Dental Manifestations of Ehlers-Danlos Syndromes: A Systematic Review.

Ehlers-Danlos syndromes (EDS) are a group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and variable tissue fragility. However, there are limited published data on the dental manifestations of EDS. This review systematically assessed the spectrum of published dental anomalies in various types of EDS. Twenty-four individual case reports/series and 3 longer case-control studies, reporting on a total of 84 individuals with a clinical diagnosis of EDS, were included in the data analysis. The main dental features listed in classical EDS were pulp calcification and localized root hypoplasia. Common dental abnormalities observed in vascular EDS were pulp shape modifications (52.2%), exceeding root length (34.8%), and molar root fusion (47.8%). Dentinogenesis imperfecta is a consistent finding in osteogenesis imperfecta/EDS overlap syndrome. Data on dental manifestations in other types of EDS are both rare and generally inconclusive.

Clinical features, molecular results, and management of 12 individuals with the rare arthrochalasia Ehlers-Danlos syndrome.

Arthrochalasia Ehlers-Danlos syndrome (aEDS) is a rare autosomal dominant connective tissue disorder that is characterized by congenital bilateral hip dislocations, severe generalized joint hypermobility, recurrent joint (sub)luxations, and skin hyperextensibility. To date, 42 patients with aEDS have been published. We report 12 patients with aEDS from 10 families with 6 unpublished individuals and follow-up data on 6 adult patients. The clinical features are largely comparable with patients reported in the literature. Most (n = 10) patients had variants leading to (partial) loss of exon 6 of the COL1A1 or COL1A2 genes. One patient did not have a previously reported likely pathogenic COL1A1 variant. Data regarding management were retrieved. Hip surgery was performed in 5/12 patients and 3/12 patients underwent spinal surgery. As much as 4/12 patients were wheelchair-bound or unable to walk unaided. Fractures were present in 9/12 individuals with 1 patient requiring bisphosphonate treatment. Echocardiograms were performed in 10 patients and 2 individuals showed an abnormality likely unrelated to aEDS. One patient gave birth to two affected children and went through preterm labor requiring medication but had no additional complications. Of the eight adults in our cohort, the majority entered a career. Our data point toward a genotype-phenotype relationship with individuals with aEDS due to pathogenic COL1A1 variants causing complete or partial loss of exon 6 being more severely affected regarding musculoskeletal features. There is a significant lack of knowledge with regard to management of aEDS, particularly in adulthood. As such, systematic follow-up and multidisciplinary treatment is essential.

Absence of Collagen Flowers on Electron Microscopy and Identification of (Likely) Pathogenic COL5A1 Variants in Two Patients.

Two probands are reported with pathogenic and likely pathogenic COL5A1 variants (frameshift and splice site) in whom no collagen flowers have been identified with transmission electron microscopy (TEM). One proband fulfils the clinical criteria for classical Ehlers-Danlos syndrome (cEDS) while the other does not and presents with a vascular complication. This case report highlights the significant intrafamilial variability within the cEDS phenotype and demonstrates that patients with pathogenic COL5A1 variants can have an absence of collagen flowers on TEM skin biopsy analysis. This has not been previously reported in the literature and is important when evaluating the significance of a TEM result in patients with clinically suspected cEDS and underscores the relevance of molecular analysis.

Four patients with Sillence type I osteogenesis imperfecta and mild bone fragility, complicated by left ventricular cardiac valvular disease and cardiac tissue fragility caused by type I collagen mutations.

Osteogenesis imperfecta (OI) type I is a hereditary disorder of connective tissue (HDCT) characterized by blue or gray sclerae, variable short stature, dentinogenesis imperfecta, hearing loss, and recurrent fractures from infancy. We present four examples of OI type I complicated by valvular heart disease and associated with tissue fragility. The diagnosis of a type I collagen disorder was confirmed by abnormal COL1A1 or COL1A2 gene sequencing. One patient was investigated with electrophoresis of collagens from cultured skin fibroblasts, showing structurally abnormal collagen type I, skin biopsy showed unusual histology and abnormal collagen fibril ultra-structure at electron microscopy. The combined clinical, surgical, histological, ultra-structural, and molecular genetic data suggest the type I collagen defect as contributory to cardiac valvular disease. The degree of tissue fragility experienced at cardiac surgery in these individuals, also reported in a small number of similar case reports, suggests that patients with OI type I need careful pre-operative assessment and consideration of the risks and benefits of cardiac surgery.

Ehlers-Danlos syndrome type IV in a young man.

We describe a 19-year-old male, with a family history of both systemic lupus erythematosus and Marfan syndrome, who had a history of bruising easily and skin lesions since childhood. He had a spontaneous colonic perforation at the age of 16 years, followed 3 years later by sudden development of bilateral renal infarctions and hypertension, which on angiography were found to be due to dissection of both renal arteries. Transient elevations of 3 types of antiphospholipid antibodies (aPL) were detected. Skin biopsy showed typical elastosis perforans serpiginosa. The history together with the generalized connective tissue phenotype, histology, and angiographic features combined to establish a diagnosis of vascular Ehlers-Danlos syndrome, type IV; the body habitus resembled the phenotypically-related condition of Marfan syndrome. The coincidental finding of transient aPL elevations combined to make this a difficult diagnostic and clinical management problem.

Autosomal dominant cutis laxa with severe lung disease: synthesis and matrix deposition of mutant tropoelastin.

Cutis laxa (CL) is a heterogeneous group of genetic and acquired disorders with at least two autosomal dominant forms caused by mutations in the elastin and fibulin-5 genes, respectively. To define the molecular basis of CL in patients negative for point mutations in the elastin gene, metabolic labeling and immunoprecipitation experiments were used to study the synthesis of elastin in dermal fibroblasts. In addition to the normal 68 kDa tropoelastin (TE) protein, an abnormal, 120 kDa polypeptide was detected in the proband and her affected daughter in a CL family characterized by hernias and unusually severe and early-onset pulmonary disease including bronchiectasis and pulmonary emphysema. Mutational and gene expression studies established that affected individuals in this family carried a partial tandem duplication in the elastin locus. Immunoprecipitation experiments showed that the mutant TE was partially secreted and partially retained intracellularly. A polyclonal antibody raised against a unique peptide in the mutant TE molecule showed both intracellular and matrix staining. We conclude that elastin mutations can cause CL associated with a severe pulmonary phenotype. Synthesis of abnormal TE may interfere with elastic fiber function through a dominant-negative or a gain of function mechanism.

Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis.

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive conditions characterized by multiple subcutaneous skin nodules, gingival hypertrophy, joint contractures, and hyaline deposition. We previously mapped the gene for JHF to chromosome 4q21. We now report the identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 (CMG2) in 17 families with JHF or ISH. CMG2 is a transmembrane protein that is induced during capillary morphogenesis and that binds laminin and collagen IV via a von Willebrand factor type A (vWA) domain. Of interest, CMG2 also functions as a cellular receptor for anthrax toxin. Preliminary genotype-phenotype analyses suggest that abrogation of binding by the vWA domain results in severe disease typical of ISH, whereas in-frame mutations affecting a novel, highly conserved cytoplasmic domain result in a milder phenotype. These data (1) demonstrate that JHF and ISH are allelic conditions and (2) implicate perturbation of basement-membrane matrix assembly as the cause of the characteristic perivascular hyaline deposition seen in these conditions.

The gene for juvenile hyaline fibromatosis maps to chromosome 4q21.

Juvenile hyaline fibromatosis (JHF) is an autosomal recessive condition characterized by multiple subcutaneous nodular tumors, gingival fibromatosis, flexion contractures of the joints, and an accumulation of hyaline in the dermis. We performed a genomewide linkage search in two families with JHF from the same region of the Indian state of Gujarat and identified a region of homozygosity on chromosome 4q21. Dense microsatellite analyses within this interval in five families with JHF who were from diverse origins demonstrate that all are compatible with linkage to chromosome 4q21 (multipoint LOD score 5.5). Meiotic recombinants place the gene for JHF within a 7-cM interval bounded by D4S2393 and D4S395.

A novel ophthalmic presentation of the Proteus syndrome.

PURPOSE: To report a patient with the Proteus syndrome who had ocular complications not previously described in the literature. DESIGN: Single observational case report. METHODS: Retrospective review of the medical record and review of the literature. RESULTS: The 26-year-old man has systemic features fulfilling the diagnostic criteria for the Proteus syndrome. His ocular abnormalities are myopia, mild calcific band keratopathy, cataract, abnormal vitreous structure, vitreous hemorrhage, a large chorioretinal mass, and a resolved serous retinal detachment. CONCLUSIONS: Ocular complications are frequently reported in patients with the Proteus syndrome. Few of the patients reported in the literature have had comprehensive ocular examination by an ophthalmologist. Our patient is unique because he has been examined by ophthalmologists from childhood, and it is clear that the ocular findings may change with time. As far as we are aware, calcific band keratopathy, abnormal vitreous structure, and chorioretinal hamartoma associated with serous retinal detachment and vitreous hemorrhage have not previously been described.