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

DISCUSSION

This is the first report of two Serbian patients with KID syndrome, caused by heterozygous p.D50N mutation in the GJB2 gene. GJB2 p.D50N mutation is the most commonly identified mutation associated with KID syndrome The mutation has been described in both sporadic and familial cases with autosomal dominant inheritance1,3,7. According to family history, KID syndrome in Patient 1 may be familial with reduced penetrance in her father and grandfather, who had strikingly dry and scaly skin with minimal visual symptoms. Patient 2 seems to be sporadic, since none of the parents were clinically affected and the mother was proven not to carry the p.D50N mutation in her blood cells. In this family, the GJB2 p.D50N mutation could have arisen de novo, or one of the parents could be germline mosaic. Nevertheless, the unavailability of the father’s DNA sample in both examined families did not allow us to unambiguously conclude whether KID syndrome was sporadic or familial. KID syndrome is considered a dysregulated hemichannel disorder because a common feature of GJB2 missense mutations appears to be an aberrant gain of function of hemichannels, leading to perturb voltage gating and the control of hemichannels by extracellular Ca2+.6 Nevertheless, a genotype–phenotype correlation has emerged among KID patients. Patients with GJB2 p.D50N mutation live into adulthood,1,11 while infant death occurred in almost all patients with GJB2 p.G45E and p.A88V.12 An affected Austrian family, mother and child showed mild-to-moderate hearing loss and the keratitis was mild to absent, while in a 12 year old Austrian, sporadic patient hearing loss was profound, and the keratitis was therapyresistant. 11 Findings on our patients confirm the variability in the clinical course of the disease caused by GJB2 p.D50N mutation. A common feature of patients described by Janecke et al.11 and ours, was an appearance of skin lesions shortly after birth, although of different severity, and normal psychomotor development and intellectual ability. Cerebellar and neuromuscular defects, extremely rarely reported in KID syndrome, was described in patients with GJB2 p.D50N mutation. A Portuguese boy had nystagmus, generalized hypotonia, spastic tetraparesia, and hypoplasia of the cerebellar vermis revealed by MRI.13 Of note, both of our patients had slurred and slow speech, while Patient 2 walked on her tiptoes until 10 years of age. Described phenotype variability implies that the effect of GJB2 p.D50N mutation can likely be modified by the genetic background of the patients. However, studying genetic modifiers is challenging in an extremely rare disease like KID syndrome. Mental retardation was described in about 10% of patients with KID syndrome.14,15 In addition, developmental delay is characteristic of autosomal recessive form of Kid syndrome (KIDAR; MIM#242150) caused by homozygous or compound heterozygous mutations in the AP1B1 gene on 22q12.2. To the best of our knowledge, our Patient 1 is the first one reported to have a higher-than-normal IQ, which is indirect proof that IQ is probably distributed among KID population in the same manner as in the general population. Although KID syndrome is a rare condition, it is both a therapeutic and a diagnostic challenge. Severe infections of the skin lesions and septicemia may have a fatal course during early childhood.16 Patients with GJB2 p.D50N mutation frequently develop squamous cell carcinomas.1,17 No therapy reported so far seems to offer long-term visual recovery. Pharmacotherapeutic strategies successes were reported to be mostly limited, due to the decrease in irritative symptoms, but not in regard to visual rehabilitation. 18 The treatment of ocular manifestation includes ocular lubricants, autologous serum, tetracycline, and antiinflammatory agents, including topical corticosteroids and topical cyclosporine A. Several studies have found that topical immunosuppressive therapy of corticosteroids and topical cyclosporine A improves ocular surface disease. Both patients have less irritable eyes and feel satisfied with therapy. Subsequently the disease progressed after discontinuation of the local corticosteroid therapy. The use of gas-permeable contact lenses may enhance visual acuity and quality of life in advanced cases with corneal neovascularization. Patients treated with subconjunctival bevacizumab, with partial response of corneal neovascularization and symptomatic improvement, have been described in the literature.19 Systemic treatment with retinoids such as isotretinoin may worsen the ocular surface disease. However, mild vision and hearing improvement have been reported with acitretin.19,20 There were some attempts in doing surgery for KID syndrome, such as corneal opacification. Results on limbal stem cell transplantation, superficial keratectomy and penetrating keratoplasty were not successful, and they lead to the recurrence of the disease. Finally, the only possibility for better visual outcome may be the Boston Keratoprosthesis.20



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