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Observation
April 2016

Well-Differentiated Syringofibrocarcinoma in a Patient With Clouston Syndrome

Author Affiliations
  • 1Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut
  • 2Department of Podiatric Surgery, Yale University School of Medicine, New Haven, Connecticut
  • 3Department of Pathology, Yale University School of Medicine, New Haven, Connecticut
JAMA Dermatol. 2016;152(4):484-486. doi:10.1001/jamadermatol.2015.4496

An elderly man presented with syringofibrocarcinoma of the foot, which prompted examination and workup that confirmed a diagnosis of Clouston syndrome (hidrotic ectodermal dysplasia).

Report of a Case

A man in his early 80s presented after surgical excision of a large tumor on the right dorsal foot. He had a lifelong history of wispy hair on the lateral scalp, short thick fingernails with distal separation, and dystrophic toenails with distal wedge-shaped subungual hyperkeratosis (Figure 1A). His palms and soles had generalized mild hyperkeratosis and discrete large areas of pink papillomatous plaques. His shins had large scales and erythema. He had no eyelid cysts, and the few teeth he retained appeared normal; he had no history of delayed loss of deciduous teeth. His mother, maternal grandmother, sister, and brother reportedly had similar skin, hair, and nail findings. Both the patient and his brother developed tumors on a foot around age 80 years. The present patient’s tumor is shown in Figure 1B. It was treated with surgical excision and fifth-ray resection followed by placement of a split-thickness skin graft and healed well.

Figure 1.
Clinical Signs of Clouston Syndrome
Clinical Signs of Clouston Syndrome

A, Wispy hair (and incidental androgenetic alopecia), short dystrophic fingernails with bulbous soft-tissue swelling surrounding the nails, and thin pink papillomatous plaque on the left hypothenar eminence. No eyelid cysts were present. B, Syringofibrocarcinoma on the right lateral foot protruded beyond the flat-topped verrucous plaques.

Pathologic review of the surgical specimen showed thin cords and anastomosing strands of epithelial cells extending down from the epidermis with adjacent fibrotic changes consistent with syringofibroadenoma (Figure 2A). Deeper were islands of well-differentiated adnexal neoplasm with areas of squamous and poroid features consistent with a well-differentiated invasive tumor in the setting of syringofibroadenoma (Figure 2B).

Figure 2.
Eccrine Syringofibroadenoma Above Invasive Syringofibrocarcinoma in Tumor Specimens From the Foot
Eccrine Syringofibroadenoma Above Invasive Syringofibrocarcinoma in Tumor Specimens From the Foot

A, Superficially, thin anastomosing strands of epidermis extend downward amid fibrous stroma; B, invasive tumor islands of well-differentiated carcinoma are present with areas of squamous and poroid features (hematoxylin-eosin, original magnification ×10 for both images).

The differential diagnosis for dominantly inherited hair and nail dysplasia with palmoplantar keratoderma and syringofibroadenomas includes Clouston syndrome, caused by mutation in GJB6, and Schöpf-Schulz-Passarge syndrome (SSPS), caused by mutation in WNT10A.1,2 In contrast to Clouston syndrome, patients with SSPS develop multiple eyelid apocrine hidrocystomas during adulthood. Therefore, the absence of eyelid hidrocystomas in our patient supported the most likely diagnosis to be Clouston syndrome. To confirm this diagnosis, we sequenced his gap junction protein, beta 6 gene (GJB6), which showed a G11R mutation. The same mutation was identified in French Canadian families with classic Clouston syndrome phenotype1 and thus confirmed the diagnosis in our patient. During 1 year of follow-up, the patient showed no evidence of recurrent tumor or development of additional tumors and plans to continue screening skin examinations on a yearly basis.

Discussion

Syringofibrocarcinoma represents malignant transformation of eccrine syringofibroadenoma (ESFA),3 a unique epidermal neoplasm that occurs with Clouston syndrome (also called hidrotic ectodermal dysplasia) and SSPS. Our patient presented with a tumor on the foot (later confirmed to be a syringofibrocarcinoma) and unusual skin findings. Closer examination revealed the classic findings of Clouston syndrome, including short dystrophic fingernails with bulbous soft tissue around the nails, pink papillomatous palmoplantar keratoderma, and thin wispy hair. Further workup with genetic sequencing of GJB6 confirmed the diagnosis.

Of at least 10 cases of carcinoma arising near or adjacent to an ESFA, 7 describe a carcinoma that developed in a preexisting ESFA.3-5 The order of onset of ESFA prior to carcinoma suggests that the carcinomas represented malignant transformation of the ESFAs. Therefore, this type of tumor was named syringofibrocarcinoma.3 One case of syringofibrocarcinoma occurred in a patient reported to have dyshidrotic ectodermal dysplasia, although no clinical characteristics were described,4 and a second occurred in a patient with SSPS.6 Neither of these patients had genetic testing. Accordingly, to our knowledge, the present case represents the first case of syringofibrocarcinoma to develop in a patient with Clouston syndrome and supports the role of screening skin examinations in this unique patient population.

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Article Information

Corresponding Author: Ian D. Odell, MD, PhD, Department of Dermatology, Yale University School of Medicine, PO Box 208059, New Haven, CT 06520 (Ian.Odell@yale.edu).

Published Online: January 20, 2016. doi:10.1001/jamadermatol.2015.4496.

Conflict of Interest Disclosures: None reported.

Additional Contributions: We thank the patient for granting permission to publish this information. We also thank Keith A. Choate, MD, PhD, Department of Dermatology, Yale University School of Medicine, who graciously let us use his laboratory for GJB6 sequencing.

References
1.
Lamartine  J, Munhoz Essenfelder  G, Kibar  Z,  et al.  Mutations in GJB6 cause hidrotic ectodermal dysplasia.  Nat Genet. 2000;26(2):142-144.PubMedGoogle ScholarCrossref
2.
Bohring  A, Stamm  T, Spaich  C,  et al.  WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes.  Am J Hum Genet. 2009;85(1):97-105.PubMedGoogle ScholarCrossref
3.
González-Serva  A, Pró-Rísquez  MA, Oliver  M, Caruso  MG.  Syringofibrocarcinoma versus squamous cell carcinoma involving syringofibroadenoma: is there a malignant counterpart of Mascaro’s syringofibroadenoma?  Am J Dermatopathol. 1997;19(1):58-65.PubMedGoogle ScholarCrossref
4.
Bjarke  T, Ternesten-Bratel  A, Hedblad  M, Rausing  A.  Carcinoma and eccrine syringofibroadenoma: a report of five cases.  J Cutan Pathol. 2003;30(6):382-392.PubMedGoogle ScholarCrossref
5.
Katane  M, Akiyama  M, Ohnishi  T, Watanabe  S, Matsuo  I.  Carcinomatous transformation of eccrine syringofibroadenoma.  J Cutan Pathol. 2003;30(3):211-214.PubMedGoogle ScholarCrossref
6.
Starink  TM.  Eccrine syringofibroadenoma: multiple lesions representing a new cutaneous marker of the Schöpf syndrome, and solitary nonhereditary tumors.  J Am Acad Dermatol. 1997;36(4):569-576.PubMedGoogle ScholarCrossref
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