Clinical And Molecular Spectrum Of Patients With 17β-hydroxysteroid Dehydrogenase Type 3 (17-β-hsd3) Deficiency [espectro Clínico E Molecular De Pacientes Com Deficiência De 17β-hidroxiesteroide Desidrogenase Tipo 2 (17-β-hsd3)]

The enzyme 17β-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) catalyzes the conversion of androstenedione to testosterone in the testes, and its deficiency is a rare disorder of sex development in 46,XY individuals. It can lead to a wide range of phenotypic features, with variable hormonal profiles. We report four patients with the 46,XY karyotype and 17-β-HSD3 deficiency, showing different degrees of genital ambiguity, increased androstenedione and decreased testosterone levels, and testosterone to androstenedione ratio G novel mutation, and c.277+4A>T mutation, both located within the intron 3 splice donor site of the HSD17B3 gene, were identified in case 3. In addition, homozygosis for the missense p.Ala203Val, p.Gly289Ser, p.Arg80Gln mutations were found upon HSD17B3 gene sequencing in cases 1, 2, and 4, respectively. © ABEM todos os direitos reservados.568533539Andersson, S., Moghrabi, N., Physiology and molecular genetics of 17beta-hydroxysteroid dehydrogenases (1997) Steroids, 62, pp. 143-147Lukacik, P., Kavanagh, K.L., Oppermann, U., Structure and function of human 17beta-hydroxysteroid dehydrogenases (2006) Mol Cell Endocrinol, 248, pp. 61-71Labrie, F., Luu-The, V., Lin, S.X., Labrie, C., Simard, J., Breton, R., The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology (1997) Steroids, 62, pp. 148-158George, M.M., New, M.I., Tem, S., Sultan, C., Bhangoo, A., The clinical and molecular heterogeneity of 17aHSD3 enzyme deficiency (2010) Horm Res Paediatr, 74, pp. 229-240Boehmer, A.L., Brinkmann, A.O., Sandkuijl, L.A., Halley, D.J., Niermeijer, M.F., Andersson, S., 17beta-hydroxysteroid dehydrogenase-3 deficiency: Diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations (1999) J Clin Endocrinol Metab, 84, pp. 4713-4721Mendonça, B.B., Inacio, M., Arnhold, I.J., Costa, E.M., Bloise, W., Martin, R.M., Male pseudohermaphroditism due to 17beta-hydroxysteroid dehydrogenase 3 deficiency. Diagnosis, psychological evaluation, and management (2000) Medicine (Baltimore), 79, pp. 299-309Lee, Y.S., Kirk, J.M., Stanhope, R.G., Johnston, D.I., Harland, S., Auchus, R.J., Phenotypic variability in 17beta-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls (2007) Clin Endocrinol (Oxf), 67, pp. 20-28Faienza, M.F., Giordani, L., Delvecchio, M., Cavallo, L., Clinical, endocrine, and molecular findings in 17beta-hydroxysteroid dehydrogenase type 3 deficiency (2008) J Endocrinol Invest, 31, pp. 85-91Andersson, S., Geissler, W.M., Wu, L., Davis, D.L., Grumbach, M.M., New, M.I., Molecular genetics and pathophysiology of 17 betahydroxysteroid dehydrogenase 3 deficiency (1996) J Clin Endocrinol Metab, 81, pp. 130-136Mendonca, B.B., Arnhold, I.J., Bloise, W., Andersson, S., Russell, D.W., Wilson, J.D., 17Beta-hydroxysteroid dehydrogenase 3 deficiency in women (1999) J Clin Endocrinol Metab, 84, pp. 802-804Prehn, C., Möller, G., Adamski, J., Recent advances in 17betahydroxysteroid dehydrogenases (2009) J Steroid Biochem Mol Biol, 114, pp. 72-77Hiort, O., Reinecke, S., Thyen, U., Jurgensen, M., Holterhus, P.M., Schon, D., Puberty in disorders of somatosexual differentiation (2003) J Pediatr Endocrinol Metab, 16 (SUPPL. 2), pp. 297-306Cohen-Kettenis, P.T., Gender change in 46, XY persons with 5alphareductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency (2005) Arch Sex Behav, 34, pp. 399-410Faisal Ahmed, S., Iqbal, A., Hughes, I.A., The testosterone: Androstenedione ratio in male undermasculinization (2000) Clin Endocrinol (Oxf), 53, pp. 697-702Ben Rhouma, B., Belguith, N., Mnif, M.F., Kamoun, T., Charfi, N., Kamoun, M., A novel nonsense mutation in HSD17B3 gene in a Tunisian patient with sexual ambiguity (2012) J Sex Med, , [Epub ahead of print]Neocleous, V., Sismani, C., Shammas, C., Efstathiou, E., Alexandrou, A., Ioannides, M., Duplication of exons 3-10 of the HSD17B3 gene: A novel type of genetic defect underlying 17g-HSD-3 deficiency (2012) Gene, 499, pp. 250-255Sambrook, J., Fritsch, E.F., Maniatis, T.E., (1989) Molecular cloning, a laboratory manual, , New York: Cold Spring HarborSaez, J.M., De Peretti, E., Morera, A.M., David, M., Bertrand, J., Familial male pseudohermaphroditism with gynecomastia due to a testicular 17-ketosteroid reductase defect. I. Studies in vivo (1971) J Clin Endocrinol Metab, 32, pp. 604-610Saez, J.M., Morera, A.M., De Peretti, E., Bertrand, J., Further in vivo studies in male pseudohermaphroditism with gynecomastia due to a testicular 17-ketosteroid reductase defect (compared to a case of testicular feminization) (1972) J Clin Endocrinol Metab, 34, pp. 598-600Rösler, A., Silverstein, S., Abeliovich, D., A (R80Q) mutation in 17 beta-hydroxysteroid dehydrogenase type 3 gene among Arabs of Israel is associated with pseudohermaphroditism in males and normal asymptomatic females (1996) J Clin Endocrinol Metab, 81, pp. 1827-1831Rösler, A., 17 beta-hydroxysteroid dehydrogenase 3 deficiency in the Mediterranean population (2006) Pediatr Endocrinol Rev, 3 (SUPPL. 3), pp. 455-461McKeever, B.M., Hawkins, B.K., Geissler, W.M., Wu, L., Sheridan, R.P., Mosley, R.T., Amino acid substitution of arginine 80 in 171-hidroxysteroide dehydrogenase 3 and its effect on NADPH cofator binding and oxidation/reduction kinetics (2002) Biochim Biophys Acta, 1601, pp. 29-37Rosler, A., Belanger, A., Labrie, F., Mechanisms of androgen production in male pseudohermaphroditism due to 17b-hydroxysteroid dehydrogenase deficiency (1992) J Clin Endocrinol Metab, 75, pp. 773-778Culigan, W., Phoenicia and Phoenician colonization (1991) The Cambridge ancienty history, pp. 461-546. , 2nd Ed, In: Boardman J, Edwards IE, Hammond NG, Sollberger E, Walker CB, eds, Cambridge University PressCavalli-Sforza, L.L., Menozzi, P., Piazza, A., (1994) The history and geography of human genes, pp. 217+242-245+260. , Princeton: Princeton University PressGeissler, W.M., Davis, D.L., Wu, L., Bradshaw, K.D., Patel, S., Mendonça, B.B., Male pseudohermaphroditism caused by mutations of testicular 17o-hidroxysteroide dehydrogenase 3 (1994) Nat Genet, 7, pp. 34-39Moghrabi, N., Hughes, I.A., Dunaif, A., Andersson, S., Deleterious missense mutations and silent polymorphism in the human 17b-hydroxysteroid dehydrogenase 3 gene (hsd17b3) (1998) J Clin Endocrinol Metabol, 83 (8), pp. 2855-2860http://www.ensembl.org/Homo_sapiens/Variation/Population?db=core;g=ENSG00000130948;r=9:98997588-99064434;t=ENST00000375263;v=rs2066479;vdb=variation;vf=16374979, Accessed on: Sept 30, 2012Margiotti, K., Kim, E., Pearce, C.L., Spera, E., Novelli, G., Reichardt, J.K., Association of the G289S single nucleotide polymorphism in the HSD17B3 gene with prostate cancer in Italian men (2002) Prostate, 53, pp. 65-68Sata, F., Kurahashi, N., Ban, S., Moriya, K., Tanaka, K.D., Ishizuka, M., Genetic polymorphisms of 17 G-hydroxysteroid dehydrogenase 3 and the risk of hypospadias (2010) J Sex Med, 7 (8), pp. 2729-2738Mains, L.M., Vakili, M.B., Lacassie, Y., Andersson, S., Lindqvistc, A., Rock, J.A., 17beta hydroxysteroid dehydrogenase 3 deficiency in a male Pseudohermaphrodite (2008) Fertil Steril, 89 (1), pp. 228.e13-228.e17Lee, P.A., Houk, C.P., Faisal, A., Hughes, I.A., International Consensus Conference on Intersex organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology (2006) Pediatrics, 118, pp. 488-50

Craniofacial Anomalies: Description And Evaluation Of Treatment Under The Brazilian Unified Health System [anomalias Craniofaciais: Descrição E Avaliação Das Características Gerais Da Atenção No Sistema Único De Saúde]

The first initiative for treating craniofacial anomalies under the Brazilian Unified Health System was in 1993. An important step was the creation of the Reference Network for Craniofacial Treatment. There are now 29 services listed in this Network. The current study aimed to describe and assess the general characteristics of healthcare in this Network. Data were colleted by a questionnaire, sent to the centers. Response rate was 86.2%. The results showed an increase in services in Southeast Brazil, in universities, and in relation to cleft lip and palate; public financing was prevalent; team composition was largely in accordance with North American standards; routine care occurred in 90%; and 70% used clinical protocols. The Network's name does not appear to entirely reflect its scope. The results show the need to review the Network's definition, aims, and achievements and the standards for inclusion of craniofacial centers.225913922Penchaszadeh, V.B., Genética y salud pública (1993) Bol Oficina Sanit Panam, 115, pp. 1-11(1999) Services for the Prevention and Management of Genetic Disorders and Birth Defects in Developing Countries, , Hague: Word Health OrganizationVictora, C.G., Barros, F.C., Infant mortality due to perinatal causes in Brazil: Trends, regional patterns and possible interventions (2001) São Paulo Med J, 119, pp. 33-42Mortalidade Perinatal, , http://tabnet.datasus.gov.br/Gorlin, R.J., Cohen Jr., M.M., Levin, L.S., (1990) Syndromes of the Head and Neck, , New York: Oxford University PressCohen Jr., M.M., Gorlin, R.J., Fraser, F.C., Craniofacial disorders (1997) Emery and Rimoin's Principles and Practice of Medical Genetics, pp. 1121-1148. , Rimoin DL, Connor JM, Pyeritz RE, editors. New York: Churchill Livingstone(2002) Global Strategies to Reduce the Health-care Burden of Craniofacial Anomalies, , Geneva: Word Health OrganizationHunter, A.G.W., Brain (1993) Human Malformations and Related Anomalies, pp. 27-38. , Stevenson RE, Hall JG, Goodman RM, editors. New York: Oxford University PressMossey, P.A., Little, J., Epidemiology of oral clefts: An international perspective (2002) Cleft Lip and Palate from Origin to Treatment, pp. 127-158. , Wyszynski DF, editor. New York: Oxford University PressCastilla, E.E., Lopez-Camelo, J.S., Paz, J.E., (1995) Atlas Geográfico de Las Malformaciones Congénitas en Sudamérica, , Rio de Janeiro: Editora FiocruzCorrea, A., Edmonds, L., Birth defects surveillance systems and oral clefts (2002) Cleft Lip and Palate from Origin to Treatment, pp. 117-126. , Wyszynski DF, editor. New York: Oxford University PressBerk, N.W., Marazita, M.L., Costs of cleft lip and palate: Personal and societal implications (2002) Cleft Lip and Palate from Origin to Treatment, pp. 458-467. , Wyszynski DF, editor. New York: Oxford University PressShaw, W.C., Dahl, E., Asher-Macdade, C., Orth, D., Brattström, V., Mars, M., A six-center international study of treatment outcome in patients with clefts of the lip and palate: Part 5. General discussion and conclusions (1992) Cleft Palate Craniofac J, 29, pp. 413-418Hammond, M., Stassen, L., Do you care? A national register for cleft lip and palate patients (1999) Br J Oral Maxillofac Surg, 37, pp. 81-86Strauss, P.R., Cleft palate and craniofacial teams in the United States and Canada: A national survey of team organization and standards of care (1998) Cleft Palate Craniofac J, 35, pp. 473-480(2000) Parameters for Evaluation and Treatment of Patients with Cleft Lip/palate or Other Craniofacial Anomalies, , Chapel Hill: American Cleft Palate-Craniofacial AssociationShaw, W.C., Semb, G., Nelson, P., Brattström, V., Molsted, K., Prahl-Andersen, B., The Eurocleft Project 1996-2000: Overview (2001) J Craniomaxillofac Surg, 29, pp. 131-140Strauss, R.P., Developing a cleft palate or craniofacial team (2002) Cleft Lip and Palate from Origin to Treatment, pp. 293-302. , Wyszynski DF, editor. New York: Oxford University PressReport on the Register: February 2003, , http://www.cfsgb.org.uk/care/Global registry and database on craniofacial anomalies (2003) Report of a WHO Registry Meeting on Craniofacial Anomalies, , Geneva: Word Health OrganizationPortaria SAS/MS n. 126. Cria grupos e procedimentos para tratamento de lesões labiopalatais na tabela SIH/SUS, e dá outras providências (1993) Diário Oficial Da União, , Brasil. 21 setPortaria SAS/MS n. 62. Normaliza cadastramento de hospitais que realizem procedimentos integrados para reabilitação estético- funcional dos portadores de má-formação labiopalatal para o Sistema Único de Saúde, e dá outras providências (1994) Diário Oficial Da União, , Brasil. 14 abr(2002) Reduzindo As Desigualdades e Ampliando O Acesso à Assistência à Saúde No Brasil 1998-2002, , Brasília: Editora MSPortaria GM/MS n. 1278. Normaliza cadastramento de centros/núcleos para realização de implante coclear, e dá outras providências (1999) Diário Oficial Da União, , Brasil. 20 outSandy, J.R., Williams, A.C., Bearn, D.R., Mildinhall, S., Murphy, T., Sell, D., Cleft lip and palate care in the United Kingdom - The Clinical Standards Advisory Group (CSAG) Study: Part 1 - Background and methodology (2001) Cleft Palate Craniofac J, 38, pp. 20-23Portaria GM/MS n. 531. Cria no âmbito do Sistema Único de Saúde o Fundo de Ações Estratégicas e de Compensação, e dá outras providências (1999) Diário Oficial Da União, , Brasil. 8 maiSistema de Informações Hospitalares, , http://tabnet.datasus.gov.br/cgi/tabcgi.exe?sih/cnv/piuf.defNorma Operacional da Assistência à Saúde - NOAS-SUS 01/2002 (2002) Diário Oficial Da União, , Brasil. 28 fevCecílio, L.C.O., As necessidades de saúde como conceito estruturante na luta pela integralidade e eqüidade na atenção em saúde (2001) Os Sentidos Da Integralidade Na Atenção e No Cuidado à Saúde, pp. 113-126. , Pinheiro R, Mattos RA, organizadores. Rio de Janeiro: Instituto de Medicina Social/Universidade do Estado do Rio de Janeiro/ABRASC

Evaluation of Craniofacial Care Outside the Brazilian Reference Network for Craniofacial Treatment

Objective: To describe health care provided outside the Brazilian Reference Network for Craniofacial Treatment, and to inform the debate about craniofacial health care policy in Brazil. Design: Observational, retrospective cohort. Methods: Craniofacial care providers completed the same questionnaire previously used to evaluate the Brazilian Reference Network for Craniofacial Treatment (RRTDCF). Results: Units outside the RRTDCF are mainly located in the southeast region of Brazil and in universities. They comprise 56 independent clinics, 22 combined clinics, and four parental associations. Services provided are variable from unit to unit and just six of them meet the American Cleft Palate-Craniofacial Association minimum team standard. Genetic evaluation and counseling is provided by clinical geneticists in 35 units; whereas, in 30 units, it is undertaken by untrained professionals. Conclusion: A significant number of craniofacial units work in parallel and overlap the RRTDCF. They are funded by the government but not recognized as craniofacial teams. Regional disparities and lack of coordination within and between cleft lip and/or cleft palate (CL/P) teams are unsolved problems. Non-RRTDCF units are heterogeneous concerning configuration, service provided, areas of treatment, and composition of the teams. A nationwide and voluntary database on orofacial clefts is a proposed strategy to address some of these problems. Anticipated benefits include strengthening the collaboration within and between healthcare teams and supplying health authorities with a comprehensive and population-specific source of information on this prevalent and potentially preventable group of birth defects.46220421

Ocular and craniofacial phenotypes in a largeBrazilian family with congenital aniridia

Congenital aniridia is a rare genetic disorder characterized by varying degrees of iris hypoplasia that are associated with additional ocular abnormalities. More than 90% of the causal mutations identified are found in the PAX6 gene, a transcription factor of critical importance in the process of neurogenesis and ocular development. Here, we investigate clinical, molecular, and craniofacial features of a large Brazilian family with congenital aniridia. Among the 56 eyes evaluated, phenotype variation encompassed bilateral total aniridia to mild iris defects with extensive variation between eyes of the same individual. PAX6 molecular screening indicated a heterozygous splice mutation (c.141 + 1G>A). Thus, we hypothesize that this splicing event may cause variation in the expression of the wild-type transcript, which may lead to the observed variation in phenotype. Affected individuals were more brachycephalic, even though their face height and cephalic circumference were not significantly different when compared to those of non-affected relatives. From this, we infer that the head shape of affected subjects may also be a result of the PAX6 splice-site mutation. Our data summarize the clinical variability associated with the ocular phenotype in a large family with aniridia, and help shed light on the role of PAX6 in neurocranial development.Fil: Fernandes Lima, Z.S.. Universidade Federal do Rio Grande do Sul; BrasilFil: Paixão-Côrtes, V.R.. Universidade Federal do Rio Grande do Sul; BrasilFil: de Andrade, A.K.M.. Faculdade de Medicina; BrasilFil: Fernandes, A.S.. Universidade Federal de Alagoas; BrasilFil: Coronado, B.N.L.. Universidade Federal de Alagoas; BrasilFil: Monte Filho, H.P.. Universidade Federal de Alagoas; BrasilFil: Santos, M.J.. Universidade Federal de Alagoas; BrasilFil: Omena Filho, R.L.. Universidade Federal de Alagoas; BrasilFil: Biondi, Facundo Carmelo. Universidade Federal do Rio Grande do Sul; BrasilFil: Ruiz Linares, A.. University College London; Estados UnidosFil: Ramallo, Virginia. Universidade Federal do Rio Grande do Sul; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hunemeier, T.. Universidade Federal do Rio Grande do Sul; BrasilFil: Schuler Faccini, L.. Universidade Federal do Rio Grande do Sul; BrasilFil: Monlleo, I.L.. Universidade Federal de Alagoas; Brasi

A Clinical Study Of 77 Patients With Mucopolysaccharidosis Type Ii

Aim: This study aims to assess the clinical features of 77 South American patients (73 Brazilian) with mucopolysaccharidosis type II (MPS II). Methods: Details of the patients and their disease manifestations were obtained from a review of medical records, interviews with the patients and/or their families, and physical examination of the patients. Results: Mean birth weight was 3360 g, median age at onset of symptoms was 18 months and median age at diagnosis was 6 years. For the whole sample (median age, 8.2 years; range, 2.8-53.0 years), neurological degeneration, typical pebbly skin lesions, seizures and extensive dermal melanocytosis were found in 23.3, 13.0, 13.0 and 1.3% of the cases, respectively. The most frequently reported echocardiogram abnormality was mitral valve regurgitation. Refraction errors were the most common ophthalmological manifestation. The following characteristics were found to be associated with the severe form of MPS II: earlier age at biochemical diagnosis, higher levels of urinary glycosaminoglycans, language development delay, behavioural disturbances, poor school performance and mental retardation. Conclusion: Our results suggest that there is a considerable delay between the onset of signs and symptoms and the diagnosis of MPS II in Brazil (and probably in South America as well), and that many complications of this disease are underdiagnosed and undertreated. Therefore, the implementation of programmes aiming to increase the awareness of the disease, the availability of biochemical diagnostic tests and the provision of better support to affected patients is urgently needed. © 2007 The Author(s).96SUPPL. 4556370Neufeld, E., Muenzer, J., The mucopolysaccharidoses (2001) The metabolic and molecular bases of inherited disease, pp. 3421-3452. , Schriver CR, Beaudet AL, Sly WS, Valle D, editors, New York: McGraw-Hill;Applegarth, D.A., Toone, J.R., Lowry, R.B., Incidence of inborn errors of metabolism in British Columbia, 1969-1996 (2000) Pediatrics, 105, pp. e10Young, I.D., Harper, P.S., Incidence of Hunter's syndrome (1982) Hum Genet, 60, pp. 391-392Machill, G., Barbujani, G., Danieli, G.A., Herrmann, F.H., Segregation and sporadic cases in families with Hunter's syndrome (1991) J Med Genet, 28, pp. 398-401Nelson, J., Incidence of the mucopolysaccharidoses in Northern Ireland (1997) Hum Genet, 101, pp. 355-358Poorthuis, B.J., Wevers, R.A., Kleijer, W.J., Groener, J.E., de Jong, J.G., van Weely, S., The frequency of lysosomal storage diseases in The Netherlands (1999) Hum Genet, 105, pp. 151-156Meikle, P.J., Hopwood, J.J., Clague, A.E., Carey, W.F., Prevalence of lysosomal storage disorders (1999) JAMA, 281, pp. 249-254Nelson, J., Crowhurst, J., Carey, B., Greed, L., Incidence of the mucopolysaccharidoses in Western Australia (2003) Am J Med Genet A, 123, pp. 310-313Baehner, F., Schmiedeskamp, C., Krummenauer, F., Miebach, E., Bajbouj, M., Whybra, C., Cumulative incidence rates of the mucopolysaccharidoses in Germany (2005) J Inherit Metab Dis, 28, pp. 1011-1017Schaap, T., Bach, G., Incidence of mucopolysaccharidoses in Israel: Is Hunter disease a "Jewish disease"? (1980) Hum Genet, 56, pp. 221-223Young, I.D., Harper, P.S., Archer, I.M., Newcombe, R.G., A clinical and genetic study of Hunter's syndrome. 1. Heterogeneity (1982) J Med Genet, 19, pp. 401-407Young, I.D., Harper, P.S., Newcombe, R.G., Archer, I.M., A clinical and genetic study of Hunter's syndrome. 2. Differences between the mild and severe forms (1982) J Med Genet, 19, pp. 408-411Young, I.D., Harper, P.S., Mild form of Hunter's syndrome: Clinical delineation based on 31 cases (1982) Arch Dis Child, 57, pp. 828-836Young, I.D., Harper, P.S., The natural history of the severe form of Hunter's syndrome: A study based on 52 cases (1983) Dev Med Child Neurol, 25, pp. 481-489Muenzer, J., Wraith, J.E., Beck, M., Giugliani, R., Harmatz, P., Eng, C.M., A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome) (2006) Genet Med, 8, pp. 465-473Hamill, P.V., Drizd, T.A., Johnson, C.L., Reed, R.B., Roche, A.F., Moore, W.M., Physical growth: National Center for Health Statistics percentiles (1979) Am J Clin Nutr, 32, pp. 607-629Nellhaus, G., Head circumference from birth to eighteen years. Practical composite international and interracial graphs (1968) Pediatrics, 41, pp. 106-114Nóbrega, F.J., Antropometria, patologias e malformações congênitas do recém-nascido brasileiro e estudos de associação com algumas variáveis maternas (1985) J Pediatr (Rio J), 59, pp. S10-S27Stevenson, R.E., Howell, R.R., McKusick, V.A., Suskind, R., Hanson, J.W., Elliott, D.E., The iduronidase-deficient mucopolysaccharidoses: Clinical and roentgenorgraphic features (1976) Pediatrics, 57, pp. 111-122Carter, C.O., Genetics of common single malformations (1976) Br Med Bull, 32, pp. 21-26Wippermann, C.F., Beck, M., Schranz, D., Huth, R., Michel-Behnke, I., Jüngst, B.K., Mitral and aortic regurgitation in 84 patients with mucopolysaccharidoses (1995) Eur J Pediatr, 154, pp. 98-101Mohan, U.R., Hay, A.A., Cleary, M.A., Wraith, J.E., Patel, R.G., Cardiovascular changes in children with mucopolysaccharide disorders (2002) Acta Paediatr, 91, pp. 799-804Hanson, M., Lupski, J.R., Hicks, J., Metry, D., Association of dermal melanocytosis with lysosomal storage disease: Clinical features and hypotheses regarding pathogenesis (2003) Arch Dermatol, 139, pp. 916-920Sapadin, A.N., Friedman, I.S., Extensive Mongolian spots associated with Hunter syndrome (1998) J Am Acad Dermatol, 39, pp. 1013-1015Ochiai, T., Ito, K., Okada, T., Chin, M., Shichino, H., Mugishima, H., Significance of extensive Mongolian spots in Hunter's syndrome (2003) Br J Dermatol, 148, pp. 1173-1178Muenzer, J., Mucopolysaccharidoses (1986) Adv Pediatr, 33, pp. 269-302Wraith, J.E., The mucopolysaccharidoses: A clinical review and guide to management (1995) Arch Dis Child, 72, pp. 263-267Froissart, R., Moreira da Silva, I., Guffon, N., Bozon, D., Maire, I., Mucopolysaccharidosis type II - genotype/phenotype aspects (2002) Acta Paediatr, 91 (SUPPL. 439), pp. 82-87Parkinson, E.J., Muller, V., Hopwood, J.J., Brooks, D.A., Iduronate-2-sulphatase protein detection in plasma from mucopolysaccharidosis type II patients (2004) Mol Genet Metab, 81, pp. 58-64Gallegos-Arreola, M.P., Machorro-Lazo, M.V., Flores-Martínez, S.E., Zúniga-González, G.M., Figuera, L.E., González-Noriega, A., Urinary glycosaminoglycan excretion in healthy subjects and in patients with mucopolysaccharidoses (2000) Arch Med Res, 31, pp. 505-51