Non‐chromosome 11‐p syndromes in Wilms tumor patients: Clinical and cytogenetic report of two Down syndrome cases and one Turner syndrome case
Wilms tumor (WT), or nephroblastoma, is a malignant embryonal tumor of the kidney affecting 1:10,000 children. While most WT cases are sporadic, it is well known its occurrence in association with certain inherited syndromes, such as the WAGR (WT, Aniridia, Genitourinary anomalies, Mental retardation) (OMIM#194072), the Denys-Drash (OMIM #194080), the Frasier (OMIM #136680), and the Beckwith–Wiedemann (OMIM #130650) syndromes. All these conditions are related to loci mapped to the short arm of chromosome 11. Cytogenetic investigations of WAGR patients identified large deletions at chromosome 11p13 encompassing a contiguous set of genes including the WT suppressor gene WT1 [Bonetta et al., 1990; Call et al., 1990; Gessler et al., 1990] and the aniridia responsible gene PAX6 [Ton et al., 1991]. WT1 gene alterations are also responsible for two other syndromic conditions: the Denys–Drash syndrome, due to point mutations most of which occur in the zinc-finger DNA binding region of the gene [Pelletier et al., 1991; Coppes et al., 1993], and the Frasier syndrome, caused by point mutations in the donor splice site of intron 9 [Barbaux et al., 1997]. The Beckwith–Wiedemann syndrome is linked instead to a different chromosomal region, the 11p15 band, where the WT2 gene has been mapped, although not yet identified [Koufos et al., 1989; Ping et al., 1989]. In addition to these 11p-linked congenital syndromes, WT has been rarely reported in individuals with other genetic disorders (for a review see Scott et al., 2006), including Down syndrome (DS) [Kusumakumary et al., 1995] and Turner syndrome (TS) [Say et al., 1971; Olson et al., 1995; Hasle et al., 1996]. Here we report on the clinical and cytogenetic description of three children, two with DS, and one with TS, who were referred to our Pediatric Oncology Unit for a newly diagnosed WT. Patient 1 was a 3-year and 8-month-old male, first of three children of unrelated healthy Caucasian parents, with an unremarkable family history. The mother was 31 years old and the father was 33 years old at the patient's birth. Pregnancy was uneventful, with no evidence of teratogen exposure. Birth weight and length were 3,400 g (50th centile) and 47 cm (10th centile), respectively, and head circumference was 33 cm (<3rd centile). The neonate had the recognizable phenotype of DS, and the clinical diagnosis was confirmed by conventional cyogenetic investigation showing a 47,XY,+21 karyotype. When he was 4 months old, he was diagnosed as having West syndrome, accompanied by a severe generalized hypotonia. At 3 years of age, a diagnosis of monolateral hyperplastic multifocal nephroblastomatosis was hypothesized, based on clinical-radiographic evidence, and a wait-and-see policy was adopted. When he was 3 years 8 months old, the child underwent an uncomplicated radical left nephrectomy because of the suspected evolution into WT. On pathological examination, the tumor was a multicentric (three foci) nephroblastoma, without anaplasia. It displayed a blastematous predominance in a nodule, and an epithelial predominance in the remaining two nodules. Perilobar nephrogenic rests, of the hyperplasic and sclerosing types, were present. Tumor tissue was obtained immediately after surgery and processed for cytogenetic analysis. Complex rearrangements were characterized by spectral karyotyping (SKY), performed according to published protocols [Lualdi et al., 2004]. Tumor karyotype showed 45,XY,der(12)t(12;17)(p11;p11),−13,der(17)t(13;17)(q11;p11),+21,−22 (data not shown). At the time of this report, the child is alive and disease-free 14 months after the diagnosis. Patient 2 was a 4-year-old girl, fourth child of unrelated healthy Caucasian parents, without a family history of relevant diseases. The mother was 35 years old and the father 44 years old at the patient's birth. Pregnancy was uneventful, with no evidence of teratogen exposure. Birth weight and lengths were 2,400 g (50th centile) and 47 cm (50th–75th centile), respectively, and head circumference was 32 cm (<3rd centile). The newborn presented with the clinical features of DS, confirmed by cytogenetic investigation showing a 47,XX,+21 karyotype. An echocardiography revealed a complicated hemodynamic situation, characterized by an inter-atrial ostium secundum defect, with left to right shunt, a complete atrio-ventricular canal, and a wide sub-aortic interventricular defect with left to right shunt, which was surgically successfully corrected at the age of 9 months. Other relevant clinical anomalies included a generalized hypotonia, associated with diffuse ligamental relaxation, left kidney pyelectasia, and generalized seizures. When she was 4 years old, she underwent a right nephrectomy because of a huge mass in the right kidney, determining asymptomatic abdominal enlargement. Histologic examination showed a predominantly blastematous WT, without anaplasia, infiltrating the peritumoral capsule, and the surrounding fat, with a metastasis in preaortic lymph nodes. Nephrogenic rests were absent. Tumor tissue showed a 47,XX,+21 karyotype (data not shown). The patient showed liver and lung recurrences 3 months following the conclusion of treatment. Patient 3 was a 24-month-old girl, fourth child of healthy, unrelated Caucasian parents. Mother's and father's ages at the patient's birth were 33 and 40 years, respectively. The mother had two abortions, one after the second child, and one after the patient's birth. Active fetal movements were detected late during pregnancy, and at the 28th week of gestation hydrops fetalis was diagnosed. Delivery was spontaneous and uncomplicated at the 37th week of gestation. Birth weight, total length, and head circumference were 3,250 g (50th centile), 48 cm (25th centile), and 34.5 cm (25th centile), respectively. At birth, the neonate showed generalized hypotonia, puffy right hand and foot, and TS was diagnosed. This was eventually confirmed by conventional cytogenetic that showed a 45,X,−X/46,X,−X,+r mosaicism, the ring chromosome being present in 10% of metaphases analyzed. Accurate clinical examination revealed additional features not typical for TS, such as generalized hypotonia, esotropia of the right eye with palpebral asymmetry, asymmetry of the neck and cheek with right deviation of the rima oris, short and broad radius, and femoral bones. At the age of 2 years, an enlargement was clinically noticed in the right abdomen, with arterial hypertension. Computed tomography examination and magnetic resonance imaging showed a 13 cm mass in the right kidney. The baby underwent a right nephrectomy plus omolateral lymphnodes dissection. Macroscopic examination showed a lesion of 16 × 9 cm. Histologically, the tumor was a unicentric triphasic nephroblastoma, without anaplasia, with focal necrosis and hemorrhage, focally infiltrating the perirenal fat. Nephrogenic rests were absent. Chromosome analysis of 10 SKY painted metaphases revealed a tumor karyotype: 47,X,r(X),+i(1q) (data not shown). Thus the ring chromosome, that was already present as a mosaic in the peripheral blood of the patient, could be recognized by SKY as a ring X chromosome, a finding reported in approximately 15% of Turner patients [Jacobs et al., 1997]. At this writing the patient is disease-free 11 months from diagnosis. Children with congenital anomalies exhibit an age-related risk of developing cancer higher than the general population [Agha et al., 2005]. Moreover, some congenital disorders are specifically associated with certain type of tumors. This is the case of a few syndromes linked to chromosome 11p, including the WAGR, the Denys-Drash, the Frasier, and the Beckwith–Wiedemann syndromes, that are characterized by an increased risk of WT [Scott et al., 2006]. However, the occurrence of a specific association of these malignancies with other, non-11p linked, syndromes remains unclear. We were interested in reviewing our and others' experience with DS and TS patients affected with WT, because three children with these phenotypes were recently registered into the presently ongoing nation-wide Italian nephroblastoma trial. The pattern of occurrence of tumors in individuals with DS is unique in comparison to the general population. While the risk of leukemia is higher and almost restricted to childhood, the risk of developing solid tumors is lower than expected, both in children and in adults [Zipursky et al., 1992; Hasle, 2001]. Analyzing 2,846 individuals with DS, Hasle et al. 2000 reported a standardized incidence ratio for solid tumors in the age group 0–29 years of 0.44, with only three solid tumors observed in individuals aged under 30 years (one retinoblastoma, one dysgerminoma, and one embryonal carcinoma). In addition, a low standardized mortality odd ratio was reported by Yang et al. 2002 in association with DS at all ages and for all common tumor type except leukemia and testicular tumors. The occurrence in DS of a reduced tendency to the development of non-hematological tumors is indirectly suggested also by a study from the British Registry of Childhood Tumors, in which only seven DS cases were identified among approximately 11,000 patients with solid malignancies [Narod et al., 1991]. Analogously, only 21 cases of solid tumors in children with DS were collected from 1980 to 2001 within the network of the Société Francaise d'Oncologie Pédiatrique [Satge et al., 2003]. These figures are in keeping with our experience, since the two DS patients affected with WT that came to our observation were the only ones detected among approximately 3,300 new cases of malignant solid tumors referred to our Pediatric Oncology Unit since 1983. The above observations would suggest the existence on chromosome 21 of both leukaemogenic genes and tumor suppressor genes specifically involved in controlling the development of solid malignancies. Remarkably, a review of 5,854 patients recruited in the National Wilms Tumor Study (NWTS) from 1969 to1992 revealed no case with trisomy 21. However, among 2,812 on-study and 219 not-on-study patients registered into the NWTS-5 from August 1995 to May 2002, two cases of DS were reported (P Grundy, JG D'Angio, NE Breslow, personal communication). In keeping with the rarity of the co-occurrence of DS and WT, to our knowledge only a single report describing one such case was published prior to the present report [Kusumakumary et al., 1995]. At variance than DS, TS is associated with an increased risk of different solid tumors, including gynecological malignancies, due to prolonged estrogen exposure, and hepatocellular carcinoma, due to progestagen therapy. Furthermore, more cases of colon cancer than expected have been described in TS individuals [Hasle et al., 1996]. A few cases of WT in patients affected by TS have been published. Say et al. 1971 described a 45,X patient with WT and imperforate anus. A study of cancer incidence in a cohort of 597 Danish women with TS, reported WT in one 45,X,/46,XX subject [Hasle et al., 1996]. Finally, among the 5,854 above-mentioned NWTS patients, four TS cases were observed. For three of them the constitutional karyotypes were available: 45,X; 45,X,/46,X,r(X)(p22.1q22) and 45,X,/46,X,,r(X)(p11.2q26) [Olson et al., 1995]. The two cases with DS and the one with TS described in this report are the only individuals with these conditions among 593 on-study and 108 not-on-study patients enrolled to date within the three sequential Italian cooperative nephroblastoma trials (1,980 onwards). In all three patients, the age of onset of the malignancy was within the usual range for WT cases and the histology pattern was similar to that observed in the majority of these tumors, with variable presence of the blastematous, epithelial, and sarcomatous components. Interestingly, the patients showed clinical features not usually associated with their congenital conditions, including severe hypotonia and, in the DS children, refractory seizures. In combining data of the NWTS with those of the Italian trials, there seems to be an underrepresentation of DS diagnosis and an overrepresentation of TS diagnosis among WT patients. In fact, the observed incidence of DS and TS cases among registered WT patients were 1;2,396 subjects of both sexes and 1:655 females, respectively, compared to estimated incidence in white population ranging from approximately 1:650 to 1:1,000 for DS [Hook, 1982] and from 1:2,000 to 1:4,000 for TS [Gravholt et al., 1996]. The scarcity of DS cases among WT patients is intriguing when considering that many different urological defects, including renal agenesis or hypoplasia, horseshoe kidney, glomerular microcysts, urinary tract obstruction, cystic displasia, or renal cysts, acquired glomerular diseases, ureteral abnormalities, cryptorchidism, and hypogonadism, have been associated with DS [Mercer et al., 2004]. This would suggest that, while DS individuals may develop a variety of urological anomalies, they are protected from other disorders of nephrogenesis leading to nephrogenic rests or nephroblastoma. However, since chromosome analyses were not routinely performed either in the NWTS or in the Italian trials, it is not possible to exclude that the apparent low rate of DS cases can be due to a lack of report. Moreover, we cannot exclude that children affected by DS were not formally registered into national WT trials. On the other hand, two of the TS subjects registered in the NWTS had a horseshoe kidney, which is a known risk factor for WT [Olson et al., 1995]. If these two patients are not considered, the rate of TS cases drops to 1:1,092, which is closer to that of the general population. While the occurrence of association between WT and non-chromosome 11p-linked syndromes, such as DS and TS, needs to be validated by further analyses, it is worth noting that the study of malignancies that arise in subjects who carry congenital genetic defects may represent, in principle, a powerful tool for the elucidation of the molecular bases of cancer predisposition and progression. This might be particularly useful in the case of WT, which is characterized by a high degree of genetic heterogeneity, which is still to be fully elucidated. Unfortunately, the data collected at present on individuals affected with both WT and DS or TS are too scarce to allow devising any hypothesis on the nature of the specific genetic factors involved, if any. Indeed, to our knowledge, this is the first study in which the tumor karyotypes of WT patients with DS or TS are reported. In the TS patient, the tumor appeared to arise from a cell containing a r(X) chromosome, which was present as a mosaic at the constitutional level, thus suggesting that this chromosome could have played a role in the pathogenesis of the neoplasia. Further anomalies frequently described in WT patients [Hoglund et al., 2004] were also observed, including the +i(1q) in the TS patient and the loss of chromosome 22 in DS Patient 1. The present data emphasize the need for collecting and studying as many as possible cancer patients with combined clinical phenotypes and for promoting the exchange of information and biological tissues of these rare but potentially highly informative cases. The authors thank Dr. P. Grundy, Prof. JG D'Angio, Dr. NE Breslow, and the NWTSG for providing unpublished data.
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