There appears to be an increased risk of non-melanoma skin cancer, mostly squamous cell carcinomas that occur on acral skin or in the mouth in KS [24–28]. The first observation that kindlin-1 may be implicated in cancer was the finding of increased expression of the FERMT1 mRNA transcript in approximately 60 and 70 % of lung and colon cancers, respectively [31]. Subsequent gene expression microarray studies comparing the transcription profiles of transforming growth factor β1 (TGFβ1)-treated human mammary epithelial cells (HMEC) with non-treated cells showed that FERMT1 is a TGFβ1-inducible gene. The increase in kindlin-1 expression resulting from TGFβ1 stimulation may cause an increase in cell spreading which correlates with epithelial to mesenchymal transition, an important step in carcinogenesis [32]. The TGFβ1 exposure can also induce a rearrangement of the actin cytoskeletal network which resembles that seen in fibroblastic cells [32]. Keratinocytes lacking kindlin-1 display alterations in the cortical actin network and increased plasticity of the plasma membrane, with increased expression of mesenchymal markers such as vimentin and fibronectin [33]. Kindlin-1 has been evaluated as a biomarker in some cancers [34]. Notably, over-expression has been associated with epithelial-mesenchymal transition, aberrant TGFβ signalling, activation of cell motility and invasion, implicating a role for kindlin-1 in breast cancer lung metastasis and lung tumourigenesis [34].

Revertant mosaicism (RM) is a genetic phenomenon that spontaneously results in the partial or complete correction of an affected phenotype [35]. In 2012, the first case of RM in KS was reported [36]. The proband was an 8-year old boy born to consanguineous parents. Soon after birth, he developed extensive blistering on both hands and progressive poikiloderma on his neck. In 2008, a small patch of normal-looking skin was identified on his dorsal right hand. Molecular investigation showed that the child harboured a homozygous frameshift mutation, c.676dupC, in the FERMT1 gene, while in the revertant skin, there was correction of the frameshift at the transcriptional level [36]. Subsequent to this study, a further six patients with KS have been described with RM resulting from slipped mispairing and mitotic recombination [37]. These cases also involved the mutation c.676dupC, as well as a similar mutation c.456dupA. KS now features on the list of inherited skin conditions in which RM has been reported, including various types of EB (EB simplex, recessive dystrophic EB and generalised intermediate junctional EB) and ichthyosis with confetti (for review, see Ref. [38]).

Since the identification of the FERMT1 gene, approximately 150 patients with KS have been described, and 56 different pathogenic mutations have been identified in the FERMT1 gene [39–41]. Most of these mutations are nonsense mutations (~40 %). The rest are mainly frameshift and splice site mutations. Recently, missense and in-frame deletions in the FERMT1 gene have been described in individuals with KS, although the precise molecular consequences of these mutations remain to be clarified [39]. Nevertheless, these particular mutations appear to be associated with milder clinical features and a later onset of disease complications [39]. In-frame skipping of exon 8 has been detected in some individuals with KS—this mutation causes aberrant β1 integrin signalling but does not reduce kindlin-1 immunostaining in skin biopsies [42]. Most mutations detected around the world in cases of KS are specific to individual families, but recurrent hotspot and founder effect mutations have been identified. For instance, the mutation p.Arg271X has been demonstrated in Panamanian, Caucasian American and Omani subjects, whereas p.Arg288X has been found in UK Caucasian and Turkish patients with KS [5]. In contrast, mutated ancestral FERMT1 alleles include c.676insC (p.Gln226fsX17), IVS7–1G > A, p.Glu304X and p.Trp616X that have been detected in several Pakistani, Italian, British Caucasian and Omani patients, respectively [25, 43]. The mutation c.676dupC has been reported as both an ancestral allele and a recurrent mutation on different genetic backgrounds.

KS can be difficult to diagnose because of its clinical overlap with other forms of EB especially in neonates and infants. With increasing age, the appearance of skin atrophy and poikiloderma and the reduction in blisters and increased photosensitivity may point to the correct diagnosis of KS. Currently, gene sequencing of the FERMT1 gene remains the most reliable method for diagnosing KS although immunofluorescence microscopy labelling using a C- or N-terminal anti-kindlin-1 antibody may be useful in the diagnosis of KS [25, 43–46]. Skin immunostaining for kindlin-1 as a diagnostic test is not totally reliable, however, since some cases of KS can show positive immunostaining, even in the presence of FERMT1 mutations [42, 47].

There are currently no reports of effective gene, protein, cell or drug therapies for KS, and treatment is therefore largely symptomatic. The skin in KS is dry and often pruritic requiring frequent application of emollients. Sun protection is recommended because of the development of photosensitivity in some individuals with KS [48]. Annual checks for premalignant keratoses and early malignancy are recommended because of the increased risk of squamous cell carcinomas in KS. Regular dental care such as scaling and root planing and careful regular hygienist attention are advised to treat/prevent the erosive gingivitis and aggressive periodontitis seen in KS [49]. Patients with dysphagia should undergo radiographic imaging to identify oesophageal stenoses that may require oesophageal dilatation [20, 21]. In cases with severe oesophageal dysfunction, temporary parenteral nutrition may be indicated [20]. Affected individuals with colitis-like symptoms may develop iron-deficiency anaemia. In some cases, the colitis can be severe enough to warrant surgical bowel resection [22]. In pregnant females with KS, careful obstetric planning such as elective caesarean section should be considered, since vaginal stenosis is a not infrequent manifestation of KS [50].

KS is a rare autosomal recessive subtype of EB resulting from pathogenic mutations in the FERMT1 gene. It is characterised by skin blistering, skin atrophy, poikiloderma, as well as varying degrees of mucosal inflammation and photosensitivity. To date, it remains the only inherited mucocutaneous disorder that has been shown to result from a focal adhesion protein defect.