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http://cpj.sagepub.com/content/16/11/1021The online version of this article can be found at:

 DOI: 10.1177/000992287701601112

1977 16: 1021CLIN PEDIATRJoao A. M. Santana, Lytt I. Gardner and Richard L. Neu

PhenotypeThe X Isochromosome-X Syndrome [46,X,i(Xq)]: Report of Three Cases with Review of the

  

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1021

GENETICS

The X Isochromosome-X Syndrome[46,X,i(Xq)]Report of Three Cases with Review of the Phenotype

Joao A. M. Santana, M.D.,* Lytt I. Gardner, M.D., Richard L. Neu, Ph.D.†

From the Genetic and Endocrine Unit, Departmentof Pediatrics, State University of New York, UpstateMedical Center, Syracuse, New York.This investigation was supported in part by Contract

C-60793 from the Birth Defects Institute, New YorkState Department of Health, Albany, New York. Dr.Santana was the recipient of a fellowship from RotaryInternational, Evanston, Illinois.

* Department of Physiology, Federal University of

Sergipe, Aracaju, Sergipe, Brazil.t Division of Human Genetics, Children’s Hospital

of Buffalo, 86 Hodge Ave., Buffalo, New York 14222.Correspondence to: Lytt I. Gardner, M.D., Depart-

ment of Pediatrics, State University of New York,

Upstate Medical Center, 750 East Adams Street, Syra-cuse, NY 13210.

It is important not to confuse the 46,X,i(Xq) syndrome with the 45,X classi-cal Turner’s syndrome. There are profound cytogenetic and clinical dif-ferences between the two syndromes, which must be borne in mind in thedifferential diagnosis of amenorrhea and of infertility.

CORRELATION of karyotype with

phenotype has become increasingly importantas the number r~f’ cytogenetic syndromes hasproliferated, in order to enable the clinicianto utilize available clinical clues as aids in

differential diagnosis. rrhis i5 exemplified inclassical 45,X Turner’s syndrome, which mustbe separated out from numerous other syn-dromes involving structural abnormalities ofthe X chromosomes. One of the most con-

fusing of these is the X isochromosome-Xsyndrome 46,X,i(Xq), in which the patient

‘

presents with some, or many, of the featuresof45,X Turner’s syndrome, yet has a positive

buccal smear for the X-chromatin t~c>cl~’.~‘The present report reviews the clinical and

cytogenetic findings in three new patients withthe 46,X,I(Xq) syndrome (and in 41 previouslypublished cases) and contrasts these findingswith those c~f 4~,X Turner’s syndrome.

‘

Materials and Methods ‘

The buccal smears from each patientwere stained with eresyl-~Tiolet; and 200 cellswere examinee! for X-chromatin bodies.

Peripheral blood leukocyte cultures were

initiated using Chromosome Medium 1A

(GIBCO, C3rancl Island, NY 14072). Thechromosome preparations were stained withGiemsa stain; 30 metaphases from each pa-tient were counted and examined for the

presence or absence of an isochromosome X.

* When the karyotype contains one normal X chromo-some and one X chromosome composed of two longarms, this is designated as: ‘46,~;i(~c~), according to

the nornencl~ture’c3f the 1971 Paris Conference. Ref.Pa-TH CoH/cr<’Kf<’ (’~97~.’ ~te~~clcta~r~zzca~abrz in Humati C~’tr~-~M~tfj. Birth Defects: Original Article Series, VMI:7,1972, The National Foundation, New York. The letter! indicates an isochromosome, and the letter q indicates

that it is composed of long arms.

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l~..atii.t&dquo;, 1. <’,7~~Yy/ itul I_rrGrrrrrta~~ ill Ihv 3 Ccr.sm.s

rjf =l~~,‘~,t~Xtf? 51’trrf~~nirar< 1)r~sr rrbr·~I in ~l.‘frl.s I~r-~~or7

Case ReportsCase 1, A white girl, was seen ttt agc ’17 4/12

years of age with the chief r:rr~tapl~tii~t of primaryamenorrhea, lack of secondary sexual characteris-tics, and short stature. There was no family historyof delayed menarche or short stature. She has foursiblings: three sisters 19, 16, and l0 years old, and abrother, age 12. She was the product of a full-termgestation and had a normal vertex delivery. Therewere no problems during the newborn period.From age 3 to 4 she had chronic otitis media.She had a moderate refractive error and wore

corrective glasses. Neck was negative to examina-tion. Heart sounds were normal, and withoutmurmurs. Pubic and axillar~~ hair was somewhatsparse, but distributed in the normal femalepattern. Her fingers and toes were short, withno abnormalities of the nails. Femoral pulses werenormal. Pelvic examination re~-ealed a very smalluterus; no ovaries could be felt. The externalgcnitalia showed signs of atrophy, with a very

granular, eroded cervix. See Table I for addi-tional physical findings.

C;hemi~al measurements on serum revealed noabnormalities. Endocrine studies were as follou,s:serum pituitary gonadotrophins (FSH) were 2.9

miihinternationa) units per rtal: (I~’~H by tV zcli{j-immunoassay:no!’n)a)4to3()f()radn)tfe)na!e).Urinary t7-ketos!eroids were 4,4 mg./24 hrs. (nor-mat5to!5mg./24hrs..adu)t fema!e).0the!resuftsare shown in ‘f <rljle 1.

Cytogenc’tic studies reveaiedahttcca) smear with34 per cent positive X-chronatin bodies. A karvo-type h’om peripheraf teucocytes demonstrated achromosoma) constitution of 46,X,i(X()).Case 2. A white girt was seen af age t6 with the

chief Complaint of anienorrheaandshort stature..She was the prodttct of a norma!!u!!term pregnancv an(i detivery. There was nofamity history of deiavedmenarche. The patientshad two.sisters with nortna! stature and normalonset of menarche.

At age I F3 the patient ha<! two menses of 3 days’duration each. with a light How. She had not hadany periods u ilic 3 %ears.sincefhen.At thetimeoi the menses she began tohaveheafi-aches which haveonninued. and which were

characterized 1)~- c>ec-ilait;ll pains witt) radiation.The patient had used corrective tenses since ~ig(.At age !3.she was said I() have Iiii(i some thy-roid entargement. which (Hsappcared. She hadta<at~rrzatl clewelc>!>,aac·rut both sociattv and acadenn-catty.She ch(t not lt;m= t~l3itniatlaaf Iialcis, few-set ears,

pterygintnconior ’e’tll~ituts ~rtl;r;lzs: the thyroidsia<aw~cc! rz<’i ~i~if>lo ftl~izc,rAtaulit~..‘~lac loiii n ttrraclc~zwy~to tnitdketoid formation, with lcat-<lI fai~rmc~i~ttzti<ii~and absence oftntis taxa. Axittary hair was scanty.Pubic bait had it normatfematefnstribution. Fe-moral f>izlsati<ar3s were 1’eivic examinationshowed a we)i-supporte(i vagina! mucosa, and actean and we!)-epithehaii/ed (et vix. The ntcrns wassmall with a f’tiii(lo(-,ervl(7~il ratio.and the fmu)usoniys)ight)y greater in cnameterthan the cervix. Neither the ovaries nor the ad-nexa were palpable. Other physical findings are inTable 1.

’

Fasting blood sugar was 108 mg.% and serumcreaunine was 0.t) rzi~.‘7c. Urinary gonadotrophinswere between 16 and 50 mouse uterine unitsper 24 hrs (tiortiial range for a~ir~ts: 6-50 MUUper 24 lirs). Urinarv total estrogens were 9 gg per24 hrs (normal range in nonpregnant women,preovuiatory phase: 5 to 25 /g/24 fir).

cyto’geiiet,ic studies reveated a chromosomalconstitution of 46,X,i(Xq) from peripheral teuco-cytes.Case 3. A white girl (Fig. I, left) was first

seen at age 6 2/12 years with a complaint ofshort stature. There had been a normal 8 months

pregnancy and delivery. Her fraternal twin died inthe newborn period from &dquo;immaturity.&dquo; Both

parents and grandparents were of average height.She has three sisters, living and well, with normalstature. There were no difficulties in the neona-tal period nor in the first few months of life,except for &dquo;heavy ’hreachirz~,&dquo; which interferedwith sucking. She was said to have had a con-

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F1~. la. Case no- 3, with a karyotype of 46,X,i(Xq),is shown in la. She was 6 4/12 years of age when

the photograph was taken. Her height-age was 3 8/12years. Her relatively normal appearance contrasts withthat of a 10 year old girt with classical 45,X Turner’ssyndrome in lb.

FIG. l b. See legend to Fig. l a.

stantly running nose for the first two years of

life. She started wearing glasses at.2 % years ofage. At age 10 years she had repeated bouts oi fotitis media, sinusitis, and headaches.Her first episode of menstrual bleeding (men-

arche) came when she was 13 ‘~112 years. After atwo-month interval she began to have regularmonthly bleeding, lasting 3 to 4 days. These arecontinuing.On examination at age 15 9/12 years she ap-

peared small and well-proportioned. Her lineargrowth was below the 3rd percentile, and herweight below the 25th for a 12 year old. Axillaryand pubic hair was found in moderate amount;

the pubic hair had a female distribution. Handswere broad and stubby. The chest and shoulderswere broad. See Table 1 for additional findings.

Cytogenetic studies revealed a buccal smear with26 per cent positive X-chromatin bodies. A karyo-type from peripheral leucocytes demonstrated achromosomal constitution of 46,X,I(Xq). (See Figs.2 and 3.)

Comments

In addition to the three patients with theX isochromosome-X syndrome [46,X;i~~.q)~here presented, we have reviewed, the pheno-type and cytogenetic findings in 41 previouslypublished cases. All 44 patients presentedwith short stature. Only 3 of the 44 had awebbed neck. When compared with 45,X

patients, these 46,X,i(Xq) cases had a lesserincidence of low posterior hair line, short

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1024

P’i(;. 2. K;tt-Notvl)c f-i-oiiiperipheral Jeucocytesof(~aseXo.3.t’heiso<:tu’o-

ntosomefortttetongarmt)f :.111 ~ C~lTt)fi7lt)SfJltlt’ t:23t71-~e Seel] oil tlle cxtl-eille

right, ihe striking dif-ferences bctweett thi.s chro-iiiosotiie pattern and thatof tnonosomy X (45,X!urner’s svndronic) me

demons! rated: there is iri-

sotnyiortheiongarmsoftheX,andnit)n<)S()!))Bforthe short arms. tn45,X(c)assicat) ’t’urncr’s s~zi-

drome there is tnonosotny{of both short andtongaz~z3zs <>f the X chromo-some. Nl()I)osoll)N refers toit ot>z7t#iti~crtt ill will(.I) ()Ile

(’111-ollio.st)tlle (tfiu a partihcrc<>I) <>I’<>iic pair is miss-ing.

neck, hypoplastic nails, tymphedcma, con-genital cardiovascular defects and higharched palate. There appears to be all unusualfrequency of thyroiditis in the latter syn-drome.

TheX-chromatinhod y was found in 30 percent or more of ceHs examined in all cases.When the comparative phenotypic charac-

teristics shown in Table 2 are examined, shortstature appears as a strikingly consistentfeature both in the 46,X,i(Xq} and the 45,Xpatients. The table lists the abnormalitiesin order of descending percentages for 45,Xpatients. The corresponding percentages for

46,X,i(Xq) are shown for comparison on theieft. The percentages which are ~3articularylydiscrepant between the two groups are indi-cated by boldface type in the 46,X,i(Xq)column. The results are similar with respectto: short stature, streak gonads, lack c~f~ovarian foi!ic!es, amenorrhea, short I V meta-carpats and pigmented nevi. hi the presentseries the frequency of mental retardationand partially developed nipples appears to behigher in the isochromosome cases (althoughnot noted in the table, this is also true for

thyroiditis). Other than these, the 46,X,i(Xq) patients exhibit far fewer phenotypic

FI(;.3.Diagran) showinghow. an isochromosomemay form. The upper por-tion shows normal, ‘‘~~e~ ti-cal&dquo; division of the centre*mere, resulting in separa-tion of two homologouschromatids. The Ic»er-

portion illustrates misdi-vision c~f~ the centromerc&dquo;horizontally,&dquo; with subse-(juent formation of iso-chromosomes. Hence, anisuchrotnosome may be defined as: abnormal chromosomewirh twoannsof equai tength, and bearing the sameloci in reverse sequence, formed by transverse rather than !ongitudina! division of the centromere.

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1025

TABLE 2. PhYrtot~ytc- (?/* Pa<:fM~ with -~6,X,~X~J ,S~rrrl~’cirrtr~ as C~m~ar<~ zuitlr -F ~ a P~~-M<.s.

The Dratrt Are E~t-M.~ cr.s :’~‘tcntber .=~~~ferted with Giveii Characteristic us. Totczl Num~’r of’/M~r/Ma/H’~ CM.;~ ,.-<T’at7a&~, rtrirl rllsir us P<’rf<’M~N~ rrf rlffeeterf C~rzaw.s

NOTE: The percentages which are especial discrepattt between the two syndromes are shown in boldface type in the46,X.i(Xq)co)umn.

* Data indicated by asterisk are from the review of Lenui and Smith (19(i3);&dquo; remainder of data on 45,X pheno-type are from Ferguson-Smith (1965).’ For an extensive comparison ofkaryotype-phenotypecorretations see the reviewby Simpson (1975).20

Other than coarctation of the aorta.

abnormalities than do the classical 45,XTurner cases.That such differences may exist is not sur-

prising, considering the profound cytogeneticdifferences between the 45,X and the 46,X,i-

(Xq) karyotypes, the former representingmonosomy X and the latter representing tri-somy for Xq and monosomy for Xp.An association between thyroid autoim-

munity and the X,i(Xq) syndrome has beensuggested by several authors.1,5,16-18 In our re-view, 13 of the 44 cases showed evidence of

thyroiditis. The exact role of the isochromo-some in the pathogenesis of Hashimoto’s

thyroiditis still remains obscure. It is interest-ing that the patients of Engel ei al.9 were

complicated with hypothyroidism and di-

abetes mellitus, and Fujii’s~ patient was com-plicated by hyperthyroidism. The incidence ofdiabetes in our survey does not seem to be

of great enough significance to support anassociation between diabetes and the X,i(Xq)syndrome; on the other hand 13 out of 44cases with thyroiditis is strongly suggestiveof some basic connection between this condi-

tion and the X,i(Xq) syndrome (it should benoted that these 13 cases were identified

in various ways: by serum autoantibodystudies or by biopsy).

In the 14 patients with &dquo;Turner’s syn-drome&dquo; studied for growth hormone byDonaldson et e~l.;l~ one had a 46,X,I(Xq)karyotype. This patient was among the 3

in that series who were described as having&dquo;limited&dquo; growth hormone responses before

‘

and after insulin hypoglycemia, with maxi-mum blood growth hormone values of lessthan 10 ng/ml. Carr et al. 13. reported histologi-cally normal ovaries at postmortem examina-tion in an 8-week-old baby with a 4fi,~;z~~.q)karyotype. That some patients enter pubertyhaving enough primordial follicles and con-sequently enough potential for ovarian func-tion may help explain ovulation and men-struation in some of these cases. Our Case 3

had her menarche at age 13 9/12, followed

by regular monthly bleeding with cycles of 28days, lasting 4 to 5 days. Bahner et c~l.~

and Nakashima and l2cabinson;~ reported twopatients with 45,X Turner’s syndrome who

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1026

had had normal menstruation, normal preg-nancies, and who had delivered normal ba-bies. Due to the lack of rmrrotil follicles instreak gonads, it is expected that most 46,X,i-(Xq) patients tvill be sterile, but they shouldnot be started on estrogen therapy unfitafter an adequate opportunity for spon-taneous menarche has been permitted.

Observations such as the foregoing permitone to make the general observation that cyyto-genetics can be a potent t<>ol in the dif-ferential diagnosis <of- primary amenorrheaor inf~ertilityy, The diagnostic schemata whichhave recently been developed for this purposemake Jtrc~ieic~rzs use of chromosome stu-

dies.21.22

AcknowledgmentI he authors wouid like to acknowledge the technical

assistance of Paula Rosenbaum. B.S. We are mdebtedtcf Dr. Mary L. Voorhess for dimca) and pttotographkdata on Case 3.

References1. Ferguson-Smith, M. A.: Karyotype-phenotype cor-

relation in gonadal dysgenesis and their bearingon the pathogenesis of malformations. J. Med.Genet. 2: 142, 1965.

2. Ree, M. J.: Ovarian dysgenesis and presumed iso-chromosome of the long arm of X. J. Med. Genet.2: 205, 1965.

3. Lindsren, J., Fraccaro, M., Ikkos. D., Kayser, K.,Klinger, H. P., and Luft, R.: Presumptive isochro-mosome for the long arm of X in man. Analysisof five families. Ann. Hum. Genet, (Lond.), 26:383, 1963.

4. Fujii, K.: XX-Isochromosome syndrome complicatedby Basedow’s disease. Jap. J. Clin. Med. 27: 207,1969.

5. Bahner, F., Schwarz, G., Heinz, H. A., and Walter,K.: Turner-syndrom mit voll ausgebildeten sekun-daren geschlectsmerkmalen und Fertilit&auml;t ActaEndocrinol. (Kbh) 35: 397, 1960.

6. Summitt, R. L., and Dobbins, W. T.: Turner syn-drome due to presumptive X-isochromosome. J.Pediatr. 67: 76, 1965.

7. Milet, R. G., Plunkett, E. R., and Carr, D. H.: Go-nadal dysgenesis with XX-isochromosome constitu-tion and abnormal thyroid patterns. Acta Endo-crinol. 54: 609, 1967.

8. Stafford, T. M., Palmer. C. G., and Cleary, R. E.:

Gonadal dysgenesis with isochromosome X andmenstruation. Am. J. Obstet. Gynecol. 116: 886,1973.

9. Engel, E., Northcutt, R. C., and Bunting, K. W.: Dia-betes and hypothyroidism with thyroid auto-antibodies in a patient with a long arm X-isochromosome. J. Clin. Endocrinol. Metab. 29:130, 1969.

10. Grumbach, M. M., Morishima, A., and Taylor, J. H.:Human sex chromosome abnormatities in relationto DNA replication and heterochromatinization.Proc. Nat. Academy Sci. (USA) 49: 581, 1963.

11. Taft, P. D., and Brooks, S. E. H.: Late labelingof X-isochromosome. Lancet 2: 1069, 1963.

12. Donaldson, C. L., Hegienko, L. C., Miller, D., andForsham, P. H.: Growth hormone studies in

Turner’s syndrome. J. Clin. Endocrinol. 28: 383,1968.

13. Carr. D. H., Barr, M. L., and Rathbun, J. C.: Proba-ble isochromosome in a child with multiple con-genital anomalies. J. Pediatr. 62: 696. 1963.

14. Nakashima, I., and Robinson, A.: Fertility in a 45,Xfemale. Pediatrics 47: 770, 1971.

15. Engel, E., and Forbes, A. P.: Cytogenetic and clini-cal findings in 48 patients with congenitally de-fective or absent ovaries. Medicine 44: 135, 1965.

16. Goldberg, M. B., Scully, A. L., Solomon, I. L., andSteinbach, H. L.: Gonadal dysgenesis in pheno-typic female subjects. A review of eighty-sevencases, with cytogenetic studies in fifty-three. Am. J.Med. 45: 529, 1968.

17. Grumbach, M. M., and Morishima, A.: X-chromo-some abnormalities in gonadal dysgenesis: DNAreplication of structurally abnormal X-chromo-somes; relation to thyroid disease. J. Pediatr.65: 1087, 1964.

18. Williams, E. D., Engel E. and Forbes, A. P.: Thyroidi-tis and gonadal dysgenesis. N. Engl. J. Med.270: 805, 1964.

19. Lemli, L., and Smith, D. W.: The XO syndrome:A study of the differential phenotype in 25 pa-tients. J. Pediatr. 63: 577, 1963.

20. Simpson, J. L.: Gonadal dysgenesis and abnormali-ties of the human sex chromosomes: Current sta-tus of phenotypic-karyotypic correlations. In:

Bergsma, D., Ed.: Genetic Forms of Hypogonad-ism, Birth Defects Original Article Series, TheNational Foundation, Vol. XI. No. 4, pp. 23-60,New York. 1975.

21. Khoo, S. K., and Mackay, E. V.: Primary amenor-rhea : Study based on clinical examination, endo-crine assay, chromosomal arralysis and laparo-scopy. Med. J. Aust. 2: 991, 1972.

22. Gilson, M. D., and Knab, D. R.: Primary amenorrhea:A simplified approach to diagnosis. Am. J. Obstet.Gynecol. 117: 400, 1973.

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