Novel and Recurrent KIND1 Mutations in Two Patients with Kindler Syndrome and Severe Mucosal Involvement

Abstract

Kindler syndrome (KS) is a rare genodertnatosis characterized by acral skin blistering and photosensitivity. followed by diffuse progressive poikiloderma, and various degrees of mucosal involvement (1). Mutations in the KIND! gene (20pl2.3) have been disclosed in tiiost patients w ith clinical signs consistent witb KS (2-4). The gene product, kindlin-1, is a 78-kDa phospbo-protein expressed in skin in the basal keratinocytes (5). It fonns complexes with [31 and p3 integrin subunits and. accordingly, kindIin-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 ofthe digestive and genitourinary mucosa, and discusses genotype/phenotype correlations. CASE REPORTSPatient I. A 16-year-old Albanian female, born lo non-consanguineous parents, developed acral blistering during infancy, followedby progressive skin atrophy and poikiloderma (Fig. IA). Al 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 periodontilis and started lo suffer from dysphagia, Oesophagoscopy and a barium oesophagogram confirmed oesophageal stenosis and web formation. Her body weight was 29 kg, height L5X m and she had profound anaemia. She had proximal webbing ofthe fingers and toes, pseudo-syndaeiily, coniraciurcs of the fingers, palmoplantar keraioderma. loss of dcrmaioglyphics, and nail dystrophy (Fig. 1B). There was complete eiTacement ofthe 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 ihal ber vagina and urethra terminated at the same orifice. The results olabdominal, urinary system and pelvic ullrasonography were normal. Pelvic magnetic resonance imaging showed normal organs. The eonfigurations ofthe uterus, cervix and vaginal eanal were normal on T2-weighied sagittal images, except for the visible end-point ofthe vagina, which was located at the level ofthe symphysis pubis. X-rays of her hands showed difTusc osteoporosis, dctbrnied tips ofthe phalanges wiih peri-plialangeal soft tissue nol exlending to the melaearpal area, Histopalhology of a skin specimen from ihe patient's neck showed epidermal atrophy with dilYuse fiattening ofthe rete ridges, telangieclatic vessels, melanophages, and minimal sclerosis of the dermis. Since she had insutlkieni oral intake, a balanced nulritional oral solution containing protein, lipid. carbohydrates, mineral and vitamins, and 5% de.xtiose 1000 cc iv infusion per day was slarled. She has been scheduled to undergo a series of oesophageal dilatation sessions, following temporal parenteral nutrition to improve her general condition.Patient 2. A 25-year-old Turkish man born lo non-consanguineous, but geograpbieally-linked parents. Family history revealed three mildly affected young...

Epidermolysis bullosa in Greece: the patients’ journey so far

“…Mutation c.676dupC, common in all four patients, has been reported in several other studies recording patients originated from Albania and Pakistan. 37,39,41 Mutation c.676dupC has been recognized as a hotspot and a founder mutation for KS; this was also confirmed by our findings. 37,38,41 The mutations present in two of these cases were reported in literature for the first time.…”

Kindler syndrome: Extension of FERMT1 mutational spectrum and natural history

“…Skin and mucous membranes, which form the barrier to the environment, are permanently exposed to mechanical factors, UV irradiation, and pathogens. Increased environmental noxae may explain the extent of symptoms in severely affected KS patients described before [Has, et al 2008a;Kern et al, 2007;Mansur et al, 2007].…”

Induction of phenotype modifying cytokines by FERMT1 mutations

“…Their age, mutations and phenotypic features indicating fibrosis in skin and mucous membranes are summarized in Table 1. Patients 1 -4, 6 -8 have been described in detail before (Has, et al, 2008a;Has, et al, 2008b;Herz, et al, 2006;Kern, et al, 2007;Mansur, et al, 2007). Importantly, at the time of presentation and skin biopsy, none had blisters, wounds, or skin fragility.…”