Dermatologic findings in individuals with Turner syndrome: A cross-sectional study across the lifespan

To the Editor: Turner syndrome (TS) is a common sex-chromosome–associated condition defined by complete or partial loss of 1 X chromosome.1Lowenstein E.J. Kim K.H. Glick S.A. Turner's syndrome in dermatology.J Am Acad Dermatol. 2004; 50: 767-776https://doi.org/10.1016/j.jaad.2003.07.031Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Lymphedema, nail dysplasia, increased pigmented and halo nevi, and keloids have been previously reported in association with TS1Lowenstein E.J. Kim K.H. Glick S.A. Turner's syndrome in dermatology.J Am Acad Dermatol. 2004; 50: 767-776https://doi.org/10.1016/j.jaad.2003.07.031Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar; however, their frequencies have not been well defined. We sought to investigate cutaneous features associated with TS to better understand their prevalence and uncover possible karyotype-phenotype correlations.In this study, we summarized the cutaneous features of 236 patients with karyotype-confirmed TS from a TS-specific clinic with integrated dermatology care (Supplementary Fig 1, available via Mendeley at https://doi.org/10.17632/d5n6m8wghs.1.) A cross-sectional chart review of Massachusetts General Hospital Turner Syndrome Clinic patients was conducted from June 1, 2010 to December 31, 2019. Dermatologic findings were extracted primarily from dermatology notes, with consensus between 2 researchers. Fisher's exact tests were used to compare frequencies between patients with 45,X monosomy and those with pooled nonmonosomy karyotypes.Table I summarizes the characteristics and karyotypes of the 236 individuals (mean age: 26.7 years; adult: 71.6%; 45,X monosomy: n = 79, 33.5%). Table II presents the dermatologic findings, including prevalence data on acne (n = 7, 3.0%), atopic dermatitis (n = 43, 18.2%), psoriasis (n = 21, 8.9%), alopecia areata (n = 7, 3.0%), and vitiligo (n = 5, 2.1%). Increased or prominent melanocytic nevi was the most observed dermatologic feature (n = 168, 71.2%; halo: 2, 0.8%). Seventeen (7.2%) individuals had keloids (7 on the head or neck, 4 on the trunk, 3 on extremities, 3 multisite, 4 unknown).2Tucker M.A. Melanoma epidemiology.Hematol Oncol Clin North Am. 2009; 23: 383-395https://doi.org/10.1016/j.hoc.2009.03.010Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar The keloids occurred after cardiothoracic surgery (3/17); neck webbing reduction (3/17); upper extremity fracture repair (2/17); skin biopsy, excision, or grafting (6/17); or ear piercing (3/17). Nail changes were common (hyperconvex: n = 63, 26.3%; dysplastic: n = 46, 19.5%). Lymphedema was reported in 64 (27.1%) patients; symptomatic lymphedema was more prevalent in the 45,X monosomy group than in the nonmonosomy group (29.1% vs 12.1%, respectively, P < .01). No other dermatologic features significantly differed between these 2 karyotyping groups. The complete data stratified by karyotype and age are provided in Supplementary Material (available via Mendeley at https://doi.org/10.17632/d5n6m8wghs.1.)Table IClinical characteristics and karyotypes of study participantsClinical characteristicsN (%)45,X (%)Nonmonosomy (%)P value∗All P values represent the comparison of all 45,X individuals with all individuals with nonmonosomy.Total individuals (%)236 (100.0)79 (33.5)157 (66.5)Age, mean (y)†Age was calculated from the date of birth to the date of the end of clinical data collection on December 31, 2019.26.728.725.7.17 Median262726 Interquartile range222321.5 <1867 (28.4)22 (27.8)45 (28.7) ≥18169 (71.6)57 (72.2)112 (71.0)Lack of spontaneous breast development Yes137 (58.1)57 (72.2)80 (51.0)<.01Lack of spontaneous menarche Yes174 (73.7)71 (89.9)103 (65.6)<.01Growth failure Yes163 (69.1)61 (77.2)102 (65.0).07Hormone treatments GH130 (55.1)55 (69.6)75 (47.7)<.01 SHRT149 (63.1)57 (72.2)92 (58.6).04Bold text indicates statistically significant values (P < .05).GH, Growth hormone; SHRT, sex hormone replacement therapy.∗ All P values represent the comparison of all 45,X individuals with all individuals with nonmonosomy.† Age was calculated from the date of birth to the date of the end of clinical data collection on December 31, 2019. Open table in a new tab Table IIDermatologic findings in Massachusetts General Hospital Turner Syndrome Clinic cohort by karyotype groupDermatologic findingTotal (%, N = 236)45,X (%, N = 79)Nonmonosomy (%, N = 157)P value∗All P values represent the comparison of all 45, X individuals with all nonmonosomy individuals.Skin growths and neoplasms Benign growthsKeloid17 (7.2)4 (5.1)13 (8.3).44Angioma10 (4.2)1 (1.3)9 (5.7).17Seborrheic keratosis9 (3.8)3 (3.8)6 (3.8)1.00 NeviIncreased or prominent melanocytic nevi†In our retrospective chart review, we defined "increased" as having greater than approximately 50 nevi or having nevi that were documented as being too numerous to count. Our cutoff at approximately 50 nevi is consistent with melanoma epidemiology literature noting an increased lifetime risk of melanoma with more than 50 melanocytic nevi (https://www.aad.org/media/stats-melanoma). Nevi that were large (>5 mm in diameter) or "congenital-appearing" (eg, mamillated in texture with terminal hairs) were considered "prominent."168 (71.2)60 (75.9)128 (81.5).39Halo nevi2 (0.8)1 (1.3)1 (0.6)1.00Atypical or dysplastic nevi16 (6.8)8 (10.1)8 (5.1).17 Skin cancersBasal cell carcinoma5 (2.1)3 (3.8)2 (1.3).34Squamous cell carcinoma2 (0.8)2 (2.5)0 (0.0).11Malignant melanoma3 (1.3)1 (1.3)2 (1.3)1.00Infectious, inflammatory, and immune-mediated disorders Follicular disordersAcne vulgaris7 (3.0)3 (3.8)4 (2.5).69Bacterial folliculitis1 (0.4)1 (1.3)0 (0.0).33 Inflammatory disordersAtopic dermatitis43 (18.2)17 (21.5)26 (16.6).37Psoriasis vulgaris21 (8.9)7 (8.9)14 (8.9)1.00 Autoimmune disordersAlopecia areata7 (3.0)1 (1.3)6 (3.8).43Vitiligo5 (2.1)1 (1.3)4 (2.5).67Lichen sclerosis1 (0.4)0 (0.0)1 (0.6)1.00Bullous pemphigoid1 (0.4)1 (1.3)0 (0.0).33Other features and lymphedema Pigmented lesions and related conditionsCafé au lait macule22 (9.3)4 (5.1)18 (11.5).15Hypopigmented macule12 (5.1)4 (5.1)8 (5.1)1.00Pigmentary mosaicism3 (1.3)0 (0.0)3 (1.9).55 Ectodermal disordersHyperconvex nails62 (26.3)24 (30.4)38 (24.2).35Dystrophic nails46 (19.5)20 (25.3)26 (16.6).12Hirsutism9 (3.8)2 (2.5)7 (4.5).72Hypohidrosis1 (0.4)1 (1.3)0 (0.0).33 LymphedemaYes, ongoing symptoms42 (17.8)23 (29.1)19 (12.1)<.01‡The Fisher's exact test was performed as a binary categorical comparison for "Yes, ongoing symptoms" or any other response in each group. Unknown data were excluded.Yes, resolved symptoms13 (5.5)10 (12.7)3 (1.9)Yes, asymptomatic9 (3.8)3 (3.8)6 (3.8)No165 (69.9)41 (51.9)124 (79.0)<.01§The Fisher's exact test was performed as a binary categorical comparison for "No" or any other response in each group. Unknown data were excluded.Unknown7 (3.0)2 (2.5)5 (3.2)Bold text indicates statistically significant values (P < .05).∗ All P values represent the comparison of all 45, X individuals with all nonmonosomy individuals.† In our retrospective chart review, we defined "increased" as having greater than approximately 50 nevi or having nevi that were documented as being too numerous to count. Our cutoff at approximately 50 nevi is consistent with melanoma epidemiology literature noting an increased lifetime risk of melanoma with more than 50 melanocytic nevi (https://www.aad.org/media/stats-melanoma). Nevi that were large (>5 mm in diameter) or "congenital-appearing" (eg, mamillated in texture with terminal hairs) were considered "prominent."‡ The Fisher's exact test was performed as a binary categorical comparison for "Yes, ongoing symptoms" or any other response in each group. Unknown data were excluded.§ The Fisher's exact test was performed as a binary categorical comparison for "No" or any other response in each group. Unknown data were excluded. Open table in a new tab Acne vulgaris is known to be less common among individuals with TS partially because of decreased sebum production, consistent with our data showing acne vulgaris in only 7 individuals.3Brazzelli V. Calcaterra V. Muzio F. Klersy C. Larizza D. Borroni G. Reduced sebum production in Turner syndrome: a study of twenty-two patients.Int J Immunopathol Pharmacol. 2011; 24: 789-792https://doi.org/10.1177/039463201102400325Crossref PubMed Scopus (6) Google Scholar Our finding of psoriasis in 8.9% of the individuals corroborates prior work reporting a 2.25-fold increase in the prevalence of psoriasis in individuals with TS, compared with a 1%-3% estimated prevalence in the general population.4Gravholt C.H. Juul S. Naeraa R.W. Hansen J. Morbidity in Turner syndrome.J Clin Epidemiol. 1998; 51: 147-158https://doi.org/10.1016/s0895-4356(97)00237-0Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar We also noted that the study individuals often presented with guttate psoriasis rather than with classic plaques (Supplementary Fig 1, E).The association of TS with T-cell–driven immune-mediated or autoimmune disease (eg, psoriasis, alopecia areata, and vitiligo) has been described, occurring in nearly one quarter of previous cohorts.5Gawlik A.M. Berdej-Szczot E. Blat D. et al.Immunological profile and predisposition to autoimmunity in girls with turner syndrome.Front Endocrinol (Lausanne). 2018; 9: 307https://doi.org/10.3389/fendo.2018.00307Crossref PubMed Scopus (19) Google Scholar This phenomenon can be likely explained by X chromosome gene haploinsufficiency as well as downstream increase in CD8+ T cells and decrease in regulatory T cells.5Gawlik A.M. Berdej-Szczot E. Blat D. et al.Immunological profile and predisposition to autoimmunity in girls with turner syndrome.Front Endocrinol (Lausanne). 2018; 9: 307https://doi.org/10.3389/fendo.2018.00307Crossref PubMed Scopus (19) Google Scholar The increased or prominent melanocytic nevi may be partially explained by exogenous estrogen acting on melanocyte-expressed estrogen receptors.1Lowenstein E.J. Kim K.H. Glick S.A. Turner's syndrome in dermatology.J Am Acad Dermatol. 2004; 50: 767-776https://doi.org/10.1016/j.jaad.2003.07.031Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Although melanocytic nevi occur frequently in patients with TS and the risk of skin malignancy in patients with TS has not been well established, decisions to perform biopsy must be balanced with the risk of keloids. Finally, we sampled no pilomatricomas despite their debated-upon association with TS.1Lowenstein E.J. Kim K.H. Glick S.A. Turner's syndrome in dermatology.J Am Acad Dermatol. 2004; 50: 767-776https://doi.org/10.1016/j.jaad.2003.07.031Abstract Full Text Full Text PDF PubMed Scopus (77) Google ScholarThe study limitations include our retrospective single-center design and the limited number of individuals to power karyotype-phenotype correlation. We hope that this work substantiates the previous findings of smaller studies, advocating for the integration of dermatologic care for TS patients. To the Editor: Turner syndrome (TS) is a common sex-chromosome–associated condition defined by complete or partial loss of 1 X chromosome.1Lowenstein E.J. Kim K.H. Glick S.A. Turner's syndrome in dermatology.J Am Acad Dermatol. 2004; 50: 767-776https://doi.org/10.1016/j.jaad.2003.07.031Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Lymphedema, nail dysplasia, increased pigmented and halo nevi, and keloids have been previously reported in association with TS1Lowenstein E.J. Kim K.H. Glick S.A. Turner's syndrome in dermatology.J Am Acad Dermatol. 2004; 50: 767-776https://doi.org/10.1016/j.jaad.2003.07.031Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar; however, their frequencies have not been well defined. We sought to investigate cutaneous features associated with TS to better understand their prevalence and uncover possible karyotype-phenotype correlations. In this study, we summarized the cutaneous features of 236 patients with karyotype-confirmed TS from a TS-specific clinic with integrated dermatology care (Supplementary Fig 1, available via Mendeley at https://doi.org/10.17632/d5n6m8wghs.1.) A cross-sectional chart review of Massachusetts General Hospital Turner Syndrome Clinic patients was conducted from June 1, 2010 to December 31, 2019. Dermatologic findings were extracted primarily from dermatology notes, with consensus between 2 researchers. Fisher's exact tests were used to compare frequencies between patients with 45,X monosomy and those with pooled nonmonosomy karyotypes. Table I summarizes the characteristics and karyotypes of the 236 individuals (mean age: 26.7 years; adult: 71.6%; 45,X monosomy: n = 79, 33.5%). Table II presents the dermatologic findings, including prevalence data on acne (n = 7, 3.0%), atopic dermatitis (n = 43, 18.2%), psoriasis (n = 21, 8.9%), alopecia areata (n = 7, 3.0%), and vitiligo (n = 5, 2.1%). Increased or prominent melanocytic nevi was the most observed dermatologic feature (n = 168, 71.2%; halo: 2, 0.8%). Seventeen (7.2%) individuals had keloids (7 on the head or neck, 4 on the trunk, 3 on extremities, 3 multisite, 4 unknown).2Tucker M.A. Melanoma epidemiology.Hematol Oncol Clin North Am. 2009; 23: 383-395https://doi.org/10.1016/j.hoc.2009.03.010Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar The keloids occurred after cardiothoracic surgery (3/17); neck webbing reduction (3/17); upper extremity fracture repair (2/17); skin biopsy, excision, or grafting (6/17); or ear piercing (3/17). Nail changes were common (hyperconvex: n = 63, 26.3%; dysplastic: n = 46, 19.5%). Lymphedema was reported in 64 (27.1%) patients; symptomatic lymphedema was more prevalent in the 45,X monosomy group than in the nonmonosomy group (29.1% vs 12.1%, respectively, P < .01). No other dermatologic features significantly differed between these 2 karyotyping groups. The complete data stratified by karyotype and age are provided in Supplementary Material (available via Mendeley at https://doi.org/10.17632/d5n6m8wghs.1.) Bold text indicates statistically significant values (P < .05). GH, Growth hormone; SHRT, sex hormone replacement therapy. Bold text indicates statistically significant values (P < .05). Acne vulgaris is known to be less common among individuals with TS partially because of decreased sebum production, consistent with our data showing acne vulgaris in only 7 individuals.3Brazzelli V. Calcaterra V. Muzio F. Klersy C. Larizza D. Borroni G. Reduced sebum production in Turner syndrome: a study of twenty-two patients.Int J Immunopathol Pharmacol. 2011; 24: 789-792https://doi.org/10.1177/039463201102400325Crossref PubMed Scopus (6) Google Scholar Our finding of psoriasis in 8.9% of the individuals corroborates prior work reporting a 2.25-fold increase in the prevalence of psoriasis in individuals with TS, compared with a 1%-3% estimated prevalence in the general population.4Gravholt C.H. Juul S. Naeraa R.W. Hansen J. Morbidity in Turner syndrome.J Clin Epidemiol. 1998; 51: 147-158https://doi.org/10.1016/s0895-4356(97)00237-0Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar We also noted that the study individuals often presented with guttate psoriasis rather than with classic plaques (Supplementary Fig 1, E). The association of TS with T-cell–driven immune-mediated or autoimmune disease (eg, psoriasis, alopecia areata, and vitiligo) has been described, occurring in nearly one quarter of previous cohorts.5Gawlik A.M. Berdej-Szczot E. Blat D. et al.Immunological profile and predisposition to autoimmunity in girls with turner syndrome.Front Endocrinol (Lausanne). 2018; 9: 307https://doi.org/10.3389/fendo.2018.00307Crossref PubMed Scopus (19) Google Scholar This phenomenon can be likely explained by X chromosome gene haploinsufficiency as well as downstream increase in CD8+ T cells and decrease in regulatory T cells.5Gawlik A.M. Berdej-Szczot E. Blat D. et al.Immunological profile and predisposition to autoimmunity in girls with turner syndrome.Front Endocrinol (Lausanne). 2018; 9: 307https://doi.org/10.3389/fendo.2018.00307Crossref PubMed Scopus (19) Google Scholar The increased or prominent melanocytic nevi may be partially explained by exogenous estrogen acting on melanocyte-expressed estrogen receptors.1Lowenstein E.J. Kim K.H. Glick S.A. Turner's syndrome in dermatology.J Am Acad Dermatol. 2004; 50: 767-776https://doi.org/10.1016/j.jaad.2003.07.031Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Although melanocytic nevi occur frequently in patients with TS and the risk of skin malignancy in patients with TS has not been well established, decisions to perform biopsy must be balanced with the risk of keloids. Finally, we sampled no pilomatricomas despite their debated-upon association with TS.1Lowenstein E.J. Kim K.H. Glick S.A. Turner's syndrome in dermatology.J Am Acad Dermatol. 2004; 50: 767-776https://doi.org/10.1016/j.jaad.2003.07.031Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar The study limitations include our retrospective single-center design and the limited number of individuals to power karyotype-phenotype correlation. We hope that this work substantiates the previous findings of smaller studies, advocating for the integration of dermatologic care for TS patients. None disclosed.