Dermatological and genetic data in tuberous sclerosis: A prospective single-center study of 38 patients.

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder involving the TSC1 or TSC2 gene. Skin signs are prominent, but dermatological data are scarce. This study aims to describe the cutaneous signs of TSC with the genotype. METHODS: We studied the dermatological characteristics of 38 patients with TSC at the University Hospital of Montpellier. We collected details of genotypic features. RESULTS: All the patients presented at least one cutaneous sign. The dermatological examination alone was sufficient to establish a definite diagnosis of TSC based on the diagnostic criteria for 34/38 patients. No association was found between cutaneous signs and the presence of a TSC1 or TSC2 mutation. We noted skin signs that were poorly described in the disease, namely epidermal nevus in 3 patients, vascular malformation in 2 patients, and keratosis pilaris in 9 patients. DISCUSSION: While several studies demonstrate a more severe neurological phenotype in TSC2 mutated patients, skin expression does not appear to differ according to the mutated gene. Further case reports and molecular genetic studies are needed to determine the link between epidermal nevus, vascular malformations, keratosis pilaris and TSC.

Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel-Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study.

PURPOSE: PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. METHODS: Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. RESULTS: Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean -4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). CONCLUSION: Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

[Cutaneous signs of occult cranial and spinal dysraphism]. / Signes cutanés des dysraphies occultes cranioencéphaliques et spinales.

Dysraphism refers to neural tube closure abnormalities and midline closure abnormalities of the skin, paravertebral muscles, vertebrae and meninges. Cranial dysraphism (CD) and occult spinal dysraphism (OSD) may be discovered via evocative skin signs present at birth or appearing later in childhood or even in adulthood. This review describes the various types of skin signs associated with CD and OSD. All congenital midline skin lesions, particularly on the frontonasal area, the vertex or the occipitocervical and low back regions, should prompt suspicion of underlying dysraphism. The main evocative midline skin abnormalities are: (i) for underlying DCEO: a nodule, swelling, skin openings and hair collar sign or hair tuft; (ii) for underlying DSO, localized hypertrichosis, an atypical or complex lower back dimple, a dermoid fistula, infantile haemangioma, caudal appendage and lipoma. In the event of suspected DCEO or DSO, spinal or medullary MRI constitutes the reference examination.

[Use of rituximab in maintenance treatment of pemphigus: A retrospective series]. / Utilisation en pratique du rituximab en 2nde ligne et au-delà dans le traitement du pemphigus: série rétrospective.

INTRODUCTION: Rituximab (RTX), currently recommended as first-line treatment in moderate to severe pemphigus vulgaris (PV) and superficial pemphigus (PS) along with initial systemic steroids, may also be used as second-line or subsequent treatment, and this therapeutic strategy was investigated in a real-life monocentre retrospective survey. MATERIAL AND METHODS: All patients treated between January 2010 and March 2018 with RTX as second-line or subsequent treatment for moderate to severe PV or PS and followed for at least one year were included. The main objective was to evaluate rates and times of complete clinical remission (CCR) after a first course of RTX. The secondary objectives consisted mainly of treatment safety, and frequency and time to relapse after the initial CCR. RESULTS: The 24 patients selected received on average 2 cycles of RTX (i.e. 24 initial cycles and 24 additional cycles in all) over a mean follow-up period of 45 months. 18/24 (75%) patients achieved initial CCR within a mean 7.7 months. Despite at least one relapse in 13/18 initially responding patients regardless of relapse time, 59% (14/24) and 33% (8/24) were either in CCR and off treatment, or in partial remission, whether treated or untreated, according to the latest patient news, with an overall response rate of 92%. Safety was fair in these fragile patients. DISCUSSION AND CONCLUSION: This survey of the practical use of RTX confirms its interest in moderate to severe pemphigus as a second-line or subsequent treatment, a situation that probably remains relevant even if this molecule is increasingly used as first-line therapy.

Epidermolysis bullosa simplex generalized severe induces a T helper 17 response and is improved by apremilast treatment.

BACKGROUND: Epidermolysis bullosa simplex generalized severe (EBS-gen sev) is a genetic disorder caused by mutation in the KRT5 or KRT14 genes. Although it is usually considered a mechanical disease, recent data argue for additional inflammatory mechanisms. OBJECTIVES: To assess the inflammation in the skin of patients with EBS-gen sev. METHODS: A first immunohistochemical retrospective study was performed on frozen skin samples from 17 patients with EBS-gen sev. A second multicentre prospective study was conducted on 10 patients with severe EBS-gen sev. Blister fluid and epidermis were processed for immunochemical analysis and quantitative real-time polymerase chain reaction. Cytokine expression was analysed in blister fluid and compared with that in controls. RESULTS: Histological analysis showed a constant dermal perivascular CD4+ lymphocyte infiltrate in skin biopsies of both blister (n = 17) and rubbed skin (n = 5), an epidermal infiltration of neutrophils and eosinophils in 70% of cases, and increased immunostaining for CXCL9 and CXCL10 in blistering skin. High levels of T helper 17 cytokines were detected in lesional skin. Three adult patients with EBS-gen sev were treated with apremilast, with a dramatic improvement of skin blistering and good tolerance. CONCLUSIONS: Our study demonstrates the importance of inflammation in patients with EBS-gen sev and underlines the key role for T helper 17 cells in its pathogenesis. In addition, this study provides promising new therapeutic approaches for this disabling disorder.

Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients.

BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.

BACKGROUND: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS: We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and café-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS: The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

Clinical and haemodynamic risk factors associated with discrepancies in lower limb length with capillary malformations: data from the national paediatric French cohort CONAPE.

BACKGROUND: Genetics discoveries have allowed for a better understanding of capillary malformations (CMs) associated with overgrowth syndrome. However, molecular analyses are still not easy to perform or interpret. Other analytical methods are needed. OBJECTIVES: To identify clinical and haemodynamic factors associated with leg length discrepancy (LLD) in children with CMs of the lower limbs. METHODS: Data were obtained from the multicentre French national cohort CONAPE (COhorte Nationale d'enfants atteints d'Angiome Plan de membrE inférieur), from children aged 2-12 years old with CMs of the lower limbs. Clinical characteristics were prospectively collected. Haemodynamic factors were measured by an sonographer who calculated the arterial blood flow (ABF) in both lower limbs. An ABF difference ≥ 50% between the two lower limbs was considered relevant. LLD ≥ 2% was determined by the same radiologist on centralized radiographs. RESULTS: We analysed data at baseline for 96 children. The mean ± SD age was 5·6 ± 3·1 years; 49 (51%) were male; and 14 (15%) showed LLD. In total, 32 patients (33%) had venous anomalies, 13 (14%) lymphatic anomalies and in one child a diagnosis of Parkes Weber syndrome was made. Only an increased circumference above the knee was more frequent with than without LLD (43% vs. 13%, P = 0·02). In all, 10/79 patients (13%) showed a difference in ABF ≥ 50%: four had LLD. The frequency of differences in ABF ≥ 50% was greater with than without LLD [33% (n = 4/12) vs. 9% (n = 6/67), P = 0·04]. CONCLUSIONS: ABF measured by Duplex ultrasonography is a simple, low-cost and noninvasive complementary examination for help in detecting LLD, with a difference of ≥ 50% possibly associated.

Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: a prospective multicentric study of 117 patients.

BACKGROUND: Identification of myositis-specific autoantibodies (MSAs) for dermatomyositis (DM) could allow the characterization of an antibody-associated clinical phenotype. OBJECTIVE: We sought to define the clinical phenotype of DM and the risk of cancer, interstitial lung disease (ILD) and calcinosis based on MSA. METHODS: A 3.5-year multicentre prospective study of adult DM patients was conducted to determine the clinical phenotype associated with MSAs and the presence of cancer, ILD and calcinosis. RESULTS: MSAs were detected in 47.1% of 117 included patients. Patients with antimelanoma differentiation-associated protein-5 antibodies (13.7%) had significantly more palmar violaceous macules/papules [odds ratio (OR) 9.9], mechanic's hands (OR 8), cutaneous necrosis (OR 3.2), articular involvement (OR 15.2) and a higher risk of ILD (OR 25.3). Patients with antitranscriptional intermediary factor-1 antibodies (11.1%), antinuclear matrix protein-2 antibodies (6.8%) and antiaminoacyl-transfer RNA synthetase (5.1%) had, respectively, significantly more poikiloderma (OR 5.9), calcinosis (OR 9.8) and articular involvement (OR 15.2). Cutaneous necrosis was the only clinical manifestation significantly associated with cancer (OR 3.1). CONCLUSION: Recognition of the adult DM phenotype associated with MSAs would allow more accurate appraisal of the risk of cancer, ILD and calcinosis.

Schnitzler syndrome: validation and applicability of diagnostic criteria in real-life patients.

BACKGROUND: Schnitzler syndrome is characterized by an urticarial rash, a monoclonal gammopathy, and clinical, histological, and biological signs of neutrophil-mediated inflammation. The aim of this study was to assess the applicability and validity of the existing diagnostic criteria in real-life patients. METHODS: This multicentric study was conducted between 2009 and 2014 in 14 hospitals in which patients with Schnitzler syndrome or controls with related disorders were followed up. We compared the sensitivities and specificities and calculated the positive and negative predictive values of the Lipsker and of the Strasbourg criteria for the patients with Schnitzler syndrome and for the controls. We included 42 patients with Schnitzler syndrome, 12 with adult-onset Still's disease, 7 with cryopyrin-associated periodic disease, 9 with Waldenström disease, and 10 with chronic spontaneous urticaria. RESULTS: All patients with Schnitzler syndrome met the Lipsker criteria. According to the Strasbourg criteria, 34 patients had definite Schnitzler syndrome, five had probable Schnitzler syndrome, and three did not meet the criteria. One control met the Lipsker criteria and had probable Schnitzler syndrome according to the Strasbourg criteria. Sensitivity and specificity of the Lipsker criteria were 100% and 97%, respectively. For the Strasbourg criteria, sensitivity for definite and probable diagnosis was 81% and 93%, respectively, with a corresponding specificity of 100% and 97%. CONCLUSION: Diagnostic criteria currently in use to diagnose Schnitzler syndrome are reliable. More investigations must be done to attest their efficiency in patients with recent-onset manifestations.

[Chronic recurrent annular neutrophilic dermatosis]. / Dermatose neutrophilique annulaire récurrente chronique.

BACKGROUND: Chronic recurrent annular neutrophilic dermatosis (CRAND) is a rare form of neutrophilic dermatosis characterised by chronic annular progression, histological impairment similar to that seen in Sweet's syndrome and the absence of association with generalised signs, abnormal laboratory values or underlying systemic disease. Herein we report two new cases. PATIENTS AND METHODS: Case no 1. A 41-year-old woman had presented with four annular lesions on the forearms and neckline which she had had for one year. Examination revealed a 5-cm annular lesion on the right forearm and four similar adjacent lesions. The condition spontaneously resolved after 4 weeks. Treatment with hydroxychloroquine 400mg per day for three months proved ineffective in preventing a further episode. However, following treatment with colchicine at a daily dose of 1mg for two months, no further relapses in the rash occurred over a 10-year observation period. Case no 2. A 38-year-old woman consulted for recurrent annular erythema confined to the legs. Examination showed the presence of a red papular annular lesion on the right leg, encircling a yellowish macule with a central ring of fine scale; the lesion had been present for three weeks. Treatment with colchicine was initiated but the patient was lost to follow-up. In both cases, histological examination was evocative of Sweet's syndrome but no inflammatory or neutrophilic syndrome and no underlying systemic disease were demonstrated. DISCUSSION: CRAND presents as a stereotypical and benign form of neutrophilic dermatosis. A diagnosis of chronic recurrent annular dermatosis with gyrate progression should be considered in the absence of general signs, neutrophilia or underlying systemic disease.

[Multiple cephalic deep granuloma annulare of children]. / Granulomes annulaires profonds multiples céphaliques de l'enfant.

BACKGROUND: Deep granuloma annulare is a fairly rare variety of granuloma annulare. It is seen predominantly in children and mainly affects the anterior aspect of the legs and the top of the feet; cephalic presentation is rare. Below, we report three cases of deep granuloma annulare in children presenting solely at the cephalic extremity. PATIENTS AND METHODS: Case 1: a six-year-old boy presented 7 cutaneous nodules measuring 1 to 2cm that were flesh-coloured, insensitive to palpation, of hard consistency and deeply attached. The lesions were grouped together on the anterior half of the left temporal fossa. While spontaneous regression of the three nodules was noted in the month following cutaneous biopsy, these nodules recurred a few months later. Case 2: a four-year-old girl with five deep cephalic nodules measuring around one centimetre and the colour of normal skin were seen on her right temporal fossa. The child was lost to follow-up after biopsy. Case 3: a four-month-old infant was presenting some 15 deep cutaneous nodules arranged in linear fashion on the forehead next to the left temporal fossa. These nodules regressed spontaneously one month after biopsy. In all three cases, histological examination confirmed the diagnosis of deep granuloma annulare. DISCUSSION: There have been few published cases of multiple, cephalic, deep granuloma annulare at a single site in children. The condition has an extensive differential diagnosis that includes malignant tumours; in addition, histological confirmation is normally essential. Treatment is not qualified and therapeutic extension with clinical monitoring alone may frequently be recommended.

[Impact of sex and age on the clinical and epidemiological aspects of childhood psoriasis: Data from a French cross-sectional multicentre study]. / Impact de l'âge et du sexe sur les aspects cliniques et épidémiologiques du psoriasis de l'enfant. Données d'une étude transversale multicentrique française.

BACKGROUND: The prevalence of childhood psoriasis is estimated at between 0.4% and 0.7%. Clinical aspects of the diseases depend on age. The aim of this study was to investigate the clinical aspects of psoriasis according to age and sex. PATIENTS AND METHODS: A cross-sectional, multicentre study of children with psoriasis was performed by investigators belonging to the Research Group of the French Society of Paediatric Dermatology. The study was conducted from April 2012 to March 2013. Inclusion criteria were age less than 18 years and clinical diagnosis of psoriasis. The children were classified into 3 groups by age: infants: <2 years; children: ≥2 years and <13 years; adolescents≥13 years. The information collected included demographic data, clinical, epidemiological, and therapeutic aspects of the psoriasis, as well as analysis of comorbidities. RESULTS: Three hundred and thirteen children were included: 27 (8.6%) infants, 207 (66.1%) children, and 79 (25.2%) adolescents. Plaque psoriasis was the most frequent clinical type of psoriasis seen in children and adolescents (>41%), but it accounted for only 25.9% of psoriasis of infants (P<0.0001). Napkin psoriasis (37.0%) and inverse psoriasis (22.2%) were the most common forms of psoriasis seen in infants and were described significantly more frequently in this group than in the two other groups (P<0.003). Nail involvement was more common in adolescents (37.2%, P=0.03) and children (32.9%) than in infants (14.8%) and affected boys more than girls (43.6% vs 22.0%, P<0.0001). Girls presented scalp psoriasis more frequently (17.7% vs 8.7%, P=0.02). Local vitamin-D treatment and systemic therapies were used more frequently in children and adolescents than in infants. There was no significant difference for treatment use, including for acitretin, according to gender. DISCUSSION: Plaque psoriasis was the most common clinical type of psoriasis in children but affected less than 50% of the children. Age had a significant impact on extra-cutaneous skin disorders and on treatment used, while sex had little incidence. The frequency of comorbidities was not affected by age. CONCLUSION: Childhood psoriasis thus presents specific characteristics dependent on the age of the child. The results of studies exclusively dealing with adults cannot be extrapolated to children.

Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes.

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.

Psoriasis and obesity in French children: a case-control, multicentre study.

BACKGROUND: Obesity is more common in adults with psoriasis than in the general population, but there is a lack of data available regarding this association in children. OBJECTIVES: To evaluate whether obesity was more common in French children with psoriasis of any clinical type or severity. METHODS: A multicentre case-control study was performed in 23 French dermatology centres. Children without chronic or genetic inflammatory disease were selected as controls and matched for age, sex and dermatology centre. We used three weight cut-off categories to compare the two groups: overweight, overweight with abdominal obesity and overweight with obesity according to the French Health Authority guidelines. RESULTS: A total of 261 children with psoriasis were included. The mean age was 9.8 years, 126 were boys and 135 were girls. Overall, 42.5% of these children had plaque psoriasis and 32.2% had severe psoriasis. There was no difference between the psoriasis and control groups when the frequency of children who were overweight was compared (20·7% in psoriasis group vs. 17·1% in control group; P = 0·18). Overweight with abdominal obesity including obesity (18·4% vs. 10·4%; P = 0·009) and obesity alone (10·0% vs. 3·1%; P = 0·001) were more common in the psoriasis group. CONCLUSIONS: This study shows that being overweight with abdominal obesity and being obese is more common in children with psoriasis than in controls. The risk factors are the same as those that affect the French general population, i.e. female sex and having a parent who was overweight. The severity and clinical type of psoriasis do not affect overweight and obesity.