Connective Tissue Abnormalities Research Articles

Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study

We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissue abnormalities, and based on findings, patients underwent genetic testing. Ancillary diagnostic studies included echocardiography, eye exam, and histopathological examinations of skin and dura biopsies in selected patients. We identified nine patients with heritable connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome and other unclassified forms. In seven patients, spontaneous CSF leak was the first noted manifestation of the genetic disorder. We conclude that spontaneous CSF leaks are associated with a spectrum of connective tissue abnormalities and may be the first noted clinical presentation of the genetic disorder. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of heritable connective tissue disorders, and we suggest that patients with CSF leaks should be screened for connective tissue and vascular abnormalities.

The Clinical Significance of Recognizing Distinct Morphologic Features of Systemic Diseases on Breast Biopsies

Prominent lymphocytic periductal inflammation has been previously described in association with diabetes mellitus type I and II, other autoimmune diseases such as lupus, thyroid disease, and connective tissue abnormalities, and even lymphomas. When incidentally detected in a breast biopsy and without evidence of systemic disease in the patient's history, it may be prudent to alert the treating clinician to the possibility of an underlying systemic disease process, in order to ensure recognition and appropriate clinical follow-up for these patients. The purpose of this review is to familiarize the reader with this commonly encountered incidental feature on breast biopsies and to emphasize the importance and clinical implications of recognizing possible underlying systemic disease and communicating these findings to the treating physicians.

Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.

The Contribution of CLIP2 Haploinsufficiency to the Clinical Manifestations of the Williams-Beuren Syndrome

Williams-Beuren syndrome is a rare contiguous gene syndrome, characterized by intellectual disability, facial dysmorphisms, connective-tissue abnormalities, cardiac defects, structural brain abnormalities, and transient infantile hypercalcemia. Genes lying telomeric to RFC2, including CLIP2, GTF2I and GTF2IRD1, are currently thought to be the most likely major contributors to the typical Williams syndrome cognitive profile, characterized by a better-than-expected auditory rote-memory ability, a relative sparing of language capabilities, and a severe visual-spatial constructive impairment. Atypical deletions in the region have helped to establish genotype-phenotype correlations. So far, however, hardly any deletions affecting only a single gene in the disease region have been described. We present here two healthy siblings with a pure, hemizygous deletion of CLIP2. A putative role in the cognitive and behavioral abnormalities seen in Williams-Beuren patients has been suggested for this gene on the basis of observations in a knock-out mouse model. The presented siblings did not show any of the clinical features associated with the syndrome. Cognitive testing showed an average IQ for both and no indication of the Williams syndrome cognitive profile. This shows that CLIP2 haploinsufficiency by itself does not lead to the physical or cognitive characteristics of the Williams-Beuren syndrome, nor does it lead to the Williams syndrome cognitive profile. Although contribution of CLIP2 to the phenotype cannot be excluded when it is deleted in combination with other genes, our results support the hypothesis that GTF2IRD1 and GTF2I are the main genes causing the cognitive defects associated with Williams-Beuren syndrome.

Mixture of hyaluronic acid, chondroitin 6 sulphate and dermatan sulphate used to completely regenerate bone in rat critical size defect model

Skeletal bone losses are mainly filled with autologous graft or artificial materials. Osteoblasts are essential to maintain bone homeostasis and bone repair through a matrix synthesis. We have previously demonstrated that adherence and regenerative matrix composition are fundamental to bone healing, even in critical situations. In this work the critical size defect technique was used to evaluate the systemic activity on bone regeneration of a novel mixture of extracellular polysaccharides. A 5mm diameter hole was made in each parietal bone of male Wistar rats. The right parietal bone hole was filled with a mixture of hyaluronic acid, chondroitin 6 sulphate, and dermatan sulphate mixed with 2.5% NaCl solution, while the left hole was left free of material and untreated and considered as control. Twenty-one days after surgery, the holes and surrounding tissues were examined visually, using X-rays, and by histological staining. Using the matrix substitute, bone healing was almost complete after 21days in the treated hole and always complete in the control side due to some systemic effect. Neovascularization was also observed along with organized trabecular bone on both sides. No abnormal bone growth or connective tissue abnormalities were noted. At the end of the experiment, 95.1% (±3.2) bone healing (n=20) was observed on the treated side; conversely, healing bone and histological structure were better on the control side.

Proteoglycans of uterine fibroids and keloid scars: similarity in their proteoglycan composition

Fibrosis is the formation of excess and abnormal fibrous connective tissue as a result of either a reparative or reactive process. A defining feature of connective tissue is its extracellular matrix, which provides structural support and also influences cellular activity. Two common human conditions that result from fibrosis are uterine fibroids (leiomyomas) and keloid scars. Because these conditions share a number of similarities and because their growth is due primarily to excessive extracellular matrix deposition, we compared the proteoglycans of uterine fibroids and keloid scars with corresponding normal tissues. Our analysis indicates that uterine fibroids and keloid scars contain higher amounts of glycosaminoglycans relative to normal myometrium and normal adult skin respectively. Proteoglycan composition is also different in the fibrotic tissues. Compared with unaffected tissues, uterine fibroids and keloid scars contain higher relative amounts of versican and lower relative amounts of decorin. There is also evidence for a higher level of versican catabolism in the fibrotic tissues compared with unaffected tissues. These qualitative and quantitative proteoglycan differences may play a role in the expansion of these fibroses and in their excessive matrix deposition and matrix disorganization, due to effects on cell proliferation, TGF (transforming growth factor)-β signalling and/or collagen fibril formation.

Inherited Copper Transport Disorders: Biochemical Mechanisms, Diagnosis, and Treatment

Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson’s disease. Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result from low copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass screening should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination therapy with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized by connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome.Wilson’s disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson’s disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson’s disease should be implemented in infants. Patients with Wilson’s disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson’s disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.

Fetal Arthrogryposis Secondary to a Giant Maternal Uterine Leiomyoma

Arthrogryposis multiplex congenital is a rare condition defined as contractures in multiple joints at birth due to disorders starting in fetal life. Its etiology is associated with many different conditions and in many instances remains unknown. The final common pathway to all of them is decreased fetal movement (fetal akinesia) due to an abnormal intrauterine environment. Causes of decreased fetal movements may be neuropathic abnormalities, abnormalities of connective tissue or muscle, intrauterine vascular compromise, maternal diseases, and space limitations within the uterus. When the cause of arthrogryposis is space limitations in uterus, the most common etiology is oligohydramnios. The same can result from intrauterine tumours as fibroids, although to our knowledge there are only two papers reporting cases of fetal deformities related to uterine leiomyomas. We describe a well-documented exceptional case of arthrogryposis associated with the presence of a large uterine fibroid. It could illustrate the importance of a careful and appropriate assessment of uterine fibroids before and in the course of a pregnancy considering that they can cause both serious maternal and fetal complications.

Acute Aortic Dissection Associated with Cystic Medial Necrosis of Unknown Etiology

A 61-year-old man without a Marfan-like phenotype was admitted to the hospital because of acute Stanford type A aortic dissection. The patient underwent surgical repair with total arch replacement. Histological examination of the excised aorta showed a connective tissue abnormality, which could have contributed to the development of aortic dissection. The cause of the connective tissue abnormality could not be determined through physical examination. Recently, however, many novel gene mutations have been found to be related to aortic diseases that do not always produce physical signs and symptoms. In this case, unknown causes of connective tissue abnormalities might be existed.

Bicuspid Aortic Valve Disease and Ascending Aortic Aneurysms: Gaps in Knowledge

The bicuspid aortic valve is the most common congenital cardiac anomaly in developed nations. The abnormal bicuspid morphology of the aortic valve results in valvular dysfunction and subsequent hemodynamic derangements. However, the clinical presentation of bicuspid aortic valve disease remains quite heterogeneous with patients presenting from infancy to late adulthood with variable degrees of valvular stenosis and insufficiency and associated abnormalities including aortic coarctation, hypoplastic left heart structures, and ascending aortic dilatation. Emerging evidence suggests that the heterogeneous presentation of bicuspid aortic valve phenotypes may be a more complex matter related to congenital, genetic, and/or connective tissue abnormalities. Optimal management of patients with BAV disease and associated ascending aortic aneurysms often requires a thoughtful approach, carefully assessing various risk factors of the aortic valve and the aorta and discerning individual indications for ongoing surveillance, medical management, and operative intervention. We review current concepts of anatomic classification, pathophysiology, natural history, and clinical management of bicuspid aortic valve disease with associated ascending aortic aneurysms.

Fungal infection of gingiva in a patient with hyperimmunoglobulin-E (Job′s) syndrome

Hyperimmunoglobulin E syndrome (HIES), also known as Job's syndrome, is a rare primary immunodeficiency characterized by eczema, recurrent skin and lung infections, elevated serum IgE, and connective tissue and skeletal abnormalities. Individuals with HIES share a characteristic facial appearance and many oral manifestations including retained primary dentition, a high-arched palate, variations of the oral mucosa and gingiva, and recurrent oral candidiasis. An 18-year-old lady presented with gingival swelling, bleeding from the gums, recurrent skin infections, and recurrent respiratory infections with intermittent fever. After thorough extra oral, intra oral and radiographic examination, serological investigations were performed. Growth of candida hyphae in the biopsy specimen of gingiva and increased levels of serum IgE with typical extra oral findings established the diagnosis as Job's syndrome (hyper IgE syndrome). Treatment with anti-fungal antibiotics and phase-I therapy including scaling and root planing followed by gingivoplasty using diode laser (980 nm) was performed. HIES was previously defined on the basis of clinical manifestations and laboratory markers that were not specific to the disease. With the identification of STAT3 mutations as the cause of HIES, we can definitively characterize the disease at molecular and immunologic levels. This case emphasizes the role of the dentist in the diagnosis of rare syndromes which alters the treatment plan.

An update on the hyper-IgE syndromes

The hyper-IgE syndromes (HIES; originally named Job's syndrome) are a collection of primary immunodeficiency syndromes resulting in elevated serum IgE levels and typified by recurrent staphylococcal skin abscesses, eczema and pulmonary infections. The disorder has autosomal dominant and recessive forms. Autosomal dominant HIES has been shown to be mainly due to STAT3 mutations and additionally results in connective tissue, skeletal, vascular and dental abnormalities. Autosomal recessive HIES has been shown to be mainly due to mutations in DOCK8; these patients are more prone to viral skin infections instead. This review article discusses the common clinical features of the syndrome, the genetic mutations responsible and the pathogenesis of the disease, as well as treatments currently used.

ATP7A Gene Addition to the Choroid Plexus Results in Long-term Rescue of the Lethal Copper Transport Defect in a Menkes Disease Mouse Model

Menkes disease is a lethal infantile neurodegenerative disorder of copper metabolism caused by mutations in a P-type ATPase, ATP7A. Currently available treatment (daily subcutaneous copper injections) is not entirely effective in the majority of affected individuals. The mottled-brindled (mo-br) mouse recapitulates the Menkes phenotype, including abnormal copper transport to the brain owing to mutation in the murine homolog, Atp7a, and dies by 14 days of age. We documented that mo-br mice on C57BL/6 background were not rescued by peripheral copper administration, and used this model to evaluate brain-directed therapies. Neonatal mo-br mice received lateral ventricle injections of either adeno-associated virus serotype 5 (AAV5) harboring a reduced-size human ATP7A (rsATP7A) complementary DNA (cDNA), copper chloride, or both. AAV5-rsATP7A showed selective transduction of choroid plexus epithelia and AAV5-rsATP7A plus copper combination treatment rescued mo-br mice; 86% survived to weaning (21 days), median survival increased to 43 days, 37% lived beyond 100 days, and 22% survived to the study end point (300 days). This synergistic treatment effect correlated with increased brain copper levels, enhanced activity of dopamine-β-hydroxylase, a copper-dependent enzyme, and correction of brain pathology. Our findings provide the first definitive evidence that gene therapy may have clinical utility in the treatment of Menkes disease.

Hyper Immunoglobulin E Syndrome (HIES): Report of a New Case Treated with Omalizumab and Dexametasone

Abstract 4934The classical triad of eczema, recurrent skin and lung infections and high serum IgE, other connective tissue, cardiac and brain abnormalities are the accepted diagnostic criteria for HIES. The treatment of HIES is not established due to the scarce number of published cases, however is limited to skin local measures and supportive care. Herein we inform a severe case with response to Omalizumab, a monoclonal anti IgE antibody in combination with Dexametasone.A 36 year old male with family history of asthma and atopic dermatitis (AD). Since child, the patient had allergies and AD. At 8 years he presented asthma and recurrent upper airway infections at 2 to 3 times per year and 7 dental pieces removal. In the last 3 years he noted important increase of AD with very intense and disabling pruritus without response to treatment and progression to generalized erithrodermia, nodes in legs and arms, and skin trasudate, axilar and inguinal lymph nodes (6×4 cm). Laboratory positive test were eosinophils 6%, serum IgE 29,280 IU/mL. Skin biopsy showed psoriasis-like dermatitis, micro abscesses and dermatopathic lymphadenopathy. We started treatment with trimetoprim/Sulfamethoxazole 80/400 mg twice a day, oral Dexametasone 20 mg weekly and Omalizumab 200 mg subcutaneously every two weeks. After 15 days of treatment there was a rapid improvement of skin derangement and IgE levels dropped to 2000 IU/mL after 16 weeks of treatment. Patient continues on treatment with no side effects and pruritus disappears.Omalizumab is a monoclonal antibody against IgE recently introduced to the treatment of HIES in a few patients reported since 2008 with excellent response, along with intensive care of skin lesions, prompt antibiotic and antimycotic treatment for infections are the mainstay of HIES management. Disclosures:No relevant conflicts of interest to declare.

Frequent and Widespread Vascular Abnormalities in Human Signal Transducer and Activator of Transcription 3 Deficiency

Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described. We prospectively screened 21 adult STAT3-deficient patients [corrected] (median age, 26 years; range, 17-44 years) [corrected] for vascular abnormalities. We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking-based imaging specifically for the [corrected] carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models. Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.

Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation

Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation

Primary spontaneous pneumothorax and mitral valve prolapse are not associated

Mitral valve prolapse (MVP) is a common diagnosis in patients with primary spontaneous pneumothorax (PSP). This description assumes that MVP and PSP might be manifestations of a systemic connective tissue abnormality. The purpose of this study was to determine the prevalence of MVP in PSP patients of Croatian origin and evaluate their relationship with connective tissue disorders. We also examined the prevalence of PSP in patients with primary MVP. Thirty-two patients with PSP and without underlying pulmonary disease or connective tissue disease underwent two-dimensional transthoracic echocardiography performed by a certified cardiologist. Echocardiography and demographic features were analyzed using descriptive statistics. We also examined the medical records of 60 patients with primary MVP. MVP was found in none of the 32 patients suffering from PSP. The age, sex, smoking status, body mass index, side, rate, and family history were similar to previous investigations. Likewise, none of the 60 patients with primary MVP ever had PSP. By applying an updated definition of MVP, we found no MVP case among PSP patients of Croatian origin. We also found no PSP in the primary MVP group. Ethnicity may influence the occurrence of MVP in PSP patients, and PSP in primary MVP patients.

Repeated exposure to severely limited sleep results in distinctive and persistent physiological imbalances in rats.

Chronic sleep disruption in laboratory rats leads to increased energy expenditure, connective tissue abnormalities, and increased weights of major organs relative to body weight. Here we report on expanded findings and the extent to which abnormalities become long-lasting, potentially permanent changes to health status after apparent recuperation from chronic sleep disruption. Rats were exposed 6 times to long periods of disrupted sleep or control conditions during 10 weeks to produce adaptations and then were permitted nearly 4 months of undisturbed sleep. Measurements were made in tissues from these groups and in preserved tissue from the experimental and control groups of an antecedent study that lacked a lengthy recuperation period. Cycles of sleep restriction resulted in energy deficiency marked by a progressive course of hyperphagia and major (15%) weight loss. Analyses of tissue composition in chronically sleep-restricted rats indicated that protein and lipid amounts in internal organs were largely spared, while adipose tissue depots appeared depleted. This suggests high metabolic demands may have preserved the size of the vital organs relative to expectations of severe energy deficiency alone. Low plasma corticosterone and leptin concentrations appear to reflect low substrate availability and diminished adiposity. After nearly 4 months of recuperation, sleep-restricted rats were consuming 20% more food and 35% more water than did comparison control rats, despite normalized weight, normalized adipocytes, and elevated plasma leptin concentrations. Plasma cholesterol levels in recuperated sleep-restricted rats were diminished relative to those of controls. The chronically increased intake of nutriments and water, along with altered negative feedback regulation and substrate use, indicate that internal processes are modified long after a severe period of prolonged and insufficient sleep has ended.

Abnormalities of the Spinal Dura Mater: Are Multiple Clinical Syndromes with Dural Lesions Associated with Abnormal Connective Tissue?

We review several clinical and radiological entities that present with abnormalities of the spinal dura that may be related to each other. These include: the syndrome of spontaneous intracranial hypotension, neuroenteric cysts, spontaneous spinal cord herniation, degenerative disc disease associated with disc clefts or associated with intradural complications, and Hirayama disease. Our observations focus on common imaging findings of dural tears, abnormal peridural fluid and associated degenerative disc disease. We propose that T2 fat sat sequences should be routinely used in spinal imaging protocols to evaluate extradural fluid.

Hyper-IgE Syndrome: Report of Three Cases and Review of Literature

The hyper-immunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disorder characterized by high serum levels of immunoglobulin E (IgE), recurrent skin and lung infections, chronic dermatitis and a variety of connective tissue and skeletal abnormalities. The bacteria that commonly infect these patients are Staphylococcus aureus and Haemophilus influenzae. These patients share some characteristic facial appearance and many oral manifestations. Therapy should include prolonged antibiotic therapy. We report the clinical picture of three patients that presented recurrent infections and different outcomes, and then we describe and compare with our patients the clinical, laboratory and therapeutic aspects of HIES. J Med Cases. 2011;2(4):151-155 doi: https://doi.org/10.4021/jmc213w