Symptomatic mucosal involvement in pachyonychia congenita: challenges in infants and young children.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16 or KRT17). Characteristic features of PC are painful palmoplantar keratoderma, variable nail dystrophy, cysts, follicular hyperkeratosis and often oral leukokeratosis. Although oral leukokeratosis can go unnoticed, mucosal involvement of the oral cavity and upper airways can manifest with pain during feeding, hoarseness, stridor and, occasionally, life-threatening obstruction. OBJECTIVES: To characterize patients with PC with symptomatic mucosal involvement. METHODS: We present a case series of nine children with PC with symptomatic mucosal involvement, all with heterozygous mutations in KRT6A. Seven patients complained of painful feeding problems. Four patients were diagnosed with failure to thrive, three of whom required a feeding tube. Simple feeding solutions were beneficial in most cases. Seven patients had laryngeal involvement and one patient died at 4 years of age from acute laryngeal obstruction. CONCLUSIONS: It is important for dermatologists and otolaryngologists to be aware that symptomatic mucosal involvement, and very rarely laryngeal obstruction, can occur in patients with PC. Usually simple feeding solutions may prevent complications and failure to thrive. What's already known about this topic? Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes. Symptomatic mucosal involvement is an important clinical feature of PC and appears to be more pronounced in KRT6A mutation carriers. Only leukokeratosis is frequently seen in PC and can be one of the earliest signs of disease. Laryngeal involvement is a less common feature. It might be symptomatic but usually presents as hoarseness, stridor and, occasionally, as a life-threatening respiratory distress. What does this study add? In most cases of laryngeal involvement, there is no need for any intervention. Although pain and feeding difficulties are usually attributed to the oral leukokeratosis, they can be related to a phenomenon called 'first bite syndrome' (FBS). Symptomatic mucosal involvement with feeding difficulty is important but can be managed in most cases with simple feeding solutions (e.g. softer nipple with a larger hole, thicker formula and feeding with a syringe). Linked Comment: Youssefian and Vahidnezhad. Br J Dermatol 2020; 182:536-537.

Mutations in SMARCAD1 cause autosomal dominant adermatoglyphia and perturb the expression of epidermal differentiation-associated genes.

BACKGROUND: Autosomal dominant adermatoglyphia (ADG) is characterized by lack of palmoplantar epidermal ridges. Recently, ADG was found to be caused in one family by a mutation in SMARCAD1, a member of the SNF subfamily of the helicase protein superfamily. OBJECTIVES: To investigate the genetic basis of ADG. METHODS: We used direct sequencing and global gene expression analysis. RESULTS: We identified three novel heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) in a total of six patients. Surprisingly, all four ADG-causing mutations identified to date disrupt a single conserved donor splice site adjacent to the 3' end of a noncoding exon and are predicted to result in haploinsufficiency for a skin-specific isoform of SMARCAD1. These data indicate a pivotal role for the SMARCAD1-skin specific isoform in dermatoglyph formation. In order to better understand the consequences of ADG-associated mutations, we ascertained the global transcription profiles of primary keratinocytes downregulated for SMARCAD1 and of patient-derived keratinocytes. A total of eight genes were found to be differentially expressed in both patient-derived and knocked down keratinocytes. Of interest, these differentially expressed genes have been implicated in epidermal ontogenesis and differentiation, and in psoriasis, which is characterized by abnormal finger ridge patterns. CONCLUSIONS: The present data suggest that ADG is genetically homogeneous and result from perturbed expression of epidermal differentiation-associated genes.

Tar content of cigarettes in relation to lung cancer.

Although it is generally considered established that the risk of lung cancer is directly related to the tar content of cigarettes, an examination of the results of previous studies does not yield conclusive evidence in favor of the hypothesis. The authors evaluated this issue in a study of 881 cases of lung cancer and 2,570 hospital controls who were 40 to 69 years of age; data were collected by interview in hospitals in the United States and Canada from November 1981 to June 1986. For each year of smoking, cigarette brands were classified according to their tar content as published in regular Federal Trade Commission reports (from 1967 to 1985) or the Reader's Digest (from 1957 to 1966). Tar values for years for which there was no published information were estimated by interpolation. Smokers were divided, according to the tar content of their cigarette brands averaged over a specified period, into low (less than 22 mg/cigarette), medium (22-28 mg/cigarette), and high (greater than or equal to 29 mg/cigarette) tar smokers. When the average tar content was based on cigarettes smoked at least 10 years previously, the relative risk estimates for medium and high tar smokers compared with low tar smokers were 3.0 and 4.0 after control for potentially confounding factors, including the number of cigarettes smoked per day. The trend was significant (p = 0.002). The tendency for the risk of lung cancer to increase with increasing tar content was consistent among men and women. The results provide further support for the hypothesis that the tar content of cigarettes is directly related to lung cancer risk. However, the data were limited in that there were very few subjects whose lifetime tar exposure averaged less than 10 mg/cigarette.