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2.
Int J Dermatol ; 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38924070

ABSTRACT

Acquired cutis laxa (ACL) is a rare, nonhereditary cutaneous disorder characterized by saggy inelastic skin. It has been associated with various inflammatory, autoimmune, and neoplastic diseases, in addition to certain infections and medication. This article reviews ACL the demographical, clinical, and histological features of ACL, focusing on all associated disorders. Additionally, this review article provides an in-depth discussion of all the mechanisms implicated in the pathogenesis of ACL and all therapeutic options available; we also present an algorithm for the workup of patients with ACL. A systematic literature review was performed on PubMed/Medline and EMBASE databases, searching for all available articles on ACL with no limits on participant age, race, sex, nationality, or publication date. Ninety-eight articles were included. The total number of included patients was 110, with a mean age of 36.4 years at presentation (range 0.25-78) and a M:F sex ratio of 1.24. ACL was most commonly associated with inflammatory disorders (43%) followed by neoplastic disorders (27%). In 73% of the neoplastic-associated cases, ACL occurred on average 2.4 years before malignancy onset. ACL occurs months to years after an underlying inflammatory disorder. In 10% of the cases, ACL was associated with a particular drug, and in 2%, it was associated with specific infections. Data were derived from case reports, case series, letters to editors, observational studies, and abstracts. Limitations include the accuracy of published data, potential patient selection, and reporting bias. Dermatologists should be alert to these associations to provide adequate screening and management of patients with ACL.

3.
Mediterr J Rheumatol ; 35(1): 184-186, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38736957

ABSTRACT

Introduction: Wilson disease is a rare genetic disorder, characterised by excessive deposition of copper in the liver, brain, and other tissues. Penicillamine, a copper-chelating agent, is used in high doses in the treatment of Wilson disease leading to a variety of cutaneous reactions, including hyper-sensitivity reactions, pseudoxanthoma elasticum, elastosis perforans serpiginosa, anetoderma, and cutis laxa (CL). We present a rare case of localised CL induced by penicillamine for Wilson disease, in the absence of elastosis perforans serpiginosa. Case Description: A 41-year-old male with Wilson disease treated with long-term high-dose penicillamine was referred to us for a basal cell carcinoma on the scalp. On physical examination, diffusely flaccid and redundant skin on the right side of the neck were observed. Histopathology revealed findings consistent with CL. Conclusion: Long-term treatment with penicillamine for Wilson disease may induce localized CL, possibly by direct inhibition of cross-linkage of collagen fibres.

4.
Mol Biol Rep ; 51(1): 498, 2024 Apr 10.
Article in English | MEDLINE | ID: mdl-38598037

ABSTRACT

BACKGROUND: Cutis laxa is a connective tissue disease caused by abnormal synthesis or secretion of skin elastic fibers, leading to skin flabby and saggy in various body parts. It can be divided into congenital cutis laxa and acquired cutis laxa, and inherited cutis laxa syndromes is more common in clinic. METHODS: In this study, we reported a case of a Han-Chinese male newborn with ATP6V0A2 gene variant leading to cutis laxa. The proband was identified by whole-exome sequencing to determine the novel variant, and their parents were verified by Sanger sequencing. Bioinformatics analysis and minigene assay were used to verify the effect of this variant on splicing function. RESULTS: The main manifestations of the proband are skin laxity, abnormal facial features, and enlargement of the anterior fontanelle. Whole-exome sequencing showed that the newborn carried a non-canonical splicing-site variant c.117 + 5G > T, p. (?) in ATP6V0A2 gene. Sanger sequencing showed that both parents of the proband carried the heterozygous variant. The results of bioinformatics analysis and minigene assay displayed that the variant site affected the splicing function of pre-mRNA of the ATP6V0A2 gene. CONCLUSIONS: In this study, it was identified that ATP6V0A2 gene c. 117 + 5G > T may be the cause of the disease. The non-canonical splicing variants of ATP6V0A2 gene were rarely reported in the past, and this variant expanded the variants spectrum of the gene. The functional study of minigene assay plays a certain role in improving the level of evidence for the pathogenicity of splicing variants, which lays a foundation for prenatal counseling and follow-up gene therapy.


Subject(s)
Cutis Laxa , Female , Humans , Infant, Newborn , Male , Pregnancy , Asian People/genetics , China , Cutis Laxa/genetics , Proton-Translocating ATPases , RNA Splicing/genetics , Skin
6.
Rev. bras. cir. plást ; 39(1): 1-4, jan.mar.2024. ilus
Article in English, Portuguese | LILACS-Express | LILACS | ID: biblio-1525801

ABSTRACT

Cútis laxa é uma rara doença do tecido conectivo caracterizada pela disfunção das fibras elásticas. Indivíduos acometidos por essa enfermidade queixam-se de sua aparência envelhecida. Os tratamentos se baseiam no uso de cosméticos ou em técnicas cirúrgicas, sendo a cirurgia plástica uma ferramenta de extrema relevância. A blefaroplastia tem o objetivo de melhorar a aparência senil e proporcionar rejuvenescimento na área ao redor dos olhos, fazendo com que o olhar pareça mais descansado e alerta. Trata-se de um estudo observacional retrospectivo utilizando os dados do prontuário. Relato do Caso: Paciente do sexo feminino, 17 anos, encaminhada ao serviço de Cirurgia Plástica do Hospital Universitário Walter Cantídio, Fortaleza- CE, para tratamento devido à insatisfação com a sua aparência. Submetida a uma blefaroplastia superior e inferior associada a cantopexia sem cantotomia. No período pós-operatório, foi observado resultado satisfatório para a cirurgia proposta e adequada correção das alterações existentes. Conclusão: Observa-se a importância da correção cirúrgica facial nos casos de cútis laxa, ressaltando a relevância da aplicação de técnicas cirúrgicas adequadas e o aprimoramento das mesmas nesse perfil de paciente.


Cutis laxa is a rare connective tissue disease characterized by dysfunction of elastic fibers. Individuals affected by this disease complain about their aged appearance. Treatments are based on the use of cosmetics or surgical techniques, with plastic surgery being an extremely relevant tool. Blepharoplasty aims to improve the senile appearance and provide rejuvenation in the area around the eyes, making the look appear more rested and alert. This is a retrospective observational study using medical record data. Case Report: A female patient, 17 years old, was referred to the Plastic Surgery Service of the Walter Cantídio University Hospital, Fortaleza-CE, for treatment due to dissatisfaction with her appearance. She underwent upper and lower blepharoplasty associated with canthopexy without canthotomy. In the postoperative period, a satisfactory result was observed for the proposed surgery and adequate correction of existing changes. Conclusion: The importance of facial surgical correction in cases of lax skin is observed, highlighting the relevance of applying appropriate surgical techniques and improving them in this patient profile.

7.
Int J Mol Sci ; 25(4)2024 Feb 11.
Article in English | MEDLINE | ID: mdl-38396846

ABSTRACT

Vacuolar ATPases (V-ATPases), proton pumps composed of 16 subunits, are necessary for a variety of cellular functions. Subunit "a" has four isoforms, a1-a4, each with a distinct cellular location. We identified a phosphoinositide (PIP) interaction motif, KXnK(R)IK(R), conserved in all four isoforms, and hypothesize that a/PIP interactions regulate V-ATPase recruitment/retention to different organelles. Among the four isoforms, a2 is enriched on Golgi with a2 mutations in the PIP motif resulting in cutis laxa. We hypothesize that the hydrophilic N-terminal (NT) domain of a2 contains a lipid-binding domain, and mutations in this domain prevent interaction with Golgi-enriched PIPs, resulting in cutis laxa. We recreated the cutis laxa-causing mutation K237_V238del, and a double mutation in the PIP-binding motif, K237A/V238A. Circular dichroism confirmed that there were no protein structure alterations. Pull-down assays with PIP-enriched liposomes revealed that wildtype a2NT preferentially binds phosphatidylinositol 4-phosphate (PI(4)P), while mutants decreased binding to PI(4)P. In HEK293 cells, wildtype a2NT was localized to Golgi and co-purified with microsomal membranes. Mutants reduced Golgi localization and membrane association. Rapamycin depletion of PI(4)P diminished a2NT-Golgi localization. We conclude that a2NT is sufficient for Golgi retention, suggesting the lipid-binding motif is involved in V-ATPase targeting and/or retention. Mutational analyses suggest a molecular mechanism underlying how a2 mutations result in cutis laxa.


Subject(s)
Cutis Laxa , Vacuolar Proton-Translocating ATPases , Humans , Cutis Laxa/genetics , Cutis Laxa/metabolism , HEK293 Cells , Protein Isoforms/metabolism , Vacuolar Proton-Translocating ATPases/metabolism , Mutation
8.
Am J Med Sci ; 367(4): 268-273, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38278360

ABSTRACT

Cutis laxa is a rare connective tissue disorder, characterized by a reduced number and abnormal properties of elastic fibers throughout the dermis, creating a clinical appearance of premature aging. It can be subdivided into inherited and acquired, the latter rarer than the former, and skin involvement may be localized or generalized. The etiology of acquired cutis laxa (ACL) remains unknown and there is no definitive treatment. We present the case of a 30-year-old man diagnosed with type I ACL with progressive systemic involvement at the renal, pulmonary, and digestive levels. Histological analysis of the skin revealed reduction and fragmentation of elastic fibers. Immunosuppressive treatment was started with prednisone, cyclophosphamide, and rituximab, with which a complete response to proteinuria was achieved and the progression of lung damage was limited. Autoimmune, infectious, and neoplastic diseases were ruled out.


Subject(s)
Cutis Laxa , Male , Humans , Adult , Cutis Laxa/diagnosis , Cutis Laxa/drug therapy , Cutis Laxa/pathology , Skin/pathology , Immunosuppressive Agents , Cyclophosphamide/therapeutic use , Rituximab
9.
J Dermatol ; 51(2): 287-293, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37334758

ABSTRACT

Cutis laxa presents as loose redundant skin folds and loss of dermal elastic tissue. Acquired cutis laxa (ACL) is characterized by later onset. It has been reported in association with various kinds of neutrophilic dermatoses, drugs, metabolic disorders, and autoimmune disorders. Acute generalized exanthematous pustulosis (AGEP) is usually classified as a severe cutaneous adverse reaction characterized by T cell-mediated neutrophilic inflammation. We previously reported a mild case of AGEP caused by gemcitabine in a 76-year-old man. Here, we report a case of ACL secondary to AGEP in this patient. He developed AGEP 8 days after gemcitabine administration. Four weeks after beginning chemotherapy, his skin had become atrophic, loose, and darkly pigmented in areas previously affected by AGEP. Histopathological examination revealed edema and perivascular lymphocytic infiltration but no neutrophilic infiltration in the upper dermis. Elastica van Gieson staining showed that the elastic fibers in all layers of the dermis were sparse and shortened. Electron microscopy showed elevated numbers of fibroblasts and altered elastic fibers with irregular surfaces. Finally, he was diagnosed with ACL secondary to AGEP. He was treated with topical corticosteroids and oral antihistamines. Skin atrophy decreased over 3 months. We summarize 36 cases (including our case) with ACL secondary to neutrophilic dermatosis. We discuss these clinical manifestations, causative neutrophilic disorders, treatments, and outcomes. The mean age of patients was 3.5 years. Five patients had an aortic lesion as systemic involvement. The most common causative neutrophilic disorders were Sweet syndrome (24 cases), followed by urticaria-like neutrophilic dermatosis (11 cases). There were no cases of AGEP except for our case. Although treatment for ACL secondary to neutrophilic dermatosis, such as dapsone, oral prednisolone, adalimumab, and plastic surgery were reported, ACL is generally refractory and irreversible. Our patient was considered reversibly cured due to the absence of continuous neutrophil-mediated elastolysis.


Subject(s)
Acute Generalized Exanthematous Pustulosis , Cutis Laxa , Dermatitis , Sweet Syndrome , Male , Humans , Child, Preschool , Aged , Acute Generalized Exanthematous Pustulosis/diagnosis , Acute Generalized Exanthematous Pustulosis/etiology , Acute Generalized Exanthematous Pustulosis/pathology , Gemcitabine , Skin/pathology , Sweet Syndrome/pathology , Dermatitis/pathology
10.
Eur Heart J Case Rep ; 7(11): ytad530, 2023 Nov.
Article in English | MEDLINE | ID: mdl-38025136

ABSTRACT

Background: Thoracic aortic aneurysms are rarely symptomatic but can result in acute aortic syndromes, associated with a high mortality rate. While most cases may be acquired, a genetic basis is evident in approximately 20-25% of the cases, especially among patients under 50 years of age, and those exhibiting syndromic features or family history. Although autosomal dominant inheritance is predominant in familial aortopathies, exceptions exist, such as cutis laxa 1B (CL1B)-related aortic disease, caused by variants in EFEMP2 gene, that follows an autosomal recessive inheritance pattern. Case summary: We present the case of a 26-year-old male with a giant ascending aorta aneurysm and massive pericardial effusion, which was ultimately diagnosed of CL1B due to the p.Ser137Cys variant in the EFEMP2 gene in homozygosis. The patient underwent successful ascending aorta replacement (Bentall´s procedure). There were not complications or further events after 2 years of follow-up. Discussion: This case underscores the importance of genetic testing in young patients presenting with aortopathies, syndromic features, or atypical presentations, irrespective of family history.

11.
Am J Med Genet A ; 191(12): 2898-2902, 2023 12.
Article in English | MEDLINE | ID: mdl-37655511

ABSTRACT

We report a 10-year-old boy with a de novo pathogenic variant in ALDH18A1, a rare form of metabolic cutis laxa, which was complicated by atlantoaxial instability and spinal cord compression following a fall from standing height. The patient required emergent cervical spine fusion and decompression followed by a 2-month hospitalization and rehabilitation. In addition to the core clinical features of joint and skin laxity, hypotonia, and developmental delays, we expand the connective tissue phenotype by adding a new potential feature of cervical spine instability. Patients with pathogenic variants in ALDH18A1 may warrant cervical spine screening to minimize possible morbidity. Neurosurgeons, geneticists, primary care providers, and families should be aware of the increased risk of severe cervical injury from minor trauma.


Subject(s)
Cutis Laxa , Joint Instability , Spinal Diseases , Male , Humans , Child , Joint Instability/diagnosis , Joint Instability/genetics , Cutis Laxa/genetics , Mutation , Cervical Vertebrae/surgery , Cervical Vertebrae/pathology
13.
Cureus ; 15(1): e33280, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36741656

ABSTRACT

De Barsy syndrome (DBS) is an exceedingly rare autosomal recessively inherited genetic disorder that manifests as premature aging with progeroid features. Typically, the skin loses its elasticity, causing laxity, wrinkling, and sagging. Other characteristics include ophthalmological, orthopedic, and neurological abnormalities. As of 2011, only 27 DBS cases had been recorded. This paper reports the case of a two-day-old female infant who was referred to the pediatrics department with complaints of lax skin, a progeroid appearance, a short stature, hazy corneas, and bilateral claw-like hands with thin overlapping fingers. She also had features of pectus excavatum and visible veins over her chest and abdomen. There was a history of third-degree consanguineous parents in this patient. This patient was diagnosed with De Barsy syndrome due to findings on the Verhoeff Van Gieson staining, which demonstrated a marked decrease in elastic tissue fibers. Palliative care was recommended for this infant. We report this case considering its extreme rarity.

14.
Mol Syndromol ; 14(1): 80-87, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36777703

ABSTRACT

Introduction: FBLN5-related cutis laxa is a very rare, autosomal recessive syndrome that is characterized by loose, wrinkled, and redundant skin, sagging cheeks, emphysema, aortic or pulmonary artery abnormalities, inguinal hernia, and diverticula of the gastrointestinal and urinary tract. Case Presentation: In this study, we report an 8-year-old Turkish girl with a novel homozygous missense variant in the FBLN5 gene, c.862G>T, p.(Asp288Tyr). Her unaffected parents were carriers of the same variant. The patient had loose skin, short stature, broad eyebrows, large ears, inguinal hernia, frequent respiratory tract infections, a history of peripheral pulmonary artery stenosis, and fourth finger contractures on both hands. Discussion: To our knowledge, 8 families have been reported to date, and this family is the third Turkish family with FBLN5-related cutis laxa. In addition to the classical findings of cutis laxa, the patient had fourth finger contractures on both hands. This report contributes to the ongoing clinical and genetic characterization of FBLN5-related cutis laxa.

15.
Ir J Med Sci ; 192(5): 2279-2282, 2023 Oct.
Article in English | MEDLINE | ID: mdl-36520350

ABSTRACT

Cutis laxa (CL) can be caused by mutations in a number of genes. Cutis laxa with autosomal recessive inheritance due to mutations in several genes, including mutations in the ATP6V0A2 gene, causes autosomal recessive cutis laxa type 2A (ARCL2A). The ATP6V0A2 gene encodes the a2 subunit in the V-ATPases pump. The V-ATPases are located in the membrane of some organelles, including the Golgi or some vesicles, and act as ATP-dependent proton pumps to pH adjustment intracellular segments. Mutations in the ATP6V0A2 gene consist present in ARCL2A patients. We present the case of a 12-year-old girl who was referred to Rasad Laboratory (Tehran, Iran) at the age of 5 with a set of symptoms of congenital disorders. Her clinical phenotype contains distal symmetrical sensory and motor polyneuropathy, loose joints, large nasal roots, growth delay, and wrinkled skin. Also, there was a history of the parental marriage of consanguinity. A potentially pathogenic homozygous deletion mutation was detected in the ATP6V0A2 gene related to ARCL2A. This mutation has not been reported in the other patients with ARCL2A. A novel homozygous deletion mutation in ATP6V0A2 is supposed to be the reason for disease in our proband.


Subject(s)
Cutis Laxa , Female , Humans , Child , Cutis Laxa/genetics , Cutis Laxa/diagnosis , Cutis Laxa/pathology , Iran , Homozygote , Proton-Translocating ATPases/genetics , Sequence Deletion , Mutation
16.
Ophthalmic Genet ; 44(5): 509-511, 2023 10.
Article in English | MEDLINE | ID: mdl-36524384

ABSTRACT

BACKGROUND: This report describes a very rare case of progeroid syndrome of De Barsy (Cutis laxa-corneal clouding syndrome). MATERIALS AND METHODS: A 2 year-old child presented to the pediatric ophthalmology outpatients with bilateral congenital corneal opacification along with dysmorphic facial features, including loose wrinkled skin, progeroid appearance, delayed milestones, short stature, multiple hyper-extensible joints, muscular hypotonia, pectus excavatum and congenital dislocation of the hip joint. The child underwent a detailed ophthalmic work up and systemic evaluation by a clinical geneticist. RESULTS: Ophthalmic management in the form of bilateral sequential penetrating keratoplasties and a left eye trabeculectomy for medically uncontrolled angle-closure glaucoma was performed. Visual rehabilitation with glasses and amblyopia therapy is ongoing. Histopathology of the corneal button revealed loss of the bowman's layer which was replaced by a fibrous pannus while the stroma showed loss of stromal lamellar architecture with anterior and mid stroma showing vascularization. Genetic testing confirmed a mutation in the PYCR1 gene for a homozygous autosomal recessive cutis laxa type IIB. CONCLUSIONS: Although rare, De Barsy syndrome is an important cause of corneal opacification at birth with multiple systemic abnormalities that requires intervention.


Subject(s)
Abnormalities, Multiple , Corneal Opacity , Cutis Laxa , Intellectual Disability , Child , Infant, Newborn , Humans , Child, Preschool , Cutis Laxa/genetics , Cutis Laxa/pathology , Intellectual Disability/genetics , Corneal Opacity/diagnosis , Corneal Opacity/etiology , Corneal Opacity/surgery , Syndrome , Abnormalities, Multiple/genetics
17.
Clin Case Rep ; 10(12): e6573, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36518920

ABSTRACT

We present an adolescent girl with a highly stenotic ascending aortic conduit of her former during infancy corrected giant aneurysm. Genetic testing determined autosomal recessive cutis laxa type-Ib as the underlying connective tissue disorder. Re-do valve sparing root and arch replacement gained excellent restoration of the aorta; 1-year-follow-up was uneventful.

18.
Am J Hum Genet ; 109(12): 2230-2252, 2022 12 01.
Article in English | MEDLINE | ID: mdl-36351433

ABSTRACT

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elastogenesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1- or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1-/- femora show abnormal trabecular bone formation and strength. Altogether, EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vascular tissue homeostasis.


Subject(s)
Bone Diseases, Metabolic , Cutis Laxa , Animals , Humans , Mice , Collagen/genetics , Cutis Laxa/genetics , Elastin/metabolism , Extracellular Matrix Proteins/metabolism
19.
Am J Med Genet A ; 188(11): 3343-3349, 2022 11.
Article in English | MEDLINE | ID: mdl-35972031

ABSTRACT

Cutis laxa (CL) is a rare connective tissue disorder characterized by wrinkled, abundant and sagging skin, sometimes associated with systemic impairment. Biallelic alterations in latent transforming growth factor beta-binding protein 4 gene (LTBP4) cause autosomal recessive type 1C cutis laxa (ARCL1C, MIM #613177). The present report describes the case of a 17-months-old girl with cutis laxa together with a literature review of previous ARCL1C cases. Based on proband main clinical signs (cutis laxa and pulmonary emphysema), clinical exome sequencing (CES) was performed and showed a new nine base-pairs homozygous in-frame deletion in LTBP4 gene. RT-PCR and cDNA Sanger sequencing were performed in order to clarify its impact on RNA. This report demonstrates that a genetic alteration in the EGF-like 14 domain calcium-binding motif of LTBP4 gene is likely responsible for cutis laxa in our patient.


Subject(s)
Cutis Laxa , Calcium , Cartilage Diseases , Cutis Laxa/genetics , DNA, Complementary , Epidermal Growth Factor , Female , Gastrointestinal Diseases , Humans , Infant , Latent TGF-beta Binding Proteins/genetics , RNA , Respiratory Tract Diseases , Transforming Growth Factor beta , Urologic Diseases
20.
Arch Plast Surg ; 49(3): 418-422, 2022 May.
Article in English | MEDLINE | ID: mdl-35832160

ABSTRACT

Acquired cutis laxa is a rare disease. Owing to few reports on the condition, no statistical data have been produced. Cutis laxa is characterized by drooping skin, caused by decreased levels of dermal elastin, leading to reduced skin elasticity. The disease usually emerges on the neck or trunk and spreads throughout the body; however, it rarely involves the extremities. 2 Moreover, cases localized to the face are rare. The objective of this clinical case report was to highlight this unusual disease in a 24-year-old female, with localization on the face and neck. The patient underwent surgery for treatment of bilateral ear lobe and eyelid skin laxity.

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