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Research Letters |

Blue Sclera With and Without Corneal Fragility (Brittle Cornea Syndrome) in a Consanguineous Family Harboring ZNF469 Mutation (p.E1392X) FREE

Arif O. Khan, MD; Mohammed A. Aldahmesh, PhD; Jawahir N. Mohamed, BSc; Fowzan S. Alkuraya, MD
[+] Author Affiliations

Author Affiliations: Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital (Dr Khan), Department of Genetics, King Faisal Specialist Hospital and Research Center (Drs Khan, Aldahmesh, and Alkuraya and Ms Mohamed), and Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University and Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University (Dr Alkuraya), Riyadh, Saudi Arabia.


Arch Ophthalmol. 2010;128(10):1376-1379. doi:10.1001/archophthalmol.2010.238.
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Blue sclera with corneal fragility characterizes brittle cornea syndrome (BCS) (OMIM #229200), an underrecognized predominantly ocular disorder that is often confused with Ehlers-Danlos syndrome (EDS).1 Brittle cornea syndrome has recently been associated with recessive mutation in ZNF469, which encodes a classic zinc-finger protein that is likely involved in synthesis and/or organization of corneal collagens.2,3 In this report, we describe the phenotype/genotype correlation for blue sclera with or without BCS in all 3 children of a consanguineous, asymptomatic Syrian couple.

Case 1

Sibling 1 is a 13-year-old boy (Figure 1). He had blue sclera since birth and history of hernia repair, the details of which were not available. At age 2 years following minor trauma, he had bilateral corneal rupture and underwent multiple corneal operations that led to phthisis. It was suspected that he had congenital glaucoma. At approximately age 5 years, he had slightly decreased hearing following recurrent ear infections; this resolved with medical treatment and his hearing is now considered normal. At age 12 years, he had a right forearm dislocation following a significant fall down stairs that required surgical pinning.

Place holder to copy figure label and caption
Figure 1.

Sibling 1. A, Blue sclera, phthisical eyes, and small forehead skin scars are seen. Similar skin scars were scattered on the extremities. B, Abnormal skin scarring occurred following small-incision surgery to pin a dislocated forearm. C, Talipes valgus can be appreciated as well as multiple small skin scars. D, Plain-film radiography confirms talipes valgus. R indicates right.

Graphic Jump Location

Ophthalmic examination revealed visual acuity of no light perception OU. Both eyes were phthisical, had blue sclera, and were soft to palpation.

General assessment revealed a well-nourished alert boy with normal vital signs and chestnut-colored hair. Height, weight, and head circumference were age appropriate. Skin was thin, velvety, and without abnormal elasticity. Subcutaneous veins were easily appreciated. There were scattered small scars on all extremities and a large one at the right elbow where a small surgical incision had been made. There was no joint hypermobility (Beighton score 2/9) or scoliosis. Oral inspection revealed grossly normal dentition and a slightly arched palate. Extremity assessment revealed bilateral valgus foot (talipes valgus) and hallux valgus, which were confirmed by plain-film radiography. Skeletal plain-film radiography showed normal bone densities without evidence for fractures. Complete blood cell count and electrolyte levels were within normal limits.

Case 2

Sibling 2 is an 8-year-old girl (Figure 2). She had blue sclera since birth. There was a vague history of a dislocation in the right forearm following trauma at age 1 year that did not require surgery. She was treated medically for congenital glaucoma until age 5 years, at which time she was diagnosed as having keratoglobus without evidence of glaucoma. Cycloplegic refraction at age 4 years was approximately plano in both eyes and fundus examination results were unremarkable. Protective glasses were stressed but were not used. At age 7 years, she had a minor trauma in the left eye that led to Descemet membrane detachment and associated corneal edema, for which she had surgical repositioning of the Descemet membrane via air bubble injection.

Place holder to copy figure label and caption
Figure 2.

Sibling 2. A, Blue sclera, frontal bossing, and joint hyperlaxity are seen. B, Keratoglobus of the left eye can be appreciated. There is slight corneal haze, present since the repair of a traumatic Descemet membrane detachment. C, An Orbscan of the left cornea before the Descemet membrane detachment reveals corneal thinning and astigmatism. The right cornea (not shown) had comparable thinning without significant ectasia. D, Prominent lumbar lordosis can be appreciated on plain-film radiography. L indicates left. E, Irregularity of the calvaria can be appreciated on plain-film radiography, as can the relatively elongated anterior-posterior distance. F, Subcutaneous veins were prominent throughout the body. The left forearm is shown.

Graphic Jump Location

Ophthalmic examination revealed visual acuity of 20/30 OD and 20/400 OS, with no improvement by pinhole. Both eyes had keratoglobus and blue sclera and had grossly normal intraocular pressure by digital palpation. Slitlamp examination revealed thin corneas with keratoglobus and in the left eye corneal haze corresponding to the area of prior Descemet membrane detachment. At age 6 years, cycloplegic refraction was +0.75 − 1.50 × 042 OD and −11.00 − 2.50 × 090 OS with scissoring of the reflex. Fundus examination results were within normal limits.

General assessment revealed a thin alert girl with normal vital signs and chestnut-colored hair. Height, weight, and head circumference were age appropriate; however, she did have an appearance of frontal bossing and the calvaria was irregular to palpation. Skin was thin, velvety, without abnormal elasticity, and without scars. Subcutaneous veins were easily appreciated. There was significant joint hyperlaxity (Beighton score 9/9). Oral inspection revealed poor dental hygiene and an arched palate. The sternum protruded outward slightly (pectus carinatum). Scoliosis was not present but lumbar lordosis seemed exaggerated. Extremity assessment revealed bilateral talipes valgus. Skeletal plain-film radiography confirmed the irregular calvaria, exaggerated lumbar lordosis, and bilateral talipes valgus; bone densities were normal. Complete blood cell count and electrolyte levels were within normal limits.

Case 3

Sibling 3 is a 4-year-old girl (eFigure 1). This healthy-appearing, alert girl with blue sclera since birth had normal vital signs and chestnut-colored hair. Other than blue sclera, results from complete ocular examination, directed physical examination, and laboratory investigations were appropriate for her age.

Parents

The father is aged 35 years, and the mother is aged 37 years. Both parents were alert, were healthy, and had chestnut-colored hair. They had unremarkable results on ocular examinations and no history of skin disease, abnormal healing, hyperflexibility, joint dislocations, or spine or extremity deformity.

ZNF469 Analysis

The family had ZNF469 (GenBank NM_001127464.1) analysis performed (eFigure 2).The 2 older children (siblings 1 and 2) were homozygous for a novel mutation p.E1392X (c.4174G>T), while the youngest child with blue sclera only (sibling 3) and the 2 parents were heterozygous for the mutation (primers and conditions are available in the eTable).

Brittle cornea syndrome has been confused with EDS, particularly EDS type VI (OMIM #225400), which is also associated with blue sclera.1,4 Although EDS type VI was known as the ocular subtype of EDS, in fact ocular fragility in EDS type VI is less frequent than was originally thought.1,4 Ehlers-Danlos syndrome type VI can be clinically distinguished from BCS as the former includes symptomatic obvious nonocular signs in children, while the latter is characterized by obvious ocular disease in children with subtle nonocular findings. Children with EDS type VI have muscular hypotonia from birth, generalized joint laxity, congenital and progressive kyphoscoliosis, radiographically confirmable osteopenia, skin elasticity that is typical for EDS, and a risk of sudden death from arterial rupture.1,4 In addition, when ocular rupture does occur in EDS type VI, it tends to be scleral rather than corneal.1,4 Ehlers-Danlos syndrome type VI is due to recessive mutation in the gene for lysyl hydroxylase 1 (PLOD1 [OMIM *153454]).

In the current family, the youngest sister had blue sclera only and was a carrier for the mutation. In the context of her older affected siblings, this was phenocopy for the disease. Interestingly, 2 previously described families with BCS also included close relatives with blue sclera only.5,6 Although genetic confirmation was not available for the patients in these 2 previously described families, their phenotypes and the fact that they were Jewish of Tunisian ancestry strongly support that they truly had BCS.5,6 In the current family, neither parent in this study had blue sclera despite being heterozygous for the mutation, and neither had a history of blue sclera during childhood. One can speculate that heterozygous ZNF469 mutation may predispose to childhood blue sclera without BCS only in certain individuals, depending on other genetic and/or environmental conditions.

Correspondence: Dr Khan, Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, PO Box 7191, Riyadh 11462, Saudi Arabia (arif.khan@mssm.edu).

Financial Disclosure: None reported.

Funding/Support: This study was supported in part by grant 08-MED497-20 from King Abdulaziz City for Science and Technology (Dr Alkuraya).

Al-Hussain  HZeisberger  SMHuber  PRGiunta  CSteinmann  B Brittle cornea syndrome and its delineation from the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI): report on 23 patients and review of the literature. Am J Med Genet A 2004;124A (1) 28- 34
PubMed Link to Article
Abu  AFrydman  MMarek  D  et al.  Deleterious mutations in the Zinc-Finger 469 gene cause brittle cornea syndrome. Am J Hum Genet 2008;82 (5) 1217- 1222
PubMed Link to Article
Christensen  AEKnappskog  PMMidtbø  M  et al.  Brittle cornea syndrome associated with a missense mutation in the zinc-finger 469 gene. Invest Ophthalmol Vis Sci 2010;51 (1) 47- 52
PubMed Link to Article
Beighton  PDe Paepe  ASteinmann  BTsipouras  PWenstrup  RJEhlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK), Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet 1998;77 (1) 31- 37
PubMed Link to Article
Hyams  SWKar  HNeumann  E Blue sclerae and keratoglobus: ocular signs of a systemic connective tissue disorder. Br J Ophthalmol 1969;53 (1) 53- 58
PubMed Link to Article
Stein  RLazar  MAdam  A Brittle cornea: a familial trait associated with blue sclera. Am J Ophthalmol 1968;66 (1) 67- 69
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Sibling 1. A, Blue sclera, phthisical eyes, and small forehead skin scars are seen. Similar skin scars were scattered on the extremities. B, Abnormal skin scarring occurred following small-incision surgery to pin a dislocated forearm. C, Talipes valgus can be appreciated as well as multiple small skin scars. D, Plain-film radiography confirms talipes valgus. R indicates right.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Sibling 2. A, Blue sclera, frontal bossing, and joint hyperlaxity are seen. B, Keratoglobus of the left eye can be appreciated. There is slight corneal haze, present since the repair of a traumatic Descemet membrane detachment. C, An Orbscan of the left cornea before the Descemet membrane detachment reveals corneal thinning and astigmatism. The right cornea (not shown) had comparable thinning without significant ectasia. D, Prominent lumbar lordosis can be appreciated on plain-film radiography. L indicates left. E, Irregularity of the calvaria can be appreciated on plain-film radiography, as can the relatively elongated anterior-posterior distance. F, Subcutaneous veins were prominent throughout the body. The left forearm is shown.

Graphic Jump Location

Tables

References

Al-Hussain  HZeisberger  SMHuber  PRGiunta  CSteinmann  B Brittle cornea syndrome and its delineation from the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI): report on 23 patients and review of the literature. Am J Med Genet A 2004;124A (1) 28- 34
PubMed Link to Article
Abu  AFrydman  MMarek  D  et al.  Deleterious mutations in the Zinc-Finger 469 gene cause brittle cornea syndrome. Am J Hum Genet 2008;82 (5) 1217- 1222
PubMed Link to Article
Christensen  AEKnappskog  PMMidtbø  M  et al.  Brittle cornea syndrome associated with a missense mutation in the zinc-finger 469 gene. Invest Ophthalmol Vis Sci 2010;51 (1) 47- 52
PubMed Link to Article
Beighton  PDe Paepe  ASteinmann  BTsipouras  PWenstrup  RJEhlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK), Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Am J Med Genet 1998;77 (1) 31- 37
PubMed Link to Article
Hyams  SWKar  HNeumann  E Blue sclerae and keratoglobus: ocular signs of a systemic connective tissue disorder. Br J Ophthalmol 1969;53 (1) 53- 58
PubMed Link to Article
Stein  RLazar  MAdam  A Brittle cornea: a familial trait associated with blue sclera. Am J Ophthalmol 1968;66 (1) 67- 69
PubMed

Correspondence

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Blue Sclera With and Without Corneal Fragility (Brittle Cornea Syndrome) in a Consanguineous Family Harboring ZNF469 Mutation (p.E1392X)
Arch Ophthalmol.2010;128(10):1376-1379.eFigures and eTable

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eFigure 1. Sibling 3.

eFigure 2. Analysis of ZNF469.

eTable. Primers and conditions.
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