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Cystic fibrosis is characterized by lung dysfunction involving mucus hypersecretion, bacterial infections, and inflammatory response. Inflammation triggers pro-fibrotic signals that compromise lung structure and function. At present, several in vitro cystic fibrosis models have been developed to study epithelial dysfunction but none of these focuses on stromal alterations. Here we show a new cystic fibrosis 3D stromal lung model made up of primary fibroblasts embedded in their own extracellular matrix and investigate its morphological and transcriptomic features. Cystic fibrosis fibroblasts showed a high proliferation rate and produced an abundant and chaotic matrix with increased protein content and elastic modulus. More interesting, they had enhanced pro-fibrotic markers and genes involved in epithelial function and inflammatory response. In conclusion, our study reveals that cystic fibrosis fibroblasts maintain in vitro an activated pro-fibrotic state. This abnormality may play in vivo a role in the modulation of epithelial and inflammatory cell behavior and lung remodeling. We argue that the proposed bioengineered model may provide new insights on epithelial/stromal/inflammatory cells crosstalk in cystic fibrosis, paving the way for novel therapeutic strategies.

The natriuretic peptide signaling pathway has been implicated in many cellular processes, including endochondral ossification and bone growth. More precisely, different mutations in the NPR-B receptor and the CNP ligand have been identified in individuals with either short or tall stature. In this study we show that the NPR-C receptor (encoded by NPR3) is also important for the regulation of linear bone growth. We report four individuals, originating from three different families, with a phenotype characterized by tall stature, long digits, and extra epiphyses in the hands and feet. In addition, aortic dilatation was observed in two of these families. In each affected individual, we identified a bi-allelic loss-of-function mutation in NPR3. The missense mutations (c.442T>C [p.Ser148Pro] and c.1088A>T [p.Asp363Val]) resulted in intracellular retention of the NPR-C receptor and absent localization on the plasma membrane, whereas the nonsense mutation (c.1524delC [p.Tyr508 ∗ ]) resulted in nonsense-mediated mRNA decay. Biochemical analysis of plasma from two affected and unrelated individuals revealed a reduced NTproNP/NP ratio for all ligands and also high cGMP levels. These data strongly suggest a reduced clearance of natriuretic peptides by the defective NPR-C receptor and consequently increased activity of the NPR-A/B receptors. In conclusion, this study demonstrates that loss-of-function mutations in NPR3 result in increased NPR-A/B signaling activity and cause a phenotype marked by enhanced bone growth and cardiovascular abnormalities., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)

Vascular pathology in young adults has during the last 10 years been diagnosed more often during forensic medical examination of sudden death. Major morphological alterations are revealed in cerebral vessels, coronary vessels, and at the level of the ascending portion of the aorta. Generally, in the young age there is no stenosing atherosclerosis inducing vascular lesions and the development of complications. It was determined that connective tissue dysplasia is pathology wherein weakness of the vascular wall is genetically preconditioned, thus promoting formation of vascular aneurysms and rupture of the latter under conditions of provoking factors such as going in for sports, physical loads, and psychoemotional stress.

Background/purpose: Pleuroperitoneal folds (PPFs) are the source of the primordial diaphragm's muscle connective tissue (MCT), and developmental mutations have been shown to result in congenital diaphragmatic hernia (CDH). The protein paired-related homeobox 1 (Prx1) labels migrating PPF cells and stimulates expression of transcription factor 4 (Tcf4), a novel MCT marker that controls morphogenesis of the fetal diaphragm. We hypothesized that diaphragmatic Prx1 and Tcf4 expression is decreased in the nitrofen-induced CDH model., Methods: Time-mated rats were exposed to either nitrofen or vehicle on gestational day 9 (D9). Fetal diaphragms were microdissected on D13, D15, and D18, and divided into control and nitrofen-exposed specimens. Gene expression levels of Prx1 and Tcf4 were analyzed by qRT-PCR. Immunofluorescence double staining for Prx1 and Tcf4 was performed to evaluate protein expression and localization., Results: Relative mRNA expression of Prx1 and Tcf4 was significantly downregulated in PPFs (D13), developing diaphragms (D15) and fully muscularized diaphragms (D18) of nitrofen-exposed fetuses compared to controls. Confocal laser scanning microscopy revealed markedly diminished Prx1 and Tcf4 expression in diaphragmatic MCT of nitrofen-exposed fetuses on D13, D15, and D18 compared to controls., Conclusions: Decreased expression of Prx1 and Tcf4 in the fetal diaphragm may cause defects in the PPF-derived MCT, leading to development of CDH in the nitrofen model., Level of Evidence: Level 2c (Centre for Evidence-Based Medicine, Oxford)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: The aim of this before-after clinical trial was to evaluate nasolabial soft tissue changes in the frontal plane after bimaxillary surgery., Methods: A total of 20 skeletal Class III Iranian patients needing bimaxillary Le Fort I osteotomy plus mandibular setback surgery were enrolled in this trial. Patients underwent 4.02 ± 1.02 mm of maxillary advancement (Le Fort I osteotomy, 4.33 ± 1.21 mm in men, 3.81 ± 0.86 mm in women) and 7.13 ± 1.74 mm of mandibular setback (intraoral vertical ramus osteotomy, 7.71 ± 2.33 mm in men, and 6.74 ± 1.16 mm in women). Data were acquired via 2D frontal photographs. We compared pretreatment baseline (T 1 ), preoperative postorthodontic treatment (T 2 ), and postoperative (T 3 ) anthropometric measurements using repeated-measures ANOVA and Bonferroni tests (α = 0.05)., Result: The 20 patients (12 men, 8 women) were aged 21.85 ± 1.75 years. Between T 1 and T 2 , nasal width, cutaneous upper labial heights increased overall; cutaneous lower labial height decreased (P < 0.05). Between T 2 and T 3 , nasal width, widths of the philtrum and mouth, cutaneous upper-lip height, vermilion height of the lower lip, lateral upper-lip height increased; the upper-lip vermilion height and cutaneous lower lip height decreased (P < 0.05). The changes ranged between 0.5 and 5 mm., Conclusion: The applied orthognathic surgery procedures might widen the alar base and mouth width. It might increase the lateral upper-lip height, vermilion height of the lower lip, and cutaneous and overall upper-lip heights while reducing upper-lip vermilion height and shortening the overall lower-lip height.

Objective: Changes in soft tissue in various morphological regions of the face immediately after rapid maxillary expansion (RME) were examined using three-dimensional (3D) deviation analyses., Patients and Methods: A total of 50 patients were included in the study; 25 patients (11 female and 14 male) presented with a unilateral or bilateral posterior crossbite malocclusion requiring RME. In addition, 25 patients (13 female and 12 male) were included as a control group. The mean ages of the study group and control group were 9.8 years (range 8.1-12.6 years) and 9.6 years (range 8.3-12.2 years), respectively. The 3D stereophotogrammetric images acquired immediately before the appliance was cemented and after expansion had been completed in the treatment group were compared using Rapidform software. The 3D deviation analyses were made for the complete face and in the upper and lower face, upper and lower lips and nose regions. The amount of negative and positive deviations and the mean deviations were examined on the facial meshes for the 95th percentiles., Results: Immediately after RME, the mean absolute deviation over the complete face was 0.54 ± 0.16 mm. The mean change for the upper face was 0.42 ± 0.17 mm (mean positive deviation: 0.37 ± 0.17 mm; mean negative deviation: -0.48 ± 0.18 mm). The mean absolute deviation was 0.62 ± 0.28 mm in the upper lip and 0.60 ± 0.34 mm in the lower lip. In the nose area, the absolute deviation was 0.41 ± 0.21 mm (mean positive deviation: 0.39 ± 0.16 mm; mean negative deviation: -0.43 ± 0.26 mm)., Conclusions: Changes in facial soft tissues in the upper face, lower face, nasal soft tissues, and lower and upper lip regions were observed after RME.

Null alleles for the COL5A1 gene and missense mutations for COL5A1 or the COL5A2 gene underlie cases of classic Ehlers-Danlos syndrome, characterized by fragile, hyperextensible skin and hypermobile joints. However, no classic Ehlers-Danlos syndrome case has yet been associated with COL5A2 null alleles, and phenotypes that might result from such alleles are unknown. We describe mice with null alleles for the Col5a2. Col5a2(-/-) homozygosity is embryonic lethal at approximately 12 days post conception. Unlike previously described mice null for Col5a1, which die at 10.5 days post conception and virtually lack collagen fibrils, Col5a2(-/-) embryos have readily detectable collagen fibrils, thicker than in wild-type controls. Differences in Col5a2(-/-) and Col5a1(-/-) fibril formation and embryonic survival suggest that α1(V)3 homotrimers, a rare collagen V isoform that occurs in the absence of sufficient levels of α2(V) chains, serve functional roles that partially compensate for loss of the most common collagen V isoform. Col5a2(+/-) adults have skin with marked hyperextensibility and reduced tensile strength at high strain but not at low strain. Col5a2(+/-) adults also have aortas with increased compliance and reduced tensile strength. Results thus suggest that COL5A2(+/-) humans, although unlikely to present with frank classic Ehlers-Danlos syndrome, are likely to have fragile connective tissues with increased susceptibility to trauma and certain chronic pathologic conditions., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

In patients, suffering hydronephrosis stages II-III, caused by the ureteric-pelvic segment (UPS) obstruction due to inborn failures of urinary system, the collagen types I and III ratio reduction, and in acquired obstruction--its enhancement, are noted in interstitium, renal parenchyma vessels and the UPS walls. While obstruction in patients due to inborn failures in vascular basal membranes a deficiency of collagen type IV and appearance of nontypical for vascular basal membranes intersticial collagen type Il are observed. In the acquired UPS, obstruction the, enhancement of content of collagen type IV is revealed only. These disorders are mostly pronounced in patients with the disease recurrence. There was proposed diagnostic coefficient of ratio between collagens types I and III in patients, suffering hydronephrosis, caused by obstruction of various etiology. In hydronephrosis, caused by the UPS stricture, the cytokines disbalance occurs, impacting processes of collagen formation.

False formation of connective tissues have a great influence on structure and function of organs and tissues of the human body. In prosthodontics, the changes in connective tissues greatly occur during clinical stages of preparing metal ceramic dentures. The algorithm of treatment patients with connective tissue dysplasia during metal ceramic dentures was developed and introduced into practical dentistry based on studying the morphology and functionality of dentition and clinical experience.

The connective tissue metabolism was investigated in patients, suffering hydronephrosis, caused by obstruction of various etiology of pelvio-ureteric segment (PUS) and ureter, which has a recurrent course. On the 21th day postoperatively the blood indices enhancement was revealed, what characterizes the disorder of collagen synthesis and degradation, including, free (FOP), proteinbinded (PRBOP) and peptidebinded (PEBOP) oxyproline. The changes noted are more pronounced in patients with the inborn obstruction of PUS and recurrent course of the disease. A new marker--the PRBOP to FOP levels ratio--was proposed for prognostication of stricture recurrence.

Arthrogryposis has been the term used to describe multiple congenital contractures for over a century. It is a descriptive term and present in over 400 specific conditions. Responsible gene abnormalities have been found for more than 150 specific types of arthrogryposis. Decreased fetal movement is present in all affected individuals which leads to a variety of secondary deformations. Decreased fetal movement (fetal akinesia) is associated with increased connective tissue around the immobilized joint, skin dimpling overlying the immobilized joint, disuse atrophy of the muscles that mobilize the joint and abnormal surface of the joint depending on the immobilized position. Other frequently observed features include: micrognathia, mildly shortened limbs, intrauterine growth restriction, pulmonary hypoplasia and short and/or immature gut. Primary etiologies include neuropathic processes; myopathic processes; end-plate abnormalities; maternal illness, trauma and drugs; limitation of fetal space; vascular compromise; and metabolic disorders to the developing embryo/fetus., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

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 finding of a congenital fibrous band during laparotomy for intestinal obstruction is extremely rare. Preoperative diagnosis is challenging and no characteristic radiological findings have been described. We report the case of a premature baby in whom incomplete intestinal obstruction was due to a congenital band originating from the duodeno-jejunal flexure and extending across the ascending colon.

Features of accommodative response in children with myopia associated with nondifferentiated connective tissue dysplasia (NCTD) were studied using computered accommodography. A variety of accommodative response patterns were found in myopia associated with NCTD, that is indicative of a great functional potential of ciliary muscle. Theoretic side is discussed for normal accommodative response and for muscle fibers hyperfunction as well.

We report a case of a 3-year-old boy who presented with symptoms and signs of intestinal obstruction. The patient reported no previous history of abdominal surgery or trauma while clinical and radiographic examinations were not diagnostic. An open laparotomy was subsequently performed and the intraoperative findings were consistent with a congenital band extending from the antimesenteric wall of the jejunum to the root of mesentery. The band was ligated and divided with an uneventful postoperative course. Congenital bands are extremely rare. Their exact incidence is still unknown. This case, therefore, represents an unusual surgical problem in a child in which the diagnosis was clinically unexpected.

Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFβ-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFβ signaling were consistent features in GD and AD fibroblasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFβ signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Geleophysic dysplasia (GD, OMIM 231050) is an autosomal recessive disorder characterised by short stature, small hands and feet, stiff joints, and thick skin. Patients often present with a progressive cardiac valvular disease which can lead to an early death. In a previous study including six GD families, we have mapped the disease gene on chromosome 9q34.2 and identified mutations in the A Disintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2)., Methods: Following this study, we have collected the samples of 30 additional GD families, including 33 patients and identified ADAMTSL2 mutations in 14/33 patients, comprising 13 novel mutations. The absence of mutation in 19 patients prompted us to compare the two groups of GD patients, namely group 1, patients with ADAMTSL2 mutations (n=20, also including the 6 patients from our previous study), and group 2, patients without ADAMTSL2 mutations (n=19)., Results: The main discriminating features were facial dysmorphism and tip-toe walking, which were almost constantly observed in group 1. No differences were found concerning heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngo-tracheal stenosis, deafness, and radiographic features., Conclusions: It is concluded that GD is a genetically heterogeneous condition. Ongoing studies will hopefully lead to the identification of another disease gene.

One hundred young patients (aged 17-45 years) with acute cerebral blood circulation disorders (ACBCD) have been studied. Phenotypic signs of non-differential dysplasia of the connective tissue (NDDCT) have been found in 50 patients (the main group) and other 50 patients had no clinical signs of NDDCT (the comparison group). Patients underwent a complex clinico-neurological, instrumental and laboratory study. In young patients with NDDCT, transient ischemic attacks were observed in 14%, ischemic strokes in 66%, hemorrhagic strokes in 20%. Risk factors characteristic of young patients with ACBCD have been singled out. The higher content of free oxyproline, the distinct positive dynamics (the reduction of clinical symptoms severity during the acute phase of stroke) and the significantly better restoration of lost functions were observed in patients with NDDCT compared to patients without NDDCT.

Compatibility of such signs, as not differentiated connective tissue dysplasia and chronic gastroduodenitis is considered. 170 patients of school age with the confirmed diagnosis chronic gastroduodenitis are surveyed with the purpose of revealing signs of connective tissue dysplasia. It is shown, that symptoms of connective tissue dysplasia meet more often at children with chronic gastroduodenitis, than at children without inflammatory gastroduodenal disease. Following features of connective tissue dysplasia are most typical for children with gastroduodenal diseases: external (wrong bearing, flat-foot, a thin skin and others) and internal (a vegetative dysfunction, a biliary dyskinesia and others). Those features have the high informative importance for prognosis of inflammatory gastroduodenal disease in children.

Cranioectodermal dysplasia (CED) is an infrequently described autosomal recessive disorder characterized by craniofacial, ectodermal and skeletal abnormalities, and associated with increased risk of chronic renal failure. A degree of joint laxity has been noted in some CED patients, but significant skin and soft-tissue laxity has not previously been highlighted as part of the syndrome. We report on two unrelated patients with CED and significant connective tissue involvement, including cutis laxa, hernias, and joint laxity. We conclude with a brief discussion of the differential diagnosis.

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder in which patients display tortuosity of arteries in addition to hyperextensible skin, joint laxity, and other connective tissue features. This syndrome is caused by mutations in the SLC2A10 gene. In this article we describe an ATS girl of Kurdish origin who, in addition to arterial tortuosity and connective tissue features, displays stomach displacement within the thorax and bilateral hip dislocation. Clinical details of this patient have been reported previously. Sequencing of the SLC2A10 gene identified a novel homozygous non-sense c.756C>A mutation in this patient's DNA. This mutation in the SLC2A10 gene replaces a cysteine encoding codon with a stop signal. This is believed to cause a premature truncation of GLUT10 protein in this patient. We conclude that patients of Kurdish origin who display arterial tortuosity associated with skin hyperextensibility, joint hypermobility, and characteristic facial features may carry mutations in the SLC2A10 gene.

Congenital and adult-onset inherited myopathies represent a wide spectrum of syndromes. Classification is based upon clinical features and biochemical and genetic defects. Joint hypermobility is one of the distinctive clinical features that has often been underrecognized so far. We therefore present an overview of myopathies associated with joint hypermobility: Ullrich congenital muscular dystrophy, Bethlem myopathy, congenital muscular dystrophy with joint hyperlaxity, multi-minicore disease, central core disease, and limb girdle muscular dystrophy 2E with joint hyperlaxity and contractures. We shortly discuss a second group of disorders characterised by both muscular features and joint hypermobility: the inherited disorders of connective tissue Ehlers-Danlos syndrome and Marfan syndrome. Furthermore, we will briefly discuss the extent and pattern of joint hypermobility in these myopathies and connective tissue disorders and propose two grading scales commonly used to score the severity of joint hypermobility. We will conclude focusing on the various molecules involved in these disorders and on their role and interactions in muscle and tendon, with a view to further elucidate the pathophysiology of combined hypermobility and myopathy. Hopefully, this review will contribute to enhanced recognition of joint hypermobility and thus be of aid in differential diagnosis.

Megacystis-microcolon intestinal hypoperistalsis syndrome (MMHIS or Berdon syndrome) is an autosomal-recessive disorder characterized by chronic intestinal obstruction. Although the disease is often diagnosed in female infants we describe a man with late diagnosis in adulthood. Our patient presented soon after birth with intestinal obstruction and developed short bowel syndrome after multiple intestinal resections. Of note, the connective tissue net within the muscle layers of the intestinal wall was absent ('aplastic desmosis'). This case illustrates the variable clinical features of MMHIS and aplastic desmosis, which might delay the correct diagnosis of a severe disorder.

Variations involving the cervical portion of the vagus nerve are seemingly very rare. We report an adult male found to harbour a right cervical vagus nerve that crossed anterior to the right common carotid artery to terminate in the lateral aspect of the thyroid gland. A very small continuation of this nerve was found to continue distally into the thorax. Histologically, this part of the vagus nerve did not contain ganglion or other cell bodies. There were no heterologous inclusions (thyroid, parathyroid, thymus, salivary gland or branchial cleft remnants) present. Although grossly there was a connection into the thyroid gland, this was not observed histologically. No signs of trauma were found to the ipsilateral neck region. We hypothesise that this variation is due to entanglement between the thyroid gland and cervical vagus nerve during development. This rare variation might be considered by the clinician who operates in the cervical region or interprets imaging of the neck. To our knowledge, a vagus nerve with the above described morphology has not been described.

Background: Major congenital malformations place a considerable burden on the affected child, the family and society. Any kind of medicine used during pregnancy might have a harmful impact; therefore, such practice has raised concerns. The objective of the current study was to explore the relationship between the use of herbal medicines by pregnant women during the first trimester of pregnancy and the risk of major congenital malformation in their live born infants., Methods: This was a cross-sectional analysis of data from a prospective pregnancy cohort, which was established between 1984 and 1987. To assemble the cohort, pregnant women of >or=26 weeks of gestation who came to the Taipei Municipal Maternal and Child Hospital in Taiwan for prenatal care were enrolled in the study and interviewed using a structured questionnaire. Detailed information, including herbal medicine use during different periods of pregnancy, was obtained during the interview. Past medical history, current obstetric data and details on conventional medicines used during pregnancy were abstracted from medical records. Data on birth weight, gestational duration and characteristics of live born infants were gathered from the Taiwan national birth register. Congenital malformation information was obtained from multiple sources: the newborn examination record (1984-7); the national death register (1984-2003); and Taiwan National Health Insurance data (1996-2000). Multiple logistic regression was used to estimate the odds ratio [OR] of major congenital malformation by herbal medicines used during the first trimester., Results: A total of 14,551 live births were analysed. After adjustment for confounding factors, taking huanglian during the first trimester of pregnancy was found to be associated with increased risk of congenital malformations of the nervous system (adjusted OR 8.62, 95% CI 2.54, 29.24). An-Tai-Yin was associated with an increased risk of congenital malformations of the musculoskeletal and connective tissues (adjusted OR 1.61, 95% CI 1.10, 2.36) and the eye (adjusted OR 7.30, 95% CI 1.47, 36.18)., Conclusion: We found evidence for a possible link between the use of specific herbal medicines during the first trimester of pregnancy and increased risks of specific groups of congenital malformations. We could not investigate whether the adverse effects were related to direct toxicity from the herbal medicines, or were from misuse, contamination or uncontrolled confounding. Nonetheless, we would advise caution regarding use of herbal medicines during pregnancy, and we suggest that further investigation of these findings is warranted.

This review attempts to demonstrate the spectrum of soft tissue masses encountered in the child's hand. The diagnosis may be suggested by the combination of physical exam and radiographs. Frequently the etiology of a soft tissue mass cannot be established by conventional radiographs and further imaging is necessary. MRI by virtue of its ability to provide detailed soft tissue characterization is the preferred method of imaging the problematic soft tissue mass.

Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in the three genes coding for the alpha chains of collagen VI and characterized by generalized muscle weakness, striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints, and normal intellectual development. The diagnosis is supported by abnormal immunoreactivity for collagen VI on muscle biopsies. As patients with UCMD show clinical characteristics typical of classical disorders of connective tissue such as Ehlers-Danlos syndromes (EDS), we investigated the ultrastructure of skin biopsy samples from patients with UCMD (n=5). Electron microscopy of skin biopsies revealed ultrastructural abnormalities in all cases, including alterations of collagen fibril morphology (variation in size and composite fibers) and increase in ground substance, which resemble those seen in patients with EDS. Our findings suggest that there is a true connective tissue component as part of the phenotypic spectrum of UCMD and that there is considerable clinical as well as morphological overlap between UCMD and classic connective tissue disorders., ((c) 2004 Wiley-Liss, Inc.)

Arterial tortuosity syndrome (ATS) is a rare condition with autosomal recessive inheritance characterized by connective tissue abnormalities. The most specific clinical findings are cardiovascular anomalies including tortuosity, lengthening, aneurysm, and stenosis formation of major arteries. Also ventricular hypertrophy is frequently present. Other anomalies are skin hyperextensibility and cutis laxa, joint laxity or contractures of the joints, and inguinal herniae. Histology shows disruption of elastic fibers of the media. These features suggest that ATS is a connective tissue disorder. A biochemical or molecular defect has not yet been identified. We describe here nine additional ATS patients from three consanguineous Moroccan families and review a total of 35 patients with this uncommon condition.

We report a case of intestinal obstruction caused by a congenital abnormal vascular band in a 17-year-old boy. The patient was admitted with acute colicky abdominal pain, and an emergency laparotomy revealed that the ileum was strangulated by a fibrous band with vessels about 2 mm in diameter and 7 cm in length, extending from the antemesenterium of the terminal ileum to the mesoappendix. The affected intestine was resected with the band and the appendix. Histologically, the fibrous band was composed of loose connective tissue containing arteries, veins, and nerve fibers, suggesting that it was congenital and originated from a remnant of the ventral mesentery in the embryonic period. There have been few reports of intestinal obstruction being caused by a congenital vascular band, especially in patients beyond the pediatric age group.

Objective: Persistent embryonic connective tissue has been considered to be a cause of chronic otitis media with effusion in neonates and of cholesteatoma in later life. As part of a study of pneumatization and resorption of embryonic connective tissue from the middle ear of pre- and postnatal infants, inflammatory processes of variable extents have been observed within the embryonic connective tissue. The aim of the present study was to characterize this inflammation and to detect patterns in its presence and distribution., Material and Methods: Twenty fetal temporal bones obtained at 4-8 months of development and 31 temporal bones from children who died of sudden infant death syndrome aged < 1 year were studied to assess the inflammation within the middle ear cleft and specifically in the embryonic connective tissue., Results: Sixteen of 27 (59.3%) pre- and 10/31 (32.2%) postnatal specimens displayed a non-specific inflammatory lymphocytic infiltration without signs of bacterial infection or the presence of or reaction to amniotic contents. Eleven of 27 prenatal temporal bones (40.7%) and 16/31 (51.6%) postnatal specimens showed no evidence of histologic middle ear inflammation. The presence or absence of inflammation was independent of age., Conclusion: Our observations indicate resorption of the embryonic connective tissue with individual variations indicating that genetic factors are responsible for the development of the middle ear spaces during the phases of development studied.

We investigated soft tissue facial resemblance among relatives with or without syndromes and among related and unrelated individuals diagnosed with the same syndrome. Using correlation coefficients, we compared facial landmark (i.e., three-dimensional coordinate) positions and measurements gained by photogrammetry in various combinations of normal and syndrome-affected individuals. There were fewer significant correlations for the three-dimensional coordinates and measurements between the normal parent-normal child pairs than for the normal sib pairs. There was no discernible pattern for the single measurements in the parent-child pairs, whereas all of the midline vertical measurements were significantly positively correlated in the normal sib pairs. Significant correlations were always positive in all sib comparisons, but ranged from negative to positive in all parent-child correlations. The shared environment of sibs was a possible explanation for their greater resemblance in comparison with parent-child pairs. We also had measurements from 11 subjects (related and unrelated) diagnosed with one of four syndromes, and we used these to compare individuals with the same syndrome by calculating correlation coefficients based on all available pairs of measurements. The highest significant positive correlations were found for related individuals with the same syndrome (0.72 to 0.83). Unrelated individuals with the same syndrome also had significant positive correlations, but they were lower (0.35 to 0.65). We therefore inferred that the genetic similarities between unrelated individuals with syndromes played a role in the resemblance between them, and that common genes and environment in related individuals further contributed to the high correlations found for them., (Copyright 2001 Wiley-Liss, Inc.)

The purpose of this study was to reveal the relationship between temporomandibular joint (TMJ) dysfunction and dysplasia of connective tissue (DCT). This investigation included 53 (34 female and 19 male) patients with TMJ internal derangement (ID) and 53 controls; 24 patients with marked and 53 patients with mild dysfunction of this joint. The symptoms of DCT (such as scoliosis, general joint hypermorbility) and TMJ ID were revealed. Results of this study prove that DCT is one of etiological factors of TMJ ID. The relationship between type of ID and severity of DCT was revealed.

Massive intracranial hemorrhage, no history of trauma and radiographic findings that were initially interpreted as linear parietal fractures raised the possibility of nonaccidental trauma in 2 infants. Both had severe coagulopathy, 1 due to hemorrhagic disease of the newborn (vitamin K deficiency) and the other due to disseminated herpes simplex virus infection. Both infants died. At autopsy, the parietal bone abnormalities were not fractures, but proved to be an anomalous suture in 1 and a connective tissue fissure in the other., (Copyright 2001 S. Karger AG, Basel)

We investigated soft tissue facial asymmetry in normal and syndrome-affected individuals ranging in age from 1 year to adulthood. The purposes of our study were to determine if facial asymmetry was greater in syndrome-affected individuals than in normal individuals and, if true, to distinguish those measurements that could be used in routine screening to identify the presence of syndromes in uncertain patients and, lastly, to investigate the causes of measurement asymmetry at the level of the landmarks. The last purpose was possible because we used a stereophotogrammetric method with which the three-dimensional (3D) landmark positions were obtained. In the statistically significantly different measurements, those from the right side were dominant, with one exception in each group, except normal males. In all groups the landmark analyses demonstrated the same trends, and while there was far less patterning in the 3D coordinates, these results were also consistent between the four groups. We compared the statistical findings of the 3D coordinates and measurements and found that there was no predictable relationship between significant findings in the landmarks and the measurements. In particular, we noted that statistical differences in measurements did not infer significant differences in the positions of the landmarks between the right and left sides of the face. Both the normal and syndrome-affected groups appeared to be equally canalized and similarly affected by developmental noise: When the bilateral measurement differences of each syndrome-affected subject were compared to the limits of normal asymmetry, less than 10% of the comparisons exceeded the norms., (Copyright 2000 Wiley-Liss, Inc.)

Fibromodulin is a member of a family of connective tissue glycoproteins/proteoglycans containing leucine-rich repeat motifs. Several members of this gene family bind to fibrillar collagens and are believed to function in the assembly of the collagen network in connective tissues. Here we show that mice lacking a functional fibromodulin gene exhibit an altered morphological phenotype in tail tendon with fewer and abnormal collagen fiber bundles. In fibromodulin-null animals virtually all collagen fiber bundles are disorganized and have an abnormal morphology. Also 10-20% of the bundles in heterozygous mice are similar to the abnormal bundles in fibromodulin-null tail tendon. Ultrastructural analysis of Achilles tendon from fibromodulin-null mice show collagen fibrils with irregular and rough outlines in cross-section. Morphometric analysis show that fibromodulin-null mice have on the average thinner fibrils than wild type animals as a result of a larger preponderance of very thin fibrils in an overall similar range of fibril diameters. Protein and RNA analyses show an approximately 4-fold increase in the content of lumican in fibromodulin-null as compared with wild type tail tendon, despite a decrease in lumican mRNA. These results demonstrate a role for fibromodulin in collagen fibrillogenesis and suggest that the orchestrated action of several leucine-rich repeat glycoproteins/proteoglycans influence the architecture of collagen matrices.

Objective: The purpose of this study is to describe the bony and, to our knowledge, previously unreported associated soft-tissue abnormalities seen on MR imaging of dysplasia epiphysealis hemimelica., Conclusion: MR imaging accurately depicted bony and cartilagenous structural abnormalities in multiple planes and revealed previously undescribed secondary changes in menisci, tendons, ligaments, and muscle. MR imaging is of value in the assessment of patients with this disorder.

We report a girl with severe prenatal and postnatal growth retardation, congenital generalized absence of subcutaneous tissue, and facial and somatic changes with some similarities to Wiedemann-Rautenstrauch syndrome (WRS). However, the patient's condition is sufficiently different from those reported previously to suggest that this patient represents a new syndrome. The abnormalities observed in this patient overlap with those of WRS, Cockayne syndrome, type A (CSA), and osteodysplastic primordial dwarfism type III (OPD III), but also include choanal atresia and pigmentary retinopathy.

Objective: To use magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA) and spondylarthropathy (SpA) to determine if the primary site of abnormality differs., Methods: Twenty patients with recent-onset knee effusion (10 with SpA and 10 with RA) were evaluated using fat-suppressed MRI. Knee joint effusion and synovitis were confirmed using ultrasonography. MRI scans were independently scored by 2 observers who were blinded to the patient's diagnosis., Results: All 10 of the SpA patients, but only 4 of the 10 RA patients, had focal peri-entheseal high signal (compatible with fluid or edema) outside the joint (P = 0.01). Six of the SpA patients had bone marrow edema that was maximal at entheseal insertions; in 4 cases this was multifocal. No RA patients showed such an abnormality (P = 0.01)., Conclusion: Prominent entheseal abnormalities on MRI are a consistent feature of new-onset synovitis in SpA, but are a minor feature of RA. This finding has important implications for the diagnosis, classification, and mechanisms of synovitis in patients with SpA.

Thrombospondin (TSP) 2, and its close relative TSP1, are extracellular proteins whose functions are complex, poorly understood, and controversial. In an attempt to determine the function of TSP2, we disrupted the Thbs2 gene by homologous recombination in embryonic stem cells, and generated TSP2-null mice by blastocyst injection and appropriate breeding of mutant animals. Thbs2-/- mice were produced with the expected Mendelian frequency, appeared overtly normal, and were fertile. However, on closer examination, these mice displayed a wide variety of abnormalities. Collagen fiber patterns in skin were disordered, and abnormally large fibrils with irregular contours were observed by electron microscopy in both skin and tendon. As a functional correlate of these findings, the skin was fragile and had reduced tensile strength, and the tail was unusually flexible. Mutant skin fibroblasts were defective in attachment to a substratum. An increase in total density and in cortical thickness of long bones was documented by histology and quantitative computer tomography. Mutant mice also manifested an abnormal bleeding time, and histologic surveys of mouse tissues, stained with an antibody to von Willebrand factor, showed a significant increase in blood vessels. The basis for the unusual phenotype of the TSP2-null mouse could derive from the structural role that TSP2 might play in collagen fibrillogenesis in skin and tendon. However, it seems likely that some of the diverse manifestations of this genetic disorder result from the ability of TSP2 to modulate the cell surface properties of mesenchymal cells, and thus, to affect cell functions such as adhesion and migration.

We report a benign form of congenital angulation of long bones associated with shortening of soft tissues. The patients were three males and four females including two siblings. The average age at first examination was 6 months (range, 1-17 months) and that at the time of follow-up was 7 years (range, 13 months-11 years). The characteristics were short-limb type short stature, congenital multiple angulation deformities of the long bones of both upper and lower extremities, with almost the same angulation directions for all the patients and improvement of the deformities with age. There was also accelerated skeletal maturation, lack of epi-metaphyseal lesions, skin dimples, limitation of the ankle joint dorsiflexion, and inconspicuousness of skin creases on the flexor side of the elbow and knee. This phenotype is not consistent with any of the bent bone dysplasia group. Caffey's report [Caffey J (1947). Am J Dis Child 74:543-5621 included two different subtypes of bent bones, round bowing and sharp angulation, and the latter are similar to this report. However, Caffey's cases lack limitation of ankle dorsiflexion and reduced skin creases. An autosomal recessive mode of inheritance could be present in this subtype.