J . ment. Defic. Res. (1978) 22, 277 277

TRISOMY 18 IN AN 11 YEAR OLD GIRL

ARABELLA SMITH*

Oliver Latham Laboratory

M. SILINK

Royal Alexandra Hospital for Childrenand

T. RUXTONOliver Latham Laboratory,

Health Commission for New South Wales, Australia

INTRODUCTIONStudies of survival among patients with trisomy 18 have shown that approxi-

mately half the cases survive for only two months, one third survive for three monthsand only one per cent survive from birth to ten years of age (Weber, Mamunes, Dayand Miller, 1964). It was also shown that long-term survival was more common infemales than males, as was also short-term survival (Weber, 1967). The averagesurvival period for females was seven months and for males was two months.

There have been eight published reports of children with trisomy 18 who wereover six years of age, seven females and one male. A further nine cases of trisomy 18with advanced survival have been cited in the literature—six females and threemales. These cases are summarised in Table 1.

From the information in Table 1, it can be seen that a total of seventeen cases ofadvanced survival of patients with trisomy 18 are known. All these were consideredto be non-mosaics and to have complete trisomy for chromosome 18. The meanmaternal age at birth of the eleven patients concerning whom the information issupplied, is 33.7 years. There are reports of prolonged survival in mosaic individualsand cases of partial trisomy, but these will not be considered here. This report is ofanother girl with trisomy 18, now aged eleven years.

CASE REPORTPatient L.T. was born on August 25th, 1967, the first child of healthy unrelated parents

when the mother was twenty-two and the father twenty-nine years of age. There have sincebeen two normal children, no miscarriages have occurred, there is no relevant family history.The pregnancy was uneventful, foetal movements were present but there was poor increase insize of uterus in the last trimester. Labour was induced at forly-one weeks. Birth weight was1.55 kg, birth length 45.7 cm, Apgar at one minute was four and at five minutes was eight.Numerous congenital anomalies were noted and she was transferred to the Children's Hospital.Throughout her three months residence here she was slow to feed, gained weight poorly,

•Correspondence to: Dr. A. Smith, Cytogenetics Unit, Oliver Latham Laboratory, HealthCommission of N.S.W., P.O. Box 53, North Ryde 2113, New South Wales, Australia.

Received 4th October, 1978

278 TRISOMY IB

occasionally requiring tube feeding. She was continuously "mucousy" but there were noepisodes of cyanosis or rt'spiratoiy distress.

The patient has been totally institutionalised, having been in three dillertnt nursinghomes since birth, with one further hospital admission at six months of age due to broncho-pneumonia and right otitis media. She has constantly required medical attention, although itnever appeared that death was imminent. Almost every month she had ati infection of sometype, upper resplralory tract iiileclion, bronchilis and brotichoprieunionia being the com-monest. Also IVccjuenl have been episodes of othis media, otitis externa, skiii infections, styes onthe eyeiid.s and conjuiu livitis. Al fotir and a half years, an abscess on the irmple rrc|uiredincision and drainage, at six and a halfyears an episode of eczema lasted four months despiteai)i)r()priate tieatmerU. She had rubella at three and mumps at ten years of age. (Jastro-iiitesiinal symptoms have been common, ijarticularly regurgitation of food and vomiting ofcoflee-ground inucoas, frank haenioplhysis occurred on one occasion. She has not at any timehad any convulsions, however, despite freqtienl aiid ofirn high rises of temperature. She alsohas not had any symptoms of urinary tract infection.

At the age of ten and a half yeans, she is severely retarded with few attainments. She canvocalise but cannot say any words. She never eries but can look distressed, she smiles andresponds to people with whom she is familiar, but dcHS not reeogiiise her parents, who visitapproximately once every three months. She can lift her head up from the lying posilioti,cannot sit up from this position, but if seated can sit unaided for fifteen to thirty minutes. Shecan feed herself with a spoon bul cannot drink from a cup. She ap|>ears to smell the food. She isnot toilet trained. She cannot stand.

Fig. 1. Facial view of patient, aged ten and a halfyears. Note the epicanthic folds, elfin-likc ears, broadnasal roots, carious and overcrowded teeth, and small

median upper lip cleft.

Fig. 2. Palient in supine position. The extremelypoor growth is evident.

ARABELLA SMITH et al. 279

Physical t-xaininatiaii at ten and a half years of age revealed an extremely under-developedrniaciated child (Figures 1 and 2), with the following features—-head circumference 43 cm(on the 50th percentilc for a two and a half year old), no occipital protuberance, closedfontanelles, length 95 cm (on 50th percentile for a thret- year old), weight 9..') kg (below 3rdperccntile for a two year old), marked kyphoscoUosis, very fitie and thin hair on the head,hirsute on the face and extensor surfaces of the arms, bilateral cpicanthic folds, no strabismusor other eye defects, slight hypcrtelorism (inner canthal distance 3 cm, interpupillary distance4.75 cm, outer canthai distance 7.5 cm), broad nasal roots, clfm-Iikr cars, witli an increiiscddistance be twee the helix and antiheUx, but not low-set ears. She had a small mouth, thin lips, asmall right cleft lip and very irregular carious and overcrowded teeth.

The fingers of the hands were long, thin and tapering, but not overlapping, with bilateralclinodactyly of the little fingers, nails were hyperconvox and slightly hypoplastic, both thumbswere hyperextensible at the first interphalangeal joint, distal finger crt-ases were absentbilaterally on the fourth fingers and the first fingers of the left hand. The palmar creases werentji'mal. Her feet were long and thin with pes planus and bilateral talipes ec|uinovarus. aslightly prominent calcaneus, but the feet were not rocker-bottom. There was syndactyly on theright between the second, third and fourth toes and on tlic left between the second and thirdtoes.

The sternum was 9.5 cm in length, the nipples hypoplastic and placed in the anterioraxillary line. Chr-st appeared shield-like. She had hypopla.stif labia majora, with a prominentbut not enlarged clitoris.

Neurological examination showed marked muscle wasting bilaterally, with spasticquadriplegia and contractures, all deep tendon reflexes increased with spread bilaterally, bothgreat toes downgoing, generalised hypertonia, no clonus, abdominal reflexes absent. Sheappeared to hear and she also appeared to smell, biU no firm conclusion could be drawn on thispoint. Fundi were normal, she followed well, pupils were normal. The other eranial nerveswere normal.

She had a blood pressure 95/60, pulse rate 104/minute (regular), no thrills palpable, but asoft grade 2/6 pan systolic murmur was heard in the pulmonary area, and was louder when thepatient was horizontal (this murnuir was diffienlt to hear). A small patent ductus anteriosiiswas considered to be present.

METHODS

Cytogenetic studies were performed by standard methods (Moorhead, Nowell,Melltnan, Battips and Hungerford (I960) and G banding with the technique ofSeabright (1971) using trypsin and giemsa stain. Three-day cultures were harvestedafter one and a half hours treatment with colchicine. Otlicr investigations wereperformed by standard techniques in current use.

Authors who had reported (or mentioned) cases of trisomy 18 of advanced age,were contacted by mall and asked about the further progress of their case sincereporting it. In some cases this was not known (or a reply was not received) and thisis shown by the question mark in Table 1.

INVESTIGATIONS

Investigations at the age often and a half years showed the haemoglobin, whitecelt count, the packed cell volume, the mean corpuscular haemoglobin concentration,the mean corpuscular volume and tbe platelets all within the normal range, as werealso the serum sodium, potassium, chloride, serum cholesterol, total lipids, serum

280 TRISOMY 18

Table 1

Reports of long-term survivors {over 2years of age) with Trisomy 18

Reference Sex.Maternal age at .tge (jyrs.) Age at Age {yrs.)Births {yrs.) at Report Death {yrs.) 1977

W'cher etal. (1964) ;tCoffin (1977)

Cooper (1971)

Baigman andMuseles(1970)

SuranaWfl/. (1972);Bain (1977)

Hook etal. (1965);Doebler (1977)

Geiser andSchindler (1969);Geiser (1973)

Stolid a/. (1974)

Onim etal. (1969)

Gerhard (1976, 1978)

Warkany Wa^ (1966);Warkany (1978)

Weiss ei a/. (1962);Geiser andschindler (1969)

Uehidae(a/. (1962);Uchida (1978)

Townes et al. (1962);lownes (1978)

Geiser and Schindler(1969)

Geiser und Schindler(1969);Caradus(1978)

Conen ind Erkman(1966); Concn (1978)

Lewis (1964)

F

F

F

F

F

M

F

F

F

F

F

F

F

M

M

F

M

32

NM*

NM*

45

37

41

27

25

NM-

NM*

24

26

42

NM*

45

NM*

26

10.5

10.6

8.8

15

15

11.5

13

8

4.8

3.5

1.11

5 days

7 months

1.10

8

4.5

2.6

11

10.6

3

15.6

?

?

—

?

7

6

7-10

l.IO

8.8

?

2.6

*Not mentioned.fAlso reported by Ozonoff, Steinback and Mamuncs (1964).

21

27

7

6.5

ARABELLA SMITH et al. 281

triglycerides, serum creatinine, blood urea, serum uric acid, serum calcium, totalprotein, total bilirubin and random blood glucose. Serum alkaline pho.sphatase waselevated—140 /^imol/min., the upper limit of normal being 85. Electrophoresis ofserum proteins showed a normal distribution, except that the a 2 globulin wasslightly elevated (I2g/1, with the upper limit of the normal range being 8.7 g/l). Theblood film showed mild anisocytosis. The Australia antigen and Australia antibodywere negative. Urinary aminoacids, mucopolysaccharides, a micro-urine andurinalysis were normal.

AW30The HLA phenotype of the patient was A2, ' BI3, BW40, W4, W6. The

ABO blood group was A2 Positive, and the extended blood groups showed C—c +D + E + e - , CW-, K - , Fya-, JKa + , JKb + , M + N + S+s-|-, Pl-f, Lea + ,Leb —, Xga+s.

During the course of these investigations, the patient developed cervieal mumpsand immunoglobulin tested on day eight of this infection showed IgG and lgA to bewithin the normal range; the lgM was slightly raised (321, normal range 42-301lU/ml), consistent with moderately recent infection. Total serum protein on thisoccasion was normal and the electrophoretic pattern was similar to the previouspattern, with the a 2 macroglobulin slightly more elevated at 15 g/l. Imrnuno-globulins tested six months after this infection had subsided showed a similar pattern

8 9 10 11

Fig. 3. The patient's G-banded karyotype,showing complete trisomy 18.

Fig. 4. Radiograph of thelong bones of the legs par-ticularly showing thin andtortuous fibula. Patientaged ten and a half years.

282 TRISOMY 18

to the previous test, with lgG and lgA, again normal. The igM had fallen and wasnow within the normal range (291 lU/ml).

Other tests performed included serum ascorbic acid, which was low at 10/xmol/l (normal range 28-85), serum ferritin, haptoglobin estimation, serum iron,total iron binding capacity and saturation which were within the normal range.

Hormone studies showed LH to be normal, FSH 290/^g/l (LER 907), the normalrange for FSH being 50-150 for the two-to-twelve age group. Thyroid function testswere within the normal range, thyroid antibodies were not detected. Plasma cortisolshowed normal diurnal variation. A sleep study (at sixty and ninety minutes) showedgrowth hormone within the normal range.

An electrocardiogram (ECG) was normal. An electroencephalogram (EEG)was abnormal, with flattening in the right posterior temporal region.

A skeletal scan showed extremely thin long bones (Figure 4) with both hipjoints in coxa valga position. Both fibulae were extremely narrowed and the right onetortuous in outline. There was marked scoliosis of the lower thoracic and lumbarspine. Bone age was about four years three months.

Cytogenetic studies were performed at birth and at ten and a half years. A totalof 78 cells was counted, 76 were 47 XX + 18 (Figure 3), two cells showed randomlosses. We consider that the patient is not a mosaic with a normal cell line, althoughwe cannot exclude this possibility. Dermatoglyphic analysis showed simple arches onall ten fingertips with hypoplastic palmar ridges and no axial triradii could be foundon either palm. Chromosome analysis of both parents was normal.

DISCUSSIONOf the reported cases of advanced survival among patients with trisomy 18,

presumed to be non-mosaic, many features are present consistently. Mental retar-dation in these cases has always been severe to profound. The case of StoU, Levy andTerrade (1974) is of interest in this regard, as their patient could walk at two and ahalf years and she began to say simple monosyllables at about four years of age. Noneof the other cases could speak at all (including our own), and also none could walk,although the girl reported by Gerhard (1976) could stand for several minutes holdingon to parallel bars after nearly three years of physiotherapy. Our patient can situnaided for a short time, and she also is the only one who can feed herself, althoughmany of the other reports do not mention this. No child has been toilet trained, eventhe two cases in their twenties (see Table 1). Another feature consistently present issevere physical growth retardation with height and weight well below the thirdpercentile, such as in our patient.

Some features have been reported to alter with time and are not present in allolder patients. Table 2 shows features in our patient which have altered with time.Overlapping flexed fingers, a feature at birth, were no longer present in our case orthe case of Cooper (1971) Geiser and Schindler (1969) and Surana, Bain and Concn(1972) but flexed fingers were still present in the case of Stoll etal. (1974) and the caseof Weber et al. (1964). Scoliosis or kyphoscoliosis was present in the cases of Gerhard

—

normal

normal

soft

abnormal

hypoplastic labiaprominent clitoris

ARABELLA SMITH et al. 283

Table 2

Features which have altered with time

Birth 10.5 yrs.Low-set ears -f -

Elongated head + + -

(prominent occiput)

Overlapping fingers + + + —

Muscle tone ' hypotonic hypertonic

Kyphoscoliosis* - + + +

Heart murmur

EEG

Genitalia

Rocker-bottom feet -f —

•.Skeletal scan at birth and 10.5 yrs.

(1976) Surana el al. (1972); Weber et al. (1964); Cooper (1971); Bargman andMuseles (1970), and in our patient. It was not mentioned in the other reports andpresumably was absent. The shape of our patient's head has also changed; theocciput is no longer prominent, and the ears are not low-set although still elfin-like.These various changes in phenotype were commented upon by Warkany, Passargeand Smith (1966) and Surana et al. (1972), so that a clinical diagnosis at a late stagemay not be as straightforwaid as at birth.

Our patient docs not show any signs of puberty; menses had not occurred in thefifteen year old reported by Hook, Lehrke, Roesner and Yunis (1965), and no signsof puberty were present in the patient of Surana et al. (1972) reported at fifteen yearsof age. Subsequently, this patient has breast and pubic hair development at TannerStage III and she has menorrhagia requiring hormone treatment (Bain, personalcommunication).

Only one case has been reported as having recurrent urinary tract infections(Surana et al., 1972) so that although renal anomalies are frequent (Warkany et aL,1966) infection in this system is not common. Also only one case has been reportedwith seizures, the fifteen year old girl of Hook et al.., (1965) and this patient still hasfrequent seizures (all grand mal attacks) at twenty-seven years of age (Doebler,1977). On the other hand, recurrent respiratory tract infections, such as in ourpatient, are a common feature. We were able to show that our patient had auadequate immunologic response to infection, when she contracted mumps.

284 TRISOMY 18

Extensive investigations were all within the normal range, apart from a some-what low ascorbic acid level, which can be attributed to diet, and a very slightlyraised serum FSH level and a somewhat raised serum alkaline phosphatase. Otherauthors have also found routine investigations to be normal in their patients, althoughthey were not so extensively investigated as our patient.

Hecht (1973), Surana et aL (1972) and Hook et al. (1965) suggest various factorswhich may be important in long-term survival. Sex of the patients is seen in Table I.Other factors affecting survival are shown in Table 3. Females strongly outnumberthe male patients, thirteen females, four male patients. While the number of thesecases fully reported is still too few to come to any definite conclusion, it would appearthat, apart from a distinct sex factor, survival in trisomy 18 is not shown to beparticularly related to any of the known abnormalities in these children or to anyapparent genetic effect in the families, or to whether the patient is cared for at homeor in an institution.

Table 3Factors in prolonged survival of patients with Trisomy 18*

Reference Cause of death Patient care Cardiac diseaseGeiser and Respiratory At home No (heart murmurSchindler (1969) infection at birth)

Cooper (1971)

Stolid/a/. (1974)

Orsini etal. (1969)

Suraua etal. (1972);Bain (1977)

Bargman andMuseles (1970)

Hook etal. (1965);Doebler (1977)

Weber e/a/. (1964);Coffin (1977)

Gerhard (1976,1978)

Uchida (1978)

Present case

Bronochopneumonia

—

—

—

—

• — .

Died quietly

—

Apnoea duringrespiratorytract infection

At home

NMt

NM

At home

NM

Institution

Institution

At home

NM

Institution

Present

Present

NM

Present

Present

No

Present

No

Probably not

Present—ver

•Cases included iu this table are those with some detailed report published.fNM—not mentioned.

ARABELLA SMITH el al. 285

SUMMARYA case of trisomy 18, confirmed by O banded chromosome analysis, is reported

in an eleven year old Australian girl. There is no cytogcnctic evidence of mosaicismin the propositus or her parents.

The patient's salient clinical features are severe mental and motor retardationwith microcephaly, kyphoscoliosis and various congenital anomalies. She has verymild congenital heart disease. She has been totally institutionalised and has requiredconstant medical care.

Comparison of her condition with other long-term survivors with trisomy 18reported in the literature, and also considered to be non-mosaic, reveals manysimilar features. However, no pattern emerges as to why these rare patients havesurvived.

ACKNOWLEDGMENTSWe wish to thank: the Sydney Red Cross Blood Transfusion Service for the

serology; the Institute of CUnica! Pathology and Medical Research, Lidcombe, forthe immunoglobulin studies; Gai Elliott, Oliver Latham Laboratory, for the cyto-genetic studies; Sister Cross, Matron of C^ollaroy Hospital, Sydney, for her continuousco-operation; Dr. Michael Connolly, Medical Superintendent, Collaroy Hospital,for permission to publish this report; the various authors who kindly sent progressnotes of cases they had reported; and also the help of the patient's parents.

REFERENCESBAIN, H . VV'. (1977) Personal communication.BAROMAN,G..J. and ML'SELES, M. (1970) 18 trisomy syndrome in a girl of eight. I incfi 1, 143.( ARADUS, V. (1978) Personal communication.COFFIN, G . S. (1977) Personal com muni cal ion,CoNEN, P. E. and ERKMAN, B. (1966) Frequency and occurrence ofrhromosonial syndromes II.

E-Trisomy. Amer. J. hum. Genet. 18, 387.CoNEN, P. E. (1978) Personal communication.COOPER, D . M . (1971) Long survival with Trisomy EI8. South AusIralian Climes. 5, 295.DOEBLER, M . I, (1977) Personal communication.GEISER, C . G . and ScniNDLER, A . M . (1969) Long survival in a male with 18-trisomy syndrome

and Wilm's tumor. Pediat. 44, 111.(iKisER, C. G. (1973) Long survival in a male with 18 trisomy syndrome and Wilm's tumor: A

subseqtient report. Pediat. 51, 153.GERHARD, M . (1976) Development of motor skills in a child with irisomy 18. Develop. Med.

Child Neurol. 18, 538.(iERHARD, M. (1978) Personal communication.HECHT, F . (1973) Birth defects Atlas and Compendium. Bcrnsma National Foundation. Baltimore.

Williams and Wilkins, 246.HOOK, E . B., LEHRKF. R . , ROESNER, A. and YUNIS, J . J . (1965) Trisomy 18 in a 15-year-old

female. Lancet ii, 910.LEWIS, A. J. (1964) The pathology oftrisomy 18. J . Av//fl/. 65, 92.MooRHEAD, P. S., NowELL, P. C , MELLMAN, W . J., BATTH'S, D . M . and HUNGERFORD, D . A .

(1960) Chromosome preparations of lcucocyest cultured from human peripheral blood.Exp. Cell. Res. 2Q, &\?,.

ORSINI, A., STAHL, A. , SANSOT, M . , GIRAUD, F. , PERRIMOND, H . , BERNARD, P. J., BRUSQIIET, Y .

286 TRISOMY 18

and TARAMASCO, H . (1969) Hcmosiderose pulmonairc chez un enfant dc 9 ans portcurd'une trisomie 18. Pediatrie 24, 339.

OzoNOFF, M. B., STEINBACK, H . L . and MANNUNES, P. (1964) The trisomy 18 syndrome. Amer.J . Roentgen. 91,618.

SEABRtGnTM. (1971) A rapid banding technique for human chromosomes. Lancet U, 971.STOI.L. C , LEVY, J. M. aiid TERBADF,, E . (1974) Les sui-vics prolongees dans ta trisomie IB.

Ann. Pediat. 21, 185.SURANA, R . B., BAIN, H . W . and CONEN, P. E. (1972) 18 trisomy in a 15-year-old girl. Amer.J.

Dis. Child. 123, 75.TowNES, P. L., MAXNINC. J. A. and DEHART. G. K. (1962) Trisomy 18 (16-18) associated with

congenital glaucoma and optic atrophy. J. Pediat. 61, 755.TowNES, P. L. (1978) Personal communication.UcntDA, I. A., BOWMAN, J. M. and WANG, H. C. The I8-trisomy syndrome (1962). The New

Eng.J. Med. 266, 1198.UCHIDA, L A. (1978) Personal communication.WARKANY, .J., PASSAROE, R. and SMITH, L. B. (1966) Congenital malformations in autosomal

trisomy syndromes. Amer.J. Dis. Child. 112, 502.WARKANV,J. (1978) Personal communication.WEBF.R, W. W., MANNUNES, P., DAV, R. and Mit.iFR, P. (1964) Trisomy 17-18 (E): Studies in

long-term stirvival with report of two atitopsied cases. Pediatrics 34, 533.WEBER, W. W. (1967) Survival and the sex ratio in trisomy 17-18. Amer.J. him. Genet. 19, 369.WEISS, L., DIGEORGE, A. M. and BAIRD, H. \V. (1962) Four infants with trisomy 18 syndrome

and one with trisomy IB mosaicism. Amer.J. Dis. Child. 104, 533. (Abstract.)

ADDENDUMRecently a paper appeared of a further ease of advanced stirvival with trisomy

18—Crippa, Marcoz, Klein and Bourquin (1978). This female patient was sixteen-and-a-half years old, was almost totally institutionalised and was considered to havea mild ventricular septal defect. She had also considerable pubic development.Cytogenetic studies showed, typical trisomy in all cells examined from peripheralblood but a small percent of normal 46XX cells were present in skin culture. Thisis the first report of a definite disparity between blood and skin analysis in trisomy 18with prolonged survival, and while it has important implications, it is doubtftil thatall cases of trisomy 18 with prolonged survival are the result of luidetected mosaicism.

REFERENCECRIPPA, L., MARCOZ, J. P., KLEIN, D. and BOURQUIN, D. (1978) hca trisomics 18 a suivic

prolong^e (au-dela dc 10 ans), sont-elles toutes des mosaiques? J. Ginit. Hum. 26, 145.