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
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RESULTS
Patient 1
Patient 1 was a 40 year old female. Although no previous
documentation was available, the patient’s 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 patient’s 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 Raven’s 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 2’s
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 2’s 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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