Papers by Hassan Vahidnezhad
Abstract
Epidermolysis bullosa (EB), a phenotypically heterogeneous group of skin fragility disor... more Abstract
Epidermolysis bullosa (EB), a phenotypically heterogeneous group of skin fragility disorders, is characterized by blistering and erosions with considerable morbidity and mortality. Mutations in as many as 18 distinct genes expressed at the cutaneous basement membrane zone have been shown to be associated with the blistering phenotype, attesting to the role of the corresponding proteins in providing stable association of the epidermis to the dermis through adhesion at the dermo-epidermal basement membrane zone. Thus, different forms of EB have been highly instructive in providing information on the physiological functions of these proteins as integral components of the supramolecular adhesion complexes. In addition, precise information of the underlying genes and distinct mutations in families with EB has been helpful in subclassification of the disease with prognostic implications, as well as for prenatal testing and preimplantation genetic diagnosis. Furthermore, knowledge of the types of mutations is prerequisite for application of allele-specific treatment approaches that have been recently developed, including read-through of premature termination codon mutations and chaperone-facilitated intracellular transport of conformationally altered proteins to proper physiologic subcellular location. Collectively, EB serves as a paradigm of heritable skin diseases in which significant progress has been made in identifying the underlying genetic bases and associated aberrant pathways leading from mutations to the phenotype, thus allowing application of precision medicine for this, currently intractable group of diseases.
Keywords
Epidermolysis bullosa; heritable blistering diseases; cutaneous basement membrane zone; type VII collagen
Abstract
Clinical characteristics.
Lipoid proteinosis (LP) is characterized by deposition of hyal... more Abstract
Clinical characteristics.
Lipoid proteinosis (LP) is characterized by deposition of hyaline-like material in various tissues resulting in a hoarse voice from early infancy, vesicles and hemorrhagic crusts in the mouth and on the face and extremities, verrucous and keratotic cutaneous lesions on extensor surfaces (especially the elbows), and moniliform blepharosis (multiple beaded papules along the eyelid margins and inner canthus). Extra cutaneous manifestations may include epilepsy, neuropsychiatric disorders, and spontaneous CNS hemorrhage. Males and females are affected equally. Generally, the disease course is chronic and fluctuating. Affected individuals have a normal life span unless they experience laryngeal obstruction.
Diagnosis/testing.
The diagnosis of lipoid proteinosis is established in a proband with characteristic clinical findings and either identification of biallelic ECM1 pathogenic variants on molecular genetic testing or characteristic histologic and/or immuno-labeling findings on skin biopsy.
Management.
Treatment of manifestations: There are no proven treatments for the skin lesions. Microlaryngoscopic excision of laryngeal deposits can improve airway access and voice quality. Significant airway obstruction may require tracheostomy to ensure a safe airway. Seizures should be assessed and managed by a neurologist, using antiepileptic drugs (AEDs).
Surveillance: Routine follow-up of children to monitor general health as well as psychomotor, emotional, and cognitive development. Monitoring of the airway and vocal cords by an otolaryngologist.
Genetic counseling.
LP 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible when the ECM1 pathogenic variants in the family are known.
http://www.ncbi.nlm.nih.gov/pubmed/26803878
Summary
Clinical characteristics.
Kindler syndrome (KS), a rare subtype of inherited epidermolys... more 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 immunolabelling 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.
http://www.ncbi.nlm.nih.gov/books/NBK349072/
Epidermolysis bullosa (EB) comprises a clinically heterogeneous group of disorders characterized ... more Epidermolysis bullosa (EB) comprises a clinically heterogeneous group of disorders characterized by fragility of skin, leading to formation of blisters, erosions, and chronic ulcers. The cutaneous manifestations, together with extracutaneous complications, cause considerable morbidity and in some cases premature death.1,2 Epidermolysis bullosa is an orphan disease (defined in the United States as a diagnosis with < 200 000 affected individuals), yet there are up to 40 000 affected individuals in the United States and as many as half a million patients globally. The disease is characteristically diagnosed at birth or during the early postnatal period, and there is currently no effective and specific treatment beyond prevention of trauma, appropriate wound care, and prevention of infections. Thus, EB imposes a major burden for global health care, and the cost of the treatment of a severely affected patient in the United States can approach $300 000 per year ( email communication; November 24, 2015; Brett Kopelan, executive director of the dystrophic epidermolysis bullosa research association [DEBRA] of America).
Regulation of cell growth and differentiation is critical for ordered organogenesis during develo... more Regulation of cell growth and differentiation is critical for ordered organogenesis during development, and perturbations in these processes can result in tissue overgrowth. Several clinical conditions are known to manifest with overgrowth of bone and overlying soft connective tissues, with vascular and/or pigmentary abnormalities and with or without central nervous system involvement.(1) One of them is the megalencephaly-capillary malformation (MCAP) syndrome characterized by growth dysregulation with hemihyperplasia, vascular abnormalities and brain malformations. This syndrome was originally termed as M-CMTC, macrocephaly-cutis marmorata telangiectasia congenita; this name was later shortened to macrocephaly-cutis marmorata (MCM syndrome).
Abstract
Introduction: Kindler syndrome (KS) is a complex skin fragility disorder with protean ma... more Abstract
Introduction: Kindler syndrome (KS) is a complex skin fragility disorder with protean manifestations with considerable morbidity and occasional mortality from cancer development. The characteristic clinical features include blistering, erosions, poikiloderma, atrophy of the skin,
photosensitivity and severe involvement of mucous membranes. Ultrastructural findings in the affected skin include tissue cleavage at different, mixed levels at the cutaneous basement membrane zone and reduplication of the dermal-epidermal basement membrane.
Areas covered: The molecular basis of this orphan disease, a subtype of epidermolysis bullosa with autosomal recessive inheritance, has been recently elucidated, and there is increased understanding of the pathomechanistic pathways leading to phenotypic manifestations as a result of mutations in FERMT1. This gene encodes kindlin-1, a multi-functional focal adhesion protein with a role in keratinocyte adhesion and proliferation. Expert opinion: Information on the genetic basis of this disorder is helpful for confirming the diagnosis with prognostic implications, and it has formed the basis for prenatal testing and
preimplantation genetic diagnosis in families at risk for recurrence. Finally, information on the specific mutations and understanding of the pathomechanistic pathways has formed the basis to develop novel allele-specific treatment approaches for this, currently intractable disorder.
Epidermolysis bullosa simplex (EBS),
which shows blister formation within
the basal layer of the ... more Epidermolysis bullosa simplex (EBS),
which shows blister formation within
the basal layer of the epidermis, is primarily
caused by mutations in KRT5
and KRT14 (Coulombe et al., 2009;
Fine et al., 2014). Most cases result
from dominant negative missense mutations
in either one of these genes,
with an autosomal dominant inheritance.
Most mutations are in KRT14
compared with KRT5, reflecting, at
least in part, a high frequency of hotspot
mutations, such as p.Arg125His
and p.Arg125Cys, in KRT14 (Coulombe
and Lee, 2012). Only 16 keratin mutations,
have been shown to cause the
autosomal recessive form of EBS, all of
them in KRT14 (Garcia et al., 2011). In
addition to mutations in KRT5 and
KRT14, up to approximately 10% of
autosomal recessive cases of EBS have
been shown to result from mutations in
TGM5 encoding transglutaminase 5,
whereas relatively few cases, mostly
autosomal recessive, have been shown
to result from mutations in other genes,
including JUP, DSP, PKP1, EXPH5,
PLEC, and DST-e (Uitto, BrucknerTuderman,
et al., 2016; Uitto, Vahidnezhad,
and Youssefian, 2016).
Infantile systemic hyalinosis (ISH) is an extremely rare genodermatosis, characterized by thicken... more Infantile systemic hyalinosis (ISH) is an extremely rare genodermatosis, characterized by thickened skin, joint contractures and subcutaneous nodules. ISH is caused by mutations in the CMG2 gene, which encodes a protein of unknown function. In this report, we describe a patient with ISH, who was a twin born to a consanguineous Iranian couple, and who demonstrated unusual skin findings in addition to the characteristic features of ISH. Mutation analysis disclosed a homozygous deletion mutation, c.1074delT in CMG2, resulting in a frameshift and premature termination codon 50 amino acids downstream of the deletion. This information adds to the recurring nature of this mutation in ISH, with implications for genetic counselling in extended families with a history of this disease.
The Journal of investigative dermatology, Jan 24, 2015
A number of critical signaling pathways are required for homeostatic regulation of cell survival,... more A number of critical signaling pathways are required for homeostatic regulation of cell survival, differentiation, and proliferation during organogenesis. One of them is the PI3K-AKT-mTOR pathway consisting of a cascade of inhibitor/activator molecules. Recently, a number of heritable diseases with skin involvement, manifesting particularly with tissue overgrowth, have been shown to result from mutations in the genes in the PI3K-AKT-mTOR and interacting intracellular pathways. Many of these conditions represent an overlapping spectrum of phenotypic manifestations forming a basis for novel, unifying classifications. Identification of the mutant genes and specific mutations in these patients has implications for diagnostics and genetic counseling and provides a rational basis for the development of novel treatment modalities for this currently intractable group of disorders.Journal of Investigative Dermatology advance online publication, 24 September 2015; doi:10.1038/jid.2015.331.
Experimental Dermatology, 2015
Klippel-Trenaunay syndrome (KTS), originally described as a triad of cutaneous capillary malforma... more Klippel-Trenaunay syndrome (KTS), originally described as a triad of cutaneous capillary malformation, bone and soft tissue hypertrophy, as well as venous and lymphatic malformations, has been considered by dermatologists as a distinct diagnostic entity. However, cases with KTS have also been reported to have neurological disorders, developmental delay, and digital abnormalities, indicating multisystem involvement. Recently, a number of overgrowth syndromes, with overlapping phenotypic features with KTS, have been identified; these include MCAP and CLOVES syndromes as well as fibroadipose hyperplasia (FH). These conditions harbor mutations in the PIK3CA gene, and they have been included in the PIK3CA-related overgrowth spectrum (PROS). Based on recent demonstrations of PIK3CA mutations also in KTS, it appears that, rather than being a distinct diagnostic entity, KTS belongs to PROS. These observations have potential diagnostic and therapeutic implications for KTS. This article is protected by copyright. All rights reserved.
International Journal of Dermatology, 2015
Immunofluorescence antigen mapping (IFM), is a newly introduced technique for diagnosis and class... more Immunofluorescence antigen mapping (IFM), is a newly introduced technique for diagnosis and classification of epidermolysis bullosa (EB) disease. The precise level of skin cleavage can be determined using monoclonal antibodies to EB-specific basement membrane zone protein. To apply IFM technique in diagnosis and classification of EB and to identify utility and limitation of this method in our clinical setting. IFM was done according to a described protocol by Pohla-Gubo et al. Monoclonal antibodies used for antigen mapping were against cytokeratin 5, cytokeratin 14, α6 integrin, β4 integrin, laminin 332, Collagen IV, and Collagen VII. IFM was done for 95 referred patients, compromising 49 females and 46 males, aged 5 days to 45 years (mean = 9.5 years). Ninety cases were diagnosed with EB and classified as follows: EB simplex: (n = 13), junctional EB (n = 14), dystrophic EB (n = 62), and Kindler syndrome (n = 1). Diagnosis was not made in five cases as their specimens contained no blister. Confirmatory genetic analysis was done for five junctional cases from two families with clinical features of laryngo-onycho-cutaneous syndrome. Genetic molecular studies showed nonsense mutations in the last codon of exon 39 of the laminin α3a (LAMA3) gene (p.Gln57X) and a donor splice site mutation in LAMA3 (IVS57+5G&amp;amp;gt;A) in the first and second family, respectively. IFM technique is relatively simple to perform, and interpretation of the results is not sophisticated. The proportion of inconclusive results will be decreased if the specimens contain freshly induced blister.
Iranian biomedical journal, 2009
Evidence is accumulating to support disruption of tissue architecture as a powerful event in tumo... more Evidence is accumulating to support disruption of tissue architecture as a powerful event in tumor formation. For the past four decades, intensive cancer research with the premise of "cancer as a cell based-disease" focused on finding oncogenes or tumor suppressor genes. However, the role of the tissue architecture was neglected. Three dimensional (3D) cell cultures which can recapitulate major aspects of the microenvironment are appropriate models for exploring cancer. For the first time in Iran, we have launched Matrigel based non-malignant, tumorigenic and reverted breast 3D cell cultures. Non-tumorigenic MCF-10A and tumorigenic MCF-7 breast cell lines were cultured on plastic and Matrigel. MCF-7 cell lines were reverted to normal phenotype via AIIB2 and LY 294002 inhibitors against beta1 integrin and class I phosphatidylinositol 3-kinase, respectively. MCF-10A acini were distinguishably different from MCF-7 on Matrigel. MCF-10A formed organized hollow spherical structu...
Experimental Dermatology, 2014
Monilethrix is an autosomal dominant hair disorder caused by mutations in the hard keratins KRT81... more Monilethrix is an autosomal dominant hair disorder caused by mutations in the hard keratins KRT81, KRT83 and KRT86. The affected hairs are fragile and break easily, leading to scarring alopecia. Follicular hyperkeratosis in the neck and on extensor sides of extremities is a frequently associated finding. The disorder is rare, but probably underreported because its manifestations may be mild. Mutations in KRT81 and KRT86 are the most common. Here, we report new cases from Venezuela, the Netherlands, Belgium and France. The Venezuelan kindred is special for having patients with digenic novel nucleotide changes, a KRT86 mutation associated with monilethrix and a KRT81 variant of unknown clinical significance. In the French and Dutch patients, we found novel KRT86 and KRT83 mutations. Our findings expand the mutational spectrum associated with monilethrix.
Journal of Investigative Dermatology, 2015
Journal of Investigative Dermatology, 2015
Background: BMI1, TWIST1 and SNAI2/SLUG have been implicated in aggressive behavior of squamous c... more Background: BMI1, TWIST1 and SNAI2/SLUG have been implicated in aggressive behavior of squamous cell carcinoma (SCC) and melanoma and BMI1 expression could identify subtypes of Merkel cell carcinoma (MCC). However, BMI1, TWIST1 and SNAI2 expression levels in basal cell carcinomas (BCCs) have not been elucidated. We hypothesized BCC could be a good model system to decipher mechanisms which inhibit processes that drive tumor metastasis. The aim of this study was to examine the mRNA expression level of BMI1, TWIST1, and SNAI2 in BCCs. Materials and Methods: Thirty-five fresh non-metastatic BCC tissue samples and seven fresh normal skin tissue samples were evaluated by real-time RT-PCR. Results: BMI1 and TWIST1 demonstrated marked down-regulation (p<0.00l, p=0.00l respectively), but SNAI2 showed no significant change (p=0.12). Conclusions: Previous literature has clearly demonstrated a positive association between BMI1 and TWIST1 expression and metastatic BCC, aggressive SCC and melanoma. Here, we demonstrated a negative association between BMI1 and TWIST1 mRNA expression level and BCC.
European journal of clinical & medical oncology
Homeobox genes encode transcription factors that play important roles in the developmental and no... more Homeobox genes encode transcription factors that play important roles in the developmental and normal cellular processes in all metazoans. TGIFLX/Y (TGIFLX and TGIFLY) are members of the homeobox superfamily of genes. Their expression is specifically detected in human adult testis but their functions remain to be investigated. Identification of relevant target genes should make a key contribution to a complete understanding of the mechanisms by which TGIFLX/Y functions in both normal and abnormal developmental processes. In this review, we provide an overview of recent studies on different aspects of TGIFLX/Y with a focus on the current state of research about their roles in tumorigenesis and azoospermia.
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Papers by Hassan Vahidnezhad
Epidermolysis bullosa (EB), a phenotypically heterogeneous group of skin fragility disorders, is characterized by blistering and erosions with considerable morbidity and mortality. Mutations in as many as 18 distinct genes expressed at the cutaneous basement membrane zone have been shown to be associated with the blistering phenotype, attesting to the role of the corresponding proteins in providing stable association of the epidermis to the dermis through adhesion at the dermo-epidermal basement membrane zone. Thus, different forms of EB have been highly instructive in providing information on the physiological functions of these proteins as integral components of the supramolecular adhesion complexes. In addition, precise information of the underlying genes and distinct mutations in families with EB has been helpful in subclassification of the disease with prognostic implications, as well as for prenatal testing and preimplantation genetic diagnosis. Furthermore, knowledge of the types of mutations is prerequisite for application of allele-specific treatment approaches that have been recently developed, including read-through of premature termination codon mutations and chaperone-facilitated intracellular transport of conformationally altered proteins to proper physiologic subcellular location. Collectively, EB serves as a paradigm of heritable skin diseases in which significant progress has been made in identifying the underlying genetic bases and associated aberrant pathways leading from mutations to the phenotype, thus allowing application of precision medicine for this, currently intractable group of diseases.
Keywords
Epidermolysis bullosa; heritable blistering diseases; cutaneous basement membrane zone; type VII collagen
Clinical characteristics.
Lipoid proteinosis (LP) is characterized by deposition of hyaline-like material in various tissues resulting in a hoarse voice from early infancy, vesicles and hemorrhagic crusts in the mouth and on the face and extremities, verrucous and keratotic cutaneous lesions on extensor surfaces (especially the elbows), and moniliform blepharosis (multiple beaded papules along the eyelid margins and inner canthus). Extra cutaneous manifestations may include epilepsy, neuropsychiatric disorders, and spontaneous CNS hemorrhage. Males and females are affected equally. Generally, the disease course is chronic and fluctuating. Affected individuals have a normal life span unless they experience laryngeal obstruction.
Diagnosis/testing.
The diagnosis of lipoid proteinosis is established in a proband with characteristic clinical findings and either identification of biallelic ECM1 pathogenic variants on molecular genetic testing or characteristic histologic and/or immuno-labeling findings on skin biopsy.
Management.
Treatment of manifestations: There are no proven treatments for the skin lesions. Microlaryngoscopic excision of laryngeal deposits can improve airway access and voice quality. Significant airway obstruction may require tracheostomy to ensure a safe airway. Seizures should be assessed and managed by a neurologist, using antiepileptic drugs (AEDs).
Surveillance: Routine follow-up of children to monitor general health as well as psychomotor, emotional, and cognitive development. Monitoring of the airway and vocal cords by an otolaryngologist.
Genetic counseling.
LP 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible when the ECM1 pathogenic variants in the family are known.
http://www.ncbi.nlm.nih.gov/pubmed/26803878
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 immunolabelling 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.
http://www.ncbi.nlm.nih.gov/books/NBK349072/
Introduction: Kindler syndrome (KS) is a complex skin fragility disorder with protean manifestations with considerable morbidity and occasional mortality from cancer development. The characteristic clinical features include blistering, erosions, poikiloderma, atrophy of the skin,
photosensitivity and severe involvement of mucous membranes. Ultrastructural findings in the affected skin include tissue cleavage at different, mixed levels at the cutaneous basement membrane zone and reduplication of the dermal-epidermal basement membrane.
Areas covered: The molecular basis of this orphan disease, a subtype of epidermolysis bullosa with autosomal recessive inheritance, has been recently elucidated, and there is increased understanding of the pathomechanistic pathways leading to phenotypic manifestations as a result of mutations in FERMT1. This gene encodes kindlin-1, a multi-functional focal adhesion protein with a role in keratinocyte adhesion and proliferation. Expert opinion: Information on the genetic basis of this disorder is helpful for confirming the diagnosis with prognostic implications, and it has formed the basis for prenatal testing and
preimplantation genetic diagnosis in families at risk for recurrence. Finally, information on the specific mutations and understanding of the pathomechanistic pathways has formed the basis to develop novel allele-specific treatment approaches for this, currently intractable disorder.
which shows blister formation within
the basal layer of the epidermis, is primarily
caused by mutations in KRT5
and KRT14 (Coulombe et al., 2009;
Fine et al., 2014). Most cases result
from dominant negative missense mutations
in either one of these genes,
with an autosomal dominant inheritance.
Most mutations are in KRT14
compared with KRT5, reflecting, at
least in part, a high frequency of hotspot
mutations, such as p.Arg125His
and p.Arg125Cys, in KRT14 (Coulombe
and Lee, 2012). Only 16 keratin mutations,
have been shown to cause the
autosomal recessive form of EBS, all of
them in KRT14 (Garcia et al., 2011). In
addition to mutations in KRT5 and
KRT14, up to approximately 10% of
autosomal recessive cases of EBS have
been shown to result from mutations in
TGM5 encoding transglutaminase 5,
whereas relatively few cases, mostly
autosomal recessive, have been shown
to result from mutations in other genes,
including JUP, DSP, PKP1, EXPH5,
PLEC, and DST-e (Uitto, BrucknerTuderman,
et al., 2016; Uitto, Vahidnezhad,
and Youssefian, 2016).
Epidermolysis bullosa (EB), a phenotypically heterogeneous group of skin fragility disorders, is characterized by blistering and erosions with considerable morbidity and mortality. Mutations in as many as 18 distinct genes expressed at the cutaneous basement membrane zone have been shown to be associated with the blistering phenotype, attesting to the role of the corresponding proteins in providing stable association of the epidermis to the dermis through adhesion at the dermo-epidermal basement membrane zone. Thus, different forms of EB have been highly instructive in providing information on the physiological functions of these proteins as integral components of the supramolecular adhesion complexes. In addition, precise information of the underlying genes and distinct mutations in families with EB has been helpful in subclassification of the disease with prognostic implications, as well as for prenatal testing and preimplantation genetic diagnosis. Furthermore, knowledge of the types of mutations is prerequisite for application of allele-specific treatment approaches that have been recently developed, including read-through of premature termination codon mutations and chaperone-facilitated intracellular transport of conformationally altered proteins to proper physiologic subcellular location. Collectively, EB serves as a paradigm of heritable skin diseases in which significant progress has been made in identifying the underlying genetic bases and associated aberrant pathways leading from mutations to the phenotype, thus allowing application of precision medicine for this, currently intractable group of diseases.
Keywords
Epidermolysis bullosa; heritable blistering diseases; cutaneous basement membrane zone; type VII collagen
Clinical characteristics.
Lipoid proteinosis (LP) is characterized by deposition of hyaline-like material in various tissues resulting in a hoarse voice from early infancy, vesicles and hemorrhagic crusts in the mouth and on the face and extremities, verrucous and keratotic cutaneous lesions on extensor surfaces (especially the elbows), and moniliform blepharosis (multiple beaded papules along the eyelid margins and inner canthus). Extra cutaneous manifestations may include epilepsy, neuropsychiatric disorders, and spontaneous CNS hemorrhage. Males and females are affected equally. Generally, the disease course is chronic and fluctuating. Affected individuals have a normal life span unless they experience laryngeal obstruction.
Diagnosis/testing.
The diagnosis of lipoid proteinosis is established in a proband with characteristic clinical findings and either identification of biallelic ECM1 pathogenic variants on molecular genetic testing or characteristic histologic and/or immuno-labeling findings on skin biopsy.
Management.
Treatment of manifestations: There are no proven treatments for the skin lesions. Microlaryngoscopic excision of laryngeal deposits can improve airway access and voice quality. Significant airway obstruction may require tracheostomy to ensure a safe airway. Seizures should be assessed and managed by a neurologist, using antiepileptic drugs (AEDs).
Surveillance: Routine follow-up of children to monitor general health as well as psychomotor, emotional, and cognitive development. Monitoring of the airway and vocal cords by an otolaryngologist.
Genetic counseling.
LP 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible when the ECM1 pathogenic variants in the family are known.
http://www.ncbi.nlm.nih.gov/pubmed/26803878
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 immunolabelling 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.
http://www.ncbi.nlm.nih.gov/books/NBK349072/
Introduction: Kindler syndrome (KS) is a complex skin fragility disorder with protean manifestations with considerable morbidity and occasional mortality from cancer development. The characteristic clinical features include blistering, erosions, poikiloderma, atrophy of the skin,
photosensitivity and severe involvement of mucous membranes. Ultrastructural findings in the affected skin include tissue cleavage at different, mixed levels at the cutaneous basement membrane zone and reduplication of the dermal-epidermal basement membrane.
Areas covered: The molecular basis of this orphan disease, a subtype of epidermolysis bullosa with autosomal recessive inheritance, has been recently elucidated, and there is increased understanding of the pathomechanistic pathways leading to phenotypic manifestations as a result of mutations in FERMT1. This gene encodes kindlin-1, a multi-functional focal adhesion protein with a role in keratinocyte adhesion and proliferation. Expert opinion: Information on the genetic basis of this disorder is helpful for confirming the diagnosis with prognostic implications, and it has formed the basis for prenatal testing and
preimplantation genetic diagnosis in families at risk for recurrence. Finally, information on the specific mutations and understanding of the pathomechanistic pathways has formed the basis to develop novel allele-specific treatment approaches for this, currently intractable disorder.
which shows blister formation within
the basal layer of the epidermis, is primarily
caused by mutations in KRT5
and KRT14 (Coulombe et al., 2009;
Fine et al., 2014). Most cases result
from dominant negative missense mutations
in either one of these genes,
with an autosomal dominant inheritance.
Most mutations are in KRT14
compared with KRT5, reflecting, at
least in part, a high frequency of hotspot
mutations, such as p.Arg125His
and p.Arg125Cys, in KRT14 (Coulombe
and Lee, 2012). Only 16 keratin mutations,
have been shown to cause the
autosomal recessive form of EBS, all of
them in KRT14 (Garcia et al., 2011). In
addition to mutations in KRT5 and
KRT14, up to approximately 10% of
autosomal recessive cases of EBS have
been shown to result from mutations in
TGM5 encoding transglutaminase 5,
whereas relatively few cases, mostly
autosomal recessive, have been shown
to result from mutations in other genes,
including JUP, DSP, PKP1, EXPH5,
PLEC, and DST-e (Uitto, BrucknerTuderman,
et al., 2016; Uitto, Vahidnezhad,
and Youssefian, 2016).