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American Journal of Medical Genetics 80:112–114 (1998)
Brief Clinical Report
Duplication 6q21q23 in Two Unrelated Patients
V.M. Pratt,* J.R. Roberson, L. Weiss, and D.L. Van Dyke
Medical Genetics and Birth Defects Center, Henry Ford Hospital, Detroit, Michigan
We report on two patients with rare 6q duplications. The karyotype of patient 1 is
46,XY,dup(6)(q21q23.3). The karyotype of
patient 2 is 46,XX,dup(6)(q21.15q23.3). These
two patients have some nonspecific physical
findings in common including a depressed
nasal bridge, epicanthal folds, mild heart
defects, and developmental delay, but each
had other congenital anomalies. Am. J. Med.
Genet. 80:112–114, 1998. © 1998 Wiley-Liss, Inc.
KEY WORDS: chromosome 6q duplication;
mild mental retardation; congenital heart defect
Patients with distal duplication of the long arm of
chromosome 6 (bands q26-qter) have a distinct clinical
phenotype. The 6q26-qter phenotype includes microcephaly, acrocephaly, down-slanting palpebral fissures, telecanthus, micrognathia, ‘‘carp-shaped’’
mouth, short anterior webbed neck, club foot, joint contractures, and profound psychomotor retardation
[Chen et al., 1976; Tipton et al., 1979; Pivnick et al.,
1990; Uhrich et al., 1991]. Henegariu et al. [1997] recently reported a child with duplication 6q23.3q25.3.
This patient had dolichocephaly with prominent occiput, prominent forehead, horizontal almond-shaped
palpebral fissures, infraorbital crease, blue-tinted
sclerae, hypertelorism, broad, depressed nasal bridge,
short philtrum, midface hypoplasia, ‘‘carp’’ mouth,
short neck, congenital heart defects (patent ductus arteriosus and atrial septal defect), flexion contractures
at the wrists, dorsiflexion of first toes, umbilical hernia, and mild hypotonia. Here, we report two de novo
duplications of 6q21q23.
Patient 1
Patient 1 was born at 41 weeks of gestation to a
G2P1 29-year-old woman. The prenatal course was re*Correspondence to: V.M. Pratt, Laboratory Corporation of
America, 1912 Alexander Drive, Research Triangle Park, NC 27709.
Received 24 November 1997; Accepted 9 June 1998
© 1998 Wiley-Liss, Inc.
markable for gestational diabetes. Patient 1 had decreased fetal heart tones and multiple variable decelerations during labor. His birth weight was 2.1 kg (<
3rd centile), length 44 cm (< 3rd centile), and head
circumference (OFC) 35.5 cm (75th centile). Apgar
scores were 8 and 9 at 1 and 5 min, respectively. Studies of the placenta showed two cord sections with five
vessels, suggesting a section taken through a false
knot. He had a ‘‘hazy’’ left lung suggestive of pneumothorax that resolved spontaneously. He also had bilateral clubfoot, ulnar deviation of hands, prominent skull
sutures, no cry, decreased muscle tone, and decreased
subcutaneous fat. No metaphyseal or diaphyseal dysplasias were present on radiographs. Head ultrasound
findings were interpreted as a slight bleed or calcification near the basal ganglia. The corpus callosum was
not visualized in the ultrasound films. The frontal horn
of the left ventricle was greater than the right. The
orbital rim was steep. He was placed in an incubator
with 30% oxygen for a few hours and released from the
hospital with his mother after 3 days.
At 2 to 3 weeks, he was evaluated for tachypnea. A
heart murmur was noted. An echocardiogram showed
right ventricular hypertrophy and a thickened tricuspid valve with no significant obstruction or regurgitation.
At 6 weeks, he stopped breathing and became cyanotic while riding in his infant seat in the car. His
parents reported noisy breathing and some nasal congestion prior to this episode. He was hospitalized and
was placed on a ventilator for 1 week for severe pneumonia. A left pneumothorax was treated with a chest
tube, and a possible right pneumothorax resolved spontaneously.
At age 4 months, he could roll side-to-side, laugh, fix
and follow, and reach for objects, but he did not have
good head control. A developmental evaluation performed at 8 months indicated a 6 to 8 month developmental level, although his gross motor skills were at
the 3 to 5 month level. On physical examination, his
length was 59.5 cm (5th centile), weight 6.6 kg (50th
centile), and OFC 43.5 cm (80th centile). He had frontal
bossing with the right side more prominent than the
left, epicanthal folds, up-turned nose with depressed
nasal bridge, a capillary hemangioma at the nape of
the neck, a fine papular rash on the trunk, a shawl
Duplication 6q21q23 Syndrome
scrotum, bilateral transverse palmar creases, ulnar deviation of the hands, club feet, and small hands and
feet (hand length was 6 cm (< 3rd centile), palm length
3.75 cm (< 3rd centile), and foot length 8.5 cm (< 3rd
centile)). The inner canthal distance was 3 cm (97th
centile). The outer canthal distance was 6.5 cm (25th
centile) (Fig. 1).
Patient 2
Patient 2 was born at term by spontaneous vaginal
delivery to a G2P1 woman. Prenatal course was unremarkable except that the mother smoked approximately 1 pack of cigarettes per day. Apgar scores were
8 and 9 at 1 and 5 min, respectively. She had polycythemia at birth.
She began walking at 14 months and talking at 2.5
years. She has developmental delay (verbal IQ 81, performance IQ 60, and overall IQ 63), attention deficit
disorder with hyperactivity, and coordination difficulties.
Her height, weight, and head circumference were appropriate for gestational age at birth. By age 7, her
weight and head circumference were at the 5th centile
and she had down-slanting palpebral fissures with epicanthal folds, hypertelorism, Brushfield spots in the
left eye, flat nasal bridge, high-arched palate, a ventricular septal defect and pulmonic valvular stenosis,
clinodactyly of the 5th finger, and thickened nails of
Fig. 2. Patient 2 with down-slanting palpebral fissures, epicanthal
folds, and hypertelorism.
the 5th toes (Fig. 2). She has increased reflexes and
ankle clonus.
She had difficulties in gaining weight. Results of
laboratory analyses were normal except that she had
advanced bone age (18 months at a chronological age of
10.5 months) that normalized by age 2.
In patient 1, chromosome analysis of phytohemagglutinin (PHA)-stimulated lymphocyte cultures demonstrated a 46,XY,dup(6)(q21q23.3) karyotype. Fluorescent in situ hybridization (FISH) was performed using a chromosome 6 painting probe (Oncor, Inc.,
Gaithersburg, MD). A hybridization signal was seen
spanning the entire length of both chromosome 6 homologs indicating that the additional material on the
abnormal 6 is derived from chromosome 6. In patient 2,
chromosome analysis of the PHA-stimulated cultures
documented a 46,XX,dup(6)(q21.15q23.3) karyotype
(Fig. 3). The original karyotype was performed 11 years
Fig. 1. Patient 1 with frontal bossing, epicanthal folds, up-turned nose
with depressed nasal bridge, ulnar deviation of the hands, and bilateral
club feet.
Fig. 3. Partial karyotypes from patients 1 and 2. At the left is one
chromosome 6 pair from patient 1, and at the right are two chromosome 6
pairs from patient 2. In each pair, the abnormal chromosome is on the left.
Arrows point to the duplication breakpoints.
Pratt et al.
ago and the parents refused additional studies. The
original karyotype would not provide optimal conditions for FISH, therefore it was not performed. Parental chromosomes were normal in both families.
Chromosomal duplications are a common mechanism of mutation because of unequal crossing over or
asymmetric nonsister chromatid exchange. In humans,
there are several well-documented examples of duplications such as Charcot-Marie-Tooth type 1A [Lupski
et al., 1992], the visual pigment genes [Haynie and
Mukai, 1993], some hemoglobinopathies, and globinchain gene variants [Weatherall et al., 1995]. Lupski et
al. [1996] noted several common characteristics of chromosomal duplications: they occur with a high frequency, they may involve large chromosomal regions,
they are flanked by repeat sequences in direct orientation, and they are reversible.
While there is some information regarding the phenotype associated with duplications involving 6q, it is
often the result of unbalanced translocations. Thus, the
karyotype usually involves material extending to 6qter
and includes deletion of another chromosome segment.
Tipton et al. [1979] summarized the duplication 6q syndrome as microcephaly, acrocephaly, prominent forehead, flat facial profile, depressed nasal bridge, flat
malar region, small triangular mouth, micrognathia,
and mental retardation. The critical region for this 6q
duplication phenotype is 6q26-qter [Pivnick et al.,
1990]. In patients with duplications involving other
bands, there is a dearth of information that makes it
difficult to counsel families. We report two de novo direct duplications involving bands 6q21q23. Both children have multiple minor anomalies with only a heart
defect, epicanthal folds, depressed nasal bridge, and
developmental delay in common. The only anomalies in
common with those of the previously reported 6q duplication phenotype in our patients are depressed nasal
bridge, congenital heart defects, and developmental delay.
Singly, our 6q duplication patients have some common signs as compared with other 6q duplication patients. Patient 1 has a prominent forehead, abnormal
palmar creases, and clubfeet, whereas patient 2 has
down-slanting palpebral fissures, hypertelorism, higharched palate, and clinodactyly. Reports of 6q duplication syndrome suggest that the mental retardation is
profound, whereas in our patients, the mental retardation is not severe. Both of our patients had epicanthal
folds that were reported in two other 6q duplication
patients [Tipton et al., 1979; Henegariu et al., 1997].
Because the duplication region appears to be very
similar, this raises the possibility of different breakpoints, position effects, differences in genetic background, or imprinting playing a role in the different
phenotypes of these two patients. Imprinting is involved in Wiedemann-Beckwith syndrome [Elliot and
Maher, 1994] that can be caused by paternally derived
duplications of 11p15. Shield et al. [1997] recently
showed that chromosome 6 is imprinted. They report
three cases of paternal uniparental disomy of chromosome 6 and neonatal diabetes. In addition, there was a
fourth neonatal diabetes patient with paternal duplication of 6q22q23. Neither of our patients had neonatal
diabetes suggesting that the duplication may have
been maternal in origin. The parents of one of the patients declined additional testing so we were unable to
pursue possible imprinting mechanisms resulting in
the different phenotypes. In conclusion, duplication
6q21q23 syndrome is associated with developmental
delay, congenital heart defects, depressed nasal bridge,
and epicanthal folds.
We thank Anne Witkor for help with the FISH studies and figures.
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