clinical manifestations offamilial 13;18 translocation

Journal ofMedical Genetics, 1980, 17, 373-379

Clinical manifestations of familial 13;18 translocationWILLIAM A BLATTNER*, MILDRED L KISTENMACHERt,SHIEN TSAI+, HOPE H PUNNETTt, AND ELOISE R GIBLETT§

From *the Environmental Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20205;tSt Christopher's Hospital for Children, Philadelphia, Pennsylvania 19133;"Biotech Research Laboratories Inc, Rockville, Maryland 20852; and § University of Washington,School of Medicine, King County Central Blood Bank, Seattle, Washington 98104, USA

SUMMARY Female first cousins, aged 21 and 21 years, with many of the characteristic features oftrisomy 18, were found to have identical unbalanced translocations, 46,XX,- 13, +der(13)t(13 ;18)(pl3 ;ql2)mat. Clinical features of another cousin, two uncles, and an aunt suggested that they, too,had a partial trisomy 18 phenotype. The long survival and normal menstrual and secondary sexualdevelopment in one case are remarkable. A heritable balanced translocation, 46,XX or XY, t(13 ;18)(pl3;ql2), was detected in the mothers of the cases, a sib, an aunt, and two uncles. Translocationcarriers had abnormalities in gonadal structure or function, with aspermia in males and polycysticovaries with infertility in several females, suggesting that some gene controlling reproductive develop-ment occurs on the long arm of chromosome 18, with normal function interrupted at the breakpoint.Balanced translocation carriers may also be at greater risk for both benign and malignant neoplasms,which included acute leukaemia in an uncle and adenocarcinoma of the stomach at an early age inthe grandmother. Although aetiological laboratory studies identified no premalignant state, theclinical findings suggest a defect that may predispose to cytogenetic abnormalities and malignancy.

Trisomy 18 is a well-characterised cytogeneticsyndrome with an incidence in newborns of 0-01 %.1In rare instances, the trisomy 18 phenotype resultsfrom an unbalanced translocation, arising as aprimary mutation or through inheritance from aparent with a balanced translocation.2 In the presentfamily (fig 1), female first cousins had partialtrisomy 18 phenotype because they inherited identical1 3p + chromosomes from their mothers, who carrieda balanced translocation of the long arm of chromo-some 18 onto the short arm of chromosome 13.Some balanced translocation carriers over threegenerations experienced abnormalities of reproduc-tive function, as well as possible heightened suscep-tibility to neoplasia.

Materials and methods

Members of the family were interviewed andbiological specimens obtained wlth informed con-sent between 1975 and 1977. Hospital and vitalrecords were obtained when possible to confirmmedical diagnoses.

Routine haematological tests were performed byReceived for publication 6 November 1979

the National Institutes of Health Clinical Center.Quantitative immunoglobulins, immunoglobulinelectrophoresis, autoantibodies, and gonadotrophinsin males were measured on serum samples usingstandard techniques (Bioscience Laboratories, VanNuys, California). Red blood cell antigens weretested by the NIH Blood Bank, red blood cellenzymes were assayed by electrophoretic methods,3and HLA-A, -B, and -C antigens were determinedserologically.4 In vitro response to standard mitogensand pooled allogeneic cells in one-way mixedleucocyte culture was quantified by the relativeproliferation index.5Chromosome analysis was performed from phyto-

haemagglutinin stimulated peripheral lymphocytesand, in addition to conventional Giemsa staining,chromosome preparations were processed for Gbands by trypsin treatment,6 7 for R bands,8 for Cbands,9 and for N bands by a simplified silverstaining method.10

Case reports

The proband (111.8) (fig 2a) was born in 1974 tounrelated 29-year-old parents. Because of fertility

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W A Blattner, ML Kistenmacher, S Tsai, H H Punnett, and E R Giblett

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Mate or female Balanced translocation;O with malignancy 46,XX, t (13;18 )(p 13; q12)

Clinically abnormal, 0 Miscarriagenot karyotyped

TIree clinically normal>males or females

(Clinically normal withKJ normal karyotype

Clinically abnormal with&Junbalanced translocation:

46,XX, derO3),t(13;18)( p13;q 12 )mat

I Sterile

(7>arrier of pericentric

Y(2in\irsion 46,XX,'nv(9) gaonsanguineous(pll; q12 )

FIG 2 (a) Proband (11I.8) at 3 years of age.

problems, the mother took prednisone for the firsttwo weeks after conception. The vaginal deliveryof a footling breech at 38 weeks was complicated bycomplete placental separation, and severe acidosis,

muscular hypotonia, and grand mal seizures duringresuscitation. At 5 months, on referral to StChristopher's Hospital for Children (SCHC), shewas found to have partial trisomy 18 phenotype, withmicrocephaly, low set ears, high arched palate, smallmandible, alternating esotropia, close set eyes,

congenitally blocked tear ducts, pectus excavatum,partial syndactyly of the second and third toes, a

haemangioma of the second toe of the right foot,spasticity of all extremities, tight hips with difficultabduction, hypoplastic labia majora, large cleftclitoris, and a ventricular septal defect. Dermato-glyphs showed six arches and four very simple, lowcount loops. At 5 years of age, the child is severelyretarded and requires total supportive care.

A first cousin of the proband (111.3) (fig 2b) was

born one month postmature in 1956 to a 21-year-oldmother and 26-year-old father. She experienceddifficulty in feeding as an infant and had delayeddevelopmental milestones. At 21 years of age a

persistent ductus arteriosus was repaired. At 22 yearsof age, she is a severely retarded, spastic quadri-plegic who weighs 31 8 kg. Morphological abnor-malities include flexion contractures of elbows andknees, distal shortening of upper and lower extremi-ties, overlap of fingers, and valgus deformity of feet.

FIG 1 Family pedigree.

\ Dead

/ Proband

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Clinical manifestations offamilial 13;18 translocation

FIG 2 (b) First cousin ofproband (11.3) at 21 yearsof age.

She has internal strabismus, high arched andnarrow palate, an open bite with prominent uppercentral incisors, and hypertrophied gingivae. Shebegan menstrual periods at the age of 13 and hasregular cycles of approximately 28 days. Secondarysexual characteristics include large breasts, axillary,genital, and leg hair, and axillary apocrine glandfunction.

Family history

The grandparents of the proband were secondcousins, born in Riccia, a small mountain com-

munity in south central Italy.The grandmother (1.4) had 14 pregnancies with

ten live births and four spontaneous abortions in thefirst trimester of pregnancy. Three of the live births,cases 11.4, 1.9, and 11.12, died in the first 7 monthsof life with congenital heart defects. Case 11.9 had apatent foramen ovale, "anterior curvature of thesternum with depression of the epigastrium", andwas described as being immature for a term baby.Case I.12 had a ventricular septal defect.The grandmother (1.4) died at the age of 49 in 1952

of metastatic adenocarcinoma arising in the greatercurvature of the stomach. A teratoma of the leftovary (with hair and teeth-like appendages) was alsofound on exploratory laparotomy. The grandfatherof the proband is well at the age of 76 with milddiabetes mellitus.Three uncles of the proband are sterile with

documented azoospermia, and two (11.7 and 11.8) arebalanced translocation carriers, while the third (11.3)died accidentally before karyotyping. Case 11.8 alsohad a partially descended left testis that was sur-gically removed.

In 1975, at the age of 37, case 11.7 developed acuteprogranulocytic leukaemia, with a peripheral whiteblood count of 30 000 and 90% blasts. The immaturemyeloid cells on bone marrow had Auer rods andmany azurophilic cytoplasmic granules. Treatmentwith vincristine, prednisone, cytosine arabinoside,and daunomycin led to a complete remission after acomplicated 2-month period in hospital. Additionalmaintenance therapy with daunomycin was givenover an 18-month period and the patient remains incomplete clinical remission without therapy. Thepatient reported no exposure to suspected leukae-mogens.

Case II.10, the mother of the proband, had mega-colon as a child and suffers from chronic constipationas an adult. Because of irregular menses and infer-tility of 3 years' duration, culdoscopy was performedand polycystic ovaries found. Prednisone was takenfrom 2 to 6 months before each of four pregnancies.Her first (111.6) terminated prematurely at 6 monthswith polyhydramnios and a small, insufficientplacenta, despite estinyl oestradiol (Estinyl) andhydroxyprogesterone (Delalutin) for threatenedabortion. No congenital anomalies were noted atnecropsy. The second (11I.7) went to term and is aclinically normal balanced translocation carrier. Thethird (1II.8) is the proband and the fourth pregnancyended as a complete abortion at one month.

Case 11.2, a 53-year-old aunt of the proband, hadmultiple vocal cord polyps, fibrocystic disease of thebreasts, and multiple ovarian cysts noted at partialoophorectomy. She had five spontaneous abortionsin the first trimester and carried one infant (11.1) to7 months taking diethylstilbestrol for threatenedabortion. This child (11.1) died with hyalinemembrane disease of the lung and had no detectableheart defects or other anomalies at necropsy.Case 11.6, another aunt of the proband, had

polycystic ovaries, fallopian tube cysts, and endo-cervical polyps found at panhysterectomy andbilateral salpingo-oophorectomy. She had fourpregnancies. Her first child (III.2), a male infant,resembled his younger sister (111.3) with a partialtrisomy 18. He was premature, weighing 1 9 kg atbirth, and had a high arched palate, low set ears,mental retardation, poor muscle tone and co-ordina-tion, seizures, a probable ventricular septal defect,and the mother was told he was blind. He died at10 months of age. The two other male offspring(111.4 and 111.5) were clinically and karyotypicallynormal.The karyotypically normal uncle of the proband

(11.5) had no medical problems. His wife had sevennormal term pregnancies and two first trimesterspontaneous abortions.

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WA Blattner, ML Kistenmacher, S Tsai, H H Punnett, and E R Giblett

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. As u ih~~~ ~ ~ ~ ~ ~ ~ ~ ~ ~ .* *4i` I/

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FIG 3 Karyotype of the proband (111.8): 46,XX,-13,+der(13),t(J3;18) (p13;q12) mat, inv(9) (pJJ;q12). (G banding.)

Clinical information on the brothers and sistersof the proband's grandparents shows that none hadchildren or grandchildren with congenital anomalies,infertility, or cancer, and, other than adult onsetdiabetes and a cerebral vascular accident, none hadmajor medical illnesses.

CYTOGENETIC INVESTIGATIONSBoth cousins with the partial trisomy 18 phenotypehad identical unbalanced translocations with a 13p+chromosome (fig 3). The extra chromosomal materialappears to be the distal portion of chromosome 18translocated onto the short arm of 13, with thekaryotype being 46,XX,-13, +der(13)t(13 ;18)(p13;ql2)mat. Silver staining confirmed that the 13p+chromosome retained the nucleolus organiser region(fig 4a), so that the secondary constriction of 13 wasincluded in the translocation chromosome. Theproband (III.8) also carried an inverted chromosome9 (fig 4b) inherited from the father; her karyotype is46,XX, -13, +der(1 3)t(13;1 8)(pl 3 ;q12)mat,inv(9)(p11 ;ql2).'1The mothers of the partial trisomy 18 cases shared

identical balanced translocations (fig 5), 46,XX,t(13;18)(p13;q12). The proband's sister (III.7) and amaternal aunt (1.2) also had this karyotype. Twomaternal uncles (11.7 and 11.8) had the karyotype46,XY,t(13;18)(p13;q12). A third uncle (11.5) had anormal karyotype, 46,XY.Chromosome analyses performed on the proband's

cousins (III.4 and 11.5), grandfather (I.2), and otherfamily members (1.1, I.3, and I1.1) were normal.

FIG 4 (a) Silver stained metaphase of 111.3 showing13p F chromosome retaining nucleolus organiser region(arrow). (b) C banding showing a chromosome 9 withpericentric inversion from case 1H.3.

LABORATORY STUDIESComplete blood counts and routine chemistries werenormal, as were gonadotrophin levels in males.Serum immunoglobulins were slightly raised in cases11.7 (IgG), 11.2 (IgM), I.6 (IgG), and I1.10 (IgG),

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FIG 5 Chromosome pairs 13 and 18 fro46,XX,t(13;18)(p13;ql2). (a) G bandinA(c) schematic representation.

but no monoclonal rises were fouelectrophoresis. Weakly positive rhwere found in 11.5, 11.10, and I.2,antibody determinations were neimmune response to phytohaemagglvalin A, pokeweed mitogen, staph Imixed leucocyte culture was depr4case I.7, shortly after complettherapy, but these values later retuThere was no linkage of red blood (blood cell antigens, or HLA to thebalanced translocation. TranslocatiI1.7, II.10, and I1I.7 and karyotypi4inherited a 'weak B' variant of aci4marker on chromosome 2. Peptidascell marker on chromosome 18, Mcases, as was esterase D on chromo

Discussion

Reciprocal translocations are a wellheritable chromosome imbalance ifamily presented here, three gtprobably affected, with imbalanpartial trisomy 18 phenotype. Althoand her cousin were the only affected

available for karyotyping, the clinical features ofanother cousin (11I.2), two uncles (11.9 and 11.12),and an aunt (11.4) suggest that they also had partialtrisomy 18 phenotype.The unbalanced carriers of this family had

developmental and mental retardation, failure tothrive, micrognathia, high arched palate, low setmalformed ears, congenital eye defects, overlappingfingers, microcephaly, heart defects, hypertrophied

At clitoris with congenital hypoplastic labia, and hyper-tonia. These features include many, but not all, ofthe defects reported in classical trisomy 18.2 13 14The long survival of case 111.3 is exceptional and hernormal menstrual and secondary sexual develop-ment remarkable. The early deaths of cases 11.4, I1.9,

i1.12, and 1I1.2 are more typical for this syndrome.'4jz~ The tendency for females with trisomy 18 to survive

longer than males has been noted.'5The grandmother of the proband (1.4) was almost

certainly a balanced carrier and, presumably, thefirst of her generation since none of her sibs or theiroffspring showed signs of chromosomal dysfunction.In most reported cases, balanced translocation

18 18 q- carriers are phenotypically normal.'2 However, in this

om case 11.10: family, all female carriers had cystic abnormalities ofg. (b) R banding; the ovaries. Cases I1.6 and 11.10 probably had' Stein-Leventhal syndrome based on histological and

clinical evidence, and fertility was abnormal incases 11.2 and ff.10.

nd on immuno- Male carriers of the balanced translocation wereeumatoid factors sterile with a few abnormally shaped sperm ofbut other auto- absent or limited motility seen on semen analysis.gative. In vitro Case 11.3 was also sterile and presumably a trans-lutinin, Concana- location carrier. A survey of cytogenetic abnorm-phage lysate, and alities in 1599 infertile men identified nine withessed initially in autosomal translocations,16 including one with thetion of chemo- karyotype 46,XY,t(13;18)(qI2;q23). In this case, themrned to normal. balanced translocation itself appeared not to becell enzymes, red the sole cause of infertility since his father hlad an- presence of the identical karyotype. Variable fertility in subjects withion carriers 11.2, balanced translocations may result from pairingcally normal 11.5 disturbances during gametogenesis causing aspermia,d phosphatase, a preimplantation zygote loss, or miscarriage of the,e A, a red blood unbalanced fetus.'17-9 In the present family, abnorm-vas type 1 in all alities in gonadal structure or function were suggested)some 13. by aspermia in males, and polycystic ovaries with

infertility in some females. Perhaps some gene(s)controlling reproductive development occurs on thelong arm of chromosome 18, with normal function

known source of interrupted at the breakpoint. Such a mechanism mayin man.12 In the also explain the high frequency of cryptorchidismenerations were in trisomy 18 males, an abnormality found in oneice manifest as translocation carrier (11.8).13 The occurrence ofugh the proband 12 spontaneous abortions in translocation carriersI family members in this family suggests a higher than expected

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incidence, presumably because of rejection of fetuseswith lethal chromosome complements. This apparenthigh frequency contrasts with that reported by Fordand Clegg12 who found that spontaneous abortion intranslocation heterozygotes was not greater than inthe general population.

In the family reported here, one carrier had acuteprogranulocytic leukaemia and another had adeno-carcinoma of the stomach and teratoma. Benigngrowths (vocal cord polyps and endocervical polyps)were found in two other carriers, suggesting apossible link with neoplasia. In occasional families,balanced translocations have been associated withthe development of leukaemia or cancer.2>24 In oneinstance, hereditary renal cell carcinoma wasassociated in all cases with a balanced translocationbetween chromosomes 3 and 8, including severalwith previously unsuspected tumours.25 In thefamily reported here, the translocation was notlinked to a specific type of cancer, although it ispossible that an underlying defect could havepredisposed both to chromosome abnormalitiesand cancer.26Although aetiological laboratory studies identified

no premalignant abnormalities in family members,the clinical findings suggest a need for more preciselaboratory evaluation. Such studies, looking at DNArepair and other aspects of chromosomal function,are currently under way to define a suspected defectthat may predispose to the cytogenetic abnormalitiesand malignancy.

Dr Norman B Schneider, Lakeworth, Florida,successfully treated the uncle of the proband forleukaemia and generously made his office availablefor interviews and blood drawing. Drs Richard JWarren and Ronald Cantwell, Miami, Florida,assisted in the evaluation of cases I.2, 1I.5, 11.6, 11.7,11.8, and 1.3 and performed initial karyotypes.Dr Jack H Dean and Frances LeSane, Litton Bio-netics Inc, Kensington, Maryland, performed invitro immune function studies; Dr Paul I Terasakiperformed HLA typing; Robin Henson and DeborahMcGuire RN assisted with interviews, blood draw-ing, and data gathering; Drs Louise C Strong,Houston, Texas, Joseph F Fraumeni Jr, and John JMulvihill, Bethesda, Maryland, offered valuableadvice; and Ruth E Brounstein edited and typed themanuscript. Supported in part by NCI ContractsNO1-CP-61011 and NO1-CP-61016, and NIH GrantCA-19834.

Addendum

One explanation for the coincidence of malignancyand chromosomal abnormalities in this family is

that some underlying defect may predispose to both.Preliminary results of a new assay of chromosomalinstability show a higher rate of induced chromoso-mal breakage in affected family members than incontrols or unaffected family members.27 Furtherstudies employing this assay and other measures ofchromosomal stability and repair mechanisms areplanned.

References

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2 Hamerton JF. Human cytogenetics. vol 2. New York:Academic Press, 1971.

3 Giblett ER. Genetic markers in human blood. Philadelphia:Lippincott, 1969.

4 Terasaki PI, Bernoco D, Park MS, Ozturk G, Iwaki Y.Microdroplet testing for HLA-A, -B, -C, and -D antigens.Am J Clin Pathol 1978;2:103-20.

5 Dean JH, Connor R, Herberman RB, Silva J, McCoy JL,Oldham RK. The relative proliferation index as a moresensitive parameter for evaluating lymphoproliferativeresponses of cancer patients to mitogens and alloantigens.Int J Cancer 1977;20:359-70.

6 Seabright M. A rapid banding technique for humanchromosomes. Lancet 1971 ;ii:971-2.

7 Wang HC, Fedoroff S. Banding in human chromosomestreated with trypsin. Nature 1972;235:52-4.

8 Scheres JMJC. Production of C and T bands in humanchromosomes after heat treatment at high pH andstaining with 'stains-all'. Hum Genet 1974;23:311-4.

9 Craig-Holmes AP, Moore FB, Shaw MW. Polymorphismof human C-band heterochromatin. I. Frequency ofvariants. Am J Hum Genet 1973 ;25:181-92.

1 Varley JM. Patterns of silver staining of human chromo-somes. Chromosoma 1977;61 :207-14.

1 Hansmann I. Structural variability ofhuman chromosome9 in relation to its evolution. Hum Genet 1976;31 :247-62.

12 Ford CE, Clegg HM. Reciprocal translocations. Br MedBull 1969;25:1l0-4.

13 Hodes ME, Cole J, Palmer CG, Reed T. Clinical experi-ence with trisomies 18 and 13. JMed Genet 1978 ;15:48-60.

14 Taylor Al. Autosomal trisomy syndromes: a detailedstudy of 27 cases of Edwards' syndrome and 27 cases ofPatau's syndrome. Am J Med Genet 1968;5:227-52.

15 Weber WW. Survival and sex ratio in trisomy 17-18.Am J Hum Genet 1967;19:369-77.

16 Chandley AC, Edmond P, Christie S, Cytogenetics andinfertility in man. I. Karyotype and seminal analysis.Ann Hum Genet 1975;39:231-54.

17 Chandley AC, Christie S, Fletcher J, Frackiewicz A,Jacobs PA. Translocation heterozygosity and associatedsubfertility in man. Cytogenet Cell Genet 1972 ;11 :516-33.

18 Lucas M, Wallace 1, Hirschhorn K. Recurrent abortionsand chromosome abnormalities. Br J Obstet Gynaecol1972;79:1119-27.

19 LUonard C, Bisson JP, David G. Male sterility associatedwith familial translocation heterozygosity: t(8; 15)(q22;pl 1). Arch Androl 1979;2:269-75.

20 Knudson AG Jr. Genetics and etiology of human cancer.Adv Hum Genet 1977;8:1-66.

21 Garson OM, Milligan WJ. Acute leukaemia associatedwith an abnormal genotype. Scand J Haematol 1974;12:256-62.

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22 Hinkes E, Crandall BF, Weber F, Craddock CG. Acuteleukemia with C-G chromosome translocation. Blood1973 ;41(2) :259-63.

23 Goh K. Smaller G(Gp-)andt(Gp-;Dp +)chromosomes:a familial study with one member having acute leukemia.Am J Dis Child 1968;115:732-8.

24 Riccardi VM, Humbert JR, Peakman D. Acute leukemiaassociated with trisomy 8 mosaicism and a familialtranslocation 46,XY,t(7;20) (p I3 ;p l 2). Am J Med Genet1978 ;2(1) :15-21.

25 Cohen AJ, Li FP, Berg S, et al. Hereditary renal-cellcarcinoma associated with a chromosomal translocation.N Engl J Med 1979;301 :592-5.

26 Zuelzer WW, Thompson RI, Mastrangelo R. Evidence fora genetic factor related to leukemogenesis and congenital

anomalies: chromosomal aberrations in pedigree of aninfant with partial D trisomy and leukemia. J Pediatr1968 ;72(3) :367-76.

27 Hsu TC, Au WW, Strong LC, Johnston DA. A short-term cytogenetic test for genetic instability in humans.Proceedings of the International Workshop on Short-termTests for Chemical Carcinogens, Vancouver, BritishColumbia, August 1979 (in press).

Requests for reprints to Dr William A Blattner,Environmental Epidemiology Branch, NationalCancer Institute, Landow Building, Room 3C-07,Bethesda, Maryland 20205, USA.

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clinical manifestations offamilial 13;18 translocation

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