Mucosal Leukoplakia Research Articles

What is your diagnosis?: A 10-year-old female with abnormal keratinisation and epistaxis

Dyskeratosis congenita, an inherited disorder of telomere accretion primarily affects ectoderm, manifesting as skin, nail and mucosal changes. We here present a novel association of dyskeratosis congenita with systemic lupus erythematosus in a 10-year-old female. The patient had classical triad of lacy reticular skin pigmentations, nail dystrophy and mucosal leukoplakia. Also, she had pancytopenia, blepharitis, nasolacrimal duct obstruction, dental decay with gingival recession, tooth loss, hirsutism and atrophic scarring of palms. On funduscopy, pre-retinal and superficial flame shaped haemorrhages were present. Anti-double stranded DNA antibody and antinuclear antibodies were positive. On treatment with steroids, partial response was seen. It is further emphasized the need to investigate for markers of systemic lupus erythematosus in every case presenting as dyskeratosis congenita to establish the causal relationship between dyskeratosis congenita and systemic lupus erythematosus.

Telomerase and telomere in dyskeratosis congenita

Dyskeratosis congenita (DC) is a rare skin disorder with heterogeneity, which is characterized by mucosal leukoplakia, nail dystrophy, abnormal skin pigmentation, bone marrow failure, cancer predisposition and other system damage. Currently, it is revealed that the pathogenesis of DC is related to the shortening of telomere length. Gene mutation of telomerase complex may result in a decline in telomerase activity and shortening of telomere length. This paper presents the advances in researches of telomerase complex genes responsible for reduction in telomerase activity and shortening of telomerase length, which may facilitate further elucidation of DC pathogenesis. Key words: Dyskeratosis congenita; Telomere; Genes

The Effects of Pathogenic Dkc1 Mutations on Telomerase and Ribosome Biogenesis.

AbstractAbstract 1163Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome (BMF) associated with a predisposition to cancer. It is diagnosed by the triad of abnormal skin pigmentation, nail dystrophy and mucosal leukoplakia. X-linked DC, accounting for around one third of DC patients, is due to the mutations in the DKC1 gene which encodes the protein dyskerin. Dyskerin is a component of small nucleolar RNA particles (H/ACA snoRNP) active in the pseudouridylation of specific residues in nascent ribosomal RNA (rRNA). It also plays an important role in maintaining the telomere repeats at the ends of chromosomes by forming and stabilizing the telomerase complex. Patients with Dkc1 mutations show a wide variation of severity emphasizing the variable expression of the disease and the influence of other genetic and environmental factors. Most mutations are clustered, in the 3D structure, in a region important for RNA binding and few mutations are present in the pseudouridine synthesis activity domain. The relationship between the severity of DC and the position of the mutation in dyskerin is still unclear. It will be interesting to compare the pathogenic effects of Dkc1 mutations in different positions of dyskerin protein. Since the production of mutant lines of mouse is time consuming, expensive, and may be difficult, here we established a suitable in vitro system to express mutant dyskerin in MEF cells. We began with MEF cells containing a Dkc1 gene that is deleted in the presence of Cre. Mutated dyskerin introduced by a retroviral vector is expressed and wild type (WT) dyskerin is deleted by retrovirally introduced Cre-ERT2 and subsequent tamoxifen treatment, which activates the Cre-ERT2 protein. MEF cells are then single cell cloned and selected cells that grew well and contained for the mutant dyskerin gene but not the WT gene. We obtained cell lines with several mutations including I38T, H68Q, S121G and A353V as well as WT control. All of these mutations are recurrent ones and cause severe bone marrow failure in patients. Interestingly, we also obtained a D125A mutant cell line. This mutation has not been found in human patients but is an alteration of a crucial catalytic aspartic acid residue that is essential for pseudouridylation activity. All of these Flag-tagged dyskerin proteins showed a normal nucleolar sub-cellular distribution pattern. We chose the cells expressing similar levels of flag-tagged dyskerin to WT dyskerin to do further experiments. The exception to this was the D125A mutation because all the clones express tiny amounts of flag-tagged dyskerin. First, we measured the Dkc1 mRNA level of these mutant cells and found the expression of Dkc1 mRNA in these mutant cells is 3–8 fold higher than in WT cells (25 fold higher for D125A). This result indicates that the mutant dyskerin proteins in these cells are very unstable, so more mRNA has to be produced to maintain growth. Then, we studied the growth curves of these cells and found that all mutant cells showed more or less slower growth rate than WT. Notably, the D125A mutant cells showed extremely slow growth. We find that the expression of Terc is lower than WT in all mutant cells (10∼50% compared to WT) while telomerase activity was not significantly decreased except for the D125A mutant. By Q-FISH, we showed the telomere length of all mutant cells is shorter than WT control cells and the number of telomere free ends is increased in these mutant cells. These findings indicate that all Dkc1 mutations affect the telomerase function and cause rapidly shortening telomeres. In ribosome biogenesis we found that, although I38T, H68Q, S121G and A353V mutant cells did not show significant changes in the ribosomal profile and ribosomal processing, D125A mutant cell showed significantly delayed maturation of rRNA as well as dramatically decreased amounts of mature 80S ribosomes. Further investigation revealed that the D125A mutation abolished in vivo pseudouridylation of rRNA. Together with our previous results this study further indicates that compromised telomerase function is the major effect of the pathogenic Dkc1 mutations. We also show, surprisingly, that mammalian cells can grow and survive with no pseudouridine in their rRNA. Disclosures:Bessler:Alexion Pharmaceutical Inc: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taligen: Consultancy.

Compound heterozygosity for two new TERT mutations in a patient with aplastic anemia

Dyskeratosis congenita (DC) is a genetically heterogeneous syndrome characterized by reticular skin pigmentation, nail dystrophy, mucosal leukoplakia, short telomeres, and a predisposition to bone marrow failure and malignancy. Patients carrying mutations in TERT show a wide clinical spectrum of abnormalities, including classical DC, isolated bone marrow failure and lung fibrosis. Here, we report the clinical description and biological analysis of a patient with compound heterozygosity for two new missense mutations in TERT (V96L and V119L). Both mutations segregate with a short telomere phenotype, though only V96L segregates with clinical signs of DC.

A case of laryngeal carcinoma in a young adult with dyskeratosis congenita

Dyskeratosis congenita (DC) is an inherited disorder that is characterized by the triad of skin pigmentation, nail dystrophy, and mucosal leukoplakia. Individuals with DC suffer from premature mortality because of bone marrow failure, pulmonary disease, or malignant transformation within the areas of mucosal leukoplakia, caused by telomerase dysfunction. We present a case of a 31-year-old Japanese man with DC who developed laryngeal cancer (supraglottic T4aN0M0). To avoid the serious risks of accelerating the DC-associated complications by DNA-damaging therapies, he was treated with a total laryngectomy plus right modified neck dissection (levels IB, IIA, III, and IV). A contralateral nodal metastasis appeared 4 months after initial surgery and was salvaged by a left radical neck dissection. Our strategy to spare DNA-damaging therapies has proven effective so far. This is the first reported case of laryngeal cancer in a patient with DC in the English-language medical literature.

Identification of a novel mutation in DKC1 in dyskeratosis congenita

Dyskeratosis congenita (DC) is a rare congenital syndrome characterized by the triad of reticular skin pigmentation, nail dystrophy and mucosal leukoplakia, and the predisposition to bone marrow failure and malignancy. DC is genetically heterogeneous and X-linked and autosomal forms of the disease exist. Here, we report the clinical description and mutation analysis of a Russian family with X-linked DC. A novel mutation in DKC1 raised de novo in the maternal grandmother's gamete was found; this mutation is a 2 bp inversion in exon 3: NM_001363:c.166_167invCT (Leu56Ser).

ATM in breast cancer susceptibility – results of a pooled analysis of case-control mutation screening data

Dyskeratosis congenita (DKC) is a rare and fatal congenital syndrome characterized by the triad of reticular skin pigmentation, nail dystrophy and mucosal leukoplakia, and the predisposition to bone marrow failure and malignancies. Mutations in DKC1 gene encoding dyskerin are responsible for the X-linked dyskeratosis congenita. Here we report mutation analysis of two Chinese pedigrees with dyskeratosis congenita. The 15 coding exons of DKC1 and their flanking regions were amplified from genomic DNA by PCR. DNA sequencing and restriction endonuclease digestion were used for mutation detection. Transition mutation of 1226C→T (P409L) found in the first pedigree is a novel mutation. In the second pedigree, the proband's mother phenotypically normal carried a de novo transition mutation of 1058C→T (A353 V) in one allele, and transmitted the mutant allele to her two sons who had typical manifestations of dyskeratosis congenita.

Retinal hemorrhages in a patient with dyskeratosis congenita

Dyskeratosis congenita, also referred to as Zinsser-Cole-Engman syndrome, is characterized by reticular skin pigmentation, dystrophic nail changes, and mucosal leukoplakia. Other findings include carious teeth, premature graying of hair, and osteoporosis. Approximately 50% of patients develop pancytopenia. Ophthalmologic manifestations include blepharitis, conjunctivitis, obliteration of the lacrimal puncta, nasolacrimal duct obstruction, ectropion, and loss of eyelashes. We report bilateral retinal hemorrhages from pancytopenia in a patient with dyskeratosis congenita.

Significance of Telomere Length Measurement in the Diagnosis of Dyskeratosis Congenita.

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure (BMF) syndrome. The classical features of DC include nail dystrophy, abnormal skin pigmentation, and mucosal leukoplakia. The diagnosis of DC can be difficult. Originally, the diagnosis was based on the presence of the classical mucocutaneous features. However, the identification of four genes responsible for DC (DKC1, TERC, TERT, and NOP10) showed that these mucocutaneous features are only present in a proportion of patients with DC. Additionally, screening for mutations in the affected genes is expensive and is negative in about 50% of patients with classical features of DC. The products of the genes mutated in DC are the components of the telomerase ribonucleoprotein complex, which is essential for telomere maintenance. Therefore it has been postulated that DC is a disease arising from excessive telomere shortening. Here we examined whether the measurement of telomeres could be used as a screening test to identify individuals with DC. For this purpose we examined telomere length in peripheral blood mononuclear cells from 169 patients who presented with bone marrow failure including 17 patients with DC, diagnosed by the presence of classical cutaneous features or the identification of mutations in DKC1, TERC or TERT, 28 patients with paroxysmal nocturnal hemoglobinuria, 25 patients with Diamond Blackfan anemia, 5 patients with Shwachman-Diamond syndrome, 8 patients with myelodysplastic syndrome, and 74 patients with aplastic anemia of unknown cause classified as idiopathic aplastic anemia. In addition we measured telomere length in 12 patients with idiopathic pulmonary fibrosis and in 45 individuals with a de novo deletion of chromosome 5p including the TERT gene. Their telomere lengths were compared with those of 202 age-matched healthy controls. Moreover, mutations were screened in the genes associated with DC. In cases where a mutation was identified, telomere length and mutations were also examined in all the family members. Our results show that all patients with DC and bone marrow failure have very short telomeres far below the first percentile of healthy controls. Not all mutation carriers, including some carriers of apparently dominant mutations, have very short telomeres. What is more, very short telomeres could be found in healthy individuals in these families, some of whom were not mutation carriers. These findings indicate that in patients with BMF the measurement of telomere length is a sensitive screening method for DC, whether very short telomeres in this setting are also specific for DC remains to be determined. However, in contrast to a previous study, we find that telomere length does not always identify mutation carriers in the families of DC.

The Impact of Telomere Shortening in Dyskeratosis Congenita Cells on DNA Damage Response Pathways.

Dyskeratosis congenita (DC) is an inherited multisystem disorder of premature aging, typically characterized by bone marrow failure, mucosal leukoplakia, abnormal skin pigmentation, and nail dystrophy. The X-linked and autosomal dominant forms of DC are associated with mutations in genes that affect telomerase activity resulting in a decrease in telomere length. DC, like other bone marrow failure disorders, is associated with ineffective hematopoiesis and a cancer predisposition. Standard treatment of bone marrow failure or cancer requires cytotoxic therapy, and clinical observations suggest DC patients have an increased sensitivity to cytotoxic therapy. To explain this, we hypothesized that the short telomeres in somatic cells from DC patients could alter the activity and/or expression of several proteins involved in DNA repair or the response to cellular stress including p16, p53 and p21. Lymphocytes from five DC subjects and age-matched controls were stimulated to grow in vitro in the presence of various cytotoxic agents with different modes of action, including Taxol (antimitotic agent and microtubule inhibitor) and Etoposide (topoisomerase inhibitor and DNA damaging agent). In addition, we tested fibroblasts and keratinocyte extracted from skin biopsies from DC and control subjects that were serially passaged. Cellular proliferation and cell death were monitored by cell counts and flow cytometry. Western blotting was used to measure steady state and DNA damage- induced expression of tumor suppressor protein p53 and other proteins involved in DNA damage response signaling pathway, including p16 and p21 in relation to telomere length. Results of flow cytometry accompanied by direct visualization showed a decreased proliferation of DC lymphocytes compared to normal cells, and this growth disadvantage was further accentuated following cell exposure to cytotoxic agents. DC lymphocytes exposed to 10−6 M Taxol showed a decrease in cellular proliferation between 3 and 8 fold while normal control cells exposed to the same agents exhibited only a 3 to 4 fold decrease in cell growth. Similarly DC lymphocytes exposed to Etoposide were inhibited to a greater extent than control cells. Western blot analysis of whole cell lysates indicated a difference in DNA damage response proteins. Of note, lymphocytes from several DC subjects exposed to Taxol did not upregulate p53 expression, while inducible levels were noted in Taxol-treated control cells. In contrast, DC and control lymphocytes exposed to Etoposide upregulated p53 in a similar dose dependent manner. No differences were noted in DC versus control lymphocytes with regards to basal or chemotherapy induced p16 expression. Interestingly, late passage DC fibroblasts displayed enhanced basal expression of p16. These results support the clinical observation of increased “chemosensitivity” in DC subjects and suggest that diminished telomerase activity and premature telomere shortening may interfere with normal DNA damage and stress response pathways. These data are also consistent with our finding that DC fibroblasts, keratinocytes, and lymphocytes have a reduced cell proliferative lifespan. Further studies are needed to dissect the role of telomeres in the cellular response to various types of DNA damage.

Homozygous and Compound Heterozygous Mutations in the Telomerase Reverse Transcriptase Gene in Two Families with Spontaneous Dyskeratosis Congenita and Idiopathic Aplastic Anemia.

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome. Classically, DC presents with progressive bone marrow failure, abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia. The pattern of inheritance in families with DC suggests an X-linked recessive, an autosomal dominant, and an autosomal recessive form of DC. However, in the majority of patients the occurrence of the disease is sporadic or the family history is unknown. Mutations in four different genes have been associated with DC so far. Mutations in DKC1 have been shown to account for the X-linked form of DC and DKC1 de novo mutations account for about one third of male patients with sporadic disease. Mutations in the telomerase RNA TERC and in the catalytic subunit of telomerase, TERT, have been shown to be responsible for the autosomal dominant form of DC. Interestingly, patients with heterozygous mutations in TERC and TERT often show a milder form of disease and a later age of onset and often lack the classic mucocutaeous features, thus are classified as atypical DC. Very recently homozygosity for a mutation in NOP10 has been identified in one family with autosomal recessive disease. The products of the genes mutated in DC are all components of the telomerase complex, suggesting that disease in patients with DC is caused by a defect in telomere maintenance. Here we investigated two patients, one UPN # 199.001 presenting with the classic manifestations of DC and the other UPN# 284.001 presenting with progressive bone marrow failure but no other clinical features suggestive of DC. In both patients the telomeres measured in peripheral blood mononuclear cells were very short, being defined as being below the 1st percentile. Mutation analysis in the genes associated with DC revealed that patient 199.001 was homozygous for a novel TERT (C2110T) gene mutation, causing an amino acid change (P704S) within the RT domain of TERT. Both parents were heterozygous for the C to T transition. Interestingly however, the father was in addition heterozygote for a second mutation in TERT (C1234T; H412Y) a mutation which has previously been described and has been shown to reduce telomerase activity by 50%. Investigations of the family revealed that the parent's were distantly related, explaining the same TERT sequence alteration in both parents. Both arms of the family contained members with pulmonary fibrosis. In the second patient 284.001 we identified two different novel TERT gene mutations. One A2537G causes the amino acid change Y846C in the RT domain of TERT whereas the other C2628G causes H876Q also in the RT domain. One of the mutations was inherited from each parent and the parent with the A2537G mutation also had very short telomeres. These two families illustrate that the pattern of inheritance in patients with DC may be complex and show for the first time that homozygous or compound heterozygous TERT gene mutation may be associated with DC. Co-dominance of the three different TERT gene mutations and the inheritance of short telomeres have possibly contributed to development of disease in these patients who were thought to have sporadic DC and idiopathic aplastic anemia.

Dyskeratosis congenita: oral hyperkeratosis in association with lichenoid reaction

Dyskeratosis congenita is an inherited disorder that usually presents in males, consisting of a triad of leukoplakia of the mucous membranes, nail dystrophy and skin pigmentation. Whilst most cases are X-linked, autosomal dominant and recessive forms have also been reported. The significance of the condition lies in premature mortality arising from either bone marrow failure or malignant change within the areas of mucosal leukoplakia. We present a case (X-linked recessive form) where the classic triad of signs were present, along with the development of lichenoid reaction in the buccal and labial mucosa. This is believed to be the first case in which such a reaction has been noted together with the oral hyperkeratosis. The identification of a white patch within the mouth of a child, in the absence of any other obvious cause must arouse suspicion of this rare condition. All clinicians should be aware of this rare genetic disorder so that early referral can be made and appropriate management instigated.

A quantitative assessment of Langerhans cells in oral mucosal lichen planus and leukoplakia.

Quantitative analysis of Langerhans cells stained with OKT6 in the epithelium of 42 patients with oral mucosal lichen planus and 14 patients with oral mucosal leukoplakia showed significantly greater numbers of Langerhans cells in lichen planus. This may reflect the role of Langerhans cells in the pathogenesis of this condition and their identification could help in distinguishing lichen planus from leukoplakia.

Absence of DKC1 exon 3 mutation in common human cancers

Dyskeratosis congenita is a genetic disease caused by point muations in the DKC1 gene [1]. Patients with dyskeratosis congenita show bone marrow failure syndrome characterized by abnormal skin pigmentation and mucosal leukoplakia [2]. Of note, a subset of patients with dyskeratosis congenita developed malignant tumors of various histologic origins [2]. Also, DKC1 mutant mice were highly susceptible to tumor development, and the most common tumors were lung and breast tumors [3]. These observations suggested that DKC1 may be a tumor suppressor gene. DKC1 protein normally binds with small nucleolar RNAs and the RNA components of telomerase, and these functions are impaired in the cells of the DKC1 mutant mice [3]. In the individuals with dyskeratosis congenita, DKC1 gene mutation is detected usually in the exon 3, strongly suggesting that these mutations may related with the disease phenotypes [1,4,5]. It could be hypothesized that increased incidence of malignant tumors in the dyskeratosis congenita patients might be related to the DKC1 mutations. It is of interest to see whether the DKC1 gene is somatically mutated in human cancers. However, to date, the data on the somatic mutations of DKC1 in human sporadic cancers is lacking. The aim of this study was to see whether common human sporadic cancers harbor DKC1 mutation. We have analyzed methacarn-fixed tissues of 140 gastric carcinomas, 104 colorectal carcinomas, 94 breast ductal carcinomas, 100 non-small cell caners and 69 hepatocellular carcinomas. All of the patients of the cancers were Asians (Koreans). The gastric carcinomas consisted of 60 diffuse-type, 49 intestinal-type and 31 mixed-type gastric adenocarcinomas by Lauren’s classification, and 25 early and 115 advanced gastric carcinomas according to the depth of invasion. The colorectal carcinomas originated from cecum (n /2), ascending colon (n /19), transverse colon (n /6), descending colon (n /4), sigmoid colon (n /28) and rectum (n /45). The breast carcinomas consisted of 15 intraductal and 79 invasive ductal carcinomas. The non-small cell lung cancer samples consisted of 50 adenocarcinomas, 47 squamous cell carcinomas, 1 adenosquamous carcinomas and 2 large cell carcinomas. The hepatocellular carcinomas consisted of Edmondson grade I (n /8), grade II (n /30) and grade III (n / 31) according to Edmondson and Steiner’s criteria [6]. Malignant cells and normal cells from the same patients were selectively procured from hematoxylin and eosin-stained slides using a 30G1/2 hypodermic needle (Becton Dickinson, Franklin Lakes, NJ) affixed to a micromanipulator, as described previously [7]. DNA extraction was performed by a modified single-step DNA extraction method [7]. Because the most common site of the germline mutations of DKC1 was reported to be the exon 3 [1,4,5], we analyzed the exon 3 in this study. Genomic DNA each from tumor cells and corresponding normal cells were amplified with a primer pair covering the DNA sequences in the exon 3. For the detection of DKC1 mutations, we analyzed the exon by

Dyskeratosis congenita: Its connections with oral and maxillofacial surgery

Dyskeratosis congenita is characterised by abnormal pigmentation of skin, dystrophy of nails, and mucosal leukoplakia mainly on the tongue. Bone marrow failure, pulmonary complication, and premalignant leukoplakia of the tongue are serious complications of the disease.

Intensive Immunosuppression Therapy for Aplastic Anemia Associated with Dyskeratosis Congenita: Report of a Case

Dyskeratosis congenita (DC) is a very rare inherited disorder characterized by skin pigmentation, nail dystrophy, and mucosal leukoplakia. It is also associated with a variety of noncutaneous abnormalities, such as fatal pulmonary complications, malignancy, and bone marrow failure. We report the case of a 32-year-old man with DC associated with severe aplastic anemia (SAA). The traditional treatment of DC-associated SAA is allogeneic hematopoietic stem cell transplantation (HSCT). However, in this case, an HLA-matched donor was not available. Therefore our patient was given intensive immunosuppressive therapy with antilymphocyte globulin (ALG) and cyclosporine A (CsA). The hemogram findings improved after the treatment, but the patient died of pulmonary complications after being in stable condition for 6 months. The results support the possible use of intensive immunosuppression with ALG and CsA for DC-associated SAA as an alternative treatment for patients who are not eligible for HSCT.

Usual Interstitial Pneumonia Complicating Dyskeratosis Congenita

Usual Interstitial Pneumonia Complicating Dyskeratosis Congenita

A Dyskeratosis Congenita (DKC) Patient Treated with Growth Hormone

Dyskeratosis congenita (DKC) is an inherited disease characterized by the triad of mucosal leukoplakia, abnormal skin pigmentation and nail dystrophy, and it usually appears between the ages of 5 and 10 yr. Reports show that 19.5% of DKC patients have short stature (1). A major complication of DKC is progressive development of pancytopenia and there is also an increased incidence of malignancies. The X-linked form accounts for the majority of cases and is caused by mutations in the DKC1 gene. We report a 9 yr old boy, who presented with the triad of DKC, a mutation in the DKC1 gene and short stature, who was treated with human recombinant growth hormone (hGH). This is the first report of a DKC patient treated with hGH.

Dyskeratosis congenita vs. chronic graft versus host disease: Report of a case and a review of the literature

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome characterized by the triad of reticular pigmentation of the skin, nail dystrophy, and mucosal leukoplakia. DC is often associated with severe pancytopenia, and bone marrow failure is the principal cause of early mortality. Malignant transformation of mucosal leukoplakias may also occur. Rarely, aplastic anemia precedes the other clinical manifestations of the disease. We present a case of a 13-year-old boy who was diagnosed at age four with idopathic aplastic anemia, was treated successfully with an allogeneic bone marrow transplant, then subsequently developed skin, nail, and tongue lesions. While the initial impression was chronic graft-versus-host disease, additional work-up confirmed the diagnosis of DC.

Disceratose congênita: relato de caso e revisão da literatura

A disceratose congênita é doença hereditária rara, caracterizada pela tríade de pigmentação reticulada da pele, distrofia ungueal e leucoceratose em mucosas. Alterações dentárias, gastrintestinais, geniturinárias, neurológicas, oftalmológicas, pulmonares e esqueléticas associadas têm sido relatadas. A falência medular é a principal causa de morte precoce e também é descrita predisposição para doenças malignas. Afeta principalmente homens, e reconhecem-se formas recessivas ligadas ao X, autossômicas dominantes e recessivas. Relata-se o caso de uma criança do sexo masculino, que apresentava a tríade clássica das lesões sem antecedentes familiares. Faz-se revisão da literatura com o objetivo de enfatizar a necessidade do acompanhamento médico multidisciplinar, de modo a permitir diagnóstico precoce das possíveis complicações.