Edit concept Question Editor Create issue ticket

Denys Drash Syndrome

Denys-Drash Syndrome

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.


Presentation

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 [1], pulmonary hypertension [2] or congenital nephrotic syndrome [3]. 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 [4].

Respiratory Abnormalities
  • Twin girls, born at 35 weeks gestation, manifested symptoms of congenital nephrotic syndrome, renal failure, and severe respiratory abnormalities refractory to assisted ventilation. Both died at 1 month of age.[ncbi.nlm.nih.gov]
Abdominal Pain
  • pain, constipation, and anuria.[ipfs.io]
  • 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]
  • 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]
Eruptions
  • However, further teeth had erupted including all the premolars. BelleGlass NG crowns were indicated. It was also decided to replace the preformed chrome cobalt crowns with full coverage BelleGlass NG crowns.[ncbi.nlm.nih.gov]
Cryptorchidism
  • 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]
  • On examination, the child was dehydrated with bilateral palpable renal lumps; bilateral cryptorchidism and penoscrotal hypospadias [Figure 1] a and b.[jiaps.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]
  • […] defects Wilms tumor is also more common in children with certain birth defects (without known syndromes): Aniridia (complete or partial lack of the iris [colored area] of the eyes) Hemihypertrophy (an oversized arm and/or leg on one side of the body) Cryptorchidism[cancer.org]
  • The most common genitourinary anomalies in males is cryptorchidism. Females may have underdeveloped ovarian tissue and bicornuate uterus, leading to fertility issues.[invitae.com]

Workup

Diffuse mesangial sclerosis [5], 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 [6] 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 [7]. 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 [8], 9 c.1213C > G mutation [9], or p.Asp396His mutation [10].

Multiple Renal Cysts
  • Because multiple renal cysts have never been reported in DDS, we explored several genes responsible for these renal manifestations, such as HNF-1β, PAX2, PKD1, and PKD2.[ncbi.nlm.nih.gov]
  • Because multiple renal cysts have never been reported in DDS, we explored several genes responsible for these renal manifestations, such as HNF-1β , PAX2 , PKD1 , and PKD2 .[pediatrics.aappublications.org]

Treatment

  • At her last visit, 27 months after treatment, the patient was still satisfied with the restorative treatment. However, further teeth had erupted including all the premolars. BelleGlass NG crowns were indicated.[ncbi.nlm.nih.gov]
  • Of the DDS patients, dysuria due to hypospadias persisted in one patient and treatment for hypogonadism was needed in one patient. CONCLUSIONS: CNS and DDS were diagnosed early after onset and adequate treatment was started.[ncbi.nlm.nih.gov]
  • The high risk of Wilms' tumor mandates regular surveillance and the use of prophylactic bilateral nephrectomy as a treatment is not yet clear.[ncbi.nlm.nih.gov]
  • Management and treatment Treatment is supportive and consists of adequate nutrition, prevention and treatment of infectious complications, and management of renal failure.[orpha.net]
  • Please consult your own licensed physician regarding diagnosis and treatment of any medical condition! Please see also our disclaimer . This site complies with the HONcode standard for health information: verify here . Database updated 2019-02-19.[diseasesdatabase.com]

Prognosis

  • Advances in dialysis and transplantation programmes for young children offer the potential for a marked improvement in the prognosis for patients with BWT and for those with DDS.[ncbi.nlm.nih.gov]
  • BACKGROUND: The prognosis of Japanese patients with congenital nephrotic syndrome (CNS) and Denys-Drash syndrome (DDS) is not clear.[ncbi.nlm.nih.gov]
  • Prognosis A 1994 review of 150 cases reported in the literature found that 38% had died with a mean age of death of 2 years. 32% were still alive at the time of the report with a mean age of 4.65. No data were available for the remainder.[ipfs.io]
  • These mutations are usually found in exons 8 or 9, but at least one has been reported in exon 4. [1] Prognosis [ edit ] A 1994 review of 150 cases reported in the literature found that 38% had died with a mean age of death of 2 years. 32% were still alive[en.wikipedia.org]

Etiology

  • Etiology Constitutional mutations in the Wilms tumour predisposing gene, WT1, most of which are located in exons 8 and 9, have been described in the majority of patients with Denys-Drash syndrome.[orpha.net]
  • Etiology The cause of DDS is most commonly (96% of patients) an abnormality in the WT1 gene (Wilms tumor suppressor gene). These abnormalities include changes in certain exons (9 and 8) and mutations in some alleles of the WT1 gene.[ipfs.io]
  • […] associated with Wilms tumor including Sotos syndrome, Perlman syndrome, Simpson-Golabi-Behmel syndrome, Bloom syndrome, Frasier syndrome, Beckwith-Wiedemann Syndrome, Denys -Drash syndrome, and WAGR syndrome which are explained in further detail in etiology[physio-pedia.com]
  • Based on etiology, two forms of SRNS are distinguished, an immune and a genetic form, with different treatments, thus a correct clinical diagnosis becomes essential [4, 6, 8].[cyberleninka.org]

Epidemiology

  • Summary Epidemiology The prevalence is unknown but approximately 150 cases have been described so far. Clinical description Wilms tumour may be the first clinical manifestation of the syndrome.[orpha.net]
  • Epidemiology Frequency International The frequency of Denys-Drash syndrome is unknown.[d.hatena.ne.jp]
  • Epidemiology Frequency International The frequency of Denys-Drash syndrome is unknown.[emedicine.medscape.com]
Sex distribution
Age distribution

Pathophysiology

  • More than 2,000 disease genes have been identified in the last 20 years, providing important new insight into the pathophysiology of diseases in every field of medicine.[books.google.com]
  • Brenner/Rector remains the go-to resource for practicing and training nephrologists and internists who wish to master basic science, pathophysiology, and clinical best practices.[books.google.com]
  • Pathophysiology Denys-Drash syndrome is the result of mutations in the WT1 gene on chromosome band 11p13.[2, 3, 4, 5] The WT1 gene contains 10 exons that produce 4 different messenger RNAs (mRNAs) as a result of 2 alternative splicing sites in exons 5[d.hatena.ne.jp]
  • Wilms′ tumor suppressor gene WT1: From structure to renal pathophysiologic features. J Am Soc Nephrol 2000;11 Suppl 16:S106-15. 4. Chiang PW, Aliaga S, Travers S, Spector E, Tsai AC.[jiaps.com]
  • Ottens F, Gehring NH: Physiological and pathophysiological role of nonsense-mediated mRNA decay. Pflugers Arch 468:1013-1028 (2016).[karger.com]

Prevention

  • Management and treatment Treatment is supportive and consists of adequate nutrition, prevention and treatment of infectious complications, and management of renal failure.[orpha.net]
  • Treatment is based on both the stage and histology of the Wilms’ tumor. [8] Surgery : The goal of surgery is to remove the tumor in one unit to prevent the spread of cancer cells into the abdomen. [3] There are several types of nephrectomy that can be[physio-pedia.com]
  • […] individual with Wilms tumor and families with one individual with bilateral or multifocal Wilms tumor, it is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive[ncbi.nlm.nih.gov]

References

Article

  1. Devriendt K, Deloof E, Moerman P, et al. Diaphragmatic hernia in Denys-Drash syndrome. Am. J. Med. Genet. 1995;57:97-101.
  2. Antonius T, van Bon B, Eggink A, et al. Denys-Drash syndrome and congenital diaphragmatic hernia: another case with the 1097G-A (arg366his) mutation. Am. J. Med. Genet. 2008;146A:496-499.
  3. Schumacher V, Scharer K, Wuhl E, et al. Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations. Kidney Int. 1998;53:1594-1600.
  4. Jadresic L, Leake J, Gordon I, et al. Clinicopathologic review of twelve children with nephropathy, Wilms tumor, and genital abnormalities (Drash syndrome). J. Pediat. 1990;117:717-725.
  5. Roca A, Carrion A, Gutierrez M, et al. Evolutive study of children with diffuse mesangial sclerosis. Pediatr Nephrol. 2009;24(5):1013-1019.
  6. Patel P, Pappas J, Arva N, et al. Early presentation of bilateral gonadoblastomas in a Denys-Drash syndrome patient: a cautionary tale for prophylactic gonadectomy. J Pediatr Endocrinol Metab. 2013;26(9-10):971-974.
  7. Eneman B, Mekahli D, Audrezet M, et al. An unusual presentation of Denys-Drash syndrome due to bigenic disease. Pediatrics. 2014;133(1):e252-c256.
  8. Zhu C, Zhao F, Zhang W, et al. A familial WT1 mutation associated with incomplete Denys-Drash syndrome. Eur J Pediatr. 2013;172(10):1357-1362.
  9. Wang H, Sun L, Yue Z, et al. Clinical and pathological features of Denys-Drash syndrome: report of 3 cases. Zhonghua Er Ke Za Zhi. 2012;50(11):855-858.
  10. Hakan N, Aydin M, Erdogan O, et al. A novel WT1 gene mutation in a newborn infant diagnosed with Denys-Drash syndrome. Genet Couns. 2012;23(2):255-261.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2019-06-28 11:01