RESUMEN
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.
Asunto(s)
Enfermedades Óseas Metabólicas , Cutis Laxo , Animales , Humanos , Ratones , Colágeno/genética , Cutis Laxo/genética , Elastina/metabolismo , Proteínas de la Matriz Extracelular/metabolismoRESUMEN
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.
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Colágeno/metabolismo , Cutis Laxo/etiología , Variación Genética , Proteínas de Unión a TGF-beta Latente/genética , Adolescente , Alelos , Animales , Células Cultivadas , Niño , Preescolar , Cutis Laxo/patología , Matriz Extracelular/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Lactante , Masculino , Linaje , Piel/metabolismo , Piel/patología , Pez CebraRESUMEN
Epidermal nevus syndrome (ENS) comprises a heterogeneous group of neurocutaneous syndromes associated with the presence of epidermal nevi and variable extracutaneous manifestations. Postzygotic activating HRAS pathogenic variants were previously identified in nevus sebaceous (NS), keratinocytic epidermal nevus (KEN), and different ENS, including Schimmelpenning-Feuerstein-Mims and cutaneous-skeletal-hypophosphatasia syndrome (CSHS). Skeletal involvement in HRAS-related ENS ranges from localized bone dysplasia in association with KEN to fractures and limb deformities in CSHS. We describe the first association of HRAS-related ENS and auricular atresia, thereby expanding the disease spectrum with first branchial arch defects if affected by the mosaic variant. In addition, this report illustrates the first concurrent presence of verrucous EN, NS, and nevus comedonicus (NC), indicating the possibility of mosaic HRAS variation as an underlying cause of NC. Overall, this report extends the pleiotropy of conditions associated with mosaic pathogenic variants in HRAS affecting ectodermal and mesodermal progenitor cells.
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Nevo , Neoplasias Cutáneas , Humanos , Síndrome , Región Branquial/patología , Nevo/patología , Proteínas Proto-Oncogénicas p21(ras)RESUMEN
Arterial tortuosity syndrome (ATS) is a recessively inherited connective tissue disorder, mainly characterized by tortuosity and aneurysm formation of the major arteries. ATS is caused by loss-of-function mutations in SLC2A10, encoding the facilitative glucose transporter GLUT10. Former studies implicated GLUT10 in the transport of dehydroascorbic acid, the oxidized form of ascorbic acid (AA). Mouse models carrying homozygous Slc2a10 missense mutations did not recapitulate the human phenotype. Since mice, in contrast to humans, are able to intracellularly synthesize AA, we generated a novel ATS mouse model, deficient for Slc2a10 as well as Gulo, which encodes for L-gulonolactone oxidase, an enzyme catalyzing the final step in AA biosynthesis in mouse. Gulo;Slc2a10 double knock-out mice showed mild phenotypic anomalies, which were absent in single knock-out controls. While Gulo;Slc2a10 double knock-out mice did not fully phenocopy human ATS, histological and immunocytochemical analysis revealed compromised extracellular matrix formation. Transforming growth factor beta signaling remained unaltered, while mitochondrial function was compromised in smooth muscle cells derived from Gulo;Slc2a10 double knock-out mice. Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined.
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Arterias/anomalías , Deficiencia de Ácido Ascórbico/genética , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Inestabilidad de la Articulación/genética , L-Gulonolactona Oxidasa/genética , Enfermedades Cutáneas Genéticas/genética , Malformaciones Vasculares/genética , Animales , Arterias/metabolismo , Arterias/patología , Ácido Ascórbico/biosíntesis , Ácido Ascórbico/genética , Deficiencia de Ácido Ascórbico/metabolismo , Deficiencia de Ácido Ascórbico/patología , Modelos Animales de Enfermedad , Homocigoto , Humanos , Inestabilidad de la Articulación/metabolismo , Inestabilidad de la Articulación/patología , Ratones , Ratones Noqueados , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Respiración/genética , Transducción de Señal/genética , Enfermedades Cutáneas Genéticas/metabolismo , Enfermedades Cutáneas Genéticas/patología , Malformaciones Vasculares/metabolismo , Malformaciones Vasculares/patologíaRESUMEN
Mosaic RASopathies are a molecularly heterogeneous group of (neuro)cutaneous syndromes with high phenotypical variability. Postzygotic variants in KRAS have been described in oculoectodermal syndrome (OES), encephalocraniocutaneous lipomatosis (ECCL) and epidermal nevus syndrome (ENS). This study confirms the continuum of mosaic neurocutaneous RASopathies showing codon 146 KRAS variants in an individual with OES and, for the first time, in an individual with (isolated) epidermal nevus. The presence of a nevus psiloliparus in individuals with OES indicates that this finding is not specific for ECCL and highlights the phenotypical overlap between ECCL and OES. The presence of the somatic KRAS variant in the nevus psiloliparus resolves the underlying molecular etiology of this fatty-tissue nevus. In addition, this finding refutes the theory of non-allelic twin-spotting as an underlying hypothesis to explain the concurrent presence of two different mosaicisms in one individual. The identification of codon 146 KRAS variants in isolated epidermal nevus introduces a new hot spot for this condition, which is useful for increasing molecular genetic testing using targeted gene sequencing panels.
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Hamartoma , Nevo , Codón/genética , Quiste Dermoide , Displasia Ectodérmica , Oftalmopatías , Humanos , Lipomatosis , Síndromes Neurocutáneos , Nevo/genética , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Cutis laxa (CL) syndromes comprise a rare group of multisystem disorders that share loose redundant skin folds as hallmark clinical feature. CL results from impaired elastic fiber assembly and homeostasis, and the known underlying gene defects affect different extracellular matrix proteins, intracellular trafficking, or cellular metabolism. Due to the underlying clinical and molecular heterogeneity, the diagnostic work-up of CL patients is often challenging. In this review, we provide a practical approach to the broad differential diagnosis of CL syndromes, provide an overview of the molecular pathogenesis of the different subtypes, and suggest general management guidelines.
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Cutis Laxo/fisiopatología , Proteínas de la Matriz Extracelular/genética , Piel/fisiopatología , Cutis Laxo/genética , Matriz Extracelular/genética , Humanos , Mutación/genéticaRESUMEN
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.
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Anomalías Múltiples/etiología , Cutis Laxo/genética , Proteína-Lisina 6-Oxidasa/genética , Anomalías Múltiples/genética , Adulto , Cutis Laxo/etiología , Cara/anomalías , Femenino , Homocigoto , Humanos , Masculino , Mutación Missense , Linaje , EmbarazoRESUMEN
Cutis laxa (CL) syndromes are a large and heterogeneous group of rare connective tissue disorders that share loose redundant skin as a hallmark clinical feature, which reflects dermal elastic fiber fragmentation. Both acquired and congenital-Mendelian- forms exist. Acquired forms are progressive and often preceded by inflammatory triggers in the skin, but may show systemic elastolysis. Mendelian forms are often pleiotropic in nature and classified upon systemic manifestations and mode of inheritance. Though impaired elastogenesis is a common denominator in all Mendelian forms of CL, the underlying gene defects are diverse and affect structural components of the elastic fiber or impair metabolic pathways interfering with cellular trafficking, proline synthesis, or mitochondrial functioning. In this chapter we provide a detailed overview of the clinical and molecular characteristics of the different cutis laxa types and review the latest insights on elastic fiber assembly and homeostasis from both human and animal studies.
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Cutis Laxo , Animales , Cutis Laxo/genética , Tejido Elástico , Homeostasis , Humanos , Redes y Vías Metabólicas , SíndromeRESUMEN
In the published version of this paper the author Neus Baena's name was incorrectly given as Neus Baena Diez. This has now been corrected in both the HTML and PDF versions of the paper.
RESUMEN
In ATP6V0A2-related cutis laxa, the skin phenotype varies from a wrinkly skin to prominent cutis laxa and typically associates with skeletal and neurological manifestations. The phenotype remains incompletely characterized, especially in adult patients. Glycosylation defects and reduced acidification of secretory vesicles contribute to the pathogenesis, but the consequences at the clinical level remain to be determined. Moreover, the morphology of the elastic fibres has not been studied in ATP6V0A2-related cutis laxa, nor its relation with potential clinical risks. We report on the extreme variability in ATP6V0A2-related cutis laxa in 10 novel patients, expand the phenotype with emphysema and von Willebrand disease and hypothesize on the pathogenesis that might link both with deficiency of glycosylation and with elastic fibre anomalies. Our data will affect clinical management of patients with ATP6V0A2-related cutis laxa.
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Cutis Laxo/genética , ATPasas de Translocación de Protón/genética , Piel/patología , Adulto , Anciano , Agenesia del Cuerpo Calloso/genética , Catarata/genética , Niño , Preescolar , Codón sin Sentido , Consanguinidad , Cutis Laxo/patología , Tejido Elástico/patología , Enfisema/genética , Cara/anomalías , Femenino , Glicosilación , Trastornos Hemorrágicos/genética , Humanos , Masculino , Fenotipo , Procesamiento Proteico-Postraduccional , Sitios de Empalme de ARN/genética , Adulto JovenRESUMEN
Myhre syndrome is a rare multisystem connective tissue disorder, characterized by short stature, facial dysmorphology, variable intellectual disability, skeletal abnormalities, arthropathy, cardiopathy, laryngotracheal anomalies, and stiff skin. So far, all molecularly confirmed cases harbored a de novo heterozygous gain-of-function mutation in SMAD4, encoding the SMAD4 transducer protein required for both transforming growth factor-beta and bone morphogenic proteins signaling. We report on four novel patients (one female proband and her two affected children, and one male proband) with Myhre syndrome harboring the recurrent c.1486C>T (p.Arg496Cys) mutation in SMAD4. The female proband presented with a congenital heart defect, vertebral anomalies, and facial dysmorphic features. She developed severe tracheal stenosis requiring a total laryngectomy. With assisted reproductive treatment, she gave birth to two affected children. The second proband presented with visual impairment following lensectomy in childhood, short stature, brachydactyly, stiff skin, and decreased peripheral sensitivity. Transmission electron microscopy (TEM) of the dermis shows irregular elastin cores with globular deposits and almost absent surrounding microfibrils and suggests age-related increased collagen deposition. We report on the first familial case of Myhre syndrome and illustrate the variable clinical spectrum of the disorder. Despite the primarily fibrotic nature of the disease, TEM analysis mainly indicates elastic fiber anomalies.
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Criptorquidismo/diagnóstico , Trastornos del Crecimiento/diagnóstico , Deformidades Congénitas de la Mano/diagnóstico , Discapacidad Intelectual/diagnóstico , Fenotipo , Adulto , Alelos , Sustitución de Aminoácidos , Biopsia , Criptorquidismo/genética , Facies , Femenino , Genotipo , Trastornos del Crecimiento/genética , Deformidades Congénitas de la Mano/genética , Humanos , Discapacidad Intelectual/genética , Masculino , Persona de Mediana Edad , Mutación , Radiografía , Recurrencia , Piel/metabolismo , Piel/patología , Proteína Smad4RESUMEN
PURPOSE: We delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10. METHODS: We retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-ß signaling with immunohistochemistry for pSMAD2 and CTGF. RESULTS: Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-ß signaling. CONCLUSION: Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.
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Arterias/anomalías , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Hernia Diafragmática/genética , Inestabilidad de la Articulación/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Enfermedades Cutáneas Genéticas/genética , Malformaciones Vasculares/genética , Adolescente , Adulto , Aorta/diagnóstico por imagen , Aorta/fisiopatología , Arterias/diagnóstico por imagen , Arterias/fisiopatología , Biopsia , Niño , Preescolar , Factor de Crecimiento del Tejido Conjuntivo/genética , Femenino , Hernia Diafragmática/fisiopatología , Humanos , Lactante , Inestabilidad de la Articulación/epidemiología , Inestabilidad de la Articulación/fisiopatología , Masculino , Mutación , Linaje , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología , Piel/patología , Enfermedades Cutáneas Genéticas/epidemiología , Enfermedades Cutáneas Genéticas/fisiopatología , Proteína Smad2/genética , Factor de Crecimiento Transformador beta/genética , Malformaciones Vasculares/epidemiología , Malformaciones Vasculares/fisiopatologíaRESUMEN
Myhre syndrome (MS, MIM 139210) is a rare multisystemic disorder caused by recurrent pathogenic missense variants in SMAD4. The clinical features have been mainly documented in childhood and comprise variable neurocognitive development, recognizable craniofacial features, a short stature with a pseudo-muscular build, hearing loss, thickened skin, joint limitations, diverse cardiovascular and airway manifestations, and increased fibrosis often following trauma or surgery. In contrast, adults with MS are underreported obscuring potential clinical variability. Here, we describe 24 adults with MS, including 17 diagnosed after the age of 18 years old, and we review the literature on adults with MS. Overall, our cohort shows a milder phenotype as well as lower mortality rates compared to what has been published in literature. Individuals with a codon 500 variant in SMAD4 present with a more pronounced neurodevelopmental and systemic phenotype. However, in contrast to the literature, we observe cardiovascular abnormalities in individuals with the p.(Arg496Cys) variant. In addition, we describe scoliosis as a new manifestation and we report fertility in two additional males with the p.(Arg496Cys). In conclusion, our study contributes novel insights into the clinical variability of MS and underscores the importance of variant-specific considerations, and we provide recommendations for the management of MS in adulthood.
RESUMEN
Significance: Cardiovascular disorders are the most important cause of morbidity and mortality in the Western world. Monogenic developmental disorders of the heart and vessels are highly valuable to study the physiological and pathological processes in cardiovascular system homeostasis. The arterial tortuosity syndrome (ATS) is a rare, autosomal recessive connective tissue disorder showing lengthening, tortuosity, and stenosis of the large arteries, with a propensity for aneurysm formation. In histopathology, it associates with fragmentation and disorganization of elastic fibers in several tissues, including the arterial wall. ATS is caused by pathogenic variants in SLC2A10 encoding the facilitative glucose transporter (GLUT)10. Critical Issues: Although several hypotheses have been forwarded, the molecular mechanisms linking disrupted GLUT10 activity with arterial malformations are largely unknown. Recent Advances: The vascular and systemic manifestations and natural history of ATS patients have been largely delineated. GLUT10 was identified as an intracellular transporter of dehydroascorbic acid, which contributes to collagen and elastin cross-linking in the endoplasmic reticulum, redox homeostasis in the mitochondria, and global and gene-specific methylation/hydroxymethylation affecting epigenetic regulation in the nucleus. We revise here the current knowledge on ATS and the role of GLUT10 within the compartmentalization of ascorbate in physiological and diseased states. Future Directions: Centralization of clinical, treatment, and outcome data will enable better management for ATS patients. Establishment of representative animal disease models could facilitate the study of pathomechanisms underlying ATS. This might be relevant for other forms of vascular dysplasia, such as isolated aneurysm formation, hypertensive vasculopathy, and neovascularization. Antioxid. Redox Signal. 34, 875-889.
Asunto(s)
Arterias/anomalías , Ácido Ascórbico/genética , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Homeostasis/genética , Inestabilidad de la Articulación/genética , Enfermedades Cutáneas Genéticas/genética , Malformaciones Vasculares/genética , Animales , Arterias/metabolismo , Arterias/patología , Ácido Ascórbico/metabolismo , Ácido Ascórbico/uso terapéutico , Tejido Elástico/metabolismo , Tejido Elástico/patología , Humanos , Inestabilidad de la Articulación/metabolismo , Inestabilidad de la Articulación/patología , Inestabilidad de la Articulación/terapia , Mitocondrias/efectos de los fármacos , Mitocondrias/genética , Mutación/genética , Oxidación-Reducción , Enfermedades Cutáneas Genéticas/metabolismo , Enfermedades Cutáneas Genéticas/patología , Enfermedades Cutáneas Genéticas/terapia , Malformaciones Vasculares/metabolismo , Malformaciones Vasculares/patología , Malformaciones Vasculares/terapiaRESUMEN
Hereditary disorders of connective tissue (HDCT) compromise a heterogeneous group of diseases caused by pathogenic variants in genes encoding different components of the extracellular matrix and characterized by pleiotropic manifestations, mainly affecting the cutaneous, cardiovascular, and musculoskeletal systems. We report the case of a 9-year-old boy with a discernible connective tissue disorder characterized by cutis laxa (CL) and multiple herniations and caused by biallelic loss-of-function variants in EFEMP1. Hence, we identified EFEMP1 as a novel disease-causing gene in the CL spectrum, differentiating it from other HDCT.
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Cutis Laxo/genética , Proteínas de la Matriz Extracelular/genética , Mutación con Pérdida de Función , Niño , Consanguinidad , Diagnóstico Diferencial , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Linaje , Secuenciación del ExomaRESUMEN
Weill-Marchesani syndrome (WMS) is a rare genetic disorder that affects the musculoskeletal system, the eye, and the cardiovascular system. Individuals with WMS present with short stature, joint contractures, thick skin, microspherophakia, small and dislocated lenses, and cardiac valve anomalies. WMS can be caused by recessive mutations in ADAMTS10 (WMS 1), ADAMTS17 (WMS 4), or LTBP2 (WMS 3), or by dominant mutations in fibrillin-1 (FBN1) (WMS 2); all genes encode secreted extracellular matrix (ECM) proteins. Individuals with WMS 4 due to ADAMTS17 mutations appear to have less severe cardiac involvement and present predominantly with the musculoskeletal and ocular features of WMS. ADAMTS17 is a member of the ADAMTS family of secreted proteases and directly binds to fibrillins. Here we report a novel pathogenic variant in ADAMTS17 that causes WMS 4 in an individual with short stature, brachydactyly, and small, spherical, and dislocated lenses. We provide biochemical and cell biological insights in the pathomechanisms of WMS 4, which also suggest potential biological functions for ADAMTS17. We show that the variant in ADAMTS17 prevents its secretion and we found intracellular accumulation of fibrillin-1 and collagen type I in patient-derived skin fibroblasts. In accordance, transmission electron microscopy revealed elastic fiber abnormalities, decreased collagen fibril diameters, and intracellular collagen accumulation in the dermis of the proband. Together, the data indicate a possible role for ADAMTS17 in the secretion of fibrillin-1 and collagen type I or in their early assembly in the pericellular matrix or the ECM.
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Proteínas ADAMTS/genética , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Fibrilina-1/metabolismo , Polimorfismo de Nucleótido Simple , Síndrome de Weill-Marchesani/genética , Proteínas ADAMTS/química , Proteínas ADAMTS/metabolismo , Dominio Catalítico , Línea Celular , Dermis/citología , Dermis/metabolismo , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Células HEK293 , Humanos , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Modelos Moleculares , Linaje , Síndrome de Weill-Marchesani/metabolismoRESUMEN
Occipital horn syndrome (OHS) is a rare connective tissue disorder caused by pathogenic variants in ATP7A, encoding a copper transporter. The main clinical features, including cutis laxa, bony exostoses, and bladder diverticula are attributed to a decreased activity of lysyl oxidase (LOX), a cupro-enzyme involved in collagen crosslinking. The absence of large case series and natural history studies precludes efficient diagnosis and management of OHS patients. This study describes the clinical and molecular characteristics of two new patients and 32 patients previously reported in the literature. We report on the need for long-term specialized care and follow-up, in which MR angiography, echocardiography and spirometry should be incorporated into standard follow-up guidelines for OHS patients, next to neurodevelopmental, orthopedic and urological follow-up. Furthermore, we report on ultrastructural abnormalities including increased collagen diameter, mild elastic fiber abnormalities and multiple autophagolysosomes reflecting the role of lysyl oxidase and defective ATP7A trafficking as pathomechanisms of OHS.