An eHealth decision-support tool to prioritize referral practices for genetic evaluation of patients with Wilms tumor.

Nephron Sparing Surgery for Unilateral Wilms Tumor in Children with Predisposing Syndromes: Single Center Experience Over 10 Years

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.

Neuroblastoma is the most common pediatric extracranial solid tumor. Germline pathogenic variants in ALK and PHOX2B, as well as other cancer predisposition genes, are increasingly implicated in the pathogenesis of neuroblastic tumors. A challenge for clinicians is the identification of children with neuroblastoma who require genetics evaluation for underlying cancer predisposition syndromes (CPS). We developed a decisional algorithm (MIPOGG) to identify which patients with neuroblastic tumors have an increased likelihood of an underlying CPS. This algorithm, comprising 11 Yes/No questions, evaluates features in the tumor, personal and family history that are suggestive of an underlying CPS. We assessed the algorithm's performance in a retrospective cohort. Two hundred and nine of 278 consecutive patients with neuroblastic tumors at The Hospital for Sick Children (2007-2016) had sufficient clinical data for retrospective application of the decisional algorithm. Fifty-one of 209 patients had been referred to genetics for CPS evaluation; 6/51 had a genetic or clinical confirmation of a CPS. The algorithm correctly identified all six children (Beckwith-Wiedemann (n=2), Fanconi anemia, RB1, PHOX2B, chromosome duplication involving ALK) as requiring a genetic evaluation by using clinical features present at diagnosis. The level of agreement between the algorithm and physicians was 83.9%, with 15 more patients identified by the algorithm than by physicians as requiring a genetics referral. This decisional algorithm appropriately detected all patients who, following genetic evaluation, were confirmed to have a CPS and may improve the detection of CPS in patients with neuroblastic tumors compared with current practice.

BACKGROUNDIt is expected that 10-15% of children with CNS tumors have an underlying cancer predisposition syndrome (CPS). This has important implications on treatment, cancer screening and family counseling. There is no published data on this genetic risk from Jordan. METHODSWe retrospectively reviewed the medical charts of the Jordanian children <18 years old at the time of diagnosis with CNS tumors, and were treated at King Hussein Cancer Center/Jordan between January 2021 and December 2023. We reviewed their clinical characteristics and tumor diagnoses, then applied the updated Jongmans’ criteria and MIPOGG criteria and linked that with their germline genetic testing result if performed. RESULTSWe identified 198 children (53% males); median age at diagnosis was 7years (range, 0-18 years). Consanguinity was found in 30% of families, and 35% had first/second degree relatives with cancer. Most common diagnoses were LGG (41%), HGG (22%) and medulloblastoma (14%). Most tumors were non-metastatic (90%) at initial diagnosis. Fifty-five percent of patients fulfilled the updated Jongmans’ criteria and 36% the MIPOGG criteria, however germline genetic testing was only performed for 34 patients (17%). Pathogenic germline variants were found in 15 patients (44%); 6 LGG (NF1 (3), TSC2, PTPN11, MUTYH), 4 medulloblastoma (SDHB, TP53, BRCA2, CHEK2), 4 HGG (MSH6 (3), TP53), and one had pathogenic NF2 gene. The presence of CPS affected the management received: children with NF1 were treated without tumor biopsy, the child with TSC2 received everolimus, and 3 children with MSH6 received checkpoint inhibitors instead of temozolomide. The underlying CPS also predicted prognosis e.g. rapid clinical deterioration in the TP53-mutated-SHH-medulloblastoma. Partial screening was provided to children with NF1, TSC, NF2, TP53 and BMMRD mutations. CONCLUSIONSHigh proportion of our patients fulfilled the criteria for referral to genetic clinic, but less than half were referred. Increasing awareness of these criteria is important. Identification of CPS impacted treatment and prognosis, yet families’ perceptions and attitudes toward these CPS need to be captured.

BackgroundPresently, 8–10% of children and adolescents diagnosed with cancer have an underlying cancer predisposition syndrome, however the true figure may be higher. Family history alone identifies <4% of such patients...

Genetic cancer predisposition is an important cause of cancer across all age groups. Approximately ten percent of cancer patients have an underlying cancer predisposition syndrome (CPS) and we estimate that 500,000 individuals with a CPS live in Germany. Gene panel germline or tumour-germline genetic testing is increasingly employed in cancer patients resulting in rising numbers of CPS diagnoses. Such a diagnosis is only useful if affected individuals are appropriately counselled and if recommended clinical consequences in the areas of cancer prevention, surveillance, and therapy can be implemented. While care pathways for individuals with hereditary breast and ovarian cancer and familial colon cancer syndromes exist, sufficient interdisciplinary care structures for individuals with rare CPSs are currently lacking. The aim of this viewpoint is to point out that the clinical care pathways for individuals with rare CPSs need to be improved. We describe a model CPS clinic that systematically collects data to allow future evidence-based adaptation of care and propose the establishment of a collaborating network of similar clinics in Germany. This message is directed to individuals with a CPS, health care providers, insurance companies, and politicians in Germany and may be relevant for other health care systems as well.

We undertook a cost-benefit analysis of screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndrome (BWS), a known cancer predisposition syndrome. The purpose of this analysis was twofold: first, to assess whether screening in children with BWS has the potential to be cost-effective; second, if screening appears to be cost-effective, to determine which parameters would be most important to assess if a screening trial were initiated. We used data from the BWS registry at the National Cancer Institute, the National Wilms Tumor Study (NWTS), and large published series to model events for two hypothetical cohorts of 1,000 infants born with BWS. One hypothetical cohort was screened for cancer until a predetermined age, representing the base case. The other cohort was unscreened. For our base case, we assumed: (a) sonography examinations three times yearly (triannually) from birth until 7 years of age; (b) screening would result in one stage shift downward at diagnosis for Wilms tumor and hepatoblastoma; (c) 100% sensitivity and 95% specificity for detecting clinical stage I Wilms tumor and hepatoblastoma; (d) a 3% discount rate; (e) a false positive result cost of $402. We estimated mortality rates based on published Wilms tumor and hepatoblastoma stage specific survival. Using the base case, screening a child with BWS from birth until 4 years of age results in a cost per life year saved of $9,642 while continuing until 7 years of age results in a cost per life-year saved of $14,740. When variables such as cost of screening examination, discount rate, and effectiveness of screening were varied based on high and low estimates, the incremental cost per life-year saved for screening up until age four remained comparable to acceptable population based cancer screening ranges (< $50,000 per life year saved). Under our model's assumptions, abdominal sonography examinations in children with BWS represent a reasonable strategy for a cancer screening program. A cancer screening trial is warranted to determine if, when, and how often children with BWS should be screened and to determine cost-effectiveness in clinical practice.

Predisposition to cancer in children and adolescents

Simple SummaryIt is well known that different cancer predisposition syndromes are associated with characteristic WT-features. The following findings from our retrospective analysis of patients with nephroblastoma treated according to the SIOP/GPOH trials between 1989 and 2017 are relevant: (1) The outcome of patients with a cancer predisposition syndrome is not always favorable despite early diagnosis, small tumors and less metastatic disease. This finding is partly depending on complications related to the underlying syndrome. (2) Predisposition syndromes seem to be underdiagnosed as several clinical and pathological features of Wilms tumor being clearly linked to a cancer predisposition syndrome did not lead to genetic counseling before and after WT diagnosis. As a conclusion, in children with a nephroblastoma and specific clinical and pathological features that are in line with a nephroblastoma cancer predisposition syndrome such a syndrome should always be considered and ruled out if unknown at the time of tumor diagnosis.(1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, N = 66, 2.3%), Beckwith-Wiedemann spectrum (BWS, N = 32, 1.1%), isolated hemihypertrophy (IHH, N = 29, 1.0%), Denys-Drash syndrome (DDS, N = 24, 0.8%) and WAGR syndrome (N = 20, 0.7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2% vs. 18%), but more often nephroblastomatosis (12.9% vs. 1.9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4% increase) and favorable in BWS (86.9% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.

A new classification and terminology is proposed for precursor lesions of Wilms' tumor (WT), based upon morphology and natural history. The generic term nephrogenic rest (NR) is used for all WT precursors. Two major categories of NR are recognized: perilobar (PLNR) and intralobar (ILNR). Nephroblastomatosis signifies the presence of multiple or diffuse NRs. Nephroblastomatosis can be classified into four categories: (a) perilobar (PLNR only); (b) intralobar (ILNR only; (c) combined (PLNR and ILNR); and (d) universal. The individual rests can be subdivided into (a) nascent or dormant NRs; (b) maturing or sclerosing NRs; (c) hyperplastic NRs; and (d) neoplastic NRs. Of 282 evaluable unilateral WT specimens, 28.4% were definitely rest-positive, and an additional 12.4% were probably positive, with equal prevalence of PLNRs and ILNRs. Median age at diagnosis of WT was 36 months with PLNRs, 16 months with ILNRs, and 12 months if both types were present. PLNRs were strongly associated with synchronous bilateral WTs, and ILNRs with metachronous contralateral WTs. ILNRs were associated with aniridia and Drash syndrome, whereas PLNRs were more commonly found with hemihypertrophy and/or Beckwith-Wiedemann syndrome. The delineation of two distinct categories of WT precursors suggests pathogenetic heterogeneity for WTs. The biological and clinical implications of NRs are considered in the context of this classification.

A cervical rib (CR), also known as a supernumerary or extra rib, is an additional rib that forms above the first rib, resulting from the overgrowth of the transverse process of a cervical vertebra. Increasingly recognized as a potential marker of developmental disruptions and genetic instability, CRs are believed to arise from mutations in homeobox (Hox) genes that influence axial skeletal development. While often asymptomatic, CRs have been linked to thoracic outlet syndrome and a higher prevalence in individuals with certain childhood cancers. Studies have reported associations between CRs and malignancies such as neuroblastoma, brain tumors, leukemia, sarcomas, Wilms tumor, and germ cell tumors, suggesting possible shared embryological pathways or genetic predispositions. However, conflicting research findings highlight inconsistencies in these associations, underscoring the need for further investigation. This review aims to assess the association between CRs and childhood cancers by examining prevalence rates, exploring genetic and developmental links, evaluating inconsistencies in existing research, and identifying gaps for future study to clarify the clinical significance of CRs in cancer risk assessment. Introduction A Cervical rib (CR), also known as a "neck rib" or "supernumerary rib," is an extra rib that forms above the first rib, near the collarbone. It develops due to an overgrowth of the transverse process of a cervical spine vertebra. It is thought to result from mutations in homeobox (Hox) genes, which play a role in shaping the axial skeleton in humans and vertebrates. This rib can occur on either side and may be unattached (floating) or fused with the first rib. It can range from a fully formed bone to a delicate fibrous strand [1]. The CRs are present in about 2% of the general adult population. The prevalence is higher in women, who are about twice as likely to have CRs as men. Additionally, ethnic differences have been observed, with one study finding that CRs are more common in African Americans than in whites [2]. Typically, CR is discovered incidentally through radiographic imaging unless it causes symptoms [3]. In some cases, CR can contribute to thoracic outlet syndrome by narrowing the interscalene triangle, leading to pain, weakness, numbness, or cold sensitivity in the affected limb [1, 4, 5]. The first documented clinical signs of neurovascular compression associated with CRs were reported by Cooper in 1818 [6]. Studies have demonstrated a higher prevalence of CRs in individuals with childhood cancers. This association may stem from disruptions in embryonic development during critical stages of blastogenesis, which can simultaneously lead to cervical segmentation defects and increase cancer susceptibility [7, 8]. Moreover, CRs are often regarded as markers of adverse developmental events or genetic instability. Their higher prevalence in stillborn fetuses and individuals with chromosomal abnormalities further underscores their potential role as indicators of systemic vulnerabilities that may contribute to malignancy risk. These findings highlight the importance of understanding rib anomalies (RAs) as anatomical curiosities and potential markers for identifying individuals at increased risk for certain cancers [9]. This study aims to review the association between CRs and cancer, with all referenced articles assessed for eligibility [10]. Studies Linking Rib Anomalies to Childhood Cancers Despite growing awareness of a possible connection between RAs and malignancies, research on this topic remains limited. Only four studies have examined this association, each providing valuable insights into the potential link. The earliest study by Schumacher et al. (1995) investigated the relationship between RAs and childhood malignancies by reviewing chest X-rays of 1,000 children with cancer and 200 control patients with non-malignant conditions. They found a significantly higher prevalence of RAs, particularly CRs, in children with certain malignancies compared to controls. This suggested that these skeletal abnormalities might be linked to altered morphogenesis in tumor development [7]. A decade later, Merks et al. (2005) conducted a more extensive study analyzing chest radiographs of 906 children with cancer and 881 healthy Caucasian pediatric controls. Their findings confirmed previous reports, demonstrating a higher occurrence of specific RAs in children with certain malignancies. They emphasized the potential role of genetic predisposition in cancer development and suggested that skeletal anomalies could serve as markers for underlying genetic abnormalities [8]. Loder et al. (2007) expanded on these findings by focusing on rib number variations in 218 children with malignancies and 200 control children who had been admitted for polytrauma or suspected child abuse. Their study highlighted a significant difference in rib counts between children with cancer and healthy controls. They speculated that genes involved in vertebral and rib development might also play a role in cancer predisposition, suggesting the possibility of using skeletal anomalies as a screening tool for early cancer detection [11]. Finally, Zierhut et al. (2011) reinforced the association between RAs and childhood cancers through a hospital-based case-control study of 459 pediatric cancer patients and 1,135 controls who had undergone chest X-rays for non-cancer-related reasons. Their research confirmed that children with cancer were more likely to have RAs, particularly those diagnosed with specific malignancies. They underscored the need for further studies to determine the biological mechanisms linking RAs to cancer development [12]. Cancers Linked to Cervical Ribs Neuroblastoma Neuroblastoma is a highly aggressive tumor that develops from neural crest cells and is the most common cancer in infants under one year old worldwide [13]. It represents about 10% of all pediatric cancers and primarily affects children within their first five years of life [14]. A defining characteristic of neuroblastoma is its highly variable clinical behavior. In approximately 50% of affected infants, the tumor regresses spontaneously, whereas in others, it advances into an aggressive, metastatic disease that is often resistant to standard treatments like chemoradiotherapy, stem cell transplantation, and immunotherapy [15]. This unpredictability complicates treatment, especially for high-risk patients who experience chemo-resistant relapse, with survival rates remaining below 40% [14]. The initiation and progression of neuroblastoma are driven by genetic abnormalities that interfere with cell division, proliferation, and apoptosis [15]. Significant genetic factors include MYCN amplification, TP53 deletions, ALK mutations or amplifications, TERT rearrangements, ATRX deletions or mutations, and segmental chromosomal aberrations. However, whole-genome sequencing studies have identified only a limited number of recurrent somatic mutations, making the development of targeted therapies challenging. Consequently, a precise understanding of the biological complexity and diversity of neuroblastoma is crucial for improving diagnostic and treatment approaches [15]. Schumacher et al. (1992) identified a strong correlation between neuroblastoma and CRs, reporting that 33% of children with neuroblastoma had CRs, a markedly higher prevalence than in the general population. This notable disparity suggests a potential developmental or genetic connection between neuroblastoma and skeletal anomalies. Furthermore, neuroblastoma was the only malignancy in their study to exhibit a significantly increased incidence of rib bifurcation (4.5%), a rate nearly four times higher than expected, reinforcing the possibility of disrupted skeletal development linked to the disease [7]. In contrast, Merks et al. (2005) analyzed 61 neuroblastoma patients and found that 9.8% had CRs, compared to 6.1% in the control group. While this suggests a slightly increased prevalence, the difference was not statistically significant (p = 0.252). This discrepancy with Schumacher et al. (1992) may be due to differences in sample size, diagnostic criteria, or population characteristics [7, 8]. Loder et al. (2007) took a broader approach by grouping neuroblastoma with other neural malignancies. Their findings showed a higher incidence of RAs (35%) in children with neural tumors compared to those with other malignancies. However, they did not specifically find an association between neuroblastoma and CRs. Among the eight neuroblastoma patients in their study, RAs were present, but no cases of CRs were observed. Instead, the most common skeletal abnormality was a reduced rib count, with affected children having 22 or 23 ribs instead of the typical 24. This suggests that while RAs may be linked to neuroblastoma, the specific presence of CRs may not be a defining characteristic [11]. Similarly, Zierhut et al. (2011) analyzed 31 neuroblastoma cases and found that 6.4% had RAs. However, the study did not report how many of these cases involved CRs specifically. The statistical analysis yielded an odds ratio (OR) of 1.46 (95% CI: 0.34–6.30) for any rib anomaly in neuroblastoma patients, indicating a slightly higher occurrence of skeletal abnormalities but without statistical significance. The lack of a significant association between RAs and neuroblastoma may be due to the study’s small sample size, which could have limited its ability to detect a stronger relationship [12]. Overall, while Schumacher et al. (1992) identified a strong association between neuroblastoma and CRs, subsequent studies, including those by Merks et al. (2005), Loder et al. (2007), and Zierhut et al. (2011), reported weaker or non-significant links [7, 8, 11, 12]. The inconsistencies across studies highlight the need for further research with larger sample sizes and more detailed skeletal analyses to determine whether CRs represent a meaningful developmental marker for neuroblastoma or if their observed association is due to broader skeletal anomalies. Brain Tumors A brain tumor forms when cells grow irregularly and multiply uncontrollably. These tumors may arise from brain cells, the meninges (the membranes surrounding the brain), glands, or nerves. They can cause direct damage to brain cells and elevate pressure within the skull, resulting in harmful effects [16]. Due to their severity, brain tumors are classified into different grades. Grade 1 tumors are the least aggressive, typically associated with more prolonged survival. They grow slowly, resemble normal cells under a microscope, and can often be effectively treated with surgical removal. Examples include pilocytic astrocytoma, ganglioglioma, and gangliocytoma. Grade 2 tumors also grow slowly but appear abnormal under a microscope. Some may invade nearby tissues and tend to recur, occasionally progressing to a higher grade [16]. Grade 3 tumors are malignant and share similarities with grade 2 tumors but are more likely to recur as grade 4 tumors. Grade 4 tumors are the most aggressive, growing rapidly and appearing highly abnormal under a microscope. They invade surrounding brain tissue, form new blood vessels, and contain areas of dead cells at their core. Glioblastoma Multiforme is a well-known example of a grade 4 tumor [16]. Brain tumors develop due to a combination of genetic, environmental, and molecular factors. Genetic predisposition plays a key role, with inherited syndromes such as neurofibromatosis and Li-Fraumeni syndrome increasing the risk. Environmental exposures, particularly ionizing radiation, are well-established contributors, while occupational exposure to chemicals and electromagnetic fields remains inconclusive. Viral infections, immune dysfunction, and chronic inflammation may also influence tumor development [17, 18]. The study by Schumacher et al. (1992) found that 27.4% of children with brain tumors had CRs, compared to only 5.5% in the control group (p &lt; 0.001). This substantial difference suggests a potential developmental link between CRs and brain tumors, possibly due to shared embryological pathways affecting both skeletal and neural development. The high prevalence reported in this study indicates that CRs might serve as an anatomical marker for underlying genetic or developmental disruptions associated with brain tumor formation [7]. Merks et al. (2005) further supported this hypothesis by identifying a significant association between CR anomalies and astrocytomas. Their study reported that 18.2% of childhood cancer patients with astrocytomas had CRs, compared to 6.1% in the control group. This finding suggests that certain subtypes of brain tumors, particularly astrocytomas, may have a stronger developmental association with CR anomalies [8]. However, Loder et al. (2007) did not find a strong link between brain tumors and CRs. While RAs were more frequent in children with neural malignancies (35%), none of these anomalies were identified as CRs. Instead, children with neural malignancies were found to be 6.23 times more likely to have an abnormal rib count compared to the control group. This suggests that while skeletal anomalies may be associated with neural tumors in general, CRs specifically may not be a consistent marker [11]. Zierhut et al. (2011) also provided a more tempered perspective. Their study examined 34 pediatric cases of central nervous system tumors, including brain tumors, and found that 8.8% (n = 3) had some form of rib anomaly. However, they did not identify a statistically significant association between CRs and brain tumors. This finding further weakens the case for a direct link and suggests that broader skeletal anomalies may be involved rather than CRs specifically [12]. Overall, while Schumacher et al. (1992) and Merks et al. (2005) suggest a possible association between CRs and brain tumors, the findings from Loder et al. (2007) and Zierhut et al. (2011) cast doubt on the specificity of this relationship [7, 8, 11, 12]. The inconsistencies across studies highlight the need for further research to determine whether CRs are a true marker for brain tumor risk or if their association is due to broader developmental abnormalities affecting multiple organ systems. Leukemia Leukemia is a frequently occurring cancer in both children and adults. It results from disruptions in normal cell regulation that lead to the uncontrolled growth of hematopoietic stem cells in the bone marrow. It is more commonly found in males and individuals of white ethnicity, with its prevalence increasing with age. On average, about one in 70 people will develop leukemia during their lifetime. The four main types of leukemia, each with unique characteristics, are acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia, and chronic myelogenous leukemia [19]. Leukemia occurs worldwide, with a higher prevalence and overall mortality in more developed countries. However, the mortality rate tends to be greater in developing nations [20]. The development of leukemia results from a complex interaction between genetic predisposition and environmental influences, with neither factor alone provides a complete explanation. While significant strides have been made in identifying risk factors and potential disease mechanisms, the exact causes of most leukemia cases remain uncertain. Known risk factors include genetic syndromes, chromosomal abnormalities, radiation exposure, specific chemicals, certain viral infections, and prior cancer treatments, but these account for only a fraction of cases [20, 21]. The study by Schumacher et al. (1992) found a significant association between CRs and leukemia, with 26.8% (n = 227) of leukemia patients exhibiting CRs compared to only 5.5% (n = 11) in the control group (p &lt; 0.001). This finding suggests a potential developmental or genetic link between skeletal anomalies and leukemia, possibly due to disruptions in early embryonic development affecting both hematopoietic and skeletal systems [7]. Similarly, Merks et al. (2005) identified a significant association between CR anomalies and ALL, with a prevalence of 12.1% in ALL patients compared to 6.1% in controls (p = 0.011). This reinforces the idea that skeletal anomalies may serve as a marker for certain pediatric malignancies, though the underlying mechanisms remain unclear [8]. Loder et al. (2007) further examined RAs in leukemia patients. Among 218 children with malignancies, 75 had leukemia (64 with ALL and 11 with AML) [11]. The incidence of abnormal rib counts in children with lymphoproliferative malignancies (which includes leukemia and lymphoma) was 15%, compared to 8% in the control group. Logistic regression analysis revealed that children with leukemia and other lymphoproliferative malignancies were twice as likely to have an abnormal rib count compared to controls. While this supports a broader association between RAs and leukemia, the study did not specifically focus on CRs, making direct comparisons with Schumacher et al. (1992) and Merks et al. (2005) more challenging [7, 8]. In contrast, Zierhut et al. (2011) provided a more nuanced perspective. While their study confirmed an overall link between RAs and an increased risk of childhood cancers, the specific association between CRs and leukemia did not reach statistical significance. Notably, children with AML had a significantly higher likelihood of RAs, with an adjusted OR of 2.29 (95% CI: 1.02–5.13). However, when CRs were analyzed separately, the association weakened (adjusted OR = 1.63, 95% CI: 0.55–4.80), failing to reach statistical significance. This suggests that while RAs in general may be linked to leukemia, CRs alone may not be a consistent marker for the disease [12]. Overall, the studies by Schumacher et al. (1992) and Merks et al. (2005) suggest a potential association between CRs and leukemia [7, 8, 11]. However, Zierhut et al. (2011) cast doubt on the specificity of this relationship, indicating that while RAs may be more common in leukemia patients, CRs alone may not be a reliable marker [12]. Further research is needed to clarify whether CRs are a developmental indicator of leukemia risk or if their observed association is due to broader skeletal anomalies linked to pediatric malignancies. Sarcomas Sarcomas comprise a diverse group of mesenchymal tumors, with over 100 distinct diagnostic types. This variability is evident through both light microscopy and gene expression analysis. Even within the same histological category, there can be substantial differences in biological behavior [22]. Sarcomas are generally classified into two main types: soft tissue sarcomas and primary bone sarcomas, each requiring unique staging and treatment strategies. Soft tissue sarcomas are typically categorized based on genetic alterations and microscopic examination of hematoxylin-eosin–stained tissue, where morphological features resembling normal tissues are identified. Additionally, sarcomas are further assessed by histologic grade. The three key prognostic factors are the tumor’s grade, size, and primary location [22]. Sarcomas usually arise spontaneously, but certain risk factors have been identified. Exposure to ionizing radiation, often from cancer treatments, increases the likelihood of sarcomas, typically appearing 7-10 years after exposure. Other risk factors include chronic lymphedema, exposure to chemicals like vinyl chloride, and infection with human herpesvirus 8, which is linked to Kaposi sarcoma [22]. Several genetic syndromes also elevate sarcoma risk. Neurofibromatosis type 1 leads to benign and malignant nerve sheath tumors, while neurofibromatosis type 2 is associated with meningiomas and cranial nerve schwannomas. Gardner syndrome increases the risk of desmoid tumors, and hereditary retinoblastoma raises the likelihood of osteosarcoma and soft tissue sarcomas later in life. Li-Fraumeni syndrome, caused by TP53 mutations, also predisposes individuals to sarcomas [22]. Schumacher et al. (1992) found a significant association between CRs and sarcomas, reporting their presence in 24.5% of patients with soft tissue sarcomas (p &lt; 0.001) and 17.1% of those with Ewing sarcoma (p &lt; 0.01), compared to only 5.5% in the control group. These findings suggest a potential developmental or genetic link between CR anomalies and sarcomas, possibly due to early mesodermal development disruptions, which influences skeletal and soft tissue formation [7]. However, later studies did not consistently replicate these findings. Merks et al. (2005) found much lower rates of CRs in sarcoma patients, with 7.4% of rhabdomyosarcoma cases (5/68, p = 0.687), 6.3% of osteosarcoma cases (3/48, p = 0.973), and 7.7% of Ewing sarcoma cases (3/39, p = 0.692). None of these differences were statistically significant, suggesting that the initial association reported by Schumacher et al. (1992) may have been due to sample variation or other confounding factors. The stark contrast between these two studies raises questions about whether the observed link is truly biologically relevant or if it was an artifact of study design or population differences [8]. Loder et al. (2007) examined RAs in solid tumors, including osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma, finding that 13% of cases exhibited RAs. However, this association was not statistically significant (p = 0.15), suggesting that while RAs may be more common in children with cancer, they do not appear to be strongly associated with sarcomas specifically [11]. Similarly, Zierhut et al. (2011) identified a general link between RAs and childhood cancers but did not find a significant correlation between CRs and sarcomas. This further weakens the hypothesis that CRs are a marker for sarcoma risk [12]. Overall, while the Schumacher et al. (1992) study initially suggested a strong association between CRs and sarcomas, more recent studies, including those by Merks et al. (2005), Loder et al. (2007), and Zierhut et al. (2011), have not confirmed this relationship [7, 8, 11, 12]. The inconsistencies in findings suggest that if a link does exist, it may be weaker than initially thought or influenced by confounding factors. Further research with larger sample sizes and refined methodologies is needed to clarify whether CRs have any true predictive value for sarcoma development. Wilms tumor Wilms tumor (WT), or nephroblastoma, is a malignant solid tumor that arises from the primitive renal bud. It is the most common primary renal tumor in the urogenital tract of children and typically occurs unilaterally in 90–95% of cases. However, it can also present bilaterally or multicentrically, particularly in cases associated with genetic factors, occurring either simultaneously (synchronously) or at different times (metachronously). WT accounts for approximately 2% to 6% of all childhood cancers [23]. Both genetic and environmental factors influence the development of WT. Genetic mutations play a crucial role, particularly in the WT1 and WT2 genes, which are vital for kidney development [23]. WT1 mutations are linked to syndromic forms of WT, such as WAGR and Denys-Drash syndromes, while WT2 abnormalities are associated with Beckwith-Wiedemann syndrome. Additionally, mutations in CTNNB1 (β-catenin), TP53, and microRNAs contribute to tumor development. Environmental factors, including parental exposure to pesticides before conception or during pregnancy, may increase the risk, though their precise impact remains unclear. WT is frequently associated with congenital syndromes involving developmental abnormalities [23]. Schumacher et al. (1992) identified a significant association between CRs and WT, reporting that 23.5% of children with WT had CRs, compared to only 5.5% in the control group (p &lt; 0.001). This strong statistical significance suggests a potential developmental link between skeletal anomalies and WT [7]. However, Merks et al. (2005) found that 9.8% of children with WT had CRs, compared to 6.1% in the control group, but the difference was not statistically significant (p = 0.115). This suggests that while CRs may be more common in WT patients, the association is not robust enough to be considered a reliable marker [8]. Similarly, Zierhut et al. (2011) reported a statistically significant increase in overall RAs among children with renal tumors, including WT. However, when analyzing CRs specifically, they did not find a significant association, further casting doubt on their role as a consistent indicator of WT [12]. Loder et al. (2007) provided additional support for a general link between RAs and pediatric malignancies but did not specifically analyze CRs in WT patients. This broader pattern suggests that skeletal anomalies may be associated with childhood cancers but does not confirm a direct link between CRs and WT [11]. These findings indicate that while there is some evidence of a relationship between skeletal anomalies and WT, the inconsistent association with CRs suggests that other factors may be at play. Additional research is needed to explore the genetic and developmental mechanisms underlying these observations, which could provide further insights into the etiology of WT and its potential links to congenital anomalies. Germ Cell Tumors Germ cell tumors (GCTs) are the most diverse childhood neoplasms. The majority are benign teratomas, presenting as heterogeneous masses with cystic and solid components. However, approximately 20% of GCTs are malignant, accounting for 3% of pediatric cancers. Malignant GCTs can occur at any age but follow a bimodal distribution, primarily affecting infants and adolescents [24]. These tumors can develop in various anatomical locations, including the gonads, sacrococcygeal region, mediastinum, retroperitoneum, and other para-axial sites. They are believed to originate from a common progenitor germ cell but exhibit diverse histologies, such as endodermal sinus tumor (yolk sac tumor), germinoma (dysgerminoma or seminoma), embryonal carcinoma, and choriocarcinoma. Different histological types often coexist within a single tumor, with approximately 25% of pediatric GCTs containing multiple histologic components [24]. Malignant GCTs have specific genetic predispositions, and genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) in genes such as KITLG, SPRY4, DMRT1, and TERT, which are linked to the development of testicular GCTs [25]. Schumacher et al. (1992) investigated the relationship between CR anomalies and yolk sac tumors, a type of GCT, but did not find a significant association. The prevalence of RAs in patients with yolk sac tumors was 3.4%, which was not significantly different from the normal population (5.5%). This finding suggests that, unlike other pediatric malignancies, GCTs may not share a strong developmental link with skeletal anomalies [7]. In contrast, Merks et al. (2005) reported a statistically significant association between CR anomalies and GCTs, with 14.7% of GCT patients exhibiting CRs compared to 6.1% in controls (p = 0.046). This suggests a potential genetic or developmental link between GCTs and skeletal anomalies, though the mechanisms underlying this association remain unclear. The higher prevalence observed in this study raises the possibility that certain genetic mutations or disruptions in embryonic development may predispose individuals to both conditions [8]. Loder et al. (2007) did not specifically analyze CRs in relation to GCT. However, their study demonstrated a broader statistically significant association between RAs and childhood malignancies. Children with cancer had a higher prevalence of RAs (18%) compared to the control group (8%), with a p-value of 0.003. While this finding supports a general link between skeletal anomalies and pediatric cancers, it does not establish a direct connection between CRs and GCTs [11]. Similarly, Zierhut et al. (2011) did not specifically report a link between CR and GCTs. The absence of a reported association with GCTs suggests that these tumors may not be as strongly linked to skeletal anomalies as other childhood malignancies [12]. Overall, while some studies indicate a potential link between CR anomalies and GCTs, the evidence remains inconsistent. Merks et al. (2005) provided the most substantial support for an association, but findings from Schumacher et al. (1992) and Zierhut et al. (2011) did not confirm this relationship [7, 8, 12]. Additional research is needed to determine whether CR anomalies can serve as a marker for GCTs or if the observed association is due to other underlying developmental factors. Other Rib Anomalies Associated with Cancer Numerical RAs, such as having fewer than 24 ribs, were also found to be more common in children with malignancies. Loder et al. (2007) reported that 18% of children with malignancies had an abnormal rib number compared to 8% of controls. Among specific cancer types, neural tumors had the highest incidence of abnormal rib counts (35%), followed by lymphoproliferative malignancies (15%) and solid tumors (13%) [11]. Similarly, Zierhut et al. (2011) found that children with AML, renal tumors, and hepatoblastoma had a significantly higher likelihood of having an abnormal rib count (p = 0.008) [12]. Rib bifurcations, which involve rib splitting into two separate structures, have also been linked to certain malignancies. Schumacher et al. (1992) reported that 4.5% of neuroblastoma patients exhibited rib bifurcations, a rate four times higher than that of the normal population (1.07%). This suggests that developmental abnormalities affecting rib segmentation may be related to tumorigenesis in neural crest-derived cancers such as neuroblastoma [7]. Rib synostosis, or rib fusion, has also been observed in childhood malignancies. Though relatively rare, this anomaly was documented in some studies. Schumacher et al. (1992) found that 0.5% of cancer patients had rib synostosis compared to none in the control group, while Merks et al. (2005) identified synostosis in 0.2% of cancer patients. Notably, leukemia and brain tumor patients were more likely to present with this anomaly [7, 8]. Additionally, rib hypoplasia (underdeveloped ribs) and aplasia (missing ribs) have been reported in association with various malignancies. Loder et al. (2007) found that children with malignancies were more likely to have fewer ribs, with 44 cases of 22 ribs and 10 cases of 23 ribs, compared to just 16 cases in the control group (p = 0.003) [11]. Schumacher et al. (1992) also reported that 1.2% of cancer patients had rib aplasia or hypoplasia, compared to 0.5% in controls (Table 1) [7]. Table 1. Association Between Rib Anomalies and Childhood Malignancies. Study Year Sample Size Key Findings Cancer Types Types of Rib Anomalies Conclusion Schumacher et al. [7] 1992 1000 cancer, 200 controls Rib anomalies more common in cancer patients (21.8% vs. 5.5% in controls). Neuroblastoma had the highest rate (33%). Neuroblastoma, Brain tumors, Leukemia, Soft tissue sarcoma, Wilms' tumor, Ewing sarcoma CRs, Bifurcations, Synostoses, Aplasia/Hypoplasia Rib anomalies may be linked to tumor development. Further research needed. Merks et al. [8] 2005 906 cancer, 881 controls CRs were more common in cancer patients (8.6% vs. 6.1% in controls), particularly in leukemia and astrocytoma. ALL, Astrocytoma, Germ Cell Tumors CRs, Bifid ribs, Rib synostosis Rib anomalies could indicate genetic mutations linked to cancer. Loder et al. [11] 2007 218 cancer, 200 controls Rib anomalies were more frequent in cancer patients (18% vs. 8%). Neural tumors had the highest incidence (35%). Neural tumors, Lymphoproliferative malignancies, Solid tumors Fewer than 24 ribs, Rib fusions, Bifurcations Possible link between rib anomalies and homeobox gene mutations. Zierhut et al. [12] 2011 625 cancer, 1499 controls Significant association found between rib anomalies and leukemia, renal tumors, and hepatoblastoma. AML, Renal tumors, Hepatoblastoma Fewer or more than 24 ribs, CRs, Bifurcations Rib anomalies could be a marker for cancer predisposition. More research needed. ALL: Acute Lymphoblastic Leukemia, AML: Acute Myelogenous Leukemia, CR: Cervical rib Future Perspectives Future research should focus on large-scale, multicenter studies to validate these findings and establish whether RAs, particularly numerical variations, bifurcations, synostoses, and hypoplasia, can be predictive markers for specific cancers. Advances in imaging technologies, such as high-resolution computed tomography and magnetic resonance imaging, may enhance the accuracy of rib anomaly detection and contribute to more precise correlations with cancer risk. Genetic and molecular studies are also needed to explore the role of Hox genes and other developmental pathways in skeletal formation and oncogenesis. Identifying genetic mutations contributing to RAs and tumor development could lead to novel insights into cancer predisposition syndromes. Additionally, investigating the role of environmental and epigenetic factors in the occurrence of RAs and malignancies may provide a more comprehensive understanding of their shared etiology. From a clinical perspective, integrating rib anomaly screening into routine pediatric check-ups for high-risk populations could help in early cancer detection. However, before implementing such screening, further studies must determine the predictive value of RAs and whether they can be used as independent risk markers. Ultimately, interdisciplinary collaboration between geneticists, radiologists, oncologists, and developmental biologists will be crucial in advancing understanding of the link between RAs and childhood cancer. As research continues, these efforts may pave the way for novel diagnostic strategies and targeted therapies for pediatric malignancies. Conclusion CRs may serve as valuable indicators of underlying genetic and developmental abnormalities linked to pediatric cancers. Understanding these connections could ultimately contribute to improved cancer screening, early diagnosis, and personalized treatment strategies for children at risk. Declarations Conflicts of interest: The authors have no conflicts of interest to disclose. Ethical approval: Not applicable. Patient consent (participation and publication): Not applicable. Funding: The present study received no financial support. Acknowledgements: None to be declared. Authors' contributions: FHK and BAA were significant contributors to the conception of the study and the literature search for related studies. HAN and MNH involved in the literature review, study design, and manuscript writing. SKA, AKG, WNS, HSN, LJM, ASH, OMH, SOA, AHA, LAS and ADS were involved in the literature review, data collection, the study's design, and the critical revision of the manuscript. FHK and BAA confirm the authenticity of all the raw data. All authors approved the final version of the manuscript. Use of AI: Perplexity (Deep Research) and ChatGPT (GPT-4.5) were used to assist in language editing and improving the clarity of the manuscript. All content was reviewed and verified by the authors. Authors are fully responsible for the entire content of their manuscript. Data availability statement: Not applicable.

BackgroundGermline genome sequencing in childhood cancer precision medicine trials may reveal pathogenic or likely pathogenic variants in cancer predisposition genes in more than 10% of children. These findings can have implications for diagnosis, treatment, and the child’s and family’s future cancer risk. Understanding parents’ perspectives of germline genome sequencing is critical to successful clinical implementation.MethodsA total of 182 parents of 144 children (<18 years of age) with poor‐prognosis cancers enrolled in the Precision Medicine for Children with Cancer trial completed a questionnaire at enrollment and after the return of their child’s results, including clinically relevant germline findings (received by 13% of parents). Parents’ expectations of germline genome sequencing, return of results preferences, and recall of results received were assessed. Forty‐five parents (of 43 children) were interviewed in depth.ResultsAt trial enrollment, most parents (63%) believed it was at least “somewhat likely” that their child would receive a clinically relevant germline finding. Almost all expressed a preference to receive a broad range of germline genomic findings, including variants of uncertain significance (88%). Some (29%) inaccurately recalled receiving a clinically relevant germline finding. Qualitatively, parents expressed confusion and uncertainty after the return of their child’s genome sequencing results by their child’s clinician.ConclusionsMany parents of children with poor‐prognosis childhood cancer enrolled in a precision medicine trial expect their child may have an underlying cancer predisposition syndrome. They wish to receive a wide scope of information from germline genome sequencing but may feel confused by the reporting of trial results.

Nephrogenic Rests in Wilms Tumor Patients with the Drash Syndrome

At least 5%-10% of malignancies occur secondary to an underlying cancer predisposition syndrome (CPS). For these families, cancer surveillance is recommended with the goal of identifying malignancy earlier, in a presumably more curable form. Surveillance protocols, including imaging studies, bloodwork, and procedures, can be complex and differ based on age, gender, and syndrome, which adversely affect adherence. Mobile health (mHealth) applications (apps) have been utilized in oncology and could help to facilitate adherence to cancer surveillance protocols. Applying a user-centered mobile app design approach, patients with a CPS and/or primary caregivers were interviewed to identify current methods for care management and barriers to compliance with recommended surveillance protocols. Broad themes from these interviews informed the design of the mobile app, HomeTown, which was subsequently evaluated by usability experts. The design was then converted into software code in phases, evaluated by patients and caregivers in an iterative fashion. User population growth and app usage data were assessed. Common themes identified included general distress surrounding surveillance protocol scheduling and results, difficulty remembering medical history, assembling a care team, and seeking resources for self-education. These themes were translated into specific functional app features, including push reminders, syndrome-specific surveillance recommendations, ability to annotate visits and results, storage of medical histories, and links to reliable educational resources. Families with CPS demonstrate a desire for mHealth tools to facilitate adherence to cancer surveillance protocols, reduce related distress, relay medical information, and provide educational resources. HomeTown may be a useful tool for engaging this patient population.

Follow-up for a Preterm Infant with Beckwith-Wiedemann Syndrome.