Clinical and Pathological Features of Pachyonychia Congenita

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Presentation transcript:

Clinical and Pathological Features of Pachyonychia Congenita Sancy A. Leachman, Roger L. Kaspar, Philip Fleckman, Scott R. Florell, Frances J.D. Smith, W.H. Irwin McLean, Declan P. Lunny, Leonard M. Milstone, Maurice A.M. van Steensel, Colin S. Munro, Edel A. O'Toole, Julide T. Celebi, Aleksej Kansky, EBirgitte Lane Journal of Investigative Dermatology Symposium Proceedings Volume 10, Issue 1, Pages 3-17 (October 2005) DOI: 10.1111/j.1087-0024.2005.10202.x Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Keratin mutations in pachyonychia congenita (PC). A schematic representation of the protein domain organization of each of the four keratins associated with PC is shown (K6a, K6b, K16, and K17). A total of 82 mutations have been published to date including those reported in this issue (Smith et al). The approximate location of mutations is indicated by numbered boxes. The numbers within the boxes indicate the number of families reported with mutations in this region, i.e., the number of independent occurrences of mutations. Note that the vast majority of mutations are found in or near the helix initiation motif in the 1A domain or the helix termination motif at the end of the 2B domain. The numbers below the schematic represent the amino acid residue number with the protein. The domains shown include the ISIS box (green), and homology subdomains H1 and H2 (blue), and the coiled coil domains 1A, 1B, 2A, and 2B (red), separated by non-helical linkers L1, L12, and L2 (black). Stutter sequences (S) are underlined. Journal of Investigative Dermatology Symposium Proceedings 2005 10, 3-17DOI: (10.1111/j.1087-0024.2005.10202.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Features of onychodystrophy in pachyonychia congenita (PC) patients. The clinical appearance of nail dystrophy is shown in PC patients with defined keratin mutations (shown below each panel). Variation in nail thickening and subungal hyperkeratosis is apparent in all images and illustrated especially well by comparison of K6a L170F and K6a L469P. Distal hyperpigmentation of the nails is seen in patients with the K6a L469P, K6a I462N, and K16 N125D mutations. Premature tapering of the nails (nail recession) is seen in individuals carrying mutations K6a N171K, K6a N171del, and K6b E472K. Sparing of the proximal nail is seen in some patients (K6a L469P, K6b E472K, K6a L170K, K6a I462N). “Pincer” nails or “Omega” sign is apparent in some cases when examined end-on (K6a I462N). One example of onycholysis is shown (mutation K6a N171K). Journal of Investigative Dermatology Symposium Proceedings 2005 10, 3-17DOI: (10.1111/j.1087-0024.2005.10202.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Plantar keratoderma in pachyonychia congenita. The pressure point distribution of plantar keratoderma is highly variable (all images). Note the variation of keratoderma among individuals with same mutation (K16 L132P, bottom right). There is evidence of blistering preceding formation of hyperkeratosis in some patients (K6a N171del, top: second from right) and fissuring (K6a N171del, top right). Journal of Investigative Dermatology Symposium Proceedings 2005 10, 3-17DOI: (10.1111/j.1087-0024.2005.10202.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Keratotic follicular spikes. Examples of follicular spikes occurring in areas of friction such as the elbow (K6a N171del), waistband (K6a N171K), knees (K6a L468P), and palms (K6a N171K and K16 N125D) are shown. Journal of Investigative Dermatology Symposium Proceedings 2005 10, 3-17DOI: (10.1111/j.1087-0024.2005.10202.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Hemotoxylin and eosin (H&E) staining and anti-keratin immunostaining of plantar biopsy material. Plantar biopsy material from two pachyonychia congenita (PC) patients with defined mutations and a normal unrelated control were analyzed by H&E staining and immunohistochemical staining with keratin antibodies. In normal skin, there was a similar suprabasal keratin immunostaining pattern seen for K6, K16, K10, whereas K17 and K14 showed diffuse epidermal staining that included the basal cell layer. In specimens from the patients carrying the K6a N171K and K6a L469P mutations, there is a prominent orthokeratosis and parakeratosis surmounting an acanthotic epidermis. Keratin immunostaining showed diffuse epidermal staining, including the basal cell layer, for K6, K16, K17, and K14. The K6aN171K sample shows markedly decreased K10 expression. All scale bars=100 μm. Journal of Investigative Dermatology Symposium Proceedings 2005 10, 3-17DOI: (10.1111/j.1087-0024.2005.10202.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Follicular keratoses from the knee in pachyonychia congenita (PC). Epidermal biopsy material from the knees of two PC patients with defined mutations and a normal unrelated control were analyzed by hematoxylin and eosin (H&E) staining. Hyperkeratosis and epidermal papillomatosis was observed in the K6a patient as compared with the normal control and K16 subject. All scale bars=100 μm. Journal of Investigative Dermatology Symposium Proceedings 2005 10, 3-17DOI: (10.1111/j.1087-0024.2005.10202.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Comparative histology and immunostaining on biopsies from a K6a N171K mutation carrier. Dermal cyst: Cysts were seen to be lined by stratified squamous epithelium with primitive hair follicle differentiation (100 ×). The cyst was immunoreactive with K6, K16, and K10, whereas K14 stains the full thickness of the epithelium and hair follicle. Follicular hyperkeratosis: A few pyknotic keratinocytes were seen within the upper layers of the epidermis and are reminiscent of those seen in coronoid lamellae of porokeratosis (100 ×). The normal pattern of expression of epidermal keratins was seen, with suprabasal expression of K6, K16, and K10, with full-thickness staining with K14. Oral leukokeratosis: hemotoxylin and eosin (H&E) staining revealed acanthotic squamous mucosa surmounted by parakeratosis in the absence of keratinocyte ayptia. Similar suprabasal immunoreactivity with K6 and K16 was seen, although K10 staining is patchy and is present mostly within the superficial keratinocyte layers. Strong K14 immunoreactivity was observed over the full-thickness of the squamous mucosa. All scale bars=100 μm. Journal of Investigative Dermatology Symposium Proceedings 2005 10, 3-17DOI: (10.1111/j.1087-0024.2005.10202.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 Cysts associated with pachyonychia congenita (PC). Steatocysts (or pilosebaceous cysts) are commonly found on the face (K17 N92S) and are widespread across the trunk (K6b E472K) in post-pubescent PC-2 individuals. Inclusion cysts are usually found on the trunk (K16 N125D) and axilla (K6a N171del) in PC-1 cases. Journal of Investigative Dermatology Symposium Proceedings 2005 10, 3-17DOI: (10.1111/j.1087-0024.2005.10202.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 9 Oral leukokeratosis in pachyonychia congenita (PC). Oral leukokeratosis appears to be more pronounced in K6a mutation carriers. Note this is similar in clinical appearance to oral candidiasis. Angular chelitis can also be observed in PC patients (K6a L468P shown here). Journal of Investigative Dermatology Symposium Proceedings 2005 10, 3-17DOI: (10.1111/j.1087-0024.2005.10202.x) Copyright © 2005 The Society for Investigative Dermatology, Inc Terms and Conditions