Kindler Syndrome

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Summary

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.

Diagnosis/testing.

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.

Management.

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.

Diagnosis

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:

  • Biallelic FERMT1 pathogenic variants on molecular genetic testing (see Table 1)
  • Suggestive histologic findings and/or immunolabeling on skin biopsy

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
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

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

3.

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.

4.

Ashton et al [2004], Has et al [2011]

5.

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.

6.

Has et al [2006], Has et al [2008], Zhou et al [2009], Piccinni et al [2013], Fuchs-Telem et al [2014]

7.

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:

  • Squamous cell carcinomas in acral skin and the mouth (lip and hard palate) [Lotem et al 2001, Emanuel et al 2006]
  • Transitional cell carcinomas of the bladder [Alper et al 1978]

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].

Nomenclature

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].

Prevalence

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.

Management

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.

Surveillance

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 ClinicalTrials.gov 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.