Erlenmeyer Flask Deformity Research Articles

Imiglucerase, cholecalciferol, and bone-diet in skeletal health management of type I Gaucher disease patients: a pilot study and systematic review.

Skeletal anomalies represent a characteristic feature of type 1 Gaucher disease (GD1). Here we evaluated the impact of an integrated therapy comprising enzyme-replacement therapy (ERT), cholecalciferol, and a normocalcemic-normocaloric-hyposodic diet (bone diet) on bone health in GD1 patients. We also performed a systematic review to compare our results with available data. From January 1, 2015 to February 28, 2019, all GD1 patients referred to Federico II University were enrolled and treated with the integrated therapy. Bone turnover markers and bone mineral density (BMD) were evaluated at baseline (T0) and after 24months (T24). We enrolled 25 GD1 patients, all showing 25-hydroxy vitamin D (25OHD) levels < 50nmol/l (hypovitaminosis D) at T0. Response to cholecalciferol treatment was effective, showing a direct relationship between 25OHD levels before and after treatment. At T0, 2 GD1 patients showed fragility fractures, 5 the Erlenmeyer flask deformity, 3 osteonecrosis, and 7 a BMD Z-score ≤ -2. Overall, GD1 patients with bone anomalies showed higher C-terminal telopeptide levels compared with those without bone anomalies. No new bone anomalies occurred during 2 years of follow-up. At T24, BMD remained stable across the entire study cohort, including in patients with bone anomalies. The systematic review showed that our study is the first that evaluated all bone health parameters. Hypovitaminosis D is prevalent in GD1 patients. The response to cholecalciferol treatment was effective but different to healthy subjects and in patients with metabolic bone disorders. Integrated therapy including ERT, cholecalciferol, and bone diet guarantees bone health.

Genetic inheritance in tandem: Non-syndromic autosomal recessive congenital ichthyosis with beta-thalassaemia: A rare coincidence

Ichthyosis belongs to the group of Mendelian disorders of cornification. Congenital ichthyosis is inherited as an autosomal recessive trait, so it is also known as autosomal recessive congenital ichthyosis (ARCI). ARCI is classified into two types: syndromic and non-syndromic ARCI. Non-syndromic ARCIs include lamellar ichthyosis, congenital ichthyosiform erythroderma and Harlequin ichthyosis. Syndromic-ARCI is associated with multisystemic involvement, which includes Netherton syndrome, Chanarin-Dorfman disease and others. Other systemic diseases associated with ichthyosis include Gaucher disease type II and hypothyroidism. Chanarin-Dorfman and Gaucher disease-II are additionally associated with hepatosplenomegaly (HSM) and anaemia. We describe a child of congenital ichthyosis with HSM and anaemia thought to be syndromic-ARCI, but diagnosed for beta-thalassaemia (b-thal) concurrently. An infant presented with peeling skin along with absent sweating since birth and recent onset paleness of the body. Examination revealed Ichthyosis (Lamellar-variant), severe pallor and HSM, raising the possibility of Chanarin-Dorfman syndrome and Gaucher’s disease. The investigation revealed an Erlenmeyer flask deformity of the knee, but no Gaucher’s cells were found in the bone marrow. In the absence of lipid vacuoles leaden leukocytes (Jordan’s anomaly), Chanarin-Dorfman disease was also ruled out. Haemoglobin (Hb) high-performance liquid chromatography revealed β-thal major, and both parents were traits, giving us the diagnosis, which was further confirmed by the next-generation gene sequencing for clinical exomes. This report was to highlight non-syndromic ARCI involving the CYP4F22 gene variant, which is a rare finding, and the association of such ichthyosis with β-thal major was an unexpected result. Genetic counselling was provided to the parents in light of the autosomal recessive nature of both diseases. Genes of congenital ichthyosis and β-thal were unrelated, but simultaneous expressions of two autosomal-recessive diseases together are it merely by chance or a new entity.

The molecular spectrum of Turkish osteopetrosis and related osteoclast disorders with natural history (including a candidate gene, CCDC120).

Osteopetrosis and related osteoclastic disorders are a heterogeneous group of inherited diseases characterized by increased bone density. The aim of this study is to investigate the molecular spectrum and natural history of the clinical and radiological features of these disorders. 28 patients and 20 families were enrolled in the study; 20 of them were followed for a period of 1-16 years. Targeted gene analysis and whole-exome sequencing (WES) were performed. Biallelic mutations in CLCN7 or TCIRG1 were detected in three families, in TNFRSF11A or CA2 in two families, and in SNX10 in one family in the osteopetrosis group. A heterozygous variant of CLCN7 was also found in one family. In the osteopetrosis and related osteoclast disorders group, three different variants of CTSK were detected in five families with pycnodysostosis and the SLC29A3 variant causing dysosteosclerosis was detected in one family. In autosomal recessive osteopetrosis (ARO), a malignant infantile form, four patients died during follow-up, two of whom had undergone hematopoietic stem cell transplantation. Interestingly, all patients had osteopetrorachia of the long bone metaphyses in infancy, typical skeletal features such as Erlenmeyer flask deformity and bone-in-bone appearance that developed toward the end of early childhood. Two siblings with a biallelic missense mutation in CLCN7 and one patient with the compound heterozygous intronic TCIRG1 variant corresponded to the intermediate form of ARO (IARO); there was intrafamilial clinical heterogeneity in the family with the CLCN7 variant. One of two patients with IARO and distal tubular acidosis was found to have a large deletion in CA2. In one family, two siblings with a heterozygous mutation in CLCN7 were affected, whereas the father with the same mutation was asymptomatic. In WES analysis of three brothers from a family without mutations in osteopetrosis genes, a hemizygous missense variant in CCDC120, a novel gene, was found to be associated with high bone mass. This study extended the natural history of the different types of osteopetrosis and also introduced a candidate gene potentially causing osteopetrosis.

The Erlenmeyer Flask Deformity on Computed Tomography.

No abstract available.

A reappraisal of Gaucher disease patients - Clinical presentation, and diagnosis in rare disease unit of central child teaching hospital in Baghdad province

Introduction and Aim: Gaucher disease (GD) is an autosomal recessive ailment caused due to mutations in the GBA1 gene, encoding for the lysosomal enzyme, glucocerebrosidase. The aim was to evaluate the clinical, biochemical, and molecular parameters associated with this disease, as well as to identify symptoms and covariables thought to be most diagnostic of early GD presentation, allowing for early diagnosis and management. Methodology: This cross-sectional study involved twenty-six patients diagnosed with GD at the Metabolic Department of Central Child Teaching Hospital, Baghdad, Iraq. Diagnosis depended mainly on history and physical examination and confirmed by beta-glucosidase enzyme assay of dry blood spot on filter paper and Lyso-GL-1 level. Amplification-based next generation sequencing approach was used in investigating the GBA1 gene at the molecular level. Results: The mean age of the 26 (17 male and 9 female) patients was 9.13 years, with 100% consanguinity and 50% positive family history. The average number of years from the start of clinical manifestations to the diagnosis' validation was 3.82 years. The original age of presentation was 2.83 years, and the initial age of diagnosis was 6.65 years. Hepatosplenomegaly (85%), pallor (88%), splenomegaly (12%), splenectomy (12%), hemorrhage (19%), bone discomfort (23%), bone breakage (12%), and GD type III (19%) were observed. Among patients 65% exhibited radiological bone abnormalities, 54% had Erlenmeyer flask deformity, and 1.5% had osteopenia and fracture. Studies of GBA1 gene showed the mutation C.[1448T&gt;c ](P.[ Leu483Pro] to be the most common. Hepatosplenomegaly and hematological deficiencies were effectively improved by enzyme replacement therapy. Conclusion: In Gaucher disease, GBA1 gene mutation analysis could provide some predictive information about disease variance as well as severity. PCV%, platelet count, ferritin, and lyso-GL-1 levels could be employed as biomarkers for the diagnosis of GD. ERT proved effective in treating hematological and hepatosplenomegaly abnormalities.

Gaucher Disease Diagnosed During Adolescence

Gaucher's disease (GD) is an autosomal recessive lysosomal lipid storage disorder caused due to insufficient activity of the enzyme beta-glucocerebrosidase. Type 1 GD may present at any age but manifests in childhood in more than half of patients. In this case report, an adolescent who applied to our gastroenterology outpatient clinic with dyspeptic complaints and was diagnosed with type 1 GD is presented to draw attention to rare metabolic diseases. A 14-year-old girl complaining of abdominal and bone pain was admitted to the hospital. Erlenmeyer flask deformity was detected on the direct knee radiograph of the patient, as well as thrombocytopenia, ferritin elevation and hepatosplenomegaly. A preliminary diagnosis of Gaucher disease was considered upon detection of low levels of beta glucocerebrosidase enzyme for our patient. The homozygous variant was detected in the GBA gene NM_000157.4:c.1226A&gt;G (p.Asn409Ser) and diagnosed as Type 1 GD. When evaluating patients, it is important to remember that some rare metabolic diseases can be observed in older children. Our patient was diagnosed with Type 1 GD at an adolescent age, and treatment was started. Currently, improvements in clinical manifestations can be achieved with existing treatments. Therefore, it is crucial to diagnose the disease at an early stage and begin the necessary treatment.

Wnt signaling pathway inhibitors, sclerostin and DKK-1, correlate with pain and bone pathology in patients with Gaucher disease.

Patients with Gaucher disease (GD) have progressive bone involvement that clinically presents with debilitating bone pain, structural bone changes, bone marrow infiltration (BMI), Erlenmeyer (EM) flask deformity, and osteoporosis. Pain is referred by the majority of GD patients and continues to persist despite the type of therapy. The pain in GD is described as chronic deep penetrating pain; however, sometimes, patients experience severe acute pain. The source of bone pain is mainly debated as nociceptive pain secondary to bone pathology or neuropathic or inflammatory origins. Osteocytes constitute a significant source of secreted molecules that coordinate bone remodeling. Osteocyte markers, sclerostin (SOST) and Dickkopf-1 (DKK-1), inactivate the canonical Wnt signaling pathway and lead to the inhibition of bone formation. Thus, circulated sclerostin and DKK-1 are potential biomarkers of skeletal abnormalities. This study aimed to assess the circulating levels of sclerostin and DKK-1 in patients with GD and their correlation with clinical bone pathology parameters: pain, bone mineral density (BMD), and EM deformity. Thirty-nine patients with GD were classified into cohorts based on the presence and severity of bone manifestations. The serum levels of sclerostin and DKK-1 were quantified by enzyme-linked immunosorbent assays. The highest level of sclerostin was measured in GD patients with pain, BMI, and EM deformity. The multiparameter analysis demonstrated that 95% of GD patients with pain, BMI, and EM deformity had increased levels of sclerostin. The majority of patients with elevated sclerostin also have osteopenia or osteoporosis. Moreover, circulating sclerostin level increase with age, and GD patients have elevated sclerostin levels when compared with healthy control from the same age group. Pearson's linear correlation analysis showed a positive correlation between serum DKK-1 and sclerostin in healthy controls and GD patients with normal bone mineral density. However, the balance between sclerostin and DKK-1 waned in GD patients with osteopenia or osteoporosis. In conclusion, the osteocyte marker, sclerostin, when elevated, is associated with bone pain, BMI, and EM flask deformity in GD patients. The altered sclerostin/DKK-1 ratio correlates with the reduction of bone mineral density. These data confirm that the Wnt signaling pathway plays a role in GD-associated bone disease. Sclerostin and bone pain could be used as biomarkers to assess patients with a high risk of BMI and EM flask deformities.

Spectrum of Skeletal Imaging Features in Osteopetrosis: Inheritance Pattern and Radiological Associations.

Osteopetrosis (from the Greek "osteo": bone; "petrosis": stone) is a clinically and genetically heterogeneous group of rare diseases of the skeleton, sharing the same main characteristic of an abnormally increased bone density. Dense bones in radiological studies are considered the hallmark of these diseases, and the reason for the common term used: "Marble bone disease". Interestingly, a radiologist, Dr. Albers-Schonberg, described this disease for the first time in Germany in 1904. Indeed, radiology has a key role in the clinical diagnosis of osteopetrosis and is fundamental in assessing the disease severity and complications, as well as in follow-up controls and the evaluation of the response to treatment. Osteopetrosis includes a broad spectrum of genetic mutations with very different clinical symptoms, age onset, and prognosis (from mild to severe). This diversity translates into different imaging patterns related to specific mutations, and different disease severity. The main recognized types of osteopetrosis are the infantile malignant forms with autosomal recessive transmission (ARO-including the rarer X-linked recessive form); the intermediate autosomal recessive form (IAO); and the autosomal dominant ones ADO, type I, and type II, the latter being called 'Albers-Schonberg' disease. Imaging features may change among those distinct types with different patterns, severities, skeletal segment involvement, and speeds of progression. There are several classical and well-recognized radiological features related to osteopetrosis: increased bone density (all types with different degrees of severity assuming a 'Marble Bone Appearance' especially in the ARO type), different metaphyseal alterations/enlargement including the so-called 'Erlenmeyer flask deformity' (particularly of femoral bones, more frequent in ADO type 2, and less frequent in ARO and IAO), 'bone in bone' appearance (more frequent in ADO type 2, less frequent in ARO and IAO), and 'rugger-jersey spine' appearance (typical of ADO type 2). After conducting an overview of the epidemiological and clinical characteristic of the disease, this review article aims at summarizing the main radiological features found in different forms of osteopetrosis together with their inheritance pattern.

Long-term bone outcomes in Italian patients with Gaucher disease type 1 or type 3 treated with imiglucerase: A sub-study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

BackgroundGaucher disease (GD) is a lysosomal storage disorder. We evaluated the “real-world” effectiveness of first-line imiglucerase on long-term bone outcomes in Italian patients in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. MethodsPatients treated with imiglucerase for ≥2 years and with bone assessments at baseline and during follow-up were selected. Data on bone pain, bone crises, marrow infiltration, avascular necrosis, infarction, lytic lesions, Erlenmeyer flask deformity, bone fractures, mineral density, and imiglucerase dosage were evaluated. ResultsData on bone manifestations were available for 73 of 229 patients (31.9 %). Bone crises frequency decreased significantly from baseline to the most recent follow-up (p < 0.001), with some improvement observed in bone pain prevalence. Bone pain and bone crises prevalence decreased significantly from baseline at 2 to <4 and 4 to <6 years (all p < 0.05). A low median (25th, 75th percentile) baseline imiglucerase dosage was identified in patients reporting bone pain or bone crises (15.0 [13.7, 30.0] and 22.8 [17.5, 36.0] U/kg once every 2 weeks, respectively). ConclusionOur study suggests that the management of GD in Italy, with regards to imiglucerase dosage, is suboptimal and confirms the need for clinicians to monitor and correctly treat bone disease according to best practice guidelines.

Craniofacial, dental, and molecular features of Pyle disease in a South African child

IntroductionPyle Disease (PD), or familial metaphyseal dysplasia [OMIM 265900], is a rare autosomal recessive condition leading to widened metaphyses of long bones and cortical bone thinning and genu valgum. We detail the oro-dental and molecular findings in a South African patient with PD.MethodsThe patient underwent clinical, radiographic and molecular examinations. An exfoliated tooth was analysed using scanning electron microscopy and was compared to a control tooth.ResultsThe patient presented with marked Erlenmeyer-flask deformity (EFD) of the long bones and several Wormian bones. His dental development was delayed by approximately three years. The permanent molars were mesotaurodontic. The bones, including the jaws and cervical vertebrae, showed osteoporotic changes. The lamina dura was absent, and the neck of the condyle lacked normal constrictions. Ionic component analysis of the primary incisors found an absence of magnesium. Sanger sequencing revealed a novel putative pathogenic variant in intron 5 of SFRP4 (c.855+4delAGTA) in a homozygous state.ConclusionThis study has reported for the first time the implication of a mutation in the SFRP4 gene in an African patient presenting with PD and highlights the need for dental practitioners to be made aware of the features and management implications of PD.

Clinical-genetic characteristics and treatment outcomes of Turkish children with Gaucher disease type 1 and type 3: A sixteen year single-center experience

Data from 38 children were retrospectively analyzed to determine the patient characteristics of Turkish children with Gaucher disease (GD) and evaluate the impact of enzyme replacement therapy (ERT) in a pediatric cohort consisting of two different sub-types of the disease, Gaucher disease type 1 (GD1) and type 3 (GD3). Both types were represented equally (GD1/GD3 = 20/18). L444P (35.5%) was the most common mutant allele while L444P/L444P (34.2%) was the most common genotype overall. Compound heterozygosity of N370S and L444P homozygosity were the dominant genotypes in Turkish children with GD1 and GD3, respectively. None of the patients had moderate to severe thrombocytopenia at last follow-up while the percent of patients with anemia decreased from 60% to 5.7% (p < 0.001). Significant improvements in mean liver (from 2.2 to 1.6 MN, p < 0.001) and spleen (from 15.5 to 7.6 MN, p < 0.001) volumes were observed in the first year of ERT. Linear growth was ameliorated as shown by the decrease in the percent of patients having short stature from 34.3% to 13.3% (p < 0.01) at year 5. Erlenmeyer flask deformity, osteopenia and scoliosis were common skeletal findings. Although none of the patients had lung disease at diagnosis, 20% developed radiological findings suggestive of pulmonary involvement. This single center experience is the first comprehensive study from Turkey not only reporting clinical and genetic characteristics of GD patients but also providing information on the outcomes of ERT in two different sub-types of GD. Genotypic background of Turkish children with GD is similar to western populations. Although visceral and hematological therapeutic goals are reached as early as one year of ERT in both sub-types, achieving normal growth takes several more years than suggested in significant number of children with GD.

Niemann-Pick disease type A: a case report

BACKGROUND&#x0D; Niemann-Pick disease (NPD) types A result from the deficient activity of sphingomyelinase. NPD type A is characterized by early-onset, progressive neurodegenerative course; systemic disease manifestations, including massive hepatosplenomegaly, interstitial lung disease, and cherry-red macula; and death in early childhood. The objective: to enhance the recognition of health care providers about the potential undiagnosed NPD because nonspecific clinical manifestation&#x0D; &#x0D; CASE PRESENTATION &#x0D; A 18-months-old boy was admitted to Dr. Kariadi Hospital with enlarged abdomen since seventh month old with failure to thrive. He also showed progressive loss of neurologic function, microcephaly with open major fontanelle, recurrent pulmonary and systemic infection. Physical examination revealed facial dysmorphic, milestone regression, under-nutrition, crackles in both lungs, hepatosplenomegaly with petechial in extremities and floppy infants. Laboratory investigations showed anemia (9.4 g/dL) and thrombocytopenia (73.000/mm3). The lactate dehydrogenase (482 U/L) and alkaline phosphatase (159, 03 IU/L) were higher than normal. Abdominal ultrasound revealed hepatomegaly with normal parenchyma and splenomegaly without nodule. Skeletal survey revealed Erlenmeyer flask deformity. Foam cell are detected in bone marrow puncture. Retcam examination showed cherry red spot at the macula. Bera revealed auditory neuropathy. The enzyme activity showed normal ?–Glucosidase (5.55 uM/hr) and chitotriosidase (105,8 nmol/ml) but low sphingomyelinases activity (0.30 uM/hr) which confirmed the diagnosis of NPD.&#x0D; DISCUSSION&#x0D; Niemann-Pick disease (NPD) types A result from the deficient activity of sphingomyelinase. NPD type A is characterized by early-onset, progressive neurodegenerative course; systemic disease manifestations, including massive hepatosplenomegaly, interstitial lung disease, and cherry-red macula; and death in early childhood. Type A is very rare and a severe infantile form with neurologic degeneration resulting in death usually by 3 years of age. No treatment available for type A and It’s a rare disease in Indonesia. &#x0D; CONCLUSION &#x0D; These investigations were able to diagnose this child as a NPD-Type A. Patient was closely monitored and symptomatic treatment was provided.

Gaucher Disease: Case Report

Gaucher disease is the most common lysosomal storage disease. It is marked by deficient glucocerebrosidase enzyme activity, leading to elective accumulation of its substrate in the lysosomes of macrophages. Macrophages are most often deposited in the liver, spleen and bone marrow, creating typical symptomatology in these organs. It is a genetic disorder with autosomal recessive inheritance pattern. The extent of the damage and severity of the symptoms increase in proportion to the genetic damage in the culprit gene, GBA1. As a result, the symptoms and course of the disease may range from mild to quite acute, with potential death of the patient at a young age. Case: Patient, 29, was diagnosed with Gaucher disease type 1 and underwent enzyme replacement therapy, with satisfactory response. Along with the common symptoms of the disease, he had also developed the rare Erlenmeyer flask deformity.

Successful treatment of Gaucher disease type 1 by enzyme replacement therapy over a 10-year duration in a Japanese pediatric patient: A case report.

The prevalence of Gaucher disease (GD) in Japan is much lower than that in Western countries; therefore, data on Japanese pediatric patients with GD type 1 are currently limited. The present study reports on the case of a Japanese pediatric patient with GD type 1 who was diagnosed when she presented with hepatosplenomegaly, thrombocytopenia and slight anemia at the age of 2 years. Serology tests revealed high levels of acid phosphatase (ACP) and angiotensin-converting enzyme (ACE). A bone marrow biopsy revealed the presence of Gaucher cells. Abdominal MRI indicated huge hepatosplenomegaly. Erlenmeyer flask deformity was observed on X-ray examination. MRI of the femora featured a high-intensity area within the diaphysis region. The enzymatic activity of leukocyte β-glucosidase, the measurement of which is necessary for a definitive diagnosis of GD, had decreased to 186.7 nmol/h/mg (reference range, 1,424.0-2,338.0 nmol/h/mg). Based on these results, the patient was clinically diagnosed with GD. Glucocerebrosidase gene analysis identified the compound heterozygote mutation of F213I (c.754T>A) on exon 7 and L444P (c.1448T>C) on exon 11. Enzyme replacement therapy (ERT) along with an intravenous infusion of 60 U/kg of imiglucerase every other week was initiated following diagnosis. Hemoglobin levels and the platelet count gradually improved and normalized after two years. ACP and ACE levels, biomarkers of the progression of GD, also improved. Abdominal MRI at six months after the initiation of ERT revealed a decrease in the size of the liver and spleen, which normalized after 1 year. Conversely, MRI of the femora indicated no improvement in the high-intensity area within the diaphysis region for 10 years.

Radiographic imaging, densitometry and disease severity in Autosomal dominant osteopetrosis type 2.

To characterize relationships between quantitative computed tomography bone mineral density measurements and other qualitative and quantitative imaging measures, as well as clinical metrics, in patients with autosomal dominant osteopetrosis type 2 (ADO2). Clinical and radiologic parameters of 9 adults and 3 children with autosomal dominant osteopetrosis type 2 were assessed including lumbar spine quantitative computed tomography (QCT), radiographic skeletal survey (skull base thickening; Erlenmeyer flask deformity; endobone pattern; and spine density pattern (endplate sclerosis, "anvil" appearance, or diffuse sclerosis)), dual-energy x-ray absorptiometry (DXA), tibial peripheral quantitative computed tomography (pQCT) volumetric bone mineral density (vBMD), bone turnover markers, and bone marrow failure or visual impairment. The skeletal parameter most divergent from normal was lumbar spine QCT Z-score (+ 3.6 to + 38.7). Lumbar QCT Z-score correlated positively with pQCT tibial diaphysis vBMD (Pearson correlation r = 0.73, p = 0.02) and pQCT tibial metaphysis vBMD (r = 0.87, p < 0.01). A trend towards positive lumbar QCT Z-score correlation with serum P1NP/CTX ratio (r = 0.54, p = 0.10) and lumbar DXA Z-score (r = 0.55, p = 0.10) were observed. Bone marrow failure and vision impairment occurred in those with most severe quantitative and qualitative measures, while those with less severe radiographic features had the lowest QCT Z-scores. Lumbar spine QCT provided the most extreme skeletal assessment in ADO2, which correlated positively with other radiologic and clinical markers of disease severity. Given the quantification of trabecular bone and greater variation from normal with wider range of values, lumbar QCT Z-scores may be useful to determine or detect impact of future treatments.

Improving the quantitative classification of Erlenmeyer flask deformities

The Erlenmeyer flask deformity is a common skeletal modeling deformity, but current classification systems are binary and may restrict its utility as a predictor of associated skeletal conditions. A quantifiable 3-point system of severity classification could improve its predictive potential in disease. Ratios were derived from volumes of regions of interests drawn in 50 Gaucher’s disease patients. ROIs were drawn from the distal physis to 2 cm proximal, 2 cm to 4 cm, and 4 cm to 6 cm. Width was also measured at each of these boundaries. Two readers rated these 100 femurs using a 3-point scale of severity classification. Weighted kappa indicated reliability and one-way analysis of variance characterized ratio differences across the severity scale. Accuracy analyses allowed determination of clinical cutoffs for each ratio. Pearson’s correlations assessed the associations of volume and width with a shape-based concavity metric of the femur. The volume ratio incorporating the metaphyseal region from 0 to 2 cm and the diametaphyseal region at 4–6 cm was most accurate at distinguishing femurs on the 3-point scale. Receiver operating characteristic curves for this ratio indicated areas of 0.95 to distinguish normal and mild femurs and 0.93 to distinguish mild and severe femurs. Volume was moderately associated with the degree of femur concavity. The proposed volume ratio method is an objective, proficient method at distinguishing severities of the Erlenmeyer flask deformity with the potential for automation. This may have application across diseases associated with the deformity and deficient osteoclast-mediated modeling of growing bone.

Natural history of untreated patients with type 1 Gaucher disease

Data from 38 children were retrospectively analyzed to determine the patient characteristics of Turkish children with Gaucher disease (GD) and evaluate the impact of enzyme replacement therapy (ERT) in a pediatric cohort consisting of two different sub-types of the disease, Gaucher disease type 1 (GD1) and type 3 (GD3). Both types were represented equally (GD1/GD3 = 20/18). L444P (35.5%) was the most common mutant allele while L444P/L444P (34.2%) was the most common genotype overall. Compound heterozygosity of N370S and L444P homozygosity were the dominant genotypes in Turkish children with GD1 and GD3, respectively. None of the patients had moderate to severe thrombocytopenia at last follow-up while the percent of patients with anemia decreased from 60% to 5.7% (p < 0.001). Significant improvements in mean liver (from 2.2 to 1.6 MN, p < 0.001) and spleen (from 15.5 to 7.6 MN, p < 0.001) volumes were observed in the first year of ERT. Linear growth was ameliorated as shown by the decrease in the percent of patients having short stature from 34.3% to 13.3% (p < 0.01) at year 5. Erlenmeyer flask deformity, osteopenia and scoliosis were common skeletal findings. Although none of the patients had lung disease at diagnosis, 20% developed radiological findings suggestive of pulmonary involvement. This single center experience is the first comprehensive study from Turkey not only reporting clinical and genetic characteristics of GD patients but also providing information on the outcomes of ERT in two different sub-types of GD. Genotypic background of Turkish children with GD is similar to western populations. Although visceral and hematological therapeutic goals are reached as early as one year of ERT in both sub-types, achieving normal growth takes several more years than suggested in significant number of children with GD.

Gaucher disease: the role of the specialist on metabolic bone diseases.

According to European legislation, a disease can be considered rare or "orphan" when it affects less than 1 subject of 2000 (1). Often these diseases affecting the pediatric age, are complex diseases and chronically debilitating and for this motive need the intervention of multidisciplinary skills specific. Among the rare disease as affecting the skeleton more than 400 are characterized by dysplastic changes of the skeleton (2). Alongside the disorders affecting the skeleton primitively, many systemic diseases can have a bone involvement. Among these, the Gaucher disease (GD), an heterogeneous lysosomal storage determined by hereditary enzyme deficiency of β-glucosidase. Patients with this disease have skeletal disorders of varying severity (Erlenmeyer flask deformity, lytic lesions and osteonecrosis, pathological fractures) that affects both the bone marrow, both mineralized bone with progressive damage of the tissue. The bone disease is the most debilitating of GD and can have a significant impact on the quality of life of patients. Thorough evaluations by monitoring biochemical markers of bone turnover and instrumental, with a quantitative and qualitative evaluation of the bone, are of fundamental importance to intervene early so they can prevent complications irreversible.

Magnetic resonance imaging and BMB score in the evaluation of bone involvement in Gaucher's disease patients.

ObjectiveTo evaluate by magnetic resonance imaging changes in bone marrow of patients undergoing treatment for type I Gaucher’s disease.Materials and MethodsDescriptive, cross-sectional study of Gaucher’s disease patients submitted to 3 T magnetic resonance imaging of femurs and lumbar spine. The images were blindly reviewed and the findings were classified according to the semiquantitative bone marrow burden (BMB) scoring system.ResultsAll of the seven evaluated patients (three men and four women) presented signs of bone marrow infiltration. Osteonecrosis of the femoral head was found in three patients, Erlenmeyer flask deformity in five, and no patient had vertebral body collapse. The mean BMB score was 11, ranging from 9 to 14.ConclusionMagnetic resonance imaging is currently the method of choice for assessing bone involvement in Gaucher’s disease in adults due to its high sensitivity to detect both focal and diffuse bone marrow changes, and the BMB score is a simplified method for semiquantitative analysis, without depending on advanced sequences or sophisticated hardware, allowing for the classification of the disease extent and assisting in the treatment monitoring.

Long Term Outcomes of ERT in Children with Gaucher Disease. Spanish Experience

Background. Enzymatic replacement therapy (ERT) had modified the natural history of Gaucher disease (GD). Historically the GD patients had growth retardation; frequently spleen removal, and multiple bone complications. It is known that more than 70% of GD patients diagnosed in adulthood have bone complications. Nowadays we have learnt through clinical trials that patients treated regularly with ERT during childhood achieve a normal percentile of growing and avoid complications. In this report we are summarizing the Spanish experience in the last two decades treating children with GD in every day clinical practice.Patients & Methods: From 376 patients included in the Spanish Registry of Gaucher Disease working since 1993, a total of 79 patients were diagnosed under18 years old, 26 of them were classified as GD type 2; 13 developed a GD3 during follow-up and 40 were classified as GD1. For the analysis we have only included GD1 and GD3 patients, 53 patients. Statistical analysis: Descriptive and frequency analysis were performed in a SSPS data base.Results: Baseline characteristics: Gender: 18 females and 35 males. Mean age at diagnosis 5.8 y.o. (range 0.5-17), 78.4% (62) of cases were the initial case for familiar studies, mean age at start ERT 8.5 years (0.5-18), Mutational analysis: L444P/L444P was the most frequent genotype in GD3 and N370S heterozygosis in GD1, there was only one case with N370S homozygosis, Three patients were splenectomised before diagnosis and 60% underwent a bone marrow aspiration or biopsy and 3 liver biopsy during the initial workout. The paediatric Gaucher Score Index (PGSI) (Kallish S, Kaplan P 2012) shows: mild-disease: 62.5%, moderate: 31.25% and severe: 6.25%, missing data 5 patients. Mean chitotriosidase: 12,535 nmol.ml/h (871-49,031), hemoglobine: 11.4g/dL (6.9-17), 43% of patients presented anemia at diagnosis. Mean platelet count: 121 x109 (12,363), 53% of patients presents with < 100 x109 platelets. Bone assessment: 49% (26) of patients shows bone manifestations: Erlenmeyer flask deformity, 24.5%; Bone crisis, 13.2%; avascular necrosis, 5.6%; bone infiltration, 7.5%, Bone infarction: 3.7%; isolated bone pain, 13.2%. The mean follow-up was 13 y (2-21), 45 received ERT following diagnosis, mean years on therapy 13.2 (2-21). In first line: Alglucerase, 8.9% (4); Imiglucerase, 75.5% (34); Velaglucerase, 6.7% (3) and Taliglucerase 8.9% (4). Actual therapies: Imiglucerase: 47.1% (25); Velaglucerase: 17% (9); Taliglucerase: 3.7% (2); Miglustat: 7.5% (4), Eliglustat: 1.8% (1), no ERT/ loss of contact: 7.5%. Mean time on ERT: 13,2 years, twenty-one patients had received ERT during 15 or more years (15-21); 12 for > 10 years (12-14) and 11< 10 years (2-9). Actual status: mean haemoglobin levels: 13, 3g/dL, mean platelets count: 162 x109, Chitotriosidase: 497 mg.prot.h, there are no patients with hepatomegaly and only 3 patients have splenomegaly. Events related to therapy: infusion reactions G3/4: 4, all patients had IgG specific antibodies, and all reactions occurs between 1 and 7 months after start therapy; abandonment 2; changes of ERT, 7 (excluding alglucerase to imiglucerase); related to disease: growth retardation 9 (bellow 25 percentile for age/high); bone crisis 3; joint replacement 1, osteopenia 2 cases (after 2 years on ERT), normalization of coagulation factors (VW,FV,FIX,FXI), others: early diabetes 1, early menarche 1, thyroiditis 1, sacroileitis 1, pregnancies 3, lost follow-up 4.Conclusions: The incidence of GD related complications, especially bone complications, in paediatric patients on ERT is lower than in adults, probably related to early ERT onset. Endocrine complications are rare, difficult to correlate to ERT. Growth retardation was resolved with ERT in the majority of cases. The early onset of therapy in symptomatic child is highly recommended.Table 1Immune reactions and endocrine complicationsPatientAge at DxGenderGenotypeTime on ERTType of reaction14FN370S/84GG6 m (Imiglucerase)Infusion reaction23FN370S/IVS4-2ª>G;c.(-203)A>G7 m (Imiglucerase)Infusion reaction33FN370S/L444P1 m (Velaglucerase*)Infusion reaction49FN370S/ G4384delC3 m(Imiglucerase)Infusion reaction54MN370S/L444P72 m (Imiglucerase)Diabetes60,5FN370S/L444P12 m (Imiglucerase)Thyroiditis74FN370S/R47X48 m (Imiglucerase)Early manarche DisclosuresNo relevant conflicts of interest to declare.