Pentasomy X: Difference between revisions

Pentasomy X is not inherited, but rather occurs via [[nondisjunction]], a random event in [[gamete]] development. In rare cases, it may be related to a parent's chromosomal [[Mosaic (genetics)|mosaicism]]. The [[karyotype]] observed in pentasomy X is formally known as 49,XXXXX, which represents the 49 chromosomes observed in the disorder as compared to the 46 in normal human development.

Pentasomy X is associated with a number of physical anomalies, including short stature, [[clinodactyly]] (incurved [[pinky finger]]s), and distinctive facial features. Common findings include [[microcephaly]], [[low-set ears]], [[hypertelorism]] (wide-spaced eyes), and [[epicanthic folds]].<ref name="nord">{{cite web|url=https://rarediseases.org/rare-diseases/penta-x-syndrome/|title=Penta X Syndrome|work=National Organization for Rare Disorders|vauthors=NORD|date=2020|access-date=7 April 2021}}</ref> The characteristic [[Facies (medical)|facies]] have been described as "coarse",<ref name="pediatrics" /> much like those of the related disorder [[tetrasomy X]].<ref name="hkjpaed">{{cite journal|title=Tetrasomy X in a Child with Multiple Abnormalities: Case Report and Literature Review from China|journal=Hong Kong Journal of Paediatrics|volume=19|issue=1|pages=37–40|date=January 2014|vauthors=Xiong WY, Jiang ZY, Zou CC|url=http://www.hkjpaed.org/details.asp?id=945&show=1234}}</ref> Pentasomy X is unique amongst X-chromosome polysomies for its association with short stature, when most related disorders are associated with tall stature;<ref name="trisomy">{{cite journal|title=A review of trisomy X (47,XXX)|journal=Orphanet Journal of Rare Diseases|volume=5|issue=8|date=11 May 2010|vauthors=Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L|page=8|doi=10.1186/1750-1172-5-8|pmid=20459843|pmc=2883963|doi-access=free}}</ref> the average height in pentasomy X is one [[standard deviation]] below the norm.<ref name="ajmga">{{cite journal|title=Increased number of sex chromosomes affects height in a nonlinear fashion: A study of 305 patients with sex chromosome aneuploidy|journal=American Journal of Medical Genetics Part A|volume=152A|issue=5|pages=1206–1212|date=May 2010|vauthors=Ottesen AM, Aksglaede L, Garn I, Tartaglia N, Tassone F, Gravholt CH, Bojesen A, ((Sørensen K)), ((Jørgensen N)), Rajpert-De Meyts E, Gerdes T, Lind AM, Kjaergaard S, Juul A|doi=10.1002/ajmg.a.33334|pmid=20425825|pmc=5454803}}</ref> [[Hypotonia]], often severe, is a frequent finding, as are related musculoskeletal issues such as [[hip dysplasia]].<ref name="ejp">{{cite journal|title=Tetrasomy and pentasomy of the X chromosome|journal=European Journal of Pediatrics|volume=170|issue=10|pages=1325–1327|date=18 May 2011|vauthors=Schoubben E, Decaestecker K, Quaegebeur K, Danneels L, Mortier G, Cornette L|doi=10.1007/s00431-011-1491-9|pmid=21590264|s2cid=21348257}}</ref> The severity of repeated joint dislocations may lead to a differential diagnosis of [[Larsen syndrome]], as suggested in one reported case.<ref name="ajmg">{{cite journal|title=Pentasomy X with multiple dislocations|journal=American Journal of Medical Genetics|volume=4|issue=4|pages=313–321|date=1979|vauthors=Dryer RF, Patil SR, Zellweger HU, Simpson JM, Hanson JW, Aschenbrenner C, Weinstein SL|doi=10.1002/ajmg.1320040402|pmid=539601}}</ref> [[Bone maturation]] may be delayed.<ref name="hg">{{cite journal|title=X pentasomy: A case and review|journal=Human Genetics|volume=52|issue=1|pages=66–77|date=November 1979|vauthors=Archidiacono N, Rocchi M, Valente M, Filipi G|doi=10.1007/bf00284599|pmid=527976|s2cid=29475412}}</ref> Another skeletal finding is [[taurodontism]], where the [[Pulp (tooth)|pulp]] of the teeth is enlarged into the roots;<ref name="nord" /> other dental abnormalities, such as [[Hypodontia|missing teeth]] and severe [[tooth decay]], have also been reported.<ref name="rgo">{{cite journal|title=Dental care for an adolescent with chromosome pentasomy: rare case report with a two year follow-up|journal=Revista Gaúcha de Odontologia|volume=63|issue=4|pages=507–511|date=2015|vauthors=Alves NS, Assaf AV, Martins AM, Rodrigues Cajazeira MR, Antunes LS, Silveira FM|doi=10.1590/1981-863720150003000223052|doi-access=free}}</ref> These findings are not specific to pentasomy X, but rather common to sex chromosome [[Aneuploidy|aneuploidies]] in general and in particular show a strong resemblance to the male counterpart [[49,XXXXY]].<ref name="tjp">{{cite journal|title=The 49,XXXXX chromosome constitution: Similarities to the 49,XXXXY condition|journal=The Journal of Pediatrics|issue=78|volume=2|pages=285–290|date=1971|vauthors=Sergovich F, Uilenberg C, Pozsonyi J|doi=10.1016/s0022-3476(71)80013-6|pmid=5539772}}</ref> Epicanthic folds and hypertelorism are also observed in tetrasomy and [[trisomy X]],<ref name="trisomy" /> while clinodactyly and radioulnar synostosis are seen in all sex chromosome aneuploidies<ref name="pediatrics" /><ref name="ddrr">{{cite journal|title=Effects of Sex Chromosome Aneuploidies on Brain Development: Evidence From Neuroimaging Studies|journal=Developmental Disabilities Research Reviews|volume=15|issue=4|pages=318–327|date=2009|vauthors=Lenroot RK, Lee NR, Giedd JN|doi=10.1002/ddrr.86|pmid=20014372|pmc=2996824}}</ref><ref name="orphanet">{{cite journal|title=Klinefelter syndrome and other sex chromosomal aneuploidies|journal=Orphanet Journal of Rare Diseases|volume=1|issue=1|date=24 October 2006|vauthors=Visootsak J, Graham JM|page=42|doi=10.1186/1750-1172-1-42|pmid=17062147|pmc=1634840|doi-access=free}}</ref> and taurodontism is specifically common to X-chromosome polysomies.<ref name="xyclinic">{{cite journal|title=The eXtraordinarY Kids Clinic: an interdisciplinary model of care for children and adolescents with sex chromosome aneuploidy|journal=Journal of Multidisciplinary Healthcare|volume=8|issue=1|date=17 July 2015|vauthors=Tartaglia N, Howell S, Wilson R, Janusz J, Boada R, Martin S, Frazier JB, Pfeiffer M, Regan K, McSwegin S, Zeitler P|pages=323–334|doi=10.2147/JMDH.S80242|pmid=26229481|pmc=4514383 |doi-access=free }}</ref>

Puberty is altered in pentasomy X, although as few adults with the condition have been reported, the full scope of such alterations is unclear. In the sister condition of tetrasomy X, half of all women undergo puberty normally, while half have no or incomplete puberty.<ref name="pediatrics" /> Some adolescents and adults with pentasomy X have been prepubertal,<ref name="pediatrics" /> while some have had [[premature ovarian failure]] (early menopause)<ref name="ip">{{cite journal|title=Mosaic Pentasomy X/Tetrasomy X Syndrome and Premature Ovarian Failure|journal=Indian Pediatrics|volume=48|issue=5|pages=402–404|date=17 May 2011|vauthors=Wood A, Kleis L, Toriello H, Cemeroglu AP|pmid=21654007|url=https://indianpediatrics.net/may2011/402.pdf}}</ref> and some have had apparently non-noteworthy pubertal development.<ref name="mc">{{cite journal|title=Detailed analysis of X chromosome inactivation in a 49,XXXXX pentasomy|journal=Molecular Cytogenetics|volume=2|issue=20|date=7 October 2009|vauthors=Moraes LM, ((Cardoso LCA)), ((Moura VLS)), ((Moreira MAM)), Menezes AN, Llerena JC, Seuánez HN|page=20|doi=10.1186/1755-8166-2-20|pmid=19811657|pmc=2766382|doi-access=free}}</ref><ref name="eshg">{{cite journal|title=Multiple anomalies in an adult case with pentasomy X|journal= European SocietyJournal of Human Genetics|volume=27|issue=2|pages=1518–1519|date=10 October 2019|vauthors=Stoicanescu DL, Cevei ML, Gug CR, Simedrea A|doi=10.1038/s41431-019-0494-2 |pmc=6876493|doi-access=free}}</ref> Though external genitalia is generally normal, underlying gonadal dysfunction is frequent, including ovarian dysfunction or an unusually small uterus.<ref name="ajmg2" /> No cases are known of women with pentasomy X having children, but although fertility is likely reduced, some may be able to.<ref name="ajmg3">{{cite journal|title=Renal Hypodysplasia and Unilateral Ovarian Agenesis in the Penta-X Syndrome|journal=American Journal of Medical Genetics|volume=6|issue=2|pages=153–162|date=1980|vauthors=Toussi T, Halal F, Lesage R, Delorme F, Bergeron A|doi=10.1002/ajmg.1320060209|pmid=7446561}}</ref>

A number of disorders have been reported as comorbid with sex chromosome aneuploidies, including pentasomy X. In one case report, pentasomy X occurred alongside the similarly rare [[hyperimmunoglobulin E syndrome]].<ref name="ejp2">{{cite journal|title=Pentasomy X and hyper IgE syndrome: co-existence of two distinct genetic disorders|journal=European Journal of Pediatrics|volume=158|issue=9|pages=723–726|date=1999|vauthors=Boeck A, Gfatter R, Braun F, Fritz B|doi=10.1007/s004310051187|pmid=10485303| s2cid=24979780 }}</ref> Other possibly coincidental associations have included [[cerebral palsy]]<ref name="eshg" /> and [[Dandy-WalkerDandy–Walker malformation]].<ref name="fdt">{{cite journal|title=Dandy-Walker malformation in a fetus with pentasomy X (49,XXXXX) prenatally diagnosed by fluorescence in situ hybridization technique|journal=Fetal Diagnosis and Therapy|volume=10|issue=5|pages=333–336|date=October 1995|vauthors=Myles TD, Burd L, Font G, McCorquodale MM, McCorquodale DJ|doi=10.1159/000264254|pmid=7576173}}</ref>

Pentasomy X is caused by [[nondisjunction]], a process through which [[gametes]] (eggs or sperm) with too many or too few chromosomes are produced. In nondisjunction, [[homologous chromosome]]s or [[sister chromatid]]s fail to separate properly when producing gametes.<ref name="mb">{{cite journal|title=Mechanisms of oocyte aneuploidy associated with advanced maternal age|journal=Mutation Research/Reviews in Mutation Research|volume=785|date=4 July 2020|vauthors=Mikwar M, MacFarlane AJ, Marchetti F|page=108320|doi=10.1016/j.mrrev.2020.108320|pmid=32800274|s2cid=221142882 |doi-access=free}}</ref> In sex chromosome tetrasomy and pentasomy, the extra chromosomes are consistently inherited from one parent.<ref name="pediatrics" /> In the specific case of pentasomy X, all known cases have inherited the additional chromosomes from the mother. This has been suggested to relate to [[genomic imprinting]]; specifically, it is hypothesized that specific [[Locus (genetics)|loci]] on the sex chromosomes are affected by imprinting such that only maternal overimprinting is survivable, and cases of pentasomy X where the additional chromosomes were inherited from the father would be incompatible with life.<ref name="abc">{{cite journal|title=Análisis clínico y molecular de una pacientecon pentasomia del cromosoma X|journal=Acta Biológica Colombiana|volume=15|issue=2|pages=61–72|date=May 2010|vauthors=((Arbelaez HEM)), ((Aldana CTS)), ((Bravo NCC)), Ospina SY, ((Mendoza DJF))|language=es|url=https://revistas.unal.edu.co/index.php/actabiol/article/view/9351}}</ref> As well as during gamete development, nondisjunction can occur after conception, resulting in a [[Mosaic (genetics)|mosaic]] karyotype.<ref name="hru">{{cite journal|title=Meiotic and mitotic nondisjunction: lessons from preimplantation genetic diagnosis|journal=Human Reproduction Update|volume=10|issue=5|pages=401–407|date=1 October 2004|vauthors=Kuliev A, Verlinsky Y|doi=10.1093/humupd/dmh036|pmid=15319376|doi-access=free}}</ref>

Nondisjunction is related to [[advanced maternal age]],<ref name="bop">{{cite journal|title=Meiotic Origins of Maternal Age-Related Aneuploidy|journal=Biology of Reproduction|volume=86|issue=1|pages=1–7|date=1 January 2012|vauthors=Chiang T, Schultz RM, Lampson MA|doi=10.1095/biolreprod.111.094367|pmid=21957193|pmc=3313661|doi-access=free}}</ref> although due to its rarity, the maternal age effect in pentasomy X is unclear.<ref name="crog">{{cite journal|title=A New Case of Prenatally Diagnosed Pentasomy X: Review of the Literature|journal=Case Reports in Obstetrics and Gynecology|volume=2015|date=29 January 2015|vauthors=((Pirollo LMA)), Salehi LB, Sarta S, Cassone M, Capogna MV, Piccione E, Novelli G, Pietropolli P|page=935202|pmc=4325205|doi=10.1155/2015/935202|pmid=25699192|doi-access=free}}</ref> More common [[aneuploidy]] syndromes, such as [[Down syndrome]] and [[Klinefelter's syndrome]], have strong relationships with maternal age.<ref name="ds">{{cite book|title=Genetics and Etiology of Down Syndrome|chapter=Etiology of Down Syndrome: Risk of Advanced Maternal Age and Altered Meiotic Recombination for Chromosome 21 Nondisjunction|pages=23–31|last1=Dey|first1=Subrata Kumar|last2=Ghosh|first2=Sujoy|publisher=IntechOpen|location=London|date=29 August 2011|isbn=978-953-307-631-7}}</ref><ref name="jcem">{{cite journal|title=Prenatal and Postnatal Prevalence of Klinefelter Syndrome: A National Registry Study|journal=Journal of Clinical Endocrinology & Metabolism|volume=88|issue=2|pages=622–626|date=1 February 2003|vauthors=Bojesen A, Juul S, Gravholt GH|doi=10.1210/jc.2002-021491|pmid=12574191|doi-access=free}}</ref> Pentasomy X is not inherited<ref name="nord" /> and is not caused by the actions of the parents.<ref name="emm">{{cite journal|title=Etiology of nondisjunction in humans|journal=Environmental and Molecular Mutagenesis|volume=25|issue=S2|pages=38–47|date=1995|vauthors=Abruzzo MA, Hassold TJ|doi=10.1002/em.2850250608|pmid=7789361|bibcode=1995EnvMM..25S..38A | s2cid=24355576 }}</ref> However, in rare cases, pentasomy X may be related to chromosomal mosaicism in a parent.<ref name="unique" /><ref name="pr">{{cite journal|title=A penta X female (49,XXXXX): a result of parental mosaicism?|journal=Pediatric Research|volume=15|issue=556|page=1981|date=1 April 1981|vauthors=Muneer RS, Stone JR, Stupca PJ, Kamat SB, Thompson LM, Rennart OM|doi=10.1203/00006450-198104001-00768|doi-access=free}}</ref>

The phenotype of pentasomy X has also been compared to that of [[Turner syndrome]], characterisedcharacterized by a female having one copy of the X chromosome. Both Turner's and pentasomy X are female-only disorders characterisedcharacterized by short stature, heart defects, and abnormal pubertal development. However, the intellectual disabilities observed in pentasomy X are rare in Turner syndrome.<ref name="nord" />

| ICD10ICD11 = Q97{{ICD11|LD50.1Y}}

| ICD9 ICD10 = <!--{{ICD9ICD10|xxxQ97.1}}-->

| ICD10CM ICDO = <!-- {{ICD10CM|Xxx.xxxx}} = -->

| OMIMICD9 = {{ICD9|758.81}}

| ICDO DiseasesDB =

| OMIM MedlinePlus =

| DiseasesDB eMedicineTopic =

| SNOMED MeSH CT = C53531943248007

| Curlie GeneReviewsNBK =

| Orphanet eMedicineSubj = 11