Cutis Laxa and the Value of Rhytidectomy: 4 Patients and Years of Follow-Up.

The modalities of the esthetic treatment of cutis laxa (CL) patients have rarely been discussed. Here, the authors present 4 CL rhytidectomy cases. The surgery method was designed based on the traditional full-incision face-lift technique combined with lamellar superficial musculoaponeurotic system flap elevation and plication. Temporal, buccal, mandibular, and cervical regions were targeted. The shortest follow-up was 30 months, and the longest was 72. The results were assessed by subjective satisfaction and third-party photo evaluation. The subjective satisfaction was graded into worse than preoperation, no improvement, slight improvement, moderate improvement, and obvious improvement. The satisfaction rate was the sum of moderate and obvious improvement. Eighteen uncorrelated professionals participated in the third-party photo evaluation, in which the preoperative and follow-up photos were presented, and frontal, temporal, mid-face (including jowl), and cervical (including mandibular line) regions were evaluated as improved or nonimproved. The outcome of the subjective satisfaction was graded as no improvement (2/12, 16.7%), slight improvement (3/12, 25%), moderate improvement (4/12, 33.3%), and obvious improvement (3/12, 25%). The satisfaction rate was 58.3%, most investigators denied the frontal and temporal region improvement, 60% observed mid-face improvement, and 80% noticed cervical improvement. Most patients and their parents had positive attitudes towards the treatment results; however, the full expectation was not achieved. The cervical region maintained the best improvement after our treatment and the mid-face ranked second. This surgery method conduces to the esthetic requirement of CL patients; however, skin laxity remains a challenge.

Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome.

Latent transforming growth factor ß (TGFß)-binding proteins (LTBPs) are microfibril-associated proteins essential for anchoring TGFß in the extracellular matrix (ECM) as well as for correct assembly of ECM components. Variants in LTBP2, LTBP3, and LTBP4 have been identified in several autosomal recessive Mendelian disorders with skeletal abnormalities with or without impaired development of elastin-rich tissues. Thus far, the human phenotype associated with LTBP1 deficiency has remained enigmatic. In this study, we report homozygous premature truncating LTBP1 variants in eight affected individuals from four unrelated consanguineous families. Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly). In vitro studies on proband-derived dermal fibroblasts indicate distinct molecular mechanisms depending on the position of the variant in LTBP1. C-terminal variants lead to an altered LTBP1 loosely anchored in the microfibrillar network and cause increased ECM deposition in cultured fibroblasts associated with excessive TGFß growth factor activation and signaling. In contrast, N-terminal truncation results in a loss of LTBP1 that does not alter TGFß levels or ECM assembly. In vivo validation with two independent zebrafish lines carrying mutations in ltbp1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae. In addition, one of the mutant zebrafish lines shows voluminous and hypo-mineralized vertebrae. Overall, our findings in humans and zebrafish show that LTBP1 function is crucial for skin and bone ECM assembly and homeostasis.

Severe congenital cutis laxa: Identification of novel homozygous LOX gene variants in two families.

We report three babies from two families with a severe lethal form of congenital cutis laxa. All three had redundant and doughy-textured skin and two siblings from one family had facial dysmorphism. Echocardiograms showed thickened and poorly contractile hearts, arterial dilatation and tortuosity. Post-mortem examination in two of the babies further revealed widespread ectasia and tortuosity of medium and large sized arteries, myocardial hypertrophy, rib and skull fractures. The presence of fractures initially suggested a diagnosis of osteogenesis imperfecta. Under light microscopy bony matrices were abnormal and arterial wall architecture was grossly abnormal showing fragmented elastic fibres. Molecular analysis of known cutis laxa genes did not yield any pathogenic defects. Whole exome sequencing of DNA following informed consent identified two separate homozygous variants in the LOX (Lysyl Oxidase) gene. LOX belongs to the 5-lysyl oxidase gene family involved in initiation of cross-linking of elastin and collagen. A mouse model of a different variant in this gene recapitulates the phenotype seen in the three babies. Our findings suggest that the LOX gene is a novel cause of severe congenital cutis laxa with arterial tortuosity, bone fragility and respiratory failure.

Acral localized acquired cutis laxa as presenting sign of underlying systemic amyloidosis.

Acral localized acquired cutis laxa (ALACL) is a rare variant of acquired cutis laxa, and the clinical appearance is characterized by loose, redundant and wrinkled skin of the distal extremities. By definition, histopathology of affected tissue reveals sparse or fragmented elastic fibers. However, this can be difficult to assess on routine staining, and sometimes requires electron microscopy. The condition has been associated with plasma cell dyscrasias or recurrent inflammatory states. We present a case of a 65-year-old man who presented with enlarged and doughy finger pads. Skin biopsy showed diffuse dermal amyloid deposition displacing dermal stroma and reduction of elastic fibers, although these changes were subtle on routine hematoxylin and eosin staining. Mass spectrometry of laser capture microdissected tissue showed AL kappa-type amyloid and further workup revealed a diagnosis of primary systemic AL-kappa amyloidosis requiring bone marrow transplantation. This case represents an unusual presentation of acquired cutis laxa and highlights the need for a high index of suspicion when reviewing histopathology of this entity. In addition, the case highlights the importance of investigation into possible systemic associations, such as plasma cell dyscrasias.

[Multifocal chalazodermic amyloidosis: The concept of immunoglobulinemic elastopathy]. / Chalazodermie amyloïde multifocale. Le concept d'élastopathie immunoglobulinémique.

INTRODUCTION: Impairment of dermal elastic tissue occurs in different entities associated with immunoglobulins or immunoglobulin-derived protein-secreting clonal plasma cell proliferations, such as amyloid elastosis, anetodermic nodular amyloidosis or monoclonal gammopathy-associated cutis laxa. We report a case of cutaneous immunoglobulinemic amyloidosis revealed by a unique chalazodermic presentation and we review elastic tissue impairment in patients with monoclonal gammopathies. OBSERVATION: A 67-year-old woman consulted for non-infiltrated anetodermic lesions on the upper left quadrant of her abdomen present for ten years. She also had a chalazodermic plaque with abnormal skin wrinkling and laxity in her right axilla. Biopsies revealed deep dermal and subcutaneous amyloid deposits. Immunohistochemistry with lambda light chain was positive. Orcein staining and electron microscopy showed extensive elastolysis. The patient presented no signs of systemic involvement, but a very small amount of monoclonal IgGλ gammopathy was detected during follow-up. DISCUSSION: This is a unique chalazodermic presentation of immunoglobulinemic amyloidosis that does not fit into a clearly-defined nosological setting. It highlights the complex interactions between immunoglobulin-derived proteins, including light and heavy chains, and elastic tissue components, leading to different types of impairment of the latter. We therefore suggest the unifying concept of immunoglobulinemic elastopathy, underscoring the need to screen for monoclonal gammopathy in patients presenting elastic tissue impairments.

Cutis laxa for diagnosis of γ1-heavy-chain deposition disease: Report of four cases.

Heavy-chain deposition disease (HCDD) is characterized by tissue deposits of a truncated monoclonal immunoglobulin heavy-chain (HC) on basement membranes. Diagnosis is usually made on kidney biopsy, showing nodular glomerulosclerosis with HC deposits which can be missed, resulting in delay in diagnosis. We report four γ1-HCDD patients presenting with cutis laxa, hypocomplementemia and hypoalbuminemia. In two patients, unsuspected HCDD was revealed by cutis laxa and diagnosis was made on skin biopsy. In all patients, serum albumin and complement represented surrogate markers for disease monitoring. In γ-HCDD, extrarenal manifestations such as cutis laxa may precede renal injury and are precious tools for an early diagnosis, which is crucial to avoid progression of irreversible renal and elastic tissue damage.

Effect of the R119G mutation on human P5CR structure and its interactions with NAD: Insights derived from molecular dynamics simulation and free energy analysis.

Pyrroline-5-carboxylate reductase (P5CR), an enzyme with conserved housekeeping roles, is involved in the etiology of cutis laxa. While previous work has shown that the R119G point mutation in the P5CR protein is involved, the structural mechanism behind the pathology remains to be elucidated. In order to probe the role of the R119G mutation in cutis laxa, we performed molecular dynamics (MD) simulations, essential dynamics (ED) analysis, and Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations on wild type (WT) and mutant P5CR-NAD complex. These MD simulations and ED analyses suggest that the R119G mutation decreases the flexibility of P5CR, specifically in the substrate binding pocket, which could decrease the kinetics of the cofactor entrance and egress. Furthermore, the MM-PBSA calculations suggest the R119G mutant has a lower cofactor binding affinity for NAD than WT. Our study provides insight into the possible role of the R119G mutation during interactions between P5CR and NAD, thus bettering our understanding of how the mutation promotes cutis laxa.

Progressive cranial nerve involvement and grading of facial paralysis in gelsolin amyloidosis.

INTRODUCTION: Hereditary gelsolin amyloidosis (GA) is a rare condition caused by the gelsolin gene mutation. The diagnostic triad includes corneal lattice dystrophy (type 2), progressive bilateral facial paralysis, and cutis laxa. Detailed information on facial paralysis in GA and the extent of cranial nerve injury is lacking. METHODS: 29 GA patients undergoing facial corrective surgery were interviewed, examined, and studied electroneurophysiologically. RESULTS: All showed dysfunction of facial (VII) and trigeminal (V) nerves, two-thirds of oculomotor (III) and hypoglossal (XII) nerves, and half of vestibulocochlear (acoustic) (VIII) nerve. Clinical involvement of frontal, zygomatic, and buccal facial nerve branches was seen in 97%, 83%, and 52% of patients, respectively. Electromyography showed marked motor unit potential loss in facial musculature. CONCLUSIONS: Cranial nerve involvement in GA is more widespread than previously described, and correlates with age, severity of facial paralysis, and electromyographic findings. We describe a grading method for bilateral facial paralysis in GA, which is essential for evaluation of disease progression and the need for treatment.

[Skin manifestations of monoclonal gammopathies]. / Manifestations cutanées associées aux gammapathies monoclonales.

Whatever their aetiology, monoclonal gammopathies can be associated to several clinical features. Mechanisms are various and sometimes unknown. Skin is frequently involved and may represent a challenging diagnosis. Indeed, skin manifestations are either the presenting features and isolated, or at the background of a systemic syndrome. Our objective was to review the various skin manifestations that have been associated with monoclonal gammopathies.

Acquired cutis laxa with an interstitial granulomatous reaction associated with IgG lambda monoclonal gammopathy.

Acquired cutis laxa (ACL) is a rare connective tissue disorder that affects the skin elastic fibers, resulting in the loss of elasticity. In 50% of cases, this condition is associated with other diseases, particularly plasma-cell dyscrasias. This report describes a case of ACL with unusual clinical and histopathological characteristics. A 29-year-old man presented with diffuse erythematous plaques that had first appeared 5 months previously. Examination revealed multiple flaccid erythematous plaques on his trunk, neck, and skinfolds. Immunophenotyping of bone marrow aspirate revealed 7% of monoclonal plasma cells with lambda light chain expression. Skin biopsy histology revealed foci of interstitial granulomatous reaction. Weigert stain showed a loss of elastic fibers in the dermis, areas with thickened fibers and elastophagocytosis. Immunohistochemistry was positive for CD68. The cutaneous findings enabled an early diagnosis of IgG lambda monoclonal gammopathy to be made. Microscopic examination revealed an interstitial granulomatous reaction and severe alterations in the elastic fibers that varied in intensity in the different biopsies. Curiously, little has been mentioned in the literature regarding the presence of an interstitial granulomatous reaction in ACL. It is our belief that this reaction is secondary to the degenerative process of the elastic fibers.

Golgi pH, its regulation and roles in human disease.

Most organelles within the exocytic and endocytic pathways typically acidify their interiors, a phenomenon that is known to be crucial for their optimal functioning in eukaryotic cells. This review highlights recent advances in our understanding of how Golgi acidity is maintained and regulated, and how its misregulation contributes to organelle dysfunction and disease. Both its biosynthetic products (glycans) and protein-sorting events are highly sensitive to changes in Golgi luminal pH and are affected in certain human disease states such as cancers and cutis laxa. Other potential disease states that are caused by, or are associated with, Golgi pH misregulation will also be discussed.

Renal crescentic alpha heavy chain deposition disease: a report of 3 cases and review of the literature.

Heavy chain deposition disease (HCDD) is a comparatively recently described entity characterized by glomerular and tubular basement membrane deposition of monoclonal heavy chains without associated light chains. To our knowledge, review of the literature shows only 24 previously reported cases of HCDD with unequivocal evidence of monoclonal heavy chain deposition in the kidney using immunofluorescence microscopic and electron microscopic studies. The predominant heavy chain subtype was γ. There has been a single case of µ HCDD and 2 previously reported cases of α HCDD. In this report, we describe 3 additional cases of α HCDD, all with a crescentic pattern of injury and one of which was associated with cutis laxa. We compare their clinicopathologic features with all previously reported cases of HCDD.