Ophthalmoplegia and Congenital Cranial Dysinnervation Disorders.

Some forms of ophthalmoplegia are congenital and fall into the category of Congenital Cranial Dysinnervation Disorders (CCDDs). These disorders arise from a primary defect of cranial nucleus/nerve development or guidance. Many have substantial limitations of ocular motility with or without other associated features. The type and degree of ophthalmoplegia can be similar between CCDD subtypes as well as with non-congenital forms of ophthalmoplegia. Therefore diagnostic confirmation often requires neuro-imaging and/or genetic investigations. The clinician should consider this category in cases of ophthalmoplegia that are congenital and nonprogressive in nature.

Limitation of Knee Flexion by a Fibrotic Band of a Fifth Component of the Quadriceps Muscle in a Child: A Case Report.

CASE: We describe the case of a 3-year-old boy who presented with limited flexion in the left knee. High-resolution magnetic resonance imaging allowed visualization of a fibrotic muscle band in the anatomic position of the fifth component of the quadriceps muscle, which was confirmed by surgical findings. After surgical resection, the patient achieved full recovery of range of motion of the knee. CONCLUSION: To our knowledge, this is the first reported case of a fibrotic muscle band in the anatomic position of a previously described fifth accessory component of the quadriceps muscle that caused limited knee flexion in a child.

KLF 15 Works as an Early Anti-Fibrotic Transcriptional Regulator in Ang II-Induced Renal Fibrosis via Down-Regulation of CTGF Expression.

BACKGROUND/AIMS: Angiotensin II (Ang II) has been regarded as an important profibrogenic cytokine in renal fibrosis. Krüppel-like factor 15 (KLF15) has been identified as an important negative transcription factor in renal fibrosis. However, little is known about the role of KLF15 in Ang II-induced renal fibrosis. METHODS: In this study, we randomized mice into a control group, Ang II group or Ang II plus losartan group. KLF15 expression was examined with real-time PCR and immunofluorescence in these groups. In vitro, KLF15 expression was examined by Western blot in rat renal fibroblasts (NRK-49F) stimulated with Ang II, and the effect of altered KLF15 expression on the regulation of the profibrotic factor connective tissue growth factor (CTGF) was further explored with co-immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) analyses. RESULTS: Compared with the control group, the murine model of Ang II-induced renal fibrosis demonstrated a significant decrease in renal KLF15 expression at 4 weeks and presented with progressive renal fibrosis at 6 weeks. Meanwhile, losartan, an angiotensin type 1 (AT1) receptor antagonist, effectively prevented the down-regulation of KLF15 expression induced by Ang II infusion. In vitro, NRK-49F cells stimulated with Ang II exhibited a significant decrease in KLF15 expression, accompanied by a marked increase in the expression of profibrotic factors and in the production of extracellular matrix. The up-regulation of CTGF expression induced by Ang II stimulation was inhibited by KLF15 overexpression in NRK-49F cells, and losartan treatment prevented the down-regulation of KLF15 expression and the up-regulation of CTGF expression induced by Ang II stimulation. Furthermore, CoIP and ChIP assays revealed that the transcription regulator KLF15 directly bound to the co-activator P/CAF and repressed its recruitment to the CTGF promoter. CONCLUSIONS: Ang II down-regulates KLF15 expression via the AT1 receptor, and KLF15 is likely to inhibit Ang II-induced CTGF expression by repressing the recruitment of the co-activator P/CAF to the CTGF promoter.

Calcinosis en manos y síndrome antisintetasa sin afectación muscular / Calcinosis in hands and antisynthetase syndrome without muscle involvement

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La criobiopsia transbronquial en la enfermedad pulmonar intersticial: excelente relación coste/beneficio / No disponible

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Cardiomyocyte Ogt is essential for postnatal viability.

The singly coded gene O-linked-ß-N-acetylglucosamine (O-GlcNAc) transferase (Ogt) resides on the X chromosome and is necessary for embryonic stem cell viability during embryogenesis. In mature cells, this enzyme catalyzes the posttranslational modification known as O-GlcNAc to various cellular proteins. Several groups, including our own, have shown that acute increases in protein O-GlcNAcylation are cardioprotective both in vitro and in vivo. Yet, little is known about how OGT affects cardiac function because total body knockout (KO) animals are not viable. Presently, we sought to establish the potential involvement of cardiomyocyte Ogt in cardiac maturation. Initially, we characterized a constitutive cardiomyocyte-specific (cm)OGT KO (c-cmOGT KO) mouse and found that only 12% of the c-cmOGT KO mice survived to weaning age (4 wk old); the surviving animals were smaller than their wild-type littermates, had dilated hearts, and showed overt signs of heart failure. Dysfunctional c-cmOGT KO hearts were more fibrotic, apoptotic, and hypertrophic. Several glycolytic genes were also upregulated; however, there were no gross changes in mitochondrial O2 consumption. Histopathology of the KO hearts indicated the potential involvement of endoplasmic reticulum stress, directing us to evaluate expression of 78-kDa glucose-regulated protein and protein disulfide isomerase, which were elevated. Additional groups of mice were subjected to inducible deletion of cmOGT, which did not produce overt dysfunction within the first couple of weeks of deletion. Yet, long-term loss (via inducible deletion) of cmOGT produced gradual and progressive cardiomyopathy. Thus, cardiomyocyte Ogt is necessary for maturation of the mammalian heart, and inducible deletion of cmOGT in the adult mouse produces progressive ventricular dysfunction.

Congenital fibrosis of the extraocular muscles: magnetic resonance imaging findings and surgical treatment.

PURPOSE: We analyzed findings of orbital and cranial magnetic resonance imaging (MRI) in patients with congenital fibrosis of the extraocular muscles (CFEOM). We described surgery and its outcome. MATERIAL AND METHOD: Nine out of 10 patients with clinical findings of CFEOM underwent orbital and cranial MRI to perform a study of the extraocular muscles and cranial nerves. A multimodality workstation platform developed by the imaging laboratory of our hospital for PC computer allowed us to visualize and measure the cross sections of the extraocular muscles in a coronal section. Surgery was indicated to resolve strabismus. Outcome was considered favorable if the final deviation was < 10 pd in the primary position without head turn. RESULTS: In 8 cases (6 males, 5 unilateral [3 left eye]), MRI revealed atrophy of at least 1 of the extraocular muscles supplied by the third nerve. Five patients had third nerve aplasia or hypoplasia. Clinical findings were compatible with a probable diagnosis of CFEOM in all 10 patients. Four patients underwent ptosis surgery before being diagnosed with CFEOM. Four patients underwent surgery to correct strabismus and, of these, 2 required multiple interventions (1 needed 4 interventions). Outcome was successful in only 2 cases. CONCLUSION: Orbital and cranial MRI provided useful information about extraocular muscles and cranial nerves in CFEOM. Surgery must be performed on an individual basis; the number of reoperations is high. The outcome of surgery was favorable in half of the cases.

Congenital cranial dysinnervation disorders: a concept in evolution.

PURPOSE OF REVIEW: We review the congenital and genetic diagnoses that are currently included in the congenital cranial dysinnervation disorders (CCDDs). RECENT FINDINGS: Recent literature contains new genotypic and phenotypic descriptions of Duane retraction syndrome, Moebius syndrome, and other CCDDs. New genes which when mutated can result in CCDD have been identified, permitting a better understanding of associated phenotypes. More information is available regarding neurodevelopmental and clinical effects of various gene mutations associated with individual CCDDs. For certain CCDDs, the phenotype of a particular individual may not completely predict the genotype, and conversely, the genotype may not always predict the phenotype. SUMMARY: The CCDD concept has focused attention on specific congenital disturbances of human ocular motility and on the fact that these disorders are typically neurogenic in origin. The past decade has seen rapid evolution within this field with the last 2 years yielding additional information about existing diagnoses, genes, and phenotypes that may result in better classification of these disorders and new genotype-phenotype correlations in the future.

Congenital orbital fibrosis associated with fibrosis of extraocular muscle.

Congenital orbital fibrosis is a non-familial, unilateral, distinct clinical entity, characterised by the presence of a diffusely infiltrating orbital mass and is extremely a rare disease. Congenital orbital fibrosis with combined fibrosis of extraocular muscles have not been reported previously. We treated an 8-year-old boy with the presence of a diffusely infiltrating orbital mass and fibrosis of extraocular muscles with secondary involvement of extraocular muscles. Clinical examination revealed left exotropia, hypotropia and fibrosis of extraocular muscle, an irregular, retrobulbar mass located within the orbit, incorporating the optic nerve, medial, superior, inferior and lateral rectus muscle. The CT, MRI and light microscopic studies confirmed the diagnosis. We performed exploration of the orbit, release and biopsy of scar tissue and strabismus surgery. Unlike other reported cases, our case was a progressive congenital disorder with combined fibrosis of extraocular muscle.

KIF21A novel deletion and recurrent mutation in patients with congenital fibrosis of the extraocular muscles-1.

Kinesin family member 21A (KIF21A) mutation is the most common cause for congenital fibrosis of the extraocular muscles type 1 (CFEOM1) in populations worldwide. However, only 12 missense mutations have been reported to date. In this study, KIF21A screening was performed in two Chinese families with CFEOM1. Ophthalmological examinations were performed. The coding exons and adjacent intronic regions of KIF21A were analyzed with cycle sequencing. The novel mutation identified was further evaluated in 150 normal control individuals and available family members. Two heterozygous mutations in KIF21A, c.3000_3002delTGA (p.Asp1001del) and c.2861G>A (p.Arg954Gln), were detected in two families. The novel deletion involves a conserved residue in the coiled-coil domain of KIF21A and is co-segregated with the disease in the examined family, yet was absent in the 300 control chromosomes. In addition, apart from typical phenotypes for CFEOM1, optic disc hypoplasia was also observed in two patients. Deletion mutation in KIF21A has not been previously reported. Our study expands the KIF21 mutation spectrum. This study adds to the current state of knowledge about KIF21A mutations and CFEOM1, which may improve future clinical practice.

The optic nerve head in congenital fibrosis of the extraocular muscles.

OBJECTIVE: Optic nerve head abnormalities have been reported in some patients with congenital fibrosis of the extraocular muscles (CFEOM). This study prospectively assesses optic nerve head appearance in a consecutive CFEOM cohort. METHODS: All patients with CFEOM referred between 2006 and 2010 and who were mature enough to cooperate with fundus photography were included. Fundus photographs were reviewed with attention to optic nerve head features (eg, cupping >0.6, asymmetric cupping >0.3, optic nerve hypoplasia). Interested participants had CFEOM candidate gene analysis (KIF21A, TUBB3, PHOX2A) for genetic counseling purposes. RESULTS: Ten CFEOM patients (five CFEOM1, five CFEOM3, age range 5-23 years) from eight families (all consanguineous but one) participated. All 10 patients had notable disc excavation (5) or optic nerve hypoplasia (5). CFEOM candidate gene analysis was performed in all patients and revealed a heterozygous p.R954W KIF21A mutation only in the patient who was not from a consanguineous family. CONCLUSIONS: Our observations suggest the optic nerve head can be affected by the orbital dysinnervation that occurs in CFEOM. Because careful clinical optic nerve head assessment is difficult in young patients with CFEOM and associated large angle incomitant strabismus, optic nerve head abnormalities may be under-diagnosed. The absence of mutations in known CFEOM genes in our cohort of consanguineous families suggests further genetic heterogeneity of this group of conditions.

Unilateral congenital fibrosis of the extraocular muscles with lid retraction: surgical treatment with a silicon plate on the orbital floor.

Fibrosis of the extraocular muscles can be an acquired or congenital disorder (CFEOM). The congenital disorder(1) is a complex strabismus with congenital restrictive ophthalmoplegia with or without ptosis. The surgery is challenging because the eye muscles are replaced by fibrous tissue or fibrous bands and in most cases the results are not satisfactory. We present the first case report of unilateral CFEOM with palpebral adherence and hypotropia, which was managed with our technique of a silicon plate implant on the orbital floor. The purpose of the implantation of the silicon plate in the orbital floor is to improve the hypotropia caused by CFEOM.

Imaging findings in congenital cranial dysinnervation disorders.

In 2002, the term congenital cranial dysinnervation disorders (CCDDs) was proposed to group heterogeneous syndromes with congenital abnormalities of ocular muscle and facial innervations. The concept of neurogenic etiology has been supported by discovery of genes that are essential to the normal development of brainstem, cranial nerves, and their axonal connections. The CCDDs include Duane retraction syndrome, congenital fibrosis of the extraocular muscles, Möbius syndrome, horizontal gaze palsy with progressive scoliosis, the human homeobox-related disorders, pontine cap tegmental dysplasia, and an expanding list. The purpose of this review was to update the imaging features, as well as clinical and genetic information, regarding cases of CCDDs.

Congenitally dysplastic inferior rectus muscle.

The authors report an unusual presentation of an idiopathic congenitally dysplastic inferior rectus muscle that responded well to surgical correction. Isolated unilateral enlargement of extraocular muscles is rare in children, and there is no definite logical explanation for its cause. A 20-month-old child presented with a congenitally enlarged posterior part of the right inferior rectus muscle with prominent hypotropia and enophthalmos since 10 months of age. Systemic disease work-up, ultrasound B-scan, computed tomography of the orbit and brain, and inferior rectus muscle biopsy were performed. Preoperatively, the child had severe hypotropia of the right eye with retraction of the globe. Work-up for systemic diseases was negative. Computed tomography scan showed thickening of the posterior two-thirds of the inferior rectus muscle. Muscle biopsy showed non-specific fibrotic changes. Strabismus surgery was undertaken at 2 years of age. Hypotropia was reduced significantly postoperatively. Compensatory head position was eliminated.

Use of the novel myokinetic stretching technique to ameliorate fibrotic mass in congenital muscular torticollis: an experimenter-blinded study with 1-year follow-up.

OBJECTIVE: To investigate the effect of the myokinetic stretching technique (MST) on morphological changes and associated clinical outcomes. METHOD: Infantile torticollis (N=32, 17 males) between 1 and 5 months of age (50.56 +/- 20.74 days) were treated with the MST for approximately 30 minutes per session, 5 times a week at university hospital. Diagnostic real-time ultrasound imaging was used on both unaffected and affected sides before and after the treatment to measure the sternocleidomastoid (SCM) muscle thickness of the involved area. Range of motion, head symmetry, and plagiocephaly with radiographs were determined. Data were analyzed using unpaired and paired t-test at p< 0.05. RESULTS: A significant reduction in SCM muscle thickness was observed after the intervention (p< 0.05). This morphological change was associated with significant improvements in passive cervical range of motion and head symmetry (p< 0.05). The mean intervention duration was 53.59 +/- 25.12 days to completely resolve the mass. These effects continued to exist one year post-intervention. CONCLUSIONS: This was the first clinical evidence that demonstrated the efficacy of MST for improving cervical motion and muscle thickness in infants with congenital muscular torticollis as well as shortening the treatment duration.

Germline Mosaicism for KIF21A Mutation (p.R954L) Mimicking Recessive Inheritance for Congenital Fibrosis of the Extraocular Muscles.

OBJECTIVE: To document the genotype for familial congenital fibrosis of the extraocular muscles (CFEOM) with apparent autosomal recessive inheritance. DESIGN: Interventional family study. PARTICIPANTS: Two affected siblings, 3 asymptomatic siblings, and their 2 asymptomatic parents. METHODS: Ophthalmologic examination and candidate gene analysis (KIF21A and PHOX2A from venous blood samples) of the 2 affected siblings and their parents; confirmatory testing for 3 available asymptomatic siblings. MAIN OUTCOME MEASURES: Significant clinical observations and results of gene testing. RESULTS: The 2 affected siblings had large-angle exotropia, moderate bilateral hypotropia, moderate bilateral ptosis, sluggish pupils, and almost complete ophthalmoloplegia with some abnormal synkinesis. The asymptomatic parents were not related and had unremarkable ophthalmic examinations. Four other siblings were normal by history; 3 underwent venous blood sampling for confirmatory testing. Candidate gene testing of PHOX2A, the gene for recessive CFEOM (CFEOM2), did not reveal mutation in the 2 patients or their parents. Sequencing of KIF21A, the gene for dominant CFEOM (CFEOM1), revealed heterozygous p.R954L in both affected individuals but in not in their parents or 3 asymptomatic siblings, consistent with parental germline mosaicism. Haplotype analysis suggested paternal inheritance but was not conclusive. CONCLUSIONS: Parental germline mosaicism can mimic recessive inheritance in CFEOM and likely is underrecognized. Ophthalmologists should be aware of this phenomenon when counseling parents of children with apparent recessive (or de novo) hereditary eye disease. Unlike other reported KIF21A mutations that cause CFEOM1, the p.R954L variant seems to be associated with abnormal pupils. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Renal dysplasia and nephrosclerosis in calves.

Renal dysplasia and nephrosclerosis in six calves, which were aged three to six months and from different farms in western Scotland and north-west England, was characterised clinically by stunted growth and renal failure with uraemia. Affected animals were depressed and one case exhibited severe neurological signs. Reduced erythrocyte counts were evident in three of four animals from which blood samples were submitted for haematology. At postmortem examination, the kidneys were bilaterally small, pale and firm, with marked fibrosis and sometimes contraction of the capsule. Histologically, affected calves had disorganised atrophic glomeruli, dilatation of tubules, loss of nephrons, areas of undifferentiated mesenchyme and diffuse interstitial and periglomerular fibrosis. There was minimal inflammation. Renal dysplasia and nephrosclerosis is a form of juvenile nephropathy of unknown aetiology that occurs sporadically in calves in the UK.