Bilateral Wilms' tumors in an infant with Denys-Drash syndrome and rarely seen truncation mutation in the WT1 gene-exon 6.

Sir,

Denys-Drash syndrome (DDS) is a rare disease consisting of the triad of Wilms’ tumor, ambiguous genitalia and nephropathy. We present a rare type of mutation of WT1 gene in an infant with DDS.

An 8-month-old male child was brought to us for swelling of the abdomen and failure to thrive associated with decreased activity since 1-month. On examination, the child was dehydrated with bilateral palpable renal lumps; bilateral cryptorchidism and penoscrotal hypospadias [Figure 1a and b]. His routine blood investigations were normal except hemoglobin 8.3 g/dl and 1+ proteinuria in urinalysis. Ultrasound and computed tomography abdomen revealed bilateral well defined, heterogeneously enhancing mass lesions; 10.7 cm × 8.5 cm × 7.2 cm arising from the right kidney and 10 cm × 8 cm × 6.3 cm from the left kidney [Figure 1c]. Ultrasound guided percutaneous tru-cut biopsy was taken from both renal masses and normal renal parenchyma.

Figure 1

(a-c) Bilateral renal lumps in an 8-month-old malnourished infant with penoscrotal type of hypospadias with empty scrotum. Image of computed tomography scan shows bilateral well defined, heterogeneously enhancing masses from both kidneys

The histopathological examination from both renal masses was showing triphasic pattern of classic Wilms’ tumor with predominant blastema component. The biopsy from normal renal parenchyma showed mesangial matrix expansion with thickening of glomerular basement membrane suggestive of early nephropathy changes. His karyotype study revealed a normal 46, XY male genotype while genetic study revealed a nonsense mutation in the WT1 gene-exon 6, leading to stop codon and results in truncated proteins. The child was started on combination chemotherapy but, unfortunately, he succumbed due to sepsis with pneumonia after 14 weeks of detection of the tumor.

After Drash et al., in 1970, about 200 cases of DDS have been reported.[12] Most common mutations in DDS are missense changes in exons 9 or 8, which encode for the zinc fingers 3 and 2, respectively. Exon 1-6 of the WT1 gene regulates the expression of target genes by encoding the regulatory domain. The WT1 protein mediates the morphogenesis of the kidney and gonad. Very few reports of deletions or nonsense mutations have been described which result in truncated proteins.[3] Rarely mutation of exon 6 has been described.[4] The external genitalia of male DDS varies from ambiguous genitalia to female phenotype. The proteinuria due to nephropathy, usually, starts within 2 years of age, but it may develop as late as 14 years of age.[5]

The management of DDS comprises fluid and electrolyte balance, early detection and treatment of Wilms’ tumor and management of renal failure. The risk of developing Wilms’ tumor in DDS is up to 50%[5] with the mean age of 1.6 years which is earlier than isolated Wilms’ tumor.[6] In patients with bilateral tumors or patients with a solitary kidney with Wilms’ tumor, nephron sparing surgery should be performed after neoadjuvant chemotherapy.

Our case represents that while dealing with the ambiguous genitalia with cryptorchidism, possibility of DDS should be kept in mind, and genetic study should be carried out to diagnose such rare disorder. In DDS, the risk of developing bilateral renal malignancy is high especially in early age.