Arch. Dis. Childh., 1965, 40, 274.

GONADAL DYSGENESISWITH UNUSUAL ABNORMALITIES

BY

K. HUGH-JONES, SHEILA J. WALLACE, JANET M. THORNBER, and N. B. ATKINFrom Mount Vernon Hospital, Northwood, Middlesex

(RECEIVED FOR PUBLICATION NOVEMBER 19, 1964)

Gonadal dysgenesis is the generic term for a groupof conditions characterized by the absence of germcells, and the presence of female internal andexternal genital organs. It can occur on its own-ovarian agenesis (Wilkins and Fleischmann, 1944), orin association with short stature-ovarian dwarfism(Varney, Kenyon, and Koch, 1942), or with multiplecongenital abnormalities-Turner's syndrome(Turner, 1938). It is an example of the last typethat is being reported here. The whole subject hasrecently been comprehensively reviewed by bothHauser (1963) and Lindsten (1963).

Case ReportJanet is now 15 years old. Her mother was 33 and her

father 31 when she was born. She has a normal sister of12, and another sib, a girl, died within half hour of birthafter a difficult delivery. A paternal great aunt hasdiabetes.

Turner's syndrome was diagnosed at the age of 7, whenshe had a plastic operation performed elsewhere toimprove the appearance of her webbed neck. She wasreferred to this hospital because a hearing defect had beendiscovered by the School Medical Officer. Glycosuriawas then discovered during routine examination andfurther questioning revealed some thirst and loss ofweight during the previous year. Her lack of develop-ment had not been commented upon by her parents,partly because of natural reserve and partly because shehad had two menstrual periods, 4 and 8 months earlier.Otherwise she had enjoyed good health and was of normalintelligence.

Physical Findings. She is a short underdeveloped girl,weight 92 lb. (42 kg.), and height 55i in. (141 cm.); uppersegment 29 in. (731 cm.) and lower segment 26j in. (671cm.) (Fig. 1). Her hair is low on her neck, which is stillwebbed despite plastic surgery. She has slight epicanthicfolds, a receding chin, and pigmented naevi on her face.The ears appear noimal but a marked high tone deafnesshas been demonstrated by audiometry. She has bilateralastigmatism, but no colour blindness by Ishihara's charttests. There is an increase in the cariying angle at her

elbows, and her finger-nails are slightly concave longitu-dinally with very deep peri-ongular folds. The nipplesare hypoplastic with no breast development. There is noaxillary and only scanty pubic hair. The externalgenitalia are normal in appearance. The thyioid is notpalpable. In the cardiovascular system the heart is notenlarged, there is a soft apical systolic murmur, thefemoral pulses are easily felt and synchronous with theradial, and the blood pressure in the arms is 110/85 and inthe legs 140/100 mm.Hg. The remainder of the examina-tion is normal.

FIG.S-. 1.-The3X~ patient.

FIG. I.-The patient.274

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GONADAL DYSGENESIS WITH UNUSUAL ABNORMALITIES

FIG. 2 (a).

FIG. 2(b).FIG. 2.--(a) Buccal epithelial cell, showing large sex chromatin body (Orcein. x 1925.) Compare with (b) from a normal female.

Fio;. 3.

FIGS. 3 and 4.-Buccal epithelial cell, showing bipartite form of sexchromatin. (Orcein. x 1925.)

Investigations. Hb 93 %o; white blood cells 4,500.Normal differential. Wassermann and Kahn reactionnegative. Urine: no protein, deposit normal, culturesterile, 2° sugar. Random blood sugar 273 mg./l00 ml.Serum electrolytes, blood urea, normal; protein boundiodine, 7 2ptg./100 ml. Glucose tolerance test after30 g. of glucose is shown below.

Minutes . . 0 10 20 30 40 50 60 75 90Blood sugar mg./100 ml. .. 223 242 303 378 399 395 375 375 392

FiG. 4.

Minutes. .. 0 10 20 30 40 50 60 75 90Blood sugar mg./100 ml. .. 250 218 205 250 258 224 264 245 262

Urinary 17 ketosteroids 3 9 mg./24 hr. (normal 6-15),17-OH corticosteroids 10 6 mg./24 hr. (normal 6-20).Urinary gonadotrophins 3 *2 HMG 20A units/24 hr.(normal for this age 0 5-3 1). Plasma growth hormone6 - 9 m,g./ml. (well within normal range for age).Radiograph of wrist showed bone age of 13 years atchronological age 15. Chest radiograph showed clearlung fields and heart of normal size and shape. Skull

Insulin glucose test: 30 g. glucose + 5U insulin/m2.body surface, is shown opposite.

275

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HUGH-JONES, WALLACE, THORNBER, AND ATKIN

FG 5 A 4e m e s g te l e a l c e..

FIG. 5.-A 46-chromosome metaphase showing the large abnormal chromosome (arrowed).

radiograph normal. The intravenous pyelogram showednormal excretion and anatomy of kidneys, ureters, andbladder.

Chromosome Studies. Sex chromatin was seen in 50out of 200 cells (25%) in buccal smears. The sexchromatin bodies were clearly abnormal (Figs. 2-4) andcontained more chromatin material than usual; frequently

'.^... ;'....d.'.:.

iS&(§!t5m%90~~~~~~~~~~~~~~~~~~~~~~~~~........; : ' ~~~~~~~~~~~~~~~~~~~~~~~~~~~. .. .... . . ...m'~~...... ..

;;j, r':.... ';..

the chromatin was aggregated into two unequal masseswhich were usually contiguous but sometimes a micron orso apart (Fig. 4). Chromosome counts from two separateleucocyte cultures are summarized in the Table. Analysisof cells with 45 chromosomes revealed an apparently2A-XO constitution. In all cells with 46 chromosomes,a large abnormal chromosome was present, apparentlyreplacing an X chromosome (there were only 15 chromo-

Ff metaphase shown in Fig. 5.

276

FiG. 6.-Autoradiograph oi

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GONADAL D YSGENESIS WITH UNUSUAL ABNORMALITIES 277

FIG. 7.-Karyotype of a 46-chromosome metaphase. The abnormal chromosome and the presumed normalX are at the right ofthe bottom row.

TABLE 1CHROMOSOME COUNTS OF 230 CELLS FROM

TWO LEUCOCYTE CULTURES

somes in the X-6-12 group). It was as long as, or slightlylonger than, the No. 1 chromosomes, and its long armwas about 2j times its short arm (Figs. 5 and 7). Studieswith tritiated thymidine revealed that it was uniformlylate-labelling (Fig. 6).

The drumsticks of polymorphs in patients withabnormalities of the X chromosome have recently beenstudied by Fraccaro, Lindsten, Mittwoch, and Zonta(1964), who found a relation between the size of thedrumsticks and that of the abnormal X chromosome.We failed to find any drumsticks among 700 polymorphsin the present case, but on a further blood smear, whichwas kindly examined by Dr. Ursula Mittwoch, one largedrumstick was found among 400 polymorphs (Fig. 8).The chromosomes of the parents and sister were

investigated in peripheral leucocyte cultures. Noabnormalities were found; a late-labelling chromosome ina culture from the mother treated with 3H thymidine hadthe morphological characteristics of a normal X chromo-some.

FiG. 8 (a). FIG. 8 (b).FIG. 8.-(a) Polymorph leucocyte showing a large drumstick. (x 2200.) Compare with (b) taken from a normal female.

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278 HUGH-JONES, WALLACE, THORNBER, AND ATKIN

DiscussionThe unusual clinical features of this case of gonadal

dysgenesis were first that Janet was referred becauseof her deafness and, secondly, during routinemedical examination, glycosuria was discovered.Deafness of sufficient severity to be the presentingfactor is rare. Hauser (1963), in his review of about1,000 cases of gonadal dysgenesis, had 5 examples ofclinical deafness, but as Lindsten points out in hismonograph, slight hearing loss when tested for byaudiometry is relatively common. Of 41 casestested, 28 had a hearing loss of at least 20 decibelsand broader than one octave. Of these, 20 werepure perceptive hearing losses, the commonest curvebeing with a central dip. 3 cases had a high tonedeafness similar to this case.Frank diabetes has not been frequently observed

in gonadal dysgenesis, but Lichtwitz, Grivaux, andDelaville (1948) reported that hyperglycaemicglucose tolerance curves were not uncommon.Forbes and Engel (1963) found 6 cases of diabetesamongst 41 examples of gonadal dysgenesis. Theysuggested that the reason that this had not beennoticed before was that the average age of reportedexamples of gonadal dysgenesis was 21 years,whereas the average age of their own was 51, whichis within a few years of the mean age of onset ofdiabetes. But they may have somewhat overstatedtheir case. In 2 instances the diagnosis of gonadaldysgenesis appeared to have been made just on theabsence of secondary sexual characteristics. Intheir third case a normal chromosomal constitutionwas found and their fifth case was not examined forthis. It was interesting that in the 3 remaining casesin which they examined the chromosomes theydiscovered an abnormal X chromosome (a presump-tive isochromosome for the long arm): on 2 occa-sions this was the only abnormality in a normalchromosome count of 46, and on the third it wasassociated with a mosaicism with the usual XOconstitution as seen in the present case. In our casethe diabetes was noted at the age of 15, was sensitiveto insulin, and was initially controlled by a lowcarbohydrate diet. However, because of subsequentweight loss, the treatment has been changed tochlorpropamide 125 mg. daily. This controlled theglycosuria.The low incidence of sex chromatin suggested a

mosaicism. This is relatively common in gonadaldysgenesis (Polani, 1962). The large abnormalchromosome seen in the cells with 46 chromosomesclearly contains more chromosomal material than asingle X chromosome, yet from the position of itscentromere it is not an isochromosome. In view ofits late-labelling properties, and because of the large

size of the sex chromatin body, it is presumably thischromosome that forms the Barr body in interphase.It might be assumed to consist entirely of 'hot'chromosome material; however, Ohno andCattanach's (1962) studies on an X autosometranslocation in the mouse have shown that anX chromosome composed partly of X chromosomeand partly ofautosomal material can manifest positiveheteropycnosis along its entire length. It is possible,therefore, that the abnormal chromosome is theresult of a structural rearrangement either betweentwo X's or between an X and an autosome. If theformer is the case, it could represent a duplication orduplication-deficiency chromosome, such as mightarise through crossing-over within a pericentricinversion in a parent who was heterozygous for thisinversion (P. E. Polani, personal communication).The fact that the mother's late-labelling X appearsstructurally normal, though not lending directsupport to this hypothesis, does not of course rule itout. It appears that, as in other patients withgonadal dysgenesis having a cell-line with two Xchromosomes, one abnormal and the other normal,it is the abnormal chromosome that is late-labellingand forms a Barr body in interphase.

SummaryA case of gonadal dysgenesis with typical body

configuration is described. The girl also had a high-tone deafness and hyperglycaemia. Chromosomestudies revealed a mosaicism of cells with 45 chromo-somes of 2A-XO constitution, and cells with 46chromosomes in which an unusually large submeta-centric late-labelling chromosome replaced one ofthe X chromosomes.

We would like to thank Professor P. E. Polani for hishelpful advice and Miss Christine Hawes for assistance inpreparing the autoradiographs.The urinary gonadotrophins were estimated under the

guidance of Dr. Barbara Clayton by a method devised byW. H. E. Fitschen in the Department of ChemicalPathology, Hospital for Sick Children, Great OrmondStreet, London.The plasma growth hormone was estimated by W. M.

Hunter by the method described by Hunter and Green-wood (1962) (Biochem. J., 85, 39P).

REFERENCESForbes, A. P., and Engel, E. (1963). The high incidence of diabetes

mellitus in 41 patients with gonadal dysgenesis, and their closerelatives. Metabolism, 12, 428.

Fraccaro, M., Lindsten, J., Mittwoch, U., and Zonta, L. (1964).Size of drumsticks in patients with abnormalities of the X-chromosome. Lancet, 2, 43.

Hauser, G. A. (1963). Gonadal dysgenesis. In Intersexuality, ed.Claus Overzier, p. 298. Academic Press, New York.

Lichtwitz, A., Grivaux, M., and Delaville, M. (1948). Deux cas denanisme avec insuffisance ovarienne totale et hypers6cretiond'hormone gonadotrope. (Syndrome de Turner.) Sem. H6p.Paris, 24, 2823.

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GONADAL DYSGENESIS WITH UNUSUAL ABNORMALITIES 279'Lindsten, J. (1963). The Nature and Origin of X Chromosome

Aberrations in Turner's Syndrome. Almqvist and Wiksell,Stockholm.

Ohno, S., and Cattanach, B. M. (1962). Cytological study of anX-autosome translocation in Mus musculus. Cytogenetics, 1, 129.

Polani, P. E. (1962). Sex chromosome anomalies in man. InChromosomes in Medicine, ed. J. L. Hamerton, p. 73. Wm.Heinemann (Medical Books), London.

Turner, H. H. (1938). A syndrome of infantilism, congenital webbedneck, and cubitus valgus. Endocrinology, 23, 566.

Varney, R. F., Kenyon, A. T., and Koch, F. C. (1942). An associa-tion of short stature, retarded sexual development and highurinary gonadotropin titers in women. J. clin. Endocr., 2, 137.

Wilkins, L., and Fleischmann, W. (1944). Ovarian agenesis. ibid.,4, 357.

AddendumWhile this girl has been under observation she has

recently been started on stilboestrol 0 * 5 mg./day for onemonth, then 1 0 mg./day for one month. After 9 weeksshe began a heavy period. Examination under anaestheticduring a dilatation and curettage revealed normal femaleanatomy. Curettings were normal and showed the samenuclear chromatin pattern, i.e. a low incidence of Barrbodies, which were larger than normal. Stilboestrol hassince been stopped and there is no further bleeding.Recently she has had to go on to insulin for treatment ofher diabetes.

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