Ulf Tedgård

An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist

BACKGROUND Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)

Childhood idiopathic thrombocytopenic purpura in the Nordic countries: Epidemiology and predictors of chronic disease

Aim: To describe the epidemiology of idiopathic thrombocytopenic purpura (ITP) in the Nordic countries, to define clinical subgroups and to investigate factors predicting chronic disease. Methods: A prospective registration was done from 1998 to 2000, including all children with newly diagnosed ITP aged 0–14 y and at least one platelet count <30×109/l. Results: 506 children were registered and 423 followed for 6 mo. The incidence was 4.8/105 per year. Most children were aged 0–7 y (78%), with a predominance of boys, while patients aged 8–14 y had equal representation of the two sexes. There were seasonal variations determined by variations in postinfectious cases with sudden onset. The platelet count was <10×109/l in 58%, but bleeding manifestations were mild or moderate in 97%. The insidious form (symptoms for more than 2 wk) was more frequent in older children and girls, showed little seasonal variation, had milder manifestations and ran a chronic course in more than half the cases. Intracranial haemorrhages did not occur in the first 6 mo after diagnosis. Chronic ITP developed in 25%. The strongest predictor of chronic disease was insidious onset of symptoms (OR 5.97).

Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS and neurological symptoms

Several monogenic causes of familial myelodysplastic syndrome (MDS) have recently been identified. We studied 2 families with cytopenia, predisposition to MDS with chromosome 7 aberrations, immunodeficiency, and progressive cerebellar dysfunction. Genetic studies uncovered heterozygous missense mutations in SAMD9L, a tumor suppressor gene located on chromosome arm 7q. Consistent with a gain-of-function effect, ectopic expression of the 2 identified SAMD9L mutants decreased cell proliferation relative to wild-type protein. Of the 10 individuals identified who were heterozygous for either SAMD9L mutation, 3 developed MDS upon loss of the mutated SAMD9L allele following intracellular infections associated with myeloid, B-, and natural killer (NK)-cell deficiency. Five other individuals, 3 with spontaneously resolved cytopenic episodes in infancy, harbored hematopoietic revertant mosaicism by uniparental disomy of 7q, with loss of the mutated allele or additional in cisSAMD9L truncating mutations. Examination of 1 individual indicated that somatic reversions were postnatally selected. Somatic mutations were tracked to CD34+ hematopoietic progenitor cell populations, being further enriched in B and NK cells. Stimulation of these cell types with interferon (IFN)-α or IFN-γ induced SAMD9L expression. Clinically, revertant mosaicism was associated with milder disease, yet neurological manifestations persisted in 3 individuals. Two carriers also harbored a rare, in trans germ line SAMD9L missense loss-of-function variant, potentially counteracting the SAMD9L mutation. Our results demonstrate that gain-of-function mutations in the tumor suppressor SAMD9L cause cytopenia, immunodeficiency, variable neurological presentation, and predisposition to MDS with -7/del(7q), whereas hematopoietic revertant mosaicism commonly ameliorated clinical manifestations. The findings suggest a role for SAMD9L in regulating IFN-driven, demand-adapted hematopoiesis.

Duration and morbidity of chronic immune thrombocytopenic purpura in children: Five-year follow-up of a Nordic cohort

Aim:  To describe the clinical course, morbidity and platelet recovery in an unselected Nordic cohort of children with chronic Immune Thrombocytopenic Purpura (ITP).

Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia - a multicentre study from the Nordic Society of Paediatric Haematology and Oncology.

We present a prospective multicentre cohort of 20 children with acute lymphoblastic leukaemia (ALL) and cerebral sinus venous thrombosis (CSVT). The study covers a period of 5 years and comprises 1038 children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 2008 protocol. The cumulative incidence of CSVT was 2%. Sixteen of the thromboses were related to asparaginase and 16 to steroids. Most CSVTs occurred in the consolidation phase. Nearly all were treated with low molecular weight heparin without bleeding complications. Mortality related to CSVT directly or indirectly was 10%, emphasizing the importance of this complication.

Reproductive choices of haemophilia carriers

The actual reproductive choices made by slightly over a quarter of all the carriers of severe or moderate haemophilia in Sweden were investigated and compared with those of a randomly selected age‐matched group of women who were not carriers of haemophilia. In general, the 105 carriers had the same number of children as other women of similar age. However, carriers who did not choose prenatal diagnosis (PD) often abstained from further pregnancies after the birth of a haemophilic child, and they had significantly fewer children than the remainder of the carriers, as well as fewer children than women in the control group. Logistic regression analysis showed choice of PD to be correlated to a positive attitude towards abortion following PD and a family history of haemophilia. Carriers who have experienced the complications of haemophilia or its treatment appear to be more in favour of PD than women whose haemophilic children have received modern treatment without complications.

A novel 33-Gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias.

Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next‐generation‐sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical‐grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically‐reliable diagnostic test and minimize false‐negative results we developed an open‐source tool (CoverMi) to accurately determine base‐coverage and the ‘discoverability’ of known mutations for every sample. We validated our 33‐gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS‐based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.

How Do Carriers of Hemophilia Experience Prenatal Diagnosis (PND)?Carriers’Immediate and Later Reactions to Amniocentesis and Fetal Blood Sampling

ABSTRACT. A semistructured personal interview was performed with 29 carriers of hemophilia A or B, 1–5 years after a pregnancy in which prenatal diagnosis (PND) was performed by fetal blood sampling. Fetal blood sampling by fetoscopy was significantly more often reported by the women to be more trying than expected than was ultrasound‐guided heart puncture. Of 29 women 13 were classified as having experienced the PND process (amniocentesis and fetal blood sampling) as distressing, having had mental or psychosomatic symptoms associated with it. All of the women who had abortion/miscarriage after PND reported a very high frequency of psychological sequelae during the 6 months that followed PND. Of 22 women who continued their pregnancy with a healthy fetus after PND 8 experienced the period until delivery as trying and felt that their emotional and somatic status influenced their daily life activities. This was particularly common among women who after fetoscopy received routine profylactic terbutalin treatment and had continuous sickleave until the 36th gestational week. 17/29 would consider going through PND in the future. Qualified psychological assistance must be offered both before and after PND.

Muco-epidermoid tumour of the bronchus

A 7-year-old boy with recurrent pneumonia of the right lower lobe is described. At bronchoscopy a small tumour almost totally obliterating the right lower lobe was detected. Surgical treatment was undertaken. Histopathologic studies showed findings consistent with those of a muco-epidermoid tumour. The case emphasizes bronchoscopy as an important investigation in children with recurrent pneumonia. It also shows the importance of performing the bronchoscopy during a prolonged course of antibiotic prophylaxis in order to ensure a minimum of infected mucus within the bronchi. This report is completed with a short review of the literature on muco-epidermoid tumours of the bronchus in children. Their favourable prognosis and very low malignant potential is underlined.

CARRIER TESTING AND PRENATAL DIAGNOSIS OF HAEMOPHILIA : UTILISATION AND PSYCHOLOGICAL CONSEQUENCES

Summary. Attitudes towards prenatal diagnosis, and abortion vary widely between different countries, religions, cultures and over time. Carrier testing and prenatal diagnosis (PD) of haemophilia have become an integrated part of the comprehensive care for haemophilia in Sweden as well as in many other countries. Almost all carriers are interested in carrier testing if they are aware of the possibility. With the development of PD by chorionic villus sampling in the first trimester, the method became acceptable for many carriers, and it has in Sweden actually had an effect on the incidence of haemophilia in the 1990s. The use of PD is more common among women who perceive haemophilia as a very serious disease and who have a positive attitude towards legal abortion. The main reason for carriers not to use PD was that they do not find haemophilia to be a sufficiently serious disorder to justify an abortion. Women and their spouses are under a great deal of psychological pressure in association with the PD procedure, and the psychological consequences of having to terminate a pregnancy are long‐lasting. At follow‐up, about 6 years after PD and abortion, these women, however, do not have more signs of psychological distress than women without PD experience. Nevertheless, they must be offered qualified assistance both before and after PD as well as adequate follow‐up after an abortion to help them cope with the emotional strain they are under.