Prenat. Diagn. 19: 49–53 (1999)

SHORT COMMUNICATION

Prenatal Detection of a 1p36 Deletion in a Fetus with MultipleMalformations and a Review of the Literature

L. Faivre1*, N. Morichon-Delvallez1, G. Viot1, J. Martinovic2, M. P. Pinson1, J. P. Aubry3,V. Raclin1, P. Edery1, Y. Dumez3, A. Munnich1 and M. Vekemans1

1Departement de Genetique, Hopital Necker Enfants Malades, Paris, France2Unite de Foetopathologie, Hopital Saint-Antoine, Paris, France3Department de Medecine Foetale, Hopital Necker Enfants Malades, Paris, France

The prenatal diagnosis of a 1p36 deletion is reported. The pregnancy was ascertained at 24 weeks of gestationbecause of the discovery of multiple malformations at ultrasound including hypotelorism, moderate cerebralventricular dilatation and Ebstein anomaly with secondary cardiac failure. Following cytogenetic studies andcounselling, the pregnancy was terminated and a fetal autopsy performed. The phenotype of this antenatally-diagnosed case is compared with the clinical features of 44 previously reported cases with an identicaldeletion of the short arm of chromosome 1p36. Copyright ? 1999 John Wiley & Sons, Ltd.

: deletion of the short arm of chromosome 1; Ebstein anomaly; cerebral ventricular dilatation;prenatal diagnosis

INTRODUCTION

With the advent of high-resolution chromosomeanalysis and molecular cytogenetic techniques, somesmall deletions such as deletions of the short arm ofchromosome 1 are now being diagnosed more fre-quently. Since the initial observation (Hain et al.,1980), 42 additional cases with del (1)(p36) have beenreported (Yunis et al., 1981; Deslanges et al., 1983;Steele et al., 1984; Magenis et al., 1987; Abbas et al.,1990; Wexler et al., 1991; Wargowski et al., 1991; Barbiet al., 1992; Biegel et al., 1993; Howard-Peebles andBlack, 1994; Keppler-Noreuil et al., 1995; Sandlinet al., 1995; Reish et al., 1995; Blennow et al., 1996; Boset al., 1996; Giraudeau et al., 1997; Eugster et al., 1997;Shapira et al., 1997; Robbins-Furman et al., 1997).The phenotype of this deletion is now well delineated(Shapira et al., 1997). The clinical features include mod-erate to severe mental retardation, hypotony, growthdelay, eye/vision problems, hearing deficit, seizures,cardiac malformations and dysmorphic facies (pointedchin, flat nasal bridge, low-set ears, ear asymmetry,thickened ear helices, deep-set eyes, large anteriorfontanel, clinodactyly and/or short fifth finger). Here,we report the first case of a 1p36 deletion ascertainedprenatally because of abnormal ultrasound findings.

CASE REPORT

A 34-year-old Polish mother was referred to our centreat 24 weeks of gestation for her first pregnancy. Her

CCC 0197–3851/99/010049–05$17.50Copyright ? 1999 John Wiley & Sons, Ltd.

past medical history was unremarkable. She had threebrothers. Her 38-year-old husband is also Polish andthe couple are not consanguineous. A second-trimesterultrasound examination showed a moderate cerebralventricular dilatation, a hypotelorism and Ebsteinanomaly. All parameters of fetal biometry werebetween the 50th and 97th percentile. A cytogeneticstudy performed on amniotic fluid cells showed aterminal deletion of the short arm of chromosome 1(del(1)(p36)). Parental chromosomes were normal.After genetic counselling and because of the discoveryof an important hydrops fetalis due to cardiac failure,the pregnancy was terminated at 28 weeks.

External examination revealed a male fetus with ageneralized hydrops and facial dysmorphism, includingbrachycephaly, a flat profile, low-set ears and a deeppalate (Fig. 1). Unique transverse palmar creases areseen on both hands. Measurements (weight 1900 g;vertex–talus length 41·5 cm; vertex–coccyx length26 cm; OFC 29·5 cm; foot 5·5 cm) were compatiblewith term. X-ray studies of the fetus showed 11 pairs ofribs with normal ossification. At necropsy, thymichypoplasia, pleural effusion, abnormal pulmonarylobulation and Ebstein anomaly were found. Neuro-pathological examination revealed a moderate ven-tricular dilatation of the left ventricle and possiblepolymicrogyria of the left lobe. Histological examinationshowed pancreatic necrosis and an endomyocardicfibrosis.

*Correspondence to: L. Faivre, Service de Genetique Medicale,Hopital Necker Enfants Malades, 149 rue de Sevres, 75015 Paris,France.

CYTOGENETIC AND MOLECULAR ANALYSIS

Chromosome analysis of the fetus was performed onamniotic fluid cells using solid Giemsa, R and

Received 9 February 1998Revised 26 May 1998

Accepted 19 June 1998

50 . .

Fig. 1(a, b)—Pictures of the fetus after termination at 24 weeks of gestation. Note hydrops fetalis and facialdysmorphism including brachycephaly, flat profile and low-set ears

Fig. 2—Partial karyotype of the propositus showing the GTG- (left) and RHG-banded (right) chromosomes 1. The normal chromosome 1 is on the left and thedeleted chromosome 1 on the right. Note that the deletion is clearly visible with GTGbanding

G-banding techniques (Fig. 2). A distal deletion of theshort arm of one chromosome 1 (del(1)(p36)) was seenin all cells examined. Chromosome analysis of theparents performed on blood samples was normal.

Fluorescence in situ hybridization (FISH) analysiswith a chromosome 1-specific subtelomeric probe(YAC 273D11, locus HKR3, 17 cM from the telomere)was performed on the fetus (Fig. 3) and his parents.

Copyright ? 1999 John Wiley & Sons, Ltd.

These studies confirmed the presence of a deletion ofthe short arm of chromosome 1 on the fetus.

A molecular polymorphism analysis was done in thisfamily to determine the parental origin of the deletion.Total cellular DNA was prepared from amniotic fluidcell culture and from peripheral blood lymphocytes ofthe parents. Polymorphic markers D1S243 (6 cM fromthe telomere) and D1S468 (11 cM from the telomere)

Prenat. Diagn. 19: 49–53 (1999)

51 1p36

located between band 1p36.3 and the telomere wereused to establish which polymorphic loci were deletedin the fetus. The results showed that the deletion was ofpaternal origin (Fig. 4) and that the deletion was atleast 17 cM in size.

Fig. 3—Fluorescence in situ hybridization of the propositus with aspecific subtelomeric probe demonstrating the absence of signal onone chromosome 1

Fig. 4—Polymorphic marker analysis of the 1p36 deletion. Resultsfrom a fully informative 1p36 marker D1S243 are shown for thefetus and his parents. The fetus demonstrates inheritance of thematernal allele only

DISCUSSION

Here, we describe the prenatal diagnosis of a fetus withdeletion of the short arm of chromosome 1p36.Molecular cytogenetic analysis of the fetus confirmedthe terminal deletion and molecular studies showedthat the deletion was paternal in origin. To our knowl-edge, a total of 44 chromosome 1p36 deletions havebeen reported, representing today a newly delineateddeletion syndrome (Shapira et al., 1997) (Table 1). Thedetection of this deletion is difficult, however. For

Copyright ? 1999 John Wiley & Sons, Ltd.

example, in 12 out of 41 informative observations, thedeletion was not detected at the first cytogenetic analy-sis (Abbas et al., 1990; Wexler et al., 1991; Biegel et al.,1993; Howard-Peebles and Black, 1994; Giraudeau etal., 1997; Shapira et al., 1997). In addition, in one case(Giraudeau et al., 1997), the deletion was identified byscreening a sample of children with idiopathic mentalretardation to determine the frequency of subtelomericrearrangements using hypervariable polymorphicprobes. Commonly, diagnosis is made during earlychildhood in a five-year-old child with moderate tosevere mental retardation, hypotony, growth delay,eye/vision problems, hearing deficit, seizures, cardiacmalformation and a dysmorphic facies. In two cases,the diagnosis was made before birth. The first case wasdetected because of the presence of a maternal bal-anced translocation between the short arms of chromo-some 1 and 20, ascertained when the first child ofthe couple had inherited an unbalanced product ofthe translocation (Howard-Peebles et al., 1994). Thesecond case was ascertained because of the presence ofelevated maternal serum alpha-fetoprotein (Robbins-Furman et al., 1997). In both cases however, noabnormal sign was noted on ultrasound. Frequently,the deletion occurs de novo (31/39) although the segre-gation of a parental rearrangement is also observed(Hain et al., 1980; Deslanges et al., 1983; Barbi et al.,1992; Howard-Peebles and Black, 1994; Reish et al.,1995; Blennow et al., 1996). In 4/40 informative cases,the deletion resulted from a de novo unbalanced re-arrangement involving another chromosome. Studiesof the parental origin of the deletion have beenperformed in 15 de novo cases (Biegel et al., 1993;Giraudeau et al., 1997; Shapira et al., 1997). The originof the deletion was maternal in 12 cases and paternal in3 cases. Interestingly, in the present observation, thedeletion is paternal in origin.

Congenital heart malformation is a classical findingin 1p36 deletion. It is found in 20/33 cases (Table I),but no malformation is pathognomonic of the deletion.For example, cardiomyopathy is reported in fivecases (Reish et al., 1995; Keppler-Noreuil et al., 1995;Shapira et al., 1997), ductus arteriosus in four cases(Howard-Peebles and Black, 1994; Reish et al., 1995;Keppler-Noreuil et al., 1995; Shapira et al., 1997),tetralogy of Fallot in two cases (Howard-Peebles andBlack, 1994; Magenis et al., 1987), ventricular septaldefect in two cases (Biegel et al., 1993; Howard-Peeblesand Black, 1994), and left pulmonary artery branchstenosis in one case (Shapira et al., 1997). In thepresent case, Ebstein anomaly, leading to hydropsfetalis, was detected in utero. To our knowledge, nodeletion 1p36 has been associated with this malfor-mation. Ebstein anomaly is a rare defect, however,and the number of 1p36 deletions is still too small todecide whether this anomaly belongs to the phenotypicspectrum of the 1p36 deletion.

In conclusion, here we describe the first case of adeletion of the short arm of chromosome 1 ascertainedprenatally through the discovery of abnormal findingson ultrasound. A review of 44 previously reportedcases shows that the 1p36 deletion is well delineated

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lion Seizures Cardiopathy Hydrocephalus Other signs

1/2 Cardiomegaly 1/2 —" Murmur " Hydramnios, cleft lip,

finger hypoplasia? Cardiomegaly " Cleft lip+ " " Hallux valgus? + " Imperforate anus,

rectovaginal fistula+ ? Ventricular

dilatationScoliosis

+ ? ? Obesity+ ? ? Sturge–Weber, cleft of

the soft palate,nystagmus

" ? + Cleft palate, retinaldysfunction, deafness

" + " Neuroblastoma? + + ACC, eye abnormalities

1/1 2/3 " Hexadactyly, hearingloss, optic atrophy,cerebral atrophy,craniostenosis

2/2 2/3 Coloboma,polydactyly

? 2/3 2/2 Cleft palate, cleftalveolar ridge, hearingloss

e + ? " Scoliosis, deafness? + ? Alagille syndrome,

hearing losse + " " Deafness, scoliosis

+ ? " Obesity8/12 2/12 CHD

2/12 CM2/10 Cleft lip/palate 2/12,

hearing loss 6/8, eyeabnormalities 6/8,obesity 1/8

+ ? ? Abnormal serummaternal áFP

? + + Thymic hypoplasia18/26 20/33 12/35 Cleft lip/palate 8/41,

hearing loss 11/33, eyeabnormalities 11/33

52.

.

Cop

Table 1—Features of patients with del(1)(p36)

Reference(number of cases) Karyotype Inheritance

Prenataldiagnosis

Growthretardation Dysmorphy Hypotony

Mentaretardat

Hain et al. (1980) (2) der(1)t(1;5)(p36;q11) Parental " " + " ?Yunis et al. (1981) 45,XX,t(1.21)(p36;q11) De novo " + + + +

Deslanges et al. (1983) der(1)t(1;9)(p36;p12) Paternal " + + ? ?Steele et al. (1984) t(1;13)(p36.2;p11) De novo " " + + +Magenis et al. (1987) del(1)(p36) De novo " + + " ?

Abbas et al. (1990) 45,X,t(1;Y)(p36;p13) De novo " + + + +

Wargowski et al. (1991) (4) del(1)(p36) ? " + + + +Wexler et al. (1991) (2) del(1)(p36.3) De novo " ? 1/2 1/1 +

Barbi et al. (1992) der(1)t(1;15)(p36;p11.2) Maternal " + + + +

Biegel et al. (1993) del(1)(p36.1]p36.2) De novo " + + + +Howard-Peebles andBlack (1994)

der(1)t(1;20)(p36;pter) Maternal 1/2 ? + ? ?

Reish et al. (1995) (5) Translocation (4)Deletion (1)

Paternal (2)De novo (2)Unknown (1)

" 1/3 + 1/1 +

Keppler-Noreuilet al. (1995) (3)

del(1)(p36.22) De novo 2/3 + 2/2 + 1/1

Sandlin et al. (1995) (3) del(1)(p36) De novo " 2/3 + + +

Blennow et al. (1996) der(1)t(1;15)(p36;p11) Paternal " + + + SeverBos et al. (1996) del(1)(p36.31) ? " + + + +

Giraudeau et al. (1997) del(1)(p36.3) De novo " + + + SeverEugster et al. (1997) mos46,XX,del(1)(p36.33) De novo " + + + severeShapira et al. (1997) (12) del(1)(p36) De novo ? 8/8 12/12 8/8 7/8

Robbins-Furmanet al. (1997)

del(1)(p36.3) De novo + ? + ? ?

Present case 46,XY,del(1)(p36.3) De novo + ? + ? ?Total Deletion 28/45

Translocation 12/45Unknown 5/45

31/39 de novo 3/24 27/34 44/45 26/30 23/34

ACC: agenesis of corpus callosum; CHD: congenital heart disease; CM: cardiomyopathy.

yright?

1999John

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&Sons,

Ltd.

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53 1p36

postnatally but that its prenatal detection relies on thequality of cytogenetic techniques including FISH.

We would like to thank Dr T. Haaf for providing uswith the YAC 273D11 probe (http:/www.mpimg-berlin-dahlem-mpg.dc/).

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