Malformations In Patients Research Articles

Co-existence of Gastrointestinal Vascular Malformations in Patients With Congenital Head/neck and Thoracic Vascular Malformations and Vascular Birthmarks

Co-existence of Gastrointestinal Vascular Malformations in Patients With Congenital Head/neck and Thoracic Vascular Malformations and Vascular Birthmarks

PI3K/AKT Pathway and Brain Malformations

Investigators from Seattle Children's Research Institute, University of Washington, and collaborating institutions sought to evaluate 10 genes in the PI3K/AKT pathway as it relates epileptogenic brain malformations in patients with megalencephaly, hemimegalencephaly, and focal cortical dysplasia.

Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a systemic disease characterized by mucocutaneous telangiectasias, epistaxis, and arteriovenous malformations (AVMs). Intracranial hemorrhage (ICH) rates in this population are not well described. We report ICH rates and characteristics in HHT patients with brain AVMs (HHT-BAVMs). We studied the first 153 HHT-BAVM patients with follow-up data enrolled in the Brain Vascular Malformation Consortium HHT Project. We estimated ICH rates after BAVM diagnosis. The majority of patients were women (58%) and white (98%). The mean age at BAVM diagnosis was 31±19 years (range, 0-70), with 61% of cases diagnosed on asymptomatic screening. Overall, 14% presented with ICH; among symptomatic cases, 37% presented ruptured. During 493 patient-years of follow-up, 5 ICH events occurred yielding a rate of 1.02% per year (95% confidence interval, 0.42-2.44%). ICH-free survival differed significantly by ICH presentation (P=0.003); ruptured cases had a higher ICH rate (10.07%; 95% confidence interval, 3.25-31.21%) than unruptured cases (0.43%; 95% confidence interval, 0.11-1.73%). Patients with HHT-BAVM who present with hemorrhage are at a higher risk for rehemorrhage compared with patients with BAVM detected presymptomatically.

Staged Surgical Repair of Truncus Arteriosus Communis in Critically Ill Neonates with Complex Congenital Malformations

Objective: The presence of complex congenital malformations in patients with truncus arteriosus communis (TAC) increases the mortality and morbidity of the required neonatal repair. This report describes neonates with TAC and other complex malformations who underwent a staged repair. Method: 3 neonates underwent a staged TAC repair, involving an initial RV-PA valveless conduit and either aortic or pulmonary artery reconstruction followed by an intracardiac repair later in infancy. Results: There was no hospital death. 2 patients (cases 1 and 2) have proceeded to a biventricular repair, which consisted of VSD closure, takedown of the initial RV-PA conduit, and placement of a valved RV-PA conduit. A PA patch plasty was necessary in case 1. After their 2nd surgery, both patients were discharged from the hospital in excellent condition and are currently clinically stable. Patient 3 is awaiting further surgery under a stable condition. At the last follow up (range 3 months to 3 years), no re-do surgeries related to the aortic arch or truncal valve were required among survivors, no progressive truncal valve regurgitation was observed. Late pulmonary artery intervention with balloon dilatation and stent placement was required in case 1. Conclusion: In patients with TAC, complete primary repair is preferred in our institution. In critically ill neonates and in the presence of complex cardiovascular malformation however, the complexities and the time-consuming surgery could be associated with a higher mortality. In these cases, a staged TAC repair shortens the myocardial ischemic and bypass time at initial surgery. Providing an unobstructed systemic outflow is essential to prevent the development of truncal valve regurgitation and congestive heart failure. Although not seen in this series, leaving a VSD along with a valveless RV-PA-conduit might cause RV volume overload.

Variants in CUL4B are associated with cerebral malformations.

Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.

Computed Tomographic Angiography or Magnetic Resonance Angiography for Detection of Intracranial Vascular Malformations in Patients With Intracerebral Hemorrhage

Early identification of an intracranial vascular malformation (IVM; brain or pial/dural arteriovenous malformations/fistulae, and aneurysms) after intracerebral hemorrhage (ICH) may improve outcome if treatment can prevent recurrence. Intra-arterial digital subtraction angiography (IADSA) is the reference standard for detection of IVMs as the cause of ICH. Computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) are less invasive than IADSA and may be as accurate. We performed a systematic review of the diagnostic test accuracy of CTA and MRA compared with IADSA for the detection of IVMs as a cause of ICH. We searched MEDLINE (1948 to August 2013), EMBASE (1980 to August 2013), MEDION (August 2013), the Database of Abstracts of Reviews of Effects (August 2013), …

Chiari Type I Malformations in Patients with Dizziness

Objectives: (1) Investigate the association between magnetic resonance imaging (MRI) findings of Chiari Type I malformation and symptoms of dizziness in patients presenting to a neurotology clinic. (2) Recommend indications for intervention for Chiari Type I malformation in patients presenting with dizziness. Methods: A retrospective chart review was conducted for 16 patients presenting to our neurotology clinic between 2002 and 2009 found to have Chiari Type I malformation on MRI. All patients presented with symptoms of disequilibrium and/or vertigo. Charts were reviewed for demographics, symptoms, surgical procedures, videonystagmography, and degree of malformation based radiographic measurements. Results: The prevalence of Chiari Type I malformation in patients presenting to the neurotology clinic with dizziness is 16 out of 6427 (0.2%). During this time period, 16 patients were found to have radiographically confirmed Chiari Type I malformations. The mean herniation was 6.3 mm with a range of 5 to 13mm. Videonystagmography testing was done on 12 out of 16 patients and 7 out of 12 were abnormal with a mean RVR of 38%. Two of 16 patients (12.5%) underwent posterior fossa decompression. Surgical patients tended to have more severe symptoms. Conclusions: A small subset of patients who present to neurotology clinics with vertigo and/or disequilibrium will have radiographic findings of Chiari Type I malformation without the traditional symptoms of headaches and neurologic disturbances. The dilemma for clinicians is to determine if the radiographic findings are contributing to the patients symptoms or are an incidental finding. Intervention should only be considered if the herniation is greater than 10 mm, a cervical syrinx is present, or patients have the classic Chiari-type symptoms.

Computed tomography angiography or magnetic resonance angiography for detection of intracranial vascular malformations in patients with intracerebral haemorrhage.

Intracranial vascular malformations (brain or pial/dural arteriovenous malformations/fistulae, and aneurysms) are the leading cause of intracerebral haemorrhage (ICH) in young adults. Early identification of the intracranial vascular malformation may improve outcome if treatment can prevent ICH recurrence. Catheter intra-arterial digital subtraction angiography (IADSA) is considered the reference standard for the detection an intracranial vascular malformation as the cause of ICH. Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are less invasive than IADSA and may be as accurate for identifying some causes of ICH. To evaluate the diagnostic test accuracy of CTA and MRA versus IADSA for the detection of intracranial vascular malformations as a cause of ICH. We searched MEDLINE (1948 to August 2013), EMBASE (1980 to August 2013), MEDION (August 2013), the Database of Abstracts of Reviews of Effects (DARE; August 2013), the Health Technology Assessment Database (HTA; August 2013), ClinicalTrials.gov (August 2013), and WHO ICTRP (International Clinical Trials Register Portfolio; August 2013). We also performed a cited reference search for forward tracking of relevant articles on Google Scholar (http://scholar.google.com/), screened bibliographies, and contacted authors to identify additional studies. We selected studies reporting data that could be used to construct contingency tables that compared CTA or MRA, or both, with IADSA in the same patients for the detection of intracranial vascular malformations following ICH. Two authors (CBJ and RA-SS) independently extracted data on study characteristics and measures of test accuracy. Two authors (CBJ and PMW) independently extracted data on test characteristics. We obtained data restricted to the subgroup undergoing IADSA in studies using multiple reference standards. We combined data using the bivariate model. We generated forest plots of the sensitivity and specificity of CTA and MRA and created a summary receiver operating characteristic plot. Eleven studies (n = 927 participants) met our inclusion criteria. Eight studies compared CTA with IADSA (n = 526) and three studies compared MRA with IADSA (n = 401). Methodological quality varied considerably among studies, with partial verification bias in 7/11 (64%) and retrospective designs in 5/10 (50%). In studies of CTA, the pooled estimate of sensitivity was 0.95 (95% confidence interval (CI) 0.90 to 0.97) and specificity was 0.99 (95% CI 0.95 to 1.00). The results remained robust in a sensitivity analysis in which only studies evaluating adult patients (≥ 16 years of age) were included. In studies of MRA, the pooled estimate of sensitivity was 0.98 (95% CI 0.80 to 1.00) and specificity was 0.99 (95% CI 0.97 to 1.00). An indirect comparison of CTA and MRA using a bivariate model incorporating test type as one of the parameters failed to reveal a statistically significant difference in sensitivity or specificity between the two imaging modalities (P value = 0.6). CTA and MRA appear to have good sensitivity and specificity following ICH for the detection of intracranial vascular malformations, although several of the included studies had methodological shortcomings (retrospective designs and partial verification bias in particular) that may have increased apparent test accuracy.

Endoglin deficiency impairs stroke recovery.

Endoglin deficiency causes hereditary hemorrhagic telangiectasia-1 and impairs myocardial repair. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia-1 are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that endoglin deficiency impairs stroke recovery. Eng heterozygous (Eng+/-) and wild-type mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Pial collateral vessels were quantified before pMCAO. Infarct/atrophic volume, vascular density, and macrophages were quantified in various days after pMCAO, and behavioral function was assessed using corner and adhesive removal tests on days 3, 15, 30, and 60 after pMCAO. The association between ENG 207G>A polymorphism and brain arteriovenous malformation rupture and surgery outcome was analyzed using logistic regression analysis in 256 ruptured and 157 unruptured patients. After pMCAO, Eng+/- mice showed larger infarct/atrophic volumes at all time points (P<0.05) and showed worse behavior performance (P<0.05) at 15, 30, and 60 days when compared with wild-type mice. Eng+/- mice had fewer macrophages on day 3 (P=0.009) and more macrophages on day 60 (P=0.02) in the peri-infarct region. Although Eng+/- and wild-type mice had similar numbers of pial collateral vessels before pMCAO, Eng+/- mice had lower vascular density in the peri-infarct region (P=0.05) on day 60 after pMCAO. In humans, ENG 207A allele has been associated with worse outcomes after arteriovenous malformation rupture or surgery of patients with unruptured arteriovenous malformation. Endoglin deficiency impairs brain injury recovery. Reduced angiogenesis, impaired macrophage homing, and delayed inflammation resolution could be the underlying mechanism.

Longitudinal changes in seizure outcomes after resection of cerebral cavernous malformations in patients presenting with seizures: a long-term follow-up of 46 patients.

Seizure is the most common presentation in patients with cerebral cavernous malformations (CCMs). Although many articles have documented seizure outcomes after resection of CCM, few have conducted long-term follow-ups; thus, the fluctuating seizure outcomes have been neglected. The purpose of this study is to describe long-term postoperative seizure outcomes in patients with CCM and to compare seizure outcomes between patients with sporadic seizures and those with chronic seizures. Forty-six patients with CCM presenting with seizures underwent surgery. The male-to-female ratio was 1:1, and the average age at initial seizure onset was 27.6 years. The mean preoperative seizure duration was 42.7 months. Patients were divided into two groups: a chronic group (N = 20) and a sporadic group (N = 26) according to seizure frequency and duration. The mean postoperative follow-up duration was 96.3 months, and the postoperative seizure outcomes were checked annually based upon Engel's classification. After the first year of follow-up, 80.8 % of the sporadic group and 75.0 % of the chronic group were evaluated as Engel class I. These rates increased to 100.0 % and 90.0 %, respectively, at the eighth year of follow-up. Overall, 29 (63.0 %) of the 46 patients experienced changes in seizure outcomes over the follow-up period. Despite their delayed improvements, the chronic group showed less favorable outcomes throughout follow-up (p = 0.025). Long-term follow-up is indispensable for accurately assessing postoperative seizure outcomes because these outcomes change continuously. We recommend earlier surgery to achieve seizure-free status in patients with CCM. However, even in the chronic group, surgery is recommended, considering the overall delayed improvement.

ADAP2 in heart development: a candidate gene for the occurrence of cardiovascular malformations in NF1 microdeletion syndrome

BackgroundCardiovascular malformations have a higher incidence in patients with NF1 microdeletion syndrome compared to NF1 patients with intragenic mutation, presumably owing to haploinsufficiency of one or more genes included in...

Heart failure in congenital heart disease: the role of genes and hemodynamics

Heart failure can be a consequence of insufficient palliation of structural malformations in patients with congenital heart disease (CHD) or genetic perturbations resulting in cardiomyopathies. Although CHD is traditionally considered a pediatric clinical problem, there is a rapidly increasing population of patients surviving into adulthood with CHD and a corresponding increase in the rate of hospital admissions for adult CHD patients with heart failure. Therefore, there is recognition of the clinical importance in translating conventional heart failure pharmacotherapies to patients with CHD, improving management of heart failure in the context of structural consequences of CHD, and understanding the underlying genetic abnormalities which impact myocardial performance. Heart failure in CHD typically involves complex interactions between primary structural defects, the consequences of interventions (i.e., residual lesions), and the heart's response to enhanced myocardial mechanical stress which depends on many other genetic factors (i.e., gene modifiers). In this review, we will examine how altered genes and hemodynamic loading contribute to heart failure seen in congenital heart patients. Understanding mechanisms of myocardial response and remodeling within the congenital population can provide insight into physiological principles and improve our understanding of heart failure.

Brain Arteriovenous Malformations in Patients With Hereditary Hemorrhagic Telangiectasia: Clinical Presentation and Anatomical Distribution

BackgroundHereditary hemorrhagic telangiectasia is an autosomal dominant genetic disease with a wide array of vascular malformations involving multiple organs. Brain arteriovenous malformations can lead to intracranial hemorrhage and are often diagnosed only after patients become symptomatic. Early diagnosis and interventional treatment may prevent neurologic sequelae or death. Because of the rarity of defined cases, the spectrum of presentations in children with brain arteriovenous malformations and hereditary hemorrhagic telangiectasia has not been explored in detail. Here, we report our experience in children with hereditary hemorrhagic telangiectasia and brain arteriovenous malformations regarding both disease manifestations at presentation and the spectrum of brain arteriovenous malformation manifestations. MethodsA retrospective review of demographics, clinical manifestations, and brain magnetic resonance imaging/computed tomography scan findings in 115 patients with confirmed hereditary hemorrhagic telangiectasia (HHT) was conducted using the Hospital for Sick Children's HHT Clinic database for the years 1997-2012. ResultsEleven patients (four girls and seven boys) were diagnosed with hereditary hemorrhagic telangiectasia and brain arteriovenous malformations during this period. Five patients initially presented with epistaxis, four presented with intracranial hemorrhage, and two were asymptomatic with a positive family history of confirmed hereditary hemorrhagic telangiectasia. Although all children had an index case with hereditary hemorrhagic telangiectasia in the family, in three patients, hereditary hemorrhagic telangiectasia was not diagnosed before the child's presentation with intracranial hemorrhage. Multiple brain arteriovenous malformations were found in five patients, with one patient having bithalamic arteriovenous malformations. ConclusionsThis study highlights the importance of both family history and early clinical signs to prompt further diagnostic testing to avoid intracranial hemorrhage from brain arteriovenous malformations in children with hereditary hemorrhagic telangiectasia.

Midbrain–hindbrain malformations in patients with malformations of cortical development and epilepsy: A series of 220 patients

Midbrain-hindbrain malformations (MHM) may coexist with malformations of cortical development (MCD). This study represents a first attempt to investigate the spectrum of MHM in a large series of patients with MCD and epilepsy. We aimed to explore specific associations between MCD and MHM and to compare two groups of patients: MCD with MHM (wMHM) and MCD without MHM (w/oMHM) with regard to clinical and imaging features. Two hundred and twenty patients (116 women/104 men, median age 28 years, interquartile range 20-44 years at the time of assessment) with MCD and epilepsy were identified at the Departments of Neurology and Pediatrics, Innsbruck Medical University, Austria. All underwent high-resolution MRIs (1.5-T) between 01.01.2002 and 31.12.2011. Midbrain-hindbrain structures were visually assessed by three independent raters. MHM were seen in 17% (38/220) of patients. The rate of patients wMHM and w/oMHM differed significantly (p=0.004) in three categories of MCD (category I - to abnormal neuronal proliferation; category II - to abnormal neuronal migration; and category III - due to abnormal neuronal late migration/organization): MCD due to abnormal neuronal migration (31%) and organization (23%) were more commonly associated with MHM compared to those with MCD due to abnormal neuronal proliferation (9%). Extensive bilateral MCD were seen more often in patients wMHM compared to those w/oMHM (63% vs. 36%; p=0.004). In wMHM group compared to w/oMHM group there were higher rates of callosal dysgenesis (26% vs. 4%; p<0.001) and hippocampal abnormalities (52% vs. 27%; p<0.001). Patients wMHM were younger (median 25 years vs. 30 years; p=0.010) at the time of assessment and had seizure onset at an earlier age (median 5 years vs. 12 years; p=0.043) compared to those w/oMHM. Patients wMHM had higher rates of learning disability (71% vs. 38%; p<0.001), delayed developmental milestones (68% vs. 35%; p<0.001) and neurological deficits (66% vs. 47%; p=0.049) compared to those w/oMHM. The groups (wMHM and w/oMHM) did not differ in their response to antiepileptic treatment, seizure outcome, seizure types, EEG abnormalities and rate of status epilepticus. Presence of MHM in patients with MCD and epilepsy is associated with severe morphological and clinical phenotypes.

Stent Migration: A Risk in the Treatment of Renal Access Patients

Objectives: Central venous strictures often lead to significant arm swelling and access malformation in patients with chronic renal failure. The purpose of this study is to acknowledge the risk of stent migration in this subset of patients treated for failing access grafts. Methods: A retrospective chart review of patients undergoing diagnostic fistulagrams and percutanous intervention of malfunctioning accesses was done from June 2007 to November 2012 in two major hospitals in Baton Rouge, Louisiana. A total of 5184 fistulagrams were performed. 1189 (22.9%) procedures involved percutaneous thrombectomy of the accesses. 2882 (55.6%) procedures included balloon dilatation of the access or venous outflow strictures. 796 (15.3%) patients had stents placed either in the access or proximal central veins. Results: Of the 796 stents placed in this series, six migrated after deployment over varied time periods. Five stents migrated to the heart requiring open heart surgical removal. One patient had a stent migrate from the right subclavian vein to the innominate vein. Conclusions: Migration of stents can occur in the treatment of failing renal access grafts. This is the largest reported series to date in the literature of such events in renal failure patients. The majority of stents migrated to the heart. The high flow system generated by these renal access grafts and eventual gradual central vein dilatation in this patient population increase the risk of future migration. Interventionalists must be cognizant of this potential complication with the need for selective accurate placement of stents.Despite proper placement, stent migration may be unavoidable.

Parenchymal Hypointense Foci Associated with Developmental Venous Anomalies: Evaluation by Phase-Sensitive MR Imaging at 3T

The risk of hemorrhage in the context of developmental venous anomaly is considered to be very low, but it has never been evaluated by susceptibility-weighted MR imaging at 3T. The goal of the present study was to evaluate the prevalence of hypointense foci (ie, microhemorrhage or cavernous malformation) associated with DVA on phase-sensitive MR imaging, on the basis of principles similar to those of susceptibility-weighted MR imaging, and to evaluate the relationship between the hypointense foci and several factors, such as white matter hyperintense lesions adjacent to DVA on T2-weighted imaging, DVA morphology, and clinical symptoms. This study retrospectively evaluated 61 lesions in 59 consecutive patients with DVA who underwent MR imaging including phase-sensitive MR imaging. Two neuroradiologists independently assessed for the presence of hypointense foci and other factors such as DVA location, depth, size, direction of draining vein on phase-sensitive MR imaging, and white matter hyperintense lesion on T2-weighted imaging. Clinical symptoms were also assessed. Hypointense foci were observed in 62.3% (38/61) of lesions. White matter hyperintense lesion was more frequently observed in patients with hypointense foci (26/38) than in patients without hypointense foci (7/23) (P < .01). There was no significant association between hypointense foci and other factors. Our results support the hypothesis that microhemorrhage or cavernous malformation can be related to venous congestion caused by abnormal venous drainage. We conclude that phase-sensitive MR imagingis useful for the detection of microhemorrhage or cavernous malformation in patients with DVA, especially when associated with white matter hyperintense lesion.

Effect of Aortic Valve Movements on Gastrointestinal Bleeding That Occured in Continuous Flow Left Ventricular Assist Device Patients

BackgroundGastrointestinal (GI) bleeding is one of the recently reported complications with continuous flow left ventricular assist devices (LVAD). The pathophysiology and etiology are unclear. We sought to describe the relationship between aortic valve movements and GI bleeding among patients with a new generation of LVAD. MethodsWe evaluated the data of 30 patients who underwent LVAD (HeartWare VAD) implantation from December 2010 to September 2012. The most common etiologic diagnosis was dilated cardiomyopathy. Patients were considered to show GI bleeding if they had hematemesis, melena, or hematochezia. ResultsAmong 3 patients, 2 displayed upper GI bleeding and 1 had lower GI bleeding based on endoscopic and colononoscopic examinations. Pathological reports showed arteriovenous malformations in patients diagnosed with upper GI bleeding. The absence of aortic valve movements and a history of previous GI bleeding were significant risk factors (P = .021 and P = .007, respectively). ConclusionIn addition to aortic valve movements, we believe that a GI bleeding history was an equally important factor predisposing to this complication.

Prevalence of various congenital vascular malformations in patients with Klippel-Trenaunay syndrome.

Klippel-Trenaunay syndrome (KTS) is a condition defined by the association of three physical features: capillary malformation, varicosities, and hypertrophy of bony and soft tissues. However, KTS is characterized by congenital vascular malformations (CVMs) that are difficult to classify. Therefore, the present study was undertaken to analyze the various CVMs in patients with KTS. Sixty-one patients with KTS were enrolled, and their CVMs were divided into predominantly venous defects, predominantly lymphatic defects, and mixed vascular defects using the Hamburg Classification. Capillary malformations were subdivided into port-wine stain, telangiectasia, and angiokeratoma. Truncular and extratruncular vascular malformations were detected using duplex ultrasound and magnetic resonance imaging. Reflux in the superficial and deep venous systems was also evaluated. Forty-five patients (74%) had predominantly venous defects, four (6%) had predominantly lymphatic defects, and 12 (20%) had mixed vascular defects. Capillary malformations were detected in 54 patients (89%), among which port-wine stain was the most predominant (40 patients, 66%), followed by telangiectasia (31 patients, 51%) and angiokeratoma (18patients, 30%). Extratruncular venous malformations were detected in 47 patients (77%). In contrast, truncular venous malformations were found in 50 patients (82%). Among these, embryonic lateral marginal vein showed the highest occurrence, accounting for 53% (32 patients). However, reflux in this vein was detected in only nine patients (15%). Twelve patients (20%) had reflux in the great saphenous vein, and four (7%) had reflux in the small saphenous vein. Deep vein hypoplasia was found in seven patients (12%), and only five patients (8%) had deep vein aplasia. Extratruncular lymphatic malformations were found in 13 patients (21%) and truncular lymphatic malformations in 17 (28%). Patients with KTS have a variety of CVMs, but both extratruncular and truncular venous malformations continue to be targets for intervention.

Evidence that FGFR1 loss-of-function mutations may cause variable skeletal malformations in patients with Kallmann syndrome

Loss-of-function mutations in FGFR1 have been identified in approximately 10% of the Kallmann syndrome (KS) patients. Previous reports have focused mainly on olfactory, reproductive, and some other features such as cleft lip/palate and dental agenesis. Given the ubiquitous expression of FGFR1 during development, other abnormal phenotypes might, however, have been overlooked in these patients. Here, we demonstrate skeletal phenotypic characterization of patients presented with KS and FGFR1 mutations. Using the Sanger DNA sequencing technique a cohort of 29 KS patients was screened. Here, we report on 5 KS patients who carry FGFR1 mutations (Gly270Asp, Gly97Ser, Met161Thr, Ser685Phe and Ala167Ser/Ala167Ser). Three patients presented with skeletal abnormalities, i.e. spine (hemivertebra and butterfly vertebra) and limb (oligodactyly of the feet, fusion of the 4th and 5th metacarpal bones) malformations in two patients and one patient, respectively. The hand phenotype found in the patient cannot be thought of as a counter-type of the hand phenotype resulting from FGFR1 gain-of-function mutations. The skeletal anomalies identified in the 3 KS patients are close to those observed in Fgfr1 conditional knockout mice. This study demonstrates that FGFR1 loss-of-function mutations can be associated with skeletal abnormalities also in humans. Further investigations in KS patients who carry FGFR1 mutations are needed to evaluate the prevalence of skeletal defects in this genetic form of KS. Conversely, the presence of bone malformations in a KS patient should direct the geneticist towards a search for mutations in FGFR1.

A Case Series: Chiari Malformation and Sickle Cell Disease

AbstractAbstract 4772 Introduction:Chiari type I malformation is defined as tonsillar herniation of at least 3 to 5 mm below the foramen magnum. The prevalence of Chiari type I malformation in the general population is estimated to be 0.1 to 0.5%. In the SIT (Silent Infarct Transfusion) Trial in children with sickle cell disease, Chiari type I malformation was found as an incidental finding in 22 of 953 (2.3%) of the individuals imaged. Thus, the incidence of Chiari type I malformation in the SIT Trial appeared to be about five times greater than in the general population (Jordan et al Pediatrics 2010). Recently, four hemoglobin SS patients aged 6–17 years with and Chiari type I malformation were reported from one institution (Chonat el al J Pediatr Hematol Oncol 2011). Here we describe six sickle cell disease patients aged 17–24 years with Chiari type I malformation from two institutions.Case Series:Case123456Age221817202423GenderMaleMaleMaleMaleFemaleFemaleGenotypeHgb SSSickle/B0thalHgb SSHgb SSHgb SSHgb SSPresenting SymptomsFeeling “off balance” for 6 monthsDifficulty performing tandem walking, ataxia, and nystagmusSeveral weeks of headaches, lightheadedness, and the feeling “off balance”Global headaches aggravated by coughChronic headaches for several yearsBilateral hand numbness, headache, double visions, slurred speech, and gait imbalanceExam FindingsDifficulty performing tandem walking, ataxia, and nystagmusNoneWide-based ataxic gaitNoneNoneDiplopia on extreme lateral gaze and decreased gag reflexMRI FindingsChiari type I malformation with cerebellar tonsil elongation and herniation, deformity of the fourth ventricle, and mass effect on the brainstemLow-lying cerebellar tonsils and brainstem compatible with Chiari type I malformationChiari type I malformation of the cranio-cervical junction with the cerebellar tonsils 9 mm below the foramen magnumDownward displacement of the cerebellar tonsil and a small posterior fossa consistent with Chiari type I malformation.Chiari type I malformation with syringehydromyelia of the proximal cervical spinal cordHerniation of the cerebellar tonsils into the upper cervical spinal canal with ∼17 to 19 mm inferior displacement through the foramen magnum consistent with a Chiari type I malformation Discussion:All of the cases had severe sickling phenotype, either hemoglobin SS or sickle/B°thalassemia. The majority of the patients were experiencing neurologic symptoms that were subsequently attributed to Chiari type I malformation. Five of the six cases were eventually evaluated by neurosurgery. Neurosurgical intervention with posterior fossa decompression was recommended in four of these individuals. To date one patient has undergone surgery with relief of symptoms. Although Chiari type I malformation is thought to be primarily a congenital disorder, it has also been associated with disorders that are non-congenital. Individuals with sickle cell disease may have a thick calvarium as a result of erythroid hyperplasia and expansion of the diploe of the skull bones. Other conditions with severe anemia and thalassemia have been associated with increased thickness of the calvarium caused by diploic erythroid hyperplasia. One can question whether the increased thickness of the calvarium in some sickle cell patients results in craniocephalic disproportion with a subsequent acquired cerebellar ectopia, hence the increased Chiari type I malformation in patients with sickle cell disease. Central nervous system involvement in sickle cell disease is common. Any patient with sickle cell disease presenting with symptoms indicative of an ongoing or impending neurological event requires an in depth investigation and entails a broad differential. Chiari malformations may need to be part of this differential diagnosis. Disclosures:No relevant conflicts of interest to declare.