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 (most prominent during childhood and usually decreasing 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, urethral stenosis, 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 KS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in FERMT1 identified by molecular genetic testing.

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, and management of gastrointestinal and urethral complications.

Surveillance: Screening for premalignant keratoses and early squamous cell carcinomas starting in adolescence and repeated annually. Screening for oral ulcerations, gingivitis, and periodontitis starting in adolescence with regular dental checkups.

Agents/circumstances to avoid: Sun exposure.

Pregnancy management: Planning for potential complications at delivery (e.g., vaginal stenosis, labial synechiae). Breast-feeding is not advised due to risk of blistering breasts.

Genetic counseling.

KS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FERMT1 pathogenic variant, each sib of an affected individual has at conception 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 for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

KS should be suspected in individuals with the following clinical findings, skin biopsy results, and family history.

Clinical findings

• Skin fragility with trauma-induced blistering. Blisters are present at birth and result from cutaneous trauma and/or exposure to sunlight.
• Skin atrophy. Thin, wrinkled (cigarette-paper) skin, developing early in life, particularly present on the dorsa of the hands and feet
• Photosensitivity. Erythema and burning within minutes of sun exposure; tends to improve with age.
• Poikiloderma. Reticular telangiectasia and mottled hypo- and hyperpigmentation of the skin appear between ages two and three years.
• Hyperkeratosis of the palms and soles with fissuring; a waxy appearance on the palms may be associated with the loss of the dermal ridges (i.e., fingerprints).
• Pseudosyndactyly (i.e., partial fusion of the third and fourth and fourth and fifth toes) is associated with repeated blistering and scarring in infancy.
• Fragility of mucosal surfaces including the conjunctiva, periodontal tissues, gastrointestinal tract, and/or external genitourinary structures

Skin biopsy results

• 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 suggestive of 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 nonblistered skin demonstrates marked disorganization of the dermoepidermal basement membrane with reduplication of the basal lamina, focal interruptions of the lamina densa, and cleavage at or close to the dermoepidermal 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 KS 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].

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of KS is established in a proband with suggestive clinical findings and biallelic pathogenic (or likely pathogenic) variants in FERMT1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic FERMT1 variants of uncertain significance (or of one known FERMT1 pathogenic variant and one FERMT1 variant of uncertain significance) does not establish or rule out the diagnosis.

Because the phenotype of KS may be indistinguishable from many other inherited disorders with cutaneous fragility, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing:

• A skin fragility multigene panel that includes FERMT1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. (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.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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 (most prominent during childhood and usually decreasing 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.

To date, about 400 individuals have been identified with biallelic pathogenic variants in FERMT1 [Guerrero-Aspizua et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.

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 were 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, pseudoainhum, anemia, and/or malignancies.

Blisters are present at birth; those observed in childhood are mainly localized to extremities.

• Blisters result from trauma and/or exposure to sunlight.
• 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, characterized by thin, wrinkled (cigarette-paper) skin is initially primarily localized to hands and feet; atrophy 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.

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

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, which is not present at birth, appears first on sun-exposed areas, progressing with age to non-sun-exposed areas (Figure 1b). This is characterized by reticular telangiectasia and mottled hypo- and hyperpigmentation of the skin, frequently appearing 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, Rayinda et al 2021].

Hyperkeratosis of the palms and soles has been reported as fissured or punctate [Penagos et al 2004] and is 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. 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 the pseudoainhum type have also been reported (Figure 1e, 1g) [Penagos et al 2004].

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. Affected children born with an imperforate anus that required surgical repair have also been reported [Lai-Cheong & McGrath 2010].
• Genitourinary tract
  • Vaginal stenosis and labial synechiae
  • Urethral meatal stenosis and urethral strictures, phimosis

Malignancy. About half of individuals with KS will develop squamous cell carcinoma in their lifetime. 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, Guerrero-Aspizua et al 2019]
• 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

No genotype-phenotype correlations have been identified.

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].

Nomenclature

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 KS in 1954 [Kindler 1954], about 400 affected individuals have been reported worldwide.

Persons of any geographic origin can be affected and there is no sex predilection [Siegel et al 2003, Has et al 2011]. 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].

Evaluation Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with KS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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

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

Surveillance

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.

Breastfeeding 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.

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., presumed to be carriers of one FERMT1 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an FERMT1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an FERMT1 pathogenic variant, each sib of an affected individual has at conception 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

• Unless an individual with KS has children with an affected individual or a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in FERMT1.
• KS is reported more frequently in populations with high rates of consanguinity [Penagos et al 2004, Youssefian et al 2015]. Consanguinity increases the likelihood that an affected individual may have a reproductive partner who is heterozygous for an FERMT1 pathogenic variant.
• The offspring of a proband and an individual heterozygous for an FERMT1 pathogenic variant have a 50% chance of being affected and a 50% chance of being heterozygotes.

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 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 and discussion of the availability of prenatal/preimplantation genetic 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.
• FERMT1 molecular genetic testing for reproductive partners of known carriers is appropriate, particularly if consanguinity is likely.

Prenatal Testing and Preimplantation Genetic Testing

Once the FERMT1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for KS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

FERMT1 is located on chromosome 20; it consists of 15 exons and encodes kindlin-1 protein with 677 amino acids (~77.4 kd). The gene is expressed in different tissues including skin keratinocytes and epithelial cells of colon, lung, placenta, adrenal, and prostate [Jobard et al 2003]. Kindlin-1 is a focal adhesion protein that like other cytoskeletal proteins has "the four point one ezrin radixin and moesin" (FERM) and "pleckstrin" homology (PH) domains [Larjava et al 2008]. Kindlin-1 is an adaptor protein that links filamentous actin in the cell to membrane proteins and is involved in integrin-associated signaling pathways [Has et al 2011].

To date, a total of 91 loss-of-function pathogenic variants have been reported in FERMT1, including: missense, nonsense, and splicing variants; indels; and Alu-mediated gene rearrangements. The absence of kindlin-1 leads to disorganized keratinocytes as a result of aberrant integrin-mediated cell adhesion and migration [Larjava et al 2008, Rognoni et al 2016].

Mechanism of disease causation. Kindler syndrome is thought to occur via a loss-of-function mechanism; pathogenic variants may lead to absent kindlin-1 protein or production of nonfunctional protein.

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 November 2021) include 756 original articles in peer-reviewed journals, 364 text book chapters and review articles, and 1,057 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 University of Buenos Aires, Argentina. He also has honorary professorships 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 Chair 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, PhD and Hassan Vahidnezhad, PhD are researchers in medical genetics working on genodermatoses at Jefferson Institute of Molecular Medicine 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, Kindler epidermolysis bullosa, or Kindler-like syndrome interested in receiving information and free genetic testing can contact Leila Youssefian (email: leila.youssefian@jefferson.edu or phone: 610-999-9402).

Acknowledgments

Carol Kelly assisted in manuscript preparation.

Revision History

• 6 January 2022 (ha) Comprehensive update posted live
• 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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