Denys-Drash syndrome is caused by a congenital gene defect that leads to the manifestation of nephrotic syndrome. With an incidence of 1:100,000 in newborns, Denys-Drash syndrome is a rare condition.
What is Denys-Drash syndrome?
Denys-Drash syndrome is the name given to a rare autosomal recessive inherited disorder that is generally associated with the symptom triad of progressive kidney disease with manifestation of an early, often bilateral, benign Wilms tumor (nephroblastoma), diffuse mesangial sclerosis (proliferating connective tissue cells in the renal corpuscles), and genital abnormalities (masculine pseudohermaphroditism). Denys-Drash syndrome is accordingly included in the spectrum of nephrotic syndromes. The gene defect may initially manifest clinically on the basis of a Wilms tumor. Postnatally, diffuse mesangial sclerosis develops in combination with nephrotic syndrome and marked proteinuria (increased protein concentration in the urine), with renal failure expected within 1 to 4 years. Incomplete subtypes of Denys-Drash syndrome may present with diffuse mesangial sclerosis with masculine hermaphroditism or nephroblastoma.
Causes
Denys-Drash syndrome is a congenital (inherited) disorder that is inherited in an autosomal recessive manner. In all cases (about 90 percent of cases), Denys-Drash syndrome involves a mutation of the WT1 gene (Wilms tumor suppressor gene) located on chromosome 11p13, which is thought to be responsible for the manifestation of Wilms tumor. Here, exon 8 or 9 on the heterozygous germline in the zinc finger motif is affected in the majority of cases. The underlying mutation represents a de novo mutation (new mutation) in 90 percent of cases. The corresponding gene regulates the coding of a specific zinc finger protein, which is a transcription factor involved in urogenital development and nephrogenesis. As a result of the gene defect characteristic of Denys-Drash syndrome, not only do genital abnormalities and Wilms tumors manifest, but renal tissue progressively hardens and scars (scleroses), so that kidney function becomes successively more and more restricted until the kidneys fail completely.
Symptoms, complaints, and signs
Because of Denys-Drash syndrome, patients suffer from a number of different malformations and other symptoms. Usually, the malformations occur mainly on the external genital organs. Psychological complaints may also occur, as many affected persons no longer feel comfortable with the malformations and suffer from inferiority complexes or significantly reduced self-esteem. Especially in childhood, Denys-Drash syndrome can thus lead to bullying or teasing, so that patients develop psychological complaints or depression. As a rule, there is also an increased amount of protein in the urine and further also the formation of magnesium in the kidneys. This causes permanent damage to the kidneys, so that Denys-Drash syndrome, if left untreated, leads to complete renal failure and thus to the death of the affected person. Patients are thus also dependent on a transplant or dialysis. Similarly, Denys-Drash syndrome can lead to high blood pressure or swelling of the abdomen and kidney area. Renal insufficiency also increases the risk of tumor formation, which can also lead to the patient’s death. Life expectancy is significantly reduced by Denys-Drash syndrome if it is not treated.
Diagnosis and progression
Denys-Drash syndrome is usually diagnosed two weeks to 1.5 years after birth on the basis of characteristic symptoms. The malformations of the external genital organs (including a small penis in affected boys and enlarged labia in girls) can be detected immediately after birth in most cases. Nephrotic syndromes are also associated with abdominal swelling, decreased urine output, proteinuria due to diffuse mesangial sclerosis, and high blood pressure. To exclude or detect nephroblastoma, the kidneys should be examined sonographically and/or by computed tomography. Computed tomography can also be used to visualize malformations of the sexual organs.Differentially, Denys-Drash syndrome should be distinguished from WAGR syndrome, which is also a disease associated with malformations and Wilms tumor. In addition, hyperechogenic kidneys can also be detected prenatally in cystic kidneys. In all cases, children affected by Denys-Drash syndrome present with renal insufficiency (kidney failure) before the completion of the third year of life and the majority develop Wilms tumor within the first two years of life. In contrast, prognosis is good in children with transplanted kidneys.
When should you see a doctor?
In general, Denys-Drash syndrome is already a congenital syndrome, so no additional diagnosis of this disease by a doctor is necessary. Due to the various malformations and other symptoms, the child is in need of various examinations and treatments. A doctor should therefore be consulted when the malformations cause limitations in the patient’s daily life and living. Surgical intervention may be able to correct these malformations. The affected person is also dependent on medical treatment in the case of kidney failure. Furthermore, swelling or excessive blood pressure should also be examined by a physician. The examination of the disease usually takes place in a hospital. Further treatment is carried out by a specialist and, for example, with dialysis. Here, the transplantation of a kidney is also possible in order to completely combat the renal insufficiency. Since those affected suffer relatively frequently from infections and inflammations due to Denys-Drash syndrome, these should also be examined by a doctor.
Treatment and therapy
Denys-Drash syndrome cannot be treated causally because it is attributed to a congenital gene defect. Accordingly, therapeutic measures are aimed particularly at controlling and regulating renal function, treating hypertension and proteinuria, and reducing the symptoms specifically associated with nephrotic syndrome. In this context, proteinuria cannot be controlled by conventional drugs. The same applies to nephrotic syndrome, which cannot be treated by corticosteroids or other immunosuppressants and whose therapy consists primarily of blood dialysis followed by unilateral or bilateral nephrectomy (kidney removal) and kidney transplantation. The primary goal of nephrectomy is to prevent the development of a Wilms tumor. Transplanted kidneys are generally not affected by Denys-Drash syndrome. In most cases, the intersex genital organs are surgically adapted to the external phenotype. In addition, surgical removal of the abnormal sexual organs may be indicated in some cases to eliminate as much as possible the risk of tumor manifestation in these tissue structures. Supportive nutrition and appropriate prophylaxis with regard to infectious diseases are recommended in cases of Denys-Drash syndrome.
Outlook and prognosis
Because Denys-Drash syndrome is a genetic disorder, it cannot be treated by causal therapy. Therefore, only symptomatic treatment options are available to affected individuals to alleviate symptoms. If no treatment is available for Denys-Drash syndrome, those affected will suffer from severe malformations of the reproductive organs. There is no self-healing in this case, so that the affected persons cannot perform sexual acts. Similarly, malformations of the kidneys can occur, which in the further course lead to renal insufficiency. This can be fatal for the affected person and is therefore treated by dialysis or by transplantation. The treatment of the syndrome always depends on the severity of the malformations. These can be corrected by surgical procedures so that patients can participate in sexual intercourse. As a rule, the kidney complaints cannot be stopped or cured, so that the affected persons are always dependent on a transplantation. The patient’s life expectancy is usually limited by Denys-Drash syndrome. However, early initiation of therapy always has a positive effect on the further course of the disease.
Prevention
Because Denys-Drash syndrome is a congenital condition, it cannot be prevented.
Aftercare
Individuals who present with Denys-Drash syndrome usually require lifelong treatment. Therapy and follow-up care merge smoothly because of the complex symptom picture. Follow-up care may include measures after a surgical intervention, as is necessary in the case of severe genital malformations. The affected person must then attend regular follow-up examinations and also take advantage of therapeutic discussions, as there are usually also psychological complaints that need to be worked through in the long term. Medical follow-up and therapy should take place in consultation with the family doctor so that both aspects of treatment can be coordinated. After kidney disease, a nephrologist must be consulted at regular intervals. Initially, the affected person should see the doctor once a month. Later, the rotation can be reduced, always in view of the course of the disease and any complications. In any case, Denys-Drash syndrome requires ongoing follow-up and treatment, because this ensures that the medications used provide optimal support for the inpatient treatment and that the patient can lead a life appropriate to his or her state of health. In addition, if the disease has caused tumors, follow-up care by an appropriate oncologist is necessary.
What you can do yourself
Individuals suffering from Denys-Drash syndrome initially require medical treatment. However, the malformation syndrome can also be treated by oneself. For example, after the actual therapy, a healthy diet can help alleviate symptoms and promote healing. The dermatologist will recommend a diet with sufficient vitamins and nutrients. Substances that could irritate the skin should be avoided. In addition, no unhealthy foods such as fast food or anything too spicy should be consumed. Alcohol and caffeine should also be avoided at first to prevent re-infection. After a kidney transplant, the patient must initially take it easy. Strenuous physical activities should be avoided in any case. In addition, physiotherapeutic exercises are recommended to strengthen the immune system without putting too much strain on the body. Furthermore, the cause of the disease must be determined. Since Denys-Drash syndrome can run its course in very different ways and is associated with different symptoms, the individual therapy must always be worked out together with the responsible specialist. The patient should contact the medical specialist for this purpose and, if necessary, also involve a nutritionist, sports physician and psychologist in the therapy.
