2. Budalen – bygda mellom fjella
2.2 Språkforhold i Budalen
Alessandra B. Trovó-Marqui a Eny M. Goloni-Bertollo b Marta F. Teixeira b Eloiza H. Tajara b
aDepartamento de Biologia, IBILCE/UNESP – Universidade Estadual Paulista, ebPrograma NF1, Faculdade de Medicina (FAMERP), São José do Rio Preto , Brazil
Congenital ectropion uveae (CEU) is a rare, nonpro- gressive anomaly characterized by the presence of iris pig- ment epithelium on the anterior surface of the iris stroma and is occasionally associated with Rieger’s anomaly, Prader-Willi syndrome [1–3] and neurofi bromatosis type 1 (NF1) [4] . Ritch et al. [1] reported 8 patients with uni- lateral CEU of which 3 had neurofi bromatosis. Also, Burke et al. [5] described a case of NF1 in association with congenital iris ectropion. However, the most im- portant complication of ectropion uveae is congenital or juvenile glaucoma [1–3, 6–13] . Thus, the fi nding of CEU in a patient warrants continued observation for the development of glaucoma and disorders of neural crest origin.
We describe here a 62-year-old woman with unilateral ectropion uveae ( fi g. 1 A) and NF1. This patient was de- tected in a cohort composed of 55 unrelated NF1 patients screened for mutations in the exons 20–27a (GAP-related domain), 28, 29, 31 and 37 of the NF1 gene.
The clinical features of the patient included café-au- lait spots, freckling of the axillary and inguinal regions, neurofi bromas and Lisch nodules, macrocephaly, short stature, mild mental retardation (IQ = 62) and multiple skeletal anomalies. Mammography showed internal neu-
Key Words
Ectropion uveae ⴢ Neurofi bromatosis type 1 ⴢ Mutation
Abstract
Congenital ectropion uveae is a rare, nonprogressive anomaly characterized by the presence of iris pigment epithelium on the anterior surface of the iris stroma and is occasionally associated with Rieger’s anomaly, Prad- er-Willi syndrome and neurofi bromatosis type 1 (NF1). The most important complication of ectropion uveae is congenital or juvenile glaucoma. We described a patient with ectropion and the mutation R1748X in the NF1 gene. This is the third report in the literature describing ectro- pion associated with neurofi bromatosis. If this associa- tion is confi rmed by other authors, the NF1 patients should be examined for the presence of ectropion and, consequently, for the development of glaucoma.
Copyright © 2004 S. Karger AG, Basel
Received: May 3, 2004
Accepted after revision: September 10, 2004
Eloiza Helena Tajara, PhD Departamento de Biologia Molecular Faculdade de Medicina (FAMERP) 15090-000 São José do Rio Preto, SP (Brazil)
Tel. +55 17 210 5700, Fax +55 17 234 6407, E-Mail [email protected] © 2004 S. Karger AG, Basel
0030–3747/04/0366–0349$21.00/0
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E-Mail [email protected] www.karger.com
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Ophthalmic Res 2004;36:349–352
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Fig. 1. A 62-year-old woman with ectropion uveae (indicated by an arrowhead) ( A) and unilateral blepharophi- mosis probably resulting from a facial plexiform neurofi broma ( B).
Age at diagnosis, years 62
Sex female
Café-au-lait spots +++
Freckling (axillary and inguinal regions) +++
Neurofi bromas +++
Plexiform neurofi bromas +
Lisch nodules (bilateral) +
Macrocephaly – OFC 58 cm (98thcentile) + Short stature – 1.42 m (<3th centile) +
IQ/mental retardation1 62/mild
Abnormal EEG +
Abnormal ECG +
Ophthalmological anomalies ectropion, blepharophimosis
Skeletal anomalies kyphoscoliosis, osteophytosis,
abnormal vertebral body
Other headache, hypertension, early menopause,
dysplastic nails, dry skin
OFC = Occipitofrontal circumference; EEG = electroencephalogram; ECG = electro- cardiogram. The plus signs indicate the presence of a clinical sign. The number of plus signs represents the level of severity:
+ ^ 50, ++ = 51–150, +++ 6150 (café-au-lait spots and neurofi bromas). + ^ 4, ++ = 5–8, +++ 68 (freckling).
+ ^ 3, ++ = 4–6, +++ 66 (Lisch nodules).
1 Based on the Wechsler Adult Intelligence Scale. Table 1. Clinical features of a Brazilian
patient with ectropion uveae and a mutation in exon 29 (R1748X) of the NF1 gene
NF1 Mutation and Ectropion uveae Ophthalmic Res 2004;36:349–352 351
rofi bromas, and electrocardiography and electroencepha- lography revealed left deviation of the QRS axis and par- oxysmal abnormality of the left cerebral hemisphere, respectively. Furthermore, headache, hypertension, early menopause, dysplastic nails and dry skin were also ob- served as well as unilateral blepharophimosis probably resulting from a facial plexiform neurofi broma ( fi g. 1 B). In conclusion, the patient exhibited some less frequent or even never described features of NF1: mental retardation (present in 3–8% of NF1 patients), kyphoscoliosis (sco- liosis is present in about 10% of patients), ectropion and dysplastic nails ( table 1 ).
Analysis of the NF1 gene by the PCR-SSCP technique and DNA sequencing in this case revealed a mutation in exon 29 (R1748X), which affects a CpG dinucleotide (5242C - 1 T). This alteration, also reported in other 9 patients by Valero et al. [14] , Boulandet et al. [15] , Fah- sold et al. [16] and Origone et al. [17] , is expected to gen- erate a truncated protein with 1,747 amino acids. CpG dinucleotides show a high mutation rate due to spontane- ous deamination of methylated cytosine. Exon 29 is spe- cially rich in CpG dinucleotides and its methylation may contribute to C–T substitutions in patients.
No genotype-phenotype correlation has been identi- fi ed in NF1, except for deletions encompassing the entire gene or perhaps also contiguous genes in patients with facial anomalies, large number of neurofi bromas and se- vere developmental delay [18, 19] . Learning disabilities have also been observed in patients with different inacti-
vating mutations and even in NF1 mutant fl ies and mice [20, 21] . Nevertheless, relatively few learning disability data based on IQ tests are reported by molecular studies of neurofi bromatosis.
The reasons why NF1 genotype-phenotype correlation is diffi cult to establish lie in the wide diversity of muta- tion types and in the wide range of variable expressions of NF1. In this respect, it may be interesting to analyze the phenotypic consequence of the same mutation upon different genetic and environmental backgrounds. The comparison of clinical data of 10 patients with the muta- tion R1748X might offer an opportunity to reveal phe- notypic features in common dependent on the NF1 genotype, and exclude those related to other genetic fac- tors. However, clinical data from most of such patients are not available. Because ectropion uveae is a rare ocular malformation, an accurate clinical and molecular evalu- ation of patients with this condition may help the dissec- tion of the NF1 phenotype and the understanding of the pathogenesis of ectropion uveae.
Acknowledgments
This work was supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo – grant 99/02819-8), CNPq (Con- selho Nacional de Desenvolvimento Científi co e Tecnológico) and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior).
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