Information on the following diseases can be found in the Related Disorders section of this report:

• Congenital Adrenal Hyperplasia
• Klinefelter Syndrome
• 17-Beta Hydroxysteroid Dehydrogenase Deficiency
• Reifenstein Syndrome
• Wilms' Tumor

Major symptoms of the complete form of Drash Syndrome are abnormal kidney function, a cancerous tumor of the kidney called a Wilms' Tumor, and a condition in which a person has the body traits of both sexes along with either male testicles or female ovaries (pseudohermaphroditism). When a patient has the incomplete form of Drash Syndrome abnormal kidney function with either pseudohermaphroditism or Wilms' Tumor are present.

Kidney disease of Drash Syndrome often leads to complete malfunctioning of the kidney's which requires maintenance on hemodialysis or an organ transplant.

Wilms' Tumor, which is one of the characteristics of Drash Syndrome, is the most common form of kidney cancer in children. The exact cause is not known although it is thought to be inherited in some cases. Abdominal swelling is the most common symptom typically leading to early detection. Other signs of Wilms' Tumor may include blood in the urine, low-grade fever, loss of appetite, paleness, weight loss, and/or lethargy. (For more information on this disorder choose "Wilms' Tumor" as your search term in the Rare Disease Database).

Pseudohermaphroditism is another symptom of Drash Syndrome. This is a condition in which a person has the body traits of both sexes though having either male testicles or female ovaries. Males with this disorder may not develop external sexual organs until puberty.

Some patients with Drash Syndrome may develop malignancies of the testes or ovaries; abnormalities of the reproductive and urinary systems; an abnormal backflow of urine from the bladder to the tubes that carry urine from the kidney into the bladder (vesicoureteral reflux); swelling in the pelvis due to urine that cannot flow past a blockage in the tubes that carry urine from the kidney into the bladder and/or cyst formation (hydronephrosis).

Most cases of Drash Syndrome appear for no apparent reason (sporadically). There have been some cases thought to be inherited as an autosomal dominant trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

Drash Syndrome is a very rare disorder that predominantly affects males although the disorder has been reported in a few females. There have been approximately 30 cases described in the medical literature.

Symptoms of the following disorders can be similar to those of Drash Syndrome. Comparisons may be useful for a differential diagnosis:

Congenital Adrenal Hyperplasia is a group of disorders resulting from defective synthesis of the corticosteroid hormones of the adrenal gland. The adrenal gland becomes enlarged because it tries to produce more and more of the hormones to compensate for their lack of effectiveness. The adrenal gland produces "male" sex hormones (androgens) in both males and females. Because these are overproduced in certain forms of Congenital Adrenal Hyperplasia, the external genitalia of some females with this disorder are masculinized to various degrees. Lack of glucocorticoids, especially cortisol, causes various kinds of metabolic problems. Lack of mineralocorticoids, primarily aldosterone, causes salt and water imbalances. (For more information on this disorder choose "Adrenal Hyperplasia" as your search term in the Rare Disease Database.)

Klinefelter Syndrome is a rare disorder resulting from too many X chromosomes. This disorder affects males only and is characterized by unusually small testes, lack of sperm, enlarged mammary glands and an abnormally small penis. There may also be retardation of sex organ development, an absence of facial and body hair, lack of muscular development and a high pitched voice. (For more information on this disorder, choose "Klinefelter Syndrome" as your search term in the Rare Disease Database.)

17-Beta Hydroxysteroid Dehydrogenase Deficiency (also known as 17- Ketosteroid Reductase Deficiency and 17-Beta HSD) is a disorder in which the production of steroids is impaired. Male pseudohermaphroditism is present and there is no enlargement of the adrenal gland. This genetic defect is inherited as either autosomal recessive or X-linked trait.

Reifenstein Syndrome is a hereditary form of male pseudohermaphroditism. The male has testes but possesses both male and female sexual characteristics. The severity of androgen (male hormone) insensitivity determines how this syndrome will present itself. In mild cases of androgen resistance, infertility may be the only symptom. More severe cases may result in hardening of the tubules in the testes, failure of one or both testes to descend, an abnormal penis in which the urethra opens on the underside, and development of male breasts. The degree of feminization at puberty is not as marked as in other forms of pseudohermaphroditism. (For more information on this disorder, choose "Reifenstein Syndrome" as your search term in the Rare Disease Database.)

Wilms' Tumor is the most common form of kidney cancer in children, accounting for six to eight percent of all childhood cancers. The exact cause is not known, although it is thought to be inherited in some cases. This disorder may occur alone or as a part of Drash Syndrome. Abdominal swelling is the most common symptom usually leading to early detection of the disorder. Other symptoms of Wilms' Tumor may be blood in the urine, low- grade fever, loss of appetite, paleness, weight loss, and/or lethargy. (For more information on this disorder choose "Wilms" as your search term in the Rare Disease Database.)

Patients with progressive kidney failure can be maintained on dialysis, a machine that cleanses toxins from the blood which would ordinarily leave the body through urine. Some patients may choose to undergo transplant surgery.

Removal of the ovaries or testes may be recommended to avoid malignancy.

Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.

Research on birth defects and their causes is ongoing. The National Institutes of Health (NIH) is sponsoring the Human Genome Project which is aimed at mapping every gene in the human body and learning why they sometimes malfunction. It is hoped that this new knowledge will lead to prevention and treatment of genetic disorders in the future.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 194080; Last Edit:9/11/98.

TEXTBOOKS
Thoene JG., ed. Physicians’ Guide to Rare Diseases. Montvale, NJ: Dowden Publishing Company Inc; 1995:723-24

Buyce ML., ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1780-81.

Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995:830-31.

REVIEW ARTICLES
Koziell A, et al., Frasier and Denys-Drash syndromes: different disorders or part of a spectrum? Arch Dis Child. 1999;81:365-69.

MacLean HE, et al., Intersex disorders: shedding light on male sexual differentiation beyond SRY. Clin Endocrinol. 1997;46:101-08.

JOURNAL ARTICLES
Cleper R, et al., Unexpected Wilms’ tumor in a pediatric renal transplant recipient: suspected Denys-Drash syndrome. Transplant Proc. 1999;31:1907-09.

Kohler B, et al., Bilateral Wilms tumor in a boy with severe hypospadias and crytorchidism due to a heterozygous mutation in the WT1 gene. Pediatr Res. 1999;45:187-90.

Rudin C, et al., Renal transplantation in the management of bilateral Wilms’ tumor (BWT) and of Denys-Drash syndrome. Nephrol Dial Transplant. 1998;13:1506-10.

Ozbey H, et al., Wilms’ tumor and associated malformations; report of two cases with WAGR and Drash syndrome. Eur J Pediatr Surg. 1996;6:186-88.

Devrient K, et al., Elevated maternal serum and amniotic fluid alpha-fetoprotein levels in the Denys-Drash syndrome. Prenat Diagn. 1996;16:455-57.

Devrient K, et al., Diaphragmatic hernia in Denys-Drash syndrome. Am J Med Genet. 1995;57:97-101.

Mueller RF., The Denys-Drash syndrome. J Med Genet. 1994;31:471-77.