Carvajal and erythrokeratodermia cardiomyopathy syndromes (EKC) are rare, inherited cardiocutaneous disorders with potentially fatal consequences in young children. Some patients display features of ...congestive heart failure and rapidly deteriorate; others exhibit no evident warning signs until sudden death reveals underlying heart disease. We present two patients to illustrate the characteristic hair, skin, teeth, and nail abnormalities, which—especially when distinct from that of other family members—should prompt cardiac evaluation and genetic analysis. In this article, we discuss established treatments as well as a promising, novel therapeutic that has led to nearly complete resolution of the cutaneous and cardiac pathology in EKC syndrome.
We present the case of a 20-month-old girl with Schimmelpenning-Feuerstein-Mims (SFM) syndrome with extensive head, neck, and torso skin involvement successfully managed with topical trametinib. ...Trametinib interferes downstream of KRAS and HRAS in the MAPK signaling pathway, of which KRAS was implicated in our child's pathogenic variant. Although other dermatologic conditions have shown benefit from oral trametinib, its topical use has not been well reported. Our patient showed benefit from the use of twice-daily topical trametinib, applied to the epidermal and sebaceous nevi over a 16-month period, leading to decreased pruritus and thinning of the plaques.
Establishing and Validating an Ichthyosis Severity Index Marukian, Nareh V.; Deng, Yanhong; Gan, Geliang ...
Journal of investigative dermatology,
September 2017, 2017-09-00, 20170901, Letnik:
137, Številka:
9
Journal Article
Recenzirano
Odprti dostop
We designed and validated a Visual Index for Ichthyosis Severity for scale and erythema that provides (1) written descriptions of the features characteristic of each level of severity, (2) visual ...standards for four body sites, and (3) two distinct standards to account for different types of scale. We tested the Visual Index for Ichthyosis Severity 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 conference. The validation process revealed high reliability and reproducibility for both scale and erythema. The interrater and intrarater intraclass correlation coefficients for scale were consistently near or greater than 0.7 in both settings. By contrast, the interrater reliability for erythema was higher during in-person validation compared with validation on test photographs. Our analysis indicates that the Visual Index for Ichthyosis Severity performs better in person than with photographs, an important consideration in the design of clinical trials. Power analysis predicts that a 1-point difference on this 5-step scale would be detectable with 12 subjects in each of two defined groups. This index provides a tool for clinical phenotyping and assessment of therapeutic response for many disorders of keratinization.
Ichthyosis with confetti is a rare, autosomal dominant disorder caused by frameshift mutations in KRT10 or KRT1 and characterized by the development of white, genetically revertant macules in red, ...diseased skin. All cases result from mutations affecting the tail domains of keratin-10 or keratin-1, and Suzuki et al. expand the mutation spectrum for ichthyosis with confetti caused by mutations in KRT1, showing that a polyarginine frameshift in the keratin-1 tail can also cause this disorder.
Tufted angioma (TA) is a rare vascular tumor characterized by histologic tufts of proliferating capillaries that occurs in infancy or early childhood, with a poorly understood pathogenesis. Though ...benign, TA can be associated with the Kasabach‐Merritt phenomenon (KMP), a life‐threatening consumptive coagulopathy and thrombocytopenia. Here, we explored the genetic mechanism underlying a case of TA associated with KMP via targeted sequencing of laser capture micro‐dissected lesion and blood DNA, and identified a somatic, activating GNA14 mutation specific to the tumor. Our findings support aberrant GNA14 activation underlies the pathogenesis of TA associated with KMP.
CARD14‐associated papulosquamous eruption (CAPE) is a proposed term that encompasses features ranging from psoriasis to pityriasis rubra pilaris (PRP) in association with CARD14 mutations. The early ...onset of the disease, prominent facial involvement, family history of an autosomal dominant trait, and poor response to conventional treatment are characteristics of CAPE that distinguish it from classical psoriasis and PRP. We describe the clinical features, family history, and response to therapy in three unrelated children with CAPE and compare these characteristics with those of previously described pediatric patients. Testing for CARD14 mutations in children with early onset of features of psoriasis or pityriasis rubra pilaris and resistance to conventional therapy should be considered.
Appearance of mosaic disorders in thin Blaschko lines suggests that somatic mutations in keratinocyte precursors underlie their pathogenesis. Germline heterozygous mutations in POFUT1 gene cause ...Dowling-Degos disease (DDD), a skin disease that features flexural reticulated hyperpigmentation and follicular-based lesions. POFUT1 mosaicism has not been described to date. Here, we describe a 9-year-old female with segmental hyper- and hypopigmented patches with overlying eczematous plaques and follicular papules. Employing paired whole exome sequencing of saliva and keratinocytes isolated from affected skin, we found a novel germline heterozygous POFUT1 deletion causing frameshift and premature codon termination and somatic copy-neutral loss of heterozygosity on chromosome 20 encompassing POFUT1. Expression levels of POFUT1 as well as other key regulators of the notch signaling pathway-NOTCH1, NOTCH2, and HES1-were reduced in affected keratinocytes compared with normal keratinocytes. Our findings provide the first evidence of POFUT1 postzygotic mutation and a phenotypic expansion of POFUT1 loss of function mutations. We show that a recessive loss of function mutation in POFUT1 produces a distinct clinical presentation with features (e.g., dermatitis) that are absent in the generalized form of DDD. This study demonstrates how analysis of mosaic disorders can reveal unexpected phenotypes for known genes.
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