13.1–>p24.3). Genet Couns. 2011;22:327-331. https://www.ncbi.nlm.nih.gov/pubmed/22029177
Hulick PJ, Noonan KM, Kulkarni S et al. Cytogenetic and array-CGH characterization of a complex de novo rearrangement involving duplication and deletion of 9p and clinical findings in a 4-month-old female. Cytogenet Genome Res. 2010;126:305-312. https://www.ncbi.nlm.nih.gov/pubmed/20068300
Al Achkar W, Wafa A, Moassass F, Liehr T. Partial trisomy 9p22 to 9p24.2 in combination with partial monosomy 9pter in a Syrian girl. Mol Cytogenet. 2010;3:18. https://www.ncbi.nlm.nih.gov/pubmed/20920324
Jelin A, Perry H, Hogue J, et al. Clefting in trisomy 9p patients: genotype-phenotype correlation using microarray comparative genomic hybridization. J Craniofac Surg. 2010;21:1376-1379. https://www.ncbi.nlm.nih.gov/pubmed/20856024
Rossi NF, Gatto AR, Cola PC, et al. Oropharyngeal dysphagia and language delay in partial trisomy 9p: case report. Genet Mol Res. 2009;8:1133-1138. https://www.ncbi.nlm.nih.gov/pubmed/19866432
Temtamy SA, Kamel AK, Ismail S, et al. Phenotypic and cytogenetic spectrum of 9p trisomy. Genet Couns. 2007;18:29-48. https://www.ncbi.nlm.nih.gov/pubmed/17515299
Chen CP, Chen CP, Shih JC. Association of partial trisomy 9p and the Dandy-Walker malformation. Am J Med Genet A. 2005;132A:111-112. https://www.ncbi.nlm.nih.gov/pubmed/15523627
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