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Severe form of keratitis–ichthyosis–deafness (KID) syndrome associated with septic complications

2010; Wiley; Volume: 37; Issue: 7 Linguagem: Inglês

10.1111/j.1346-8138.2010.00839.x

1346-8138

Kunitaka HARUNA, Yasushi Suga, Ami Oizumi, Yuki Mizuno, Hideharu Endo, Toshiaki Shimizu, Toshio Hasegawa, Shigaku Ikeda,

Connexins and lens biology

Dear Editor, A 1-year-old Japanese girl visited our hospital with her unaffected parents. The patient was not the product of a consanguineous marriage, and no other members of the family showed similar symptoms. At birth, she had had ichthyotic erythroderma and hyperkeratosis which increased with age. She had keratotic, verrucous red plaques on her scalp. Her hair shafts were short, thin and brittle, and her hair growth seemed poor and all of her nails were dystrophic. The patient's height and weight were below the second percentile for her age. By the age of 10 months, additional cutaneous symptoms progressed. The keratinized area expanded gradually in the occipital region, palms, body trunk and diaper application site, and alopecia spread all over the head. At approximately 12 months old, these keratinized lesions were aggravated further showing a severe papilloma-like state, and impetigo-like exanthemas developed at chafing regions and the diaper application site. Therefore, at the time of initial examination, rubor and desquamation were found all over the body, and particularly erythema with a clear margin and hyperkeratinization were found in the entire occipital region and around the mouth (Fig. 1a). Most of the hair of the head, eyebrows and eyelashes had been lost, but dental abnormalities were absent. Clinical presentation and histopathology. (a) Erythema and hyperkeratinization around the mouth. (b) Pavement stone pattern hyperkeratinization of the palm and sole. A reticulated pattern of hyperkeratosis on the palms and soles are notable. (c) Erosion and hyperkeratinized surface accompanying granuloma-like lesion at the diaper application site. (d) Histopathological examination of a skin tissue specimen from the patient's back revealed epidermal acanthosis, hyperkeratosis and papillomatosis, and loss of granular layers. (e) Ultrastructural analysis showing lipid droplets and cytosolic vacuolar change within suprabasal keratinocytes of the epidermis. (f) Conjunctivitis and keratitis accompanied by opaque cornea and vascularization are seen. In particular, hyperkeratinization of a unique pavement stone pattern that looked like attachment of fine granules was observed on the palms and soles (Fig. 1b). In addition, a highly keratinized surface developed on the entire diaper application site, and furthermore erosion that seemed attributable to secondary infection and granuloma-like lesions were found around keratinized papules (Fig. 1c). A skin biopsy from her back showed marked epidermal acanthosis, hyperkeratosis and papillomatosis, and loss of granular layers (Fig. 1d). Ultrastructural analysis revealed lipid droplets and cytosolic vacuolar change within suprabasal keratinocytes of the epidermis (Fig. 1e). Change in gap junction was not clearly shown. The laboratory findings were as follows: white blood cell count, 24.3 × 103/mm3 (differential count of neutrophils, 77.0%); red blood cell count, 4.29 × 104/mm3; hemoglobin, 9.9 g/dL; platelet, 50.8 × 104 μL; total protein, 8.3 g/dL; albumin, 3.1 g/dL; immunoglobulin (Ig)G, 2395 mg/dL; IgA, 220 mg/dL; IgM, 114 mg/dL; and IgE, 870 mg/dL. In ophthalmology, decreased visual acuity and opaque cornea were found predominantly in the right eye. Under close examination, conjunctivitis, blood vessel-infiltrating keratitis accompanied by vascularization, and corneal ulceration were observed (Fig. 1f). In otorhinolaryngology, no response was found in the auditory brainstem response test, and she was diagnosed as having bilateral sensory-neural hearing loss. Because her deafness was severe, utterance was difficult. Subsequently, DNA analysis of the entire coding regions and exon–intron borders of the GJB2 gene was carried out. Oligonucleotide primers for amplification and DNA sequencing methods have been reported elsewhere.1 Following direct sequencing, from the patient and unaffected family members after informed consent, we found a single nucleotide substitution in one allele at residue position 263 of the GJB2 domain segment (GCG to GTG, alanine to valine; A88V) (Fig. 2). Neither of the parents showed this change, confirming that this substitution is a de novo mutation. In addition, 50 unrelated normal controls were shown not to have this substitution (date not shown). A88V mutation seemed to be novel as far as we have examined by the Human Gene Mutation Database (HGMD; http://www.hgmd.cf.ac.uk/ac/index.php). Sequence analysis of GJB2. Direct genomic sequencing of the patient revealed a C to T transition at the second position of codon 88 in GJB2 (arrow). The amino acid was deduced to change from alanine (Ala) to valine (Val) in patient. In the present case, clinical and histopathological manifestations indicated that the patent suffered from keratitis–ichthyosis–deafness (KID) syndrome. KID syndrome (Mendelian Inheritance in Man no. 148210) is a rare disorder, which has the following features: (i) a distinctive ichthyosis characterized by a fine dry scale, follicular hyperkeratotic spines, and a reticulated pattern of hyperkeratosis on the palms and soles; (ii) a vascularizing keratitis that results in notable visual impairment; and (iii) neurosensory deafness.2 The incidence of KID syndrome is very rare, and only approximately 70 cases have been reported in published work worldwide. Both an autosomal dominant form3 and an autosomal recessive form4 have been described, but numerous sporadic cases have also been reported.5 Recently, germ line missense mutations in GJB2, encoding connexin-26 (C×26), have been found to be associated with KID syndrome.6 In our case, molecular analysis of the GJB2 gene revealed an alanine to valine substitution at codon 88, which seems to be a novel mutation according to our review of the pertinent published work and databases on the Internet. On the basis of clinical features, our patient showed a severe form judging from the clinical symptoms and the course. Generally, prognosis for life regarding KID syndrome is described as good. However, it is notable that our present case had recurrent chronic cutaneous bacterial infections and candidiasis repeatedly in spite of various kinds of treatments. Similar difficulties were previously reported in some cases with a severe form of KID syndrome.7–9 Although congenitally abnormal immunity was not detected in a screening test in the present case, some mechanism of immunodeficiency seemed to be involved at a high probability. In fact, at the age of 3 years and 5 months, she suffered with hypoproteinemia, hypoglycemia, pneumonia and enterocolitis. In spite of strenuous treatment, her condition deteriorated and she went into septic shock. Finally, she died of cardiac failure. Gap junction is thought to contribute to intercellular transmission of information by means of various ions and intracellular signal transmitters. Local structural change of connexin accompanying amino acid variation seemed to change the permeability of ions in the gap junction and so forth, and to affect keratinization of epidermal cells, hearing ability, corneal function and so forth.10 Clearly, there are still many unanswered questions concerning how individual connexin mutations will increase the risk on the incidence of severe sepsis. For elucidating in future the mechanism of development of immunodeficiency, it is important to document the information correlating genotypes with phenotypes. Moreover, when caring for infants with a severe form of KID syndrome, it is important to be aware of the possibility of increased susceptibility to severe, systemic infections. We thank Dr Chieri Kobayashi (Department of Otorhinolaryngology, Juntendo University School of Medicine) for useful discussions and comments on this subject.