case report 45,x/47,xxx mosaicism and short stature

Case Report45X47XXX Mosaicism and Short Stature

Erica Everest12 Laurie A Tsilianidis1 Anzar Haider1 Douglas G Rogers1

Nouhad Raissouni1 and Bahareh Schweiger1

1Cleveland Clinic 9500 Euclid Avenue Cleveland OH 44195 USA2Case Western Reserve University School of Medicine 10900 Euclid Avenue Cleveland OH 44106 USA

Correspondence should be addressed to Erica Everest ericaeverestgmailcom

Received 14 March 2015 Accepted 21 May 2015

Academic Editor Ozgur Cogulu

Copyright copy 2015 Erica Everest et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

We describe the case of a ten-year-old girl with short stature and 45X47XXX genotype She also suffered from vesicoureteric refluxand kidney dysfunction prior to having surgery on her ureters Otherwise she does not have any of the characteristics of Turner norTriple X syndrome It has been shown that this mosaic condition as well as other varieties creates a milder phenotype than typicalTurner syndrome which is what we mostly see in our patient However this patient is a special case because she is exceptionallyshort Overall one cannot predict the resultant phenotype in these mosaic conditions This creates difficulty in counseling parentswhose children or fetuses have these karyotypes

1 Introduction

Turner syndrome (TS) is a condition characterized by shortstature (nearly all girls are lt5 feet tall) sexual underde-velopment a webbed neck and cubitus valgus (forearmangled away from the body) resulting from a 45X cell line[1 2] Further features may include edema of the handsand feet characteristic facies high palate and short fourthmetacarpals [3 4] Additionally renal abnormalities suchas horseshoe kidney can cause serious health problems[5] Most concerning are the cardiac abnormalities such asdilated aortic root which occur in half of the patients [6]Women with TS are unlikely to conceive spontaneously butif they do they are at a high risk of losing the pregnancy orhaving a baby with congenital anomalies or sex chromosomeabnormalities [7] TS occurs in 1 in 2000 female births [8]

Triple X syndrome is the most common female chro-mosomal abnormality occurring in approximately 1 in 1000female births and a review by Tartaglia et al reveals thesubsequent features of the condition [9] Its most commoncharacteristics are tall stature (gt75th percentile) epicanthalfolds clinodactyly and hypotonia Possible additional prob-lems can be seizures renal and genitourinary abnormali-ties and premature ovarian failure The onset of pubertysexual development and fertility are usually normal Also

more common than in the general population are delaysand psychological issues motor and speech delays learningdisabilities attention deficits and mood disorders There isconsiderable variation in the phenotype with this disorderThis is reflected by the fact that only 10 of cases are diag-nosed clinically

Mosaic forms of TS tend to have improved prognosesand milder phenotypes The improved growth and ovarianfunction of 45X46XX patients over 45X patients have beenwell established and the rarer karyotype 45X47XXX (about2 of those with TS) also results in more mildly affected girls[10] The study from Glasgow Scotland evaluated the seven45X47XXXgirls registered in the ScottishTurner Syndromedatabase Three of the seven subjects did not require growthhormone to achieve a satisfactory height in comparison tothe 45X and 45X46Xi(X)(q10) matched subjects all 21of whom required growth hormone Additionally all the45X47XXX subjects underwent spontaneous puberty andall five of those older than twelve had spontaneous menarchewith regular menstrual cycles Only 2 of the 14 girls in the45X comparison group had spontaneous puberty and noneachieved menarche without the use of estrogen This isconsistent with previous findings [11 12] Also none of the45X47XXX girls had cardiac or renal abnormalities thoughtwo had middle ear issues This is in contrast to the 13 of 21

Hindawi Publishing CorporationCase Reports in PediatricsVolume 2015 Article ID 263253 3 pageshttpdxdoiorg1011552015263253

2 Case Reports in Pediatrics

matched subjects with abnormalities to the heart renal sys-tem or both and is in contrast to the 15 of 21 girls withmiddleear issues The study also had a geneticist who was blindedto the genotype of the subjects evaluate for dysmorphicfeatures 45X47XXX subjects had themostmild expressionLastly none of the 45X47XXX subjects had special educa-tion needs in contrast to four in the comparison group Itappears that the haploinsufficiency from the single X chro-mosome in 45X ismitigated by the overtranscription of the Xchromosome that results from having a 47XXX cell line [10]

We report a case of a ten-year-old girl with short statureand a history of renal and urinary tract issues She is a45X47XXX mosaic Overall she represents a mild pheno-type in the fact that she is experiencing few of the Turnerstigmata However she has significant short stature and thishas not been previously well reported

2 Case Presentation

A ten-year-three-month-old female presented to the Pedi-atric Endocrinology Clinic for assessment of short statureAt a height of 4 feet and weight of 51 pounds she is at the054 and 086 percentiles for the CDC 2ndash20-year stature-for-age and weight-for-age data respectively Her parents are oftypical height her mother is 51015840510158401015840 (and had menarche at age12) and her father is 510158401110158401015840 Her past medical history includesvesicoureteric reflux urinary tract infections and decreasedkidney function She was treated with Bactrim from 10 weeksto 3 years for vesicoureteric reflux She had surgery on herureters in 2008 She has Tanner stage 1 pubic hair and breastsnormal genitalia and no axillary hair She has had body odorand acne for a few years Neither the review of systems nor thephysical examination revealed anything out of the ordinaryShe is a fifth grader who is performing well in school

Laboratory data showed a normal complete blood countand comprehensive metabolic panel TSH was 2260120583UmL(0400ndash5500 120583UmL) and free T4 was 13 ngdL (07ndash18 ngdL) Transglutaminase antibody (tTG) was 1 unit (normallt20 units) Insulin-like growth factor I was 243 ngmL (76ndash478 ngmL) Bone age was read and interpreted as 8 years 10months according to the standards of Greulich and Pyle [13]which is considered a normal bone age

Given the normal thyroid function levels hypothyroid-ism is not the cause of her growth failure Celiac disease isalso an unlikely cause of her growth failure because she didnot report abdominal symptoms and her tTG was normalNormal IGF-1 makes growth hormone (GH) deficiency lesslikely because GH stimulates IGF-1 production but does notnecessarily exclude it Despite the patient not having any ofthe other stigmata of TS we ordered a karyotype becausesometimes poor growth is the only presenting symptom

A chromosome analysis was performed Thirty meta-phase cells were examined from synchronized and unsyn-chronized PHA-stimulated peripheral blood cultures Threecells had 45 chromosomes with a single X chromosome(45X) This chromosome complement is associated with TSTwenty-seven cells had 47 chromosomes with three X chro-mosomes (47XXX) No karyotypically normal cells were

identified in the specimen These two cell lines were pre-sumed to have arisen by a nondisjunctional event at a veryearly stage of fetal development

3 Discussion

While 45X47XXX girls have milder phenotypes as dis-cussed previously the outcome for any individual is unpre-dictable In the case of our patient we saw urinary systemmalformations and short stature but no cardiac middle earpubertal or learning issues We are seeing the early stagesof spontaneous puberty and she will probably experiencespontaneous menarche shortly [10]

Our patient has a 1 9 ratio of 45X 47XXX karyotypesin the cells examined from her peripheral blood smearHowever this does not necessarily reflect the distribution ofcells throughout the organ systems of her body Moreovermost patients assessed for Turner syndrome have only beenkaryotyped from one tissue so we do not know whichlines dominate in which organs [2] Researchers at USCMedical Center reported the case of a patient with shortstature whose buccal smear showed 45X46XX47XXX ina 6712310 ratio whose peripheral leukocyte culture showed45X47XXX in a 11 ratio and whose skin fibroblast cultureshowed 45X47XXX in a 519 ratio [14] They confirmeda previous assertion that the proportions of chromosomallydifferent cell lines have little value for phenotype predictionbecause the chromosome makeup is so varied dependingon the sample tissue [15] However they presumed that the47XXX line was dominant because of the minor Turnersyndrome stigmata Yet the 45X line determined her height

In contrast to the notion that the ratios do not have pre-dictive value Akbas et al present the theory that patients withthe 45X47XXX karyotype demonstrate the phenotypes inproportion to their degree of mosaicism [16] They presentthe case of a patient with a 3565 45X47XXX ratioShe has short stature and a horseshoe kidney but what theyotherwise describe as amild phenotypeThey compared theirpatient to a case of a woman with a 9010 45X47XXXratio and a severe phenotype She had streak gonads amen-orrhea thyroiditis short stature and learning difficulties [17]Therefore the cell ratio may be predictive when it comesto the overall assessment of mild phenotype versus severephenotype However height is not affected proportionally asdemonstrated from this case and others reported [2] Giventhat 47XXX girls present with increased height if 90 of ourpatientrsquos sampled cells were 47XXX we would not expect herto be at the 054 percentile for height

Overall making predictions regarding what the futurehas in store for these mosaic girls is nebulous For prenataldiagnosis parents of 45X47XXX girls should be counseledfor the possibility of full Turner symptoms but with optimismfor a better outcome Intellectual impairment is reducedcompared to 45X Turner syndrome which is an importantconcern for parents who may be considering selective termi-nation [2] Future fertility also cannot be guaranteed but canbe successful in most 45X47XXX women [18]

Case Reports in Pediatrics 3

4 Conclusion

Phenotypes of 45X47XXX mosaic girls are unpredictableCell counts that provide a ratio of 45X cells to 47XXX cellsshould not be considered to have predictive value becausethey vary by tissue Fortunately phenotypes tend to bemilderbut the height may be quite short in a way that is out ofproportion to the relative mildness of the remainder of thephenotype Fortunately short stature can be corrected withgrowth hormone so families should be aware that this is apossible requirement for their girls More research will needto be done in this area to assess impact of growth hormoneon 45X47XXX mosaic female with short stature as this hasnot been well studied

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] H H Turner ldquoA syndrome of infantilism congenital webbedneck and cubitus valgusrdquo Endocrinology vol 23 no 5 pp 566ndash568 1938

[2] V P Sybert ldquoPhenotypic effects of mosaicism for a 47XXX cellline in Turner syndromerdquo Journal of Medical Genetics vol 39no 3 pp 217ndash221 2002

[3] D J Wolff D L van Dyke and C M Powell ldquoLaboratoryguideline for turner syndromerdquoGenetics inMedicine vol 12 no1 pp 52ndash55 2010

[4] V P Sybert and E McCauley ldquoTurnerrsquos syndromerdquo The NewEngland Journal ofMedicine vol 351 no 12 pp 1227ndash1270 2004

[5] B Lippe M E Geffner R B Dietrich M I Boechat and HKangarloo ldquoRenal malformations in patients with Turner syn-drome imaging in 141 patientsrdquo Pediatrics vol 82 no 6 pp852ndash856 1988

[6] A E Lin B M Lippe M E Geffner et al ldquoAortic dilationdissection and rupture in patients with turner syndromerdquo TheJournal of Pediatrics vol 109 no 5 pp 820ndash826 1986

[7] Q Zhong and L C Layman ldquoGenetic considerations in thepatient with Turner syndromemdash45X with or without mosai-cismrdquo Fertility and Sterility vol 98 no 4 pp 775ndash779 2012

[8] J Nielsen and M Wohlert ldquoChromosome abnormalities foundamong 34910 newborn children results from a 13-year inci-dence study in Arhus Denmarkrdquo Human Genetics vol 87 no1 pp 81ndash83 1991

[9] N R Tartaglia S Howell A Sutherland R Wilson and LWilson ldquoA review of trisomy X (47XXX)rdquo Orphanet Journal ofRare Diseases vol 5 no 1 article 8 2010

[10] J Blair J Tolmie A S Hollman andMD C Donaldson ldquoPhe-notype ovarian function and growth in patients with 45X47XXXTurnermosaicism Implications for prenatal counselingand estrogen therapy at pubertyrdquo Journal of Pediatrics vol 139no 5 pp 724ndash728 2001

[11] A M Pasquino F Passeri I Pucarelli M Segni and GMunicchi ldquoSpontaneous pubertal development in Turnerrsquos Syn-dromerdquo Journal of Clinical Endocrinology and Metabolism vol82 no 6 pp 1810ndash1813 1997

[12] G Massa M Vanderschueren-Lodeweyckx and P MalvauxldquoPhenotypic effects of mosaicism for a 47XXX cell line in

Turner syndromerdquo European Journal of Pediatrics vol 149 no4 pp 246ndash250 1990

[13] W W Greulich and S I Pyle Radiographic Atlas of SkeletalDevelopment of Hand Wrist vol 2 Stanford University PressStanford Calif USA 1971

[14] S D Frasier and M G Wilson ldquoGrowth pattern in 45X47XXXmosaicismrdquoThe Journal of Pediatrics vol 81 no 1 pp 187ndash188 1972

[15] L Y F Hsu and K Hirschhorn ldquoUnusual Turner mosaicism(45X47XXX 45X46XXqi45X46XXr) detection throughdeceleration from normal linear growth or secondary amenor-rheardquoThe Journal of Pediatrics vol 79 no 2 pp 276ndash281 1971

[16] E Akbas Z M Altintas S K Celik et al ldquoRare types of turnersyndrome clinical presentation and cytogenetics in five casesrdquoLaboratory Medicine vol 43 no 5 pp 197ndash204 2012

[17] L Tauchmanova R Rossi M Pulcrano L Tarantino C Baldiand G Lombardi ldquoTurnerrsquos syndrome mosaicism 45X47XXXan interesting natural historyrdquo Journal of Endocrinological Inves-tigation vol 24 no 10 pp 811ndash815 2001

[18] L Tarani S Lampariello G Raguso et al ldquoPregnancy inpatients with Turnerrsquos syndrome six new cases and review of lit-eraturerdquo Gynecological Endocrinology vol 12 no 2 pp 83ndash871998

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2 Case Reports in Pediatrics

matched subjects with abnormalities to the heart renal sys-tem or both and is in contrast to the 15 of 21 girls withmiddleear issues The study also had a geneticist who was blindedto the genotype of the subjects evaluate for dysmorphicfeatures 45X47XXX subjects had themostmild expressionLastly none of the 45X47XXX subjects had special educa-tion needs in contrast to four in the comparison group Itappears that the haploinsufficiency from the single X chro-mosome in 45X ismitigated by the overtranscription of the Xchromosome that results from having a 47XXX cell line [10]

We report a case of a ten-year-old girl with short statureand a history of renal and urinary tract issues She is a45X47XXX mosaic Overall she represents a mild pheno-type in the fact that she is experiencing few of the Turnerstigmata However she has significant short stature and thishas not been previously well reported

2 Case Presentation

A ten-year-three-month-old female presented to the Pedi-atric Endocrinology Clinic for assessment of short statureAt a height of 4 feet and weight of 51 pounds she is at the054 and 086 percentiles for the CDC 2ndash20-year stature-for-age and weight-for-age data respectively Her parents are oftypical height her mother is 51015840510158401015840 (and had menarche at age12) and her father is 510158401110158401015840 Her past medical history includesvesicoureteric reflux urinary tract infections and decreasedkidney function She was treated with Bactrim from 10 weeksto 3 years for vesicoureteric reflux She had surgery on herureters in 2008 She has Tanner stage 1 pubic hair and breastsnormal genitalia and no axillary hair She has had body odorand acne for a few years Neither the review of systems nor thephysical examination revealed anything out of the ordinaryShe is a fifth grader who is performing well in school

Laboratory data showed a normal complete blood countand comprehensive metabolic panel TSH was 2260120583UmL(0400ndash5500 120583UmL) and free T4 was 13 ngdL (07ndash18 ngdL) Transglutaminase antibody (tTG) was 1 unit (normallt20 units) Insulin-like growth factor I was 243 ngmL (76ndash478 ngmL) Bone age was read and interpreted as 8 years 10months according to the standards of Greulich and Pyle [13]which is considered a normal bone age

Given the normal thyroid function levels hypothyroid-ism is not the cause of her growth failure Celiac disease isalso an unlikely cause of her growth failure because she didnot report abdominal symptoms and her tTG was normalNormal IGF-1 makes growth hormone (GH) deficiency lesslikely because GH stimulates IGF-1 production but does notnecessarily exclude it Despite the patient not having any ofthe other stigmata of TS we ordered a karyotype becausesometimes poor growth is the only presenting symptom

A chromosome analysis was performed Thirty meta-phase cells were examined from synchronized and unsyn-chronized PHA-stimulated peripheral blood cultures Threecells had 45 chromosomes with a single X chromosome(45X) This chromosome complement is associated with TSTwenty-seven cells had 47 chromosomes with three X chro-mosomes (47XXX) No karyotypically normal cells were

identified in the specimen These two cell lines were pre-sumed to have arisen by a nondisjunctional event at a veryearly stage of fetal development

3 Discussion

While 45X47XXX girls have milder phenotypes as dis-cussed previously the outcome for any individual is unpre-dictable In the case of our patient we saw urinary systemmalformations and short stature but no cardiac middle earpubertal or learning issues We are seeing the early stagesof spontaneous puberty and she will probably experiencespontaneous menarche shortly [10]

Our patient has a 1 9 ratio of 45X 47XXX karyotypesin the cells examined from her peripheral blood smearHowever this does not necessarily reflect the distribution ofcells throughout the organ systems of her body Moreovermost patients assessed for Turner syndrome have only beenkaryotyped from one tissue so we do not know whichlines dominate in which organs [2] Researchers at USCMedical Center reported the case of a patient with shortstature whose buccal smear showed 45X46XX47XXX ina 6712310 ratio whose peripheral leukocyte culture showed45X47XXX in a 11 ratio and whose skin fibroblast cultureshowed 45X47XXX in a 519 ratio [14] They confirmeda previous assertion that the proportions of chromosomallydifferent cell lines have little value for phenotype predictionbecause the chromosome makeup is so varied dependingon the sample tissue [15] However they presumed that the47XXX line was dominant because of the minor Turnersyndrome stigmata Yet the 45X line determined her height

In contrast to the notion that the ratios do not have pre-dictive value Akbas et al present the theory that patients withthe 45X47XXX karyotype demonstrate the phenotypes inproportion to their degree of mosaicism [16] They presentthe case of a patient with a 3565 45X47XXX ratioShe has short stature and a horseshoe kidney but what theyotherwise describe as amild phenotypeThey compared theirpatient to a case of a woman with a 9010 45X47XXXratio and a severe phenotype She had streak gonads amen-orrhea thyroiditis short stature and learning difficulties [17]Therefore the cell ratio may be predictive when it comesto the overall assessment of mild phenotype versus severephenotype However height is not affected proportionally asdemonstrated from this case and others reported [2] Giventhat 47XXX girls present with increased height if 90 of ourpatientrsquos sampled cells were 47XXX we would not expect herto be at the 054 percentile for height

Overall making predictions regarding what the futurehas in store for these mosaic girls is nebulous For prenataldiagnosis parents of 45X47XXX girls should be counseledfor the possibility of full Turner symptoms but with optimismfor a better outcome Intellectual impairment is reducedcompared to 45X Turner syndrome which is an importantconcern for parents who may be considering selective termi-nation [2] Future fertility also cannot be guaranteed but canbe successful in most 45X47XXX women [18]


4 Conclusion




References

























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















4 Conclusion




References

























of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















case report 45,x/47,xxx mosaicism and short stature

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