Linkage of familial Wilms' tumor predisposition to chromosome 19 and a two-locus model for the etiology of familial tumors.

Familial predisposition to Wilms' tumor (WT), a childhood kidney tumor, is inherited as an autosomal dominant trait. For most WT families studied, the 11p13 gene WT1 and genomic regions implicated in tumorigenesis in a subset of tumors can be ruled out as the site of the familial predisposition gene. Following a genome-wide genetic linkage scan, we have obtained strong evidence (log of the odds ratio = 4.0) in five families for an inherited WT predisposition gene (FWT2) at 19q13.3-q13.4. In addition, we observed loss of heterozygosity at 19q in tumors from individuals from two families in which 19q can be ruled out as the site of the inherited predisposing mutation. From these data, we hypothesize that alterations at two distinct loci are critical rate-limiting steps in the etiology of familial WTs.

Evidence for genetic heterogeneity in familial Wilms' tumor.

Wilms' tumor (WT), a childhood kidney cancer, occurs both sporadically and, less frequently, in a familial context. Genetic linkage studies of several large WT families have excluded the one cloned WT gene, WT1, as the locus responsible for familial predisposition. These data demonstrate the existence of a familial predisposition gene distinct from WT1 and, more broadly, imply that the genetic etiology of WT is heterogenous. However, it has been unknown whether the predisposition observed in large WT families is also heterogenous or perhaps is due to mutations at a single locus. Recently, examination of a large French-Canadian WT family has demonstrated genetic linkage to 17q12-q21. We report here the results from a genetic linkage study of six WT pedigrees. Analyses of genotype data from eight loci within the 17q12-q21 region in these families resulted in cumulative lod scores of <-4.0 through the region, thereby excluding linkage. The ability to rule out the 17q region as the site of a predisposition gene in several of these pedigrees individually demonstrates the existence of more than one gene that predisposes to WT in large pedigrees and again emphasizes that the etiology of WT is genetically heterogenous.

Ulnar stress fracture of the nondominant arm in a tennis player using a two-handed backhand.

Stress fractures are infrequently seen in non-weight-bearing bones. However, stress fractures may be present in any bone that undergoes repetitive stress. We report an unusual case of stress fracture in the nondominant arm of a tennis player who uses a two-handed backhand stroke.

Nonlinkage of 16q markers to familial predisposition to Wilms' tumor.

Wilms' tumor (WT), a childhood cancer of the kidney, occurs in both familial and sporadic forms. Chromosome 11 genes have been implicated in the etiology of WT, and mutations in a gene at chromosomal band 11p13, WT1, have been identified in a few WT cases. However, 11p13 has been excluded as the site of the predisposition mutation segregating in several large WT families, which implies the existence of a non-11p familial predisposition gene. Recently, loss of heterozygosity for 16q markers located between chromosomal bands 16q13 and 16q22 has been reported in approximately 20% of sporadic Wilms' tumors. To determine if this region of 16q harbors the non-11p familial WT gene, a genetic linkage study of five WT families was undertaken. Using multipoint analyses, we ruled out genetic linkage of familial WT predisposition to 16q.

Postoperative chemotherapy for primary intracranial germ cell tumor.

Two children with primary intracranial mixed germ cell tumors are described who were successfully treated by partial resection of the tumor followed by sequential combination chemotherapy without radiation therapy. The chemotherapy consisting of VP-16 and cisplatin alternating with vincristine, methotrexate, and bleomycin resulted in apparent complete response after 6 to 7 months of treatment. Disease-free remission has continued 30-34 months off therapy. A small residual mass in one patient continues to decrease in size on magnetic resonance imaging and is presumed to represent postsurgical change rather than malignant tumor. This report demonstrates that chemotherapy may be effective in primary germ cell tumors of the suprasellar and pineal regions and could be considered for primary treatment instead of radiotherapy.

Lack of linkage of familial Wilms' tumour to chromosomal band 11p13.

Wilms' tumour (WT), a paediatric renal neoplasm, affect approximately 1 in 10,000 children. One or both kidneys can be affected and 5-10% of tumours are bilateral. Most tumours occur sporadically; however, around 1% of the cases are familial, with siblings or cousins most often being affected. Familial cases are more frequently bilateral, and familial and bilateral tumours are diagnosed at an earlier age. On the basis of these observations, it was proposed that the development of WT requires two mutations. In most sporadic unilateral WT, both are somatic; in familial and bilateral tumours the first is thought to be germinal. Cytogenetic and molecular studies have demonstrated germinal mutations in WT/aniridia patients and somatic mutations in sporadic WT at chromosomal band 11p13. To investigate whether familial predisposition to WT is due to a germinal 11p13 mutation, we studied a WT family with seen DNA markers that span the 11p13 region. We found that familial WT predisposition was not genetically linked to any of the 11p13 markers. This suggests that the gene involved in familial WT predisposition is outside 11p13 and is distinct from the gene involved in tumorigensis and in WT predisposition in WT/aniridia 11p13-deletion patients.

Herpes zoster in children with acute lymphocytic leukemia.

Herpes zoster (HZ) occurred in 25% (28/88) of a population of children with acute lymphocytic leukemia (ALL) who were seropositive for varicella zoster virus antibody before its onset; 16.5% (33/199) of the total group of children with ALL developed HZ. There were no deaths and only one significant complication, cutaneous disseminated disease, as a result of HZ. The small number of patients studied may have accounted for the failure to find a significant association between the occurrence of HZ and the type of ALL or chemotherapy protocol employed. Although HZ seemed to be more common in those patients who experience relapses of their leukemia, it did not portend a poor outcome for ALL.

Varicella-like illness caused by live varicella vaccine in children with acute lymphocytic leukemia.

A varicella-like illness occurred in five of 52 children with acute lymphocytic leukemia following the administration of live varicella vaccine. Only one of the children required treatment with acyclovir. Virus isolated from two of the children was "vaccine-like" but differed slightly from the original vaccine strain when tested by restriction enzyme analysis. There did not appear to be a reversion to virulence because two of the household contacts who seroconverted had mild or subclinical infections. Vaccinees in whom this reaction developed tended to have a poor cellular immune response to varicella-zoster virus.

Effect of transfusions on serologic testing for antibody to varicella.

Serologic testing of patients with acute lymphocytic leukemia for susceptibility to varicella was confounded by prior administration of blood products. Packed red cell transfusions produced fewer problems than plasma-rich transfusions. Seronegative individuals may be transiently seropositive for several weeks. Specimens submitted for serologic testing should be accompanied by information on recent receipt of blood products.

Risk of herpes zoster in children with leukemia: varicella vaccine compared with history of chickenpox.

A study was undertaken to determine whether children immunized with live varicella vaccine are at greater risk of acquiring herpes zoster than children who have had varicella. Children with acute lymphocytic leukemia who had had varicella were compared with those who received live varicella vaccine. During the period of observation, 15 of 73 children who had varicella acquired herpes zoster and none of the 34 children who had been vaccinated. If the time of observation was adjusted for and the vaccinees who failed to have a sustained antibody response or who acquired chickenpox were removed, the risk of herpes zoster was still less in vaccinees (P = .0075). Because herpes zoster is common in children with acute lymphocytic leukemia, differences in the two groups could be discerned more readily than if normal children were compared. There is no reason to suspect that recipients of live varicella vaccine would be more likely to acquire herpes zoster than children who get varicella.

Administration of live varicella vaccine to children wtih leukaemia.

Live varicella vaccine was given to twenty-three children with lymphoreticular malignancies, twelve whose chemotherapy was complete and eleven who were still receiving therapy. Seroconversion was observed in all twenty-three children, only one of whom lost his vaccine-induced antibody. Eight of the children experienced thirteen exposures to varicella, including four continuing exposures in their households. Varicella, manifested by the appearance of seven vesicular lesions, developed in only one. In all but two of the children an invitro blastogenic response to varicella/zoster-virus (VZV) antigen developed; both children had a biphasic rash after immunisation. A sibling of one of these children seroconverted without clinical evidence of varicella, presumably because of infection with vaccine virus. None of the other household contacts had significant rises in VZV antibody. VZV was not isolated from the blood, throat, or urine samples of the twenty-three vaccinees tested.

Prophylaxis of varicella in children with neoplastic disease: comparative results with zoster immune plasma and gamma globulin.

The incidence and severity of varicella following a close family contact were evaluated in children with neoplastic diseases who received prophylaxis either with commerical gamma globulin or with zoster immune plasma, as compared to patients who did not receive any prophylaxis. In the untreated group, all 14 patients developed varicella, complicated by 1 case of encephalitis and 2 cases of fatal pneumonia. In the group of 17 patients who received 0.6-1.2 ml/kg body weight of gamma globulin, 16 developed varicella, complicated by pneumonia in 2 cases, with 1 death. In the third group of 27 patients who received 10 ml/kg body weight of zoster immune plasma (ZIP), obtained from healthy adults convalescing from herpes zoster, there were only 8 cases of varicella, all very mild. Thus, prophylaxis with ZIP significantly reduced the incidence of clinical varicella (p less than 0.01) and attenuated the severity of its course.

Acute monocytic leukemia in children and its response to vinblastine (NSC-49842).

Seventeen children with acute monocytic leukemia were treated with (a) vinblatine (with or without prednisone), 0.2 mg/kg of body weight twice a week (13 patients); (b) 6-mercaptopurine plus prednisone patient). Four patients died within the 1st week, before having an adequate chemotherapeutic trial, and a fifth patient died of spesis at 12 days. Five patients achieved complete remissions and two achieved in this study was 41%. For the 13 patients who survived more than 1 week, the remission rate was 53.8%. Remission occurred with vinblastine inall but one patient. Of the ten patients who recieved more than one dose of vinblastine, 60% achieved a remission, indicating that vinblastine is an active agent in this rare form of leukemia.

Adverse effects of intrathecal methotrexate in children with acute leukemia in remission.

A toxic syndrome characterized by fever, headache, and vomiting, lasting 2-5 days, occurred in 61% of 39 children with acute leukemia in complete remission, receiving central nervous system prophylaxis with intrathecal methotrexate, and in 14% of 34 children receiving the same plus cranial radiation. The syndrome was accompanied by pleocytosis with lymphocytes, monocytoid cells, and neutrophils. There was evidence of cumulative Mtx toxicity, since the toxic syndrome occurred mostly after the third and fourth dose and did not recur with longer intervals between doses. The incidence of the syndrome was significantly reduced by the use of Elliott's B solution as Mtx diluent, rather than water or normal saline. The occurrence of pleocytosis and toxic clinical syndrome was also significantly reduced in patients receiving concomitant cranial radiation, probably due to the lympholytic action of radiotherapy and the depressed cellular response of irradiated tissues. The use of Elliott's B solution as diluent for IT Mtx and an appropriate interval between Mtx doses are suggested for prevention of this toxic syndrome.