Prenat. Diagn. 18: 384–389 (1998)

SHORT COMMUNICATION

PRENATAL CONFIRMATION OF TRUE FETAL

TRISOMY 22 MOSAICISM BY FETAL SKIN

BIOPSY FOLLOWING NORMAL FETAL BLOODSAMPLING

1*, . 1, . -2 . 2

1Department of Obstetrics and Gynecology, Jefferson Medical College at Thomas Jefferson University Hospital,Philadelphia, PA, U.S.A.

2Department of Genetics, Yale University, New Haven, CT, U.S.A.

Received 23 April 1997Revised 21 July 1997

Accepted 25 July 1997

SUMMARY

Trisomy 22 mosaicism diagnosed at 20 weeks’ gestation by amniocentesis in a 35-year-old woman was notconfirmed by fetal blood sampling. Subsequent fetal skin biopsy revealed trisomy 22 in 7 of the 15 fibroblastsanalysed. We conclude that, depending on the chromosome involved, fetal skin biopsy should be considered in thediagnostic work-up when mosaicism is found in amniotic fluid. ? 1998 John Wiley & Sons, Ltd.

: amniocentesis; amniotic fluid mosaicism; cordocentesis; fetal skin biopsy; trisomy 22

INTRODUCTION

The presence of mosaicism in routine prenatal

amniotic fluid, absent in fetal blood, but present infetal skin.

A 35-year-old gravida 2, para 1001 had amnio-

diagnostic samples requires further evaluation todetermine the clinical significance. Fetal bloodsampling may help to resolve many cases but therecent discoveries of mosaicism confined to extrafetal tissues and uniparental disomy make theevaluation of prenatal mosaicism increasinglymore complex. To add to this difficulty, specificchromosome abnormalities may be absent fromfetal haematological lines while present in amnio-cytes and fibroblasts. We report the first case of thein utero evaluation of mosaic trisomy 22 present in

*Correspondence to: Vincenzo Berghella, MD, Departmentof Obstetrics and Gynecology, Division of Maternal–FetalMedicine, Thomas Jefferson Medical College, 834 ChestnutStreet, The Ben Franklin Building, Suite 400, Philadelphia,

CASE REPORT

PA 19107, U.S.A. E-mail: berghel1@jeflin.tju.edu

CCC 0197–3851/98/040384–06 $17.50? 1998 John Wiley & Sons, Ltd.

centesis at 18 weeks’ gestation for a choroid plexuscyst which revealed 46,XY/47,XY,+22 mosaicism(15/4) from two independent cultures and normalamniotic fluid alpha-fetoprotein. Ultrasoundexamination and fetal echocardiogram revealed anappropriate-for-gestational-age fetus with no grossstructural abnormalities. One hundred and onecells from umbilical cord blood sampling allrevealed a 46,XY karyotype, and parental karyo-types were normal. Because of previous reports oftrisomy 22 confined to fetal skin in karyotypicallyabnormal infants, a fetal skin biopsy wasperformed at 20 weeks’ gestation.

Table I—Incidence of trisomy 22 cells cultured from different organs

Tissue 46,XY 47,XY,+22

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sites on the upper back and side using a 7 FrenchStortz biopsy forceps inserted through a 14-gaugeangiocath port. The fetal skin was manuallypulverized and the cells were separated withcollagenase and placed both on coverslips andin flasks. Subsequent results revealed a 46,XY/47,XY,+22 (8/7) karyotype.

Based on reports of phenotypically abnormalinfants with mosaic trisomy 22 present in skin butnot in blood, the parents decided to terminatethe pregnancy. Autopsy revealed hypertelorism,bilateral pulmonary polylobation, large low-setears, and a flat nasal bridge. The frequency oftrisomy 22 cells in different organs is shown inTable I.

The parent of origin of the two #22 chromo-somes in fetal blood was studied using polymerasechain reaction (PCR) amplification of 12 shorttandem repeat polymorphisms. Two loci wereinformative and demonstrated biparental origin.

DISCUSSION

Under continuous real-time ultrasound scan-ning, fetal skin was biopsied from three individual

in the fetus is suggested. While fetal blood sam-pling may be helpful, this approach is limited by

PrenatalAmniocytes 15 (79%) 4 (21%)Blood T-lymphocytes 101 (100%) 0 (0%)Skin fibroblasts 8 (53%) 7 (47%)

AutopsyLung 34 (97%) 1 (3%)Placental villi 1 (1%) 34 (97%)

Full trisomy 22 rarely, if ever, presents as a

viable pregnancy with a liveborn baby (Petersenet al., 1987) and, therefore, most cases reported todate have been mosaics. The phenotype of mosaictrisomy 22 is well defined and includes micro-cephaly, abnormal ears, webbed neck, cardiacanomalies, long fingers, and growth retardation(Lund et al., 1990; Hsu et al., 1997). While in uteroevaluation of a mosaic trisomy 22 amniocentesisshould include ultrasound scanning for fetal struc-tural anomalies, some of the phenotype character-istics are subtle and may not be identifiable.Therefore, in many cases direct fetal sampling toevaluate the distribution of the aneuploid cell line

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the potential absence of trisomic cells in fetalblood, despite a phenotypically abnormal infantwith the mosaic trisomy 22 cell line in other tissues.To date, seven cases of phenotypically abnormalinfants having only euploid lymphocytes butmosaic trisomy 22 skin cells have been reported(Pagon et al., 1979; Wertelecki et al., 1986; Lessicket al., 1988; Lund et al., 1990; Desilets et al., 1996).Hsu et al. have recently reported on 11 cases ofmosaic trisomy 22 in amniocytes, of which seven(64 per cent) had an abnormal outcome (Hsu et al.,1997).

Cases involving chromosomes other than 22 inwhich the haematological cell line is euploid whileskin is aneuploid have been reported. Table IIsummarizes 21 prenatal diagnostic cases of tri-somic mosaicism detected in amniocytes in whichthe aneuploid cell line was subsequently found inthe skin of the fetus or infant but not in bloodlymphocytes. Twenty of the 21 cases had pheno-typic abnormalities. [Cartolano et al. (1993) didreport a normal autopsy on an 18-week fetusterminated for mosaic trisomy 12 with only 1/15trisomic fibroblasts.] Additionally, at least 25 phe-notypically abnormal children have been reportedwith only euploid blood lymphocytes but trisomicmosaicism in skin fibroblasts (Table II). Inaddition to the cases of mosaic trisomy includingchromosomes 2, 4, 5, 8, 9, 12, 15, 16, 17, 18, 20, 21,22, and X, similar cases of isochromosome 12p(Pallister–Killian syndrome) (Hunter et al., 1985;Kawashima, 1987; Priest et al., 1992; Zakowskiet al., 1992; Donnenfeld et al., 1993; Horneff et al.,1993; Larramendy et al., 1993; Ohashi et al., 1993;Gamal et al., 1994; Horn et al., 1995; Wilson et al.,1994), hexasomy 12p (Van den Veyer et al., 1993),and tetrasomy 5p (Sijmons et al., 1993) have beenreported.

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Table II—Chromosomes in which trisomic mosaicism was present in fibroblasts but not in lymphocytes (allabnormal phenotype except Cartolano et al., 1993)

386 . .

It is unclear why in some cases ectodermally-derived tissue such as skin would be more

marrow precursor cell lines than in ectodermprecursor cell lines.

Chromosome

No. of cases diagnosed:

ReferencesPrenatally Postnatally

2 1 — Casey et al., 19904 1 — Marion et al., 19905 1 1 Sciorra et al., 1992

8 — 5 HKosztolanyi et al., 1976; Neu et al., 1969; Schinzel et al., 1974;DeBray-Ritzen et al., 1974; Meisel-Stoisiek et al., 1983

9 4 [1] — HSherer et al., 1992; Merino et al., 1993; Saura et al., 1995;Schwartz et al., 1989

12 2 (1) 2 HCartolano et al., 1993; von Koskull et al., 1989; Aughton et al.,1996; Patel et al., 1996

15 1 [1] — Sundberg et al., 1994

16 7 1 HPletcher et al., 1994; Lindor et al., 1993; Gilbertson et al., 1990;Hsu et al., 1996

17 1 1 Kingston et al., 1993; Shaffer et al., 199618 — 1 Pagon et al., 197920 1 — Hsu et al., 1987

21 — 7 [3] 5Yokoyama et al., 1992; Pagon et al., 1979; Warkany et al., 1964;Ridler et al., 1965; Zellweger et al., 1966; Haberlandt, 1973;Ladda et al., 1977

22 (1) 7 HOur case; Pagon et al., 1979; Wertelecki et al., 1986;Lessick et al., 1988; Lund et al., 1990; Desilets et al., 1996

X 1 — Schlesinger et al., 1990

[ ]=Low-level mosaicism present in lymphocytes (<5 per cent); high level present in fibroblast (>50 per cent).( )=Complete in utero evaluation including amniocentesis, cordocentesis, and skin biopsy.

predictive of an abnormal phenotype than It remains uncertain what whole uniparental

mesodermally-derived tissue such as blood. It isnow known that true fetal mosaicism can occureither secondary to post-zygotic somatic non-disjunction or alternatively by ‘rescue’ of an ini-tially trisomic zygote. The number of abnormalcells and their tissue distribution are dependent onthe timing of the rescue non-disjunction and thetissue compartment in which it occurs. Whilesomatic cell non-disjunction occurring after initialcompartmentalization may explain mosaicism iso-lated to the ectoderm, this probably does notexplain the occurrence in our case, since recentevaluation of the mechanisms leading to confinedplacental mosaicism has demonstrated that mostcases of mosaic trisomy 22 occur following tri-somic rescue (Robinson et al., 1997). Therefore,aneuploid cells were most likely present in precur-sors of all tissue layers. The most likely hypothesisis that selective pressures against abnormal celllines may be greater in the actively dividing

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disomy (UPD) may have in causing phenotypeabnormalities. In cases in which the involved chro-mosome is known to be imprinted, studies forUPD may be indicated when the amniotic fluidreveals aneuploid cells. At present, chromosomes2, 3, 7, 11, 14, 15, 16, 21, and 22 have beendemonstrated to possibly require this furtherevaluation. However, the clinical implications ofUPD on fetal growth and development remainunclear. Studies for UPD were performed in five ofthe cases summarized in Table II (two cases ofmosaic trisomy 16, one of mosaic trisomy 17, oneof mosaic trisomy 21, and our case). Only one case(mosaic trisomy 16) revealed UPD (Lindor et al.,1993). The phenotype of this child did not differsignificantly from the phenotype of the child withmosaic trisomy 16 in whom UPD was not found(Pletcher et al., 1994).

Before skin biopsy can be included in the routineevaluation of amniotic fluid mosaicism, there are

Prenat. Diagn. 18: 384–389 (1998)

remaining clinical questions such as which skin siteto biopsy and how many biopsies to obtain. It hasbeen suggested that if a dysmorphic organ or body

centesis or chorionic villus sampling was isolatedfrom blood lymphocytes but not from skin fibrob-lasts. Both of these fetuses were found to have

Aughton, D.J., AlSaadi, A.A., Harper, C.E., Biesecker,

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part is identified, this should be preferentiallybiopsied to maximize the probability of detectingthe mosaicism (Papenhausen et al., 1991;Yokoyama et al., 1992). However, in many in uteroclinical situations the fetus will appear normal andit is unknown whether sampling only limited areasis sufficient to exclude mosaicism.

The technical aspects of fetal skin sampling havecontinued to improve as ultrasound guidance hasreplaced the use of fetoscopy and as samplinginstruments have become smaller. Skin biopsieshave traditionally been performed for the diagno-sis of hereditable skin diseases and have requiredrelatively large samples. The amount of tissueneeded for a karyotypic study is much smaller andadequate skin samples can be obtained with a21-gauge biopsy forceps through a 19-gauge angi-ocath port (Cartolano et al., 1993). With thesesmall instruments, the safety of skin biopsy hasbeen excellent. In the largest reported series of 54cases performed with a small forceps under ultra-sound guidance, no complications were observedin continuing pregnancies (Nicolini and Rodeck,1992). In another series of 11 cases, whenultrasound-guided skin biopsy was performed, allpregnancies delivered at term (Elias et al., 1993).This experience with fetal skin biopsy, at least inexpert hands, compares extremely well with the1–2 per cent incidence of pregnancy loss followingfetal blood sampling (Nicolini and Rodeck, 1992).

From the above information, we conclude thatskin biopsy may have higher diagnostic value thanfetal blood sampling in certain cases of mosaicismdetected in amniocytes. When mosaic trisomy 5,12, or 20 or mosaic tetrasomy or hexasomy 12 isdetected in amniocytes, a skin biopsy shouldclearly be part of the routine evaluation beforecounselling that the abnormal cell line is isolatedto extra fetal tissues. In these cases, fetal bloodsampling will not be of value since mosaicismfor these chromosomes has rarely, if ever, beendemonstrated in this tissue, despite significant phe-notype aberration. When mosaic trisomy 2, 4, 8, 9,15, 16, 17, 18, 21, 22, or X is detected in amnio-cytes, skin biopsy should be strongly considered asthe initial test for fetal involvement. It is unclear ifblood sampling should then be offered if the skinbiopsy reveals only euploid cells. Two cases havebeen reported in which trisomic mosaicism ofchromosomes 8 and 13 initially detected at amnio-

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normal phenotypes at follow-up (Fejgin et al.,1992; Klein et al., 1994). Further experience isneeded to determine if fetal skin biopsy is indicatedwhen a mosaic trisomy for chromosomes 3, 6, 7,11, 13, and 14 is detected in amniocytes. It hasbeen recently reported that trisomic cells will bedetected in either fibroblasts or placental cellsor both in 96 per cent of cases with amnioticfluid trisomic mosaicism and eventual abnormaloutcome (Hsu et al., 1997).

To improve the gathering of data, we wouldpropose the formation of a registry of mosaictrisomies detected at amniocentesis, includingdata on lymphocyte and fibroblast karyotypes, thepresence of uniparental disomy, and perinataloutcome.

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