Dermatologic manifestations in paediatric neurofibromatosis type 2: a cross sectional descriptive multicentric study.

BACKGROUND: Neurofibromatosis type 2 (NF2) is characterized by bilateral vestibular schwannoma (VS) more often in adults but a severe paediatric form with multiple neurological tumours is also described. In this population, a early diagnosis is important to prevent the onset of neurological complications but is difficult, particularly without a familial history. Cutaneous manifestations, which may precede VS or neurological tumours by several years, may contribute to an early diagnosis, but specific studies are lacking. The objective of this study was to characterize cutaneous manifestations of NF2 in a paediatric population. RESULTS: This observational, descriptive and multicentric study was conducted from April 2019 to April 2020 in seven academic French hospitals. We included patients ≤ 18 years old who fulfilled the Manchester diagnostic criteria or had a pathogenic mutation identified in the NF2 gene. All patients underwent a dermatological examination guided by a standardized questionnaire. 21 children were included, of whom 20 had at least one skin tumour (mean number 5 ± 4.6 [range 0-15]), which led to a diagnosis in four cases. In the other 17 cases, the diagnosis of NF2 was based on neurosensory complications (n = 10), family screening (n = 4) or ocular signs (n = 3). Before the NF2 diagnosis, 15 children had at least one "undiagnosed" cutaneous tumour that did not lead to a specific management. Patients' dermatological examination also revealed < 6 non specific café au lait macules (n = 15), hypopigmented macules (n = 12) with more than 3 lesions in 4 cases, and purple reticulated macules of the trunk (n = 4). CONCLUSION: Dermatological lesions are frequent and early in children with NF2 but rarely lead to the diagnosis. Cutaneous schwannomas are the most frequent but are often underdiagnosed. Café au lait macules are frequent, but atypical and mostly in small numbers. Multiple hypopigmented macules seem suggestive although inconsistent. The sensitivity of reticulated capillary malformation-like lesions remains to be assessed by further studies.

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.

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.

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.

[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.

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.

[Type I interferonopathies]. / Interféronopathies de type I.

Type I interferonopathies are a group of Mendelian disorders characterized by a common physiopathology: the up-regulation of type I interferons. To date, interferonopathies include Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, PRoteasome-associated auto-inflammatory syndrome (PRAAS) and Singleton-Merten syndrome. These diseases present phenotypic overlap including cutaneous features like chilblain lupus, that can be inaugural or present within the first months of life. This novel set of inborn errors of immunity is evolving rapidly, with recognition of new diseases and genes. Recent and improved understanding of the physiopathology of overexpression of type I interferons has allowed the development of targeted therapies, currently being evaluated, like Janus-kinases or reverse transcriptase inhibitors.

[PENS (papular epidermal nevus with "skyline" basal cell layer)]. / Syndrome PENS (papular epidermal nevus with "skyline" basal cell layer).

BACKGROUND: PENS is a rare neuro-cutaneous syndrome that has been recently described. It involves one or more congenital epidermal hamartomas of the papular epidermal nevus with "skyline" basal cell layer type (PENS) as well as non-specific neurological anomalies. Herein, we describe an original case in which the epidermal hamartomas are associated with autism spectrum disorder (ASD). PATIENTS AND METHODS: A 6-year-old boy with a previous history of severe ASD was referred to us for asymptomatic pigmented congenital plaques on the forehead and occipital region. Clinical examination revealed a light brown verrucous mediofrontal plaque in the form of an inverted comma with a flat striated surface comprising coalescent polygonal papules, and a clinically similar round occipital plaque. Repeated biopsies revealed the presence of acanthotic epidermis covered with orthokeratotic hyperkeratosis with occasionally broadened epidermal crests and basal hyperpigmentation, pointing towards an anatomoclinical diagnosis of PENS. DISCUSSION: A diagnosis of PENS hamartoma was made on the basis of the clinical characteristics and histopathological analysis of the skin lesions. This condition is defined clinically as coalescent polygonal papules with a flat or rough surface, a round or comma-like shape and light brown coloring. Histopathological examination showed the presence of a regular palisade "skyline" arrangement of basal cell epidermal nuclei which, while apparently pathognomonic, is neither a constant feature nor essential for diagnosis. Association of a PENS hamartoma and neurological disorders allows classification of PENS as a new keratinocytic epidermal hamartoma syndrome. The early neurological signs, of varying severity, are non-specific and include psychomotor retardation, learning difficulties, dyslexia, hyperactivity, attention deficit disorder and epilepsy. There have been no reports hitherto of the presence of ASD as observed in the case we present. CONCLUSION: This new case report of PENS confirms the autonomous nature of this neuro-cutaneous disorder associated with keratinocytic epidermal hamartoma syndromes.

[Sporadic anterior cervical hypertrichosis]. / Hypertrichose cervicale antérieure sporadique.

BACKGROUND: Anterior cervical hypertrichosis is a rare and little-known form of congenital localized hypertrichosis. It is characterized by the presence of a tuft of terminal hairs in the anterior cervical region. We report four typical clinical observations of this condition. PATIENTS AND METHODS: Four patients aged from 5 to 21 years were seen for a tuft of terminal long hair on the neck, next to the cricoid cartilage, recorded at birth or during early childhood. There was no indication of previous trauma or topical drug application. No similar familial history was found. In one case, histological examination performed for suspicion of an "atypical" smooth muscle hamartoma contributed nothing of note. No neurological abnormalities were observed. In one case there was a history of chronic juvenile idiopathic arthritis and familial thyroid disease. Treatment with 5 sessions of laser hair removal was proposed in one case and the improvement was considered satisfactory by the patient. DISCUSSION: Anterior cervical hypertrichosis constitute a specific clinical picture of a benign nature, and is sometimes associated with neurological, orthopaedic or ocular abnormalities. Although rarely reported, its frequency is probably underestimated.

Aplasia cutis congenita with dystrophic epidermolysis bullosa: clinical and mutational study.

BACKGROUND: Aplasia cutis congenita (ACC) has been associated with all clinical forms of inherited epidermolysis bullosa (EB), including dominant and recessive dystrophic EB (DDEB and RDEB). To date, only a few patients with DEB specifically combined with ACC have been described and genotyped and almost all cases represent dominant forms of the condition. OBJECTIVES: The aim of this study was to describe new mutations of COL7A1 in patients with DEB and ACC and investigate possible genotype-phenotype correlations. METHODS: Twenty-two patients with DEB and ACC were included among the 123 patients with DEB whose COL7A1 mutations have been identified in the Reference Centre in Nice. RESULTS: Seven patients presented a severe generalized RDEB phenotype (RDEB-sev-gen), while the other 15 suffered from milder phenotypes. We identified 28 mutations in COL7A1, of which nine are novel. Patients with severe phenotypes have mostly mutations leading to premature termination codon (PTC) and/or splice-site or missense mutations. Patients with the milder phenotypes have mostly glycine or arginine substitutions associated or not with other types of mutations. All amino acid substitutions fell within the carboxyl portion of the triple helix domain (THD) of collagen VII, close to the THD interruptions. CONCLUSIONS: Our findings suggest that ACC is a frequent manifestation in patients with DEB irrespective of the severity of the disease, and is due to leg rubbing in utero. In children with a moderate form of DEB with no or moderate skin fragility, a glycine substitution near the THD interruption domain of the collagen VII leading to thermolabile protein could explain this phenomenon.

[Dermatomyositis and acute interstitial lung disease associated with MDA-5 antibodies: an atypical case]. / Dermatomyosite et pneumopathie interstitielle rapidement évolutive associées aux auto-anticorps anti-MDA-5 : une présentation clinique atypique.

BACKGROUND: A new antibody known as anti-MDA-5 has recently been identified in association with a specific phenotype of dermatomyositis (DM), in which muscular involvement is minimal or absent, but where there is a particularly high risk of onset of aggressive interstitial lung disease. Below, we report a case associated with the presence of anti-MDA-5 antibodies complicated by aggressive interstitial lung disease ; the cutaneous phenotype of this patient is novel due to the constitution of diffuse ichthyosis and of profuse subcutaneous calcinosis. PATIENTS AND METHODS: A 35-year-old man was hospitalised for a skin rash associated with arthralgia, dry cough, asthenia and weight-loss of 8 kg in 5 months. The dermatological examination revealed purple erythema of the upper eyelids and cheeks, diffuse acquired ichthyosis of the trunk and limbs, and striated erythema on the proximal and distal metacarpal and interphalangeal joints of the fingers. A diagnosis of DM was suspected in patients treated with prednisolone, 1.5 mg/kg/d. Immunological tests identified the presence of anti-MDA-5 antibodies. One month later, the cutaneous signs continued to progress and were marked by the development of painful ulcers on the back of the fingers, as well as dyspnoea accompanying the slightest effort. Chest images showed constituted pulmonary fibrosis lesions. At the same time, within several months, diffuse, pseudo-tumoural calcifications developed in the subcutaneous tissue of the trunk and limbs. The patient was treated successively with intravenous gammaglobulins, cyclophosphamide, mycophenolate mofetil, azathioprine and rituximab in combination with oral corticosteroids, but with no improvement in respiratory function or in the skin lesions. Because of the decline in the patient's respiratory status, a lung graft was envisaged but subsequently abandoned because of the patient's excessively precarious state of health. DISCUSSION: Anti-MDA-5 antibody appears to constitute a specific immunological marker for a special dermatological phenotype of adult DM, significantly associated with the presence of: 1) keratotic papules in the skin folds of the palms and fingers ; 2) cutaneous ulcers along the periungueal edges, Gottron's papules on the back of the hands and on the extensor surface of the elbows and knees ; 3) pain and ulceration in the oral mucosa, diffuse alopecia, and appearance of "mechanic's hands" and Gottron's sign on the elbows and knees. To our knowledge, the presence of extensive ichthyosis and profuse subcutaneous calcinosis has not been previously reported in this particular form of DM. The risk of aggressive interstitial lung disease is particularly high and worsens the prognosis, since 40% of patients with anti-MDA-5 die, usually within the first year. CONCLUSION: Herein, we describe a patient presenting amyopathic DM complicated by aggressive interstitial lung disease associated with the presence of anti-MDA-5 antibodies, but with a hitherto unreported cutaneous phenotype combining diffuse ichthyosis and profuse subcutaneous calcinosis.

[Multiple familial "eruptive" dermatofibromas]. / Dermatofibromes multiples « éruptifs ¼ familiaux.

BACKGROUND: Multiple eruptive dermatofibromas (DF) are rare and frequently associated with immune and neoplastic diseases. There have also been reports of rare familial cases. Herein we report a new such case. PATIENTS AND METHODS: A 79-year-old woman and her 37-year-old daughter were seen for disseminated DF over a period of several decades, from adolescence onwards. Neither had any history of diseases or treatments normally associated with multiple DF. History-taking revealed similar lesions in other family members. DISCUSSION: DF are common benign cutaneous tumours, generally seen on the lower limbs of young or middle-aged women. These lesions occur either in isolation or are relatively few. Multiple or so-called eruptive DF, defined by the presence of more than 15 lesions in a single patient, is rare and is associated in 60% of cases with autoimmune diseases, HIV infection, neoplastic disease or immunosuppressant therapy. Familial forms such as those described herein are extremely rare.

Treatment of Gorlin syndrome (nevoid basal cell carcinoma syndrome) with methylaminolevulinate photodynamic therapy in seven patients, including two children: interest of tumescent anesthesia for pain control in children.

OBJECTIVE: To report our experience of methylaminolevulinate photodynamic therapy (MAL-PDT) in the treatment of multiple basal cell carcinoma (BCC) in adults and children with Gorlin syndrome (GS). DESIGN: Report of cases. SETTING: University of Montpellier, Department of Dermatology. PATIENTS: Seven Gorlin patients (41 superficial or nodular carcinomas), including two children. INTERVENTIONS: Prior superficial curettage for superficial BBCs or debulking for nodular BCCs was systematically performed. Methylaminolevulinic acid was applied topically to lesions 3 h before illumination with 635 nm red light for 10 min (37 J/cm(2)). To prevent treatment discomfort, analgesics and/or cooling by sprayed water were most often provided, and occasionally 1% lidocaine local anesthesia. A ropivacaine-lidocaine tumescent anesthesia was performed on the youngest patient. MAIN OUTCOME MEASURES: The initial response rate; tolerance, particularly in children; cosmetic outcome. RESULTS: Overall clearance in patients was 60% after one session of MAL-PDT and 78% after three sessions. Resolution of the lesions was accompanied by an excellent cosmetic outcome in all patients. Treatments were well tolerated in adults with moderate pain sensation during illumination. In a child, tumescent anesthesia assured excellent tolerance in all treatment stages. CONCLUSION: We add our experience to previous articles that consider PDT as an interesting option in the treatment of GS. To our knowledge, this study is the first report of MAL-PDT in GS children using tumescent anesthesia. Specific guidelines for adult and pediatric patients remain to be established.