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 INTRODUCTION 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.  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. CLINICAL REPORTS 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 113 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. CYTOGENETICS 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. 114 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. DISCUSSION 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.  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.  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.  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. 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