What Is Denys-Drash Syndrome?
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Denys-Drash Syndrome - A Rare Genital Disorder in Children

Published on Feb 12, 2024   -  4 min read

Abstract

Denys-Drash syndrome presents with a triad of disorders that are ambiguous genitalia, kidney failure, and Wilm’s tumor.

What Is Denys-Drash Syndrome?

Denys-Drash syndrome is a condition that affects the kidneys and genitalia. Kidney disease develops within the first few months of life. Individuals affected by the syndrome develop diffuse glomerulosclerosis (hardening of glomeruli in the kidney) or nephropathy (kidney damage). The condition progresses to cause hypertension and kidney failure during childhood. Individuals with Denys-Drash syndrome have a 50 percent chance of developing a rare type of kidney cancer known as Wilms tumor in native kidneys and gonadoblastoma in dysgenetic gonads. Such individuals develop multiple tumors in one or both kidneys.

Males affected by the syndrome have male chromosome patterns but exhibit gonadal dysgenesis (a developmental disorder of reproductive organs) resembling ambiguous genitalia (the infant's external genitals are not differentiated as males or females). The testes may not descend and get lodged in the pelvis, abdomen, or groin, causing infertility. Females affected by the syndrome have normal genitalia but have kidney involvement. Since women do not develop all the syndrome's characteristics, the condition in women is called isolated nephrotic syndrome.

What Is the Incidence of Denys-Drash Syndrome?

The syndrome is a rare condition with only 150 reported cases and is inherited in an autosomal dominant pattern. Most individuals develop this syndrome due to new genetic changes where the disorder's prior history is absent within the family. Morbidity and mortality among affected individuals are high because of the formation of nephropathy and elevated malignancy risk.

What Causes Denys-Drash Syndrome?

The syndrome develops due to a WT1 (Wilms tumor) gene mutation. The gene encodes for a protein that regulates other genes by binding to specific sites in their DNA (deoxyribonucleic acid). The WT1 gene is also a transcription factor and has a role in developing kidneys and gonads before birth. Point mutation to the WT1 gene causes loss of regulatory function, leading to an abnormality in glomerular formation and gonadal differentiation. Single allele mutation of the WT1 gene causes gonadal abnormalities, whereas both allele mutations in the WT1 gene result in Wilm's tumor.

What Are the Symptoms of Denys-Drash Syndrome?

The symptoms begin at birth and appear up to 18 months. The condition can progress to end-stage renal disease within 2 to 3 years of life. The frequently observed symptoms are:

  • Male Pseudohermaphroditism: The most typical symptom where the discrepancy between gonad morphology and external genitalia is seen. Individuals with this feature have the male genotype (XY) but exhibit virilized, ambiguous, or complete female external genitalia. Some anomalies seen in external genitalia are penoscrotal hypospadias (opening of the urethra is not at penis tip) with cryptorchidism (undescended testis), enlarged clitoris with labial fusion, bifid scrotum with palpable gonads, and micropenis (unusually small penis).

  • Nephroblastoma: It is a neoplasm of the kidney that is common in children.

  • Nephropathy: It is a common symptom where kidneys become diseased or damaged.

  • Nephrotic Syndrome: The condition includes clinical symptoms of severe protein loss from the kidney, proteinuria (protein in urine), hypoalbuminemia (low levels of albumin in blood), edema, and hyperlipidemia (high level of lipid in blood). The syndrome develops because of glomerular dysfunction in which the glomerular capillary wall permeability increases, leading to proteinuria.

  • Kidney Failure: Reduction in glomerular function causes end-stage renal disease to develop. Symptoms include decreased activity, poor feeding and growth, missed developmental milestones, oliguria (low urine output), and nonspecific pain.

  • Wilms Tumor: An abdominal mass becomes noticeable in children. The clinical symptoms of a tumor are abdominal distention, pain, hematuria (blood in urine), weight loss, poor feeding, inguinal hernia, and acute abdomen. In severe cases, respiratory distress or congestive heart failure may develop.

  • Hypertension: Elevation in blood pressure occurs because of kidney damage.

  • Gonadal Dysgenesis: Abnormality of internal reproductive organs in males where there is the presence of the uterus or vagina, streak ovaries (a developmental disorder of ovaries), or dysgenetic testes.

How Is Denys-Drash Syndrome Diagnosed?

A healthcare provider advises the following tests to facilitate diagnosis:

  • Urine Analysis: Proteinuria is the most prominent feature of the syndrome and is in the nephrotic range. Hematuria can also be detected.

  • Renal Function Test: During the early stages of the syndrome, serum creatinine levels may be within the normal range but can worsen with advanced nephropathy or bilateral Wilm's tumor. Patients with kidney failure have hyperkalemia (elevated potassium level in blood) and hyperphosphatemia (high phosphorus level in blood).

  • Wilm Tumor Markers: Individuals that develop Wilms tumor have increased levels of hyaluronic acid-stimulating activity, erythropoietin, and renin pheromone.

  • Chromosome Analysis: Determination of WT1 mutation is needed in all suspected syndrome patients. Individuals with nephropathy but lack genital abnormalities or Wilms tumor must undergo the test.

  • Abdominal or Pelvic Ultrasound: Individuals exhibiting symptoms need to undergo ultrasonography. In diagnosed patients, continuous kidney monitoring for Wilm's tumor is needed.

  • Abdominal or Pelvic CT (Computed Tomography): The scan is more sensitive for diagnosing Wilm's tumor and its metastasis. Based on the scan report, tumor resection or chemotherapy is planned.

  • Kidney Biopsy: Histological findings observed are diffuse mesangial sclerosis. Rarely, focal segmental glomerulosclerosis is noted.

How Is Denys-Drash Syndrome Managed?

The measures to manage Denys-Drash syndrome are:

  • Fluid and electrolyte balance.

  • Treatment of hypertension.

  • Renal replacement therapy for kidney failure or bilateral nephrectomy patients.

  • Chemotherapy for patients with Wilms tumor.

The patients that have developed Wilm's tumor at diagnosis are handled through a radical and conservative approach. The radical approach includes prophylactic bilateral nephrectomy before the renal issues progress to kidney failure to evade Wilm's tumor from developing. The conservative approach involves monitoring Wilms's tumor with radiographic imaging at regular intervals. Patients with Wilm's tumor are ideally suggested radical bilateral nephrectomy over nephron-sparing surgery to preserve renal function.

After nephrectomy (surgical removal of kidney) and chemotherapy, kidney transplantation is done following two years of tumor-free period. All patients who need kidney transplants must undergo dialysis before surgery. Patients who undergo prophylactic nephrectomy before Wilm's tumor development need a shorter duration of dialysis.

What Are the Complications Caused by Denys-Drash Syndrome?

Patients who develop nephrotic syndrome may experience recurrent infections, nutritional deficiencies, and rarely venous thrombosis. All nephrotic syndrome results in end-stage renal disease. Patients with Wilm's tumor undergoing chemotherapy can develop life-threatening infections or secondary malignancies.

What Is the Prognosis for Denys-Drash Syndrome?

Almost all patients develop nephropathy and progress to end-stage renal disease by two years of life. Most patients are at risk for developing Wilm's tumor. Patients with unilateral tumors have a higher chance of developing contralateral tumors. Mortality is high if patients are not diagnosed and treated.

Conclusion

Deny-Drash syndrome is a rare disorder with few reported cases worldwide. The condition presents at birth and can progress to kidney failure or the development of Wilm's tumor by the third year of life. The genitals of male infants are also affected, causing ambigiousness and infertility. Currently, treatments focus on managing the disease symptoms and are not preventative.

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Last reviewed at:
12 Feb 2024  -  4 min read

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