A Gene for an Autosomal Dominant Scleroatrophic Syndrome Predisposing to Skin Cancer (Huriez Syndrome) Maps to Chromosome 4q23

摘要: To the Editor: Huriez syndrome (MIM 181600), also referred to as “sclerotylosis,” is an autosomal dominant genodermatosis, characterized by triad of congenital scleroatrophy distal extremities, palmoplantar keratoderma (PPK), and hypoplastic nail changes, that was first described in two large pedigrees from northern France (Huriez et al. 1968). Several additional families have since been ( Lambert 1977; Fischer 1978; Shaw Hamm 1996; Kavanagh 1997). The development aggressive squamous cell carcinoma (SCC) affected skin a distinctive feature syndrome, occurring ∼15% individuals. SCC Huriez early onset, mostly third fourth decade life, metastasis formation (Hamm 1996). pathogenetic mechanism tumorigenesis unknown. Linkage MN–blood-type locus on chromosome 4q28-q31 reported initially has subsequently refuted (Delaporte 1995; We therefore embarked linkage analysis for with highly polymorphic microsatellite markers, beginning 4. After informed consent obtained, 22 35 unaffected members one (family A) second family originating same region B) were included analysis. calculated two-point LOD scores between each marker under assumption inheritance complete penetrance, frequency .0005 disease allele, equal allele frequencies using LINKAGE version 5.21 software (Lathrop 1984). With reference Human Gene Map (Schuler 1996), we identified D4S424 within 2 cM glycophorin A gene (GYPA), which erythrocyte membrane protein encodes MN–blood-group receptors. yielded score −10.7 at recombination fraction (θ) 0.01. In investigation, excluded candidate syndrome. Our finding consistent exclusion MN English (Kavanagh contrast, D4S1560 gave evidence linkage, 4.4 θ=0. Subsequent flanking markers confirmed localization this region, highest (Zmax) 12.22 θ=0, D4S2380 (table 1). For fine mapping selected mapped high-resolution Stanford Genome Center TNG radiation hybrid panel. Relative distances centirays (fig. 1) determined G3 panel (Stewart 1997). Figure 1 Pedigrees B Affected are denoted blackened symbols. most likely haplotype seven 8-cM interval D4S1544 D4S2966 shown below individual. Table 1 Combined Pairwise Scores Families Syndrome Markers Chromosome 4q[Note] Under more conservative incomplete defined events individual A, member 6.1). Here, 17-cM delimited centromerically D4S395 distally D4S411. Under probands further limit 2): (member 4.11), localizing telomeric D4S1544, other 2.5), centromeric D4S2966. thus confined Haplotypes constructed both use 16 D4S2963 D4S1564. Comparison alleles revealed three adjacent identical state (IBS) these D4S2973 D4S1559, shared common found among all individuals, relative .87 .58, respectively. There no known relationship investigated. However, view rarity condition fact originate neighboring villages France, inferred IBS status reflects existence founder haplotype. If verified, would indicate located 3.1-cM D4S2909 D4S1578. Further must be investigated substantiate finding, although exhausted region. families, linked 4q some 30 D4S424. Epidermal growth factor (EGF) potential 4q21-24 human-rodent somatic (Brissenden EGF induces cellular proliferation differentiation various epidermal epithelial tissues potent mitogen (Carpenter Cohen 1979). Increased levels receptor associated malignant transformation cells (Lee 1997) observed (Springer Robinson 1991), esophagus (Yano head neck 1997), cervix (Kim lung (Pfeiffer 1998). According map human genome D4S411 Haplotype individuals 6.1 2.5, respectively, exclude syndrome. Figure 2 Linkage 4q23. Genetic indicated centimorgans. arranged order according final Genethon (Dib ... Affected patients sclerotylosis greatly increased risk cutaneous SCC. clinical presentation strongly indicates disorder precancerous condition. carry >100-fold higher (Levi Gray age onset cancer much lower than general population, tumors arise areas skin. Sclerosis (Nachbar 1993; Ozturk 1998), atrophy, scarring (Hagiwara 1996) well-recognized factors Clinically, bears striking similarity Marjolin's ulcer, refers malignancies arising chronic ulcers skin, scar tissue, burn scars (Fleming 1990). fragility leads scarring, scleroatrophic changes may represent process similar predisposing cancer. addition, exposure exogenous mutagens such arsenic (Jackson Grainge 1975) recognized atrophic anatomy type PPK disturb barrier function facilitating penetration putative physical, chemical, infectious mutagens. PPKs not (Stevens there SCC, expect observe if local solely attributable defective exogenic carcinogens. It noteworthy loss heterozygosity 81% neoplasms (Pershouse 46% cervical (Mitra 1994). deletions 4q, consistently involved extends possibly overlaps it its end. tumor-progression model proposed serial mutagenesis exceeds threshold level, leading tumor (Grossman Leffell mutation underlying event series. Identification characterization causing provide important insights into pathogenesis