A Case of Noonan Syndrome and Kyrle Disease: Casualty or Causality?

A 39-year-old Caucasian woman affected by Noonan Syndrome (NS) mutated in RAF1 was referred to us with itchy lesions on her limbs that had appeared two months earlier. Clinically, there were multiple umbilicated papules with a hyperkeratotic central plug, localized on the upper and lower limbs (Figure 1, a-b). The patient had no personal history of diabetes mellitus or chronic renal failure, but suffered from hypertrophic cardiomyopathy. Blood tests showed no abnormalities. On histological examination of a skin lesion, an ectatic hair follicle with a hyperkeratotic ostium was observed with fragments of hair, inflammatory cells, and epidermal perforation. A final diagnosis of Kyrle disease (KD) was established. The patient underwent narrowband UVB (NB-UVB) phototherapy with residual atrophic scars (Figure 1, c-d), but with a complete and long-lasting resolution of symptoms. KD belongs to perforating dermatoses (PD), a heterogeneous group of skin diseases characterized by the transepidermal elimination of dermal components. Despite the classification of PD still being under debate, four primary forms are traditionally recognized: reactive perforating collagenosis, elastosis perforans serpiginosum, perforating folliculitis, and KD (1). The typical skin manifestation of KD is an eruption of dome-shaped papules and nodules, with a whitish central keratotic plug, mainly localized on the extremities and the buttocks. Described by Kyrle in 1916, KD is frequently associated with systemic diseases, especially chronic renal failure and diabetes mellitus. Other associated conditions include chronic hepatic disease, internal malignancies, and congestive heart disease (1). Despite the absence of a consensus, the control of the underlying disease remains the first therapeutic target. Both topical (keratolytics, retinoids, and corticosteroids) and systemic treatments (corticosteroids, retinoids, antibiotics, and phototherapy) have been reported to control skin manifestations (2). In our experience, NB-UVB is an effective option as first-line therapy in case of diffuse lesions, both in KD and in other PD (3). NS is a relatively common RASopathy, a heterogenous group of genetic diseases characterized by a defect of the Ras-mitogen-activated protein kinase (Ras-MAPK) pathway, with an estimated prevalence of 1/1000-2500. PTPN11 is the most frequent mutated gene, accounting for 50% of cases, but more than ten genes have been identified as causing NS (4). Classical features include a distinctive facial dysmorphism, short stature, pulmonic stenosis, and other anomalies of different organs. The skin is commonly involved. Keratinization disorders and hair abnormalities such as keratosis pilaris, ulerythema ophryogenes, wavy or curly hair, and scarce scalp hair, are often described. Other cutaneous signs include easy bruising, skin hyperlaxity, multiple lentigines, and café-au-lait spots (5). To the best of our knowledge, no cases of KD in patients with NS have been previously reported to date. The exact etiopathogenesis of KD is not clear, but it has been hypothesized that systemic diseases, such as diabetes and chronic renal failure, can cause a deposit of substances or dermis alterations, which triggers the inflammatory process with subsequent transepidermal extrusion (1). In our patient, we ruled out all the causes commonly associated with KD. It is however possible that this manifestation could be a direct result of the patient's illness. Our patient suffered from diffuse keratosis pilaris, and an abnormal epidermal keratinization with a secondary inflammatory dermic response is among the suggested possible pathogenetic mechanisms of KD (1). On the other hand, the hyperlaxity and fragility of the skin typical of NS suggest the presence of altered connective tissue, which could trigger an abnormal keratinization and, subsequently, the transepidermal extrusion, as well as perforating elastosis, which is associated with genetic connective tissue diseases (1). Moreover, our patient suffered from a cardiac disease, another condition associated with KD (5). Although these explanations have their appeal, there is currently insufficient evidence of a link between KD and NS, and it will be necessary to collect additional data to confirm this hypothesis.

Management of patients with atopic dermatitis undergoing systemic therapy during COVID-19 pandemic in Italy: Data from the DA-COVID-19 registry.

BACKGROUND: Few and small studies have described the management of immunomodulant/immunosuppressive therapies or phototherapy in atopic dermatitis (AD) patients during coronavirus disease 2019 (COVID-19) pandemic. METHODS: A national registry, named DA-COVID-19 and involving 35 Italian dermatology units, was established in order to evaluate the impact of COVID-19 pandemic on the management of adult AD patients treated with systemic immunomodulant/immunosuppressive medications or phototherapy. Demographic and clinical data were obtained at different timepoints by teledermatology during COVID-19 pandemic, when regular visits were not allowed due to sanitary restrictions. Disease severity was assessed by both physician- and patient-reported assessment scores evaluating itch intensity, sleep disturbances, and AD severity. RESULTS: A total of 1831 patients were included, with 1580/1831 (86.3%) continuing therapy during pandemic. Most patients were treated with dupilumab (86.1%, 1576/1831) that was interrupted in only 9.9% (156/1576) of cases, while systemic immunosuppressive compounds were more frequently withdrawn. Treatment interruption was due to decision of the patient, general practitioner, or dermatologist in 39.9% (114/286), 5.6% (16/286), and 30.1% (86/286) of cases, respectively. Fear of increased susceptibility to SARS-CoV-2 infection (24.8%, 71/286) was one of the main causes of interruption. Sixteen patients (0.9%) resulted positive to SARS-CoV-2 infection; 3 of them (0.2%) were hospitalized but no cases of COVID-related death occurred. CONCLUSIONS: Most AD patients continued systemic treatments during COVID pandemic and lockdown period, without high impact on disease control, particularly dupilumab-treated patients.

Characteristic of chronic plaque psoriasis patients treated with biologics in Italy during the COVID-19 Pandemic: Risk analysis from the PSO-BIO-COVID observational study.

Background: The susceptibility of patients with chronic plaque psoriasis and the risks or benefits related to the use of biological therapies for COVID-19 are unknown. Few data about prevalence, clinical course and outcomes of COVID-19 among psoriatic patients were reported. The aims of this study were 1) to assess the prevalence and severity of COVID-19 in psoriatic patients treated with biologic agents during the first phase of the emergency (22 February to 22 April 2020) in Italy, and 2) to report the clinical outcomes of patients who have been exposed to individuals with confirmed SARS-CoV-2 infection. Methods: Patients with moderate-to-severe chronic plaque psoriasis, aged ≥18 years and undergoing treatment with biologic agents as of 22 February 2020, were eligible to be included in PSO-BIO-COVID study. Demographic and clinical characteristics of patients using any biologic for psoriasis treatment between 22 February and 22 April 2020 were registered. Results: A total of 12,807 psoriatic patients were included in the PSO-BIO-COVID study. In this cohort 26 patients (0.2%) had a swab confirmation of SARS-CoV-2 infection. Eleven patients required hospitalization and two died. Conclusion: The incidence of COVID-19 observed in our cohort of psoriatic patients (0.2%) is similar to that seen in the general population (0.31%) in Italy. However, the course of the disease was mild in most patients. Biological therapies may likely lessen 'cytokine storm' of COVID-19, which sometimes lead to multiple organ failure, ARDS, and death.

The Effectiveness of Narrow Band Uvb (Nb-Uvb) In the Treatment of Pityriasis Lichenoides Chronica (PLC) In Vietnam.

AIM: This prospective clinical study presents the experiences with NB-UVB monotherapy in the treatment of PLC on Vietnamese patients. METHODS: We enrolled at National Hospital of Dermatology and Venereology (NHDV), Vietnam, 29 PLC patients with generalised disease involving at least 60% of the total body surface (based on Nine's Rule) and/or failed to respond to other modalities of treatment. Patients were treated with NB-UVB followed the guideline of the psoriatic treatment of AAD-2010, three times weekly. RESULTS: A complete response (CR) was seen in 24 out of 29 PLC patients (82.8%) with a mean cumulative dose of 9760.5 mJ/cm2 after a mean treatment period of 4.6 weeks (13.8 ± 7.4 exposures). Mild side effects were observed: 69% erythema minimum, 55.2% irritation related to dry skin. No severe side effects were seen during the study. No relapses occurred in 24 CR patients within a mean period of 3 months after the last treatment. CONCLUSION: NB-UVB therapy is an effective and safe option for the treatment and management of PLC.

Efficacy of Narrow - Band UVB Phototherapy versus PUVA Chemophototherapy for Psoriasis in Vietnamese Patients.

BACKGROUND: Psoralen UVA (PUVA) and narrow-band UVB (NBUVB) chemophototherapy are treatment options for psoriasis. AIM: To compare the effectiveness of NBUVB with PUVA in Vietnamese psoriasis patients. METHODS: We conducted a non-randomized trial on 60 patients with plaque-type psoriasis (30 NBUVB, 30 PUVA). Both regimens were thrice-weekly. The extent of lesion was assessed by the Psoriasis Area Severity Index (PASI). Clearance was defined as a ≥ 75% reduction in a follow-up PASI score from baseline. Patients with clearance were followed-up until 6 months after stopping treatment. Relapse was defined as 50% or more of the original extent. RESULTS: The proportion of patients achieving PASI75 was comparable (76.7% in NBUVB versus 80% in PUVA; p > 0.05). Patients in both groups had a similar number of sessions to achieve clearance but patients in the PUVA group exposed to a significantly higher cumulative UV dose. After six months, the relapse rate was higher in the NBUVB group compared with in the PUVA group (p > 0.05). CONCLUSION: Thrice weekly NBUVB is as effective as thrice weekly PUVA in treating psoriasis for Vietnamese patients.

The Decline of PUVA Therapy in Vietnam: Effective Treatment of Narrow Band UVB in Vietnamese Vitiligo Patients.

AIM: To examine the efficacy and safety of Narrowband ultraviolet B (NB-UVB) in Vietnamese vitiligo patients. METHODS: We recruited thirty-one patients (14 males, 17 females), aged from 7 to 67 years, with both segmental vitiligo (SV) and non-segmental vitiligo (NSV), treated three times weekly with NB-UVB. The starting dose for adults from 15 years old and children less than 15 years old was 200 mJ/cm2 and 150 mJ/cm2, respectively, with 50 mJ/cm2 and 20 mJ/cm2 dose increments at each subsequent visit, respectively, until mild erythema lasting less than 24 hrs reported by patient, given for a period of 6 months. Response to therapy was assessed based on VASI score changes. RESULTS: Based upon our results, 38.7% (12/31) of patients achieved a very good response of more than 50% VASI changes, 41.9% (13/31) obtained a good response (VASI changed from 25 to 50%). Total good and very good response to therapy significantly increased with prolonged treatment, increasing from 19.4% to 64.5% and 80.6% after 2, 4 and 6 months, respectively. Localised NSV patients obtained good and very good response significantly more frequently than generalised NSV (55.6% versus 18.2%). Adverse effects were minimal, of which one case developed herpes simplex, and 4 cases reported mild photo burn reaction which completely disappeared after adjusting the dose. CONCLUSION: NB-UVB therapy is an effective and safe tool in the management of Vietnamese vitiligo patients.

Successful Treatment of Vitiligo Vietnamese Patients with Vitilinex® Herbal Bio-Actives in Combination with Phototherapy.

BACKGROUND: Vitiligo is an acquired pigmentary disease, that causes progressive loss of melanocytes, resulting in hypopigmented skin patches. Current treatments aim at stopping the disease progression and achieving repigmentation of the amelanotic areas. Corticosteroids, surgery, topical immunomodulators, total depigmentation of normal pigmented skin and phototherapy are current treatment options for vitiligo although phototherapy remains the treatment of choice. There is no documented evidence that herbal bio-active products may also be effective treatment options for vitiligo. AIM: This study aimed to investigate the efficacy and safety of Vitilinex® (herbal bio- actives) alone and in combination with UVB narrowband (311 nm) phototherapy, in the treatment of localised stable or active forms of vitiligo. MATERIAL AND METHODS: Sixty two subjects with mean age 34.5 years (range: 18-58 years) with mild to moderate vitiligo, consisting of 36 females and 26 males were randomly divided into three treatment groups - Group A (13 females, 10 males) treated with Vitilinex® alone; Group B (12 females, 11 males) were treated with Vitilinex® in combination with narrowband UVB (311 nm) phototherapy for 15 seconds, using a handheld lamp and Group C (8 females, 8 males) were treated with nbUVB (311 nm) phototherapy alone, for 15 seconds over a 12-week period. RESULTS: In Group A, 9 patients (39%) achieved outstanding improvement with a re-pigmentation rate higher than 75%, with 2 patients experiencing total repigmentation. 6 patients (26%) had marked improvement with a repigmentation rate between 50-75% while 5 patients (22%) showed a moderate response between 25-50% re-pigmentation rate. 3 patients (13%) had minimal or no improvement. In Group B, 16 patients (69.5%) achieved outstanding improvement with a re-pigmentation rate higher than 75%, with 12 patients experiencing total re-pigmentation. 4 patients (17.5 %) achieved a marked improvement with a re-pigmentation rate between 50-75%; 2 patients (8.7%) showed a moderate response with a re-pigmentation rate between 25-50%. 1 (4.3%) patient had minimal or no improvement. In Group C, 6 patients (37.5%) achieved a re-pigmentation rate higher than 75%, with 2 patients experiencing total re-pigmentation. 4 patients (25%) achieved marked improvement with a re-pigmentation rate between 50-75% while 3 patients (18.75%) had a re-pigmentation rate between 25-50%. 3 patients (18.75%) had minimal or no improvement. CONCLUSION: Vitilinex® herbal bio-actives in combination with nbUVB is a more effective treatment option for vitiligo with 87% of the patients achieving a re-pigmentation rate higher than 50%, compared to Vitilinex® alone (65%) or nbUVB alone (62.5%).

Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat.

BACKGROUND: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. METHODS: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS: The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS: Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

Topical preparations for the treatment of psoriasis: results of a retrospective study over 15 years.

BACKGROUND: Psoriasis requires lifelong treatments that depend on the extent, clinical forms and associated conditions. OBJECTIVE: To retrospectively analyze which topical treatments were used, their efficacy, and potential advantages and disadvantages. METHODS: A total of 666 patients admitted for the first time over 15 years who were topically treated were retrospectively reviewed and subdivided using clinical forms and PASI into four groups and four subgroups for the applied treatments. For each treatment the mean PASI was calculated daily: on the first, third and sixth day. An X sample statistical analysis and Mann--Whitney U-test were performed. The hospitalization time and correlation with the response to treatment were analyzed. RESULTS: A statistically significant response was recorded for every regimen. The best combination was clobetasol propionate plus eosin on alternate days with eosin plus cade oil. The highest score was recorded for the 'en plaques' psoriasis. The average length of treatment was of 7.5 days in the best combination. No statistically significant difference among the groups was recorded with respect to the length of hospitalization and PASI. CONCLUSION: The statistically significant response for all the topical treatments analyzed and recorded in this study does not exclude a potential benefit due to hospitalization per se.