Date of Award

January 2017

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)



First Advisor

Keith A. Choate


The ichthyoses, also known as disorders of keratinization (DOK), encompass a group of genetic skin disorders linked by the common finding of abnormal barrier function, which initiates a default compensatory pathway of hyperproliferation, resulting in the characteristic clinical manifestation of localized or generalized scaling.

Ichthyoses are a highly heterogenous group of disorders, both genetically and clinically. Despite the identification of causative mutations in over 50 genes, clear genotype-phenotype correlations have been difficult to establish due to the rarity of the ichthyoses and because mutations in the same gene can have widely divergent phenotypes, even in individuals with the same disease-causing mutation.

In partnership with the Foundation for Ichthyosis and Related Skin Types (FIRST), we have served as a major national and international referral center and recruited over 800 kindreds with DOK, utilizing whole exome sequencing to identify novel, rare mutations that cause DOK, many of which represent phenotypic expansion.

We systematically evaluated genotypic and phenotypic data for 407 kindreds with ichthyosis, the largest cohort published to date. We identified 156 novel mutations and assessed phenotypic features of DOK with respect to genetic diagnosis to help refine our understanding of this heterogeneous group of disorders (Chapter 1). Such a systematic classification of DOK holds promise for the development of customized management plans, generation of targeted therapeutics, and improved understanding of prognostication based on genetic diagnosis.

In the process of performing a large scale genotype-phenotype characterization, we identified kindreds with rare clinical subtypes of ichthyosis, including Bathing Suit Ichthyosis (BSI), a rare disorder caused by mutations in the transglutaminase 1 gene (TGM1) and characterized by the restriction of scale to sites of relatively higher temperature such as the trunk, with cooler areas remaining unaffected (Chapter 2). We identified novel and recurrent mutations in sixteen subjects with BSI, the largest cohort published to date. Our findings expand the genotypic spectrum of BSI and the understanding of temperature-sensitivity of TGM1 mutations. Increased awareness of temperature-sensitive TGM1 genotypes should aid in genetic counseling, and provide insights into the pathophysiology of TGM1 ichthyoses, and potential therapeutic approaches.

In the course of unifying genetic and clinical data to advance the understanding of the different subtypes of ichthyosis, we realized the critical importance of tools to assess the clinical severity of ichthyosis. We designed a Visual Index for Ichthyosis Severity (VIIS) and tested the instrument for reliability and reproducibility using two different settings: one that utilized scoring of 60 test photographs by 10 dermatologists, and one with in-person evaluations on 85 subjects by 12 dermatologists at the Foundation for Ichthyosis and Related Skin Types (FIRST) conference (Chapter 3). The validation process revealed high reliability and reproducibility for both scale and erythema and indicated that the VIIS performs better in person than with photographs, an important consideration in design of clinical trials. This index provides a tool for clinical phenotyping and assessment of therapeutic response for many disorders of keratinization.


This is an Open Access Thesis.

Open Access

This Article is Open Access