KERATITIS-ICHTHYOSIS-DEAFNESS SYNDROME WITH HETEROZYGOUS P.D50N IN THE GJB2 GENE IN TWO SERBIAN ADULT PATIENTS
Kalezić T.1,*, Vuković I.2, Stojković M.1, Stanojlović S.1, Karanović J.3, Brajušković G.3, Savić-Pavićević D.3
*Corresponding Author: Tanja Kalezić, School of Medicine, University of Belgrade; Clinic for Eye Disease, University Clinical Centre of Serbia, Address: Pasterova Street No 2 , Tel. +381638148843, e-mail address: tanjakalezic@gmail.com
page: 6

RESULTS

Patient 1 Patient 1 was a 40 year old female. Although no previous documentation was available, the patientís mother reported that a diagnosis for the patient of an ichthyosiform skin lesion with hearing impairment was established shortly after birth, while corneal signs appeared in the second year of life, leading to the diagnosis of KID syndrome. Severely slurred and slow speech was noticeable from early childhood. Family history revealed that the father and paternal side grandfather had strikingly dry and scaly skin, with minimal visual symptoms. Due to red and irritated eyes from the second year of life, therapy with artificial tears was applied during the patientís lifespan, but it has not been continuous. The patient was referred to the Clinic for Eye Disease, University Clinical Center of Serbia due to recent worsening of visual acuity, grittiness, tearing, and photophobia. She presented with hypotrichosis of the whole body, with multiple scars on the capillitium. Skin was in total xerosis, with lichenification and ichthyasiform skin lesions. Nails were dystrophic and dark colored, some nails were missing. The patient had no obvious problems in hearing the questions and commands uttered in a normal voice. Regardless of the obvious problems in communication, Patient 1 seemed unusually cooperative and outspoken. Without any formal education and with the help of her mother, she developed good reading and writing skills. When an intelligence test was performed, her IQ measured, with Ravenís progressive matrices, at 130. Genetic testing revealed a heterozygous missense mutation, c.148G>A, in exon 2 of the GJB2 gene (Fig. 1: A1), which results in amino acid change from aspartic acid (Asp) to asparagine (Asn) at codon 50 (p.D50N). This mutation was not found in the unaffected mother (Fig. 1: A2). Thickening and keratinization of eyelid margins, lash loss, diffuse opacification of cornea, loss of conjunctival luster caused by keratinization of eye surface, superficial as well as deep corneal vascularization, and corneal edema were noticed during the ophthalmological examination (Fig.1: A2). Esotropia with amblyopia in the right eye were detected. Best corrected visual acuity (BCVA) was counting fingers in the right eye and 0.2 to 0.3 using Snellen chart in the left eye. Central corneal thickness (CCT) using tomography (Orbscan 2z, Baush and Lomb) was 462 μm for the right and 584 μm for the left eye. The four month regime of topical therapy with corticosteroids and artificial tears, with intensified topical corticosteroid therapy during the last month, resulting in improved vision in the left eye of Patient 1. There was an increase in BCVA in follow up time of six months and it was better in the left eye (from 0.3 to 0.7, Snellen chart). No intraocular pressure increase was noticed throughout the course of therapy. Patient 2 Patient 2 was 34 year old females at the time of the ophthalmological examination. According to Patient 2ís history, skin lesions were present from birth. The patient manifested difficulty since walking and, up to 10 years of age, she walked on her tiptoes. Her whole skin, including the face, was affected from the second year of life. At times, she had red circles on the capillitium. Her diagnosis of KID syndrome was set at 16 years of age. Family members were with no remarkable ophthalmologic nor skin problems. Patients 2ís mother and father had difficulties with hearing. Patient 2 was referred to the Clinic for Eye Disease, University Clinical Center of Serbia due to the blurred vision that was worse in the left eye. Her skin was with typical ichthyasiform erythroderma and lash loss. Facial skin was xerotic with local lichenification. The extensor sides of the arms and hull of the body also had lichenification and darker pigmented zones of the skin. The dorsal side of the hands and feet were covered with diffuse, yellow hyperkeratosis. Nails on the hands were normal while, on the feet, they were yellow colored. Speech pattern and hearing for Patient 2 was severely impaired. The same heterozygous missense mutation c.148G>A (p.D50N) in exon 2 of GJB2 gene, as in Patient 1, was identified in the Patient 2 (Fig. 1: B1). This mutation was not found in the unaffected mother and sister (Fig. 1: B2 and B3). However, the sister had heterozygous deletion c.35delG in the GJB2 gene, a particularly common mutation associated with autosomal recessive non-syndromic hearing loss (Fig. 1: B3) (Tsukada et al. 2015).10 On ophthalmological examination for Patient 2, BCVA, using the Snellen chart, was counting fingers in both eyes. Corneal opacification and loss of corneal and conjunctival luster was found. CCT using tomography (Orbscan 2z, Baush and Lomb) were 555 μm for the right and 620 μm for the left eye. Local corticosteroid therapy during follow up time of six months did not improve vision in Patient 2 (Fig. B: B1). Still, her eyes were less irritated with blood vessels slightly less engorged and corneal surfaces had more luster then upon presentation. Corneal thickness was steady.



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