Kindler syndrome (KS) is a rare genodermatosis characterized by acral skin blistering and photosensitivity, followed by diffuse progressive poikiloderma, and various degrees of mucosal involvement (1). Mutations in the KIND1 gene (20p12.3) have been disclosed in most patients with clinical signs consistent with KS (2–4). The gene product, kindlin-1, is a 78-kDa phospho-protein expressed in skin in the basal keratinocytes (5). It forms complexes with β1 and β3 integrin subunits and, accordingly, kindlin-1-deficient keratinocytes have adhesion, proliferation, polarization and migration defects (6, 5). This report examines the genetic basis of KS in one Albanian and one Turkish patient with KS with severe involvement of the digestive and genitourinary mucosa, and discusses genotype/phenotype correlations.
Patient 1. A 16-year-old Albanian female, born to non-consanguineous parents, developed acral blistering during infancy, followed by progressive skin atrophy and poikiloderma (Fig. 1A). At 13 years of age, surgical repair of a severe acquired vaginal stenosis had been performed. One year later, she lost all of her teeth due to severe periodontitis and started to suffer from dysphagia. Oesophagoscopy and a barium oesophagogram confirmed oesophageal stenosis and web formation. Her body weight was 29 kg, height 1.58 m and she had profound anaemia. She had proximal webbing of the fingers and toes, pseudo-syndactily, contractures of the fingers, palmoplantar keratoderma, loss of dermatoglyphics, and nail dystrophy (Fig. 1B). There was complete effacement of the external female genitalia; the labia majora, labia minora, clitoris and introitus were absent, and only one 4–5 mm orifice, supposed to be the vestibulum, was present. As she had been menstruating regularly, it is thought that her vagina and urethra terminated at the same orifice. The results of abdominal, urinary system and pelvic ultrasonography were normal. Pelvic magnetic resonance imaging showed normal organs. The configurations of the uterus, cervix and vaginal canal were normal on T2-weighted sagittal images, except for the visible end-point of the vagina, which was located at the level of the symphysis pubis. X-rays of her hands showed diffuse osteoporosis, deformed tips of the phalanges with peri-phalangeal soft tissue not extending to the metacarpal area. Histopathology of a skin specimen from the patient’s neck showed epidermal atrophy with diffuse flattening of the rete ridges, telangiectatic vessels, melanophages, and minimal sclerosis of the dermis. Since she had insufficient oral intake, a balanced nutritional oral solution containing protein, lipid, carbohydrates, mineral and vitamins, and 5% dextrose 1000 cc iv infusion per day was started. She has been scheduled to undergo a series of oesophageal dilatation sessions, following temporal parenteral nutrition to improve her general condition.
Fig. 1. (A) Poikiloderma on the neck of patient 1. (B) Skin atrophy over the dorsa of the hands, webbed fingers and palmar keratosis in patient 1. (C) Poikiloderma on the trunk of patient 2.
Patient 2. A 25-year-old Turkish man born to non-consanguineous, but geographically-linked parents. Family history revealed three mildly affected younger patients among his remote cousins. He developed skin blistering 15 days after birth. His skin was atrophic, especially on the dorsal aspects of his hands and feet, and he had progressive poikiloderma (Fig. 1C). There were erosions and scaly crusts on his lips and white membranes on the labial commissures and adjacent, atrophic buccal mucosa. He developed photosensitivity in infancy. He complained of dysphagia and had a history of annual oesophageal dilatation since the age of 15 years. He also had anal and urethral strictures. He had bilateral proximal webbing of the fingers and toes and severe toe-nail dystrophy.
Genomic DNA extracted from peripheral lymphocytes was used for polymerase chain reaction (PCR) amplification of the entire coding region and exon-intron boundaries of KIND1, as described previously (3). The PCR products were used for sequencing reactions and then submitted to automated nucleotide sequencing in an ABI 3130XL genetic analyser (ABI, Darmstadt, Germany). DNA sequences were compared with the reference sequence from the NCBI Entrez Nucleotide database (NM_017671) using Mutation Surveyor software (Softgenetics, State College, PA, USA; www.softgenetics.com). Each mutation was confirmed by re-sequencing a PCR product obtained from a second amplification reaction.
In patient 1, the homozygous mutation c.676dupC was identified (Fig. 2A). The duplication of cytosine at position 676 in exon 5 of the kindlin-1 mRNA resulted in frameshift and the formation of a premature termination codon, 16 codons downstream, p.Q226fsX16. In the DNA sample of patient 2, a novel homozygous mutation was disclosed in exon 3 of the KIND1 gene, c.170C > A (Fig. 2B), leading to a premature termination codon instead of codon 57 for serine, p.S57X. In both cases, the parents were found to be heterozygous carriers of the respective mutations.
Fig. 2. (A) Partial DNA sequence of exon 5 of the KIND1 gene. Wild-type sequence (upper panel) and the homozygous mutation c.676dupC (lower panel) in the DNA sample of patient 1. (B) Partial DNA sequence of exon 3 of the KIND1 gene. Wild-type sequence (upper panel) and the homozygous mutation c.170C > A (lower panel) in the DNA sample of patient 2. Red arrows indicate the mutations.
While the skin phenotype is typical in KS, fragility of mucous membranes seems to vary between cases. The most frequent are the oral mucosal manifestations, which include white patches, atrophy, blistering, gingival bleeding, severe periodontitis, ankyloglossia, restricted mouth opening and malocclusion (7). Development of oesophageal, anal and urethral stenosis, and phimosis are rare findings (7). So far, involvement of the female genitalia has been reported in only two patients, who had vaginal stenosis and vulvar synechia (8, 9).
Both patients described here had severe oesophageal stenosis, necessitating dilatation. Due to poor oral intake, the general condition of patient 1 degraded progressively, leading to severe anaemia and malnutrition, comparable to patients with dystrophic epidermolysis bullosa. She also showed severe vulvo-vaginal synechia, completely effacing the external genital architecture. To the best of our knowledge, this is the third reported case of KS with severe scarring of the female genital tract. It is not clear why the female genitalia are less often reported to be involved in KS compared with males with KS. However, this sex-related difference may not be accurate, for lesions of the vulvo-vaginal area might simply be overlooked.
All 25 KIND1 mutations described in the literature were nonsense, splice-site or frame-shift mutations, predicted to lead to a premature termination codon and to RNA decay and absence of the full-length protein (10–14). Nevertheless, the associated phenotypes were variable. Several KIND1 mutations occurred in more than one family, either as ancestral alleles, or as recurrent mutations in diverse ethnic groups (10, 13).
In this report we disclosed one recurrent, c.676dupC, and one novel, c.170C > A, KIND1 mutation in patients originating from Albania and Turkey, respectively. Both mutations lead to premature termination codons and are predicted to cause absence of the full length kindlin-1 protein. The mutation c.676dupC was previously identified in affected individuals from Pakistani families and was shown to be both a hotspot and a founder mutation (10, 12). Among the patients with KS investigated in our laboratory, patient 1 reported here from Albania-Kosovo, and one previously reported patient originating from Kosovo, were homozygous for this mutation (5). Although they are unrelated, both had the same KIND1 SNP haplotype, different from the ancestral Pakistani haplotype (10). Thus, our findings confirm c.676dupC, to be both, a hotspot and a founder mutation (10). Including the present case, 13 patients with KS homozygous for the c.676dupC mutation have been published (5, 10, 15). Their skin phenotypes were similar, but mucosal involvement varied: our patient 1 and one 37-year-old patient (15) were similarly severely affected. Genotype-phenotype correlations are difficult in patients of different ages, but it is clear that the same KIND1 mutation can lead to various degrees of disease severity (2). These data suggest that in KS clinical manifestations are age-dependent and may be influenced by environmental exposure as well as by other currently unknown factors.
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