Two families confirm Schöpf‐Schulz‐Passarge syndrome as a discrete entity within the WNT10A phenotypic spectrum

To the Editor : Schöpf-Schulz-Passarge syndrome (SSPS; OM IM 224750) is a rare ectodermal dysplasia which combines classical features of defective skin organogenesis with facial telangiectases and adnexal tumors, often presenting as palmoplantar keratoderma (PPK) and multiple eyelid cysts (1–3). Although SSPS follows autosomal recessive inheritance (1, 4–7), apparent vertical transmission has been reported (3, 8, 9), probably related to pseudodominance and/or incomplete disease expression in heterozygote carriers (7, 10). Odonto-onycho-dermal dysplasia (OODD) is an autosomal recessive ectodermal dysplasia which shares with SSPS features like PPK and facial telangiectases, but lacks eyelid cysts. Recently, a homozygous non-sense mutation in the WNT10A gene has been identified in three inbred Lebanese families with OODD (11). Further reports expanded the mutational and clinical spectrum of WNT10A to include three sporadic patients with features compatible with SSPS (10, 12–14). We ascertained two consanguineous Italian families with SSPS (Fig. 1a). Family 1 consisted of a sporadic 65-year-old female (II,3), whereas family 2 comprised a 73-year-old man (II,4) and his two older affected brothers (II,2 and II,3). Clinical features of both families were previously reported (7). In brief, all patients displayed PPK, nail dystrophy, rosacea-like lesions on the face, universal hypotrichosis and multiple eyelid cysts (Fig. 1b–h). Oligo/hypodontia and hypoplastic nipples were additional findings. In the proband of family 2 punch biopsies of an eyelid lesion and foot keratoderma were consistent with apocrine hidrocystoma (Fig. 1i) and eccrine syringofibroadenoma (data not shown), respectively. In family 1, the mother (I,2) of the proband who died by that time was reportedly affected by similar eyelid lesions. In family 2, two additional subjects (III,4 and III,7) showed hypodontia with four missing non-molar teeth, whereas II,10 had mild, finely desquamating, hyperkeratosis of palms. All these individuals were offspring of affected family members and, thus, according to autosomal recessive inheritance, obligate heterozygote carriers. A genomic search using a high density Illumina SNP chip, Human Hap 370K Quad followed by microsatellite analysis (data not shown) showed in both families homozygosity at the WNT10A locus. The 2 families did not share a common haplotype. Mutation analysis of WNT10A, performed as described (10), revealed two novel homozygous missense mutations: p.Gly266Cys (resulting from the c.796G>T transversion) in family 1 and p.Ala131Thr (resulting from the c.391G>A transition) in family 2 (Fig. 2a,b). Both mutations were absent in a panel of 270 ethnically matched control chromosomes. Tested siblings resulted heterozygote for the respective mutations (Fig. 1a). In silico analysis revealed that both mutated residues are highly conserved among WNT10A orthologs (Fig. 2c) and human paralogs of WNT family (Fig. 2d). Present and previously reported WNT10A mutations are scattered throughout the coding region of the gene (Fig. 2e). However, specific aminoacidic residues represent true hot-spots. In particular, p.Cys107X affects 15 of the 42 mutated alleles (35.7%) and, although it originates from a common ancestor in some families, it is not always associated with the same haplotype. The second most common alteration is p.Phe228Ile, occurring in 11.9% alleles (5/42), while codon Ala131 is affected in family 2 and in the OODD pedigree reported by Nawaz et al. (12). Overall, these three residues, namely Cys107, Phe228 and Ala131, are mutated in 57.1% alleles reported to date. The WNT10A phenotypic spectrum observed in 25 patients from 21 pedigrees so far described is wide and includes not only SSPS and OODD but also incomplete odonto-onychial, tricho-odonto and tricho-odonto-onychial forms, according to