TO THE EDITOR
Familial keratoacanthomas (KAs) are characterized by the appearance of multiple epithelial
tumors that are believed to arise from adjoining hair follicles (Schwartz, 1994).
These lesions, which phenotypically and histologically resemble squamous cell carcinomas
(SCCs) (Cribier et al., 1999), have a fast evolution and spontaneous regression. To
date, four familial forms of multiple KAs have been described: (1) multiple self-healing
squamous epithelioma (MSSE; Smith, 1948); (2) the Grzybowski syndrome (Grzybowski,
1950); (3) the Witten–Zak syndrome (Witten and Zak, 1952); and 4) the Muir-Torre syndrome
(Muir et al., 1967). The Muir-Torre syndrome (MIM#158320) is caused by mutations in
the DNA-repair genes MSH2/MLH1 (Bapat et al., 1996; Kruse et al., 1998), and MSSE
(MIM#132800) is due to mutations in TGFBR1 (Goudie et al., 2011), but the causative
genes underlying the other two familial KAs are still not known.
We describe here, in a five-generation Tunisian family comprising 27 affected individuals
with autosomal dominant transmission of palmoplantar KAs, an unreported syndrome that
we have named multiple self-healing palmoplantar carcinoma (MSPC) (Figure 1). MSPC
has the distinctive feature of mainly affecting epithelial tissues that are devoid
of hair follicles, such as palmoplantar skin and the conjunctival epithelium.
Phenotypically, the development of skin lesions begins with a progressive appearance
of multiple ulcerative-nodular tumors on plantar skin (Figure 1b–e). The average age
of onset was 8.8 years for the 15 propositi studied and ranged from 1 to 25 years
(Supplementary Figure S1a online). Palmoplantar tumors (5–50 mm in diameter, 8–12
in number) grew over a period of 3 months and spontaneously regressed after 6 months,
leaving atrophic scars consistent with KAs (Figure 1e). Histological examination of
a primary plantar lesion and peri-lesional skin of patient IV:2 showed a massive epidermal
hyperkeratosis overlying an endophytic squamoproliferative tumor with prominent keratin
cyst formation and crypt abscesses and a dense stromal inflammatory infiltrate at
the base (Supplementary Figure S1b–f online). Notably, the granular layer, which is
prominent in normal palmoplantar epidermis, was nearly absent. Histological findings
are suggestive of a verrucous carcinoma, a low-grade SCC.
In addition to palmoplantar tumors, 80% of studied propositi also developed conjunctival
lesions, which appeared in the second decade of life (Figure 1h and i). All were surgically
removed, and histological examination of one such tumor revealed squamous epithelial
lobules with a dyskeratotic center, suggestive of a conjunctival KA (data not shown).
The use of retinoids (Etretinate or Acitretin) halted the progression of the palmoplantar
tumors but also stopped their self-regression to a final pitted-scar stage. In cases
of resistance to retinoid treatment, palmoplantar tumors were operated upon. Despite
these precautions, 5 out of 15 (33%) affected patients whose medical records were
available had developed malignant tumors in the lungs (III:10) and head and neck (III:11
and IV:19), SCC on the nose (IV:5), and SCC with bone metastasis (IV:2) (Supplementary
Figure S1a online). Patient IV:2 developed both labial (Figure 2a) and heel SCC, which
infiltrated the calcaneus bone (Figure 2b–e), requiring bilateral leg amputation.
On the basis of its autosomal dominant transmission and multiple self-regressive presentations,
we initially hypothesized that this syndrome could be a clinically heterogeneous form
of MSSE. However, neither Sanger sequencing of all nine exons of TGFBR1 nor haplotype
mapping of its locus on chromosome 9q22.33 revealed any common allele shared by all
propositi. No DNA-repair defects were observed consistent with the patient's normal
karyotypes and absence of chromatin fragility in patients' B-lymphocytes, arguing
against a phenotype related to the Muir-Torre syndrome.
To unambiguously map the causative allele for this uncommon genodermatosis, we obtained
DNA from blood samples from 11 affected and 5 unaffected members after obtaining informed
written consent and Institutional Review Board approval. Members were single-nucleotide
polymorphism genotyped using human 660W-Quad BeadChips from Illumina (Figure 1a),
and identity-by-descent mapping was performed (Reversade et al., 2009). Assuming autosomal
dominant transmission, only one identity-by-descent block on chromosome 17p13.3-p12
was found to be shared by all genotyped probands and not by any of the five unaffected
family members tested (Figure 2f). Meeting genome-wide significance, parametric and
non-parametric linkage analyses yielded a maximum LOD score of 1.69 (Abecasis et al.,
2002) and 4.21 (manual calculation), respectively. This 11.4 Mb locus bracketed by
single-nucleotide polymorphisms rs8065368 and rs2322788 contains 288 genes (GRCh37/hg19:
chr17:1541109-12964181) (Figure 2f) including TP53, a prominent tumor suppressor often
mutated in skin cancer (Giglia-Mari and Sarasin, 2003). Sanger sequencing excluded
mutations in TP53, arguing that a hitherto unidentified causative gene for MSPC lies
within this haplotype.
The combination of clinical presentations primarily affecting palmoplantar and conjunctival
skin and autosomal dominant genetic transmission argues that this syndrome is an inherited
skin disease that to our knowledge is previously unreported. Six characteristics distinguish
MSPC from the other four familial KA syndromes: (1) the earlier age of onset varying
between 1 and 25 years; (2) the primary lesions that do not arise in sun-exposed areas
but rather at points of pressure and friction; (3) the presence of conjunctival KA;
(4) the ulcerative-nodular aspects of tumors; (5) the larger size of tumors, which
vary between 5 and 50 mm; and (6) the tendency to transform into SCC with metastases,
a feature only seen in MSSE patients subjected to radiotherapy (Chakrabarty and Perks,
1996). These differences, together with the presence of exclusive linkage to chromosome
chr.17p13.3-p12, argue that MSPC is clinically and genetically distinct from MSSE,
other inherited multiple KA, or punctate palmoplantar-specific genodermatosis (Pohler
et al., 2012). To the best of our knowledge, only one similar case with multiple self-healing
palmoplantar lesions has been reported in the literature (Feldman and Maize, 2007).
Unlike KAs, which are believed to originate from hair follicles, the presence of lesions
on hairless palmoplantar skin and on conjunctival epithelia argues instead that MSPC
can originate from interfollicular keratinocyte progenitors.
We propose that this different syndrome should be classified as an inherited predisposition
to skin cancer with primary palmoplantar and conjunctival tumors. We anticipate that
the causative gene for MSPC will be rapidly identified as awareness is raised about
its existence and correct clinical diagnosis.