OPHTHALMIC MOLECULAR GENETICS SECTION EDITOR: JANEY L. WIGGS, MD, PhD A Novel Mutation in the GJA1 Gene in a Family With Oculodentodigital Dysplasia José P. C. Vasconcellos, MD, PhD; Mônica B. Melo, PhD; Rui B. Schimiti, MD, PhD; Norisvaldo C. Bressanim, MD; Fernando F. Costa, MD, PhD; Vital P. Costa, MD, PhD Objectives: To describe a Brazilian family with oculo- closure glaucoma, and 1 had open-angle glaucoma. A new dentodigital dysplasia (ODDD) and to screen for muta- mutation in the GJA1 gene was identified, consisting of tions in the gap junction protein alpha 1 (GJA1) gene in a change from proline to histidine at codon 59. This mu- this family. tation segregated through members with the ODDD phe- notype. Analysis of the control group by means of re- Methods: Twelve members of a 3-generation family with striction fragment length polymorphism (MvaI enzyme) ODDD underwent screening for mutations of the GJA1 gene did not disclose this mutation. and a comprehensive ophthalmic examination. We defined ODDD on the basis of clinical characteristics described in Conclusion: Our results demonstrate a new mutation this syndrome (microdontia, caries, enamel hypoplasia, thin (P59H) in the GJ1A gene, identified in a family with nose,andsyndactyly)andeyeabnormalitiessuchasmicroph- ODDD syndrome. thalmos, iris atrophy, and glaucoma. Direct sequencing of the GJA1 gene was performed using DNA collected from Clinical Relevance: The presence of different forms peripheral blood. A control group of 60 healthy individu- of glaucoma in families with ODDD may indicate a new als underwent evaluation by means of enzyme digestion. mutation in the GJA1 gene. Results: Among the 8 members of this family who were characterized as having ODDD, 2 showed chronic angle- Arch Ophthalmol. 2005;123:1422-1426 CULODENTODIGITAL DYS- fourth and fifth fingers and/or the third or plasia (ODDD) is a syn- fourth toes, camptodactyly of the fifth fin- drome characterized by ger, midphalangeal hypoplasia or aplasia of malformations that in- 1 or more digits or toes, and other abnor- volve the face, eyes, teeth, malities such as a mandible with a wide al- Oand bones and by neurological alterations.1 veolar ridge and broad tubular bones.13 Neu- Although sporadic cases are reported in the rological deficits have been reported in a few literature (most of them involving elderly studies, including spastic paraparesis, qua- parents), ODDD is inherited in an autoso- driparesis, gait disturbance, neurogenic mal dominant pattern with high penetrance bladder disturbances, ataxia, hearing loss, andvariableexpression.2 Thisconditionwas dysarthria, and seizures.4 Magnetic reso- first described in 1920 by Lohmann3 in 2 nance imaging shows diffuse abnormali- Author Affiliations: patients with bilateral camptodactyly of the ties of the subcortical cerebral white mat- Departments of Ophthalmology fifth finger and microphthalmos.4 In 1957, ter that have been suggested as the cause of (Drs Vasconcellos, Schimiti, and 5 4,14 V. P.Costa) and Clinical Meyer-Schwickerath et al introduced the neurological manifestations. Other char- Medicine–Hemocentro term ODDD to describe 2 patients with mal- acteristics that may be found in ODDD are (Dr F.F.Costa), State University formations in the eyes, including bilateral depressed nasal bridge, thin nose with hy- of Campinas, Campinas, Brazil; microphthalmoswithglaucomaandanoma- poplastic alae nasi, small anteverted nares, Department of Physiological lies of the iris, nose, teeth, and bones, and cleft palate.13 Sciences, Santa Casa de São whereas in 1963, Gorlin et al6 subsequently The ocular manifestations of ODDD Paulo, São Paulo, Brazil defined it as a syndrome. Since then, sev- may involvetheentireocularglobe(microph- (Dr Melo); Cascavel University eral authors reported this condition in more thalmos), associated with anterior segment Hospital, UNIOESTE (State than 240 individuals.4,7-13 dysgenesis.7,8 Otherwise,theaxiallengthmea- University of the West of Paraná), Cascavel, Brazil The teeth anomalies observed in ODDD surementsmaybenormalandtheabnormali- (Dr Bressanim); and include microdontia, caries, enamel hypo- ties restricted to the anterior segment (iris Department of Ophthalmology, plasia, and partial anodontia. The skeletal atrophy, remnants of the pupillary mem- University of São Paulo, São malformations occur mainly in the extremi- brane, iridoschisis, and cataract).9 Posteri- Paulo, Brazil (Dr V. P.Costa). ties and consist of syndactyly involving the or segment abnormalities include remnants (REPRINTED) ARCH OPHTHALMOL / VOL 123, OCT 2005 WWW.ARCHOPHTHALMOL.COM 1422 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 of the hyaloid artery and an increased number of retinal 9 vessels at the optic disc. Other less frequent ocular I Individuals Without ODDD features of ODDD are nystagmus, palpebral fissure hy- 12 8 Individuals poplasia, epicanthal folds, and convergent strabismus. With ODDD Glaucoma is one of the causes of visual loss in ODDD. Open-angle and angle-closure glaucomas have been re- ported in eyes with ODDD, as well as goniodysgenesis.8-13 II 14 12 3 456 In 1997, Gladwin et al evaluated ODDD in 6 fami- 44/+ 42/+ 37/+ lies (autosomal dominant pattern) using linkage analy- sis. The authors identified the locus associated with ODDD III 1 2 3 4 5 at chromosome 6q22-q24 in a 28-centimorgan (cM) re- 22/− 16/− 19/− 16/− 8/− gion, delimited by markers D6S474 proximally and D6S292 distally. Boyadjiev et al2 performed 2-point link- Figure 1. Pedigree of a family with oculodentodigital dsyplasia (ODDD) age analysis in 7 families with ODDD and significantly syndrome harboring the proline→histidine mutation at codon 59. The age at reduced the size of the critical region (11 cM in male and last examination is shown by each symbol. Individual I:1 died with a history 15 of glaucoma and blindness. Circle indicates female family member; square, 20 cM in female subjects). Subsequently, Paznekas et al ϩ identified structural changes in the gene responsible for male family member; −, absence of glaucoma; and , presence of glaucoma. synthesis of connexin 43 (Cx43), the gap junction pro- tein alpha 1 (GJA1) gene, in all 17 families with ODDD autosomal dominant inheritance pattern (Figure 1). The who underwent screening for mutations in this gene. affected individuals had the classical characteristics de- The goals of this study were to describe a Brazilian fam- scribed in ODDD, including microdontia, caries, enamel ily with ODDD and to screen for mutations in the GJA1 hypoplasia, syndactyly involving the second and third toes, gene in this family. and mild clinodactyly (Figure 2). These individuals also had a thin nose due to a hypoplastic alae nasi. METHODS The only member of the family who was not exam- ined was individual I:1, described by relatives as having Twelve members of a family with ODDD from Cascavel, Bra- clinical characteristics typical of ODDD, who died at 63 zil, underwent screening for mutations in the GJA1 gene and a years of age, blind due to glaucoma. The Table gives the comprehensive ophthalmic examination. We defined ODDD ocular findings of all family members. Among the 8 af- on the basis of clinical characteristics described in the litera- fected individuals who were examined, all had micro- ture. Informed consent was obtained from the members of the family. Ophthalmic examination included intraocular pres- cornea (corneal diameters, 8-9 mm) and peripupillary iris sure measurement by means of applanation tonometry; slit- atrophy (Figure 3). Three (40%) of the affected indi- lamp biomicroscopy and gonioscopy; evaluation of the optic viduals, all of them belonging to the second generation, disc with a 78-diopter lens; automated perimetry (Humphrey had glaucoma. One of these was found to have open- System 24.2; Zeiss-Humphrey-Zeiss Systems, Dublin, Calif) in angle glaucoma and had undergone trabeculectomy individuals older than 15 years; measurements of the axial length in both eyes. In this individual, results of gonioscopy and corneal diameters and keratometry; and ocular history ob- disclosed a wide open angle, allowing the visualization tained by interview, including the age at diagnosis of glau- of the ciliary band. The other 2 family members had coma and clinical and surgical treatment. angle-closure glaucoma. Both had shallow anterior cham- Glaucoma was defined as the presence of at least 2 of the bers, and gonioscopy allowed the visualization of the following characteristics: (1) intraocular pressure above 24 mm Hg; (2) optic disc changes, including thinning of the neu- Schwalbe line. Results of indentation gonioscopy did not roretinal rim, hemorrhage, notch, cup-disc ratio greater than disclose peripheral anterior synechiae. 0.7, or asymmetry of cup-disc ratio greater than 0.2; and (3) The screening for mutations in the GJA1 gene iden- glaucomatous visual field defect, defined as a corrected pat- tified a new mutation at codon 59, changing a proline tern standard deviation outside the 95% normal limits or a glau- (CCT) for a histidine (CAT) in heterozygosis (P59H) coma hemifield test result outside the 99% limits. (Figure 4). This alteration segregated in members with We extracted DNA from peripheral blood and performed the ODDD phenotype (Figure 1). Results of analysis by direct sequencing of the GJA1 gene using fluorescent dideoxy- means of restriction fragment length polymorphism (MvaI nucleotides on an automated sequencer (ABI 310; Applied Bio- 15 enzyme) in the control group did not disclose this struc- systems, Foster City, Calif), according to Paznekas et al. Con- tural alteration. nexin amino-acid alignment was performed with the ClustalW program (http://www.ebi.ac.uk/clustalw/). Sequences were ob- tained from the Entrez-Protein Web site of the National Cen- COMMENT ter for Biotechnology Information (http://www.ncbi.nlm.nih .gov/entrez/). A control group of 60 healthy individuals This study described a Brazilian family with ODDD that underwent evaluation by means of digestion of the GJA1 gene carries a new mutation in the GJA1 gene. Among the ocu- PCR product with the MvaI enzyme.