PRENATAL DIAGNOSIS, VOL. 13,637-642 (1993)

SHORT COMMUNICATION

46,XY/47,XY, + 17p+ MOSAICISM IN AMNIOCYTES ASSOCIATED WITH FETAL

ABNORMALITIES DESPITE NORMAL FETAL BLOOD KARYOTYPE

HELEN M. KINGSTON, UMBERTO NICOLINI*, JOHN HASLAM AND TONY ANDREWS

Regional Genetics Centre. St Mary’s Hospital, Manchester M I 3 OJH. U.K.; ‘Institute of Obstetrics and Gynaecology, Queen CharlotteS and Chelsea Hospital, London W6 OXG. U.K.

SUMMARY 46,XY/47,XY, + 17p + mosaicism was found in two primary amniotic fluid cultures (AFCs). Fetal blood karyotype was normal, but ultrasonography revealed Dandy-Walker mal- formation and bilateral choroid plexus cysts. Following termination of pregnancy, fetal examination revealed post-axial polydactyly and neuroblastoma-in-siru affecting both adrenals in addition to the cerebellar abnormalities. Mosaicism for the aberrant cell line was confirmed in all fetal tissues sampled and in the placenta.

KEY WORDS Chromosome mosaicism Chromosome 17 Dandy-Walker malformation Fetal blood karyotype Prenatal diagnosis

INTRODUCTION

Mosaicism complicates the interpretation of prenatal diagnosis of chromosomal abnormalities, although less commonly encountered in AFCs than in chorionic villus samples. Level 3 mosaicism (with multiple abnormal cells in more than one primary culture) occurs in about 0.25 per cent of AFCs (Benn et al., 1984; Bui et al., 1984; Wilson et al., 1989; Worton and Stern, 1984). A considerable proportion of these will not represent true fetal mosaicism, and further investigation with fetal blood sampling has been recommended (Watson et al., 1984; Gosden et al., 1988; Vekemans et al., 1981). We report a case of true fetal mosaicism associated with structural abnormalities of the central nervous system in which the fetal blood karyotype was normal, and suggest that high resolution ultrasonography must be included as part of the investigation of such cases.

CASE REPORT

A 39-year-old gravida 4, para 2+ I , was referred for prenatal diagnosis because of advanced maternal age. An amniocentesis was performed at 17 weeks’ gestation, and three primary cultures were established. Chromosome analysis of 90 cells revealed an extra chromosome 17 with additional material of unidentified origin

Addressee for correspondence: Dr H. Kingston, Consultant Clinical Geneticist, Regional Genetics Centre, St Mary’s Hospital, Whitworth Park, Manchester MI3 OJH, U.K.

0 197-385 1/93/070637-06$08.00 0 1993 by John Wiley & Sons, Ltd.

Received 7 August 1992 Accepted 28 November 1992

638 H. M. KINGSTON ETAL.

J

17 Figure 1. Partial karyotype demonstrating the additional abnormal chromosome 17

Table 1. Cell counts in cultures of different samples and tissues

46,XY 47,XY, + 17p + Amniotic fluid cells

Culture A Culture B Culture C Total

Fetal blood samples* Fetal tissues

Skin Brain Lung Kidney

Placenta

30 29 28 87 (96.7%)

100 (100~0)

36 (72%) 6 (12%)

15 (44%) 19 (38%)

17 (34%)

0 1 2 3 (3.3%)

0 (0%)

14 (28%)

19 (62%)

33 (66%)

44 (88%)

19 (56%)

*Sampleexamined at thecytogenetics Department, Queen Charlotte’s Maternity Hospital, London.

attached to the short arm (+ 17p+) in a total of 3 cells from two independent cultures (Figure 1 and Table 1). Fetal blood sampling was performed at 19 weeks’ gestation by transabdominal needling of the umbilical vein at the placental cord insertion under ultrasound guidance using a 20-gauge needle. Fetal haematocrit was 32 per cent and pH, pCO,, and PO, were normal for gestational age. Chromosome analysis revealed a normal male karyotype in 100 cells. Ultrasonography performed at the same time demonstrated a small Dandy-Walker cyst (1.2 cm in diameter) and bilateral choroid plexus cysts without hydrocephalus (Figure 2). No other fetal malformations were detected.

After counselling, the couple elected to terminate the pregnancy. External examination of the male fetus revealed post-axial polydactyly of the left foot, low-set ears, wide sagittal suture, and large anterior fontanelle. Internal examination demonstrated absence of the inferior cerebellar vermis and hypoplasia of the cerebellar hemispheres, characteristic of Dandy-Walker malformation. In addition,

46,XY/47,XY, + 17p + MOSAICISM 639

Figure 2. Ultrasound appearance of (a) Dandy-Walker cyst and (b) choroid plexus cyst

both adrenals displayed neuroblastoma-in-situ. Various fetal tissues and the placenta were cultured for chromosome analysis, and all demonstrated mosaicism for the + 17p + abnormality (Table 1).

DISCUSSION Determining the origin and significance of mosaic chromosome abnormalities detected in AFCs is always difficult. Gosden et al. (1988) confirmed an abnormal fetal karyotype on only 9 out of 41 cases of AFC mosaicism. They suggested that

640 H. M. KINGSTON ET AL.

AFC mosaicism for de-now translocations, rearrangements, and supernumary chromosomes was more likely to reflect true fetal karyotype than AFC mosaicism for autosomal trisomies and sex chromosome aneuploidies. Other studies have confirmed abnormal fetal karyotypes in a greater proportion of cases (Bui et al., 1984; Hsu and Perlis, 1984; Worton and Stern, 1984; Kaffe et al., 1988). This dis- parity may reflect differences in the criteria used to define true AFC mosaicism, although even cases thought to represent pseudomosaicism have been found to reflect an abnormal fetal karyotype (Benn et al., 1984; Watson et al., 1984; Kaffe et al., 1988; Terzoli et al., 1990).

Gosden et al. (1988) documented a normal pregnancy outcome in all cases where the fetal blood karyotype was normal and recommended fetal blood sampling in all cases of AFC mosaicism. A normal fetal blood karyotype does not completely exclude the possibility of fetal abnormality, however. In addition to our case, von Koskull et al. (1 989) reported trisomy 12 mosaicism in AFC with subsequent delivery of a dysmorphic child despite a normal fetal blood karyotype, and Sherer et al. (1992) described a pregnancy with non-mosaic trisomy 9 in AFC in which trisomy 9 mosaicism was confirmed in subsequent post-mortem tissue from the clinically affected baby, whose cord blood at delivery and neonatal blood karyotype had demonstrated no trisomy 9 cells. Lessick et al. (1988) reported a develop- mentally delayed, dysmorphic infant with trisomy 22 mosaicism detected in skin fibroblasts but not in blood lymphocytes, and in other mosaic abnormalities, such as tetrasomy 12p, the abnormal cell line is generally absent in blood lymphocytes and detection requires fibroblast culture (Reynolds et al., 1987).

The absence of reported cases of non-mosaic trisomy 17 at amniocentesis and the rarity of mosaic trisomy 17 in spontaneous first-trimester abortions (Hassold, 1982; Simpson, 1990) suggest that this autosomal trisomy is very strongly selected against in vivo. There are a few reports of mosaic trisomy 17 in second-trimester AFC (Djalali et al., 1991; Hsu and Perlis, 1984; Kalousek et al., 1987; Wilson etal., 1989; Welborn and Lewis, 1990), but in none of these cases was the abnormality con- firmed in the fetus or newborn, suggesting an extraembryonal origin of the trisomic cells. One report of mosaic trisomy 17 in a newborn with severe malformations (Bullerdick and Bartnitzke, 1982) indicates that this abnormality may occasionally result in a liveborn infant. In our case, interpreting the significance of the mosaic AFC abnormality was further complicated by the presence of additional unidentified material attached to the short arm of the extra chromosome 17.

Djalali et al. (1991) suggested that mosaic trisomy 17 in AFC may be similar to the finding of trisomy 20 mosaicism, in which the majority of pregnancies result in normal healthy babies, and the rare cases with trisomic fetal cells resulting in mal- formations are likely to have a high proportion of trisomic cells in AFC (Djalali et al., 1985; Hsu et al., 1987). This suggestion is not borne out by our case, in which only 3.3 per cent of the amniotic fluid cells demonstrated the mosaic + 17p + abnormality, but between 14 and 88 per cent of cells in fetal tissues were trisomic.

Despite the normal fetal blood karyotype in our case, high resolution ultra- sonography demonstrated a small Dandy-Walker cyst and bilateral choroid plexus cysts. Dandy-Walker malformation is a developmental abnormality of the central nervous system comprising hydrocephalus, partial or complete absence of the cerebellar vermis, and a posterior fossa cyst continuous with the fourth ventricle

64 1 46,XY/41,XY, + 17p + MOSAICISM

(Hart et al., 1972). Hydrocephalus was not present in our case, but this may develop postnatally (Hirsch et al., 1984; Russ et al., 1989). Dandy-Walker malformation has been described in association with various chromosomal abnormalities (Murray et al., 1985; Constantini et al., 1989; Russ et al., 1989). The prognosis for Dandy-Walker malformation is variable and difficult to predict. In some cases, the condition may not be diagnosed until adult life (Unsgaard et al., 1987). Studies by Sawaya and McLaurin (1981) and Hirsch et al. (1984) suggested survival rates of 74 and 88 per cent, with an IQ above 80 in 30 and 60 per cent of cases, respectively. More recent surveys suggest a more favourable outcome for postnatally diagnosed cases. Golden et al. (1987) and Maria et al. (1987) reported normal intelligence in 75 and 88 per cent of cases, respectively, where there were no other associated abnormalities. Russ et al. (1989) reviewed 15 cases diagnosed by prenatal sono- graphy and found hydrocephalus in 60 per cent of fetuses and extracranial abnormalities in 60 per cent. Of 12 karyotypes available, 4 (33 per cent) were abnormal. Excluding terminated pregnancies, the overall mortality was 55 per cent, indicating that Dandy-Walker malformation diagnosed prenatally is associated with a worse prognosis.

In the case reported here, the presence of the Dandy-Walker cyst together with the choroid plexus cysts and low-level AFC mosaicism led to the couple’s decision to terminate the pregnancy despite the normal fetal blood karyotype. Subsequent post- mortem examination revealed additional abnormalities in the fetus, and all fetal tissues sampled demonstrated chromosomal mosaicism. It is interesting that the highest proportion of abnormal cells was found in fetal brain tissue and the lowest in skin fibroblasts. This case highlights the fact that a normal fetal blood karyotype does not always indicate fetal normality in the presence of AFC mosaicism, and demonstrates the value of high resolution ultrasonography in identifying associated structural fetal abnormalities that affect prognosis.

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