Wilms tumor is the most common embryonal malignancy of the kidney and is not infrequently associated with congenital anomalies. Approximately 10–15% of Wilms tumors are attributed to genetic predisposition syndromes, such as the WAGR and Denys-Drasch syndromes associated with WT1
Increased risk of Wilms tumor also occurs in the Beckwith-Wiedemann syndrome, uncommon familial syndromes associated with FWT1
mutations, and various other constitutional and tumor-associated genetic alterations that have been described in detail elsewhere.10–12
In addition, patients with vertebral anomalies, including spina bifida, may have an increased risk of Wilms tumor.13,14
Nephrogenic rests (persistent metanephric remnants occurring in fully developed kidneys) are classified as nephroblastomatosis when multifocal or diffuse. These embryonal remnants may be intralobar or perilobar in location and are considered pluripotential; they may senesce entirely or undergo neoplastic evolution.15
Perilobar rests, as seen in this patient, are strongly associated with evolution to bilateral Wilms tumors.15
To our knowledge, an association between nephroblastomatosis and polycystic kidney disease has not been reported.
Due to the observed association of DSD with nephroblastomatosis, this patient was appropriately monitored from birth with serial renal ultrasounds. He underwent biopsy of multiple lesions in both kidneys when new abnormalities were first detected via imaging. Histopathologic examination at that time revealed perilobar hyperplastic nephroblastomatosis and no evidence of Wilms tumor. He was initially evaluated at another cancer center, but no therapy was recommended due to his DSD and significant medical co-morbidities. Due to concern for potential worsening of the patient’s respiratory status should the nephrogenic rests grow further or undergo neoplastic transformation, we elected cautiously to treat his hyperplastic nephroblastomatosis with vincristine and dactinomycin, as has been recommended by Beckwith and other experts.16,17
Unfortunately, his nephroblastomatosis indeed evolved into Wilms tumor, which spontaneously ruptured and likely seeded the retroperitoneal space. Despite whole abdomen radiation therapy, radical nephrectomy, and adjuvant chemotherapy, he developed recurrent Wilms tumor with diffuse anaplasia that ultimately proved recalcitrant to multi-modal therapy. No autopsy was performed, so it is unknown whether or not his right-sided nephroblastomatosis also evolved into Wilms tumor or if he developed occult distant metastasis.
Point mutations in BMPER
resulting in premature stop codons have been recently reported in tissues from four patients with DSD.5
To our knowledge, germline or tumor specimens from this patient have not been submitted for BMPER
mutation research testing. A BMPER
knock-out mouse model has been reported to demonstrate a similar phenotype to that of DSD patients with craniofacial and vertebral ossification anomalies, renal abnormalities, and perinatal mortality due to thoracic insufficiency, which highlights the likely causal nature of BMPER
mutations in the DSD syndrome.5
he link between BMPER
mutations in DSD and the molecular pathogenesis of Wilms tumor remains unclear, however. Signaling pathways involving the bone morphogenetic protein (BMP; a member of the transforming growth factor-beta superfamily) have been linked to the regulation of cellular proliferation, mesenchymal differentiation, and skeletal morphogenesis.5
Earlier studies have suggested a role for BMP signaling in Wilms tumor and other renal cancers via phosphorylation of receptor-regulated SMAD proteins and via mitogen-activated protein kinase (MAPK) pathway signal transduction.18–20
SMAD complexes accumulate in cellular cytoplasm, then translocate to the nucleus to act as transcription factors for the regulation of target gene expression.20
The current case and genetic data from other DSD patients suggest that additional characterization of BMP signaling pathways and BMPER
mutations may provide insight into the pathogenesis of DSD itself, as well as into DSD-associated nephroblastomatosis and Wilms tumor.
This child is the only known patient with DSD-associated Wilms tumor. The natural course of DSD-associated nephroblastomatosis and Wilms tumor pathogenesis remains unknown due to the limited life expectancy of patients with DSD. The largest case series of 16 DSD patients (reported when this patient was nine months old) notes 8 of 11 evaluated patients with radiographic or pathologic evidence of intralobar or perilobar nephroblastomatosis.4
This patient, who survived the perinatal period due to multiple pulmonary interventions, lived long enough for his perilobar nephroblastomatosis, perhaps not surprisingly, to evolve into anaplastic Wilms tumor that proved refractory to all anti-cancer therapy utilized. Nonetheless, we were able to treat this extremely medically fragile patient with multi-modality therapy for over three years from the time of his initial nephroblastomatosis diagnosis, and he had an excellent quality of life, even while receiving palliative care. Children with DSD who survive the perinatal period should thus be serially monitored for nephroblastomatosis, as near-universal evolution of perilobar nephroblastomatosis into Wilms tumor has been reported.15,16
DSD appears to be a Wilms tumor predisposition syndrome.