NORD gratefully acknowledges Carole A. Samango-Sprouse, EdD, Director, Neurodevelopmental Diagnostic Center for Children, Associate Clinical Professor in the Department of Pediatrics at George Washington University; Adjunct Associate Professor in the Department of Human and Molecular Genetics at Florida International University, for assistance in the preparation of this report.
Penta X syndrome is an extremely rare chromosomal disorder in which females have three extra X chromosomes. Typically, females have only two X chromosomes, resulting in a 46,XX karyotype. However, in those with penta X syndrome, there are a total of five X chromosomes, resulting in a karyotype of 49,XXXXX. The condition is typically characterized by moderate to severe intellectual disability, short stature, upslanting eyelid folds (palpebral fissures), a flat nasal bridge, malformed ears, and a short neck with a low hairline. Penta X syndrome may also be characterized by mild angulation of the fifth finger (pinky) toward the fourth finger (ring finger) (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers, heart and/or kidney defects, and deficient development of the ovaries and uterus. The disorder results from random errors during the division of reproductive cells in one of the parents. While the exact incidence of this disorder is unknown, researchers believe it occurs in close to one in 85,000 live births, comparable to the male equivalence (49,XXXXY).
Penta X syndrome is characteristically associated with growth delays before birth (prenatal growth deficiency), failure to grow and gain weight at the expected rate after birth (failure to thrive), and short stature. In addition, infants and children with penta X syndrome typically have delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor deficits) and are affected by moderate to severe intellectual disability.
There are several physical features this disorder is characterized by, with the most common being short stature, facial differences and clinodactyly. Because penta X is so rare, there is still much unknown about the phenotype, and associated symptoms vary. It is important to note that affected individuals may not have all of the symptoms discussed below.
Females with 49,XXXXX typically have distinctive facial features. These often include a small head (microcephaly), a round face, upslanting eyelid folds (palpebral fissures), a flat nasal bridge, low-set malformed ears, and/or a short neck with a low hairline. Some affected individuals may also have additional eye (ocular) abnormalities, such as widely spaced eyes (ocular hypertelorism), vertical skin folds that may cover the eyes’ inner corners (epicanthal folds), drooping of the upper eyelids (ptosis), and/or partial absence of tissue from the irides or the colored regions of the eyes (iris colobomas). Additional craniofacial features reported in association with penta X syndrome have included abnormal, rudimentary outgrowths of tissue in front of the external ears (preauricular tags), a small jaw (micrognathia), thick lips, and/or incomplete closure of the roof of the mouth (cleft palate).
Dental abnormalities have been reported in females with 49,XXXXX such as abnormal contact of the upper jaw teeth with those of the lower jaw (malocclusion), unusually shaped molars with large pulp spaces (taurodontism), and/or enamel defects, potentially resulting in premature loss of certain “baby” (deciduous or primary) teeth.
Females with penta X syndrome may have various musculoskeletal defects, such as abnormal fusion of the forearm bones (radioulnar synostosis), narrow shoulders, and/or unusually small hands with abnormal deviation (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers. Additional findings may include overlapping toes, a foot deformity in which the sole is turned inward (metatarsus varus), and/or an abnormality in which the knees are unusually close together and the space between the ankles is increased (“knock knees” [genua valga]). Some affected females also have overflexion, bending (i.e., hyperflexion), or dislocations of multiple joints, including those of the fingers, wrists, shoulders, elbows, and/or hips. Further, reports indicate that some affected individuals may have abnormal skin ridge patterns (dermatoglyphics) on the fingers and palms of the hands.
In some cases, penta X syndrome may be associated with certain structural malformations of the heart at birth (congenital heart defects). Such defects may include an abnormal opening in the fibrous partition (septum) that normally separates the two lower chambers of the heart (ventricular septal defect [VSD]), and/or patent ductus arteriosus (PDA). In PDA, the channel that is present between the aorta and the pulmonary artery during fetal development fails to close after birth, leaving an abnormal opening between the arteries and affecting the supply of oxygenated blood to body tissues.
Some females with penta X syndrome may also have certain kidney (renal) abnormalities, such as underdevelopment of the kidneys (renal hypoplasia) and/or a congenital abnormality in which the two kidneys are joined at the base (horseshoe kidney).
Less often, affected females may have an unusually small uterus, and/or deficient development of the ovaries. Delayed puberty has also been reported.
Penta X syndrome is a chromosomal disorder characterized by the presence of three extra X chromosomes in females. Chromosomes are found in the nucleus of all body cells and carry the genetic characteristics of each individual. There are 46 human chromosomes arranged into 23 pairs, with the 23rd pair determining the sex of the individual. Females with a normal chromosomal make-up (karyotype) have two X chromosomes (46,XX karyotype), receiving one chromosome from the mother and one from the father in each of the 23 pairs.
However, females with penta X syndrome have 49 chromosomes, five of which are X chromosomes (49,XXXXX karyotype). The presence of the three additional X chromosomes results from sporadic, random errors during the division of reproductive cells in one of the parents (nondisjunction during meiosis). Research suggests that the extra X chromosomes are typically derived from the mother, and the risk of such errors may increase with advanced maternal age.
Penta X syndrome is a rare chromosomal disorder that affects only females. Since the syndrome was originally described in 1963 by Kesaree and Wooley, only approximately 40 cases have been reported in the medical literature. The exact incidence of 49,XXXXX is still unknown, however, researchers believe it is close to that of 49,XXXXY (1:85,000).
Some females with penta X syndrome were originally thought to be affected by Down syndrome due to the presence of certain features sometimes associated with the latter disorder. (For further information, please see the “Related Disorders” section of this report below.)
Penta X syndrome may be suspected upon thorough clinical examination and the detection of characteristic physical findings. However, a diagnosis may be confirmed by chromosomal analysis performed on blood samples that can reveal the presence of three extra X chromosomes in body cells.
In some instances, the abnormality may be detected before birth (prenatally) based on non-invasive prenatal testing (NIPT), which screens the fetus for chromosomal disorders and determines those at risk. Chromosomal analysis such as amniocentesis or chorionic villus sampling (CVS) will confirm the diagnosis. 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.
Due to the wide variability in phenotypic outcome, the treatment of penta X syndrome 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 clinical geneticists, clinical psychologists, pediatric speech therapists, physical therapists, and speech and language pathologists. If there are other abnormalities noted then appropriate pediatric medical specialists should be seen.
For some affected individuals with congenital heart defects, treatment with certain medications, surgical intervention, and/or other measures may be necessary. The specific surgical procedures performed will depend upon the severity and location of the anatomical abnormalities and their associated symptoms.
Early intervention is important in ensuring that all girls with penta X reach their optimal outcome. Special services that may be beneficial include special education, pediatric physical, speech, occupational, and developmental therapy, counseling, and/or medical, social, and vocational services. Genetic counseling will also be of benefit for affected individuals and their families.
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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For 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., craniofacial abnormalities, congenital heart defects, intellectual disability].)
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