Karyotype/phenotype correlations in duplication 4q: Evidence for a critical region within 4q27‐28 for preaxial defects

Varying degrees of partial duplication of 4q (dup 4q) have been reported in over 70 patients since 1972 [reviewed by Lundin et al., 2002; Rinaldi et al., 2003]. The majority of the cases include partial trisomy with breakpoints at q25 to ter, mostly due to unbalanced inherited translocations. The different breakpoints, the associated monosomies, and the varying ages of reported patients make it difficult to delineate a recognizable syndrome. However, there are six patients reported with preaxial defects, ranging from thumb hypoplasia to duplication, mostly having renal malformations as well. In the past, Zollino et al. [1995] suggested the presence of genes involved in the development of the acrorenal field at 4q22-23. Since then additional informative patients with partial 4q trisomy have been reported [Mikelsaar et al., 1995; Guillen Navarro et al., 1996; Goodman et al., 1997; Celle et al., 2000]. The karyotype-phenotype correlations derived from these recently described patients have moved the proposed critical region for preaxial defects (or acrorenal field defect) more telomeric to 4q25-28. We describe two patients with dup 4q28.1 to ter and dup 4q31.3 to ter, respectively, the first one of which is especially helpful in elucidating the critical region for thumb defects in dup 4q. The proposita was the first child of healthy, nonconsanguineous parents. Family history was noncontributory. Pregnancy was complicated by bleeding at around 3-month gestation; but there was no exposure or history of chronic illnesses, alcohol, tobacco, or street drugs. She was born at 42 weeks with a nuchal cord, but had no significant problems after birth. Weight was 3,600 g and length 47 cm. She had a cardiac murmur, and a PDA was diagnosed on echocardiography. We first saw her at the age of 50 days. She appeared to be alert and would fix and follow. Weight was 4,100 g (25th centile), and length 55 cm (25–50th centile). Microcephaly was evident with the anterior fontanel soft and flat; eyelashes were quite long; nasal bridge and nasal root were somewhat prominent; ears appeared to be prominent with a prominent antihelix and a simple outer helix; palate was intact, but there was a bifid uvula. A very small umbilical hernia was noted. The thumb was absent on the right; the left thenar eminence was somewhat hypoplastic. At 6 months of age, she had a single cluster of very brief seizures, associated with fever; and, following serious feeding difficulties, she had required a G tube and Nissan fundoplication. She had a single kidney on the right and a hearing loss on the right. The PDA had closed. We saw her again at the age of 11 months. Although making steady progress, she was significantly delayed in all areas of development. Constipation was a concern. On examination, length was 67.9 cm (5th centile), weight 6.5 kg (<3rd centile), and OFC 42 cm (2nd centile). She had an alternating exotropia with bushy eyebrows; long eyelashes; some narrowness of her bifrontal diameter; small mouth and small jaw. The fingers were thin with absence of the right thumb, and hypoplasia of the left thumb. Figures 1 and 2 show her findings at 8 years of age. She now has a moderate developmental disability. Patient 1 at age 8 years. The hands of Patient 1. Peripheral blood samples were obtained from the patient and her parents. Cytogenetic analysis on the mother's blood showed an apparently balanced translocation between chromosomes 4 and 11 in all 20 cells analyzed. The karyotype was designated as 46,XX, t(4;11)(q28.3;q24.3). The father's karyotype was normal. All 20 metaphase cells analyzed from peripheral blood of the patient showed a derivative chromosome 11 apparently resulting from the maternal chromosome 4;11 translocation. Her karyotype was designated as 46,XX,der(11)t(4;11)(q28.3;q24.3)ish der(11)t(4;11)(wep4+)mat. The patient, therefore, has a partial 4q trisomy and a very small deletion of 11q. Figure 3 depicts a partial karyotype of Patient 1 and her mother. A composite karyotype of Patient 1 and her mother showing the balanced translocation between chromosomes 4 and 11 in the mother (left) and the derivative chromosome 11 resulting from the maternal chromosome 4;11 translocation in the patient (right). The propositus was the first child of healthy, nonconsanguineous parents. Family history showed a previous girl who was stillborn and known to have an unbalanced translocation. The patient was born after a normal pregnancy with a birth weight at 50th centile, length at 10th centile, and OFC at 60th centile. Truncus arteriosus was repaired neonatally. He was found to have Hirschsprung disease of the long segment type, which was repaired at age 1 month; pyloric stenosis was repaired at age 2 months. He also had vescicoureteric reflux, but the kidneys were structurally normal. We saw him at follow-up at the age of 25 months with growth delay, all three parameters falling below the 2nd centile. He had marked developmental delay with skills at 6–7 months level in all areas. On examination (Fig. 4), he had prominent forehead, mildly prominent nasal bridge, cupped ears, short neck, brachydactyly with structurally normal thumbs, small feet, and generalized hypotonia. At an age of 4 years, the patient became acutely ill and died of overwhelming sepsis. Patient 2 at age 25 months. Peripheral blood samples were obtained from the patient and his parents and prepared as in Patient 1. Cytogenetic analysis on the father's blood showed a male chromosome complement with an apparently balanced translocation between chromosomes 4 and 10 in all 20 cells analyzed. The karyotype was designated as 46,XY, t(4;10)(q31.3;q26.1). The mother's karyotype was normal. All 20 metaphase cells analyzed from peripheral blood of the patient showed a male chromosome complement with a derivative chromosome 10, apparently resulting from the paternal chromosome 4;10 translocation. His karyotype was designated as 46,XY, der(10) t(4;10)(q31.3;q26.1)pat. The patient, therefore, had a partial 4q trisomy and a small deletion of 10q due to an unbalanced, paternally inherited translocation (Fig. 5). The patient's sister had the der(10) like our patient. Characterization of the breakpoints in the patients by molecular cytogenetics is in progress. A composite karyotype of Patient 2 and his father showing the balanced translocation between chromosome 4 and 10 in the father (left) and the derivative chromosome 10 resulting from the paternal chromosome 4;10 translocation in the patient (right). Partial 4q trisomy usually results from an unbalanced segregation of a familial translocation [Yunis et al., 1977; Schinzel, 2001]. The wide phenotypic variability observed in such patients can be related to the different breakpoints and consequent different sizes of the duplicated 4q segment, to the associated monosomies, and to the varying ages of reported propositi. Nevertheless, a number of shared findings seem to emerge from several reviews [Biedermann and Bower, 1976; Yunis et al., 1977; Bonfante et al., 1979], such as microcephaly, abnormal ears, congenital heart defects, varying renal malformations, and growth and mental retardation. Preaxial defects, ranging from thumb hypoplasia to duplication, seem to be a less frequent but a characteristic finding [Surana and Conen, 1972; Dutrillaux et al., 1975; Vogel et al., 1975; Biedermann and Bower, 1976; Lundin et al., 2002; Rinaldi et al., 2003]. To date, 14 cases with de novo partial 4q duplication have been reported [Jeziorowska et al., 1993; Zollino et al., 1995; Guillen Navarro et al., 1996; Rinaldi et al., 2003]. Genitourinary abnormalities were described only in five, in which the minimal duplicated region was 4q25q31.3. However, this was not observed in other patients with a similar duplication, demonstrating the variability of these findings in dup4q. Congenital heart defects were reported in three patients, and apparently seemed to be associated with the 4q26q27 duplication, as this region is the minimal common duplicated region in all cases. However, this possibility should now be reviewed based on our second patient who had truncus arteriosus and a duplication of 4q31.3. Hypoplastic thumb has been observed in five patients, and the minimal common duplicated region is 4q25q28. This seems to be supported by our first patient, who has absence of the right thumb and hypoplasia of the left thumb, with a duplication of 4q28.3; whereas our second patient with normal thumbs has a duplication of 4q31.1. The case reported by Lundin et al. [2002] narrows the critical region to 4q27-28. Thus, there seems to be enough evidence for a critical region within 4q27q28 for preaxial defects. This region is more distal than originally suggested by Zollino et al. [1995]. Since most of the patients with preaxial defects have structural renal defects, including Patient 1, genes important in the development of the acrorenal field are likely present in 4q25q28. This work was supported in part by the International Program for Consultation and Research in Clinical Genetics of the University of Utah and the Primary Children's Research Foundation. This work was presented, in part, to the Annual Meeting of the ASHG in Baltimore, MD (October 15–19, 2002). We thank the families of our patients for help and support.