In the past 2 decades, there has been enormous progress in determining the molecular bases of genodermatoses. This progress has expanded the interface between dermatology and genetics. Integration of clinical and molecular data has simplified disease classification and highlighted relationships among conditions. However, the recent explosion in genetic knowledge has not yet been fully incorporated into clinical dermatology practice or dermatology resident education. This article highlights strategies to overcome barriers and correct practice and educational gaps, enhancing the ability of dermatologists to diagnose, counsel, evaluate, and treat patients and families affected by genodermatoses.
Key points
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The recent explosion in genetic knowledge has not yet been fully incorporated into clinical dermatology practice or dermatology resident education.
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The interface between dermatology and genetics has expanded with recognition of new heritable disorders and broader phenotypic spectrums; updated classification systems integrate clinical and molecular data, clarifying relationships among conditions.
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Online databases and next-generation sequencing provide important tools for the diagnosis of genodermatoses.
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This article highlights strategies to overcome barriers and correct practice and educational gaps, enhancing the ability of dermatologists to diagnose, counsel, evaluate, and treat patients and families affected by genodermatoses.
Introduction
In recent years, there has been tremendous progress in determining the molecular bases of genodermatoses, with greater than 1000 genes now associated with a cutaneous phenotype. A paradigm shift is occurring in genetic skin disease, with revised definitions and classification of these conditions and considerable expansion of their limits. Genodermatoses are no longer confined to a small group of rare, clearly familial, monogenic disorders that become apparent by early childhood. It is important that dermatologists be aware of the spectrum of clinical presentations of genetic skin disease in patients of all ages as well as the many recent advances in available diagnostic studies and (for some conditions) molecularly directed treatments.
Introduction
In recent years, there has been tremendous progress in determining the molecular bases of genodermatoses, with greater than 1000 genes now associated with a cutaneous phenotype. A paradigm shift is occurring in genetic skin disease, with revised definitions and classification of these conditions and considerable expansion of their limits. Genodermatoses are no longer confined to a small group of rare, clearly familial, monogenic disorders that become apparent by early childhood. It is important that dermatologists be aware of the spectrum of clinical presentations of genetic skin disease in patients of all ages as well as the many recent advances in available diagnostic studies and (for some conditions) molecularly directed treatments.
Genodermatoses in clinical dermatology practice
Characterization and Classification of Patients with Genodermatoses
Begin with the basics
When evaluating patients suspected to have genodermatosis, the first step is a thorough history and review of systems, together with a complete dermatologic examination that includes the hair, nails, oral mucosa, and teeth. Results of previous histologic, radiographic, and laboratory studies should be collected. To help establish the mode of inheritance, history and (if applicable) physical examination should be used to determine whether or not family members have similar findings.
Gaps in current practice
The short time allotted for most dermatology visits makes it difficult to fully assess patients with complicated histories and multisystem findings. Logistical problems getting access to previous records may lead to unnecessary and costly repetition of testing. Potentially affected family members may be deceased, live far away, or not be available for assessment; and descriptions may be inaccurate. Furthermore, assessment of complex disease and recognition of patterns of inheritance can be challenging and outside the comfort zone of general dermatologists.
Strategies to overcome barriers
Longer or additional visits would ideally be planned for patients with complex or multisystem disease. Appropriate release forms should be obtained to enable access to medical records. Assessment of family members may require review of photographs or collaboration with dermatologists and other physicians in their region.
Genetic skin disease clinics providing specialized multidisciplinary care that includes genetics as well as dermatology services are becoming more widely available with the expansion of pediatric dermatology centers, but more are needed. Involving patients’ primary physicians can be helpful, and referrals to geneticists and other subspecialists should be made as indicated.
Clinical characterization and classification
It is useful to first categorize patients with genodermatoses based on the general type of primary skin finding. Examples include, mechanical fragility/blister formation, abnormal cornification, hypopigmentation or hyperpigmentation, adnexal anomalies (eg, hypotrichosis, ectodermal dysplasia), connective tissue or vascular defects, and tumor predisposition. Considering the large number of potential diagnoses and genetic causes within each category, online databases, such as Online Mendelian Inheritance in Man (OMIM) and PubMed, represent important tools. The differential diagnosis can be narrowed based on specific clinical features, histologic findings, distribution patterns, and time courses of cutaneous manifestations as well as by the presence or absence of associated extracutaneous manifestations. This assessment process often helps to direct additional studies and referrals.
Gaps in current practice
Unfortunately, the recent explosion in genetic knowledge has not yet been widely incorporated into clinical practice ( Table 1 ). The enormous amount of available information may be difficult to access, interpret, synthesize, and apply in a way that is meaningful to patient care. Although basic OMIM and PubMed have open access, individual articles may be costly to dermatologists who are not part of a university or hospital system. Moreover, navigation to obtain relevant information can be a challenge, and databases such as OMIM are not set up to provide the explicit details on cutaneous manifestations that are often required for the clinical diagnosis of genodermatoses. The literature is laden with outdated and inconsistent terminology using descriptive names, eponyms, and synonyms. Multiple complex and disparate classification systems also add to the confusion and potential for misdiagnosis.
| Goal | Best Practice Strategies | Barriers to Best Practice Implementation | Strategies to Overcome Barriers |
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| Disease characterization and classification |
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| Molecular diagnosis |
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| Management |
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As a result of the tremendous progress in elucidating the genetic bases of inherited skin disorders, the large number of genetically distinct conditions in categories such as epidermolysis bullosa (EB), ichthyoses, and ectodermal dysplasias can be overwhelming. The phenotypic spectrum of a particular disorder often extends beyond the classic textbook presentation, with milder, late-onset, atypical, or mosaic variants. Infants and young children may have incomplete or nonspecific phenotypes before the development of key diagnostic features, whereas conditions with delayed onset may not be recognized as genetic in origin. In addition, as many new genetic skin diseases have been identified, the limits of genodermatoses have been expanded to include entities previously considered as acquired, including predisposition to particular infections and inflammatory disorders ranging from pustular psoriasis to interferonopathies.
Clinical and genetic (locus) heterogeneity are also common and further complicate classification. Clinical heterogeneity in genetic diseases refers to mutations in a single gene causing more than one disorder. This clinical variability classically reflects different mutations ( allelic heterogeneity ), such as TP63 mutations that affect various domains of the p63 protein leading to separate types of ectodermal dysplasia. However, clinical heterogeneity sometimes results from the same mutation occurring in patients with other genetic differences. For example, identical germline mutations in the PTEN gene can result in early onset Bannayan-Riley-Ruvalcaba syndrome versus later-onset Cowden syndrome, depending on the timing and extent of somatic second-hit PTEN mutations. Conversely, genetic heterogeneity refers to mutations in different genes producing the same clinical disorder, which often occurs when the encoded proteins interact with one another in a complex or signaling pathway.
Strategies to overcome barriers
Attempts are being made to integrate molecular and clinical data in order to simplify genodermatosis classification, better define disease spectrums, and eliminate redundant terminology. This process has been successfully accomplished for disorders, such as EB and ichthyoses; however, it represents a work in progress, to be continually refined as additional genotype-phenotype correlations are established. In addition, grouping hereditary skin disorders according to their molecular bases highlights relationships between conditions and their shared pathomechanisms (see later discussion).
Once a patient’s condition is categorized, further user-friendly information and assistance can be obtained from accessible online resources, such as expert-authored GeneReview summaries and support groups, with examples including the Dystrophic EB Research Association (DEBRA; www.debra.org or www.debra-international.org ), Foundation for Ichthyosis and Related Skin Types (FIRST; www.firstskinfoundation.org ), and National Foundation for Ectodermal Dysplasias ( www.nfed.org ). Other options include referral to genetic skin disease or other specialty clinics and potentially obtaining expert consultation via teledermatology.
Keep an open mind to alternative diagnoses
Because most genodermatoses are rare and there is little awareness of these disorders among the medical community, patients often present with another “established” diagnosis. It is important that dermatologists consider alternative possibilities that may have a better fit and make referrals to specialists as indicated.
Gaps in current practice
In a recent survey, patients with rare diseases in the United Kingdom and United States reported an average delay of 5 to 8 years before their diagnosis was determined. During this time, they saw an average of 8 physicians and received 2 to 3 incorrect diagnoses, which often led to costly investigations and inappropriate treatments.
Strategies to overcome barriers
Take a fresh look at patients without preexisting labels, and do not be afraid to expand the differential diagnosis.
Molecular Diagnosis in Patients with Genodermatoses
Recognize available options for genetic testing
Detection of a germline (constitutional) mutation can be accomplished via analysis of DNA from a blood sample (1–5 mL in ethylenediaminetetraacetic acid) or oral rinse/buccal brush specimen (which may not be adequate for some tests). For type 1 mosaic conditions, which are caused by a dominant heterozygous postzygotic mutation, identification of the underlying mutation often requires DNA to be obtained from a sample of affected tissue. In contrast, a mutation can be detected in a standard blood or oral/buccal sample from patients with type 2 mosaic conditions, which are due to a postzygotic second hit in the setting of a heterozygous germline mutation, as well as in female patients with X-linked genodermatoses who present with skin lesions along Blaschko lines due to functional mosaicism.
Traditional genetic testing involves analysis of the genes that cause a particular disorder through bidirectional sequencing (Sanger method). This method may be used in conjunction with mutation scanning to identify variant regions, deletion/duplication analysis, and other methods, such as RNA studies to assess for splice site mutations in introns. The turnaround time for assessment of a single gene is typically in the range of 2 to 10 weeks. When a condition is often caused by certain hot-spot mutations, a tiered approach first targeting these mutations or sequencing selected high-yield exons can be used. Sequencing particular exons first may also be recommended for patients with phenotypic features or ethnic backgrounds associated with specific mutations.
Multigene panels enable a large group of genes associated with a particular phenotype to be evaluated in a cost-effective manner. These tests use next-generation sequencing, a rapid process in which millions of small DNA segments are analyzed at the same time. Multigene panels are especially valuable for conditions and phenotypes that have substantial genetic heterogeneity. Currently available multigene panels that may be useful to dermatologists include those for EB, ichthyoses, albinism, RASopathies, and periodic fever syndromes. Customized panels targeting genes associated with phenotypes and molecular pathways relevant to an individual patient can also be designed.
Whole-exome sequencing (WES) and whole-genome sequencing (WGS) represent important tools in gene discovery and are options in patients with a constellation of clinical manifestations that are not typical of a disorder with a known genetic basis. WES and WGS are offered by a growing number of university-based medical centers and companies. In addition, the National Institutes of Health Centers for Mendelian Genomics work with collaborating investigators to provide WES/WGS and extensive analysis for patients with Mendelian phenotypes with unknown genetic causes.
Gaps in current practice
Practicing dermatologists may not be aware of the possible applications of traditional genetic testing or newer next-generation sequencing approaches for diagnosis of genodermatoses. For example, panels that include all known EB genes can potentially serve as a sensitive primary diagnostic test for this group of conditions, with increased availability and decreased costs likely in the future.
Although the potential of WES/WGS is exciting, its overall success rate in finding the causative gene for Mendelian disorders is currently only approximately 20% to 50%. Further filtering of the genomic deluge of data requires computational tools that use published reference sequences, predicted effects on protein function, and phenotypic information.
Strategies to overcome barriers
Dermatology textbooks, review articles, and educational meetings need to provide dermatologists with updated, practical information on the genetic testing methods available for patients with genodermatoses ( Table 2 ). Dermatologists should work together with geneticists and genetic counselors in determining the best approach for individual patients and families.
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