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Carcinoma de Células Escamosas , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias Cutáneas , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/tratamiento farmacológico , Humanos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacosRESUMEN
Importance: Darier disease (DD) is a rare genetic skin disorder caused by heterozygous variants in the ATP2A2 gene. Clinical manifestations include recurrent hyperkeratotic papules and plaques that occur mainly in seborrheic areas. Although some of the lesions wax and wane in response to environmental factors, others are severe and respond poorly to therapy. Objective: To investigate the molecular mechanism underlying the persistency of skin lesions in DD. Design, Setting, and Participants: In this case series, DNA was extracted from unaffected skin, transient and persistent lesional skin, and blood from 9 patients with DD. Genetic analysis was used using paired-whole exome sequencing of affected skin and blood or by deep sequencing of ATP2A2 of affected skin. Chromosomal microarray analysis was used to reveal copy number variants and loss of heterozygosity. All variants were validated by Sanger sequencing or restriction fragment length polymorphism. Interventions or Exposures: Paired whole-exome sequencing and deep sequencing of ATP2A2 gene from blood and skin samples isolated from persistent, transient lesions and unaffected skin in patients with DD. Main Outcomes and Measures: Germline and somatic genomic characteristics of persistent and transient cutaneous lesions in DD. Results: Of 9 patients with DD, all had heterozygous pathogenic germline variants in the ATP2A2 gene, 6 were female. Participant age ranged from 40 to 69 years on enrollment. All 11 persistent skin lesions were associated with second-hit somatic variants in the ATP2A2 gene. The somatic variants were classified as highly deleterious via combined annotation-dependent depletion (CADD) scores or affect splicing, and 3 of them had been previously described in patients with DD and acrokeratosis verruciformis of Hopf. Second-hit variants in the ATP2A2 gene were not identified in the transient lesions (n = 2) or the normal skin (n = 2). Conclusions and Relevance: In this study, persistent DD lesions were associated with the presence of second-hit somatic variants in the ATP2A2 gene. Identification of these second-hit variants offers valuable insight into the underlying mechanisms that contribute to the lasting nature of persistent DD lesions.
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Enfermedad de Darier , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Darier/genética , Enfermedad de Darier/diagnóstico , Enfermedad de Darier/patología , Variaciones en el Número de Copia de ADN , Secuenciación del Exoma , Secuenciación de Nucleótidos de Alto Rendimiento , Pérdida de Heterocigocidad , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Piel/patologíaRESUMEN
Background: Bullous pemphigoid (BP) is the most common autoimmune subepidermal bullous disease. Topical or systemic corticosteroids are often used as the first-line treatment. However, long-term corticosteroid use may lead to significant side effects. Therefore, various adjuvant immunosuppressant therapies are used as steroid-sparing agents, with accumulating reports of biological treatments for severely recalcitrant BP. Objective: To describe the clinical and immunological features of a series of patients with recalcitrant BP treated with immunobiological therapies. To assess the efficacy and safety of their therapies. Methods: Patients receiving biological treatment for BP from two centers were assessed. Here, we described the clinical, immunopathological, and immunofluorescence findings of adult patients with BP and analyzed the clinical response and adverse events associated with various biological therapies. Results: We identified nine eligible patients treated with rituximab (seven), omalizumab (three), or dupilumab (one). The mean age at diagnosis was 60.4 years, the average BP duration before biologic initiation was 1.9 years, and the average previous treatment failure was 2.11 therapies. The mean follow-up period from the first biological treatment to the last visit was 29.3 months. Satisfactory response, defined as clinical improvement, was achieved in 78% (7) of the patients, and total BP clearance was achieved in 55% (5) of the patients at the last follow-up visit. Additional rituximab courses improved the disease outcomes. No adverse events were reported. Conclusions: Efficient and safe novel therapies can be considered in recalcitrant steroid-dependent BP non-responsive to conventional immunosuppressant therapies.
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Penfigoide Ampolloso , Enfermedades Cutáneas Vesiculoampollosas , Adulto , Humanos , Rituximab/uso terapéutico , Inmunosupresores/uso terapéutico , Omalizumab/uso terapéutico , Enfermedades Cutáneas Vesiculoampollosas/tratamiento farmacológicoRESUMEN
Basaloid follicular hamartomas (BFH) are benign small basaloid skin tumors that can present as solitary or multiple lesions. Congenital BFH lesions arranged in a segmental distribution have been described, suggesting they derive from a somatic post-zygotic mutational event. Previously, BFH were described in Happle-Tinschert syndrome, which results from a post-zygotic SMO variant and is characterized by segmental BFH with variable involvement of the teeth, skeleton, and central nervous system. Here, we describe two patients with isolated segmental BFH and no systemic involvement. Paired whole exome sequencing of BFH and normal tissue revealed a pathogenic SMO c.1234 C>T, p.L412F variant restricted to BFH tissue. We characterized the proliferation index and expression of Hedgehog and Wnt/beta-catenin pathway related proteins in segmental BFH compared to sporadic basal cell carcinomas (BCCs) and found that segmental BFH had a lower proliferation index. Although segmental BFH expressed a similar level of Gli-1 compared to BCCs, levels of LEF-1 and SOX-9 expression in BFH were weaker for both and patchier for LEF-1. Our results show that a somatic SMO activating variant causes segmental BFH. Since these patients are prone to developing BCCs, differences in SOX9, LEF1, and Ki-67 expression can help distinguish between these two basaloid lesions.
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Carcinoma Basocelular , Hamartoma , Enfermedades de la Piel , Neoplasias Cutáneas , Humanos , Folículo Piloso/anomalías , Folículo Piloso/metabolismo , Folículo Piloso/patología , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/genética , Carcinoma Basocelular/metabolismo , Hamartoma/diagnóstico , Hamartoma/genética , Hamartoma/metabolismo , Enfermedades de la Piel/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Receptor Smoothened/genéticaRESUMEN
BACKGROUND: Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare skin disease characterized by pruritic erythematous scaly plaques distributed along the lines of Blaschko. Two cases of ILVEN with CARD14 mutations and one case with a GJA1 mutation have been previously reported. OBJECTIVE: To elucidate the genetic cause of a cohort of patients diagnosed based on clinical and histopathological evaluation with ILVEN. METHODS: We recruited patients diagnosed with ILVEN based on clinical and histopathological criteria. Exome sequencing of affected skin with or without blood/saliva was performed and germline and somatic pathogenic variants were identified. RESULTS: Five patients were enrolled. All had skin lesions from birth or early childhood. Two patients developed psoriasis vulgaris after the diagnosis of ILVEN. The first had a germline heterozygous CARD14 mutation and a post-zygotic hotspot mutation in KRT10. The histopathologic evaluation did not show epidermolytic hyperkeratosis. The second had a post-zygotic hotspot mutation in HRAS. Her ILVEN became itchy once psoriasis developed. One patient was re-diagnosed with linear porokeratosis based on a germline mutation in PMVK and a post-zygotic second-hit mutation. Two patients were re-diagnosed with congenital hemidysplasia with ichthyosiform nevus and limb defect nevus based on germline NSDHL mutations. CONCLUSION: ILVEN is a clinical descriptor for a heterogenous group of mosaic inflammatory disorders. Genetic analysis has the potential to more precisely categorize ILVEN and permits pathogenesis-directed therapies in some cases.
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Nevo Pigmentado , Nevo Sebáceo de Jadassohn , Nevo , Psoriasis , Enfermedades de la Piel , Neoplasias Cutáneas , Femenino , Humanos , Preescolar , Nevo Sebáceo de Jadassohn/diagnóstico , Nevo Sebáceo de Jadassohn/genética , Neoplasias Cutáneas/patología , Nevo/diagnóstico , Nevo/genética , Nevo/patología , Psoriasis/tratamiento farmacológico , Guanilato Ciclasa/uso terapéutico , Proteínas de la Membrana , Proteínas Adaptadoras de Señalización CARD , 3-Hidroxiesteroide DeshidrogenasasRESUMEN
[This corrects the article DOI: 10.1016/j.xhgg.2021.100028.].
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BACKGROUND: There is a paucity of data regarding demodicidosis-associated facial hyperpigmentation. OBJECTIVE: To delineate the clinical, dermoscopic, and histopathologic features of demodicidosis-associated facial hyperpigmentation. METHODS: Clinical and diagnostic data were collected from the medical files of patients who were referred to our outpatient dermatology clinic in 2006-2019 for evaluation of facial hyperpigmentation and were diagnosed with demodicidosis. RESULTS: The cohort included 19 patients (13 male) aged 42-76 years, all with Fitzpatrick skin type 3-4. All presented with mostly asymptomatic dusky, brown-gray, facial pigmentation, localized or diffuse with background erythema in 36.8% of cases, and skin roughness in 26.3%. Dermoscopy yielded characteristic findings of white gelatinous or opaque protrusions from hair follicles or infiltration of follicular openings with an amorphic material. A specific finding was perifollicular and reticulated pigmentation of the affected areas. Findings were confirmed on microscopic (n = 7) and histopathologic (n = 5) studies. Anti-demodectic treatment led to complete (73.6%) or partial (23.4%) resolution of pigmentation within 2 years. CONCLUSION: We describe unique clinicopathological and dermoscopic findings associated with an under-recognized type of facial hyperpigmentation caused by demodex for which we propose the term "pigmented demodicidosis." Demodicidosis should be added to the list of causes of facial hyperpigmentation.
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Dermoscopía , Hiperpigmentación , Diagnóstico Diferencial , Cara , Femenino , Folículo Piloso/patología , Humanos , Hiperpigmentación/diagnóstico , Hiperpigmentación/etiología , Hiperpigmentación/patología , MasculinoRESUMEN
The term "cavernous hemangioma" has been used to describe vascular anomalies with histology featuring dilated vascular spaces, vessel walls consisting mainly of fibrous stromal bands lined by a layer of flattened endothelial cells, and an irregular outer rim of interrupted smooth muscle cells. Hepatic hemangiomas (HHs) and cutaneous venous malformations (VMs) share this histologic pattern, and we examined lesions in both tissues to identify genetic drivers. Paired whole-exome sequencing (WES) of lesional tissue and normal liver in HH subjects revealed a recurrent GJA4 c.121G>T (p.Gly41Cys) somatic mutation in four of five unrelated individuals, and targeted sequencing in paired tissue from 9 additional HH individuals identified the same mutation in 8. In cutaneous lesions, paired targeted sequencing in 5 VMs and normal epidermis found the same GJA4 c.121G>T (p.Gly41Cys) somatic mutation in three. GJA4 encodes gap junction protein alpha 4, also called connexin 37 (Cx37), and the p.Gly41Cys mutation falls within the first transmembrane domain at a residue highly conserved among vertebrates. We interrogated the impact of the Cx37 mutant via lentiviral transduction of primary human endothelial cells. We found that the mutant induced changes in cell morphology and activated serum/glucocorticoid-regulated kinase 1 (SGK1), a serine/threonine kinase known to regulate cell proliferation and apoptosis, via non-canonical activation. Treatment with spironolactone, an inhibitor of angiogenesis, suppressed mutant SGK1 activation and reversed changes in cell morphology. These findings identify a recurrent somatic GJA4 c.121G>T mutation as a driver of hepatic and cutaneous VMs, revealing a new pathway for vascular anomalies, with spironolactone a potential pathogenesis-based therapy.
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BACKGROUND: Bullous pemphigoid commonly affects older adults and has a detrimental effect on both quality of life and longevity. Systemic corticosteroids, the mainstay of therapy, may cause significant adverse effects, especially in older patients. Therefore, safer therapeutic options are being sought. OBJECTIVE: The objective of this article was to systematically review the published evidence on the efficacy and safety of different treatment modalities for bullous pemphigoid in older patients. METHODS: We performed a systematic review of all publications until May 2020 in PubMed, Google Scholar, and the ongoing trials registry of the US National Institutes of Health databases evaluating the efficacy and safety of bullous pemphigoid treatments in patients aged older than 80 years. The primary outcome was complete response. The secondary outcomes were partial response, complete remission on minimal therapy or during tapering, recurrence, adverse events, and mortality. RESULTS: Twenty-eight publications were included: 2 randomized controlled trials, 5 prospective cohort studies, 10 retrospective cohort studies, and 11 case series, with a total of 153 older patients. The overall complete response rate was 31%. Topical corticosteroids had the highest complete response rate (55%) with a low side-effect profile. Biologics (omalizumab and rituximab) were effective in achieving complete remission on minimal therapy (29%) without recurrence, although rituximab was associated with a relatively high mortality rate (29%). CONCLUSIONS: Current data suggest that topical corticosteroids are effective and safe and should remain the first line of treatment for bullous pemphigoid in older adults. However, their application is difficult and requires a high-functioning patient, third-party assistance, or a relatively mild disease. Biological agents are effective but warrant meticulous patient selection owing to the relatively high mortality rate associated with rituximab. CLINICAL TRIAL REGISTRATION: PROSPERO registration number CRD42020186686.
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Penfigoide Ampolloso , Anciano , Humanos , Recurrencia Local de Neoplasia , Penfigoide Ampolloso/tratamiento farmacológico , Estudios Prospectivos , Calidad de Vida , Estudios Retrospectivos , Estados UnidosRESUMEN
Recent studies suggest that folliculotropic mycosis fungoides (FMF), the most common variant of mycosis fungoides (MF), presents with 2 distinct clinicopathological stages: early indolent stage and more aggressive advanced/tumour stage. To further characterize these stages, miR-155 expression was studied with qRT-PCR and found to be significantly higher in biopsies of tumour-stage FMF compared with early-stage FMF and inflammatory dermatoses. There was no statistically significant difference in miR-155 expression between early-stage FMF and early-stage MF, nor between tumour-stage FMF and tumour-stage MF. Immunohistochemical analysis revealed a significantly increased number of dermal Ki-67+ proliferating lymphocytes in tumour-stage FMF, together with an increased number of CD20+ B cells and CD68+ macrophages compared with early-stage FMF. Thus, similar to classic MF, miR-155, Ki-67 tumour cell immunoreactivity, and certain tumour-infiltrating inflammatory cells are differentially expressed in early- vs tumour-stage FMF. The results of this study corroborate the notion that FMF presents with 2 distinct stages.
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MicroARNs , Micosis Fungoide , Neoplasias Cutáneas , Biopsia , Humanos , Antígeno Ki-67 , MicroARNs/genética , Micosis Fungoide/genética , Neoplasias Cutáneas/genéticaRESUMEN
Basal cell carcinoma (BCC) is the most common human malignant neoplasm. However, there are multiple BCC subtypes that share clinical features while demanding different management. We present a case of a woman with hundreds of BCCs throughout her body that were resistant to vismodegib and without other features of basal cell nevus syndrome. Histological results of biopsies taken from various sites revealed three lesions characteristic of infundibulocystic BCCs (IBCCs) and two BCCs. Paired whole-exome sequencing performed using DNA isolated from blood and one of her IBCCs uncovered a germline heterozygous SUFU (Suppressor of Fused) mutation. The downstream location of SUFU in the hedgehog pathway explains why its mutation results in IBCCs that will not respond to any therapeutics that target upstream components of SUFU These results capture the significance of histological and genetic analysis in directing treatment.
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Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma Basocelular/genética , Resistencia a Antineoplásicos/genética , Síndrome de Hamartoma Múltiple/genética , Piridinas/uso terapéutico , Proteínas Represoras/genética , Anciano , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/patología , Femenino , Mutación de Línea Germinal , Síndrome de Hamartoma Múltiple/tratamiento farmacológico , Síndrome de Hamartoma Múltiple/patología , HumanosRESUMEN
BACKGROUND: Congenital smooth muscle hamartomas (CSMHs) are benign lesions that share clinical and histopathological features with Becker nevus, a mosaic disorder associated with post-zygotic ACTB mutations. Given the clinical and histopathological overlap between CSMH and Becker nevus, we hypothesized that post-zygotic mutations in ACTB may underlie CSMH. METHODS: Direct sequencing of ACTB gene in affected and unaffected tissue isolated from one case of hemihypertrichosis and hemihypertrophy corresponding to giant segmental CSMH and hemihypertrophy. This was followed by direct sequencing with and without enrichment assay for hotspot ACTB mutations in affected tissue from 12 samples of isolated CSMH from unrelated individuals. RESULTS: In total we identified somatic missense ACTB mutations in 9 out of 13 CSMHs (69%). Mutations were either novel or previously reported in Becker nevi and Becker nevus syndrome. CONCLUSIONS: CSMHs result from post-zygotic ACTB mutations. This study proves that CSMHs and Becker nevi are nosologically related, and expand the phenotypic spectrum of ACTB mutations.
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Actinas/genética , Hamartoma/congénito , Hamartoma/genética , Músculo Liso/patología , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Hamartoma/diagnóstico , Humanos , Hiperplasia/genética , Hiperplasia/patología , Hipertricosis/genética , Hipertricosis/patología , Lactante , Masculino , Mutación Missense/genética , Nevo/diagnóstico , Fenotipo , Neoplasias Cutáneas/diagnóstico , CigotoRESUMEN
BACKGROUND: Epidermolytic acanthoma (EA) is a rare acquired lesion demonstrating a characteristic histopathological pattern of epidermal degeneration referred to as epidermolytic hyperkeratosis (EHK). On histopathological analysis, EA appears nearly identical to inherited EHK-associated dermatoses such as epidermolytic ichthyosis and ichthyosis bullosa of Siemens. While it has been speculated that EA is caused by mutations in KRT10, KRT1, or KRT2 found in these inherited dermatoses, none have yet been identified. Herein, we aim to identify the contributions of keratin mutations to EA. METHODS: Using genomic DNA extracted from paraffin-embedded samples from departmental archives, we evaluated a discovery cohort using whole-exome sequencing (WES) and assessed remaining samples using Sanger sequencing screening and restriction fragment length polymorphism (RFLP) analysis. RESULTS: DNA from 16/20 cases in our sample was of sufficient quality for polymerase chain reaction amplification. WES of genomic DNA from lesional tissue revealed KRT10 c.466C > T, p.Arg156Cys mutations in 2/3 samples submitted for examination. RFLP analysis of these samples as well as eight additional samples confirmed the mutations identified via WES and identified four additional cases with Arg156 mutations. In sum, 6/11 screened cases showed hotspot mutation in KRT10. CONCLUSIONS: Hotspot mutations in the Arg156 position of KRT10, known to cause epidermolytic ichthyosis, also underlie EA.
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Acantoma/congénito , Hiperqueratosis Epidermolítica/genética , Queratina-10/genética , Neoplasias Cutáneas/patología , Acantoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genómica/métodos , Humanos , Hiperqueratosis Epidermolítica/patología , Ictiosis Ampollosa de Siemens/patología , Queratinas/genética , Masculino , Persona de Mediana Edad , Mutación , Secuenciación del Exoma/métodosRESUMEN
BACKGROUND: Porokeratosis is associated with mevalonate pathway gene mutations. Therapeutic options are few and often limited in efficacy. We hypothesized that topical therapy that aims to replenish cholesterol, an essential mevalonate pathway end-product, and block the accumulation of mevalonate pathway toxic metabolites could alleviate porokeratosis. OBJECTIVE: To study the efficacy of topical cholesterol/lovastatin in different variants of porokeratosis. METHODS: We enrolled a series of 5 porokeratosis patients,1 with disseminated superficial actinic porokeratosis, 2 with porokeratosis palmaris et plantaris disseminata, and 2 with linear porokeratosis. Patients were genotyped before initiation of therapy. Patients then applied topical cholesterol/lovastatin twice daily to a unilaterally defined treatment area for up to 3 months. The response was evaluated and patients photographed at every visit. RESULTS: Three patients had MVD mutations, and 2 patients had PMVK mutations. Treatment with topical cholesterol/lovastatin (but not cholesterol alone) resulted in near complete clearance of disseminated superficial actinic porokeratosis lesions after 4 weeks of therapy and moderate improvement of porokeratosis palmaris et plantaris disseminata lesions and linear porokeratosis lesions. There were no adverse events. LIMITATIONS: Case series design with a small number of patients. CONCLUSION: Topical cholesterol/lovastatin is an effective and well-tolerated therapy for porokeratosis that underscores the utility of a pathogenesis-based therapy that replaces deficient end products and prevents accumulation of potentially toxic precursors.
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Anticolesterolemiantes/administración & dosificación , Carboxiliasas/genética , Colesterol/administración & dosificación , Lovastatina/administración & dosificación , Poroqueratosis/tratamiento farmacológico , Poroqueratosis/genética , Administración Cutánea , Adulto , Preescolar , Combinación de Medicamentos , Genotipo , Humanos , Persona de Mediana Edad , Mutación , Pomadas , Fosfotransferasas (Aceptor del Grupo Fosfato)/genética , Adulto JovenRESUMEN
Familial and sporadic porokeratosis are associated with germline heterozygous mutations in mevalonate pathway genes. Kubo et al. show that each skin lesion of disseminated superficial actinic porokeratosis originates from a postnatal keratinocyte clone with a different second-hit genetic event in the wild-type allele of the corresponding gene. They also confirm that linear porokeratosis derives from a single prenatal clone of keratinocytes with a second-hit genetic event.
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Poroqueratosis , Heterocigoto , Humanos , Queratinocitos , Ácido Mevalónico , Recombinación GenéticaRESUMEN
Appearance of mosaic disorders in thin Blaschko lines suggests that somatic mutations in keratinocyte precursors underlie their pathogenesis. Germline heterozygous mutations in POFUT1 gene cause Dowling-Degos disease (DDD), a skin disease that features flexural reticulated hyperpigmentation and follicular-based lesions. POFUT1 mosaicism has not been described to date. Here, we describe a 9-year-old female with segmental hyper- and hypopigmented patches with overlying eczematous plaques and follicular papules. Employing paired whole exome sequencing of saliva and keratinocytes isolated from affected skin, we found a novel germline heterozygous POFUT1 deletion causing frameshift and premature codon termination and somatic copy-neutral loss of heterozygosity on chromosome 20 encompassing POFUT1. Expression levels of POFUT1 as well as other key regulators of the notch signaling pathway-NOTCH1, NOTCH2, and HES1-were reduced in affected keratinocytes compared with normal keratinocytes. Our findings provide the first evidence of POFUT1 postzygotic mutation and a phenotypic expansion of POFUT1 loss of function mutations. We show that a recessive loss of function mutation in POFUT1 produces a distinct clinical presentation with features (e.g., dermatitis) that are absent in the generalized form of DDD. This study demonstrates how analysis of mosaic disorders can reveal unexpected phenotypes for known genes.