Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).

BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disease characterised by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9 and 16 after PHA stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients which is explained by mutations in the DNA methyltransferase gene DNMT3B in some, but not all, ICF patients. OBJECTIVE: To obtain a comprehensive description of the clinical features of this syndrome as well as genotype-phenotype correlations in ICF patients. METHODS: Data on ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. RESULTS AND CONCLUSIONS: 45 patients all with proven centromeric instability were included in this study. Facial dysmorphism was found to be a common characteristic (n = 41/42), especially epicanthic folds, hypertelorism, flat nasal bridge and low set ears. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (n = 39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Haematological malignancy was documented in two patients. Life expectancy of ICF patients is poor, especially those with severe infections in infancy or chronic gastrointestinal problems and failure to thrive. Early diagnosis of ICF is important since early introduction of immunoglobulin supplementation can improve the course of the disease. Allogeneic stem cell transplantation should be considered as a therapeutic option in patients with severe infections or failure to thrive. Only 19 of 34 patients showed mutations in DNMT3B, suggesting genetic heterogeneity. No genotype-phenotype correlation was found between patients with and without DNMT3B mutations.

Marfanoid features in a child with combined methylmalonic aciduria and homocystinuria (CblC type).

Cobalamin is an essential cofactor for two mammalian enzymes: methionine synthase and methylmalonyl-CoA mutase. Patients with the cobalamin C (CblC) defect have combined methylmalonic aciduria and homocystinuria. Recently, the gene responsible for the CblC type, MMACHC, was identified, which enables molecular diagnostics. In this study, we describe two siblings, a 16-year-old girl and her 11-year-old brother, of a consanguineous family who presented with a very distinct clinical manifestation. The girl presented at the age of 13 years with macrocytic anaemia, cognitive regression and Marfanoid features such as increased arm-span, arachnodactyly, joint hyperlaxity and scoliosis. Her brother presented at the age of 10 months with developmental delay and behavioural abnormalities. Biochemical analysis showed severely increased homocysteine and methylmalonic acid levels in plasma of both siblings. In addition, plasma cysteine levels were decreased in the girl but not in her brother. The diagnosis of CblC defect was confirmed by genomic sequencing of the coding exons of the MMACHC gene. Two heterozygous mutations were identified in both siblings; the common c.271dupA p.Arg91LysfsX14 and a novel mutation, c.1A > G p.Met1?. Therapy consisting of folic acid, vitamin B6, l-carnitine and intramuscular vitamin B12 resulted in a clear improvement of biochemical parameters and, importantly, resulted in amelioration of the Marfanoid features in the girl. These data might suggest that low cysteine levels account for the Marfanoid features observed in the girl and indicate that the CblC type of combined methylmalonic aciduria and homocystinuria should be considered in the differential diagnosis of patients with Marfanoid features.

Serological testing for Bartonella henselae infections in The Netherlands: clinical evaluation of immunofluorescence assay and ELISA.

Cat-scratch disease (CSD), caused by Bartonella henselae infection, can mimic malignancy and can manifest atypically. Reliable serological testing is therefore of great clinical importance. The diagnostic performance of immunofluorescence assay (IFA) and ELISA was evaluated in a group of Dutch patients with proven CSD (clinical diagnosis confirmed by PCR). Sera of 51 CSD patients and 56 controls (patients with similar symptoms, but who were B. henselae PCR-negative and had an alternative confirmed diagnosis) were tested for anti-B. henselae IgM and IgG by IFA and ELISA. A commercially available IFA test for IgM had a sensitivity of 6%. In-house assays for IgM showed specificities of 93% (IFA) and 91% (ELISA), but with low sensitivities (53% and 65%, respectively). With a specificity of 82% (IFA) and 91% (ELISA), in-house IgG testing showed a significantly higher sensitivity in IFA (67%) than in ELISA (28%, p <0.01). Sensitivity was higher for genotype I (38-75%) than for genotype II (7-67%) infections, but this was only statistically significant for IgG ELISA (p <0.05). In conclusion, detection of IgM against B. henselae by in-house ELISA and IFA was highly specific for the diagnosis of CSD. The high seroprevalence in healthy individuals limits the clinical value of IgG detection for diagnosing CSD. Given the low sensitivity of the serological assays, negative serology does not rule out CSD and warrants further investigation, including PCR. Adding locally isolated (e.g., genotype II) B. henselae strains to future tests might improve the sensitivity.

[Rituximab instead of splenectomy in 4 children with chronic or refractory autoimmune haemolytic anaemia]. / Rituximab in plaats van splenectomie bij 4 kinderen met chronische of refractaire auto-immune hemolytische anemie.

4 children, a boy aged 10 years and 3 girls aged 3, 3, and 16 years, suffering from chronic or refractory autoimmune haemolytic anaemia (AIHA), who were dependent on high doses of steroids and were refractory to immunosuppressants, were treated with rituximab at a dose of 375 mg/m2 once a week for 3 or 4 weeks as an alternative to splenectomy. Rituximab is a monoclonal anti-CD20 antibody that prevents the production ofautoantibodies by selective destruction of B-lymphocytes. Haemoglobin levels increased and the parameters of chronic haemolysis (reticulocyte count, lactate dehydrogenase activity, bilirubin concentration) decreased to normal values. 3 patients were taken off corticosteroids completely; 1 of these was also no longer dependent on blood transfusions. Circulating B-lymphocytes were absent for 6 to 15 months after the treatment and the rituximab was well-tolerated. During the treatment, immunoglobulins were substituted and infectious complications were not seen. Rituximab was valuable in the treatment of chronic or refractory AIHA and eliminated the need for splenectomy. 1 patient did not respond to rituximab.

Anaphylaxis after first exposure to ceftriaxone.

UNLABELLED: Life-threatening anaphylaxis developed in a 5-y-old boy with septic shock within minutes of receiving his first intravenous injection of ceftriaxone. Hypersensivity could not be demonstrated by skin testing and ceftriaxone-specific IgE. However, an in vivo, controlled, intravenous challenge was clearly positive. CONCLUSION: Clinicians should be aware of the possibility of anaphylaxis occurring with the first dose of ceftriaxone, especially since such a reaction could go unnoticed in patients with life-threatening infections and unstable vital signs.

A new autosomal recessive syndrome. Early onset of pancytopenia, distinct facial features, growth retardation and developmental delay.

The association of dysmorphic features and failure of one or more bone marrow cell lines is well known. Examples are Fanconi's anemia and Diamond-Blackfan anemia. This report describes 3 similarly affected children from consanguineous parents, all showing low birth weight, severe growth retardation, distinct facial features, microcephaly, mental retardation and onset of severe pancytopenia in infancy without increased chromosomal breakage. We conclude that these cases represent a new familial autosomal recessive bone marrow failure syndrome.

Deep vein thrombosis after hemolytic crisis in a glucose-6-phosphate dehydrogenase deficient boy with antithrombin-III deficiency.

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A patient with meningioma showing multiple cytogenetic abnormalities and a constitutional translocation (3;9)(q13.3;q22).

Several different clonal abnormalities in both hypo- and hyperdiploid cell lines were observed in tumor cells of a 35-year-old man with a syncytial meningioma. A translocation involving chromosomes 3 and 9, t(3;9)(q13.3;q22), was present in all analyzable tumor cells and proved to be constitutional. The breakpoints 3q13.3 and 9q22 are involved in acquired karyotypic abnormalities in a number of tumors and might be situated near a tumor suppressor gene. The development of malignancies has been observed in patients with constitutional translocations involving 3q13.3 but not 9q22. We conclude that translocations involving 3q13.3 and maybe 9q22 could present constitutional chromosomal abnormalities predisposing for the development of a malignancy. Patients in whose tumor cells a translocation involving 3q13.3 or 9q22 is observed should be checked for a similar constitutional abnormality.

Iron therapy resistant microcytic anaemia in a 13-year-old girl with Castleman disease.

UNLABELLED: We describe the case history of a 13-year-old girl with chronic fatigue and prolonged microcytic anaemia. She received oral iron since the age of 11 but failed to respond to it. Laboratory studies revealed elevated C-reactive protein and hypergammaglobulinaemia. A large solitary mesenterial lymph node could be demonstrated by ultrasonography and CT. A diagnosis of Castleman disease was suspected and confirmed histologically. After surgical removal of the lymphoma the patient recovered completely. CONCLUSION: Castleman disease should be considered in cases of chronic fatigue, unexplained fever, microcytic anaemia and hypergammaglobulinaemia.

Familial thrombocytosis in infancy presenting with a leukaemoid reaction.

Familial thrombocytosis (FT) is a hereditary disorder probably involving the regulation of megakaryopoiesis. This report is the first documented case of FT in infancy. The clinical course was complicated by a leukaemoid reaction which lasted for several months, in combination with failure to thrive and hepatosplenomegaly. At the age of 5 years the patient, with the exception of thrombocytosis, is healthy and without medication.

Isolated hepatic mucormycosis in an immunocompetent child.

A case of isolated localized hepatic mucormycosis in an immunocompetent 3 1/2-yr-old girl with concomitant acute toxoplasmosis is described. Mucormycosis is rare in immunocompetent patients, and hepatic mucormycosis has so far been described only in the context of disseminated disease. The infection resolved spontaneously without surgical debridement and/or appropriate medical therapy with amphotericen B.

Diamond-Blackfan anemia and malignancy. A case report and a review of the literature.

BACKGROUND: Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome involving the erythropoietic lineage. A preleukemic predisposition has been suggested but not proven. METHODS: The development of Hodgkin's disease in a 15-year-old boy with DBA, in remission for 13 years after cessation of steroid therapy, is described. Review of the literature revealed 11 other cases of malignancy (10 hematologic) in DBA. RESULTS: This patient, together with those described in the literature, shows that the incidence of hematological malignancy in DBA is increased (2.5% of all reported cases of DBA). Treatment was successful in three, including one after allogeneic bone marrow transplantation and our patient in whom recurrence of DBA complicated treatment. CONCLUSIONS: The incidence of hematologic malignancies in patients with DBA is increased. Treatment can be successful but may be complicated by recurrence of DBA. Bone marrow transplantation should be considered for patients with a suitable donor as part of treatment of patients with DBA and hematologic malignancy.

Extramedullary blastic transformation in a child with adult chronic myelocytic leukemia.

We report a case of Philadelphia chromosome positive (Ph+) chronic myelocytic leukemia (CML) in a 4-year-old child presenting with a one-sided cervical chloroma (granulocytic sarcoma) of 5 months duration preceded by an inflammatory reaction in the same area. Blood and bone marrow were consistent with CML in chronic phase. Cytogenetic analysis of blood, bone marrow and chloroma showed, in addition to the classical Ph+ cell line, another clone with additional aberrations: 50,XY,+Y,+8,t(9;22)(q34;q11), +19,+21, present predominantly in the chloroma. In conclusion, this is the first report of a Ph+ CML in a young child with a chloroma as an isolated extramedullary localization of blastic transformation. It is hypothesized that local events such as inflammation might be inductive of extramedullary blastic transformation.

Failure to thrive is an early symptom of the imerslund Gräsbeck syndrome.

PURPOSE: The Imerslund-Gräsbeck syndrome (IGS) is a rare inherited disorder characterized by a megaloblastic anemia due to a selective vitamin B12 malabsorption in association with a mild proteinuria. Usually recurrent infections, gastrointestinal complaints, and pallor are presenting symptoms. We report two cases of IGS with an unusual presentation. PATIENTS AND METHODS: Two girls are described with the Imerslund-Gräsbeck syndrome who had a failure to thrive as a presenting symptom without infections or gastrointestinal complaints. The diagnosis of IGS was based on marked macrocytic anemia, very low serum vitamin B12 levels, abnormal Schilling urinary excretion test results, and mild proteinuria. When parenteral vitamin B12 was started, a rapid catch-up growth was seen in both girls. CONCLUSIONS: The absence of well-known causes of failure to thrive, such as recurrent infections and gastrointestinal complaints, favors the concept that the metabolic disturbances caused by an isolated cobalamin deficiency as seen in IGS causes a failure to thrive.

[Vitamin B12 deficiency due to abnormal eating habits]. / Vitamine B12-deficiëntie bij 2 kinderen door afwijkende voedingsgewoonte.

Vitamin B12 deficiency is an uncommon disorder in a prosperous western country. In two children a nutritional vitamin B12 deficiency was observed. The first was a 2-year-old girl with neurodevelopmental regression and macrocytic anaemia, a result of a combination of a maternal vitamin B12 deficiency and inadequate feeding after birth. The second patient was a 14-year-old adipose girl with severe polyneuropathy and mild macrocytic anaemia as a result of a nutritional vitamin B12 deficiency. In her case the deficiency resulted from a bizarre feeding pattern. She turned out to be the victim of child abuse. It is concluded that even in a prosperous western country like the Netherlands vitamin B12 deficiency in children can develop as a result of an inadequate feeding pattern. It can lead not only to macrocytic anaemia but also to severe neurological abnormalities.

[Congenital hypoplastic anemia in The Netherlands (1963-1989)]. / Congenitale hypoplastische anemie in Nederland (1963-1989).

Congenital hypoplastic anemia (CHA; syn: Diamond-Blackfan syndrome) is a rare disorder with one of two patients a year in the Netherlands. To get a better understanding of this disorder in the Netherlands we conducted a national retrospective study over a 25-year period (1963 till 1989). The medical reports of 19 patients who fulfilled the diagnostic criteria for CHA were studied. Almost all patients were diagnosed during the first three months of life. Dysmaturity was found in 50% of the patients and in 25% physical anomalies were observed. In 17 patients the bone marrow showed a hypoplastic erythropoiesis, but in 2 patients erythropoiesis was quantitatively normal. All patients were treated with prednisone and 74% of them responded initially. Five of these patients (26%) had a complete remission and 4 of them (21%) are in remission on low dose prednisone maintenance-treatment. Remarkably one patient went only into remission at the age of 17 years. Nine patients (47%) are transfusion-dependent and one patient has a stable hemoglobin level of about 5.0 mmol/l without treatment. This study further shows that the chance of achieving a remission was positively correlated with an early start of prednisone treatment and negatively with the manifestation of symptoms on the first day of life.

Effect of graft-versus-host disease on hematopoiesis after bone marrow transplantation in mice.

We have examined the effect of graft-versus-host disease (GVHD) on the reconstitution of donor hematopoiesis in a murine bone marrow transplant (BMT) model of GVHD to minor histocompatibility antigens. GVHD had no effect on peripheral blood counts, which normalized by 1 month after BMT, and did not affect numbers of hematopoietic progenitors in the BM, which remained decreased in all transplant recipients. Donor stem cells (colony-forming unit-spleen day 8) and stem cell self-renewal remained low in all mice for 5 months after transplant, but GVHD further damaged the stem cell compartment. Peripheral counts 1 month after transplant were supported by increased numbers of stem cells in cycle and increased splenic hematopoiesis. However, GVHD altered the pattern of extramedullary hematopoiesis, causing dramatically decreased activity in the spleen and increased activity in the liver. We conclude that GVHD further decreases hematopoietic reserve and causes damage to the donor stem cell compartment during hematopoietic reconstitution after transplant, despite unaffected progenitor frequencies and peripheral blood counts.