Denys Drash syndrome is a rare condition characterized by an association between diffuse glomerulosclerosis that rapidly progresses to renal failure, high prevalence of Wilms tumor due to mutations in the Wilms tumor suppressor (WT1) gene and intersexual status. Incomplete forms, consisting of nephropathy and either Wilms tumor or intersexual disorder have also been described.
Denys Drash syndrome affects both males and females. Girls more often have normal genitalia, thus exhibiting the incomplete form of the disease, while boys have gonadal dysgenesis, with ambiguous or female genitalia, but 46,XY or 46,XY/46,XX karyotype. If the testes are present, they are usually located in the pelvis or abdomen, as the normal descent does not occur and are at risk for neoplasia. Other abnormalities in boys include penoscrotal hypospadias, bifid scrotum, micropenis or even female genitalia, with persistent clitoris, vagina and uterus.
Newborns usually appear otherwise healthy, but symptoms subsequently develop before they turn 1 year old and consist of nephrotic type edema, multiple infections and abdominal distension. Progression is rapid and, as end-stage renal disease approaches, patients experience oliguria, regression of motor milestones, prefer inactivity and fail to properly feed and thrive. The abdominal distension may be due to the presence of a palpable Wilms tumor, that may also induce other symptoms: pain, macroscopic hematuria, low grade fever, weight loss, acute surgical abdomen or inguinal hernia. Venous thrombosis in various locations, due to the hypercoagulable status that is characteristic to the nephrotic syndrome, may also be present. As disease progresses, patients become severely hypertensive and pale. Skeletal abnormalities occur, secondary to renal osteodystrophy. Pleural liquid accumulation leads to respiratory distress. Affected children may also exhibit congestive heart failure signs.
Various reports describe other uncommon associated abnormalities: congenital diaphragmatic hernia , pulmonary hypertension  or congenital nephrotic syndrome . Therefore, it is safe to conclude that Denys Drash syndrome should be considered in any child that presents with nephropathy or Wilms tumor during the first year of life, especially if ambiguous genitalia is noticed .
Entire Body System
- Abdominal Pain
The presenting characteristics of DDS include loss of playfulness, decreased appetite, weight loss, growth delay, abnormal skeletal development, insomnia, abdominal pain, constipation, and anuria. [en.wikipedia.org]
pain, constipation, and anuria. [ipfs.io]
However, in some cases, children may experience the following: Abdominal pain /swelling Blood in the urine Constipation Fever High blood pressure Loss of appetite Nausea Shortness of breath Who to See and Types of Treatments Available Children with a [docdoc.com]
- Hypertrophic Pyloric Stenosis
Abstract We report a novel mutation in WT1 exon 9 (1214 A G) resulting in an amino acid change from H to R at codon 405 in a 46 XY female patient who had congenital hypertrophic pyloric stenosis, pseudohermaphroditism masculinus, renal failure, and Wilms [ncbi.nlm.nih.gov]
Patient 1 was a boy with complete DDS who was presented with progressive nephropathy, unilateral Wilms' tumor, bilateral cryptorchidism, and renal histology showing diffuse mesangial sclerosis (DMS). [ncbi.nlm.nih.gov]
[…] and hypospadias 8 HD 1 19 4 M 13 months WT and NS NA 13 Unilateral cryptorchidism and micropenis 60 HD 6 33 5 M 21 days NS WT1 exon 9 (394A G) 16 Bilateral cryptorchidism 3 PD 3 2 F, female; M, male; WT, Wilms’ tumour; NS, nephrotic syndrome; NA, not [academic.oup.com]
On examination, the child was dehydrated with bilateral palpable renal lumps; bilateral cryptorchidism and penoscrotal hypospadias [Figure 1] a and b. [jiaps.com]
Although pure gonadal dysgenesis with male pseudohermaphroditism is typical, the clinical variability of the external genitalia ranges from bifid scrotum with micropenis and palpable gonads to penoscrotal hypospadias with cryptorchidism or clitoral hypertrophy [accessanesthesiology.mhmedical.com]
Ultrasound revealed microcalcifications in the left testis, right cryptorchidism and a right testis in the right iliac fossa. Magnetic resonance imaging revealed that prostate and seminal vesicles dysplasia could not be ruled out. [ajandrology.com]
Diffuse mesangial sclerosis , usually leading to end stage renal disease before the child reaches the age of 3 years. Urinalysis reveals the presence of proteinuria, the hallmark of nephrotic syndromes, as well as hematuria. Renal function markers, such as creatinine and blood urea nitrogen may be initially normal, but increase as the disease advances. They will also rise if a Wilms tumor develops, because the neoplastic mass will replace renal tissue and compress neighboring nephrons. Late stages are characterized by electrolyte imbalance: hyperphosphatemia and hyperkalemia.
The presence of Wilms tumor is established using imaging methods, but there are several blood markers that can point to its existence, like increased erythropoietin level, high hyaluronic acid, hyaluronic acid-stimulating activity and elevated renin prohormone levels. Unfortunately, these markers are not widely available.
An abdominal and pelvic ultrasound examination should be performed whenever Denys Drash syndrome is suspected and periodically afterwards, for early detection of a Wilms tumor. Furthermore, the physician should be aware of the high risk of gonadoblastoma in these patients  and regularly evaluate internal genital organs. It is recommended to also order computer tomography scanning in order to detect small tumors, metastasis and invasion and to define tumor margins and resectability. As lung metastasis can occur, a chest radiograph is essential to detect their presence.
A kidney biopsy is indicated in order to confirm that the substrate of the deteriorating renal function is diffuse mesangial sclerosis, not renal cysts . If the patient presents with a Wilms tumor, histological examination of the biopsy specimen in performed.
Another useful tool in the workup of Denys Drash syndrome is chromosome analysis, in order to demonstrate WT1 mutation. However, multiple genetic defects have been described: 1180C>T mutation , 9 c.1213C > G mutation , or p.Asp396His mutation .
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