Interstitial Tandem Duplication of 6p: A Case WithPartial Trisomy (6)(p12p21.3)

Amelia Villa,1* Enrique Galán Gomez,2,3 Laura Rodríguez,1 Ramon Hernandez Rastrollo,2,3

M. Emilia Martínez Tallo,2,3 and María-Luisa Martínez-Frías1,4

1ECEMC, Facultad de Medicina, Universidad Complutense, Madrid, Spain2Departamento de Genetica, Hospital Materno Infantil de la Seguridad Social, Badajoz, Spain3Departamento de Pediatría, Hospital Materno Infantil de la Seguridad Social, Badajoz, Spain4Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain

A de novo interstitial tandem duplication of6p12p21.3 was observed in a 7-month-oldboy with growth retardation, psychomotordelay and craniofacial, brain, limb, andgenital anomalies. Fluorescent in situ hy-bridization using a chromosome 6 paintprobe demonstrated that the extra materialbelonged to chromosome 6. Although it hasbeen suggested that 6p25 is the critical bandinvolved in the expression of the phenotypeof 6p duplication, comparison of the clinicalfindings of this case with those from the lit-erature cases showed strong similarities.Am. J. Med. Genet. 90:369–375, 2000.© 2000 Wiley-Liss, Inc.

KEY WORDS: interstitial duplication; chro-mosome duplication; humanchromosome 6; tandem dupli-cation; chromosome anom-aly; choanal atresia

INTRODUCTION

In 1971, Therkelsen et al. reported on four membersof a family with partial trisomy 6p; since then about 37cases with partial duplications of 6p have been re-ported. All cases had terminal duplications, withbreakpoints ranging from 6p11 to 6p25. In these cases,partial trisomy of 6p generally is due to a reciprocaltranslocation, and these patients may also have partialmonosomy or trisomy of a portion of the other chromo-some involved in the translocation [Therkelsen et al.,1971; Chiyo et al., 1975; Breuning et al., 1977; Cote etal., 1978; McGillivray et al., 1978; Turleau et al., 1978;

Bernheim et al., 1979; Rosi et al., 1979; Dev et al.,1980; Morton et al., 1980; Pagano et al., 1980; Yuekselet al., 1980; Ferrando et al., 1981; Fryns et al., 1983,1986; Muneer et al., 1984; Eden et al., 1985; Smith andPettersen, 1985; Scarbrough et al., 1986; Burd et al.,1988; Chauveau et al., 1988; Lytle et al., 1989; Kata-fuchi et al., 1992; Schinzel et al., 1990; Song and Li,1996; Rudnik-Schoneborn et al., 1997]. Moreover threepatients were recombinants of a familial pericentric in-

Contract grant sponsor: Instituto de Salud Carlos III, Ministe-rio de Sanidad y Consumo of Spain.

*Correspondence to: Amelia Villa, ECEMC, Facultad de Me-dicina, Universidad Complutense, 28040 Madrid, Spain.

Received 4 May 1999; Accepted 22 October 1999 Fig. 1. Frontal view of the newborn patient.

American Journal of Medical Genetics 90:369–375 (2000)

© 2000 Wiley-Liss, Inc.

version of chromosome 6, and so partial 6p duplicationwas accompanied by partial 6q deletion [Pearson et al.,1979; Wauters et al., 1993].

The anomalies described in some of the patients withpartial 6p duplication associated with reciprocal trans-locations or pericentric inversions reflected concurrentaneuploidies, even though most of them showed a simi-lar clinical picture. Moreover, partial trisomy 6p wasconsidered by several authors [Breuning et al., 1977;Cote et al., 1978; Fryns et al., 1983] to be a recognizablesyndrome characterized by low birth weight, psycho-motor and growth retardation, craniofacial anomaliessuch as high prominent forehead, abnormal sutures,flat or prominent occiput, bulbous nose, microstomia,thin lips, low-set and/or malformed ears, ocular abnor-malities, congenital heart malformations, small kid-neys, and proteinuria. Furthermore, from the compari-son of reported cases it was concluded that 6p25 is thecritical band involved in the expression of manifesta-tions in patients with 6p partial duplications [Scar-brough et al., 1986].

On the other hand, tandem duplications of 6p arevery rare, and to our knowledge, only one case with apartial terminal tandem duplication has been previ-ously reported [Phelan et al., 1986]; but as far as weknow, no interstitial tandem duplication of 6p has beenreported to date.

Here we report on a patient with a tandem duplica-

tion 6p12p21.3, whose clinical findings are similar tothose described in individuals with partial duplicationsof the short arm of chromosome 6, even though distalband of 6p is not apparently involved in the duplicatedsegment.

CLINICAL REPORT

The propositus was identified through the SpanishCollaborative Study of Congenital Malformations(ECEMC) [Martínez-Frías et al., 1990]. The infant wasa male, the product of the third pregnancy of a 33-year-old mother and 32-year-old father, both healthy andnonconsanguineous. The two previous pregnancies ofthis couple ended in normal boys. Family history wasunremarkable, except for a paternal first cousin withDown syndrome, a paternal second cousin dead at age21 months because of a congenital heart defect, and amaternal first cousin dead soon after birth with an un-specified malformation. The pregnancy was compli-cated with vaginal bleeding during the third trimesterand ended at 36 weeks of gestation in a vaginal deliv-ery. Prenatal ultrasonography (US) showed enlargedbrain lateral ventricles and rhizomelic shortness oflimbs. Birth weight was 2,490 g (25th–50th centile),length 44 cm (10th–25th centile) and head circumfer-ence (OFC) 33.5 cm (75th centile). He showed general-ized edema and multiple craniofacial anomalies includ-

Fig. 2. Lateral view of the newborn patient.

Fig. 3. Frontal view of the patient at age 7 months.

370 Villa et al.

ing dolichocephalic skull, narrow forehead with hyper-trichosis, short downslanted palpebral fissures,blepharophimosis, bilateral epicanthus, corneal cloud-ing, wide nasal bridge, beaked left-deviated nose, mi-croretrognathia, and malformed and apparently low-set ears (Figs. 1 and 2). The child presented respiratorydistress secondary to choanal atresia, which was re-paired. He also had bilateral inguinal hernia, rightcryptorchidism, and limb abnormalities such as con-Fig. 4. Idiogram (850 band stage) and G-banded chromosomes 6 from

the patient.

Fig. 6. Whole chromosome paint with chromosome 6 specific library onmetaphase from the patient.

Fig. 5. G-banded karyotype of the patient.

Interstitial Tandem Duplication of 6p 371

tracted tapering fingers, with the fifth and second fin-gers overlapping the fourth and third fingers, left sim-ian crease, right metatarsus varus, and rockerbottomleft foot. Brain US showed slight enlargement of brainlateral ventricles and cerebellar hypoplasia. Cardiacand abdominal US findings were normal.

At age 2 months the patient was admitted because ofcardiorespiratory arrest. The child had an abnormalelectroencephalogram with hypertonia and seizures.From age 4 months frequent readmissions were neces-sary owing to recurrent lower respiratory tract infec-tions with bronchospasm and fever. The child also hadseveral episodes of gastroenteritis. At age 6 months aright hydrocele was noted. A CT-scan showed a relaps-ing choanal atresia. At 7 months weight was 4,500 gand OFC 39.1 cm (both four standard deviations belowthe mean). He had microcephaly, opisthotonus, psycho-motor retardation, closed anterior fontanelle, narrowforehead, prominent occipital bone, anteriorly placedhair line, synophrys, arched eyebrows, long eyelashes,short palpebral fissures, wide nasal bridge, antevertednares, smooth philtrum, thin upper lip, high archedpalate, gingival hypertrophy, micrognathia, and abnor-mally modeled and low-set ears (Fig. 3). The child diedat age 16 months. The parents did not give permissionfor an autopsy.

CYTOGENETIC STUDIES

Chromosome analyses of the propositus and his par-ents were performed on PHA-stimulated peripheralblood lymphocytes, using Trypsin G banding at the 550to 850 band level.

The cytogenetic study of the child showed an appar-ent interstitial tandem duplication of the short arm ofchromosome 6 in all 20 analyzed cells, with tentativebreakpoints in 6 p12 and p21.3 (Fig. 4). His karyotypewas designated as 46, XY, dup(6)(p12p21.3) (Fig. 5).Parental chromosomes were apparently normal. Fluo-rescent in situ hybridization (FISH) was done using awhole chromosome 6 paint probe (FPF610, Biovation,Ltd.), showing signal throughout the abnormal chro-mosome, confirming the extra genetic material to be ofchromosome 6 origin (Fig. 6).

DISCUSSION

Partial trisomy 6p is considered to be an establishedsyndrome comprising low birth weight, failure to thrivewith feeding problems and recurrent respiratory tractinfections, growth and psychomotor retardation, minorfacial anomalies consisting of abnormal sutures, highforehead, close-set eyes with long eyelashes, blepharo-phimosis and other ocular anomalies, high nasalbridge, small mouth with thin lips, and apparently low-set and/or malformed ears, congenital heart defects,and small kidneys. Brain anomalies such as hydro-cephaly have also been described in several cases.

About 37 cases have been reported, all of them withterminal duplications with breakpoints ranging from6p11 to 6p25 (Fig. 7). One case had the breakpoint in6p11 [Lytle et al., 1989], two in 6p12 [McGillivray et

al., 1978], eighteen in 6p21 [Therkelsen et al., 1971;Chiyo et al., 1975; Breuning et al., 1977; Berheim et al.,1979; Pearson et al., 1979; Dev et al., 1980; Pagano etal., 1980; Muneer et al., 1984 (case 2); Eden et al., 1985;Smith and Pettersen, 1985; Phelan et al., 1986;Chaveau et al., 1988; Katafuchi et al., 1992; Rudnik-Schoneborn et al., 1997], eight in 6p22 [Cote et al.,1978; Rosi et al., 1979; Morton et al., 1980; Yueksel etal., 1980; Ferrando et al., 1981; Fryns et al., 1983,1986; Song and Li, 1996], seven in 6p23 [Turleau et al.,1978; Muneer et al., 1984 (case 1); Burd et al., 1988;Schinzel et al., 1990; Wauters et al., 1993], and one in6p25 [Scarbrough et al., 1986].

Table I summarizes the clinical data of patients withpartial trisomy 6p. In most cases, duplication of 6p isaccompanied by another aneuploidy due to reciprocaltranslocations or pericentric inversions, and thereforesome of these patients show several clinical featuresthat reflect double partial aneuploidies [Bernheim et al.,1979, Rosi et al., 1979; Eden et al., 1985; Scarbrough etal., 1986; Burd et al., 1988; Lytle et al., 1989], but most

Fig. 7. Duplicated regions in cases with partial trisomy of 6p. [Lytle etal., 1989; McGillivray et al., 1978; Therkelsen et al., 1971; Chiyo et al.,1975; Breuning et al., 1977; Bernheim et al., 1979; Pearson et al., 1979;Dev et al., 1980; Pagano et al., 1980; Muneer et al., 1984; Eden et al., 1985;Smith and Pettersen, 1985; Phelan et al., 1986; Chauveau et al., 1988;Katafuchi et al., 1992; Rudnik-Schoneborn et al., 1997; Cote et al., 1978;Rosi et al., 1979; Morton et al., 1980; Yueksel et al., 1980; Ferrando et al.,1981; Fryns et al., 1983, 1986; Song and Li, 1996; Turleau et al., 1978; Burdet al., 1988; Schinzel et al., 1990; Wauters et al., 1993; Scarbrough et al.,1986].

372 Villa et al.

of them share the striking clinical features of the dup(6p) syndrome.

“Pure” duplications of 6p are very rare; in addition tothe present report only three cases have been previ-ously reported. One case had a terminal tandem dupli-cation [Phelan et al., 1986], and two patients had aterminal duplication of 6p with deletion of short armmaterial of acrocentric chromosomes owing to a recip-rocal translocation [Chiyo et al., 1975; Morton et al.,1980]. As far as we know our patient is the firstreported case with an interstitial tandem duplicationof 6p.

Table II shows the clinical features of patients withpure 6p duplication, including ours. All patients had

many of the craniofacial features of the dup (6p) syn-drome, but our case had in addition brain, genital, andlimb anomalies. Limb malformations were also foundin the case reported by Phelan et al. Congenital heartdefects and renal anomalies are frequent findings inthis chromosomal syndrome (Table I), although theywere not described in cases with “pure” duplications(Table II). Therefore, these defects could be related tothe associated aneuploidy in patients with not “pure”6p duplication. Choanal atresia has been reported inseveral chromosome abnormalities involving chromo-somes 1, 3, 4, 7, 8, 9, 10, 12, 14, 18, 21, and 22 [Schinzel,1994]. Besides our case, five previously reported casesof partial 6p duplication had choanal atresia [Muneer

TABLE I. Clinical Findings in Patients With Partial Trisomy of 6p

Duplicated segment p11-pter p12-pter p21-pter p22-pter p23-pter p25-pter

Number of cases 1 2 18 8 7 1Low birth weight +a NR 10 5 5 −Mental retardation/psychomotor delay + 2 11 5 6 +Growth retardation + 2 11 6 5 +Craniofacial anomalies

Microcephaly (pre- and/or postnatal onset) + 2 4 3 5 +Large anterior fontanel NR NR 6 2 3 −Abnormal sutures NR NR 6 NR 1 +Flat/prominent occiput NR NR 5 2 1 NRHigh/prominent forehead + NR 10 6 5 +Close-set eyes NR NR 5 1 1 −Small/short palpebral fissures NR 2 7 1 1 NRLong eyelashes NR 2 NR 2 NR NRMicrophthalmia NR NR 5 1 3 +Epicanthus NR NR 2 1 2 NRBlepharophimosis/blepharoptosis NR 2 13 4 4 +Nystagmus/strabismus NR NR 7 2 1 +Cataract/corneal clouding NR NR 2 3 2 NRLow-set and/or abnormal ears + NR 16 8 6 +High/prominent nasal bridge NR NR 6 6 3 NRHooked/bulbous nose + NR 4 2 NR +Anterverted nares NR NR 2 1 NR NRChoanal atresia NR NR 4 NR 1 NRLong/smooth philtrum + NR 6 3 4 NRSmall mouth and/or thin lips + 2 12 7 5 +High arched palate/cleft palate + NR 4 2 3 NRMicrognathia/pointed chin + 2 7 3 2 −

Limbs and skeletal anomaliesShort limbs NR NR 1 NR NR NRTalipes + NR 4 NR 1 NRSyndactyly NR NR 1 1 NR +Clinodactyly NR NR 3 3 2 NROverlapping fingers and/or toes NR NR 1 NR NR NRScoliosis/kiphosis NR NR 4 1 NR NRSacral dimple NR NR 5 4 3 NR

Genital anomalies + NR 3 NR 3 +Brain anomalies NR NR 6 NR 1 NRCongenital heart defects + 1 11 3 3 +Abnormal lungs lobulation NR NR 2 1 NR NRRenal anomalies − NR 8 2 3 NRProteinuria NR NR 5 1 1 NRGastrointestinal abnormalities NR NR 2 2 1 NROther

Inguinal hernia + NR 1 NR NR NRRecurrent respiratory infections NR NR 4 NR 2 NRFeeding problems NR NR 3 4 2 NRSeizures NR 1 3 1 1 NRHypertonia NR NR 2 NR 1 NRHypotonia NR NR 2 1 1 NRCapillary angiomata NR NR 2 2 1 NR

a+, present; −, absent; NR, not reported.

Interstitial Tandem Duplication of 6p 373

et al., 1984; Smith and Pettersen, 1985; Katafuchi etal., 1992] (Table I). Thus, this anomaly together withlimb and genital anomalies may be components of the6p duplication syndrome. However, in an attempt toobtain a more accurate definition of the clinical mani-festations of the syndrome, more reports of cases with“pure” 6p duplication are needed.

A comparison of the cases with partial trisomy of 6pindicates that the size of the duplication does not ap-pear to modify the phenotype (Table I). Furthermore, ithas been suggested that most of the cardinal findingsof the syndrome reflect the duplication of merely the6p25 band [Scarbrough et al., 1986]. Nevertheless, inour case the duplicated region is 6p12-6p21.3, butshows many of the clinical signs of the syndrome, al-though the terminal band of 6p is apparently not in-volved in the duplication. Consequently, this chromo-somal syndrome might not be causally related to thetrisomic state of a defined region of 6p, but may be

related to a less-specific type of genetic mechanism,suggesting that the duplication of different regions of6p may modulate the expression of some genes, result-ing in similar phenotypes [Wilson, 1990]. On the otherhand, we can not rule out that a more distal duplica-tion, or a more complex chromosome rearrangementinvolving 6p25 band, undetectable with a standard cy-togenetic analysis, could have occurred in our patient.Further molecular studies with locus-specific DNAprobes for the duplicated regions, in patients with 6ptrisomy, may allow the identification of importantgenes for the expression of this chromosomal syn-drome.

ACKNOWLEDGMENTSWe appreciate the technical assistance of Teresa

Lopez Jimenez. This work was supported by a grantfrom the Instituto de Salud Carlos III, Ministerio deSanidad y Consumo of Spain.

TABLE II. Clinical Findings in Patients With “Pure” Duplications of 6p

Duplicated segmentChiyo et al. [1975]

p21-pterPhelan et al. [1986]

p21-pterMorton et al. [1980]

p22-pterPresent case

p12-p21.3

Sex Female Female Female MaleGestational age (weeks) Term Term 25 36Birthweight (g) 2630 1814 525 2490Age at exam 18 months 13 years 7 monthsDeath age ? ? 16 monthsMental retardation/psychomotor delay +a + +Pre- and/or postnatal growth retardation NR + + +Microcephaly (pre- and/or postnatal onset) NR + NR +Abnormal sutures NR + NR +Prominent occiput NR NR NR +High/prominent forehead + + + −Small/short palpebral fissures NR + NR +Long eyelashes NR NR NR +Epicanthus + NR NR +Blepharophimosis/blepharoptosis + + NR +Strabismus + NR NR −Cataract/corneal clouding NR NR NR +Low-set and/or abnormal ears + + + +Broad/high nasal bridge NR + + +Hooked/bulbous nose + NR NR +Anteverted nares NR NR NR +Choanal atresia NR NR NR +Long/smooth philtrum NR NR NR +Small mouth and/or thin lips NR + + +High arched palate NR NR NR +Micrognathia NR + NR +Short limbs NR NR NR +Upper and lower limbs deformities NR + NR −Talipes NR − NR +Syndactyly of fingers and/or toes NR + NR −Overlapping fingers and/or toes NR NR NR +Scoliosis NR + NR −Sacral dimple + NR + −Genital anomalies NR NR NR +Congenital heart defects NR − NR −Brain anomalies NR NR NR +Renal anomalies NR NR NR −Gastrointestinal anomalies NR + NR −Inguinal hernia NR NR NR +Recurrent respiratory infections NR NR NR +Hypertonia NR NR NR +Seizures NR + +

a+, present; −, absent; NR, not reported.

374 Villa et al.

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