Clinical phenotype, fibrinogen supplementation, and health-related quality of life in patients with afibrinogenemia.

Due to the low prevalence of afibrinogenemia, epidemiologic data on afibrinogenemia are limited, and no data are available on health-related quality of life (HRQoL). We conducted a cross-sectional international study to characterize the clinical features, the fibrinogen supplementation modalities, and their impact on HRQoL in patients with afibrinogenemia. A total of 204 patients (119 adults and 85 children) from 25 countries were included. The bleeding phenotype was severe: 68 (33.3%) patients having at least one bleed per month and 48 (23%) a history of cerebral bleeding. About 35% (n = 72) of patients were treated with fibrinogen concentrates or cryoprecipitates as prophylaxis, 18.1% (n = 37) received ≥1 injection per week, and 16.6% (n = 34) were on home treatment. A thrombotic event was reported in venous and/or arterial territories by 37 (18.1%) patients. Thrombosis occurred even in young patients, and recurrence was frequent (7.4%). The total HRQoL was lower in children than in adults. Discomfort linked to treatment and limitations to sports and leisure were the main concerns. Women and children were particularly affected in family relationships. In multivariate analyses, younger age, residence in Asia or Africa, and a previous thrombotic event were statistically correlated with a worse HRQoL. In summary, our study underlines the severe bleeding and thrombotic phenotype and their impact on HRQoL in afibrinogenemia. The optimal strategy for fibrinogen supplementation needs to be determined. This trial was registered at www.clinicaltrials.gov as #NCT03484065.

High incidence of intracranial haemorrhage in Egyptian children with congenital afibrinogenaemia.

INTRODUCTION: Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality in patients with congenital afibrinogenaemia. Details on location of cerebral haemorrhage, management and neurological outcomes are lacking. METHODS: We performed a retrospective study on Egyptian children with congenital afibrinogenaemia who experienced ICH, in order to estimate frequency, symptoms and neurological outcomes. RESULTS: Among 58 children with congenital afibrinogenaemia treated on demand, 18 (31%) had an history of ICH (28 episodes). The first ICH occurred at a median age of 1 year (Q1-Q3 1-7 years). Impaired consciousness level, vomiting and seizures were the most common presenting symptoms. Spontaneous bleeding was associated with a more severe clinical presentation and worse neurological outcomes, including hydrocephaly and impaired cognitive development. Only half of ICH events (n = 14) were treated in less than 24 h from the onset of symptoms. Fibrinogen replacement by Fresh Frozen Plasma (FFP), cryoprecipitate or fibrinogen concentrates was administered in seven (25%), 19 (68%) and three (10%) ICH events, respectively. Overall, seven (25%) ICH occurring in four patients required a surgical intervention. After the ICH, six patients started secondary prophylaxis. The cumulative incidence of ICH at 10 years was 35% (95% CI 23-51) and at 20 years was 40% (95 CI% 26.7-58.8). CONCLUSION: In our cohort of children with congenital afibrinogenaemia, ICH was very frequent and associated with adverse neurological outcomes and death. Further studies are required to determine whether primary prophylaxis starting early in childhood is indicated after diagnosis.

Investigation of a dysmorphic facial phenotype in patients with Gaucher disease types 2 and 3.

Gaucher disease (GD) is a rare lysosomal storage disorder that is divided into three subtypes based on presentation of neurological manifestations. Distinguishing between the types has important implications for treatment and counseling. Yet, patients with neuronopathic forms of GD, types 2 and 3, often present at young ages and can have overlapping phenotypes. It has been shown that new technologies employing artificial intelligence and facial recognition software can assist with dysmorphology assessments. Though classically not associated nor previously described with a dysmorphic facial phenotype, this study investigated whether a facial recognition platform could distinguish between photos of patients with GD2 and GD3 and discriminate between them and photos of healthy controls. Each cohort included over 100 photos. A cross validation scheme including a series of binary comparisons between groups was used. Outputs included a composite photo of each cohort and either a receiver operating characteristic curve or a confusion matrix. Binary comparisons showed that the software could correctly group photos at least 89% of the time. Multiclass comparison between GD2, GD3, and healthy controls demonstrated a mean accuracy of 76.6%, compared to a 37.7% chance for random comparison. Both GD2 and GD3 have now been added to the facial recognition platform as established syndromes that can be identified by the algorithm. These results suggest that facial recognition and artificial intelligence, though no substitute for other diagnostic methods, may aid in the recognition of neuronopathic GD. The algorithm, in concert with other clinical features, also appears to distinguish between young patients with GD2 and GD3, suggesting that this tool can help facilitate earlier implementation of appropriate management.

Throwing a spotlight on under-recognized manifestations of Gaucher disease: Pulmonary involvement, lymphadenopathy and Gaucheroma.

BACKGROUND: Gaucher disease (GD) is a rare lysosomal storage disorder classically subdivided into type 1 (non-neuronopathic) GD, and types 2 and 3 (neuronopathic) GD. It is typically characterized by clinical manifestations including anemia, thrombocytopenia, hepatosplenomegaly, bone lesions, and (in more severe forms) neurological impairment. However, less-commonly reported and often under-recognized manifestations exist, which potentially have a significant impact on patient outcomes. Greater efforts are needed to understand, recognize, and manage these manifestations. OBJECTIVES: This review provides a synthesis of published information about three under-recognized GD manifestations (pulmonary involvement, lymphadenopathy, and Gaucheroma) and recommends diagnostic, management, and treatment strategies based on the available literature and author experience. The authors aim to raise awareness about these serious, progressive, and sometimes life-threatening conditions, which are often diagnosed late in life. CONCLUSIONS: Little is known about the incidence, pathophysiology, prognostic factors, and optimal management of pulmonary involvement, lymphadenopathy, and Gaucheroma in patients with GD. Enzyme replacement therapy (ERT) has shown limited efficacy for the prevention and treatment of these manifestations. More research is needed to evaluate the potential effect of substrate reduction therapy (SRT) with glucosylceramide synthase (GCS) inhibitors, and to develop additional approaches to treat these GD manifestations. Improvements in data collection registries and international data-sharing are required to better understand the impact of these manifestations on GD patients, help develop effective management strategies, and, ultimately, improve patient outcomes.

The definition of neuronopathic Gaucher disease.

Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form-Gaucher type 2-from the subacute or chronic form-Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials.

Scoring system to facilitate diagnosis of Gaucher disease.

BACKGROUND: Gaucher disease (GD) manifests heterogeneously and other conditions are often misdiagnosed in its place, leading to diagnostic delays. The Gaucher Earlier Diagnosis Consensus (GED-C) initiative proposed a point-scoring system (PSS) based on the signs and covariables that are most indicative of GD to help clinicians identify which individuals to test for GD. AIMS: To validate the PSS retrospectively in a test population including patients with GD and other conditions with overlapping manifestations. METHODS: Four cohorts of adults with GD, liver disease, haematological malignancy or immune thrombocytopenia were identified from hospital records. Clinical data were audited for GED-C factors identified as potentially indicative of GD and aggregate scores calculated (sum of scores/number of factors) based on published PSS weightings. Threshold discriminatory PSS scores, sensitivity and specificity were determined by receiver-operating characteristic analysis. RESULTS: Among 100 patients (GD, n = 25; non-GD, n = 75), analyses based on 11 possible factors estimated group mean (standard deviation) PSS scores of: GD (n = 14), 1.08 (0.25); non-GD (n = 38), 0.58 (0.31). Mean between-group difference (95% confidence interval) was -0.49 (-0.68, -0.31) and area under the receiver-operating characteristic analysis curve (95% confidence interval) was 0.88 (0.78, 0.97). A threshold PSS score of 0.82 identified all 14 patients with GD in the analysis set (100% sensitivity) and 27 of 38 patients in the non-GD group (71% specificity). Patients with liver disease and haematological malignancy were most likely to have manifestations overlapping GD. CONCLUSIONS: Preliminary validation of the GED-C PSS discriminated effectively between patients with GD and those with overlapping signs.

Mesenteric and Mediastinal Lymphadenopathy in Egyptian Children With Gaucher Disease Types 1 and 3 Treated With Enzyme Replacement Therapy.

Gaucher disease (GD) is characterized by 3 clinical subtypes; type 1 GD (non-neuronopathic) and types 2 and 3 GD (acute and chronic neuronopathic forms, respectively). There are few reports of mesenteric and mediastinal lymphadenopathy, and none in type 1 GD or in African people. We report 8 Egyptian GD children (3 type 1 GD and 5 type 3 GD) who developed mesenteric and mediastinal lymphadenopathy despite receiving enzyme replacement therapy. Biopsy showed infiltration with Gaucher cells and no malignant changes. Pediatric physicians should be aware of possible lymphadenopathy associated with both types 1 and 3 GD as it can mimic malignancy.

Management of pregnancy and delivery in congenital fibrinogen disorders: communication from the ISTH SSC Subcommittee on Factor XIII and Fibrinogen.

Congenital fibrinogen disorders (CFDs) are a heterogeneous group of rare congenital quantitative and/or qualitative fibrinogen deficiencies. The spectrum of molecular anomalies is broad, leading to several subtypes of fibrinogen disorders (ie, afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia). Pregnancy in women with CFDs is a high-risk clinical situation, with an increased tendency for miscarriages, bleeding, and thrombosis. Even though it is well established that management of such pregnancies requires a multidisciplinary approach involving specialists (hematologists and maternal/fetal medicine experts with expertise in the management of inherited bleeding disorders), specific guidelines are lacking. In this International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee communication, we aim to propose an expert consensus opinion with literature evidence where available on the strategy for management of pregnancy, delivery, and puerperium in CFDs.

Transition of patients with Gaucher disease type 1 from pediatric to adult care: results from two international surveys of patients and health care professionals.

Introduction: Gaucher disease (GD) is a rare, autosomal recessive lysosomal storage disorder caused by a deficiency in the enzyme glucocerebrosidase. The most common subtype in Europe and the USA, type 1 (GD1), is characterized by fatigue, cytopenia, splenomegaly, hepatomegaly, bone disease, and rarely pulmonary disease. Increased life expectancy brought about by improved treatments has led to new challenges for adolescents and their transition to adult care. Efficient healthcare transition to adult care is essential to manage the long-term age-related complications of the disease. Methods: This international study consisted of two online surveys: one survey for patients with GD1 and one survey for healthcare professionals (HCPs) involved in treatment of patients with GD1. The aims of this international, multi-center project were to evaluate the current transition process in various countries and to understand the challenges that both HCPs and patients experience. Results: A total of 45 patients and 26 HCPs took part in the survey, representing 26 countries. Our data showed that a third (11/33) of patients were aware of transition clinics and most stated that the clinic involved patients with metabolic diseases or with GD. Seven patients attended a transition clinic, where most patients (5/7) received an explanation of the transition process. Approximately half of HCPs (46%; 12/26) had a transition clinic coordinator in their healthcare center, and 10 of HCPs had a transition clinic for patients with metabolic diseases in their healthcare center. HCPs reported that transition clinics were comprised of multi-disciplinary teams, with most patients over the age of 18 years old managed by hematology specialists. The main challenges of the transition process reported by HCPs included limited funding, lack of expertise and difficulty coordinating care amongst different specialties. Discussion: Our study demonstrates the lack of a standardized process, the need to raise awareness of transition clinics amongst patients and the differences between the transition process in different countries. Both patients and HCPs expressed the need for a specialist individual responsible for transition, efficient coordination between pediatricians and adult specialists and for patient visits to the adult center prior to final transition of care.

Genotyping of intron 22-related rearrangements of F8 by inverse-shifting PCR in Egyptian hemophilia A patients.

Hemophilia A (HA) is the most common severe bleeding disorder in humans, affecting one in 5,000 male births. In severe HA, intron 22 inversion of F8 is the most prevalent mutation, accounting for 40-50% of all mutations; however, little is known about the disease-causing mutations among Egyptian hemophiliacs. We aimed at genotyping all possible known DNA rearrangements of intron 22 of F8 in Egyptian HA patients. Peripheral blood samples were collected from 30 Egyptian HA patients (13 severe, ten moderate, and seven mild cases). Genotyping of F8 intron 22 rearrangements was performed by inverse-shifting PCR (IS-PCR). Our study revealed that seven patients (23.3%) had inversion 22, three patients (10%) had deletion 22, and 20 patients (66.7%) carried the wild-type allele. No intron 22 duplication was detected. The relative proportion of inversion 22-type 1 to inversion 22-type 2 was 85.7% and 14.3%, respectively, whereas the relative proportion of deletion 22-type 1 to deletion 22-type 2 was 33.3% and 66.7%, respectively. A statistically highly significant relation was found between disease severity and F8 intron 22 rearrangements (p = 0.008). Among severe cases, 46.1% had inversion 22, 23.1% had deletion 22, and 30.8% carried the wild-type allele. We conclude that F8 intron 22 inversion/deletion is responsible for about one third of disease-causing mutations among Egyptian hemophiliacs and for nearly 70% in severe cases. In addition, F8 intron 22 inversion/deletion by IS-PCR has proven to be a rapid and robust technique and might be the recommended tool for genetic analysis of HA patients specially with severe cases in developing countries.

Intracranial hemorrhage in acute and chronic childhood immune thrombocytopenic purpura over a ten-year period: an Egyptian multicenter study.

Intracranial hemorrhage (ICH) is a rare but major cause of death in immune thrombocytopenic purpura (ITP). The authors reviewed data of 1,840 patient with ITP, from 5 pediatric hematology centers in Egypt from 1997 to 2007, to study the incidence and risk factors of ICH. Ten cases of ICH were identified with a median age at presentation of 7.5 years; 4 patients had acute ITP, 2 persistent and 4 chronic. The platelet count was <10 x 10(9)/l in 7 cases, and only 1 patient had a history of head trauma. Seven children were on treatment prior to or at the time of occurrence of ICH and all were treated by pharmacotherapy. Two children died shortly afterwards due to late referral to a specialized center. Our results suggest that treatment does not prevent ICH and that it can occur at any time during the course of the disease. Delayed referral can be considered a risk factor for unfavorable outcome of ICH, highlighting the importance of teaching sessions for patients and their parents to minimize subsequent morbidity and mortality of ICH in children with ITP.

Previously unrecognized behavioral phenotype in Gaucher disease type 3.

OBJECTIVE: To provide a comprehensive description of abnormal behaviors in patients with Gaucher disease type 3 (GD3) and relate these behaviors to demographic, neurodevelopmental, and neurologic characteristics. METHODS: Thirty-four Egyptian patients with GD3 (mean age of 7.9 years) were enrolled in the study. They were selected based on parent report and/or physician observation of one or more abnormal behaviors documented in 2 settings and by 2 different individuals and/or by video recording. Behaviors were grouped into 4 categories: Crying/Withdrawal, Impatience/Overactivity, Anger/Aggression, and Repetitive Acts. Baseline and follow-up 6-12 monthly neurologic evaluations included IQ assessment and an EEG. All patients were receiving enzyme replacement therapy (30-60 IU/kg every 2 weeks) and were followed for periods of 3-10 years. RESULTS: Supranuclear palsy of horizontal gaze, and of both horizontal and vertical gaze, bulbar symptoms, seizures, convergent strabismus, abnormal gait, and neck retroflexion were present in 97.1%, 50%, 55.9%, 29.4%, 29.4%, 20.6%, and 4.4% of patients, respectively. The most abnormal behavioral features were excessive anger (88.2%) and aggression (64.7%), and both were significantly higher in males. Anger/Aggression scores were highly correlated with IQ but not with either EEG/Seizure status or neurologic signs. CONCLUSIONS: We describe behavioral problems with a unique pattern of excessive anger and aggression in patients with GD3. Defining these components using quantitative behavioral scoring methods holds promise to provide a marker of neurologic disease progression and severity.

Long-term follow-up and sudden unexpected death in Gaucher disease type 3 in Egypt.

OBJECTIVE: To describe the long-term follow-up and distinct phenotype of a large cohort of patients with Gaucher disease type 3 on enzyme replacement therapy (ERT) in Egypt. METHODS: A prospective cohort study of 78 patients on ERT who were followed for up to 9 years with yearly evaluations that included EEG and cognitive testing. RESULTS: Of the patients, 73% were homozygous for the L444P GBA1 mutation; all but 7 were neurologically symptomatic. Supranuclear gaze palsy with variable but stable cognitive function was present in 91% of patients. Convergent strabismus and bulbar dysfunction were noted in 22% and 37%, respectively. Features of oppositional defiant disorder were present in 54% of patients. Twenty-three patients (30%) developed seizures while on ERT for 1-9 years. Of those, 12 patients (15%) died suddenly and unexpectedly at a mean age of 6.7 ± 5.0 years (range 1.5-18). Sudden death was usually associated with a seizure disorder or a terminal seizure, but 7 of 12 patients had a preceding normal EEG. An additional 11% had background slowing or epileptogenic activity on EEG without clinical seizures. There were 3 familial cases of sudden unexpected death. CONCLUSIONS: Despite having the most common GBA1 genotype known to be associated with neuronopathic Gaucher disease, patients with Gaucher disease type 3 in Egypt have a phenotype and a clinical outcome on ERT that are very different from those observed in other populations. Identifying putative modifying genes of this ethnic group is likely to lead to better therapy for neuronopathic Gaucher disease generally.

Lysosomal Storage Disorders in Egyptian Children.

OBJECTIVE: To describe the spectrum, relative prevalence and molecular background of lysosomal storage disorders in Egypt. METHODS: The authors evaluated the selective screening program for the diagnosis of lysosomal storage disorders in Egyptian children presenting to the inherited metabolic disease unit at Cairo University Children's Hospital, the largest tertiary care pediatric hospital in Egypt, over a six-year period (April 2008 through April 2014). During this period, 1,065 suspected children were assessed clinically, biochemically and some genetically. RESULTS: Two hundred and eleven children (aged 44 ± 32 mo; 56 % boys, 82 % with consanguineous parents) were confirmed with 21 different lysosomal disorders. The diagnostic gap ranged between 2 mo and 14 y (average 25 mo). Mucopolysaccharidoses were the most common group of diseases diagnosed (44.5 %), while Maroteaux-Lamy, Gaucher and nephropathic cystinosis were the most commonly detected syndromes (17.1, 14.7 and 13.7 %, respectively). Eighty mutant alleles and 17 pathogenic mutations were detected in 48 genetically assessed confirmed patients (30 Gaucher, 16 cystinosis and two Niemann-Pick type C patients). CONCLUSIONS: This report is the first to describe relative frequency and spectrum of clinical and molecular data in a large cohort of Egyptian lysosomal patients. The crude estimate denotes that over 80 % of Egyptian lysosomal patients do not have access to optimal diagnosis. Upgrading diagnostic and genetic services for lysosomal storage disorders in Egypt is absolutely necessary.

Prevalence of hepatitis C virus infection and human immunodeficiency virus in a cohort of Egyptian hemophiliac children.

BACKGROUND AND OBJECTIVE: The risk of blood-borne infections, especially hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection still remains in developing countries among children receiving blood products as hemophiliacs, but the risk is not known in Egypt. The objective of this study was to detect the prevalence of HCV and HIV infection among hemophiliac children to know the magnitude of the problem and determine potential risk factors. PATIENTS AND METHODS: This was a cross-sectional study conducted on 100 hemophiliac children that assessed the liver clinically and by laboratory tests. All children were screened for HCV and HIV antibodies by enzyme-linked immunosorbent assay. Those with positive HCV antibody titre were tested by polymerase chain reaction (HCV-PCR). RESULTS: Forty were positive for HCV antibodies with 19 children (47.5%) HCV-PCR positive as well. The mean age, average frequency of bleeds/year, dose of replacement therapy/year and alanine aminotransferase (ALT) levels were significantly high in HCV-antibody and PCR positive patients as compared to HCV antibody and PCR negative ones. None of our patients had clinical evidence of hepatic involvement or was co-infected with HIV. CONCLUSION: HIV infection does not appear to be a current health problem in Egyptian hemophiliac children though the prevalence of HCV infection is still high.