Journal of Medical Genetics, 1982, 19, 49-56

Cytogenetic and histological studies of testicularbiopsies from subfertile men with chromosomeanomalyM J W FAED,* M A LAMONT,* AND K BAXBYt

From *the Cytogenetics Laboratory, University of Dundee, Ninewells Hospital and Medical School, andtDepartment of Urology, Dundee Royal Infirmary, Dundee.

SUMMARY Testicular biopsies from eight men with abnormal karyotypes have been examined forhistological and cytogenetic evidence of disturbances of meiosis. Quantitative analysis of this materialshowed one, with a 13 ;14 Robertsonian translocation, to have apparently normal spermatogenesis.Three patients, one with a 47,XYY and two with 46,XY, inv 9 karyotypes, had an overall depressionof spermatogenesis. Four others, all with major chromosomal abnormalities, had apparently normalspermatogenesis until the primary spermatocyte stage. Two of these had sex autosomal trans-locations. One, 46,Y,t(X;21), had a complete block at MI, the other, 46,X,t(Y;16), had a

partial block at spermatid formation. One man with a reciprocal 2; 10 translocation showed delayat all stages beyond spermatocyte formation and one man with an inversion of chromosome 3showed impaired spermatid maturation.

The association between subfertility andchromosome anomaly has been noted in a numberof surveys of male subfertility clinics.1-3 Althoughthis may be the result of loss of zygotes with anunbalanced chromosome complement, it is evidentthat there may also be a direct effect on spermato-genesis.4 However, the role of chromosomalanomaly in spermatogenic failure is not clear, astesticular biopsies from subfertile men withchromosome abnormality are not often available.

In the course of a continuing study of theReceived for publication 26 March 1981.

karyotypes of all patients presenting at a malesubfertility clinic, part of which has already beenreported,3 we have obtained testicular biopsies forhistological and cytogenetic studies from eight men

with abnormal karyotypes, including two with sexchromosome/autosome translocations.

These observations and our attempts to relatethe chromosomal and histological findings form thesubject of this report.

Material and methods

All eight patients in this report had attended a male

TABLE 1 Karyotypes, ages, sperm counts, reproductive histories, and available family studies of 8 subfertile menSuccessfulpregnancy

No ofyears Reported within ISperm count of involuntary abortions in year of

Patient Karyotype Age (x 106/ml) subfertility spouse attending clinic Family studies

269/76 46,Y,t(X;21)(q23;ql 1) 30 0 4 - _489/79 46,X,t(Y;16)(ql 1 ;q13) 36 1 7 2 _ Father 46,XY

Brother 46,XY452/75 47,XYY 28 3 4 - - Father 46,XY22/76 45,XY,t(13ql4q) 25 20 2 - + Daughter 46,XX136/76 46,XY,t(2;10)(q33;q24) 40 20 7 - + Father 46,XY,t(2;10)

Mother 46,XXSister 46,XX

625/78 46,XY,inv 3(p25q21) 33 8 10 - - Parents deadSister 46,XX

695,78 46,XY,inv 9(p12ql2) 39 2 6 1518/75 46,XY,inv 9(pllql2) 29 1 2 -

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subfertility clinic and belonged to a group biopsiedas part of their investigation. Before biopsy sevenwere known, from studies on lymphocytes, to havea chromosomal abnormality, but one translocationcarrier was recognised only after meiotic studies hadrevealed the presence of a quadrivalent. Biopsiesfrom ten subfertile patients with an apparentlynormal 46,XY karyotype are reported elsewhere.5The karyotype, age, sperm count, reproductive

history, and available family studies of each of themen are shown in table 1.

Biopsies were taken under general anaesthesiafrom both testes in two patients and from the righttestis only in the others. Each specimen wasimmediatelydivided into two. One part, forhistologicalexamination, was fixed in Bouin's fluid, and the otherplaced in 1 % sodium citrate for cytogenetic studies.

M J W Faed, M A Lamont, and K Baxby

Cytogenetic preparations were made by themethod of Evans et a16 or of Luciani et a17 forpachytene preparations. Counts were made of cellsin spermatogonial metaphase, at diakinesis, and atmetaphase II. A minimum of 50 dividing cells wascounted from each biopsy. The average number ofchiasmata per cell was obtained from at least tenwell spread Giemsa stained cells, and all availablecells at diakinesis, up to a maximum of 100, wereexamined for abnormal chromosomal configurationsand for dissociation of the sex chromosomes.For assessment of the histological status of the

biopsy, 7 ,um paraffin embedded sections werestained with haematoxylin and eosin. Details of themethods of assessment are given in our previousreport of biopsies from 16 fertile and ten subfertilemen with normal karyotype.5 Briefly, 100 tubules

TABLE 2 Cytogenetic analysis of testicular biopsies from 8 men with abnormal somatic karyotypesCell distribution (%)

Chiasma count Y. cells withSpermatogonial Total cells (average for X, Y dissociation

Karyotype division Diakinesis Metaphase II counted 10 cells) at diakinesis

46,Y,t(X;21) 0 No cells seen beyond pachytene - -

46,X,t(Y;16) 12 68 20 132 53-1 647,XYY 29 46 25 205 47-6 1 345,XY,t(13;14) 16 52 32 159 47-6 1946,XY,t(2;10) 9 58 33 58 51-0 1746,XY,inv 3 6 56 38 75 46.0 1046,XY,inv 9 5 58 37 53 52-4 946,XY,inv 9 8 57 35 83 53-1 16Normal range (Lamont et a15) 4-20 33-60 31-55 52-68 42.6-536 6-21

FIG 1 Mitotic karyotype ofmale with karyotype 46, Y,t(X;21);(q23;qll).

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Cytogenetic and histological studies of testicular biopsies from subfertile men with chromosome anomaly 51

from each biopsy were each scored on a scale forspermatogenesis from 1 (atrophic tubules) to 10(complete spermatogenesis)8 and a mean biopsyscore was calculated. The percentage volume oftubular epithelium was assessed by point counting9and tangent counts were studied for any evidence ofhypercurvature by the method of Averback andWight.10

Results

CYTOGENETIC STUDIES

The cytogenetic findings for all eight men are shownin table 2 with the corresponding values for fertilemen for comparison.The distribution counts of dividing cells in all the

patients were unremarkable and were within normallimits except in the two sex/autosome translocationcarriers and the XYY patient. The X;21 trans-location carrier had too few active cells to assess,the Y;16 translocation carrier had a high proportionof cells at diakinesis, and the XYY patient showed a

relative increase in the number of cells inspermatogonial metaphase. Chiasma counts and theproportion of dissociated X and Y chromosomeswere within normal limits in all the biopsies.

Sex chromosome/autosome translocationsThe mitotic karyotype of the patient with theX;autosome translocation is shown in fig 1. In themeiotic preparations there were no cells seen indivision and no cells were seen beyond pachytene.The sex vesicle usually appeared to be of irregularshape (fig 2).A partial karyotype of the patient with the Y;16

translocation is shown in fig 3. All cells at diakinesis

.....1

FIG 2 Pachytene cell with irregularly shaped sex vesicle

from patient with X;-21 translocation.

FIG 3 Partial mitotic karyotype from patient withkaryotype 46,X,t(YY;16)(qll;q13) with G band, C band,and orcein staining. Chromosomes 21 and 22 are

includedfor size comparison.

(fig 4) revealed an extended chain made up, as shownin the diagram in fig 5, of the X chromosome, theY; 16 translocation chromosome, the normal 16, andthe 16;Y translocation chromosome, of which theYq portion on the end is clear both after atebrinstaining and with C banding (fig 4). A total of 75 cellsshowed a simple chain formation, but in 14 cells

MI

FIG 4 Cell in diakinesis from patient with Y;16

translocation, showing the extended chain seen in all

of the X chromosome. ~- indicates the q portion of the

Y chromosome.

ftI*All.Y

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M J W Faed, M A Lamont, and K Baxby

, ::.:i .. :..

*:: .2

;W!.. .. :} : .:.*, .... F ...* - se.. ffi ...

..S-ifli' ,2MZ

.'S. ,.

A 16 16

FIG 5 Extended chain configurations seen in diakinesesfrom patient with Y;16 translocation. Giemsa stained.Figures on right indicate number of cells withconfiguration illustrated. Position of centromeres isindicated in the diagram. Thick lines denote Ychromosome material.

chiasmata in the region 16ql3-*qter and in fivecells in 16p resulted in the other forms illustrated infig 5. In cells in pachytene, stained with atebrin, thefluorescent portion of the Y chromosome could beseen within the sex vesicle (fig 6) and the vesicle wasalways found to be attached to uncondensedchromosomal material.

FIG 7 Diakineses from man with 2;10 translocationshowing the large ring quadrivalent seen in all 34 cellsexamined. (a) Giemsa stained. (b) C banded preparation.

47,XYYThe cytogenetic findings for the 47,XYY patienthave been fully reported elsewhere.'

Autosome translocationsAll 66 cells analysed at diakinesis from the patientwith a Robertsonian 13;14 translocation showed atrivalent; there was no evidence of failure ofpairing.

FIG 6 Cells at pachytene stained- ~~~with atebrin from man with Y;-16

translocation. The fluorescentportion of the Y can be seenwithin the sex vesicle.

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Cytogenetic and histological studies of testicular biopsies from subfertile men with chromosome anonmaly 53

.4

4

4

FIG 8 No 3 chromosomes from man with inversion ofchromosome 3. Stained with trypsin Giemsa. Theinverted chromosome is on the right.

Chromosome anomaly had not been suspected inone patient before biopsy but all 34 diakinesesexamined contained a large ring quadrivalent (fig7 a, b). Careful re-examination of banded mitoticpreparations revealed a reciprocal exchange between2q and lOq (breakpoints at q33 and q24,respectively).

InversionsA total of 60 cells at diakinesis were analysed fromthe patient with an inversion of chromosome 3 (fig8). In 58 of these there was no detectable abnormalityof pairing (fig 9a), but in two cells the position of thecentromeres appeared to be asymmetrical (fig 9b).No abnormalities were detected at pachytene or atMIl.No abnormal configurations were seen in cells

either at pachytene or at diakinesis in preparationsfrom biopsies of the two men with an inversion ofchromosome 9.

TESTICULAR HISTOLOGYThe results of the histological analysis are shownin table 3. Since there was no evident differencebetween biopsies from left and right testes, theseobservations were combined. The mean biopsy scorewas below the normal range for all patients exceptthe 13;14 translocation carrier, whose tubular scoredistribution or 'profile' (fig 10) was indistinguishablefrom that of a normal fertile male.

It is apparent from fig 10 that the other fourpatients with major chromosome rearrangementshave biopsy profiles which are characterised by a

i- m3 S .1

MA

b

FIG 9 Cells in diakinesis from man with inversion ofchromosome 3: the arrows indicate the presumedchromosome 3 bivalent. In (a), as seen in 58 cells, noabnormality is apparent. In (b), as seen in 2 cells, thecentromeres appear to be asymmetrically placed.

failure of spermatogenesis which starts at thespermatocyte stage with no evidence of earliersuppression. In the case of the X;21 translocationthere was complete suppression at this stage but inthe others there was a less sharp effect with sometubules proceeding to more advanced stages. Inparticular, in the Y; 16 translocation, 10% of tubulescontained scanty spermatozoa and the main blockwas at the second, rather than the first, meioticdivision.

In contrast, the patient with the 47,XYYkaryotype and the two patients with inversions ofchromosome 9 had a general suppression ofspermatogenesis with tubules showing a block at allstages.Tangent counts/mm2 were within the limits

TABLE 3 Histological analysis of testicular biopsiesfrom 8 men with abnormal somatic karyotype

% volumeMean tubular Tangent

Karyotype biopsy score epithelium counts/mm2

46,Y,t(X;21) 5-2 Insuffient material for analysis46,X,t(Y;16) 6-3 57 2447,XYY 4-0 34 1646,XY,t(13;14) 9-6 57 2046,XY,t(2;10) 6.0 52 2446,XY,inv 3 6-3 55 2646,XY,inv 9 5-4 43 2646,XY,inv 9 5-2 55 20Normal range (Lamont et al5) 8.3-9.9 43-67 12-27

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MJ W Faed, M A Lamont, andK Baxby

KN 46,Xt(Y;16)MS 63

0 5 1(

DJ 46,XY inv 3MS 63

-_.5 10 0 5 10 0

Spermatogenic score

FIG 1O Tubular score 'profiles' from 8 men with abnormal karyotypes.

established for biopsies from normal fertile men.5The percentage volume of testicular tissue occupiedby tubular epithelium for all biopsies assessed, apartfrom that from the XYY patient, was also within thenormal range. Only 34% of the total testicular tissuein the XYY patient consisted of tubular epithelium.Twenty percent of the tubules in this patient wereatrophic.

Discussion

In this study we have attempted to quantify thetesticular histology and stages of spermatogenesis ofeight men with an abnormal chromosome comple-ment and have examined these findings in the lightof the behaviour of the abnormal chromosomesduring meiosis.One patient, with a 13;14 Robertsonian trans-

location and a history of only 2 years of involuntaryinfertility showed a biopsy profile indistinguishablefrom those we found in our series of normal fertilemales.5 This patient had a sperm density of 20 x 106sperms/ml and his wife has subsequently given birthto a daughter with a normal 46,XX chromosomecomplement. In all cells examined at diakinesis therewas satisfactory pairing of the 13 and 14 with thetranslocation chromosome with chiasma countswithin the normal range. Nevertheless, Robertsoniantranslocations between chromosomes 13 and 14have been found in most surveys of subfertile malesand appear to be four or five times more frequentthan in the newborn population.3 Slightly reduced

5

WC 45,XY,t (13;14)MS 96

10 0 5 10

chiasma counts have been reported in both fertileand subfertile 13q;14q translocations carriers.4The other patients fall into one of two groups

determined by the stage at which spermatogenesisbecomes affected. This is evident from the biopsyprofiles. Four patients have tubules which developnormally until the primary spermatocyte stage butdevelopmental blocks occur thereafter. Thesepatients all have major rearrangements ofchromosomal material. Three other patients had abiopsy profile which reflects spermatogenic failureaffecting all stages, a pattern which is similar to thatfound in many subfertile men with normal 46,XYkaryotype.5 Two of these three patients hadinversions of chromosome 9, widely regarded asbeing a normal variant and probably without effecton meiosis12 and the other was the patient with a47,XYY karyotype. Although XYY men are notuniformly subfertile, Skakkebaek et al"3 have shownthat out of eight XYY men not selected for sub-fertility, testicular histology was impaired in five.Most studies on meiosis in 47,XYY males haveshown that some process leads to the loss of thesecond Y chromosome even for spermatogonialcells and it is not surprising that this apparentrequirement results in the failure of a proportion ofcells throughout spermatogenesis.'4Of particular interest because very few other cases

have been studied at meiosis are the sex chromosome/autosome translocations.The patient with an X;21 translocation showed a

complete block at the spermatocyte stage with only

wvFS 46,Yt(X;21)MS 4-8

50

0±10 5 10

J K 47, XYYMS 40

GG 46,XYt (2;10)MS 61

U)

-0

D

0

z

'0

0 5 10

DR 46,XY,inv9MS 55

i~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

5 iCMG 46,XY,inv9MS 52

54

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Cytogenetic and histological studies of testicular biopsies from subfertile men with chromosome anomaly 55

a few degenerate pachytene figures. The few otherreports of meiotic studies on human X;autosometranslocation carriers have shown inactive testiculartissue'5 or a block in spermatogenesis which allowedonly a few cells of degenerate appearance to reachmetaphase I.16 A block at this stage is not charac-teristic of human autosomal translocations whichsuggests that the X chromosome may have some

specific effect on spermatogenesis. The possible roleofX chromosome inactivation in the vesicle has beendiscussed by Lifschytz and Lindsley.17 In the lightof the possible importance of the sex vesicle it isinteresting that the Y;16 translocation does notresult in a complete block at this stage despite theclear evidence that the fluorescent part of the Ychromosome, which is translocated to chromosome16, is included in the sex vesicle. Pajares et al18reported a case of apparently balanced reciprocaltranslocation between chromosomes Y and 10. Theyfound a halt at MI with just two cells, of poor

quality, at diakinesis. In two different cases ofY;autosome translocation in which Yq was trans-located to chromosome 519 or to chromosome 14,20the fluorescent part of the Y was, as in our case,found in the sex vesicle and the effect on

spermatogenesis was similar to ours. Thus the effectof a close association of autosomal material with thesex vesicle differs when the material is translocatedto an X and to a Y. X and Y autosome translocationshave also been studied in male mice21 and the effectson spermatogenesis are essentially similar to thosereported here for men.

All diakineses from the patient with a 2;10translocation contained a ring quadrivalent. Thispatient was not azoospermic and his wife has sincedelivered a phenotypically normal male child. Theazoospermic males reported by Chandley et al4 andSan Roman et a122 had chain quadrivalents incontrast to the ring quadrivalents found in maleswith apparently unimpaired spermatogenesis.423This agrees well with the findings in mice in whichthe proportion of chains was found to be positivelycorrelated with the extent of the depression of spermproduction.24 Determination of the meiotic pairingbehaviour in translocation heterozygotes may there-fore have value in counselling subfertile males.The patient with the inversion of chromosome 3

showed a late block in spermatogenesis with anabundance of spermatids but few spermatozoa. Thepossible relevance of the inversion to a block at thisstage is not clear. There are at least five otherapparently unrelated families known with inversionsof chromosome 3 with breakpoints at the same orvery similar positions and all were ascertainedthrough an unbalanced child25-28 (Sutherland, 1979,personal communication) and showed no evidence

of primary infertility in carriers: both the American27and the Australian (Sutherland, 1979, personal com-munication) pedigrees are very extensive. In our casethe centromeres of most of the bivalents seen atdiakinesis, as shown on C banded preparations,were symmetrically placed and in only a few cellsdid the centromeres appear asymmetrical.Asymmetrically placed centromeres may be inter-preted as being the result of homologous pairingbetween the distal uninverted portions of thechromosome.12 Whereas uneven numbers ofchiasmata occurring between the limits of theinversion may be expected to lead to unbalancedrecombinant chromosomes, exchanges occurringbetween distal uninverted segments would not. Therelatively few cells seen with asymmetricalcentromeres may therefore indicate a high risk ofabnormal recombinants in this patient.We have argued before29 that large inversions

which are likely to give rise to small duplication/deficiencies are more likely to result in viable butabnormal zygotes, and Winsor et al12 have shownthat this holds for most published cases. This,however, leaves open the question as to whetherlarge duplications and deficiencies bring about theearly and undetected loss of zygotes or whethergametes with grossly unbalanced genetic materialfail to be produced. In the cases reported here thereare defects in spermatogenesis and it is striking thatin the two autosomal translocation carriers, inwhom the configurations at diakinesis give thegreatest prospect of balanced gametes, spermato-genesis is least affected and the wives of both havesubsequently given birth to normal children.The comparison of biopsy score profiles with

chromosomal status gives a valuable insight into theeffect of the chromosomal abnormality on spermato-genesis. This study would further suggest, by com-parison with the biopsy score profiles of subfertilemen with a known 46,XY karyotype, that patientswith certain categories of chromosomal anomalymay have characteristic biopsy profiles.

We thank Dr J Robertson for helpful discussions,Doris McLean for cytogenetic preparations fromtesticular biopsies, the staff of the HistopathologyLaboratory for preparation of histological material,and Dorothy Morrison for typing the manuscript.

References1 Koulischer L, Schoysman R. l2tude des chromosomesmitotiques et m6iotiques chez les hommes infertiles. JGenet Hum (Suppl) 1975 ;23 :58-70.

2 Chandley AC, Edmond P, Christie S, Gowans L, FletcherJ, Frackiewicz A, Newton M. Cytogenetics and infertilityin man. 1. Karyotype and seminal analysis. Ann HumGenet 1975;39:231-54.

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3 Faed MJW, Robertson J, Lamont MA, et al. Acytogenetic survey of men being investigated for sub-fertility. J Reprod Fertil 1979;56:209-16.Chandley AC, Christie S, Fletcher J, Frackiewicz A,Jacobs PA. Translocation heterozygosity and associatedsubfertility in man. Cytogenetics 1972;11:516-33.Lamont MA, Faed MJW, Baxby K. Comparative studiesof spermatogenesis in fertile and subfertile men. J ClinPathol 1981 ;34:145-50.

6 Evans EP, Breckon G, Ford CE. An air-drying methodfor meiotic preparations from mammalian testes.Cytogenetics 1964;3:289-94.

7 Luciani JM, Morazzani MR, Stahl A. Identification ofpachytene bivalents in human male meiosis using G-banding technique. Chromosoma 1975;52 :275-82.

8 Johnsen SC. Testicular biopsy score counts. A method forregistration of spermatogenesis in human testes. Normalvalues and results in 335 hypogonadal males. Hormones1970;1 :2-25.

9 Dunnill MS. Quantitative methods in histology. In: DykeSC, ed. Recent advances in clinical pathology. Series V.London: Churchill, 1968: 401-6.

0 Averback P, Wight D. Seminiferous tubule hyper-curvature: a newly recognised common syndrome ofhuman male infertility. Lancet 1979 ;i :181-3.Faed MJW, Robertson J, MacIntosh WG, Grieve J.Spermatogenesis in an infertile XYY man. Hum Genet1976 ;33 :341-7.

12 Winsor EJT, Palmer CG, Ellis PM, Hunter JLP,Ferguson-Smith MA. Meiotic analysis of a pericentricinversion, inv (7) (p22q32) in the father of a child with aduplication-deletion of chromosome 7. Cytogenet CellGenet 1978;20:169-84.

13 Skakkebaek NE, Hulten M, Jacobsen P, Mikkelsen M.Quantitation of human seminiferous epithelium II.Histological studies in eight 47,XYY men. J Reprod Fertil1973 ;32:391-401.

14 Melynk J, Thompson H, Rucci A, Vanasek F, Hayes S.Failure of transmission of the extra chromosome insubjects with 47,XYY karyotype. Lancet 1969;ii:797.

15 Buckton KE, Jacobs PA, Rae LA, Newton MS, Sanger R.An inherited X-autosome translocation in man. Ann HumGenet 1971;35:171-8.

16 Dutrillaux B, Couturier J, Rotman J, Salat J, Lejeune J.Sterilite et translocation familiale t(lq-; Xq +). C RAcad Sci Paris (D) 1972;274:3324-7.

17 Lifschytz E, Lindsley DL. The role of X-chromosomeinactivation during spermatogenesis. Proc NatI Acad SciUSA 1972;69:182-6.

18 Pajares IL, Delicado A, Colbos PV, Corral FS, CuadradoC. An azoospermic male with a Y/autosome trans-location. Hum Genet 1979 ;46:155-8.

19 Dutrillaux B, Gueguen J. Etude meiotique et mitotiquedans un cas de translocation t(5 ;Y). Humangenetik1975 ;27:241-5.

20 Laurent C, Dutrillaux B. Translocation t(Y;14) chez unhomme azoospermique. Ann Genet (Paris) 1976 ;19 :207-9.

21 Searle AG, Beechey CV, Evans EP. Meiotic effects inchromosomally derived male sterility of mice. Ann BiolAnimn Biochim Biophys 1978;18 (2B):391-8.

22 San Roman C, Sordo MT, Garcia-Sagredo JM. Meiosisin two human reciprocal translocations. J Med Genet1979;16:56-9.

21 Ferguson-Smith MA, Page B (1973). Quoted in Winsoret al. Cytogenet Cell Genet 1978;20:169-84.

24 Searle AG. Nature and consequences of inducedchromosome damage in mammals. Genetics 1974;78:173-86.

2;; Boue J, Hirschhorn K, Lucas M, Goutier M, Moszer M,Bach C. Aneusomies de recombinaison. Consequencesd'une inversion pericentrique d'un chromosome 3paternel. Ann Pediatr 1974;21:567-73.

26 Lurie 1W, Lazyuk GI, Gurevich DB. Medico-geneticalconsulting of persons with pericentric inversions. Genetika1974;10:136-41.

27 Allderdice PW, Browne N, Murphy DP. Chromosome 3duplication q21 -+qter deletion p25 -- pter syndromein children of carriers of a pericentric inversion inv (3)(p25 q21). Am J Hu,n Genet 1975;27:699-718.

28 Kawashima H, Maruyama S. A case of chromosome 3duplication q deletion p syndrome born to the motherwith a pericentric inversion, inv (3) (p25 q21) Jpn J HuimGenet 1979;24:9-12.

29 Faed MJW, Marrian VJ, Robertson J, Robson EB, Cook,PJL. Inherited pericentric inversion of chromosome 5.A family with history of neonatal death and a case of the'cri du chat' syndrome. Cytogenetics 1972;11:400-11.

Requests for reprints to Dr M J W Faed,Cytogenetics Laboratory, Ninewells Hospital andMedical School, Dundee DDl 9SY.

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