Malignant Proliferating Pilar Tumors Arising in KID Syndrome: a Report of Two Patients

ß 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:734–741 (2007)

Clinical Report Malignant Proliferating Pilar Tumors Arising in KID Syndrome: A Report of Two Patients

Gurston G. Nyquist,1 Christina Mumm,2 Renee Grau,2 A. Neil Crowson,2 Daniel L. Shurman,3 Paul Benedetto,3 Pamela Allen,2 Kelli Lovelace,2 David W. Smith,4 Ilona Frieden,5 C. Patrick Hybarger,6 and Gabriele Richard3,7* 1Department of Otolaryngology, Head and Neck Surgery, Kaiser Permanente, Oakland, California 2Department of Dermatology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 3Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 4Department of Pathology, Head and Neck Surgery, Kaiser Permanente, San Rafael, California 5Department of Dermatology, University of California San Francisco, California 6Department of Otolaryngology, Head and Neck Surgery, Kaiser Permanente, San Rafael, California 7GeneDx Inc., Gaithersburg, Maryland Received 1 May 2006; Accepted 17 November 2006

We report on two young adults with KID syndrome proliferating pilar tumors with poor prognosis. and follicular hyperkeratosis, hidradenitis suppurativa of ß 2007 Wiley-Liss, Inc. the groin, progressive development of proliferative pilar cysts and dissecting cellulitis of the scalp, who developed meta- static malignant pilar tumors. Based on our findings, we Key words: KID syndrome; skin cancer; squamous cell believe that cancer surveillance in patients with KID carcinoma; malignant pilar tumor; proliferating trichilemmal syndrome should include screening for pilar tumors and tumor; hidradenitis suppurativa; cystic acne; connexin; their early removal to avoid development of malignant Cx26

How to cite this article: Nyquist GG, Mumm C, Grau R, Crowson AN, Shurman DL, Benedetto P, Allen P, Lovelace K, Smith DW, Frieden I, Hybarger CP, Richard G. 2007. Malignant proliferating pilar tumors arising in KID syndrome: A report of two patients. Am J Med Genet Part A 143A:734–741.

INTRODUCTION with asparagine (D50N). Cx26 is a gap junction protein involved in intercellular communication Keratitis–Ichthyosis–Deafness (KID) syndrome and control of cellular differentiation in ectoderm- is a rare ectodermal dysplasia (OMIM 148210) derived stratifying epithelia of cochlea, cornea, characterized by sensorineural hearing loss palmoplantar epidermis and sweat glands and ducts. (SNHL), photophobia and corneal vascularization, In addition, Cx26 is highly expressed in the hair hyperkeratosis of the palms and soles (palmoplantar follicle inner and outer root sheath (ORS) in human keratoderma, PPK), erythrokeratoderma, follicular hair follicles [Arita et al., 2004]. Cx26 expression hyperkeratosis (keratosis pilaris) and recurrent bacterial and fungal infections. Since the first description by Burns [1915], more then 90 KID syndrome cases have been reported worldwide. The disorder can be transmitted as autosomal Abbreviations Used: KID, syndromeKeratitis–Ichthyosis–Deafness syndrome;SNHL, sensorineural hearing loss;PPK, palmoplantar kerato- dominant, albeit nine out of ten cases are sporadic derma;SCC, squamous cell carcinoma;Cx, connexin;CT, computerized due to a very high rate of new mutations. KID tomography;MRI, magnetic resonance imaging;STSG, split-thickness skin syndrome is caused by missense mutations in the graft;PTT, proliferating trichilemmal tumor. connexin (Cx) 26 gene, GJB2. Almost 80% of patients Grant sponsor: National Foundation for Ectodermal Dysplasias; Grant sponsor: NIH/NIAMS; Grant numbers: K08-AR02141, P01-AR38923. with KID syndrome harbor a common, recurrent *Correspondence to: Gabriele Richard, MD, GeneDx Inc., 207 Perry mutation, which replaces the highly conserved Parkway, Gaithersburg, MD 20877. E-mail: [email protected] aspartic acid residue at position 50 of the polypeptide DOI 10.1002/ajmg.a.31635 American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

MALIGNANT PROLIFERATING PILAR TUMORS IN KID SYNDROME 735 pattern and function overlaps with that of Cx30 SCC extending into the subcutis with clear in ectodermal epithelia and in one patient with surgical margins. Uninvolved skin at the borders of KID syndrome and congenital atrichia, a missense the tumor showed multiple epidermal cysts, chronic mutation of the Cx30 gene, GJB6, was reported [Jan inflammation and marked dermal scarring. Two et al., 2004]. superficial inguinal lymph nodes contained meta- Remarkably, KID syndrome is also associated with static tumor nests. The patient was treated with an increased susceptibility for squamous cell carci- adjuvant radiation and chemotherapy and was free noma (SCC) of the skin and tongue, which have been of local recurrence 3 years later. observed in at least 10% of patients [Lancaster and At age 32, the patient presented with another Fournet, 1969; Baden and Alper, 1977; Madariaga significant, ulcerating skin tumor on the left occipital et al., 1986; Morris et al., 1991; Hazen et al., 1992; scalp draining serous fluid (Fig. 1). The fungating van Steensel et al., 2002]. We report here on two tumor was 12 cm  10 cm in size and the suboccipital young patients with KID syndrome who developed lymph nodes were enlarged. A superficial shave hundreds of proliferating pilar (trichilemmal) scalp biopsy of the skin, which did not include the deeper cysts transforming into metastatic malignant pilar pilo-sebaceous structures, showed full-thickness tumors and make recommendations for cancer epidermal keratinocytic dysplasia and hence was surveillance and treatment of these tumors in KID interpreted as a primary, well-differentiated SCC. syndrome. Computerized tomography (CT) scans showed a large skin and subcutaneous lesion extending into the skull bone with erosion of the posterior aspect of CLINICAL REPORTS the mastoid air cells. There were several enhancing Patient 1 lymph nodes inferior to the left parotid gland suspicious for metastases. Staging CT of the chest, A 31-year-old African American woman presented abdomen and pelvis were negative for disease with a history of KID syndrome and recalcitrant involvement. The magnetic resonance imaging hidradenitis suppurativa. Family history revealed (MRI) of the brain was negative. The patient under- that the patient’s paternal aunt had been also went a complete surgical excision of the skin tentatively diagnosed with KID syndrome and tumor and draining lymph nodes. Final histological passed away in her young adulthood. The patient examination of the entire resected tumor demon- did not have a relationship with this aunt and, strated morphological hallmarks of a primary therefore, did not know her clinical course or her malignant proliferating pilar tumor (PPT), clearly cause of death. There were no vision, hearing, or skin originating from the pilosebaceus unit but reaching disorders, including follicular tumors or skin cancers the epidermis. There were sheets of fully trans- in other family members. The patient’s father is formed malignant squamous cells with extensive estranged and was unavailable for physical exam, areas of abrupt tricholemmal keratinization lacking thus the segregation of KID syndrome in this family a granular cell layer (Fig. 1). In several foci, the could not be confirmed. malignant epithelial sheets arose in continuity with The patient had bilateral SNHL first diagnosed in cystic structures lined by banal squamous epithelium infancy, photophobia and corneal vascularization, showing pilar differentiation, in continuity with areas which were slowly progressing since adolescence. of progressive dysplasia of the ORS epithelium, held Her skin was dry. She had PPK with a ‘stippled’ to be further morphologic evidence of derivation appearance typical for KID syndrome (Fig. 1) and from cysts arising from the deep components of deep atrophic scars on both cheeks from previous the hair follicle apparatus. There was perineural cystic acne. Seven years earlier she was diagnosed invasion. Metastatic deposits were identified in 3 of with hidradenitis suppurativa of her groins as well as 25 sampled lymph nodes. Within the excised scalp dissecting cellulitis of the scalp. Both were recalci- skin, the hair follicle density was greatly reduced; trant and progressive and were aggressively yet residual hair follicles were dilated and plugged with unsuccessfully treated with multiple courses of keratin material and the dermis was sclerotic, antibiotics and a 5-month course of isotretinoin consistent with her history of scarring alopecia (80 mg/day). By age 28, the dissecting cellulitis had secondary to dissecting cellulitis. After a hiatus of finally resolved with diffuse scarring alopecia invol- 4 months, during which the patient did not receive ving the occipital, parietal, and frontal scalp (Fig. 1). radiation or chemotherapy, she returned for a The hidradenitis remained a therapeutic challenge dermatological follow up visit with a 4 cm  4cm and eventually a surgical en bloc resection as tumor mass along the left anterior cervical chain. She performed, which lead to the discovery of a was immediately referred back to otorhinolaryn- moderately differentiated SCC upon histological gology and oncology and is currently undergoing examination. The tumor mass was surgically excised chemotherapy. and a lymph node dissection was performed. Mutation analysis of the Cx26 gene was performed to The resection showed a moderately differentiated confirm the clinical diagnosis of KID syndrome. The American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

736 NYQUIST ET AL.

FIG.1. Patient 1: Female with KID syndrome. A: Large, exophytic, ulcerated tumor mass and numerous small cystic tumors on the scalp at age 32 y. B: Typical ‘stippled’ appearance of the palmar surface of the digits. C: Depicted are the remnants of a cyst containing amorphous eosinophilic debris. The cyst wall shown on the left demonstrates abrupt keratinization indicative of a proliferating tricholemmal tumor. The cyst wall shows progressive neoplastic transformation. Tumor cells radiate from the wall into the stroma, 40Â magnification. D: Fully transformed malignant neoplastic cells grow as tongues through the stroma, provoking a proliferative fibroblastic reaction. In concert with the features shown in (C), the atypical mitoses, fully transformed malignant cytology and the infiltrative growth pattern indicate a malignant pilar tumor, 600Â magnification. patient was heterozygous for a G to A nucleotide profound hearing loss in the left. MRI of the brain change resulting in the missense mutation D50N and CT of the temporal bones did not show any (Asp50Asn) commonly associated with KID syndrome. brain, internal auditory canal, or bony inner ear malformations. Mild, punctate keratitis developed by Patient 2 the age of 3 years but was stable and did not lead to subjective symptoms or visual decline. Based on This 24-year-old man of mixed Japanese/African- these findings, a clinical diagnosis of KID syndrome American background was born with generalized, was made. red and thickened skin and follicular hyperkeratosis. The patient’s skin condition worsened with age, There was no family history of skin abnormalities, especially during puberty. Besides PPK, he had spiny, skin cancer, eye disorder or hearing loss. Since verrucous, hyperkeratotic plaques on the extremities. infancy, he has had PPK with a reticulate, pitted Recurrent episodes of bacterial skin infections neces- surface and interrupted dermatoglyphs. At age sitated treatment with oral antibiotics. The patient’s 2 years bilateral SNHL was diagnosed and serial nails were thickened and showed longitudinal audiograms from the age of 3–17 years revealed a ridging. He had malalignment of the left great toenails stable mild-moderate hearing loss in the right ear and and thinning of the lateral eyebrows. He also American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

MALIGNANT PROLIFERATING PILAR TUMORS IN KID SYNDROME 737 developed severe cystic acne with hard, erythematous Six months later, enlarging nodules of the right and papules and pustules in typical distribution. In left sides of the scalp appeared and were excised addition, there were multiple small, hard or cystic (Fig. 2). Histopathological examination showed a nodules on the back, shoulders and scalp, which spectrum of disease from pilar (trichilemmal) evolved into large, fluctuant, boggy masses of 1–8 cm cysts, to PPTs, to areas showing fully transformed in diameter. The cystic nodules intermittently became malignant changes of the associated squamous infected but responded well to systemic antibiotic epithelia with an infiltrative pattern of growth and a treatment. Several of these scalp tumors proliferated desmoplastic stromal reaction indicating a primary and grew explosively leading to ulceration, necrotiza- malignant PPT (Fig. 2). tion and widespread plaques of scarring alopecia on Over the next several years, the patient developed his scalp with intermittent bunches of hair. At age multiple masses of the scalp that were treated 13 years, the patient began a 20-week course of oral with intralesional methotrexate. While some lesions isotretinoin to treat severe facial acne, and the scalp resolved, those that did not respond to this regimen nodules became less active during this regimen. were excised with Mohs technique. Because of However, another course of isotretinoin was aborted disease progression, the patient ultimately required secondary to cheilitis, epistaxis, and fear of skeletal subtotal full-thickness scalp resection. It was toxicity. successfully reconstructed with a split-thickness skin At age 19, the patient presented with a fleshy, graft (STSG) after an Integra bilayer dermal substitute ulcerated, 5 cm  4 cm nodule on the right temporal scaffolding was placed and given 3 weeks to scalp that was larger then any of the multiple scalp heal (Fig. 2). On each occasion, histopathological cysts. The nodule had a soft consistency and released examination showed SCCs arising in a field of a white exudate when punctured. No cervical multiple proliferating trichilemmal tumors. Despite lymphadenopathy was present. Results of a shave the radical surgical treatment, the patient suffered a biopsy showed features of a SCC. Micrographic, local recurrence of the tumors through the STSG with margin-controlled excision was performed and transcalvarial dural spread and compression of the resulted in a 6 cm  9 cm defect, which was superior sagital sinus on MRI. A work-up revealed reconstructed with a large rotation flap. As dis- pulmonary metastases, and the patient developed covered during surgery, the scalp contained hun- later also new metastases to the base of the skull and dreds of small and larger cysts. cavernous sinus. He underwent cyberknife radiation

FIG.2. Patient 2: Male with KID syndrome. A: Large, fungating and ulcerated malignant pilar tumor and hundreds of proliferating trichilemmal cysts of the scalp at age 23 years. Note the scarring alopecia. B: Postoperative status after subtotal full-thickness scalp resection and interim placement of an Integra bilayer dermal substitute scaffolding, which was later successfully constructed with a split-thickness skin graft. C: Shown is a dermal tumor characterized by proliferating lobules of neoplastic squamous epithelia that show abrupt (i.e., tricholemmal) keratinization without a granular cell layer. Tongues of tumor infiltrate the stroma, which shows fibroplasia and a granulation tissue reaction. There are areas of dystrophic calcification (indicated by their deep purple stain) in both the tumor lobules and in the stroma, 100Â magnification. D: Depicted toward the left is the wall of a tricholemmal cyst lined by squamous epithelium with a glassy, eosinophilic appearance. In the lower levels of the banal cyst wall, the epithelial cells show typical features of malignancy. The adjacent stroma contains an infiltrating component with tongues of tumor and a sheet- like pattern of growth. Numerous mitoses are evident, 200Â magnification. American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

738 NYQUIST ET AL. treatment to treat the sagittal sinus metastases, and cytoplasmic pattern (Fig. 3). These observations later whole brain radiation therapy in conjunction are consistent with an upregulation and shift in the with multiple cycles of systemic chemotherapy; expression of connexins in malignant pilar tumors in however, the patient ultimately succumbed to the a patient with KID syndrome. The abnormal cyto- disease. plasmic distribution of these gap junction proteins Mutation analysis of the Cx26 gene revealed a could be the result of a failure in intracellular homozygous A-to-G nucleotide substitution leading trafficking or, alternatively, reflect a different func- to replacement of the highly charged glutamic acid tion of connexins in tumor cells. residue at position 114 with a small, neutral glycine (E114G). In addition, the patient was heterozygous DISCUSSION for another sequence variant of Cx26 with codons present for both valine and isoleucine (V27I). Both KID Syndrome belongs to a diverse group of variants are common among individuals of Asian genetic connexin disorders with disturbed gap descent and are can be found together on the same junction function. Nonetheless, it appears to be the Cx26 allele (in cis) [Posukh et al., 2005]. A pathogenic only connexin defect that is associated with an dominant mutation could not be identified in GJB2. increased susceptibility for SCC. The first patient with Similarly, no mutation was found in several other KID Syndrome and cutaneous SCC was reported in connexin genes that are expressed in the skin and 1969 [Lancaster and Fournet, 1969]. Since then, at ectodermal epithelia, including GJB3, GJB4, GJB5, least nine additional cases have come to light, and GJB6. including six patients with SCC of the skin and three Results of immunostaining of the patient’s acantho- patients with SCC of the tongue and oral mucosa, tic, tumor-free scalp epidermis with antibodies which translates to an incidence rate of about 10%. In against 10 different gap junction proteins, including some of the cases with epidermal SCC, preexisting Cx26, was comparable to normal human epidermis hyperkeratosis of the skin was noted [Richard et al., with exception of Cx26. Normally, this connexin is 2003]. When considering also the young age of KID expressed in the epithelial cells of the eccrine sweat syndrome patients at time of tumor development, glands and ducts as well as in the hair follicle but not (age range between 6 and 55 years, mean: 25 years) in interfollicular epidermis. The patient skin showed, [Baden and Alper, 1977; Madariaga et al., 1986; however, an ectopic punctate plasma membrane Morris et al., 1991; Hazen et al., 1992; Richard et al., staining in the granular layer (Fig. 3), similar to a 2003; van Steensel et al. 2002; Grob et al. 1987; previous report [Richard et al., 2002]. In a malignant Lancaster et al., 1969] it seems evident that the cystic pilar tumor, immunoreactivity for Cx26 was underlying genetic cause of KID syndrome, namely limited to a few clusters of tumor cells, while no Cx30 mutations in the Cx26 gene, are directly or indirectly staining was found. Cx43 staining was detected in a responsible for the increased SCC risk. The patho- typical punctate plasma membrane pattern as well as genesis of SCC in KID syndrome patients remains in an aberrant diffuse cytoplasmic distribution. unclear, especially since none of the other known Positive connexin staining of cell clusters for Cx31 Cx26 disorders, that is, non-syndromic SNHL and and Cx36 was seen in the malignant tumor, but not PPK and SNHL, including Vohwinkel syndrome in surrounding skin, and showed an unusual and Bart–Pumphrey syndrome, apparently do not

FIG.3. Patient 2: Immunostaining of scalp skin (top row) and malignant pilar tumor (bottom row) with antibodies against Cx26, Cx30, Cx43, Cx36 and Cx31. Note the ectopic expression of Cx26 in the granular and upper spinous layers of the scalp skin, where also Cx30 is expressed. Only a few tumor cells show punctate staining for Cx26, while no signal is found for Cx30. Immunostaining in scalp skin for Cx43 and Cx31 shows a normal punctate pattern and distribution, and Cx36 is not reactive. In contrast, tumor cells demonstrate strong yet irregular immunostaining and predominantly cytoplasmic distribution. American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

MALIGNANT PROLIFERATING PILAR TUMORS IN KID SYNDROME 739 convey an increased risk of malignant tumors when extensive keratinocyte proliferation occurs in [Richard 2005]. However, these allelic disorders also the basal cell layer. Microscopically, the well- lack other features of KID syndrome, such as circumscribed tumors are formed by proliferating involvement of cornea and pilosebaceous units and lobules of squamous cells showing multiple central abnormalities of the immune system, suggesting that areas of trichilemmal keratinization (without the those Cx26 mutations leading to KID syndrome have presence of a granular layer) and formation of unique detrimental consequences. homogeneous keratin cysts. Typically, the transition We report here two patients with KID syndrome from pale, enlarged peripheral cells to a densely who developed primary malignant proliferative pilar packed keratin layer is abrupt and there is tumors (PPT) of the scalp. Both patients shared a some cellular atypia and increased mitotic activity constellation of features that has not been previously [Mehregan and Lee, 1987; Park et al., 1997; Lopez- recognized as an entity: (1) history of severe cystic Rios et al., 2000]. These histological characteristics acne, hidradenitis suppurativa and/or dissecting may overlap with those of epidermis-derived SCC, in cellulitis of the scalp with scarring alopecia; (2) particular since in up to 24% of PPT the epidermis progressive development of a large number of pilar may be involved [Sau et al., 1995], also illustrated in cysts with onset in early teens; (3) sudden onset of Patient 1. The classification of pilar tumors is debated rapid tumor growth and transformation into malig- [see Cassarino et al., 2005], some consider pilar nant pilar tumors with (4) highly invasive and (tricholemmal) cysts and proliferating pilar (tricho- metastatic behavior leading to a poor prognosis. lemmal) cysts/tumors benign in nature, others Benign and malignant pilar (trichilemmal) tumors on believe they represent low-grade SCC as a review the buttocks, elbows and knees have been reported of the literature in 2002 showed 30 cases of PPT’s once before in a Korean patient with KID syndrome, transforming into malignant PPT/SCC [Folpe et al., albeit in this case no clear history of a follicular 2003]. Nevertheless, it has been recognized that once inflammatory processes was reported, [Kim et al., transformation into malignant PPT (aka malignant 2002]. In contrast, two unrelated KID syndrome proliferating tricholemmal tumor) has occurred, patients from the USA and Germany exhibited these tumors behave more aggressive with respect features of a ‘follicular occlusion triad’ characterized to local invasiveness and distant metastasis than by follicular plugging, chronic follicular inflamma- many other more common subtypes of epidermal tion and scarring (dissecting folliculitis), hidradenitis SCC. Recently, Cassarino et al. [2005] proposed a suppurativa, and cystic acne but without malignant classification of SCC based upon their malignant tumors [Montgomery et al., 2004; Maintz et al., 2005]. potential into those with low (2% metastatic rate), The mounting number of KID patients with follicular intermediate (3–10%), high (greater than 10%), and occlusion syndrome strongly suggests that the indeterminate behavior. Malignant PPTs were underlying genetic defect in KID syndrome results grouped as high-risk tumors, similar to Bowen in a perturbed keratinization not only of the disease, adenosquamous and desmoplastic carci- epidermis but also of the hair follicles and thus noma. Based on our experience, we support the predisposes to follicular occlusion triad and follicular viewpoint that malignant PPT represent a distinct tumors. Montgomery et al. [2004] hypothesized that form of SCC arising from the deep component of the abnormal epidermal and follicular keratinization in hair follicle apparatus, which have a very high KID syndrome leads to plugging of the follicular malignant potential. orifices with subsequent cyst formation, rupture and The current management of PTT is excision with spillage of keratin and glandular secretions into the clear margins of those tumors that have grown subcutaneous tissue, which in turn causes an rapidly and begin to ulcerate. This treatment strategy inflammatory response. It is conceivable that recur- proofed insufficient for the presented KID syndrome rent and chronic inflammation and scarring may be patients. Both required extensive and repeated one additional factor in triggering transformation of surgical excision of the scalp tumors due to invasion benign pilar cysts to malignant PPTs during a multi- into local structures and lymph node metastases. The step carcinogenesis process as demonstrated for invasion into the calvarium and dura in Patient 2 other subtypes of SCC and many other malignant resulted also in neurological abnormalities and a tumors. high morbidity. Based on our experience in the cases Pilar (tricholemmal) cysts of the scalp are common reported here, we believe that the surgical treatment and arise from the ORS of the hair follicle isthmus. in KID syndrome patients must be especially They are characterized histologically as a nodule aggressive with wide local excision of proliferating formed by an outer wall of keratinizing epithelium tumors and, ideally, Mohs micrographic surgery without a granular layer at the base of the hair follicle. because of the apparent high potential for malignant Most nodules are solitary and less than 5 mm, but it is transformation and metastatic progression. It has to not unusual for them to be greater than 5 cm. be considered that the presence of many adjacent Transformation into a PPT, also referred to as proliferating tricholemmal cysts can make the proliferating trichilemmal cyst/tumor, is possible precise margin analysis difficult and that an early American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

740 NYQUIST ET AL. removal of the entire scalp with preliminary ligation staining was usually cytoplasmic and heterogeneous of feeding vessels and Integra/split-thickness skin in contrast to the normal plasma cellular localization grafting may be beneficial. of gap junction proteins [Jamieson et al., 1998]. Considering the increased SCC risk, the early age of Similarly, we also observed intense and abnormal tumor onset, and aggressive behavior of tumors cytoplasmic immunostaining for Cx26 as well as in some KID syndrome patients, KID syndrome three other connexins (Cx31, Cx31.1, and Cx36) in a belongs to the list of cancer-associated genoderma- malignant pilar tumor in Patient 2. Since connexins toses, such as Gorlin syndrome, Cowden syndrome, are usually localized at the plasma membrane, where Xeroderma pigmentosum and others [Brose et al., they form hemichannels and intercellular gap junc- 2003]. The guidelines for dermatologic surveillance tion channels, the predominantly cytoplasmic loca- in patients with KID syndrome should be most lization of Cx26 in tumor cells suggests that gap stringent for those patients with clinical evidence of junction communication is reduced. Indeed, a follicular occlusion. We recommend that these decrease of gap junction communication has been patients perform monthly self-examinations of the correlated previously with stepwise progression of skin and oral cavity and be fully examined by a benign papillomas to SCC in a mouse carcinogenesis dermatologist at 3- to 6-month intervals with a low model [Budunova et al., 1996]. Moreover, this finding threshold for biopsy of proliferating, ulcerating or implies that Cx26 plays a role in tumorigenesis, otherwise suspicious lesions. In particular pilar cysts tumor progression and/or metastasis independent of should be removed in toto (if possible) to avoid gap junction communication. This hypothesis is proliferation malignant transformation. Similarly, supported by recent studies demonstrating that regular full oral examination should be included in Cx26 suppresses tumor growth and induces apop- the surveillance program because of the reported tosis in tumor cells via association with apoptotic, cell KID syndrome cases with SCC of the tongue and cycle control and focal adhesion proteins [Tanaka mouth. Such a regimen is expected to lead to early and Grossman, 2004; Kanczuga-Koda et al., 2005]. It cancer detection and might therefore be of major is feasible that KID syndrome associated mutations in importance for the survival of KID syndrome Cx26 selectively alter any of these interactions with patients. Bak, Bcl2, focal adhesion kinase and others, thus Gap junctions formed by Cx26 are found in many promoting tumor growth and metastasis. However, epithelia organs, including the cochlea, palmoplan- this hypothesis remains to be investigated. Based on tar epidermis, hair follicles, and sweat glands and the co-existence of benign, proliferating and malig- ducts. In the hair follicle, Cx26 expression is found in nant pilar tumors in patients with KID syndrome, it is the ORS and inner root sheath (IRS) but most conceivable that tumor development follows a two- pronounced in the outermost layer of the ORS in or multihit model similar to other genetic cancer contrast to Cx43, which shows predominantly syndromes. Chronic festering inflammations, such as staining in the inner part of the ORS, IRS, cortex recalcitrant hidradenitis suppurativa or dissecting and medulla [Arita et al., 2004]. Connexin 26 has been cellulitis of the scalp could represent crucial local considered a tumor suppressor gene, which can factors contributing to malignant transformation. modulate development, growth and differentiation In summary, a subset of patients with KID in epithelial tissues [Lee et al., 1991] and its syndrome develops multiple cystic pilar tumors, upregulation has been linked to epidermal hyper- which are prone to malignant transformation and plasia, for example, in psoriasis and viral warts metastasis. The sheer number and aggressive malig- [Lucke et al., 1999]. Based on the strong follicular nant behavior of these tumors is a therapeutic expression of Cx26 in keratinizing cells and the challenge and results in considerable morbidity and observation of follicular occlusion syndrome and mortality. We suggest including pilar (tricholemmal) cystic pilar tumors in patients with KID syndrome, we cysts and proliferative pilar tumors in the cancer suspect that hyperplasia in the isthmus of the hair surveillance of KID syndrome patients and recom- follicle may cause proliferation and subsequent mend their early excision to prevent malignant increased incidence of malignant transformation transformation and metastatic disease. resulting in SCC mimicking or arising from PPTs. Cx26 has been also tight to different steps during ACKNOWLEDGMENTS carcinogenesis and several recent reports have described abnormalities in Cx26 structure and We like to extend our special thanks to the patients regulation in various internal organ malignancies, who so generously supported our work and research such as breast, lung, prostate, colorectal and hepatic on KID syndrome. We are grateful to Dr. Jason Lee cancer [Muramatsu et al., 2002; Momiyama et al., and Dr. David Cassarino for helpful comments and 2003; Tanaka and Grossman, 2004; Kanczuga-Koda stimulating discussions. This work was partly sup- et al., 2005, 2006; Ito et al., 2006]. For example, ported by the National Foundation for Ectodermal upregulation of Cx26 was found in cells of 15 out of Dysplasias and NIH/NIAMS grants K08-AR02141 and 27 invasive breast carcinoma tumors, although the P01-AR38923 (GR). American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

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