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Transgrediens lesions in patients with pachyonychia congenita
P2002
P2004
Extending the phenotypic spectrum of keratitis-ichthyosis-deafness syndrome: Report of a patient with GJB2 (g12R) connexin 26 mutation and unusual clinical findings Tamara Lazic, MD, Roger Williams Medical Center/Boston University School of Medicine, Providence, RI, United States; Jouni Uitto, MD, PhD, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States; Linda Zhou, MD, Roger Williams Medical Center/Boston University School of Medicine, Providence, RI, United States; Michael Frank, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States; Qiaoli Li, PhD, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States Keratitis-ichthyosis-deafness (KID) syndrome is a rare ectodermal dysplasia that is characterized by the presence of skin lesions, neurosensory hearing loss, and vascularizing keratitis. Additional features included in the diagnostic criteria of KID syndrome include erythrokeratodermic plaques, palmoplantar hyperkeratosis, alopecia, nail dystrophy, dental abnormalities, increased susceptibility to mucocutaneous infections, and an increased risk of squamous cell carcinoma. Most mutations that have so far been discovered as a cause KID syndrome are autosomal dominant, found in exon 2 of the connexin (Cx) 26 gene. One of the described mutations, G12R (p.Gly12Arg), is a GJB2 mutation reported in only two patients with KID syndrome to date. In our report, we describe a patient with the G12R mutation and KID syndrome with interesting additional features, including a porokeratotic eccrine ostial and dermal duct nevus (PEODDN), follicular occlusion triad, and unusual persistent oral mucosal papules. To our knowledge, this is the first patient found to have an association of KID syndrome and PEODDN. Furthermore, we compare and contrast this patient’s phenotype to the only two other patients described with the same (G12R) mutation. To date, follicular occlusion triad has been reported in association with KID syndrome in two cases, with distinct Cx 26 mutations. Our case is the first reported case to our knowledge of a G12R mutation causing the above mentioned association. In all three patients with the G12R mutation, some form of acneiform lesions is present, whether it is follicular occlusion triad (as seen in our patient), or isolated severe nodulocystic acne (as seen in the other two patients with the same mutation). This leads us to speculate that the patients harboring this particular mutation might be at an increased risk for cystic acne or hidradenitis suppurativa.
Recessive dystrophic epidermolysis bullosa with squamous cell carcinoma M. H. Kim, Department of Dermatology, St. George Hospital, Kogarah, Australia; D. F. Murrell, MD, MBChB, Department of Dermatology, St. George Hospital, Kogarah, Australia; L. R. A. Intong, MD, Department of Dermatology, St. George Hospital, Kogarah, Australia; Y. C. Kho, MBBS, Department of Dermatology, St. George Hospital, Kogarah, Australia Background: Epidermolysis bullosa (EB) is a rare group of genodermatoses defined by fragile skin, recurrent blistering, erosions of the skin and mucous membrane, and impaired wound healing. Recessive dystrophic epidermolysis bullosa (RDEB) carries a very high risk of developing squamous cell carcinoma (SCC). At present, no epidemiologic or clinical data have been published documenting RDEB-SCC cases in Australia. This retrospective study reports characterization of SCC and SCC-related cumulative risks amongst individuals with RDEB in the Australasian EB cohort. Methods: Individuals with RDEB who had previously developed SCC according to the Australasian EB Registry (AEBR) participated in the study. Medical information on RDEBSCC cases were obtained by contacting relevant hospitals and clinics across Australia. Results: Thirty-seven individuals have RDEB, which accounts for 13% of the EB population in Australasian cohort. Thirteen (35%) of the RDEB individuals have developed at least one SCC, and medical records on 11 of them were accessible. A total number of 80 primary SCCs were observed from 11 RDEB-SCC cases (5 males; 6 females) with an average of eight SCCs per person. Ninety-four percent of the SCCs developed on the upper and lower extremities and 30% of the SCCs were multifocal SCCs. Eight out of 11 RDEB-SCC individuals (72.7%) eventually developed metastatic SCCs, with the most frequent metastatic site being the regional lymph nodes, followed by lungs and bones. The age range at first diagnosis of SCC was 16 to 39 years, with a median of 24 years. The time between the diagnosis of one SCC and the next primary SCC in each patient was 5 months (median), with the mode being 3 months. The majority of the tumors were well and moderately differentiated. The cumulative risk of SCC development by age 45 was 85% and the cumulative risk of death from SCC in RDEB individuals that develop SCC by age 45 was 60%. Approximately half of the RDEB individuals died from metastatic complications of SCC within 10 years of developing their first SCC, and 86% by 15 years.
The phenotypic heterogeneity of KID syndrome, inexplicable by our current understanding of these proteins, speaks to the complexity of the connexin system and its overlapping expression patterns in different tissues.
Conclusion: Given the highly aggressive nature of RDEB-SCC, its high frequency of development, and its high mortality rate, rigorous follow up of RDEB patients every 3 months starting from 12 years of age is imperative for early detection and successful SCC treatment to improve patient management and survivability. Furthermore, a pathologic report of well differentiated SCC does not match the aggressive behavior of these tumors.
Commercial support: None identified.
Commercial support: None identified.
P2005
P2003 Ectodermal dysplasia associated to B-cell lymphoma resulting from mutation of the p63 gene Miguel Cabanillas, MD, Complejo Hospitalario Arquitecto Marcide-Novoa Santos, Ferrol, Spain; Aquilina Ramırez-Santos, Complejo Hospitalario Arquitecto MarcideNovoa Santos, Ferrol, Spain; Cristina de las Heras, MD, Complejo Hospitalario Arquitecto Marcide-Novoa Santos, Ferrol, Spain; Daniel Gonzalez-Vilas, MD, Complejo Hospitalario Arquitecto Marcide-Novoa Santos, Ferrol, Spain; Oscar Suarez-Amor, MD, Complejo Hospitalario Arquitecto Marcide-Novoa Santos, Ferrol, Spain Background: The transcription factor gene p63 is a key regulator of ectodermal, orofacial, and limb development. Mutations in this gene are associated with different combinations of ectodermal dysplasia (ED), orofacial clefting, and limb malformations, which are the hallmark of p63-associated syndromes. The p63 protein might also play a role in tumor suppression.
Transgrediens lesions in patients with pachyonychia congenita KaLynne Harris, MD, University of Utah Department of Dermatology, Salt Lake City, UT, United States; C. David Hansen, MD, University of Utah Department of Dermatology, Salt Lake City, UT, United States; Sancy Leachman, MD, PhD, University of Utah Department of Dermatology, Salt Lake City, UT, United States; Frances Smith Irwin McLean, PhD, Epithelial Genetics Group, Division of Molecular Medicine, University of Dundee, Dundee, United Kingdom; Jack Arbiser, MD, PhD, Department of Dermatology, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Atlanta, GA, United States; Peter Hull, MBBCh, PhD, Department of Dermatology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Background: Pachyonychia congenita (PC) is a rare, autosomal dominant negative keratin disorder. PC manifests commonly with nail dystrophy and focal nontransgrediens plantar keratoderma. We present seven cases of PC patients from the International Pachyonychia Congenita Research Registry with transgrediens involvement of the dorsal surfaces of the feet, a nonclassical finding.
Discussion: The combination of ectodermal dysplasia (ED) and clefting characterizes the p63 syndromes, which include the ankyloblepharon-ectodermal defectscleft lip and palate syndrome (AEC), the ectrodactyly-ectodermal dysplasia-cleft lip and palate) syndrome (EEC, the Rapp-Hodgkin syndrome (RHS), and the limbmammary syndrome (LMS). Mutations in p63 gene are also responsible of split-hand and split-foot malformation (SHFM; isolated ectrodactyly) and acro-dermatounguallacrimal-tooh (ADULT) syndrome. There is considerable overlap between all these syndromes, suggesting that they are variable manifestations of the same clinical entity. In our case, the patient’s mother carried the same mutation with no clinical expression, probably because other genetic factors are necessary to develop the phenotypic manifestations of the disorder. Interestingly, an uncle of the mother suffered from syndactyly since birth. Syndactyly has also been reported in association with mutations of the p63 gene. This case emphasizes the spectrum of different phenotypic manifestations of mutations in the p63 gene and underlines the possible role of this gene as a tumor supressor.
Methods: Telephone surveys were conducted asking about the quality, duration, and treatment of transgrediens lesions. Results: Patients ranged in age from 14 to 67 years. Six patients had KRT6A mutations and one had a KRT16 mutation. In all but one case, the transgrediens lesions occurred after plantar lesions. Patients frequently reported that extended time standing, wearing shoes, foot moisture, and infection exacerbated transgrediens lesions. Multiple patients reported that antibiotics improved transgrediens lesions. In three cases, regular topical antimicrobial regimens correlated with marked improvement of transgrediens lesions. Two of the three patients using prophylactic antimicrobial regimens used gentian violent. Conclusion: We do not understand the cause(s) of transgrediens foot involvement in PC. Certain keratin mutations may predispose patients to involvement of the dorsal surface of the feet. PC plantar keratoderma is known to be exacerbated by trauma, and our patients also reported that trauma and skin friction exacerbated transgrediens lesions. ‘‘Infection’’ was frequently reported as causing or exacerbating transgrediens foot lesions. Whether the infection is an inciting event or secondary process cannot be determined based on this limited series. It is possible that infection may traumatize the skin and lead to increased mutant keratin expression. It is also possible what patients and clinicians label as infection may represent noninfectious inflammation or chronic microbial colonization. Antimicrobial regimens likely have antiinflammatory effects as well. It can be difficult to determine what is a ‘‘normal’’ manifestation of PC and what is a secondary process. This series highlights that some PC patients who develop transgrediens lesions may benefit from yeast and bacterial cultures, followed by appropriate antimicrobial treatments. Prophylactic antimicrobial and/or antiinflammatory regimens, such as gentian violet, may decrease transgrediens PC involvement. Efforts to decrease skin friction and moisture are also likely to improve and/or prevent transgrediens spread.
Commercial support: None identified.
Commercial support: None identified.
Case report: We report a 7-year-old boy with a medical history of B-cell lymphoma who also had dysmorphic features including cleft palate, hypotrichosis with trichorrhexis nudosa, hypohidrosis, oligodontia, and ridging of nails. He also presented a variegate pigmentation involving the axillae and proximal areas of the arms, and mild atopic dermatitis with keratosis pilaris. A heterozygous germline mutation, Ala111Thr, in the p63 gene was detected, and also in his mother, who had no phenotypic expression. However, an uncle of the mother suffered from syndactyly since birth.
AB84
J AM ACAD DERMATOL
FEBRUARY 2011
P2004
Extending the phenotypic spectrum of keratitis-ichthyosis-deafness syndrome: Report of a patient with GJB2 (g12R) connexin 26 mutation and unusual clinical findings Tamara Lazic, MD, Roger Williams Medical Center/Boston University School of Medicine, Providence, RI, United States; Jouni Uitto, MD, PhD, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States; Linda Zhou, MD, Roger Williams Medical Center/Boston University School of Medicine, Providence, RI, United States; Michael Frank, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States; Qiaoli Li, PhD, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States Keratitis-ichthyosis-deafness (KID) syndrome is a rare ectodermal dysplasia that is characterized by the presence of skin lesions, neurosensory hearing loss, and vascularizing keratitis. Additional features included in the diagnostic criteria of KID syndrome include erythrokeratodermic plaques, palmoplantar hyperkeratosis, alopecia, nail dystrophy, dental abnormalities, increased susceptibility to mucocutaneous infections, and an increased risk of squamous cell carcinoma. Most mutations that have so far been discovered as a cause KID syndrome are autosomal dominant, found in exon 2 of the connexin (Cx) 26 gene. One of the described mutations, G12R (p.Gly12Arg), is a GJB2 mutation reported in only two patients with KID syndrome to date. In our report, we describe a patient with the G12R mutation and KID syndrome with interesting additional features, including a porokeratotic eccrine ostial and dermal duct nevus (PEODDN), follicular occlusion triad, and unusual persistent oral mucosal papules. To our knowledge, this is the first patient found to have an association of KID syndrome and PEODDN. Furthermore, we compare and contrast this patient’s phenotype to the only two other patients described with the same (G12R) mutation. To date, follicular occlusion triad has been reported in association with KID syndrome in two cases, with distinct Cx 26 mutations. Our case is the first reported case to our knowledge of a G12R mutation causing the above mentioned association. In all three patients with the G12R mutation, some form of acneiform lesions is present, whether it is follicular occlusion triad (as seen in our patient), or isolated severe nodulocystic acne (as seen in the other two patients with the same mutation). This leads us to speculate that the patients harboring this particular mutation might be at an increased risk for cystic acne or hidradenitis suppurativa.
Recessive dystrophic epidermolysis bullosa with squamous cell carcinoma M. H. Kim, Department of Dermatology, St. George Hospital, Kogarah, Australia; D. F. Murrell, MD, MBChB, Department of Dermatology, St. George Hospital, Kogarah, Australia; L. R. A. Intong, MD, Department of Dermatology, St. George Hospital, Kogarah, Australia; Y. C. Kho, MBBS, Department of Dermatology, St. George Hospital, Kogarah, Australia Background: Epidermolysis bullosa (EB) is a rare group of genodermatoses defined by fragile skin, recurrent blistering, erosions of the skin and mucous membrane, and impaired wound healing. Recessive dystrophic epidermolysis bullosa (RDEB) carries a very high risk of developing squamous cell carcinoma (SCC). At present, no epidemiologic or clinical data have been published documenting RDEB-SCC cases in Australia. This retrospective study reports characterization of SCC and SCC-related cumulative risks amongst individuals with RDEB in the Australasian EB cohort. Methods: Individuals with RDEB who had previously developed SCC according to the Australasian EB Registry (AEBR) participated in the study. Medical information on RDEBSCC cases were obtained by contacting relevant hospitals and clinics across Australia. Results: Thirty-seven individuals have RDEB, which accounts for 13% of the EB population in Australasian cohort. Thirteen (35%) of the RDEB individuals have developed at least one SCC, and medical records on 11 of them were accessible. A total number of 80 primary SCCs were observed from 11 RDEB-SCC cases (5 males; 6 females) with an average of eight SCCs per person. Ninety-four percent of the SCCs developed on the upper and lower extremities and 30% of the SCCs were multifocal SCCs. Eight out of 11 RDEB-SCC individuals (72.7%) eventually developed metastatic SCCs, with the most frequent metastatic site being the regional lymph nodes, followed by lungs and bones. The age range at first diagnosis of SCC was 16 to 39 years, with a median of 24 years. The time between the diagnosis of one SCC and the next primary SCC in each patient was 5 months (median), with the mode being 3 months. The majority of the tumors were well and moderately differentiated. The cumulative risk of SCC development by age 45 was 85% and the cumulative risk of death from SCC in RDEB individuals that develop SCC by age 45 was 60%. Approximately half of the RDEB individuals died from metastatic complications of SCC within 10 years of developing their first SCC, and 86% by 15 years.
The phenotypic heterogeneity of KID syndrome, inexplicable by our current understanding of these proteins, speaks to the complexity of the connexin system and its overlapping expression patterns in different tissues.
Conclusion: Given the highly aggressive nature of RDEB-SCC, its high frequency of development, and its high mortality rate, rigorous follow up of RDEB patients every 3 months starting from 12 years of age is imperative for early detection and successful SCC treatment to improve patient management and survivability. Furthermore, a pathologic report of well differentiated SCC does not match the aggressive behavior of these tumors.
Commercial support: None identified.
Commercial support: None identified.
P2005
P2003 Ectodermal dysplasia associated to B-cell lymphoma resulting from mutation of the p63 gene Miguel Cabanillas, MD, Complejo Hospitalario Arquitecto Marcide-Novoa Santos, Ferrol, Spain; Aquilina Ramırez-Santos, Complejo Hospitalario Arquitecto MarcideNovoa Santos, Ferrol, Spain; Cristina de las Heras, MD, Complejo Hospitalario Arquitecto Marcide-Novoa Santos, Ferrol, Spain; Daniel Gonzalez-Vilas, MD, Complejo Hospitalario Arquitecto Marcide-Novoa Santos, Ferrol, Spain; Oscar Suarez-Amor, MD, Complejo Hospitalario Arquitecto Marcide-Novoa Santos, Ferrol, Spain Background: The transcription factor gene p63 is a key regulator of ectodermal, orofacial, and limb development. Mutations in this gene are associated with different combinations of ectodermal dysplasia (ED), orofacial clefting, and limb malformations, which are the hallmark of p63-associated syndromes. The p63 protein might also play a role in tumor suppression.
Transgrediens lesions in patients with pachyonychia congenita KaLynne Harris, MD, University of Utah Department of Dermatology, Salt Lake City, UT, United States; C. David Hansen, MD, University of Utah Department of Dermatology, Salt Lake City, UT, United States; Sancy Leachman, MD, PhD, University of Utah Department of Dermatology, Salt Lake City, UT, United States; Frances Smith Irwin McLean, PhD, Epithelial Genetics Group, Division of Molecular Medicine, University of Dundee, Dundee, United Kingdom; Jack Arbiser, MD, PhD, Department of Dermatology, Emory University School of Medicine, Atlanta Veterans Administration Medical Center, Atlanta, GA, United States; Peter Hull, MBBCh, PhD, Department of Dermatology, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan, Canada Background: Pachyonychia congenita (PC) is a rare, autosomal dominant negative keratin disorder. PC manifests commonly with nail dystrophy and focal nontransgrediens plantar keratoderma. We present seven cases of PC patients from the International Pachyonychia Congenita Research Registry with transgrediens involvement of the dorsal surfaces of the feet, a nonclassical finding.
Discussion: The combination of ectodermal dysplasia (ED) and clefting characterizes the p63 syndromes, which include the ankyloblepharon-ectodermal defectscleft lip and palate syndrome (AEC), the ectrodactyly-ectodermal dysplasia-cleft lip and palate) syndrome (EEC, the Rapp-Hodgkin syndrome (RHS), and the limbmammary syndrome (LMS). Mutations in p63 gene are also responsible of split-hand and split-foot malformation (SHFM; isolated ectrodactyly) and acro-dermatounguallacrimal-tooh (ADULT) syndrome. There is considerable overlap between all these syndromes, suggesting that they are variable manifestations of the same clinical entity. In our case, the patient’s mother carried the same mutation with no clinical expression, probably because other genetic factors are necessary to develop the phenotypic manifestations of the disorder. Interestingly, an uncle of the mother suffered from syndactyly since birth. Syndactyly has also been reported in association with mutations of the p63 gene. This case emphasizes the spectrum of different phenotypic manifestations of mutations in the p63 gene and underlines the possible role of this gene as a tumor supressor.
Methods: Telephone surveys were conducted asking about the quality, duration, and treatment of transgrediens lesions. Results: Patients ranged in age from 14 to 67 years. Six patients had KRT6A mutations and one had a KRT16 mutation. In all but one case, the transgrediens lesions occurred after plantar lesions. Patients frequently reported that extended time standing, wearing shoes, foot moisture, and infection exacerbated transgrediens lesions. Multiple patients reported that antibiotics improved transgrediens lesions. In three cases, regular topical antimicrobial regimens correlated with marked improvement of transgrediens lesions. Two of the three patients using prophylactic antimicrobial regimens used gentian violent. Conclusion: We do not understand the cause(s) of transgrediens foot involvement in PC. Certain keratin mutations may predispose patients to involvement of the dorsal surface of the feet. PC plantar keratoderma is known to be exacerbated by trauma, and our patients also reported that trauma and skin friction exacerbated transgrediens lesions. ‘‘Infection’’ was frequently reported as causing or exacerbating transgrediens foot lesions. Whether the infection is an inciting event or secondary process cannot be determined based on this limited series. It is possible that infection may traumatize the skin and lead to increased mutant keratin expression. It is also possible what patients and clinicians label as infection may represent noninfectious inflammation or chronic microbial colonization. Antimicrobial regimens likely have antiinflammatory effects as well. It can be difficult to determine what is a ‘‘normal’’ manifestation of PC and what is a secondary process. This series highlights that some PC patients who develop transgrediens lesions may benefit from yeast and bacterial cultures, followed by appropriate antimicrobial treatments. Prophylactic antimicrobial and/or antiinflammatory regimens, such as gentian violet, may decrease transgrediens PC involvement. Efforts to decrease skin friction and moisture are also likely to improve and/or prevent transgrediens spread.
Commercial support: None identified.
Commercial support: None identified.
Case report: We report a 7-year-old boy with a medical history of B-cell lymphoma who also had dysmorphic features including cleft palate, hypotrichosis with trichorrhexis nudosa, hypohidrosis, oligodontia, and ridging of nails. He also presented a variegate pigmentation involving the axillae and proximal areas of the arms, and mild atopic dermatitis with keratosis pilaris. A heterozygous germline mutation, Ala111Thr, in the p63 gene was detected, and also in his mother, who had no phenotypic expression. However, an uncle of the mother suffered from syndactyly since birth.
AB84
J AM ACAD DERMATOL
FEBRUARY 2011