Histopathological significance of connective tissue disease-associated interstitial lung disease in transbronchial lung cryobiopsy specimens.

Differentiating between idiopathic interstitial pneumonia (IIP) and secondary interstitial pneumonia, particularly connective tissue disease-associated interstitial lung disease (CTD-ILD), can be challenging histopathologically, and there may be discrepancies among pathologists. While surgical lung biopsy has traditionally been considered the gold standard for diagnosing interstitial pneumonia, the usefulness of transbronchial lung cryobiopsy (TBLC) has been reported. If TBLC could effectively distinguish between primary and secondary diseases, it would provide a less invasive option for patients. The aim of this study was to identify specific pathologic findings in TBLC specimens that could assist in distinguishing CTD-ILD from IIP. A total of 93 underwent TBLC at Tenri Hospital between 2018 and 2022. We retrospectively reviewed cases of CTD-ILD exhibiting a nonspecific interstitial pneumonia (NSIP) pattern (CTD-NSIP) and cases of NSIP with an unknown etiology (NSIP-UE), as determined through multidisciplinary discussion. Nineteen patients with CTD-NSIP and 26 patients with NSIP-UE were included in the study for clinicopathological analysis. The CTD-NSIP group had a significantly higher proportion of female patients compared to the NSIP-UE group (79% vs. 31%; p = 0.002). The presence of both fresh and old intraluminal fibrosis within the same TBLC specimen was significantly more frequent in CTD-NSIP group than in the NSIP-UE group (p = 0.023). The presence of an NSIP pattern with co-existing fresh and old intraluminal fibrosis in TBLC specimens raised suspicion for CTD-ILD.

Annular dermatoses with rheumatologic implications.

A wide variety of cutaneous disorders present with annular (ringlike) skin lesions, and some of them carry rheumatologic implications because they may involve the joints or belong to the spectrum of connective tissue diseases. The diagnosis of an annular rheumatologic skin disease is possible with a correct clinicopathologic correlation, with a correct anamnesis of the patient, with the evaluation of systemic symptoms, laboratory and instrumental investigations, and finally with a cutaneous biopsy.

Spectrum of high-resolution computed tomography pattern in lungs in patients with connective tissue disorders.

Background: Connective tissue disease associated with interstitial lung disease, or CT-ILD, is a lung condition that affects a large number of patients with a connective tissue disease. Objective: Our aim in this study is to correlation between images of high-resolution computed tomography (HRCT) of different connective tissue diseases associated interstitial lung diseases (CTD-ILDs). Methods: We shall be aiming to investigate the feasibility of HRCT imaging and thereby avoid lung biopsy in such patients. Results: Rheumatoid arthritis predominantly presented with usual interstitial pneumonia (UIP) (47.8%), followed by nonspecific interstitial pneumonia (NSIP) (30.4%). Mixed connective tissue disorder predominantly presented with NSIP and UIP (42.8%), followed by organizing pneumonia (OP) (14.2%). Systemic lupus erythematosus predominantly presented with UIP (38.8%), followed by NSIP (27.7%). Sjogren's syndrome predominantly presented with lymphocytic interstitial pneumonia (40%), followed by UIP (26.6%). Scleroderma predominantly presented with UIP (45.4%), followed by NSIP (36.4%). Sarcoidosis predominantly presented with UIP (75%), followed by NSIP (25%). Dermatomyositis predominantly presented with NSIP (50%), followed by UIP and OP each (25%). Conclusion: Both clinicians and radiologists should be aware of the expected evolution of HRCT changes in a variety of CT-ILDs.

Résumé Contexte: La maladie du tissu conjonctif associée à la maladie pulmonaire interstitielle, ou CT ILD, est une affection pulmonaire qui affecte un grand nombre de patients atteints d'une maladie du tissu conjonctif. Objectif: Notre objectif dans cette étude est de mettre en corrélation des images de tomodensitométrie à haute résolution (HRCT) de différentes maladies du tissu conjonctif associées à des maladies pulmonaires interstitielles (CTD ILDs). Méthodes: Notre objectif sera d'étudier la faisabilité de l'imagerie HRCT et d'éviter ainsi la biopsie pulmonaire chez ces patients. Résultats: La polyarthrite rhumatoïde se présentait principalement avec une pneumonie interstitielle habituelle (PUI) (47,8 %), suivie d'une pneumonie interstitielle non spécifique (NSIP) (30,4 %). Trouble mixte du tissu conjonctif présenté principalement avec NSIP et UIP (42,8 %), suivi d'une pneumonie organisée (OP) (14,2 %). Le lupus érythémateux disséminé présentait principalement une UIP (38,8 %), suivie d'une NSIP (27,7 %). Le syndrome de Sjogren présentait principalement une pneumonie interstitielle lymphocytaire (40 %), suivie d'une PUI (26,6 %). La sclérodermie se présentait principalement avec l'UIP (45,4 %), suivi du NSIP (36,4 %). La sarcoïdose se présentait principalement avec l'UIP (75 %), suivi du NSIP (25 %). La dermatomyosite se présentait principalement avec NSIP (50 %), suivi par UIP et OP chacun (25 %). Conclusion: Les cliniciens et les radiologues doivent être conscients de l'évolution attendue des changements HRCT dans une variété d'ILD CT. Mots-clés: Tissu conjonctif, CT ILDs, tomodensitométrie haute résolution, poumon interstitiel.

Potential role of type I interferon/IP-10 axis in the pathogenesis of anti-MDA5 antibody-positive dermatomyositis.

OBJECTIVES: Dermatomyositis (DM) patients with anti-melanoma differentiation-associated protein 5 (MDA5) antibodies are known for poor prognosis. This study was designed to identify humoral factors that are readily detectable in the disease and may reflect its activity and pathophysiology. METHODS: We first quantified the serum level expression of 28 cytokines in the serum of patients with collagen vascular diseases using bead-based multiplex immunoassays. We completed these evaluations at hospital admission and followed up with three DM patients with anti-MDA5 antibodies during hospitalisation. We also performed an immunohistochemical analysis of skin samples obtained from two patients. RESULTS: The serum level of interferon gamma-induced protein 10 (IP-10) was significantly higher in DM patients with anti-MDA5 antibodies than in those without the antibody, decreasing drastically upon treatment. Interestingly, this time course paralleled not that of interferon (IFN)-γ, which was originally reported to be the inducer of IP-10, but that of IFN-α2. Immunohistochemical analysis revealed that most of the IP-10-positive cells were macrophages. Furthermore, monocytes stimulated with type I IFN in vitro produced IP-10 in a dose-dependent manner. CONCLUSIONS: IP-10 is a potentially useful disease activity marker of DM with anti-MDA5 antibodies, correlating more with IFN-α2 then IFN-γ. IP-10 released from macrophages might prompt the infiltration of macrophages themselves. Thus, the type I IFN/IP-10 axis may play a pivotal role in the pathogenesis of this intractable disease.

Dominant Stickler Syndrome.

The Stickler syndromes are a group of genetic connective tissue disorders associated with an increased risk of rhegmatogenous retinal detachment, deafness, cleft palate, and premature arthritis. This review article focuses on the molecular genetics of the autosomal dominant forms of the disease. Pathogenic variants in COL2A1 causing Stickler syndrome usually result in haploinsufficiency of the protein, whereas pathogenic variants of type XI collagen more usually exert dominant negative effects. The severity of the disease phenotype is thus dependent on the location and nature of the mutation, as well as the normal developmental role of the respective protein.

Identification of three novel homozygous variants in COL9A3 causing autosomal recessive Stickler syndrome.

BACKGROUND: Stickler syndrome (STL) is a rare, clinically and molecularly heterogeneous connective tissue disorder. Pathogenic variants occurring in a variety of genes cause STL, mainly inherited in an autosomal dominant fashion. Autosomal recessive STL is ultra-rare with only four families with biallelic COL9A3 variants reported to date. RESULTS: Here, we report three unrelated families clinically diagnosed with STL carrying different novel biallelic loss of function variants in COL9A3. Further, we have collected COL9A3 genotype-phenotype associations from the literature. CONCLUSION: Our report substantially expands the molecular genetics and clinical basis of autosomal recessive STL and provides an overview about allelic COL9A3 disorders.

Expanding the phenotypic spectrum of Mendelian connective tissue disorders to include prominent kidney phenotypes.

Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively.

Predictors for progressive fibrosis in patients with connective tissue disease associated interstitial lung diseases.

BACKGROUND: Connective tissue disease associated interstitial lung disease (CTD-ILD) is associated with decreased quality of life and high mortality risk. Outcome and treatment response is unpredictable. This study aimed to identify clinical predictors for CTD-ILD with poor outcome. METHODS: We performed a retrospective single centre cohort study in outpatients with CTD-ILD seen between 2004 and 2018. Clinical and biochemical data, pulmonary function tests (PFT) and high-resolution computed tomography (HRCT) results were analysed. Overall survival and progressive fibrosing ILD (PF-ILD, defined as a significant deterioration of PFT or HRCT) after two years of follow-up were assessed. RESULTS: In total, 150 patients with CTD-ILD were included. Thirty (20%) deaths occurred during a median follow-up of 40 months (IQR 27.3-60.8), which were attributed to pulmonary infection in six (4%), respiratory failure due to PF-ILD in ten (7%) and due to other causes in fourteen patients. PF-ILD occurred in 76 (50.7%) patients and was associated with poor overall survival (adjusted HR 5.73, 95%CI 1.17-28.11). Age, smoking, C-reactive protein, and steroid-use were independently associated with increased mortality risk as well. Furthermore, patients with diabetes mellitus (adjusted OR 4.52, 95%CI 1.10-18.51), steroid-use (adjusted OR 2.26, 95%CI 1.04-4.93), and a fibrotic HRCT pattern at baseline (adjusted OR 3.11, 95%CI 1.15-8.38) had a higher risk of PF-ILD. CONCLUSION: PF-ILD is associated with increased mortality in patients with CTD-ILD. Patients with a fibrotic HRCT pattern at baseline, diabetes mellitus and steroid-use have a higher risk of developing PF-ILD.

Prognostic role of NK cell percentages in bronchoalveolar lavage from patients with different fibrotic interstitial lung diseases.

BAL cellularity and lymphocyte immunophenotyping offer insights into lung inflammatory status. Natural killer (NK) cells are efficient effector cells, producing pro-inflammatory cytokines. A better understanding of the biology of NK cells in BAL in the lungs is necessary to improve the pathogenesis of fibrotic ILD and develop prospective targeted treatments. Our aim was to analyse NK and NKT-like cell percentages in BAL from 159 patients with different ILD: f-HP, f-NSIP, IPF and CTD-ILD, to evaluate their potential diagnostic/prognostic role. BAL NK cell percentages showed significantly higher values in IPF than in f-HP and f-NSIP, while BAL NKT-like cells showed significantly lower values in the f-NSIP than the f-HP and IPF. A cut-off of 4%NK cells in BAL of IPF showed a significant difference in survival rate. It suggests a possible new marker of survival and raises the possibility of new targeted approach in treatment and management of IPF.

The role of interleukin-6 as a prognostic biomarker for predicting acute exacerbation in interstitial lung diseases.

BACKGROUND: Interstitial lung diseases (ILDs) are chronic, parenchymal lung diseases with a variable clinical course and a poor prognosis. Within various clinical courses, acute exacerbation (AE) is a devastating condition with significant morbidity and high mortality. The aim of this study was to investigate the role of interleukin-6 (IL-6) to predict AE and prognosis in patients with ILD. METHODS: Eighty-three patients who were diagnosed with ILD from 2016 to 2019 at the Haeundae Paik Hospital, Busan, South Korea, were included and their clinical data were retrospectively analyzed. RESULTS: The median follow-up period was 20 months. The mean age was 68.1 years and 65.1% of the patients were men with 60.2% of patients being ever-smokers. Among ILDs, idiopathic pulmonary fibrosis was the most common disease (68.7%), followed by connective tissue disease-associated ILD (14.5%), cryptogenic organizing pneumonia (9.6%), and nonspecific interstitial pneumonia (6.0%). The serum levels of IL-6 were measured at diagnosis with ILD and sequentially at follow-up visits. During the follow-ups, 15 (18.1%) patients experienced an acute exacerbation (AE) of ILD and among them, four (26.7%) patients died. In the multivariable analysis, high levels of IL-6 (OR 1.014, 95% CI: 1.001-1.027, p = 0.036) along with lower baseline saturations of peripheral oxygen (SpO2) were independent risk factors for AE. In the receiver operating characteristic curve analysis, the area under the curve was 0.815 (p < 0.001) and the optimal cut-off value of serum IL-6 to predict AE was 25.20 pg/mL with a sensitivity of 66.7% and specificity of 80.6%. In the multivariable Cox analysis, a high level of serum IL-6 (HR 1.007, 95% CI: 1.001-1.014, p = 0.018) was only an independent risk factor for mortality in ILD patients. CONCLUSIONS: In our study, a high level of serum IL-6 is a useful biomarker to predict AE and poor prognosis in patients with ILD.

Clinical and laboratory prognosticators of atrophic papulosis (Degos disease): a systematic review.

BACKGROUND: Degos disease is a rare vascular disorder with a cutaneous-limited form, benign atrophic papulosis (BAP), and a systemic variant, malignant atrophic papulosis (MAP). Despite the poor prognosis of MAP, no study has established features associated with systemic disease. OBJECTIVES: The aims of this systematic review were to: (1) summarize clinical features and treatments implemented for patients with MAP and BAP (2) identify clinical and laboratory factors associated with the development of MAP, compared to BAP. METHODS: We systematically searched MEDLINE and Embase from inception to April 2020. Demographic and clinical features of Degos patients were presented descriptively; multivariable logistic regression was performed to identify associations with MAP. RESULTS: We identified 99 case studies, comprising 105 patients. MAP (64%) had a 2.15 year median survival time from cutaneous onset, most often with gastrointestinal or central nervous system involvement. We found that elevations in either of erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) were associated with systemic involvement (OR 2.27, p = 0.023). Degos secondary to an autoimmune connective tissue disease was found to be inversely associated with MAP (OR 0.08, p = 0.048). CONCLUSIONS: Elevated ESR or CRP is associated with MAP and may be a predictor of systemic involvement for patients with Degos disease. In addition, secondary Degos disease is associated with a favourable prognosis. Clinicians should be aware of the differences between primary and secondary Degos and the utility of ESR or CRP in identifying disease evolution to systemic involvement. The utility of ESR and CRP to identify systemic involvement should be further explored.

Clinical features of acute fibrinous and organizing pneumonia: An early histologic pattern of various acute inflammatory lung diseases.

BACKGROUND: Acute fibrinous and organizing pneumonia (AFOP) is a rare histologic pattern of acute lung involvement with intra-alveolar fibrin deposition. However, the clinical significance of the pathological findings of AFOP remains unclear. This study aimed to explore the clinical significance of AFOP through a comprehensive clinical examination. METHODS: The medical records of patients with lung diseases accompanied by the pathological finding of intra-alveolar organization between January 2010 and December 2019 were retrospectively reviewed. The clinical and radiological findings were compared between the groups with and without the histologic pattern of AFOP. RESULTS: We identified 34 patients with AFOP (AFOP group) and 143 without AFOP (non-AFOP group). The underlying diseases of the AFOP group were as follows: 19 patients had cryptogenic organizing pneumonia (OP), 5 had connective tissue diseases, 3 had radiation pneumonitis, 3 had chronic eosinophilic pneumonia, 2 had myelodysplastic syndromes, and 2 had drug-induced pneumonia. Fever was more common, the time from symptom onset to biopsy was shorter, and the serum C-reactive protein level was higher in the AFOP group than in the non-AFOP group. On high-resolution computed tomography, 85% of patients had OP pattern, and halo sign was more common in the AFOP group. Corticosteroids were effective in 94% of the patients in the AFOP group; however, recurrences were more frequent, and a higher corticosteroid dose was needed during recurrence. CONCLUSIONS: AFOP might be an early phase of a histologic pattern associated with known etiologies. In addition, it could be a marker indicating intense inflammatory diseases with a tendency of recurrence.

Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene.

BACKGROUND: Stickler syndrome (STL) is a clinically variable and genetically heterogeneous collagenopathy characterized by ophthalmic, auditory, skeletal, and orofacial abnormalities. STL is mainly inherited in an autosomal dominant pattern with mutations in the COL2A1, COL11A1, and COL11A2 genes. Autosomal recessive forms are rare. However, 19 patients have been reported to date, with STL caused by homozygous or compound heterozygous mutations in genes that encode for the three chains of type IX collagen: COL9A1, COL9A2, and COL9A3. METHODS: Genetic analysis was performed using the next-generation sequencing of 166 genes associated with skeletal disorders and sequenced on an Ion Torrent S5 system with a minimum coverage of 100X. The two variants in the COL9A3 gene identified in the proband and the parents were confirmed by Sanger sequencing on an ABI3130xl sequencer. RESULTS: We describe a novel case of autosomal recessive Stickler syndrome caused by two undescribed mutations in the COL9A3 gene: c.268C>T (p.Arg90Ter) and c.1729C>T (p.Arg577Ter). The clinical features included severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early-onset arthropathy of the lower limbs. Radiography revealed mild spondyloepiphyseal dysplasia. CONCLUSION: This case further expands the mutational and phenotypic spectrum of COL9A-associated STL with a more severe presentation.

ADAMTSL2 gene variant in patients with features of autosomal dominant connective tissue disorders.

Ehlers-Danlos syndrome (EDS) consists of a heterogeneous group of genetically inherited connective tissue disorders. A family with three affected members over two generations with features of Dermatosparaxic EDS (dEDS) autosomal dominant transmission was reported by Desai et al. and having a heterozygous nonsynonymous missense variant of ADAMTSL2 (c.1261G > A; p. Gly421Ser). Variation in this gene is also reported to cause autosomal recessive geleophysic dysplasia. We report five unrelated patients with the Gly421Ser variant identified from a large series of patients presenting with features of connective tissue disorders, each with a positive family history consistent with autosomal dominant transmission. Clinical features of a connective tissue disorder included generalized joint hypermobility and pain with fragility of internal and external tissues including of skin, dura, and arteries. Overall, our analyses including bioinformatics, protein modeling, and gene-protein interactions with the cases described would add evidence for the Gly421Ser variant in ADAMTSL2 as causative for variable expressivity of autosomal dominant connective tissue disorders.

Histologic features suggesting connective tissue disease in idiopathic pulmonary fibrosis.

Some patients with idiopathic pulmonary fibrosis (IPF) have histopathologic features suggesting connective tissue disease (CTD); however, their clinical course and prognosis remain unclear. Thus, we aimed to investigate the clinical course and prognosis of these patients with histologic autoimmune features. Among 114 patients with biopsy-proven IPF, the histologic features were semi-quantitatively graded, and CTD scores (range: 0-9) were calculated as the sum of each score of plasma cell infiltration, lymphoid aggregates, and germinal centres. Patients with high CTD scores (≥ 4) were classified into the interstitial pneumonia with histologic autoimmune features (IP-hAF) group. The mean age of the patients was 60.0 years; 74.6% were men, 69.3% were ever-smokers, and 35.1% had IP-hAF. During follow-up, the IP-hAF group showed slower decline in lung function, and better prognosis (median survival, 48.7 vs. 40.4 months; p = 0.015) than the no-IP-hAF group. On multivariate Cox analysis, IP-hAF was an independent prognostic factor (hazard ratio, 0.522; p = 0.016), along with the lower diffusing capacity for carbon monoxide, higher scores of reticulation and honeycombing, and usual interstitial pneumonia pattern on high-resolution computed tomography. Patients with IPF having histologic autoimmune features show distinct clinical characteristics and better outcome than those without histologic autoimmune features.

[Pathogenetic aspects of magnesium deficiency in connective tissue dysplasia syndrome].

The problem of connective tissue dysplasia is currently becoming particularly relevant because of significant increase of individuals with characteristic abnormalities in the structure of connective tissue. The lack of some micronutrients, arising during ontogenesis in the organism, can determine a high risk of worsening connective tissue homeostasis. Recently, the decisive role of magnesium deficiency in the progression of this disease has been demonstrated. The aim of the study was to substantiate the need for magnesium diet therapy in individuals with connective tissue dysplasia basing on the study of the pathogenetic significance of magnesium deficiency in this pathology. Material and methods. The electronic resources of the portals PubMed-NCBI, MEDLINE, the Scientific Electronic Library eLIBRARY.RU, CyberLeninka and the Google Academy were used. Results and discussion. The analysis of the obtained data made it possible to identify fundamentally new provisions on the main mechanisms of the magnesium influence on the metabolic state of all components of connective tissue. It was proved that magnesium deficiency is a predictor of worsening connective tissue homeostasis, increasing in the number of dysplastic symptoms and their severity. This pathogenetically justifies prescribing a balanced diet to patients with connective tissue dysplasia, including products rich in magnesium, taking into account its recommended daily intake, depending on age of patients. Conclusion. Adequate daily intake of magnesium will increase the mechanical properties and functionality of the connective tissue, and should be recommended for patients with connective tissue dysplasia to prevent the development of complications, maintain the quality of life and improve the prognosis for this disease.

Bronchoalveolar lavage: role in the evaluation of pulmonary interstitial disease.

INTRODUCTION: Bronchoalveolar lavage (BAL), a noninvasive, well-tolerated procedure is an important diagnostic tool that can facilitate the diagnosis of various lung diseases. This procedure allows the assessment of large alveolar compartments, by providing cells as well as non-cellular constituents from the lower respiratory tract. Alterations in BAL fluid and cells ratio reflects pathological changes in the lung parenchyma. In some cases, clinicians use BAL as a differential diagnosis guide for interstitial lung disease. AREAS COVERED: In this review, we summarized the diagnostic criteria for BAL in interstitial lung diseases, pulmonary infections, lung cancer and other pathologies such as fat embolism, gastroesophageal reflux and collagen vascular disease. For this review, we have selected scientific papers published in the PubMed database in our area of interest. We aimed to highlight the usefulness of BAL in respiratory pathology. EXPERT OPINION: Although BAL fluid analyzes has an essential role in the diagnostic work-up of many lung pathologies, it should be performed in selected patients. For accurate results, the BAL technique is very important to be standardized.

Evaluation of health-related quality of life and the related factors in a group of Chinese patients with interstitial lung diseases.

INTRODUCTION: Interstitial lung diseases (ILDs) include a wide variety of chronic progressive pulmonary diseases characterized by lung inflammation, fibrosis and hypoxemia and can progress to respiratory failure and even death. ILDs are associated with varying degrees of quality of life impairments in affected people. Studies on the quality of life in patients with ILDs are still limited, and there are few studies with long-term follow-up periods in these patients. METHODS: Data from patients who were clinically diagnosed with ILDs in the Respiratory Department, Beijing Chaoyang Hospital, Capital Medical University from January 2017 to February 2018 were collected. Clinical status and HRQoL were assessed at baseline and subsequently at 6- and 12-month intervals with the LCQ, mMRC, HADS, SF-36, and SGRQ. Multivariate linear regression was used to evaluate the determinants of the decline in HRQoL. RESULTS: A total of 139 patients with idiopathic interstitial pneumonia (IIP) and 30 with connective tissue disease-associated ILD (CTD-ILD) were enrolled, 140 of whom completed the follow-up. The mean age was 63.7 years, and 92 patients were men. At baseline, the decline in HRQoL assessed by the SF-36 and SGRQ was significantly associated with the mMRC, LCQ and HADS depression score. In the follow-up, changes in FVC%, DLco%, mMRC and LCQ were significantly associated with changes in HRQoL. CONCLUSIONS: HRQoL in both IIP and CTD-ILD patients deteriorates to varying degrees, and the trend suggests that poor HRQoL in these patients is associated with many determinants, primarily dyspnea, cough and depression. Improving HRQoL is the main aim when treating patients living with ILDs.

A lumpy back: extensive cutaneous collagenomas.

A widespread form of eruptive collagenomas in a 12-year-old man is presented for the impressive iconography, challenging differential diagnosis, and histopathological considerations associated with such rare connective tissue disorders. Syndromic forms should be carefully investigated for the different course and prognosis. Treatment is a major unsolved issue as aesthetic concerns are significant, especially in young adults.