Late Loeys-Dietz Syndrome Diagnosis in an Adolescent With Severe Phenotype

Objective – To present a case of a bladder diverticula that was found to be a part of occipital horn syndrome, a rare X-linked recessive connective tissue disorder due to a copper transport defect (OMIM 304150). The syndrome is considered to be a milder variant of Menkes disease, with variable prognosis but substantially longer life expectancy. Case reports - We report the case of an eight-year-old boy with occipital horn syndrome who has a large bladder diverticula as a part of a connective tissue disorder. Diagnosis was based on the clinical features (hypotonia, hypotrophia, hyperextensible joints, hyperelastic, bruisable skin, psychomotoric development delay, recurrent UTI, large bladder diverticula), supported by low serum copper and ceruloplasmin levels, and confirmed by identification of mutations in the ATP7A gene (duplication in exons 11 and 12) at the age of 2 years. Conclusion - Large bladder diverticula can be a part of an underlying connective tissue disorder. Our case showed a boy with large bladder diverticula as part of occipital horn syndrome, a rare X-linked connective tissue disorder caused by a deficiency in the transport of copper, associated with mutations in the ATP7A gene. As bladder diverticula can be part of an underlying connective tissue disorder, it should be excluded in such patients presenting with a urinary tract infection.

Stepwise Total Aortic Repairs With Fenestrated Endografts in a Patient With Loeys-Dietz Syndrome

Marfan syndrome is a rare connective tissue disorder with a prevalence of approximately 2 to 3 per 10,000 individuals. There have been some reports of young patients with Marfan syndrome developing arteriovenous thromboembolism. These events were unprovoked and recurrent. Owing to its rarity, hypercoagulopathy and other metabolic derangement in patients with Marfan syndrome remains largely unknown. Herein, we report a case of a young man with Marfan syndrome who had myocardial infarction and pulmonary embolism. We hope that this case adds to the scant body of knowledge about this patient population.

Ehlers-Danlos Syndrome (EDS) type IV is a rare genetic disorder of connective tissue. Most patients with EDS type IV are frequently unaware of this disorder until the catastrophic rupture of an artery or bowel occurs. We are reporting an association between this and another uncommon autosomal dominant disorder, Charcot Marie Tooth disease. The neurologic problem led to painful foot deformities, requiring surgery, which was complicated by difficulty controlling bleeding in the friable tissues. Other reported associations of heritable disorders of connective tissue and neuropathies are described.

Marfan's syndrome is an autosomal dominant condition with an estimated prevalence of one in 10,000 to 20,000 individuals. This rare hereditary connective tissue disorder affects many parts of the body. The diagnosis of Marfan's syndrome is established in accordance with a review of the diagnostic criteria, known as the Ghent nosology, through a comprehensive assessment largely based on a combination of major and minor clinical manifestations in various organ systems and the family history. Aortic root dilation and mitral valve prolapse are the main presentations among the cardiovascular malformations of Marfan's syndrome. The pathogenesis of Marfan's syndrome has not been fully elucidated. However, fibrillin-1 gene mutations are believed to exert a dominant negative effect. Therefore, Marfan's syndrome is termed a fibrillinopathy, along with other connective tissue disorders with subtle differences in clinical manifestations. The treatment may include prophylactic β-blockers and angiotensin II-receptor blockers in order to slow down the dilation of the ascending aorta, and prophylactic aortic surgery. Importantly, β-blocker therapy may reduce TGF-β activation, which has been recognized as a contributory factor in Marfan's syndrome. The present article aims to provide an overview of this rare hereditary disorder.

Anti-synthetase syndrome (ASyS) is a rare autoimmune connective tissue disorder (CTD) characterized by the presence of autoantibodies targeting tRNA synthetase, most notably the anti-Jo1 antibody. Clinically, it typically manifests with interstitial lung disease (ILD), inflammatory myopathy, arthritis, Raynaud’s phenomenon, and the so-called mechanic’s hands. Diagnosis can be challenging due to clinical overlap with other pulmonary and rheumatological disorders.We report a case of a young woman in her early 20s who presented at our same day emergency care (SDEC) with a four-week history of exertional dyspnea, low-grade fever, and productive cough, initially managed as a lower respiratory tract infection in the community. Persistent symptoms prompted further evaluation, and CT imaging of the chest, abdomen, and pelvis revealed bilateral ground-glass opacities suggestive of ILD. Five days later, she re-presented with hemoptysis, worsening breathlessness, new-onset myalgia, arthralgia, facial erythema, and hyperkeratosis of the fingertips. Autoimmune screening revealed strongly positive anti-Jo-1 and anti-Ro52 antibodies, confirming the diagnosis of anti-synthetase syndrome. She was treated with intravenous (IV) pulse methylprednisolone, mycophenolate mofetil, and rituximab, with partial clinical improvement and ongoing follow-up for advanced ILD management in a tertiary center. This case highlights how an initial diagnosis of lower respiratory tract infection (LRTI) may mask an underlying autoimmune syndrome (anti-synthetase syndrome), which later manifests as progressive respiratory failure requiring lung transplant.Therefore, as acute medicine physicians, it is imperative to maintain a broad differential diagnosis, particularly in young females newly diagnosed with possible ILD. There may be underlying conditions that require careful examination by acute care physicians, especially in the presence of systemic symptoms, notably rheumatological symptoms. This vigilance is crucial to avoid delayed diagnosis of anti-synthetase syndrome, which necessitates early multidisciplinary involvement to achieve better outcomes.

An 18-year-old girl with uncomplicated ostium secundum defect and an Ehlers-Danlos syndrome of moderate severity was subjected to open-heart surgery with closure of the defect. The coagulation mechanism was normal. Recovery was uneventful with fairly normal healing of incisions and suture lines.Only a few instances of cardiac malformations have been reported in connection with this rare connective tissue disorder. To our knowledge, one patient with this syndrome has previously been subjected to open-heart surgery.

Introduction: ST-elevation myocardial infarction (STEMI) rarely occurs among patients 18 to 34 years old. Spontaneous coronary artery dissection (SCAD) is a rare cause of STEMI that is frequently described among patients in peripartum period. SCAD has a high mortality rate when not recognized and treated immediately. We present a case of SCAD presenting as STEMI in a nineteen-year-old non pregnant patient. Case: A nineteen-year-old female with chronic kidney disease complained of sudden-onset substernal chest pain. Physical examination showed blood pressure of 140/90 mmHg, heart rate of 112 beats per minute, with findings of of bibasilar rales, pedal edema and cold and clammy extremities. Electrocardiogram (ECG) showed ST-elevation in leads V3 to V6. Cardiac troponin was elevated, and echocardiography revealed left ventricular segmental hypokinesia and depressed systolic function. Patient was diagnosed with acute anterolateral wall STEMI. Coronary angiogram revealed total occlusion of the mid segment of the left anterior descending artery (LAD), while the rest of the coronary arteries were strikingly normal. After initial balloon angioplasty and stenting of the mid LAD, coronary artery dissection was noted at the distal LAD. A stent was successfully deployed, achieving thrombolysis-in-myocardial-infarction (TIMI) flow grade III with no residual stenosis. Patient remained stable and was discharged improved. Discussion: STEMI rarely happens in young adults. Moreover, literature highlights the rarity of STEMI caused by SCAD. SCAD usually occurs among young pregnant patients who have no risk factors for atherosclerosis. In this report, we highlight the importance of suspecting SCAD among young patients who present with STEMI and of prompt treatment with revascularization in similar clinical situations. Conclusion: SCAD remains a rare cause of STEMI, but it should be considered when young individuals present with STEMI. Treatment is primarily urgent revascularization especially if there is persistent chest pain or ischemic ECG changes, hemodynamic instability, or unstable arrhythmia. Keywords: spontaneous coronary artery dissection, SCAD, acute coronary syndrome, ACS, ST-elevation myocardial infarction, STEMI

Osteogenesis imperfecta is a rare connective tissue disorder with an estimated number of 4-20 cases per 100 000 inhabitants. Although the prevalence differs among regions, there are only a few number of national registry studies published previously. The aim of this study was to determine the prevalence of osteogenesis imperfecta among the pediatric age group in Türkiye, together with the patient and hospital characteristics. Via the e-health database of the Turkish Ministry of Health, we collected and retrospectively evaluated the medical records of the patients who were under 18 years of age with the diagnosis of osteogenesis imperfecta between 2016 and 2022. Total number of fractures, treatment modalities, and the hospital characteristics were also recorded. Two thousand seven hundred forty patients were extracted with a mean age of 9.77 ± 4.81 years. The prevalence of osteogenesis imperfecta in Türkiye among the pediatric population was calculated as 11.6 per 100 000 individuals. The median annual incidence was 31.5 per 100 000 live births between 2016 and 2022. There were 17.4 hospital admissions per patient per year. The mean age at the time of in-hospital mortality was 4.08 ± 5.03 years. The fracture rate per patient per year was 0.56 and conservative treatment was the most commonly preferred modality for all ages. This is the first registry-based nationwide study of osteogenesis imperfecta patients in Türkiye, providing important characteristics of the disease. Together with the help of the ongoing development of national health database systems, precision in patient identification would yield substantial benefits in terms of management of osteogenesis imperfecta.

Eosinophilic fasciitis (EF, also called Shulman syndrome) is a rare connective tissue disorder with poorly understood pathogenesis and unknown etiology. EF is characterized initially by limb or trunk erythema and edema and later by collagenous thickening of the subcutaneous fascia. Here, we present the case of a 16-year-old boy who presented with typical clinical features of EF with a history of typical trigger factor – preceding strenuous physical activity and had a rarer atypical association of hypercalcemia and raised angiotensin converting enzyme (ACE) levels.

Radial lattice degenerations and foveal hypoplasia: Late diagnosis of stickler syndrome in a patient without high myopia.

Musculocontractural Ehlers-Danlos syndrome caused by dermatan sulfate epimerase deficiency (mcEDS-DSE) is a rare connective tissue disorder. This is the first report describing the detailed and comprehensive clinical and pathophysiological features of mcEDS-DSE. The patient, with a novel homozygous nonsense variant (NM_013352.4:c.2601C>A:p.(Tyr867*)), exhibited mild skin hyperextensibility without fragility and small joint hypermobility, but developed recurrent large subcutaneous hematomas. Dermatan sulfate (DS) moieties on chondroitin sulfate/DSproteoglycans were significantly decreased, but remained present, in skin fibroblasts. Electron microscopy examination of skin specimens, including cupromeronic blue-staining to visualize glycosaminoglycan (GAG) chains, revealed coexistence of normally assembled collagen fibrils with attached curved GAG chains and dispersed collagen fibrils with linear GAG chains from attached collagen fibrils across interfibrillar spaces to adjacent fibrils. Residual activity of DS-epi1, encoded by DSE, and/or compensation by DS-epi2, a minor homolog of DS-epi1, may contribute to the mild skin involvement through this "mosaic" pattern of collagen fibril assembly.

Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder. In LDS patients with normal arch morphology, whether the arch should be prophylactically replaced at the time of proximal aortic replacement remains unknown. We evaluated the risk of long-term arch complications in genetically confirmed LDS patients who underwent proximal ascending aortic replacement. We retrospectively reviewed the records of patients with LDS who have been followed at our institution between 1994 and 2020. Patients were only included if whole exome genetic testing confirmed a mutation in an LDS-causing gene (TGFBR1, TGFBR2, SMAD3, TGFB2, or TGFB3). Mutations were categorized as pathogenic, benign, or of unknown significance. We collected demographic information, aortic dimensions, comorbidities, mortality, and operative course from patients' charts. Descriptive statistics and freedom from reoperation plots were generated. Of the 18 patients with a mutation in an LDS-causing gene, 15 had known pathogenic variants, two had mutations of unknown significance, and one had a benign genetic variant. For the 15 patients with confirmed pathogenic variants of LDS the median follow-up duration was 5 years (interquartile range [IQR]: 4-8). Eleven patients underwent ascending aortic replacements (AAR) ± aortic valve replacement. Two patients required an additional operation; one required arch and staged elephant trunk for a dissection 18 years post-AAR and the other patient required an isolated descending aortic replacement for dissection 5 years post-AAR. Among patients who underwent surgery, the median ascending aortic diameter at intervention was 5.0 cm (IQR: 4.3-5.3). There was no surgical or late follow-up mortality observed for any of the 18 patients in the study. LDS patients who underwent proximal aortic replacement appeared to have low long-term risk of arch complications. While our study is somewhat limited by its sample size and follow-up duration, it suggests that routine prophylactic total arch replacement may not be warranted in LDS patients with nonaneurysmal aortic arches.

The vascular type of the Ehlers-Danlos syndrome (Ehlers-Danlos syndrome type IV, EDS IV; OMIM #130050) is a rare connective tissue disorder with autosomal dominant transmission caused by mutations in the COL3A1 gene resulting in increased fragility of connective tissue with arterial, intestinal, and uterine ruptures and premature death. We present a 28-year-old female who in addition to typical EDS IV symptoms had severe peripheral artery occlusive disease (PAOD) and subtotal stenosis of the abdominal aorta. COL3A1 sequencing resulted in detection of an as yet undescribed mutation in exon 36 at position 2465 leading to a nucleotide replacement (c.2465G>C; p.G822A). Ultrastructural analysis of a skin biopsy revealed abnormal morphology and distribution of dermal collagen fibres. We conclude that PAOD is a possible manifestation of EDS IV and that further research is required to define its true prevalence among patients with EDS IV and its molecular pathology including genotype-phenotype correlation.

Background: Lateral meningocele syndrome (LMS) is an exceedingly rare connective tissue disease with phenotypic anomalies similar to those seen in Marfan syndrome, Ehler-Danlos syndrome, and Loeys-Dietz syndrome. However, this syndrome is invariably associated with the presence of multiple lateral thoracolumbar spinal meningoceles: a distinct point of phenotypic divergence from other connective tissue disorders. The etiopathogenesis of this syndrome has recently been linked to truncating mutations within exon 33 of NOTCH3. Despite numerous reports, neurosurgical management of multiple spinal meningoceles remains poorly defined in the literature. We conducted a literature review to provide insight into the nosology, clinical significance, and neurosurgical management strategies of this distinct connective tissue disorder. Summary: Our literature search revealed 11 articles (16 cases) of LMS, which included 9 males and 7 females, belonging to 14 different families. Half of these cases underwent genetic screening: all of which were discovered to exhibit a truncating mutation within exon 33 of NOTCH3. All patients exhibited multiple lateral thoracolumbar spinal meningoceles with craniofacial dysmorphisms. Other clinical characteristics included pathologic changes in spine morphology, Chiari I malformation, syringomyelia, hydrocephalus, and tethered cord. Operative management of multiple spinal meningoceles in LMS is complicated by the presence of such coexisting structural neurologic pathologies, which may alter cerebrospinal fluid flow dynamics and, ultimately, impact operative intervention. Key Messages: LMS is an exceedingly rare connective tissue disorder with severe spinal dural involvement. Neurosurgical management of multiple spinal meningoceles is complex, which is further complicated by the presence of coexisting neuropathology, such as pathologic transformation of spine morphology and Chiari I malformation. Patients with a connective tissue disorder phenotype found to have multiple spinal meningoceles on imaging studies may benefit from evaluation by a medical geneticist and a pediatric neurosurgeon.