Denys-Drash Syndrome Clinical Presentation
- Author: Agnieszka Swiatecka-Urban, MD; Chief Editor: Maria Descartes, MD more...
Denys-Drash syndrome (DDS) symptoms related to nephropathy: Placental size, pregnancy, and delivery are usually normal. At onset (usually within the first year of life), typical symptoms are those of nephrotic syndrome (eg, edema, abdominal distention, recurrent infections). With the rapid decline of the glomerular filtration rate (GFR) and progression to ESRD, the following additional symptoms develop:
Poor feeding and growth
Loss of developmental milestones
Nonspecific aches and pains
Denys-Drash syndrome symptoms related to Wilms tumor: Palpable abdominal mass is the most common manifesting symptom, noticed in 90% of children by a physician on routine physical examination or by the parent during routine care. Other symptoms include the following:
Signs related to nephropathy: At onset, signs of nephrotic syndrome predominate (eg, generalized edema, ascites). Evidence of venous thrombosis occasionally may develop secondary to nephrotic syndrome. With the decline of GFR, severe hypertension becomes apparent. Pallor reflecting anemia develops. When ESRD ensues, the following signs develop secondary to renal osteodystrophy:
Loss of developmental milestones
Decline in the growth rate
Skeletal abnormalities (similar to those of vitamin D-deficient rickets)
Signs related to Wilms tumor: A palpable abdominal mass, hematuria, and hypertension are the most common signs. Other findings may include the following:
Acute surgical abdomen
Respiratory distress from pleural effusions
Signs of congestive heart failure (CHF)
Signs related to intersex disorders include the following:
Most individuals with Denys-Drash syndrome who carry the 46,XY or 46,XX/46,XY karyotype have male pseudohermaphroditism. The spectrum of anomalies of the external genitalia may include penoscrotal hypospadias with cryptorchidism, enlarged clitoris with labial fusion, bifid scrotum with palpable gonads, and micropenis.
Abnormalities of the internal reproductive organs in these individuals may include presence of the vagina and uterus, streak ovaries, and dysgenetic testes. Individuals with the 46,XX karyotype may have streak gonads but usually display a normal phenotype and are considered to have the incomplete form of Denys-Drash syndrome.
More than 96% of individuals with a clinical diagnosis of Denys-Drash syndrome have been found to carry a mutation in the WT1 gene. The vast majority of these mutations are missense changes in exons 9 or 8, which encode for the zinc fingers 3 and 2, respectively.
The exon 9 amino acid, arginine-394, critical in the DNA binding activity of the WT1 protein, is considered a mutational hot spot for Denys-Drash syndrome. A mutation of arginine-394 was present in 14 of 30 patients with Denys-Drash syndrome in one review of the literature.
Increasing number of mutations in other exons have been described. Another review identified missense mutations in 30 patients and mutations that lead to premature chain termination (truncation mutations) in 66 patients. Patients with truncation mutations had high frequency of bilateral Wilms tumor compared with patients with missense mutations (52% vs. 17%, respectively), with a higher percentage of bilateral tumors in patients with truncations that occurred in the 5' half of the WT1 gene. Such mutations result in a WT1 protein that lacks a functional nuclear localization signal.
The mutant cytoplasmic WT1 protein is thought to sequester some of the wild-type WT1 protein in the cytoplasm, resulting in a reduced amount of nuclear WT1. Furthermore, other putative WT1 interacting partners may also be sequestered in the cytoplasm, where they cannot perform their normal function.
Mutation in a single allele of the WT1 gene is sufficient to produce nephropathy and intersex disorder. One hypothesis suggests the abnormal WT1 allele product interacts with the function of the unaffected wild-type WT1 allele in a dominant-negative fashion and changes its normal regulatory functions.
The vast majority of patients with Denys-Drash syndrome have male karyotype and present with a wide spectrum of gonadal abnormalities; conversely, individuals with Denys-Drash syndrome and female karyotype have less severe or no gonadal abnormalities. Note the following:
In patients with 46,XY, the KTS-negative isoform of the WT1 protein associates and achieves synergy with steroidogenic factor 1 (SF1). SF1, in turn, promotes expression of the gene-encoding müllerian inhibiting substance (MIS).
In addition, DAX1, a gene that directs ovarian development, antagonizes this synergy. In the presence of the WT1 mutations characteristic in Denys-Drash syndrome, the abnormal WT1 protein cannot associate with SF1, and testis development fails because of the decreased expression of MIS and the unopposed action of the DAX1 gene.
The degree to which the synergy between WT1 and SF1 is interrupted determines the severity of gonadal abnormalities in 46,XY individuals. In contrast, in 46,XX individuals, an intact WT1 gene has not been shown absolutely necessary for normal female development; these patients have less severe or no gonadal abnormalities.
Development of Wilms tumor in patients with Denys-Drash syndrome results from mutations in both alleles of the WT1 gene. According to the 2-hit genetic model, Wilms tumor is a consequence of 2 independent events that lead to loss of function of both alleles of the WT1 gene. A constitutional or germline mutation in a single allele of the WT1 gene (first hit) leads to persistence of an undifferentiated mesenchyme. A somatic mutation (second hit) or loss of heterozygosity in the second allele causes uncontrolled cell proliferation and Wilms tumor formation.
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