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Summary 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.

A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

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Acral localised acquired cutis laxa (ALACL) is a very rare form of acquired cutis laxa characterised by loose redundant skin folds confined to the hands and feet, giving the appearance of premature aging, and histological loss of dermal elastic tissue (1-9). We report here a new case of ALACL associated with IgA multiple myeloma and also, for the first time, with joint hyperlaxity and recurrent neutrophilic urticarial dermatosis.CASE REPORT (for detailed methods see Appendix S1 1 )A 40-year-old man presented in 2007 for the management of ALACL and monoclonal IgA gammapathy. He had chronic urticarial dermatosis of the extremities, mostly involving the hands, which had manifested in 1996 and progressively worsened, with repeated swelling of the fingers. ALACL was diagnosed at that time in association with an unusual hyperlaxity of the distal interphalangeal joints. Over the past several years, he has received multiple treatments including methotrexate, colchicine, hydroxychloroquine, intravenous gammaglobulins and dapsone. All have either been ineffective or had debilitating side effects. Oral prednisone resulted in complete remission of the urticarial lesions, with steroid dependence estimated at 20-30 mg/day, but this did not prevent the progression in joint laxity or cutis laxa. Physical examination disclosed the loose, redundant skin of all fingers (Fig. 1A). On demand, he was able to completely dislocate multiple interphalangeal joints painlessly and effortlessly (Fig. 1B). Laboratory tests showed a monoclonal IgA lambda peak with hypogammaglobulinemia (4.9 g/l; normal 7.1-15.6 g/l) with decreased IgG (3.92 g/l; normal 6.9-14 g/l) and normal serum levels of IgM and IgA. Urinary immunoelectrophoresis showed increased lambda light chains. Hand X-rays revealed articular dislocations of most of the proximal and distal interphalangeal joints. Bone marrow aspiration revealed 13% plasma cells with dystrophy, consistent with IgA myeloma. A biopsy specimen taken from an urticarial papule of the palmar hand revealed a dense dermal interstitial and perivascular neutrophilic infiltrate and leukocytoclasia without oedema or vasculitis (Fig. 2), consistent with neutrophilic urticarial dermatosis. Amyloid Congo red staining was negative in all biopsy specimens. Between 2007 and 2012, the following treatments were all ineffective: plasmapheresis (6 sessions), anakinra (3 months), infliximab (4 months), rituximab (4 sessions) and alkeran (2 sessions). Unfortunately, the patient chose not to follow-up.Direct immunofluorescence investigation of lesional skin revealed abundant IgA deposits that decorated the dermoepidermal junction (DEJ) and the capillary network of the dermal papillae (Fig. 3A). A control specimen from non-lesional forearm skin showed only faint staining in the DEJ (data not shown). Electron microscopy showed conspicuous diminution of the elastic fibres with normal-appearing collagen fibres; macrophages were observed phagocyting the elastic fibres. Direct immunoelectron microscopy further localised the IgA depos...