Göran Elinder

Contemporary classification of histiocytic disorders

Pathologists and pediatric hematologist/ oncologists of the World Health Organizations Committee on Histiocytic/Reticulum Cell Proliferations and the Reclassification Working Group of the Histiocyte Society present a classification of the histiocytic disorders that primarily affect children. Nosology, based on the lineage of lesional cells and biological behavior, is related to the ontogeny of histiocytes (macrophages and dendritic cells of the immune system). Dendritic cell-related disorders of varied biological behavior are dominated by Langerhans cell histiocytosis, but separate secondary proliferations of dendritic cells must be differentiated. Juvenile xanthogranuloma represents a disorder of dermal dendrocytes, another dendritic cell of skin. The hemophagocytic syndromes are the most common of the macrophage-related disorders of varied biological behavior. Guidelines for distinguishing the exceedingly rare malignant diseases of histiocytes from large cell lymphomas through the use of a battery of special studies are provided.

Incidence in Sweden and Clinical Features of Familial Hemophagocytic Lymphohistiocytosis

ABSTRACT. We retrospectively studied the incidence of familial hemophagocytic lymphohistiocytosis (FHL) in children during the 16‐year period 1971–86. First, all departments of pediatrics, pathology, and infectious diseases were enquired for children with FHL or disorders resembling FHL. Secondly, the causes of death of all children who died during the study period in Sweden (n= 19 542) were also investigated. Files and histological specimens were further studied in selected children. By using a set of inclusion/exclusion criteria, we found 32 children with FHL. The incidence was 1.2/1000000 children per year. One child per 50 000 live borns developed FHL during this period. The sex ratio was close to 1:1. Prominent early clinical signs were fever (91%), splenomegaly (84%), hepatomegaly (90%), rash (43%), and lymph node enlargement (42%). Neurological symptoms, which developed in 47%, could totally dominate the clinical picture and develop prior to other symptoms and signs. Common laboratory findings were pancytopenia, hypertriglyceridemia, hypofibrinogenemia, elevated serum transaminases, hyperbilirubinemia, hyponatremia, hypoalbuminemia, and a moderate spinal fluid pleocytosis. Chest X‐ray often revealed mostly discrete pulmonary infiltrates. FHL is an underdiagnosed disease and in only 11/32 children was diagnosis made during their lifetime. It is important to be aware of the disorder as potential therapy now exists.

Safety of rituximab therapy during the first trimester of pregnancy: a case history

The optimal treatment of non‐Hodgkins lymphoma (NHL) during pregnancy is currently undefined. The potential teratogenic effects of conventional chemotherapy preclude its use during the first trimester of pregnancy. We report the case of a pregnant woman with relapsed indolent follicular NHL who was treated with rituximab (unintentionally) during the first trimester. The treatment stabilised the disease. Following an uncomplicated pregnancy, a healthy child was born at full term and careful haematological and immunological monitoring has revealed no adverse effects resulting from exposure to rituximab. Data of using rituximab during pregnancy are scarce, but the present case shows that rituximab may be one option for treatment of NHL in early pregnancy.

Duration and morbidity of newly diagnosed idiopathic thrombocytopenic purpura in children: a prospective nordic study of an unselected cohort☆

OBJECTIVEnTo determine the duration of the risk period with platelet counts <20 x 10(9)/L and the frequency of bleeding episodes in unselected children with idiopathic thrombocytopenic purpura (ITP).nnnSTUDY DESIGNnWe established a registry for patients with newly diagnosed ITP in the five Nordic countries, enrolling children aged 0 to 14 years with platelet counts <30 x 10(9)/L. Treatment centers prospectively reported presenting features, management details, and disease-related events during the first six months after diagnosis.nnnRESULTSnAt presentation (n=501), more than half of the children had a platelet count <10 x 10(9)/L, but only 15 (3.0%) had a hemorrhage requiring blood transfusion. During follow-up of 409 patients, thrombocytopenia resolved uneventfully in 277. A risk period was present in 376 cases. Among 283 with self-limiting ITP, 26 were at risk >1 month and 25 had 30 events. Among 93 patients with chronic ITP, 73 were at risk >1 month and 44 had 111 events. Events occurred with an average frequency of 0.39 per month at risk. Life-threatening hemorrhages did not occur in the first six months after diagnosis.nnnCONCLUSIONnMost children with ITP are at risk for serious bleeding for less than one month. Continuing severe thrombocytopenia is associated with little morbidity, bleeding episodes being infrequent and very rarely serious.

Identification of microdeletions spanning the Diamond-Blackfan anemia locus on 19q13 and evidence for genetic heterogeneity.

Summary Diamond-Blackfan anemia (DBA) is a rare pure red-cell hypoplasia of unknown etiology and pathogenesis. A major DBA locus has previously been localized to chromosome 19q13.2. Samples from additional families have been collected to identify key recombinations, microdeletions, and the possibility of heterogeneity for the disorder. In total, 29 multiplex DBA families and 50 families that comprise sporadic DBA cases have been analyzed with polymorphic 19q13 markers, including a newly identified short-tandem repeat in the critical gene region. The results from DNA analysis of 29 multiplex families revealed that 26 of these were consistent with a DBA gene on 19q localized to within a 4.1-cM interval restricted by loci D19S200 and D19S178; however, in three multiplex families, the DBA candidate region on 19q13 was excluded from the segregation of marker alleles. Our results suggest genetic heterogeneity for DBA, and we show that a gene region on chromosome 19q segregates with the disease in the majority of familial cases. Among the 50 families comprising sporadic DBA cases, we identified two novel and overlapping microdeletions on chromosome 19q13. In combination, the three known microdeletions associated with DBA restrict the critical gene region to ∼1 Mb. The results indicate that a proportion of sporadic DBA cases are caused by deletions in the 19q13 region.

Familial hemophagocytic lymphohistiocytosis. Clinical review based on the findings in seven children.

Clinical, laboratory, and histological findings in FHL of diagnostic importance were intermittent fever, hepatosplenomegaly, peripheral blood cytopenia, hypertriglyceridemia, hypofibrinogenemia, and a lymphohistiocytic accumulation with hemophagocytosis in the mononuclear phagocytic system. Fine-needle aspiration biopsy from the spleen appeared to be a useful method for revealing hemophagocytosis. The treatment of induction and relapses, as well as the maintenance therapy, included administration of teniposide, etoposide, and corticosteroids. The regimen had to be individualized for each child since the clinical course was highly variable. Half of the children given successful induction therapy (3/6) are still alive with over a 3-year survival after diagnosis.

Insufficient evidence for 'shaken baby syndrome' - a systematic review

Shaken baby syndrome has typically been associated with findings of subdural haematoma, retinal haemorrhages and encephalopathy, which are referred to as the triad. During the last decade, however, the certainty with which the triad can indicate that an infant has been violently shaken has been increasingly questioned. The aim of this study was to determine the diagnostic accuracy of the triad in detecting that an infant had been shaken. The literature search was performed using PubMed, Embase and the Cochrane Library up to October 15, 2015. Relevant publications were assessed for the risk of bias using the QUADAS tool and were classified as having a low, moderate or high risk of bias according to predefined criteria. The reference standards were confessions or witnessed cases of shaking or accidents. The search generated 3773 abstracts, 1064 were assessed as possibly relevant and read as full texts, and 30 studies were ultimately included. Of these, 28 were assessed as having a high risk of bias, which was associated with methodological shortcomings as well as circular reasoning when classifying shaken baby cases and controls. The two studies with a moderate risk of bias used confessions and convictions when classifying shaken baby cases, but their different designs made a meta‐analysis impossible. None of the studies had a low risk of bias.

Lipoprotein Alterations and Plasma Lipoprotein Lipase Reduction in Familial Hemophagocytic Lymphohistiocytosis

ABSTRACT. Serum lipid abnormalities are common in familial hemophagocytic lymphohistocytosis (FHL), a disorder also characterized by fever, hepatosplenomegaly, pancytopenia and a prominent lymphohistiocytic accumulation in the mononuclear phagocyte system. The lipoprotein pattern in nine children with FHL was studied with a quantitative method measuring cholesterol and triglycerides in each major class of lipoproteins. Triglycerides were markedly elevated during active FHL in serum, very low density lipoproteins, and low density lipoproteins. Cholesterol was increased in very low density lipoproteins whereas both triglycerides and cholesterol were extremely low in high density lipoproteins. These lipoprotein abnormalities, reversible on successful therapy, are compatible with a depressed lipolytic activity. Post‐heparin levels of lipoprotein lipase and hepatic lipase in plasma were studied in four children and found to be markedly low during active FHL. We suggest that inflammatory cytokines, which may strongly suppress lipoprotein lipase activity, can be important mediators in the pathophysiology of FHL and that they may participate in the development of the lipid abnormalities.

Randomized study of IVIg and high-dose dexamethasone therapy for children with chronic idiopathic thrombocytopenic purpura

Purpose To investigate whether pulsed high-dose dexamethasone is more efficacious than intravenous immunoglobulin (IVIg) as treatment of symptomatic chronic idiopathic thrombocytopenic purpura (ITP) in childhood. Methods In a 2:1-randomized study, 23 children with chronic ITP received dexamethasone (0.6 mg/kg per day for 4 consecutive days once monthly for 6 months, n = 15) or IVIg (800 mg/kg intravenously once monthly for 6 months, n = 8). After four courses of treatment a crossover was offered to nonresponders. A total of 20 children received dexamethasone and 11 received IVIg. Results One of the 8 IVIg patients and 2 of the 15 dexamethasone patients achieved complete response, defined as a platelet count of at least 150 × 109/L for more than 3 months without treatment. Two of the 15 dexamethasone patients achieved partial response, defined as a platelet count of at least 30 × 109/L for more than 3 months without treatment. One of the 8 IVIg patients and 5 of the 15 dexamethasone patients discontinued treatment. Five patients crossed over from IVIg to dexamethasone (one complete response) and three from dexamethasone to IVIg (none responded). In summary, 5 of the 20 dexamethasone patients achieved a complete or partial response and 1 of the 11 IVIg patients achieved a complete response. Platelet counts of at least 30 × 109/L by day 3 were reached in 9 of the 12 (75%) dexamethasone patients and all 8 (100%) IVIg children using available data. Five years after study completion, two of the three children who achieved a complete response and one of the two with a partial response to dexamethasone were in remission, as was the child with a complete response to IVIg. Conclusions Treatment with pulsed high-dose dexamethasone is not always effective in children with chronic ITP, but it is worth trying in severe symptomatic chronic childhood ITP.

A microdeletion in 19q13.2 associated with mental retardation, skeletal malformations, and Diamond-Blackfan anaemia suggests a novel contiguous gene syndrome

Diamond-Blackfan anaemia (DBA) is a constitutional red blood cell hypoplasia which may be associated with a variety of developmental abnormalities. A gene for DBA was recently mapped to chromosome 19q13.2 and subsequently cloned. Analysis of 19q marker alleles in DNA of sporadic DBA cases showed de novo microdeletions in three patients also presenting with mental retardation. We have studied one of these patients and characterised the deletion by fluorescence in situ hybridisation (FISH) to extended DNA fibres. The deletion was shown to be continuous over a 3.2 Mb region and the fibre-FISH analysis showed both chromosomal breakpoints. In combination, the clinical and molecular findings suggest a contiguous gene syndrome with a gene locus for mental retardation and, probably, skeletal malformations included in the deletion.