Prenat. Diagn. 19: 986–989 (1999)

SHORT COMMUNICATION

Prenatal Diagnosis of Partial Trisomy 3p(3p23]pter) andMonosomy 7q(7q36]qter) in a Fetus with MicrocephalyAlobar Holoprosencephaly and Cyclopia

Chih-Ping Chen1,3*, Koenraad Devriendt2, Chen-Chi Lee1, Wen-Lin Chen1, Wayseen Wang3 andTao-Yeuan Wang4

1Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan, ROC2Centre of Human Genetics, University Hospital Leuven, Leuven, Belgium3Department of Medical Research, Mackay Memorial Hospital, and National Yang-Ming University, Taipei, Taiwan, ROC4Department of Pathology, Mackay Memorial Hospital, Taipei, Taiwan, ROC

We report the prenatal diagnosis of partial trisomy 3p(3p23]pter) and monosomy 7q(7q36]qter) in a fetuswith microcephaly, alobar holoprosencephaly and cyclopia. A 26-year-old primigravida woman was referredfor genetic counselling at 23 gestational weeks due to sonographic findings of intra-uterine growthretardation and cranio-facial abnormalities. Level II ultrasonograms further demonstrated alobar holopros-encephaly, a proboscis above the eye and a single median orbit consistent with cyclopia. Genetic analysis andfluorescence in situ hybridization on cells obtained from amniocentesis showed distal 3p trisomy(3p23]pter) and 7q36 deletion, 46,XX,der(7)t(3;7)(p23;q36), resulting from a paternal t(3;7) reciprocaltranslocation. The pregnancy was terminated. Autopsy further confirmed the presence of arrhinencephaly,agenesis of the corpus callosum and a single ventricle of the brain. The phenotype of this antenatallydiagnosed case is compared with those observed in 10 previously reported cases with simultaneousoccurrence of partial trisomy 3p and terminal deletion 7q. All cases are associated with severe forms ofholoprosencephaly and facial dysmorphism. This delineates an autosomal imbalance syndrome or a dosageeffect involving duplication of distal 3p/deficiency of terminal 7q and dysmorphogenesis of the forebrain andmid-face. Copyright ? 1999 John Wiley & Sons, Ltd.

: holoprosencephaly; chromosome 3p; chromosome 7q; prenatal diagnosis; cyclopia

INTRODUCTION

Holoprosencephaly (HPE) is a developmental abnor-mality characterized by congenital malformations ofthe forebrain and the mid-face. There are variabletypes of HPE, ranging from severe alobar HPE withcyclopia, ethmocephaly, cebocephaly or premaxillaryagenesis, to microforms with microcephaly, corpuscallosum agenesis/dysgenesis, mental retardation, ocu-lar hypotelorism only or a single maxillary centralincisor (Muenke, 1989, 1994). Chromosomal aberra-tions, mendelian mutations and teratogens are well-known causes of HPE. Cytogenetic abnormalities havebeen reported in half of infants born with HPE (Minget al., 1976; Muenke, 1994), trisomy 13 being the mostcommon. Other chromosomal abnormalities includetrisomy 18, triploidy, del(2p), dup(3p), del(7q),del(13q), del(18p) and del(21q) (Muenke, 1994;Peebles, 1998). We present an unusual case of HPEwith concomitant partial trisomy 3p(p23]pter) and

CCC 0197–3851/99/100986–04$17.50Copyright ? 1999 John Wiley & Sons, Ltd.

7q36 deletion ascertained by fluorescence in situhybridization.

*Correspondence to: C.-P. Chen, Department of Obstetrics andGynecology, and Department of Medical Research, MackayMemorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei,Taiwan, ROC.

Contract/grant sponsor: National Science Council, Taiwan, ROC;Contract/grant number: NSC-86-B-195-006.

CASE REPORT

A 26-year-old primigravida was referred for geneticcounselling at 23 gestational weeks due to sonographicfindings of intra-uterine growth retardation andcranio-facial abnormalities. She and her husband wereChinese, non-consanguineous and healthy. There wasno family history of diabetes mellitus or congenitalmalformations. The mother denied any exposure toalcohol, teratogenic agents, irradiation or infectiousdiseases during this pregnancy. Maternal urinethroughout the pregnancy contained no glucose. LevelII ultrasonograms at our hospital demonstrated micro-cephaly, alobar HPE with centrally fused thalamisurrounded by a monoventricle, a proboscis above theeye and a single median orbit consistent with cyclopia(Fig. 1), a femur length equal to 20 gestational weeks,and an abdominal circumference equal to 21 gesta-tional weeks. Genetic analysis and fluorescence in situhybridization (FISH) on amniotic fluid cells obtainedfrom amniocentesis showed 7q36 deletion and distal 3ptrisomy (3p23]pter), 46,XX,der(7)t(3;7)(p23;q36)

Received 20 January 1999Revised 10 May 1999Accepted 3 June 1999

987PRENATAL DIAGNOSIS OF PARTIAL TRISOMY AND MONOSOMY

Fig. 1—Prenatal ultrasonograms at 23 gestational weeks reveal (a)alobar holoprosencephaly with the presence of a single ventricle (v)and fused thalami (t), and (b) a median orbit (o) with a proboscis (p)above the eye

Copyright ? 1999 John Wiley & Sons, Ltd.

Fig. 2—(a) Chromosome preparation shows (lower) the balancedreciprocal translocation identified in the father, and (upper) chromo-somes 3, 7 and der(7) in the proband. Arrowheads indicate thebreakpoints. (b) FISH metaphase from proband’s cells hybridizedwith the Williams critical region probe (7q11.23) (Oncor,Gaithersburg) and a 7q36 probe (Oncor, Gaithersburg). The arrow-head indicates the der(7) chromosome without a signal for probe7q36. The normal chromosome 7 contains signals for both theWilliams and 7q36 probes. (c) FISH metaphase from father’s cellshybridized with the Williams critical region probe (7q11.23) and a7q36 probe. The arrowheads indicate absence of a signal for the 7q36probe on chromosome der(7) and its presence on chromosome der(3)

(Fig. 2). Analysis of the father’s blood showed abalanced reciprocal translocation between the shortarm of chromosome 3 and the long arm of chromo-some 7, 46,XY,t(3;7)(p23;q36) (Fig. 2). The mother’skaryotype was normal. Owing to an unbalanced segre-gation of paternal t(3;7), the proband had two normalchromosomes 3, one normal chromosome 7 and onederivative chromosome 7 resulting in duplication ofchromosome 3p23]pter, and a deficiency of chromo-some 7q36]qter. The parents opted to terminate thepregnancy. At 24 gestational weeks, a female newbornmeasuring 21 cm in length and weighing 324 g wasdelivered. The placenta was normal. The umbilicalcord had three vessels. Examination of the probandshowed cyclopia with a single median orbit and a singleocular structure, a proboscis above the eye, malformedlow-set ears, and micrognathia (Fig. 3). Autopsyrevealed microcephaly, alobar holoprosencephaly,arrhinencephaly, agenesis of the corpus callosum and asingle ventricle of the brain. There were no abnormali-ties of other organs.

DISCUSSION

HPE occurs in about 10 per cent of cases with dupli-cation 3p syndrome and in about 20 per cent of cases

Prenat. Diagn. 19: 986–989 (1999)

988 C.-P. CHEN ET AL.

Fig. 3—Anterior view of the proband

Table 1—Reported cases with dup(3p)/del(7q) and holoprosencephaly

Cases Karyotype Phenotype

Pfitzer et al. (1982) der(7)t(3;7)(p23;q36)mat CyclopiaKurtzman et al. (1987) der(7)t(3;7)(p21;q36)de novo CyclopiaBurrig et al. (1989) der(7)t(3;7)(p23;q36)pat CyclopiaKent et al. (1990) der(7)t(3;7)(p25;q34)mat Cyclopiaa

Gurrieri et al. (1992) der(7)t(3;7)(p23;q36)? CyclopiaKuller et al. (1992) der(7)t(3;7)(p25.3;q36)pat HPE-PMAVan Zalen-Sprock et al. (1995) der(7)t(3;7)(p21;q32)mat CyclopiaChen et al. (1996) der(7)t(3;7)(p23;q36)de novo HPE-PMAVance et al. (1998) der(7)t(3;7)(p21.3;q36)? CyclopiaVance et al. (1998) der(7)t(3;7)(p22;q35)? CebocephalyPresent case der(7)t(3;7)(p23;q36)pat Cyclopia

HPE: holoprosencephaly; PMA: premaxillary agenesis.aAccording to Lurie (1993).

with deletion 7q syndrome (Siebert et al., 1990). Table1 summarizes the karyotype and phenotype of thepresent case and 10 previously reported cases withsimultaneous occurrence of dup(3p) and del(7q)(Pfitzer et al., 1982; Kurtzman et al., 1987; Burriget al., 1989; Kent et al., 1990; Gurrieri et al., 1992;Kuller et al., 1992; Van Zalen-Sprock et al., 1995;Chen et al., 1996; Vance et al., 1998). Eight cases wereassociated with cyclopia, two with HPE-premaxillaryagenesis (PMA) and one with cebocephaly. All casesare associated with severe forms of HPE and facialdysmorphism.

The association between duplication of distal 3p andHPE is well documented. In addition to cases withdup(3p)/del(7q), simultaneous occurrence of dup(3p)and deletion of other chromosomal segmentsassociated with HPE have been reported. Buchingeret al. (1981) first reported a case of der(18)t(3;18)(p21;p11)mat with microcephaly, bilateral cleft lip andpalate, and a flat and retracted nose which looked verymuch like HPE-PMA. Martin and Steinberg (1983)described a case of cebocephaly with der(4)t(3;4)(p25;q35)mat. Van Regemorter et al. (1983) presented

Copyright ? 1999 John Wiley & Sons, Ltd.

a case of HPE-PMA with der(10)t(3;10)(p21;q26)mat.Gimelli et al. (1985) reported a case of cyclopiawith der(2)t(2;3)(p25;p23)mat. Gillerot et al. (1987)reported a case of cyclopia with der(10)t(3;10)(p12;q26)pat. Chen et al. (1996) additionally reportedtwo sib cases of der(2)t(2;3)(q37;p21)pat, one withcyclopia and the other with HPE-PMA. The presenceof HPE as well as other mid-line developmentaldefects, such as cardiac anomalies, cleft lip and palate,meningocoele and hypospadias in patients with dupli-cation 3p syndrome suggests that dup(3p) may result indysmorphogenesis of the mid-line development field(Kurtzman et al., 1987; Lurie, 1993).

At least four putative loci for HPE have beenidentified through the analysis of chromosomal re-arrangements in HPE patients: HPE 1 on chromosome21q22.3; HPE 2 on 2p21; HPE 3 on 7q36-qter; andHPE 4 on 18pter-q11 (Frezal and Schinzel, 1991). HPE3 mapped on 7q36 is characterized as the locus con-taining the human sonic hedgehog gene (Roessler et al.,1996, 1997). Lurie (1993) suggested a specific gene on3p antagonistic to the gene on 7q36, nevertheless noholoprosencephalic locus has been found on 3p. Othergenes at distal 7q that are important for brain devel-opment include En2 on 7q36 (Joyner, 1996), HTR5Aon 7q36.1 (Schanen et al., 1996) and PAX4 on 7q32(Tamura et al., 1994). Either loss-of-function muta-tions or cytogenetic rearrangements involving deletionor disruption of one of the sonic hedgehog alleles at7q36 has been shown to cause HPE (Roessler et al.,1996, 1997). However, a broad spectrum of HPE existsin patients with de novo 7q terminal deletions, withfamilial chromosomal rearrangements involving distal7q, or with autosomal dominant HPE having a linkageon 7q36 (Frints et al., 1998). Furthermore, somepatients with 7q deletion syndrome do not have typicalHPE (Lurie, 1993; Frints et al., 1998). Comparativemolecular studies are needed to investigate the preci-sion of the breakpoints involved and the disruption ofthe human sonic hedgehog gene in the previous reports.Roessler et al. (1997) reported cytogenetic rearrange-ments involving 3p;7q translocations in five families ofwhich the balanced parents had normal phenotype and

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989PRENATAL DIAGNOSIS OF PARTIAL TRISOMY AND MONOSOMY

This work was supported by a research grant (NSC-86-B-195-006) to Chih-Ping Chen for fetal cerebralmalformations from the National Science Council,Taiwan, ROC.

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all of the unbalanced offspring were associated withholoprosencephaly and complete deletion of one of thehuman sonic hedgehog alleles. Our case further adds tothe evidence that the interaction of partial trisomy of3p and partial monosomy of 7q is invariably associatedwith severe forms of HPE and facial dysmorphism.This delineates an autosomal imbalance syndromeor a dosage effect involving duplication of distal3p/deficiency of terminal 7q and dysmorphogenesis ofthe forebrain and mid-face.

Prenat. Diagn. 19: 986–989 (1999)