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Case Report: Denys--Drash syndrome.

Abstract

Background: Denys-Drash Syndrome (DDS) is an uncommon disorder that appears sporadically and in rare cases may be inherited as an autosomal dominant trait. It manifests either at birth or within the first year of life and typically consists of the triad of congenital nephropathy, Wilms tumour and intersex disorder. Case Report: A 10 year-old Caucasian girl was referred to the Dental Department, at Glasgow Royal Hospital for Sick Children by her Paediatric Nephrologist Consultant. The patient was being teased by her peers over her markedly discoloured teeth. The dental history revealed that the patient was a regular dental attendee from an early age. She was dentally anxious having only experienced dental treatment under general anaesthesia when she was 4 years old. Apparently her primary dentition also showed a generalised discolouration. Treatment: This consisted of multiple visits for diet analysis and tooth brushing instruction with the use of disclosing tablets. Plaque control significantly improved when using a battery operated toothbrush because of its larger handle which the patient found easier to use and a 0.05% sodium fluoride mouthwash was given for daily use. Dyract (AP) veneers directly bonded onto maxillary permanent incisors and mandibular permanent anterior teeth was carried out. This was an interim measure to improve the patient's appearance while assessing the patient co-operation. The compomer facings were replaced with belleGlass NG veneers which were cemented onto the maxillary incisors and mandibular anterior teeth using Adhesive By Choice (ABC) system under rubber dam on two separate visits. Follow-up: 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.

Key words: Denys Drash syndrome, Nephrotic syndrome, renal transplant, intrinsic discolouration, hypoplastic dentition, belleGlass NG Veneers

Background

Denys-Drash Syndrome (DDS) is an uncommon disorder that appears sporadically and in rare cases may be inherited as an autosomal dominant trait [Eddy and Mauer, 1985; Coppes et al., 1993; Mueller, 1994; Koziell and Grudny, 1999] It manifests either at birth or within the first year of life and typically consists of the triad of congenital nephropathy, Wilms tumour and intersex disorder [Coppes et al., 1993; Schumacher et al., 1998; Koziell and Grudny, 1999; Pritchard-Jones, 1999; Heathcott et al., 2002]. In some cases the incomplete form of the disorder is present, consisting of abnormal kidney function with either Wilms' tumour or genital abnormalities (pseudohermaphroditism) [Jadresic et al, 1990; Coppes et al., 1993; Mueller, 1994; Schumacher et al., 1998; Koziell and Grudny 1999]. The frequency of DDS is unknown and it has no racial predilection. However, 150 cases have been reported world wide [Mueller, 1994] since first described by Denys et al. [1967] and by Drash et al., [1970].

Although DDS predominantly affects males, a few female cases have been reported. However, the presence of inter-sex disorder makes the estimation misleading as individuals with DDS who are assigned the female gender may be genotypic males (i.e. XY karyotype with female phenotype) [Eddy and Mauer, 1985; Mueller, 1994]. It seems that the majority of patients with DDS have male karyotype and present with a wide spectrum of gonadal abnormalities, while female karyotype patients have less severe or no gonadal abnormalities [Jadresic et al., 1990; Koziell and Grudny, 1999].

DDS (Online Mendelian Inheritance in Man #194080) is a result of mutation in the Wilms tumour suppressor (WT1) gene on chromosome band 11p13 [Rauscher, 1993; Habib, 1993; Koziell and Grudny, 1999]. The WT1 gene encodes a zinc finger DNA-binding protein that acts as a transcriptional activator or repressor depending on the cellular or chromosomal context. WT1 is required for normal formation of the genitourinary system and gonadogenesis before sex differentiation [Rauscher, 1993; Schumacher et al, 1998]. The point mutation in the WT1 gene results in loss of its regulatory function, with the consequent abnormalities in gonadal differentiation seen in DDS [Coppes et al., 1993; Habib, 1993; Schumacher et al., 1998].

Nephropathy is a constant feature in the incomplete forms of DDS, which coexists with either Wilms tumour or intersex disorders [Jadresic et al., 1990; Koziell and Grudny, 1999]. The vast majority of DDS patients are destined to develop Wilms tumour in any renal tissue and are also at risk for development of gonadoblastoma in the dysgenetic gonads [Eddy and Mauer, 1985; Rudin et al., 1998]. Due to the nephropathy which manifests in infants aged 2 weeks to 18 months and Wilms tumour with a median age for occurrence of 18 months [Eddy and Mauer, 1985; Koziell and Grudny, 1999], the syndrome has a high morbidity and mortality rate.

There is no cure for DDS, but the management relies on the fluid and electrolyte balance, treatment of hypertension, renal replacement therapy for patient with bilateral nephrectomy and chemotherapy for DDS with Wilms tumour. Many surgeons advocate a prophylactic total bilateral nephrectomy as the very high risk of development of Wilms tumour in any residual renal tissue [Eddy and Mauer, 1985; Jadresic et al., 1990; Schumacher et al., 1998; Rudin et al., 1998]. The treatment of choice after bilateral nephrectomy would be kidney transplantation [Eddy and Mauer, 1985; Rudin et al., 1998].

The authors are not aware of reports of dental findings in the Dental or Medical literature on DDS apart from one paper which documented cleft lip and palate in a patient suffering with this condition [Jadresic et al., 1990].

Case Report

Medical history. A 10 year-old Caucasian girl was 'referred to the Dental Department, at Royal Hospital for Sick Children (Glasgow) by her Paediatric Nephrologist Consultant. The patient was being teased by her peers over her markedly discoloured teeth. The dental history revealed that the patient was a regular dental attender from an early age. She was dentally anxious having only experienced dental treatment under general anaesthesia (GA) when she was 4 years old. Apparently her primary dentition also showed a generalised discolouration.

The patient's medical history included epilepsy, behavioural difficulty and developmental delay. She was born at 31 weeks gestation and was diagnosed with congenital nephrotic syndrome at age 2 weeks when haemodialysis commenced, which was followed by peritoneal dialysis until the age of 4.5 years. At age 4.5 years she underwent a cadaveric renal transplant and was diagnosed of developing Post Transplant Lymphatic Disorder (PTLD) nine months post transplant which was managed by reducing her immuno-suppressant drugs. Coincidentally due to PTLD she had both tissue and peripheral lymphocyte chromosome analysis carried out which showed an XY genotype and WT1 gene deletion (R366H mutation detected). Further tests were carried out which showed streaks of fibrous tissue instead of properly formed ovaries which led to the diagnosis of DDS.

At the time of presentation the patient's medications included Tacrolimus, Prednisolone, Nifedipine, Epilim and Augmentin.

Dental condition. An intra-oral examination revealed fair oral hygiene. However, there was generalised gingival overgrowth, as the result of Epilim and Nifedipine medication (Fig 1a, 1b).

The following teeth were present 16, 55, 14, 53, 12, 11, 21, 22, 24, 65, 26, 36, 75, 34, 33, 32, 21, 41, 42, 43, 44, 85, 46

[FIGURE 1a OMITTED]

[FIGURE 1b OMITTED]

There was generalised dark amber discolouration and hypoplasia of all the erupted teeth (Fig1a, b). A dental orthopantomogram (Fig 2) revealed noticeable enamel hypoplasia affecting the developing second permanent molars and the developing premolars. There was prominent divergence of the roots of the first permanent molar teeth and the developing roots of the second permanent molars had a similar appearance. The roots of the remaining teeth, particularly the maxillary incisors, had an increased width which made the cervical constriction look much more apparent.

Histology. Two exfoliated primary teeth were sent to the Dept. Oral Pathology for ground section. The report showed that the enamel was prismatic, with evidence of enamel hypoplasia. There were unusual prominent striae of Retzius present (Fig 3). The dentine showed unusual prominent contour lines of Owen and areas of interglobular dentine. The enamel and dentine features were consistent with a development abnormality of environmental origin

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Treatment. In view of the patients' age, medical history, developmental delay and dental anxiety and following discussions with the patient and her mother a preventive program was started to keep the teeth and soft tissues healthy. This consisted of multiple visits for diet analysis and tooth-brushing instruction with the use of disclosing tablets. Plaque control significantly improved when using a battery operated toothbrush because of its larger handle which the patient found easier to use. In view of the hypoplastic teeth which are more prone to caries [Daneshkazemi and Davari, 2005] and a history of caries in the primary dentition a 0.05% sodium fluoride mouthwash was given for daily use.

After achieving good oral hygiene, and following dietary advice, Dyract([R]) veneers directly bonded onto maxillary permanent incisors and mandibular permanent anterior teeth was carried out. This was an interim measure to improve the patient's appearance while assessing the patient co-operation for treatment and establishing if more permanent veneers were feasible, taking into account the histological nature of the enamel and dentine. The patient coped very well, but although the initial result was good, over time it deteriorated. The compomer facings were replaced with belleGlass NG veneers which were cemented onto the maxillary incisors and mandibular anterior teeth using Adhesive By Choice (ABC) system under rubber dam on two separate visits (Fig 4a). The patient and her family were pleased with the results and later reported that the teasing has stopped and her confidence at school had increased. The first permanent molars were subsequently restored with preformed chrome cobalt crowns and cemented with AquaCem under local analgesia (Fig 4b).

Follow-up. The patient was reviewed on a four monthly basis, when her toothbrushing was assessed and reinforced, as well as diet advice. The long term treatment plan was to cover the premolars with belleGlass NG crowns once they had fully erupted. As the patients plaque control was good, there were no signs of gingivitis and the gingival overgrowth was stable and not progressive, chlorhexidine mouthwash or gel was not indicated. The patient continued to be seen on a regular basis to reinforce the preventive message and review the performance of the veneers and chrome cobalt crowns. 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. It was also decided to replace the preformed chrome cobalt crowns with full coverage belleGlass NG crowns.

Discussion

Therefore renal graft survival after cadaver grafting reaches 83% after the first year and 65% after 5 years, general dental practitioners are likely to encounter patients requiring dental care who have received a renal transplant [Davidovich et al., 2005a]. It is important that dentists are aware of complications that may arise in the dental treatment of these patients as a result of the disease itself and/or the medical treatment. This includes the use of immunosuppressive drugs to prevent rejection of the renal transplant e.g Tacrolimus and Prednisolone as in this case report. Tacrolimus is a relatively new immunosuppressive drug preferred for its more aggressive immunosuppression and more desirable side effects including less gingival overgrowth [Davidovich et al., 2005a].

Prednisolone in children can cause growth retardation, mineralocorticoid and glucocorticoid side effects, adrenal suppression and susceptibility to infections. Hypertension, a mineralcorticoid side effect, was controlled, in this case, with a calcium channel blocker, Nifedipine, which can also lead to gingival overgrowth. The latter is believed to be related to an alteration of fibroblast metabolism by Cyclosporine and its metabolities, or due to increase in protein syntheses [Alfonso et al., 2003; Davidovich et al., 2005a;]. Patients with drug induced gingival overgrowth may be psychologically affected due to the unpleasant appearance. In severe cases normal oral function may also be affected. The gingival overgrowth makes it more difficult to maintain oral hygiene and delayed and / or ectopic eruption may also be seen [Chabria et al., 2003; Davidovich et al., 2005a].

[FIGURE 4a OMITTED]

[FIGURE 4b OMITTED]

In patients with renal transplant the prevalence of gingival overgrowth is extremely variable as it depends on the age of the patients (children have higher prevalence than adults), gender as males have higher prevalence and the degree of immunosuppression [Davidovich et al., 2005a]. Treatment may be conservative as in this case where meticulous oral hygiene is practiced, this could be coupled with gingivectomy/ gingivoplasty. The patient needs to be made aware that recurrence is common, a delay in surgery for at least three years may be beneficial in reducing the recurrence rate [Chabria et al., 2003].

One study which compared children and adolescents with renal failure to a control group found that the renal failure group had higher gingival index, bleeding on probing and attachment loss [Davidovich et al., 2005b]. If deposition of enamel is temporarily disturbed during its development the corresponding layers will appear hypoplastic after eruption [Li, 1999]. The dental findings in patients with nephrotic syndrome, renal failure and/or renal dialysis, including enamel hypoplasia in the form of white and brown discolouration has been well documented in the literature [Cark et al., 1988; De Rossi and Glick, 1996]. It is well known that renal disease leading to chronic renal failure may affect enamel formation of primary teeth in early postnatal life resulting in lesions different from those observed in the secondary dentition [Cark et al., 1988; De Rossi and Glick, 1996]. An ultra structural study confirmed that the disturbances in the mineralization of hard tissues in patients suffering from chronic renal failure are the result of complex pathophysiologic alterations in calcium and phosphorus metabolism [Cark et al., 1988].

It is likely that the hypoplasia in this patient's teeth was due to her early renal disease which caused disturbances in the formation of the enamel although the radiographic features are not distinctive of a particular disease [Spolnik et al., 1981]. However, the prominent divergence of the roots of the first and second permanent molars and the roots of the remaining teeth, particularly the maxillary incisors, which had an increased width, could be related to DDS. The pathology report suggested that the enamel and dentine features were most likely the result of environmental factors. The dental findings in this case could be the result of the patients nephrotic syndrome and early renal failure as the findings are similar to a study carried out by Bublitz et al. [1981] where 73 paediatric patients with nephrotic syndrome were examined and the enamel changes in the permanent teeth consisted of white discolouration and enamel hypoplasia but in this case the teeth were amber in colour.

The amber discolouration of the teeth was successfully masked with belleGlass NG veneers as tooth preparation is not necessary and at this age the teeth are still not fully developed. The belleGlass NG veneers consist of a mixture of aliphatic and urethane dimethacrylate resins with the smallest, most uniform glass crystals available. Excellent aesthetics with long term durability particularly in adults have been reported but details of its use in Paediatric Dentistry are scarce. The belleGlass NG veneers have a unique curing process in which it is the only polymer glass material which is finally cured in a high-heat, nitrogen dry atmosphere. The curing in the presence of heat, pressure and an inert gas allows for the creation of more free radicals and this results in more resin volume being polymerized as compared to 60-70% traditionally achieved with light curing alone. This makes them longer lasting and stronger than ordinary composite fillings [Gaintantzopouluo et al., 2005]. The clinical advantages of belleGlass NG veneers are that they may be adjusted, modified, and refinished at the chair side. The annual wear rate is equal or slightly less than natural enamel and it has excellent abrasive resistance and surface finish. Porcelain veneers / crowns and gingivectomy will be considered when the patient is older.

Acknowledgements

The authors would like to thank Dr L. Cooper, Consultant Histopathologist at Department of Pathology at Glasgow Dental Hospital and School for providing the pathology slide, Mr D. Thomson specialist registrar in Oral Radiology at Glasgow Dental Hospital and School for reporting on the radiographs, and Medical Illustration at the Royal Hospital for Sick Children for providing digital radiographs and clinical photographs of this patient

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A. B. Ammari, D. E. Fung

Child Dental Health Department, Royal Hospital for Sick Children, Glasgow, Scotland

Postal address: Dr A. B Ammari, Child Dental Health Department, Royal Hospital for Sick Children Dalnair Street, Glasgow G3 8JJ, Scotland.

Email: amera.ammari@northglasgow.scot.nhs.uk
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Author:Ammari, A.B.; Fung, D.E.
Publication:European Archives of Paediatric Dentistry
Date:Dec 1, 2007
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