# Oculodentodigital Dysplasia: A Case Report and Major Review of the Eye and Ocular Adnexa Features of 295 Reported Cases

Authors: Virang Kumar; Natario L. Couser; Arti Pandya
Journal: Case Reports in Ophthalmological Medicine
 (2020)

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## Abstract

Oculodentodigital dysplasia (ODDD) is a rare genetic disorder associated with a characteristic craniofacial profile with variable dental, limb, eye, and ocular adnexa abnormalities. We performed an extensive literature review to highlight key eye features in patients with ODDD and report a new case of a female patient with a heterozygous missenseGJA1 mutation (c.65G>A, p.G22E) and clinical features consistent with the condition. Our patient presented with multiple congenital anomalies including syndactyly, microphthalmia, microcornea, retrognathia, and a small nose with hypoplastic alae and prominent columella; in addition, an omphalocele defect was present, which has not been reported in previous cases. A systematic review of the published cases to date revealed 91 literature reports of 295 individuals with ODDD. There were 73 different GJA1 mutations associated with these cases, of which the most common were the following missense mutations: c.605G>A (p.R202H) (11%), c.389T>C (p.I130T) (10%), and c.119C>T (p.A40V) (10%). Mutations most commonly affect the extracellular-1 and cytoplasmic-1 domains of connexin-43 (gene product of GJA1), predominately manifesting in microphthalmia and microcornea. The syndrome appears with an approximately equal sex ratio. The most common eye features reported among all mutations were microcornea, microphthalmia, short palpebral fissures, and glaucoma.


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## Body

## 1. Introduction

Oculodentodigital dysplasia (ODDD, OMIM #164200) is a rare disorder mainly characterized by abnormal craniofacial, dental, ocular, and digital development. The autosomal dominant form has been the most frequently reported inheritance pattern, although a few cases of autosomal recessive inheritance have been described [1–3]. Craniofacial abnormalities may include microcephaly, prominent columella, and underdeveloped nasal alae [2–4]. Dental abnormalities, such as hypoplastic enamel, small teeth, and premature loss of teeth, are often present [2–4]. Digit abnormalities may include syndactyly, camptodactyly, and midphalangeal hypoplasia [2–4]. Ophthalmic manifestations are common, such as microcornea and microphthalmia, and may involve a wide spectrum of eye and ocular adnexa structures, although previous analyses of prior cases show that full ocular physical exams were not performed on all patients [3, 5].The gap junction protein alpha 1 (GJA1) gene codes for connexin-43, which is a protein that assists in the transmembrane transport of molecules through gap junctions, and mutations in the GJA1 may cause an alteration of the channel conduction properties [1–3, 6]. We report a case of an 8-month-old female patient with an identified GJA1 mutation and common clinical features associated with ODDD. This patient had an omphalocele at birth, which has not been reported in previous cases. Her eye features included microphthalmia, microcornea, narrow palpebral fissures, blonde fundus, deep anterior chambers, hyperopia, and epiphora in both eyes secondary to bilateral nasolacrimal duct obstructions. We conducted an extensive literature review to summarize the eye features in patients with ODDD reported to date.


## 2. Case Report

The patient, an 8-month-old female, was born to a nonconsanguineous couple from a healthy 37-year-old mother of Native American descent and a healthy 30-year-old father of German and Irish descent. Family history is notable for an older sibling with cleft palate, paternal uncle with autism, paternal second cousin with congenital heart defect, and distant paternal great-great uncle with Down syndrome and webbed/fused 4th and 5th digits of one hand. A normal pregnancy was noted until the second trimester when an omphalocele was detected on ultrasound. A subsequent ultrasound revealed possible syndactyly of the hands. The patient was born at 39 weeks by vaginal delivery with induction. The birth weight was 3.552 kg (75th percentile), birth length was 50 cm (68th percentile), and birth head circumference was 34.5 cm (70th percentile). Apgar scores were 9 at both one minute and five minutes.Multiple congenital anomalies noted at birth included an omphalocele that measured 4 cm at base and 3.5 cm across with intestines present in the sac, but no liver. The patient had a normocephalic head with sparse wispy hair, a small nose with hypoplastic alae, a prominent columella, small-appearing palpebral fissures, a small cornea, microphthalmia, a wide anterior fontanelle, and retrognathia (Figure1). Syndactyly of digits 4 and 5 and webbing of digits 3 and 4 of the right (Figure 2) and left hands were present. Cardiac echocardiogram on the day of birth showed the presence of a mild patent ductus arteriosus, mild patent foramen ovale, and a normal aorta. Feeding difficulties were exacerbated by the presence of the omphalocele; surgical correction was performed on day 2 of life.Figure 1
Facial photograph of a patient with oculodentodigital dysplasia; note the beaked nose with hypoplastic alae and prominent columella, microphthalmia, microcornea, small palpebral fissures, retrognathia.Figure 2
Complete syndactyly of the 4th and 5th digits of the right hand.An ophthalmologic assessment at 4 months of age was notable for deep anterior chambers, bilateral nasolacrimal duct obstruction, microphthalmia, small 8 mm corneas, a blonde fundus, and moderate hyperopia in both eyes.At her last examination at 8 months of age, the patient continues to have poor feeding with self-limiting volumes but has improved weight gain. The patient is at the 9th percentile for weight and 12th percentile for length. Cognitive and motor developments are delayed.Sequencing of theGJA1 gene (transcript number: NM_000165.3) from patient genomic DNA revealed a heterozygous missense mutation in the GJA1 gene: c.65G>A (p.G22E). Deletion/duplication analysis of the GJA1 gene using the aCGH test was negative.


## 3. Methods

We performed a systematic review of the literature to summarize the ocular findings in individuals with ODDD. A PubMed/Medline search of “oculodentodigital syndrome” led us to find a total of 177 articles. No articles were excluded based on the year published. We reviewed the references to identify other articles that did not appear in our original search. 91 articles describing patients with a description consistent with the clinical syndrome, either with or without molecular confirmation ofGJA1 pathogenic variants, were included. Within these selected articles, we identified 295 cases of ODDD with 73 different GJA1 mutations, including those that exhibited features of ODDD in the absence of molecular confirmation. Such individuals were either clinically diagnosed or were relatives of individuals with molecularly confirmed GJA1 pathogenic variants. Twelve reported that GJA1 gene coding alterations were omitted due to insufficient clinical information and data reported and are listed in Table 1 [3, 6].Table 1
GJA1 variants without clinical information.
Sources
GJA1 variant
Cases
Nucleotide
Protein
Paznekas et al. [3]
c.7G>A
p.D3N
1
Paznekas et al. [3]
c.64G>A
p.G22R
1
Paznekas et al. [3]; Richardson et al. [6]
c.79T>C
p.S27P
1
Paznekas et al. [3]
c.163A>G
p.N55D
1
Paznekas et al. [3]
c.174A>C
p.Q58H
1
Paznekas et al. [3]
c.175C>G
p.P59A
1
Paznekas et al. [3]
c.221A>T
p.H74L
1
Paznekas et al. [3]
c.428G>A
p.G143D
1
Paznekas et al. [3]
c.430A>G
p.K144E
1
Paznekas et al. [3]
c.434T>G
p.V145G
1
Paznekas et al. [3]
c.442C>G
p.R148G
1
Paznekas et al. [3]
c.578C>T
p.P193L
1


## 4. Discussion

Oculodentodigital dysplasia (ODDD) is a rare congenital disorder manifested with developmental anomalies of the eyes, face, dentition, heart, skeletal system, and digits. The syndrome appears to be more common in Caucasian populations with an equal sex ratio [3]. Heterozygous mutation of the GJA1 gene located at chromosome 6q22.31 has been identified as the most common mutation resulting in ODDD [2, 3]. However, a compound heterozygous individual with missense mutations demonstrated mutations in the GJA1 gene (p.V41L) and the GJB2 gene (p.R127H), which encode for connexin-43 and connexin-26, respectively, and has been reported and classified as having overlapping features of Clouston syndrome and ODDD [3, 7].In addition to the classic phenotypic features of the syndrome, a wide variety of additional physical manifestations have been observed. Ocular findings of microphthalmia and microcornea have been observed commonly in previous cases [2–4]. Craniofacial anomalies of microcephaly, poor hair growth, hypoplastic nasal alae, and prominent columella have been reported previously [2–4]. Bilateral syndactyly of the 4th and 5th digits is common [2, 3].A systematic review of the published cases to date (ranging from 1963 to 2019) revealed 91 literature reports of 295 individuals with ODDD [1–91]. Table 2 [1–91] summarizes the sex distribution across all reviewed reports of ODDD. Patients with ODDD present with an approximately equal sex distribution (47% male and 53% female). Of the 295 individuals reported, 32 were clinically diagnosed with ODDD without molecular confirmation, 98 presented with features of ODDD and had a known relative with molecular confirmation of a GJA1 pathogenic variant, and 165 individuals had a molecularly confirmed GJA1 pathogenic variant.Table 2
Summary of sex distribution.
Males
Females
Total
Individuals with clinical diagnosis of ODDD (with no molecular confirmation)
14
45%
18
56%
32
Untested individuals with both ODDD phenotype and known relative with molecular confirmation
52
53%
46
47%
98
Individuals with a molecular confirmedGJA1 pathogenic variant
72
44%
93
56%
165
Totals
138
47%
157
53%
295There were 73 differentGJA1 mutations identified from the 165 individuals that had a molecularly confirmed GJA1 pathogenic variant. Table 3 [1–3, 5–71, 92] summarizes the number of patients with each mutation. Patients with confirmed pathogenic variants and their relatives with no molecular confirmation but with features of ODDD were grouped separately. These two groups comprised 263 of the patients included in this study.Table 3
ReportedGJA1 mutations and sex distribution in ODDD.
Sources
Multiple mutations?
GJA1 mutation
Individuals with a molecular confirmedGJA1 pathogenic variant
Untested individuals with both ODDD phenotype and known relative with molecular confirmation
Total individuals with the ODDD phenotype
Nucleotide
Protein
Unspecified
Male
Female
Male
Female
Male
Female
Total
Cavusoglu et al. 2019
No
c.168_169insT
p.Q57SfsTer6
N/A
1
0
0
0
1
100%
0
0%
1
Aminabadi et al. 2009 & Aminabadi et al. 2010
No
N/A
N/A
Missense mutation exon 2 (unspecified)
1
0
2
1
3
75%
1
25%
4
Dwarakanathan et al. 2015 & Furuta et al. 2012
No
c.75G>T
p.W25C
N/A
1
1
0
0
1
50%
1
50%
2
Quick and Dobersen 2014; National Center for Biotechnology Information 2020
Yes
c.605G>A
p.R202H
N/A
1
0
0
0
1
100%
0
0%
1
c.717G>A
p.R239R
Paznekas et al. 2003 & Paznekas et al. 2009
No
c.605G>A
p.R202H
N/A
1
7
4
5
5
29%
12
71%
17
Jamsheer et al. 2010
Yes
c.301C>T
p.R101X
N/A
1
0
0
0
1
100%
0
0%
1
c.6delT
p.G2fsX7
Jamsheer et al. 2010
No
c.301C>T
p.R101X
N/A
0
1
0
0
0
0%
1
100%
1
Paznekas et al. 2009; Joss et al. 2008; & Richardson et al. 2006
No
c.97C>T
p.R33X∗
N/A
0
2
0
0
0
0%
2
100%
2
Paznekas et al. 2009; Richardson et al. 2004; Paznekas et al. 2003; & Gladwin et al. 1997
No
c.93T>C
p.I31M
N/A
0
0
4
4
4
50%
4
50%
8
Wang et al. 2019
No
c.91A>T
p.I311P
N/A
1
0
0
0
1
100%
0
0%
1
Paznekas et al. 2009 & van Steensel et al. 2005
No
c.780_781delTG
p.C260fsX306
N/A
1
2
0
0
1
33%
2
67%
3
Paznekas et al. 2009; Paznekas et al. 2003; & Gorlin et al. 1963
No
c.68A>C
p.K23T
N/A
1
0
0
0
1
100%
0
0%
1
Dwarakanathan et al. 2015; Paznekas et al. 2009; & Vreeburg et al. 2007
No
c.689_690delAT
p.Y230fsX236
N/A
0
3
1
0
1
25%
3
75%
4
This study; Gumus 2018; Paznekas et al. 2009; Paznekas et al. 2003; & Traboulsi and Parks 1990
No
c.65G>A
p.G22E
N/A
0
3
0
0
0
0%
3
100%
3
Wiest et al. 2006
No
c.659C>A
p.S220Y
N/A
0
1
0
0
0
0%
1
100%
1
Paznekas et al. 2009; Paznekas et al. 2003; & Norton et al. 1995
No
c.646G>T
p.V216L
N/A
1
0
4
1
5
83%
1
17%
6
Park et al. 2017; Paznekas et al. 2009; & Paznekas et al. 2003
No
c.61G>A
p.G21R
N/A
0
2
0
0
0
0%
2
100%
2
Brice et al. 2013
No
c.617A>G
p.K206R
N/A
1
2
1
1
2
40%
3
60%
5
Paznekas et al. 2009
No
c.602C>T
p.S201F
N/A
0
1
0
0
0
0%
1
100%
1
Paznekas et al. 2009 & de la Parra et al. 2007
No
c.5G>T
p.G2V
N/A
1
0
0
0
1
100%
0
0%
1
Vitiello et al. 2005 & Vingolo et al. 1994
No
c.581A>C
p.H194P∗
N/A
3
5
3
3
6
43%
8
57%
14
Paznekas et al. 2009; Paznekas et al. 2003; & Judisch et al. 1979
No
c.52T>C
p.S18P
N/A
0
0
1
3
1
25%
3
75%
4
Paznekas et al. 2009 & Paznekas et al. 2003
No
c.50A>C
p.Y17S
N/A
3
4
0
0
3
43%
4
57%
7
Paznekas et al. 2009 & Debeer et al. 2005
No
c.504_506delCTT
p.F169del
N/A
0
1
0
0
0
0%
1
100%
1
Wiest et al. 2006 & Thomsen et al. 1998
No
c.461C>A
p.T154N
N/A
0
2
0
1
0
0%
3
100%
3
Paznekas et al. 2009 & van Es et al. 2007
No
c.460A>G
p.T154A∗
N/A
0
2
0
0
0
0%
2
100%
2
Paznekas et al. 2009; Richardson et al. 2004; Paznekas et al. 2003; Gladwin et al. 1997; & Schrander-Stumpel et al. 1993
No
c.443G>A
p.R148Q
N/A
0
0
2
2
2
50%
2
50%
4
Taşdelen et al. 2018
No
c.442C>T
p.R148Ter
N/A
1
0
0
0
1
100%
0
0%
1
Paznekas et al. 2009; Debeer et al. 2005; & Spaepen et al. 1991
No
c.440Y>C
p.M147T
N/A
0
1
0
0
0
0%
1
100%
1
Paznekas et al. 2009; Richardson et al. 2004; & Brueton et al. 1990
No
c.427G>A
p.G143S
N/A
0
0
8
1
8
89%
1
11%
9
Orosz et al. 2018
No
c.413G>A
p.G138D
N/A
1
0
0
0
1
100%
0
0%
1
Paznekas et al. 2009; Paznekas et al. 2003; & Shapiro et al. 1997
No
c.412G>C
p.G138R
N/A
1
2
2
2
3
43%
4
57%
7
Kogame et al. 2014
No
c.412G>A
p.G138S
N/A
1
0
0
0
1
100%
0
0%
1
Paznekas et al. 2009; Richardson et al. 2004; Paznekas et al. 2003; & Gladwin et al. 1997
No
c.402G>T
p.K134N
N/A
0
0
0
2
0
0%
2
100%
2
Paznekas et al. 2009 & Paznekas et al. 2003
No
c.400A>G
p.K134E
N/A
0
1
0
0
0
0%
1
100%
1
Nishat et al. 2012; Paznekas et al. 2009; Paznekas et al. 2003; & Amador et al. 2008
No
c.389T>C
p.I130T
N/A
7
4
5
1
12
71%
5
29%
17
Paznekas et al. 2009; Musa et al. 2008; Wiest et al. 2006; & Loddenkemper et al. 2002
No
c.338T>C
p.L113P
N/A
2
2
1
0
3
60%
2
40%
5
Paznekas et al. 2009 & Debeer et al. 2005
No
c.330G>C
p.E110D
N/A
2
3
1
2
3
38%
5
63%
8
Paznekas et al. 2009 & Kelly et al. 2006
No
c.32T>C
p.L11P
N/A
0
1
0
0
0
0%
1
100%
1
Gabriel et al. 2011 & Jamsheer et al. 2009
No
c.31C>T
p.L11F
N/A
0
2
0
0
0
0%
2
100%
2
Porntaveetus et al. 2017
No
c.31C>A
p.L11I
N/A
1
0
0
0
1
100%
0
0%
1
Jamsheer et al. 2014
No
c.317T>G
p.L106R
N/A
2
0
0
0
2
100%
0
0%
2
Paznekas et al. 2009 & Nivelon-Chevallier et al. 1981
No
c.317T>C
p.L106P
N/A
1
0
0
0
1
100%
0
0%
1
Paznekas et al. 2009 & Paznekas et al. 2003
No
c.306G>C
p.K102N
N/A
1
2
0
0
1
33%
2
67%
3
Paznekas et al. 2009; Paznekas et al. 2003; & Wooldridge et al. 1977
No
c.293A>G
p.Y98C
N/A
1
3
1
1
2
33%
4
67%
6
Paznekas et al. 2009
No
c.287T>C
p.V96A
N/A
0
1
0
0
0
0%
1
100%
1
Wiest et al. 2006
No
c.287T>A
p.V96E
N/A
0
1
0
0
0
0%
1
100%
1
Paznekas et al. 2009 & Kjaer et al. 2004
No
c.286G>A
p.V96M
N/A
2
2
0
0
2
50%
2
50%
4
Paznekas et al. 2009 & Honkaniemi et al. 2005
No
c.284A>G
p.H95R
N/A
0
1
0
1
0
0%
2
100%
2
Paznekas et al. 2009; Paznekas et al. 2003; & Opjordsmoen and Nyberg-Hansen 1980
No
c.268C>G
p.L90V
N/A
4
0
3
2
7
78%
2
22%
9
Jamsheer et al. 2014
No
c.257C>A
p.S86Y
N/A
0
1
0
0
0
0%
1
100%
1
Pizzuti et al. 2004
No
c.227G>A
p.R76H
N/A
1
0
0
0
1
100%
0
0%
1
Izumi et al. 2013
No
c.226C>T
p.R76C
N/A
1
0
0
0
1
100%
0
0%
1
Paznekas et al. 2009; Paznekas et al. 2003; & Stanislaw et al. 1998
No
c.226C>A
p.R76S
N/A
0
2
0
2
0
0%
4
100%
4
Choi et al. 2018
No
c.221A>C
p.H74P∗
N/A
1
0
0
0
1
100%
0
0%
1
Paznekas et al. 2009; Richardson et al. 2004; Paznekas et al. 2003; & Gladwin et al. 1997
No
c.206C>A
p.S69Y
N/A
0
0
2
5
2
29%
5
71%
7
Paznekas et al. 2009 & Vasconcellos et al. 2005
No
c.176C>A
p.P59H
N/A
4
4
1
0
5
56%
4
44%
9
Paznekas et al. 2009
No
c.145_147dupCAG
p.Q49dup
N/A
0
1
0
0
0
0%
1
100%
1
Pazenkas et al. 2009; Paznekas et al. 2003; Weintraub et al. 1975; & Gellis and Feingold 1974
No
c.154_156dupTTT
p.F52dup
N/A
1
0
1
1
2
67%
1
33%
3
Hadjichristou et al. 2017 & Paznekas et al. 2009
No
c.146A>C
p.Q49P
N/A
1
1
0
0
1
50%
1
50%
2
Izumi et al. 2013
No
c.145C>G
p.Q49E
N/A
0
1
0
0
0
0%
1
100%
1
Paznekas et al. 2009 & Paznekas et al. 2003
No
c.145C>A
p.Q49K
N/A
3
2
0
0
3
60%
2
40%
5
Amano et al. 2012; Feller et al. 2008; Paznekas et al. 2009; & Itro et al. 2005
No
c.142G>A
p.E48K
N/A
3
0
0
0
3
100%
0
0%
3
Jamsheer et al. 2014
No
c.139G>C
p.D47H
N/A
0
3
0
0
0
0%
3
100%
3
Tumminelli et al. 2016
No
c.125G>C
p.E42Q
N/A
1
0
0
0
1
100%
0
0%
1
Gabriel et al. 2011
No
c.120delGGTTGAGTCAGC
p.V41_A44del
N/A
0
1
1
2
1
25%
3
75%
4
Paznekas et al. 2009 & Kellermayer et al. 2005
Yes (compound heterozygous withGJB2 mutation)
c.121G>C
p.V41L
N/A
0
1
0
0
0
0%
1
100%
1
N/A
p.R127H (GJB2 mutation)
Park et al. 2019; Hayashi et al. 2014; Paznekas et al. 2009; Debeer et al. 2005; & Paznekas et al. 2003
No
c.119C>T
p.A40V
N/A
6
4
4
3
10
59%
7
41%
17
Wittlieb-Weber et al. 2015
No
c. 175C>T
p.P59S
N/A
1
2
0
0
1
33%
2
67%
3
Attig et al. 2016
No
c.396_398delAAA
p.I132_K133delinsM
N/A
3
2
0
0
3
60%
2
40%
5
Paznekas et al. 2009
No
c.19T>G
p.L7V
N/A
1
0
0
0
1
100%
0
0%
1
Himi et al. 2009
No
c.13A>T
p.S5C
N/A
0
1
0
0
0
0%
1
100%
1
Pace et al. 2019
No
c.287T>G
p.V96G
N/A
0
1
0
0
0
0%
1
100%
1
No
c.77T>C
p.L26P
N/A
0
1
0
0
0
0%
1
100%
1
Totals
72
93
52
46
124
47%
139
53%
263
∗Unknown which specific individuals tested.The eye features of all 295 patients are summarized in Table4 [1–91]. The most common ophthalmic manifestations reported were microcornea (n=111), microphthalmia (n=110), short palpebral fissures (n=56), and glaucoma (n=51, 4 closed-angle and 1 open-angle).Table 4
Eye and ocular adnexa features reported in ODDD.
Orbit
—
Microphthalmia (110/37%)
Hypotelorism (24/8%)
Hypertelorism (22/7%)
Short axial length (4/1%)
Anterior segment
Anterior chamber
Shallow anterior chamber (12/4%)
Deep anterior chambers (2/<1%)
Cornea
Microcornea (111/38%)
Thick corneas (4/1%)
Corneal opacities (3/1%)
Corneal farinata (1/<1%)
Band keratopathy (1/<1%)
Corneal keratosis (1/<1%)
Abnormal Descemet’s membrane (1/<1%)
Anteriorly deviated Schwalbe’s line (1/<1%)
Sclera
Blue sclera (1/<1%)
Pupil
Persistent pupillary membranes (13/4%)
Eccentric pupils (3/1%)
Lens
Cataracts (17/6%)
Lens opacities (2/<1%)
White retrolental masses (1/<1%)
Uvea (iris, ciliary body)
Pale/atrophic irides (11/4%)
Uveitis (10/3%)
General iris abnormalities (7/2%)
Synechiae (4/1%)
Hypoplastic anterior iris stroma (3/1%)
Ciliary body cysts (2/<1%)
Flat iris (1/<1%)
Iridoschisis (1/<1%)
Inferior iris coloboma (1/<1%)
Dysplastic iris (1/<1%)
Posterior segment
Uvea (choroid)
Thick choroid (2/<1%)
Thin choroid (1/<1%)
Vitreous
Vitreous degeneration (1/<1%)
Vitreous membrane attachment to optic nerve and lens (1/<1%)
Persistent hyperplastic primary vitreous (1/<1%)
Retina/fundus
Dysplastic retina/fundus (3/1%)
Pale retina/fundus (2/<1%)
Thread-like retinal vasculature (2/<1%)
Dystrophic retinal epithelium (1/<1%)
Hypoplastic macula (1/<1%)
Absent fundal glow with B-scan ultrasound (1/<1%)
Optic disc
Pale/atrophic optic disc (3/1%)
Dysplastic optic disc (2/<1%)
Ellipsoid optic disc (1/<1%)
Optociliary vein presence (1/<1%)
Optic disc hypervascularity (1/<1%)
Ocular adnexa
Eyelid
Short/narrow palpebral fissures (56/19%)
Epicanthus (36/12%)
Telecanthus (11/4%)
Ptosis (7/2%)
Blepharophimosis (1/<1%)
Entropion (1/<1%)
Ectropion (1/<1%)
Epiblepharon (1/<1%)
Mucosal hypertrophy (1/<1%)
Eyebrow/eyelash
Madarosis (19/6%)
Flared eyebrows (3/1%) (2 medially flared)
Synophyrs (1/<1%)
Nasolacrimal duct
Nasolacrimal duct abnormalities (2/<1%)
Hypolacrimation (1/<1%)
Other
Refractive errors
Myopia (16/5%) (2 anisometropic)
Hyperopia (8/3%) (2 anisometropic)
Astigmatism (1/<1%)
Eye movement disorders
Strabismus (27/9%) (9 esotropic, 1 exotropic)
Nystagmus (8/3%)
Amblyopia (3/1%)
Duane syndrome (2/<1%)
Brown syndrome (1/<1%)
Additional eye disorders
Glaucoma (51/17%) (4 closed-angle, 1 open-angle)
Paracentral scotoma (1/<1%)
ERG/neurological
Abnormal ERG (2/<1%)
Delayed visual evoked responses (2/<1%)
Occipital subcortical white matter changes (1/<1%)Twenty-three patients presented with refractive error, of which isolated myopia was the most frequently noted (n=14), followed by isolated hyperopia (n=6), anisometropia (n=2), and astigmatism (n=1). Forty patients presented with eye movement disorders, with strabismus (n=27, 9 esotropic, 1 exotropic) being the most common, followed by nystagmus (n=8), amblyopia (n=3), Duane syndrome (n=2), and Brown syndrome (n=1). Note that 1 patient had both nystagmus and esotropia [71]. Other common findings included epicanthus (n=36), hypotelorism (n=24), hypertelorism (n=22), madarosis (n=19), cataracts (n=17), persistent pupillary membranes (n=13), shallow anterior chambers (n=12), pale/atrophic irides (n=11), telecanthus (n=11), and uveitis (n=10).A variety of abnormal findings for the retina and optic disc were noted (n=18), with dysplasia of the retina/fundus (n=3) and pale/atrophic optic discs (n=3) being the most common documented findings.Of the individuals with molecularly confirmed mutations, the most common mutations present were c.605G>A (p.R202H) (11%; with 1 patient also having a c.717G>A synonymous mutation), c.389T>C (p.I130T) (10%), and c.119C>T (p.A40V) (10%). Table5 [2, 3, 12, 30, 40, 41, 66, 67, 92] summarizes the eye features present in the patients with these mutations.Table 5
CommonGJA1 mutations with associated eye features.
Sources
Multiple mutations?
GJA1 mutation
Individuals withGJA1 mutation (confirmed and affected relatives)
Associated eye features
Nucleotide
Protein
Total
Quick and Dobersen 2014; National Center for Biotechnology Information 2020
Yes
c.605G>A
p.R202H
1
Microphthalmia (1)
c.717G>A
p.R239R
Paznekas et al. 2009; Paznekas et al. 2003
No
c.605G>A
p.R202H
17
Microphthalmia (1), microcornea (2)
Nishat et al. 2012; Paznekas et al. 2009; Paznekas et al. 2003; and Amador et al. 2008
No
c.389T>C
p.I130T
17
Microphthalmia (4), hypotelorism (6), cataract (1), pale/atrophic optic disc (1), and short palpebral fissures (4)
Park et al. 2019; Hayashi et al. 2014; Paznekas et al. 2009; Debeer et al. 2005; and Paznekas et al. 2003
No
c.119C>T
p.A40V
17
Microphthalmia (9), hypertelorism (3), hypotelorism (4), short axial length (4), cataract (1), microcornea (8), thick cornea (4), macular hypoplasia (1), shallow anterior chamber (4), myopia (4), strabismus (6) (1 esotropic), glaucoma (6), and epicanthus (3)Less common features of the phenotype observed in our presented case were also reported in other cases as well. These include nasolacrimal duct abnormalities (n=2), pale/atrophic retina/fundus (n=2), and deep anterior chambers (n=2). Additionally, including this study, the three patients with the p.G22E mutation have the following findings: microphthalmia (n=3), cataracts (n=1), microcornea (n=2), blonde fundus (n=1), persistent pupillary membrane (n=1), deep anterior chamber (n=1), hyperopia (n=1), strabismus (n=2, 1 esotropic), amblyopia (n=1), glaucoma (n=1), short palpebral fissures (n=1), nasolacrimal duct abnormalities (n=1), and epicanthus (n=1) [2, 3, 21, 22].Some unique genotype-phenotype correlations were noted upon further analysis. Three patients presented with eccentric pupils, but only 2 of these patients were reported with an associated mutation. Both mutations (p.Q49dup and p.Q49P) seem to affect the same amino acid in connexin-43 [3, 61, 72]. Additionally, uveitis was reported in 10 patients, 9 of which were associated with similar mutations. Eight of these patients were within the same study and had the p.H194P mutation, another patient had no molecular confirmation of a GJA1 mutation, and the other patient was reported with a missense mutation on exon 2 [4, 9, 10, 27, 28]. However, since the majority of these patients were reported within the same study, the apparent genotype-phenotype correlation of p.H194P and uveitis might be due to underreporting of uveitis from other sources with different pathogenic variants or may be due to other factors of the family not identified within the study.Further analysis of the genotype-phenotype correlation was conducted by pairing the phenotypic manifestations of each mutation with the corresponding defects in the connexin-43 domains. The domains were defined by the amino acid ranges provided on UniProt (P17302–CXA1_HUMAN) [93]. Table 6 [1–3, 5–71, 92, 93] provides a summary of the phenotypes associated with mutations from each domain.Table 6
Mutant connexin-43 domains and associated phenotype.
GJA1 mutation
Protein domain (amino acid range) (obtained from UniProt-P17302)
Associated phenotype (no. of individuals)
p.G2fsX7 (with p.R101X)p.G2Vp.L11Pp.L11Fp.L11Ip.L7Vp.S5C
Cytoplasmic N-terminus(1-13)
Microcornea (7), microphthalmia (5), epicanthus (4), strabismus (3) (1 esotropic), short palpebral fissures (2), telecanthus (2), amblyopia (1), dysplastic fundus (1), optociliary vein (1), dysplastic optic disc (1), pale/atrophic optic disc (1), persistent pupillary membrane (1), myopia (3), hyperopia (1) (anisometropic), glaucoma (1), ptosis (1), entropion (1), madarosis (1), hypertelorism (1), and cataract (1)
p.W25Cp. R33Xp.I31Mp.K23Tp.G22Ep.G21Rp.S18Pp.Y17Sp.L26P
Transmembrane-1 (14-36)
Microcornea (21), microphthalmia (14), short palpebral fissures (11), persistent pupillary membrane (6), madarosis (6), epicanthus (6), glaucoma (5), anterior iris stroma hypoplasia (3), hypertelorism (2), cataract (2), iris abnormalities (2), blonde fundus (1), iridoschisis (1), deep anterior chamber (1), hyperopia (2), strabismus (7) (3 esotropic), amblyopia (1), nystagmus (1), ptosis (1), epiblepharon (1), nasolacrimal duct obstruction (1), and flared eyebrows (1) (medially flared)
p.Q57SfsTer6p.R76Hp.R76Cp.R76Sp.H74Pp.S69Yp.P59Hp.Q49dupp.F52dupp.Q49Pp.Q49Ep.Q49Kp.E48Kp.D47Hp.E42Qp.V41_A44delp.V41L (with p.R127H (GJB2 mutation))p.A40Vp.P59S
Extracellular-1 (37-76)
Microphthalmia (32), microcornea (30), glaucoma (15) (2 closed-angle, 1 open-angle), hypertelorism (11), epicanthus (10), strabismus (9) (3 esotropic), short palpebral fissures (9), iris atrophy (peripupillary) (8), cataract (6), shallow anterior chamber (6), hypotelorism (5), short axial length (4), myopia (4), corneal farinata (4), telecanthus (3), iris abnormalities (2), eccentric pupils (2), persistent pupillary membrane (2), dysplastic fundus (1), dysplastic optic (1), macular hypoplasia (1), synechiae (1), ciliary body cysts (1), deep anterior chamber (1), hyperopia (1), ptosis (1), blepharophimosis (1), madarosis (1), nasolacrimal duct abnormalities (1), and low-voltage ERG (1)
p.Y98Cp.V96Ap.V96Ep.V96Mp.H95Rp.L90Vp.S86Yp.V96G
Transmembrane-2 (77-99)
Hypertelorism (5), microcornea (2), microphthalmia (3), glaucoma (3), strabismus (2) (1 esotropic), short palpebral fissures (2), eyelid mucosal hypertrophy (1), telecanthus (1), epicanthus (1), optic disc atrophy (1), hyperopia (1), myopia (1), strabismus (1), paracentral scotoma (1), madarosis (1), and delayed visual evoked potentials (1)
p.R101X (with p.G2fsX7)p.R101Xp.T154Np.T154Ap.R148Qp.R148Terp.M147Tp.G143Sp.G138Dp.G138Rp.G138Sp.K134Np.K134Ep.I130Tp.L113Pp.E110Dp.L106Rp.L106Pp.K102Np.I132_K133delinsM
Cytoplasmic-1 (100-154)
Microphthalmia (20), microcornea (18), short palpebral fissures (14), hypotelorism (14), glaucoma (9), myopia (7), epicanthus (5), cataract (3), strabismus (3), shallow anterior chamber (3), hypertelorism (2), opaque lens (1), optic disc hypervascularity (1), pale/atrophic optic disc (1), pale irides (1), iris abnormalities (2), astigmatism (1), Duane syndrome (1), ptosis (1), occipital subcortical white matter changes (1), and delayed visual evoked responses (1)
p.F169del
Transmembrane-3 (155-177)
Short palpebral fissures (1)
p.R202H (with p.R239R)p.R202Hp.K206Rp.S201Fp.H194P
Extracellular-2 (178-208)
Microphthalmia (18), uveitis (8), glaucoma (8), microcornea (4), opaque cornea (2), thick choroid (2), cataract (1), shallow anterior chamber (1), nystagmus (2), and ptosis (1)
p.S220Yp.V216L
Transmembrane-4 (209-231)
Microphthalmia (1), glaucoma (1), microcornea (1), and persistent pupillary membrane (1)
p.Y230fsX236
Transmembrane-4 & cytoplasmic C-terminus (209-382)
Hypertelorism (2), hypotelorism (1), and flared eyebrows (2) (1 medially flared)
p.R239R (with p.R202H)p.I311Pp.C260fsX306
Cytoplasmic C-terminus(232-382)
Short palpebral fissures (3), epicanthus (2), hypotelorism (2), microcornea (2), pale irides (2), myopia (2), hyperopia (1) (1 anisometropic), corneal opacity (1), microphthalmia (1), retinal dysplasia (1), choroid thinning (1), glaucoma (1), madarosis (1), and loss of flash ERG (1)
Missense mutation exon 2 (unspecified)
Unknown
Microphthalmia (1), cataract (1), microcornea (1), uveitis (1), glaucoma (1), epicanthus (1), telecanthus (1), short palpebral fissures (1), and ptosis (1)The domains most commonly affected byGJA1 mutations are the extracellular-1 loop and the cytoplasmic-1 loop of connexin-43, accounting for 19 and 20 mutations, respectively. Disruptions in the extracellular-1 loop presented primarily as microphthalmia (n=32) and microcornea (n=30). A similar pattern can be seen in the cytoplasmic-1 loop, as the most common presentations were microphthalmia (n=20) and microcornea (n=18). Other clinical findings, however, may be able to distinguish mutations resulting from these domains. The next most common findings associated with mutations in the extracellular-1 loop were glaucoma (n=15) and hypertelorism (n=11), as opposed to short palpebral fissures (n=14) and hypotelorism (n=14) for the cytoplasmic-1 loop.Mutations affecting the cytoplasmic N-terminus and the transmembrane-1 domain shared similar features to the ones in the extracellular-1 and cytoplasmic-1 domains, as microphthalmia and microcornea were the most common clinical findings. However, the mutations in the cytoplasmic N-terminus and transmembrane-1 domain presented with microcornea (n=17 and n=21, respectively) more frequently than microphthalmia (n=5 and n=14, respectively). The opposite pattern is true for the extracellular-1 and cytoplasmic-1 domains.The mutations in the extracellular-2 loop demonstrate a different phenotypic pattern, as microphthalmia (n=14) occurs the most frequently, while microcornea is less frequent (n=4). Mutations in the transmembrane-2 domain also display a unique pattern, with hypertelorism (n=5) being the most frequent clinical finding. Other domains listed in Table 6 also demonstrate some unique clinical patterns, but this may be due to variability from the small number of samples. The patterns mentioned previously, however, still provide insight into the role of different connexin-43 domains in providing phenotypic variability among patients with ODDD.In conclusion, this report provides a comprehensive review of the eye and ocular adnexa abnormalities that are currently known to be associated with the ODDD phenotype. Limitations of this report include the possibility of an incomplete ophthalmologic evaluation and/or lack of reporting of eye features in all of the evaluated case reports or misdiagnosis in the individuals with the ODDD phenotype without molecular confirmation. As such, it is possible that the reported common eye features within this summary may be over or underrepresented. Ophthalmic manifestations are commonly associated within the phenotype, and a wide spectrum of eye and ocular adnexa structures may be affected. The rarity of this condition provides further incentive to further investigate the phenotype.



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*Source: 6535974-2020-04-06.xml*