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Kindler Syndrome

Synonym: Congenital Bullous Poikiloderma

, MSc, , MSc, and , MD, PhD.

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Initial Posting: ; Last Revision: December 1, 2016.

Estimated reading time: 24 minutes


Clinical characteristics.

Kindler syndrome (KS), a rare subtype of inherited epidermolysis bullosa, is characterized by skin fragility and acral blister formation beginning at birth, diffuse cutaneous atrophy, photosensitivity (which is most prominent during childhood and usually decreases after adolescence), poikiloderma, diffuse palmoplantar hyperkeratosis, and pseudosyndactyly. Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth, and labial leukokeratosis. Other mucosal findings can include ectropion, esophageal strictures/stenosis, anal stenosis, colitis, urethral stenosis/strictures, and severe phimosis. Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas. Manifestations can range from mild to severe.


The diagnosis of Kindler syndrome is established in a proband with characteristic clinical findings and identification of either biallelic FERMT1 pathogenic variants on molecular genetic testing or suggestive histologic findings and/or immunolabeling on skin biopsy.


Treatment of manifestations: When possible, children with KS should be managed by a multidisciplinary team (dermatologist, pediatrician, ophthalmologist, dentist, gastroenterologist, urologist, nurse specialist, and dietitian) in a center experienced in caring for children with skin fragility. Skin care includes standard blister care, use of moisturizers, and protection from trauma and the sun. Mucosal involvement can require lubrication of the cornea, regular dental care to ensure optimal oral hygiene to reduce periodontal disease, management of GI complications (esophageal strictures/stenosis, anal stenosis, colitis) and urethral complications (meatal stenosis/strictures).

Prevention of secondary complications: Monitoring for iron-deficiency anemia in those with colitis and esophageal strictures.

Surveillance: Screening for premalignant keratoses and early squamous cell carcinomas starting in adolescence and repeated annually.

Agents/circumstances to avoid: Sun exposure.

Pregnancy management: Planning for potential complications at delivery (e.g., vaginal stenosis, labial synechiae)

Genetic counseling.

KS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the FERMT1 pathogenic variants have been identified in an affected family member, carrier testing is possible and prenatal testing or preimplantation genetic diagnosis for a pregnancy at increased risk may be an option that a couple may wish to consider.


Suggestive Findings

Kindler syndrome should be suspected in individuals with the following clinical findings (in order of their specificity and importance for clinical diagnosis) [Lai-Cheong & McGrath 2010, Sybert 2010].

Skin fragility with trauma-induced blistering. Blisters, the most common clinical manifestation of KS, result from cutaneous trauma and/or exposure to sunlight. Blisters are present at birth.

Skin atrophy, characterized by thin, wrinkled (cigarette-paper) skin, develops early in life, particularly on the dorsa of the hands and feet. It usually becomes generalized by adolescence and is often present on the abdomen, thighs, knees, and elbows (Figure 1a, 1f, 1g) [Jobard et al 2003].

Figure 1.

Figure 1.

Characteristic clinical features of Kindler syndrome a. Child age nine years: atrophy of skin on the dorsum of the hands and poikiloderma on the neck and axillary area

Some individuals have nail dystrophy. The plate of the nails is thin, with atrophy and onycholysis (Figure 1a, 1e, 1f, 1g) [Jobard et al 2003].

Photosensitivity, characterized by erythema and burning after sun exposure, tends to improve with age; however, some degree of photosensitivity usually persists (e.g., facial erythema after minimal sun exposure) [Ashton et al 2004]. Note: Affected individuals can develop redness within minutes of sun exposure.

Poikiloderma, characterized by reticular telangiectasia and mottled hypo- and hyperpigmentation of the skin, frequently appears between ages two and three years. Generalized poikiloderma (in both sun-exposed and non-sun-exposed areas) eventually develops and persists throughout adult life in most affected individuals.

Axillary freckling may be observed in some (Figure 1a) [Jobard et al 2003, Siegel et al 2003].

Hyperkeratosis of the palms and soles with fissuring observed in about 65% of affected individuals. Palmar hyperkeratosis often has a waxy appearance, occasionally leading to the loss of the dermal ridges (i.e., fingerprints). Dermatoglyphics can be flattened or lost. Some individuals may have ridged, ribbed hyperkeratosis of the lateral and anterior ankles reminiscent of epidermolytic hyperkeratosis.

Pseudosyndactyly (i.e., partial fusion of the third and fourth and fourth and fifth toes) may be the result of repeated blistering and scarring in infancy (Figure 1g).

Mucosal involvement can include the following [Jobard et al 2003, Penagos et al 2004]:

  • Eyes. Conjunctivitis, conjunctival scarring, corneal erosion, and ectropion of the lower eyelids [Lelli 2010, Martinez & Siegel 2011, Signes-Soler et al 2013]
  • Mouth and periodontium. Severe periodontal disease (e.g., hemorrhagic mucositis, gingivitis, periodontitis, premature loss of teeth, and labial leukokeratosis), usually beginning in early adolescence [Lai-Cheong & McGrath 2010]
  • Gastrointestinal tract. Esophageal stenosis, severe colitis, bloody diarrhea, constipation, and rectal mucosal fissures and stenosis. Also, there are reports of affected children born with an imperforate anus that required surgical repair [Lai-Cheong & McGrath 2010].
  • Vagina. Vaginal stenosis and labial synechiae
  • Urethra. In some individuals, urethral meatal stenosis and urethral strictures
  • Phimosis

Establishing the Diagnosis

The diagnosis of Kindler syndrome is established in a proband with characteristic clinical findings and identification of EITHER of the following:

Molecular Genetic Testing

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of FERMT1 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multigene panel that includes FERMT1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes FERMT1) fails to confirm a diagnosis in an individual with features of Kindler syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Kindler Syndrome

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
FERMT1Sequence analysis 3~ 95% 4
Gene-targeted deletion/duplication analysis 5~ 3% 6
UnknownNot determined 7

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Although there is no proof of a second locus for Kindler syndrome, several pedigrees showing consanguinity have been reported with either no evidence of homozygosity at FERMT1 or no pathogenic variant detected, indicating that some pathogenic variants may not be readily detectable by these methods [Siegel et al 2003, Youssefian et al 2015].

Skin Biopsy

Histopathologic examination shows hyperkeratosis, nonspecific epidermal atrophy, dermal edema, incontinence of pigment with or without cytoid bodies, loss of rete ridges, and focal vacuolization of the basal layer of the epidermis and pigmentary incontinence in the upper dermis, consistent with poikiloderma [Shimizu et al 1997]. A characteristic feature is a split within the basement membrane zone at different levels. However, the most frequently encountered cleavage plane is through the lowermost portion of the basal layer of the epidermis. Extensive reduplication of the basement membrane and associated collagen deposition within the clefts are unique ultrastructural and histopathologic findings in KS.

Electron microscopy. The level of cleavage of blisters can be variable; intradermal, junctional, and dermal cleavage planes have been reported in a single biopsy from one individual.

Transmission electron microscopy of non-blistered skin demonstrates marked disorganization of the dermo-epidermal basement membrane with reduplication of the basal lamina, focal interruptions of the lamina densa, and cleavage at or close to the dermo-epidermal junction. Desmosomes, hemidesosomes, tonofilaments, anchoring filaments, and anchoring fibrils appear normal [Shimizu et al 1997, Lanschuetzer et al 2003].

Immunofluorescence staining. Antigen mapping analysis revealed that the major diagnostic criterion for Kindler syndrome is intense, broad, reticulate, and branching staining pattern with antibodies directed against laminin-332 and type IV and type VII collagen. Although anti-kindlin-1 immunostaining is also applied as a diagnostic test for KS, the final confirmation is made by FERMT1 molecular genetic testing [Lanschuetzer et al 2003, Barzegar et al 2015].

Clinical Characteristics

Clinical Description

Kindler syndrome (KS), a rare subtype of epidermolysis bullosa, is characterized by skin fragility and acral blister formation beginning at birth or in early infancy, diffuse cutaneous atrophy, photosensitivity (which is most prominent during childhood and usually decreases after adolescence), poikiloderma, palmoplantar hyperkeratosis, and pseudosyndactyly. Mucosal manifestations are also common and include hemorrhagic mucositis and gingivitis, periodontal disease, premature loss of teeth, and labial leukokeratosis. Other mucosal findings include ectropion, urethral stenosis, and severe phimosis. Severe long-term complications of KS include periodontitis, mucosal strictures, and aggressive squamous cell carcinomas. See the reviews by Lai-Cheong & McGrath [2010] and Has et al [2011], which are the basis of much of the following discussion.

The phenotypic spectrum ranges from mild to severe based on age of onset, organs involved, and severity of manifestations. The mild end of the spectrum is characterized by minimal skin involvement (such as that observed in adults with KS), with or without other mild manifestations. Some individuals with mild manifestations are not diagnosed until late in life; for example, two individuals diagnosed by molecular genetic testing in their 60s and 70s after early-stage cutaneous precancerous lesions and epithelial skin cancer were identified and treated in their 50s [Has et al 2010]. In contrast, the severe end of the spectrum is characterized by such findings as severe mucosal involvement, severe esophageal stenosis, pseudo-ainhum, anemia, and/or malignancies.

Blisters observed in childhood are mainly localized to extremities. The number of blisters decreases by age ten to 12 years [Siegel et al 2003, Penagos et al 2004]. Pyogenic skin infections can be a complication of blistering.

Skin atrophy, initially primarily localized to hands and feet, becomes generalized by adolescence [Jobard et al 2003].

Poikiloderma, which is not present at birth, appears first on sun-exposed areas, progressing with age to non-sun-exposed areas.

Hyperkeratosis of the palms and soles has been reported as fissured or punctate [Penagos et al 2004].

Pseudosyndactyly. Typically, interdigital webbing develops (Figure 1f), but without the scarring or milia noted in other forms of epidermolysis bullosa (EB) [Jobard et al 2003, Siegel et al 2003].

Constricting bands of pseudoainhum type have also been reported (Figure 1e, 1g) [Penagos et al 2004].

Fragility of mucosal surfaces can include [Jobard et al 2003, Penagos et al 2004]:

  • Gums resulting in severe periodontal disease;
  • Esophagus, anus, urethra, and vagina resulting stenosis and strictures (Figure 1c);
  • Colitis;
  • Conjunctiva resulting in ectropion.

An increased risk for malignancies has been reported:

Other findings that may be present:

  • Xerosis, eczema, and dermatitis
  • Variable hypermobility of the thumb, fingers, knees, and elbows without skin hyperextensibility [Penagos et al 2004]
  • Nail dystrophy (Figure 1e)

Morbidity and mortality mostly result from mucosal strictures and associated complications, secondary infections or cutaneous bullae, and cancer.

Genotype-Phenotype Correlations

Most FERMT1 variants associated with Kindler syndrome are null variants. It has been proposed that FERMT1 pathogenic missense variants and in-frame deletions are associated with milder disease manifestations and later onset of complications [Maier et al 2016]. Also, environmental factors and as-yet unknown modifiers likely influence the course of the disease [Has et al 2010, Has et al 2011].


Kindler syndrome (KS) was first described by Theresa Kindler [Kindler 1954].

In May 2007, 18 leading authorities on epidermolysis bullosa (EB) revised the EB classification to include KS based on its biologic and clinical findings [Fine et al 2008, Fine et al 2014].


Since the first description of Kindler syndrome in 1954 [Kindler 1954], about 250 affected individuals have been reported worldwide.

Persons of any race can be affected and there is no sex predilection [Penagos et al 2004, Has et al 2011, Youssefian et al 2015]. A cluster of 26 Panamanian affected individuals and 24 Iranian affected individuals with the syndrome have been identified [Penagos et al 2004, Youssefian et al 2015].

Differential Diagnosis

The differential diagnosis of Kindler syndrome (KS) includes the following disorders, which can exhibit features of poikiloderma but are distinguishable by other clinical features.

The clinical features of KS overlap with those of other inherited blistering skin disorders (e.g., dystrophic, junctional, and simplex epidermolysis bullosa) and congenital poikilodermas (e.g., Rothmund-Thomson syndrome). Before the onset of the photosensitivity and poikiloderma in the first few years of life, KS is frequently confused with other variants of epidermolysis bullosa; however, acral skin atrophy is indicative of KS. Furthermore, in contrast to blistering in other types of epidermolysis bullosa, the blistering in KS significantly improves with age.

The designation Weary-Kindler syndrome (WKS) has been used for a disorder with features that overlap with Kindler syndrome including vesicopustules, eczema, poikiloderma, and acral keratotic papules in infancy. In WKS the bullae are not congenital and photosensitivity and mucosal involvement are not observed [Weary et al 1971, Larrègue et al 1981, Lai-Cheong et al 2009]. WKS is inherited in an autosomal dominant manner; the associated gene(s) have not been identified. Several authors have noted the similarity of the findings in these patients to those in the original case described by Theresa Kindler, and some believe that Weary and Kindler syndromes are aspects of the same disorder [Lee et al 2012].

Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. Poikiloderma and nail dystrophy occur in late childhood. Individuals with DC are at increased risk for progressive bone marrow failure, myelodysplastic syndrome or acute myelogenous leukemia, solid tumors, and pulmonary fibrosis. Pathogenic variants in CTC1, DKC1, TERC, TERT, TINF2, NHP2, NOP10, and WRAP53 have been identified in approximately half of individuals who meet clinical diagnostic criteria for DC. DC is inherited in an X-linked, autosomal dominant, or autosomal recessive manner depending on the involved gene.

Mendes da Costa syndrome, also referred to as hereditary bullous dystrophy, macular type (OMIM 302000), is characterized by microcephaly, short stature, mild intellectual disability, cone-shaped fingers, and poikiloderma. The disorder has been described in Dutch and Italian families [Sybert 2010]. Mendes da Costa syndrome is linked to the Xq27.3-qter region; the associated gene(s) are unknown.

Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma; sparse hair, eyelashes, and/or eyebrows; small stature; skeletal and dental abnormalities; cataracts; and an increased risk for cancer, especially osteosarcoma. The skin is typically normal at birth; the rash of RTS develops between age three and six months as erythema, swelling, and blistering on the face and subsequently spreads to the buttocks and extremities. The rash evolves over months to years into the chronic pattern of reticulated hypo- and hyperpigmentation, punctate atrophy, and telangiectases, collectively known as poikiloderma. To date, RECQL4 is the only gene in which mutation is known to cause RTS. RTS is inherited in an autosomal recessive manner.

Poikiloderma with neutropenia (poikiloderma with neutropenia, Clericuzio-type) is characterized by post-inflammatory poikiloderma and permanent (noncyclic) moderate to severe neutropenia. Findings include poikiloderma, moderate neutropenia, defective neutrophil oxidative burst, anemia, thrombocytopenia, and recurrent sinopulmonary and skin infections. Myelodysplastic syndrome has been seen in adults. Poikiloderma with neutropenia is caused by mutation of USB1 and inherited in an autosomal recessive manner.

Xeroderma pigmentosum (XP) is characterized by sun sensitivity, ocular involvement, and greatly increased risk of cutaneous neoplasms. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. XP is caused by mutation of XPA, ERCC1, ERCC3, XPC, ERCC2, DDB2, ERCC4, ERCC5, or POLH and is inherited in autosomal recessive manner.

XP typically does not have acral bullae whereas in KS acral bullae are observed in childhood.

Bloom syndrome (BSyn) is characterized by severe pre- and postnatal growth deficiency, highly characteristic sparseness of subcutaneous fat tissue throughout infancy and early childhood, and short stature throughout postnatal life that in most affected individuals is accompanied by an erythematous and sun-sensitive skin lesion of the face (but not true poikiloderma). Gastroesophageal reflux (GER) is common and very possibly responsible for infections of the upper respiratory tract, the middle ear, and the lung that occur repeatedly in most persons with BSyn. Although most affected individuals have normal intellectual capability, many exhibit a poorly defined (and little studied) learning disability. Serious medical complications that are much more common than in the general population and that also appear at unusually early ages are chronic obstructive pulmonary disease, diabetes mellitus resembling the adult-onset type, and cancer of a wide variety of types and anatomic sites. BSyn is caused by mutation of BLM and inherited in an autosomal recessive manner.

Hereditary sclerosing poikiloderma (OMIM 173700) is characterized by progressive poikiloderma in flexural areas (manifest as hyper- and hypopigmentation without telangiectasia or atrophy), sclerotic bands, poor dentition, and, occasionally, calcinosis cutis [Weary et al 1969]. A later-onset complication is stenosis of cardiac valves. Absence of bullae and photosensitivity distinguish hereditary sclerosing poikiloderma from KS. Hereditary sclerosing poikiloderma is inherited in an autosomal dominant manner.

Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is characterized by the skin findings of poikiloderma (typically beginning in the first six months and mainly localized to the face), hypohidrosis with heat intolerance, mild lymphedema of the extremities, chronic erythematous and scaly skin lesions on the extremities, sclerosis of the digits, and mild palmoplantar keratoderma. Typically scalp hair, eyelashes, and/or eyebrows are sparse; nail dysplasia may be associated. Muscle contractures are usually seen in childhood and can be present as early as age two years. The majority of affected individuals develop progressive weakness of the proximal and distal muscles of all four limbs. Some adults develop progressive interstitial pulmonary fibrosis which can be life threatening within three to four years after respiratory symptoms appear. Other features are exocrine pancreatic insufficiency, liver impairment, hematologic abnormalities, relative short stature, and cataract. POIKTMP is caused by mutation of FAM111B and inherited in an autosomal dominant manner.


Evaluation Following Initial Diagnosis

To establish the extent of the disease and needs in an individual diagnosed with Kindler syndrome (KS), the following are recommended:

  • Evaluation by a dermatologist for management of skin fragility, blistering, photosensitivity, and risk for squamous cell carcinoma
  • Evaluation for mucosal involvement of the eyes (ophthalmologic consultation), mouth (dental consultation) GI tract (gastroenterology consultation), urethra, foreskin (in males) (urology consultation), and vagina (in females) (gynecology consultation)
  • Evaluation of nutritional status, diet, and oral intake
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No established treatment for Kindler syndrome exists. The goals of care are to treat manifestations and prevent complications.

When possible, children with KS should be managed by a multidisciplinary team in a center experienced in caring for children with skin fragility. When possible, the team should include a dermatologist, pediatrician, ophthalmologist, dentist, gastroenterologist, urologist, nurse specialist, and dietitian.

Skin. The following are recommended:

  • Standard blister care in childhood. If a blister is not painful, it should be kept intact. Otherwise alleviate blister-related pain by draining the fluid using a sterile needle, leaving the overlying skin in place. Apply an ointment to the blister and cover it with nonstick gauze bandage. Antibiotics may be used to treat an infected blister.
  • Protection from trauma, for example, by use of soft and protective clothing and avoiding contact sports to prevent physical trauma
  • Use of moisturizers for dry, pruritic skin
  • Sun-safety education, including use of high sun protective factor (>30 SPF) sunscreens, use of sun-protective clothing (hats and long-sleeve shirts) and avoidance of sun exposure as much as possible

Pseudosyndactyly is usually relatively mild and does not require surgical treatment.

Mucosal involvement

Eyes. Lubrication of the cornea by artificial tears and eye drops and prevention of infections by use of local antibiotics; surgical correction of corneal scarring as needed by an ophthalmologist

Mouth and periodontium. Regular dental care to ensure optimal oral hygiene to reduce periodontal disease

  • Gastrointestinal tract
    • Esophageal dilatation may be indicated for those with dysphagia.
    • Esophageal strictures and stenosis may require fluoroscopically guided balloon dilations [Sadler et al 2006].
    • Temporary parenteral nutrition may be necessary when esophageal dysfunction is severe.
    • Anal stenosis and bleeding requires regular laxatives.
    • Severe colitis may require surgical bowel resection in some cases.
  • Urethra. Meatal stenosis may require dilatation. Strictures may require stenting and/ or surgical intervention.
  • Phimosis. Most males require circumcision [Penagos et al 2004].

Prevention of Secondary Complications

Monitor for secondary iron-deficiency anemia.


Screen for premalignant keratoses and early squamous cell carcinomas starting in adolescence and repeat annually.

Agents/Circumstances to Avoid

Avoid sun exposure by using sunscreen (SFP >30) and sun-protective clothing.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although the cutaneous manifestations of KS are not exacerbated by pregnancy, vaginal stenosis and labial synechiae have been reported; thus, obstetric planning, such as consideration of delivery by elective cesarean section, warrants consideration [Mansur et al 2007]. Of note, specialized perioperative cesarean section management is needed to protect vulnerable skin and mucosa.

Breast-feeding is not advised because of the risk of blistering the breasts [Hayashi et al 2007].

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Kindler syndrome (KS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one FERMT1 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an FERMT1 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the FERMT1 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
  • Carrier testing for reproductive partners of known carriers is appropriate, particularly if consanguinity is likely.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the FERMT1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for Kindler syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • DEBRA International
    Am Heumarkt 27/3
    Vienna 1030
    Phone: +43 1 876 40 30-0
    Fax: +43 1 876 40 30-30
  • DebRA of America, Inc. (Dystrophic Epidermolysis Bullosa Research Association)
    16 East 41st Street
    3rd Floor
    New York NY 10017
    Phone: 866-332-7276 (toll-free); 212-868-1573
  • DebRA UK
    DebRA House
    13 Wellington Business Park
    Crowthorne Berkshire RG45 6LS
    United Kingdom
    Phone: +44 01344 771961
    Fax: +44 01344 762661
  • EBCare Registry
    The EBCare Registry is a resource for individuals and families affected by all forms of epidermolysis bullosa (EB) and qualified researchers working on approved EB research projects.
    Phone: 866-332-7276
    Fax: 888-363-0790

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Kindler Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
FERMT120p12​.3Fermitin family homolog 1FERMT1 databaseFERMT1FERMT1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Kindler Syndrome (View All in OMIM)


Molecular Pathogenesis

In contrast to other types of epidermolysis bullosa in which keratin intermediate filament-extracellular matrix linkage is defective, Kindler syndrome (KS) is caused by defective actin cytoskeleton ECM linkage [Lai-Cheong et al 2009].

Gene structure. FERMT1 spans 48.5 kb of genomic DNA and contains 14 coding (exons 2 to 15) and one noncoding exon (exon 1). Large gene rearrangements have previously been reported in GenBank reference AL118505. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants (severe phenotype). To date, 73 unique pathogenic variants have been reported in FERMT1 (11/2015, The Human Gene Mutation Database). Missense, nonsense, splice site, and frameshift variants as well as gross insertion and deletion variants have been reported (Table 2). Most FERMT1 pathogenic variants are nonsense and lead to loss of kindlin-1 function.

The majority of FERMT1 pathogenic variants are private variants identified in consanguineous families. For example, nine pathogenic variants (c.550_551insA, c.1139+2T>C, c. 889A>G, c.957+1G>A, c.1176T>G, c.910G>T, c.994_995delCA, c.1383C>A, and g.6109607_6112272del) were identified in the Iranian population [Youssefian et al 2015].

Population-specific pathogenic variants have also been reported:

  • Ngobe-Bugle Native American tribe in Panama: c.811C>T (p.Arg271Ter) [Ashton et al 2004, Penagos et al 2004]
  • Pakistani, Brazilian, and Balkan; c.676insC (p.Gln226fsTer16)
  • UK, of northern European origin: c.910G>T (p.Glu304Ter)
  • Omani: c.1848G>A (p.Trp616Ter)
  • Italian: c.958-1G>A

The pathogenic variants p.Arg271Ter and p.Arg288Ter have been described in individuals with KS from different ethnic backgrounds.

The insertion variant c.676insC was found in British-born Pakistani families with Kindler syndrome who share a common haplotype background, suggesting a founder effect [Ashton et al 2004, Shaiq et al 2012].

A large deletion, g.6116239_ 6120157del (reported as g.70250_74168del), is relatively common in the Italian population (23.8% of pathogenic alleles) and should be considered when choosing a testing algorithm [Has et al 2006]. Other large deletions or unusual and complex sequence alterations have been reported [Has et al 2008, Fuchs-Telem et al 2014, Chmel et al 2015, Gao et al 2015].

Large deletions due to Alu/Alu recombination. Approximately 50% of the noncoding regions of FERMT1 are repetitive sequences, with nearly half being Alu elements (24% of all intronic sequences) [Has et al 2006, Zhou et al 2009].

Three large Alu⁄Alu recombination-mediated pathogenic deletions have been reported:

Other sequence alterations. Variants in introns and regulatory regions have been reported in persons with KS:

  • A large deletion g.6045219_6047230del (reported as g.-711-1241del) beginning in promoter sequence and encompassing the noncoding exon 1 co-segregated with the disease [Fuchs-Telem et al 2014].
  • A c.-20A>G pathogenic variant within the 5́ untranslated region (UTR) was shown to have reduced transcriptional activity in a luciferase reporter assay. The potential effects of the c.-20A>G variant include perturbing the binding to a transcriptional activator, creating a new binding site for a transcriptional repressors, or altering the DNA structure. These observations suggest that the first noncoding exon and flanking intron comprised cis-acting elements that are crucial for transcription [Has et al 2015].
  • An insertion of 124 bp in intron 9 (c.1139+742ins124) results in the creation of a 124-bp pseudo-exon containing a stop codon (p.Pro381HisfsTer16) [Chmel et al 2015].

Pathogenic variants (mild phenotype). A few pathogenic missense variants, p.Ser400Pro, p.Trp559Arg, and p.Arg297Gly, have been associated with milder KS phenotypes. The molecular consequences of these amino acid substitutions have not been confirmed [Has et al 2011, Youssefian et al 2015].

Two in-frame deletions, p.Arg100del and p.Ile623del, are predicted to interfere with integrin binding/activation [Has et al 2011, Maier et al 2016] (see Table 2).

Table 2.

FERMT1 Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
(mild phenotype)
(severe phenotype)
[intron 7 – intron 9]
[intron 9 – intron 11]
[exon 5]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions

Normal gene product. FERMT1 encodes the 677-amino acid protein kindlin-1, an essential integrin activator and component of keratinocyte focal adhesions that is thought to play a regulatory role in keratinocyte migration, proliferation, and adhesion.

FERMT1 is well conserved throughout evolution with closely related homologs in Drosophila and Caenorhabditis elegans. It is mainly expressed in basal keratinocytes. Loss of kindlin-1 is associated with abnormal shape of basal keratinocytes.

The human FERMT1 mRNA transcript is 4.9 kb and expressed in cultured keratinocytes, colon, periodontal tissues, kidney, and placenta, and at low levels in the heart, liver, and small intestine [Jobard et al 2003, Siegel et al 2003, Lai-Cheong at al 2009].

Kindlin-1 has several important functional domains including a pleckstrin homology (PH) domain, two 4.1, ezrin, radixin, moesin (FERM) domains on either side of the PH domain, a C-terminus homologous to talin, and an N-terminus homologous to the protein filopodin [Larjava et al 2008].

The three mammalian kindlin family members (kindlin-1, kindlin-2 and kindlin-3) have architectural similarities and appear to play essential roles in integrin binding and activation, which is critical in cell-cell adhesion. Kindlin-2 is not known to be associated with a particular disease but may be involved in cardiomyopathy and peri-implantation lethality. Kindlin-3 is associated with leukocyte adhesion deficiency type III (LAD-III) [Moser et al 2008].

Abnormal gene product. Most of the reported FERMT1 pathogenic variants result in loss of function and may lead to absent kindlin-1 protein or production of nonfunctional protein.


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Chapter Notes

Author Notes

Jouni Uitto, MD, PhD, has been Professor of Dermatology and Cutaneous Biology, and Biochemistry and Molecular Biology, and Chair of the Department of Dermatology and Cutaneous Biology at The Sidney Kimmel Medical College at Thomas Jefferson University, in Philadelphia, Pennsylvania, since 1986. He is also Director of the Jefferson Institute of Molecular Medicine at Thomas Jefferson University. He received his MD and PhD degrees from the University of Helsinki, Finland, and completed his residency training in dermatology at Washington University School of Medicine, St. Louis, Missouri. Dr Uitto is internationally recognized for his research on connective tissue biology and molecular genetics in relation to cutaneous diseases. Dr Uitto’s publications (as of 8/2015) include 662 original articles in peer-reviewed journals, 310 text book chapters and review articles, and 961 abstracts on presentations in national and international meetings. Dr Uitto has been the recipient of numerous national and international awards, including honorary doctorate degrees from the University of Kuopio, University of Oulu, and University of Turku, all in Finland, as well as honorary professorship at China Medical University, Shenyang; Hebei United University, Tangshan; and The Fourth Military Medical University, Xi’an, all in China. Dr Uitto has held office in several scientific and professional societies, including as President of the Society for Investigative Dermatology and President and Chairman of the Board of Trustees of Dermatology Foundation. Dr Uitto is also Section Editor of the Journal of Investigative Dermatology, Associate Editor of the American Journal of Pathology, and he is on the editorial boards of numerous peer-reviewed journals.

Leila Youssefian and Hassan Vahidnezhad are PhD candidates in Medical Genetics program working on genodermatoses at the Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia, Pennsylvania.

Leila Youssefian and Hassan Vahidnezhad contributed equally to this work.

DEBRA Molecular Diagnostics Laboratory

Department of Dermatology and Cutaneous Biology
Thomas Jefferson University
233 South 10th Street
Bluemle Life Sciences Building, Suite 431
Philadelphia, PA, USA 19107
Phone: 215-503-5785

Individuals with Kindler syndrome, EB Kindler, or Kindler-like syndrome interested in receiving information and free genetic testing can contact Leila Youssefian (email: or phone: 610-999-9402).


Carol Kelly assisted in manuscript preparation.

Revision History

  • 1 December 2016 (aa) Revision: addition to Differential Diagnosis
  • 3 March 2016 (bp) Review posted live
  • 3 August 2015 (ly) Original submission
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