Brief Clinical Report

Duplication 6q21q23 in Two Unrelated Patients

V.M. Pratt,* J.R. Roberson, L. Weiss, and D.L. Van DykeMedical Genetics and Birth Defects Center, Henry Ford Hospital, Detroit, Michigan

We report on two patients with rare 6q du-plications. The karyotype of patient 1 is46,XY,dup(6)(q21q23.3). The karyotype ofpatient 2 is 46,XX,dup(6)(q21.15q23.3). Thesetwo patients have some nonspecific physicalfindings in common including a depressednasal bridge, epicanthal folds, mild heartdefects, and developmental delay, but eachhad other congenital anomalies. Am. J. Med.Genet. 80:112–114, 1998. © 1998 Wiley-Liss, Inc.

KEY WORDS: chromosome 6q duplication;mild mental retardation; con-genital heart defect

INTRODUCTIONPatients with distal duplication of the long arm of

chromosome 6 (bands q26-qter) have a distinct clinicalphenotype. The 6q26-qter phenotype includes micro-cephaly, acrocephaly, down-slanting palpebral fis-sures, telecanthus, micrognathia, ‘‘carp-shaped’’mouth, short anterior webbed neck, club foot, joint con-tractures, and profound psychomotor retardation[Chen et al., 1976; Tipton et al., 1979; Pivnick et al.,1990; Uhrich et al., 1991]. Henegariu et al. [1997] re-cently reported a child with duplication 6q23.3q25.3.This patient had dolichocephaly with prominent occi-put, prominent forehead, horizontal almond-shapedpalpebral fissures, infraorbital crease, blue-tintedsclerae, hypertelorism, broad, depressed nasal bridge,short philtrum, midface hypoplasia, ‘‘carp’’ mouth,short neck, congenital heart defects (patent ductus ar-teriosus and atrial septal defect), flexion contracturesat the wrists, dorsiflexion of first toes, umbilical her-nia, and mild hypotonia. Here, we report two de novoduplications of 6q21q23.

CLINICAL REPORTSPatient 1

Patient 1 was born at 41 weeks of gestation to aG2P1 29-year-old woman. The prenatal course was re-

markable for gestational diabetes. Patient 1 had de-creased fetal heart tones and multiple variable decel-erations during labor. His birth weight was 2.1 kg (<3rd centile), length 44 cm (< 3rd centile), and headcircumference (OFC) 35.5 cm (75th centile). Apgarscores were 8 and 9 at 1 and 5 min, respectively. Stud-ies of the placenta showed two cord sections with fivevessels, suggesting a section taken through a falseknot. He had a ‘‘hazy’’ left lung suggestive of pneumo-thorax that resolved spontaneously. He also had bilat-eral clubfoot, ulnar deviation of hands, prominent skullsutures, no cry, decreased muscle tone, and decreasedsubcutaneous fat. No metaphyseal or diaphyseal dys-plasias were present on radiographs. Head ultrasoundfindings were interpreted as a slight bleed or calcifica-tion near the basal ganglia. The corpus callosum wasnot visualized in the ultrasound films. The frontal hornof the left ventricle was greater than the right. Theorbital rim was steep. He was placed in an incubatorwith 30% oxygen for a few hours and released from thehospital with his mother after 3 days.

At 2 to 3 weeks, he was evaluated for tachypnea. Aheart murmur was noted. An echocardiogram showedright ventricular hypertrophy and a thickened tricus-pid valve with no significant obstruction or regurgita-tion.

At 6 weeks, he stopped breathing and became cya-notic while riding in his infant seat in the car. Hisparents reported noisy breathing and some nasal con-gestion prior to this episode. He was hospitalized andwas placed on a ventilator for 1 week for severe pneu-monia. A left pneumothorax was treated with a chesttube, and a possible right pneumothorax resolved spon-taneously.

At age 4 months, he could roll side-to-side, laugh, fixand follow, and reach for objects, but he did not havegood head control. A developmental evaluation per-formed at 8 months indicated a 6 to 8 month develop-mental level, although his gross motor skills were atthe 3 to 5 month level. On physical examination, hislength was 59.5 cm (5th centile), weight 6.6 kg (50thcentile), and OFC 43.5 cm (80th centile). He had frontalbossing with the right side more prominent than theleft, epicanthal folds, up-turned nose with depressednasal bridge, a capillary hemangioma at the nape ofthe neck, a fine papular rash on the trunk, a shawl

*Correspondence to: V.M. Pratt, Laboratory Corporation ofAmerica, 1912 Alexander Drive, Research Triangle Park, NC 27709.

Received 24 November 1997; Accepted 9 June 1998

American Journal of Medical Genetics 80:112–114 (1998)

© 1998 Wiley-Liss, Inc.

scrotum, bilateral transverse palmar creases, ulnar de-viation of the hands, club feet, and small hands andfeet (hand length was 6 cm (< 3rd centile), palm length3.75 cm (< 3rd centile), and foot length 8.5 cm (< 3rdcentile)). The inner canthal distance was 3 cm (97thcentile). The outer canthal distance was 6.5 cm (25thcentile) (Fig. 1).

Patient 2

Patient 2 was born at term by spontaneous vaginaldelivery to a G2P1 woman. Prenatal course was unre-markable except that the mother smoked approxi-mately 1 pack of cigarettes per day. Apgar scores were8 and 9 at 1 and 5 min, respectively. She had polycy-themia at birth.

She began walking at 14 months and talking at 2.5years. She has developmental delay (verbal IQ 81, per-formance IQ 60, and overall IQ 63), attention deficitdisorder with hyperactivity, and coordination difficul-ties.

Her height, weight, and head circumference were ap-propriate for gestational age at birth. By age 7, herweight and head circumference were at the 5th centileand she had down-slanting palpebral fissures with epi-canthal folds, hypertelorism, Brushfield spots in theleft eye, flat nasal bridge, high-arched palate, a ven-tricular septal defect and pulmonic valvular stenosis,clinodactyly of the 5th finger, and thickened nails of

the 5th toes (Fig. 2). She has increased reflexes andankle clonus.

She had difficulties in gaining weight. Results oflaboratory analyses were normal except that she hadadvanced bone age (18 months at a chronological age of10.5 months) that normalized by age 2.

CYTOGENETICS

In patient 1, chromosome analysis of phytohemag-glutinin (PHA)-stimulated lymphocyte cultures dem-onstrated a 46,XY,dup(6)(q21q23.3) karyotype. Fluo-rescent in situ hybridization (FISH) was performed us-ing a chromosome 6 painting probe (Oncor, Inc.,Gaithersburg, MD). A hybridization signal was seenspanning the entire length of both chromosome 6 ho-mologs indicating that the additional material on theabnormal 6 is derived from chromosome 6. In patient 2,chromosome analysis of the PHA-stimulated culturesdocumented a 46,XX,dup(6)(q21.15q23.3) karyotype(Fig. 3). The original karyotype was performed 11 years

Fig. 2. Patient 2 with down-slanting palpebral fissures, epicanthalfolds, and hypertelorism.

Fig. 3. Partial karyotypes from patients 1 and 2. At the left is onechromosome 6 pair from patient 1, and at the right are two chromosome 6pairs from patient 2. In each pair, the abnormal chromosome is on the left.Arrows point to the duplication breakpoints.

Fig. 1. Patient 1 with frontal bossing, epicanthal folds, up-turned nosewith depressed nasal bridge, ulnar deviation of the hands, and bilateralclub feet.

Duplication 6q21q23 Syndrome 113

ago and the parents refused additional studies. Theoriginal karyotype would not provide optimal condi-tions for FISH, therefore it was not performed. Paren-tal chromosomes were normal in both families.

DISCUSSION

Chromosomal duplications are a common mecha-nism of mutation because of unequal crossing over orasymmetric nonsister chromatid exchange. In humans,there are several well-documented examples of dupli-cations such as Charcot-Marie-Tooth type 1A [Lupskiet al., 1992], the visual pigment genes [Haynie andMukai, 1993], some hemoglobinopathies, and globin-chain gene variants [Weatherall et al., 1995]. Lupski etal. [1996] noted several common characteristics of chro-mosomal duplications: they occur with a high fre-quency, they may involve large chromosomal regions,they are flanked by repeat sequences in direct orienta-tion, and they are reversible.

While there is some information regarding the phe-notype associated with duplications involving 6q, it isoften the result of unbalanced translocations. Thus, thekaryotype usually involves material extending to 6qterand includes deletion of another chromosome segment.Tipton et al. [1979] summarized the duplication 6q syn-drome as microcephaly, acrocephaly, prominent fore-head, flat facial profile, depressed nasal bridge, flatmalar region, small triangular mouth, micrognathia,and mental retardation. The critical region for this 6qduplication phenotype is 6q26-qter [Pivnick et al.,1990]. In patients with duplications involving otherbands, there is a dearth of information that makes itdifficult to counsel families. We report two de novo di-rect duplications involving bands 6q21q23. Both chil-dren have multiple minor anomalies with only a heartdefect, epicanthal folds, depressed nasal bridge, anddevelopmental delay in common. The only anomalies incommon with those of the previously reported 6q du-plication phenotype in our patients are depressed nasalbridge, congenital heart defects, and developmental de-lay.

Singly, our 6q duplication patients have some com-mon signs as compared with other 6q duplication pa-tients. Patient 1 has a prominent forehead, abnormalpalmar creases, and clubfeet, whereas patient 2 hasdown-slanting palpebral fissures, hypertelorism, high-arched palate, and clinodactyly. Reports of 6q duplica-tion syndrome suggest that the mental retardation isprofound, whereas in our patients, the mental retarda-tion is not severe. Both of our patients had epicanthalfolds that were reported in two other 6q duplicationpatients [Tipton et al., 1979; Henegariu et al., 1997].

Because the duplication region appears to be very

similar, this raises the possibility of different break-points, position effects, differences in genetic back-ground, or imprinting playing a role in the differentphenotypes of these two patients. Imprinting is in-volved in Wiedemann-Beckwith syndrome [Elliot andMaher, 1994] that can be caused by paternally derivedduplications of 11p15. Shield et al. [1997] recentlyshowed that chromosome 6 is imprinted. They reportthree cases of paternal uniparental disomy of chromo-some 6 and neonatal diabetes. In addition, there was afourth neonatal diabetes patient with paternal dupli-cation of 6q22q23. Neither of our patients had neonataldiabetes suggesting that the duplication may havebeen maternal in origin. The parents of one of the pa-tients declined additional testing so we were unable topursue possible imprinting mechanisms resulting inthe different phenotypes. In conclusion, duplication6q21q23 syndrome is associated with developmentaldelay, congenital heart defects, depressed nasal bridge,and epicanthal folds.

ACKNOWLEDGMENT

We thank Anne Witkor for help with the FISH stud-ies and figures.

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