In the largest cohort to date, we demonstrate a wide spectrum of phenotypes and biological profiles in patients with 5α-reductase deficiency, whatever their geographical or ethnic origins.

Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders.

a b s t r a c tSince heterozygous familial hypercholesterolemia (HeFH) is a disease that exposes the individual from birth onwards to severe hypercholesterolemia with the development of early cardiovascular disease, a clear consensus on the management of this disease in young patients is necessary. In Belgium, a panel of paediatricians, specialists in (adult) lipid management, general practitioners and representatives of the FH patient organization agreed on the following common recommendations.

SummaryIn first-degree relatives of type 1 diabetic patients, we investigated whether diabetes risk assessment solely based on insulinoma antigen 2 (IA-2) and zinc transporter 8 (ZnT8) antibody status (IA-2A, respectively, ZnT8A) is as effective as screening for three or four autoantibodies [antibodies against insulin (IAA), glutamate decarboxylase 65 kDa (GAD) glutamate decarboxylase autoantibodies (GADA) and IA-2A with or without ZnT8A] in identifying children, adolescents and adults who progress rapidly to diabetes (within 5 years). Antibodies were determined by radiobinding assays during follow-up of 6444 siblings and offspring aged 0-39 years at inclusion and recruited consecutively by the Belgian Diabetes Registry. We identified 394 persistently IAA + , GADA + , IA-2A + and/or ZnT8A + relatives (6·1%). After a median follow-up time of 52 months, 132 relatives developed type 1 diabetes. In each age category tested (0-9, 10-19 and 20-39 years) progression to diabetes was significantly quicker in the presence of IA-2A and/or ZnT8A than in their joint absence (P < 0·001). Progression rate was age-independent in IA-2A + and/or ZnT8A + relatives but decreased with age if only GADA and/or IAA were present (P = 0·008). In the age group mainly considered for immune interventions until now (10-39 years), screening for IA-2A and ZnT8A alone identified 78% of the rapid progressors (versus 75% if positive for Ն 2 antibodies among IAA, GADA, IA-2A and ZnT8A or versus 62% without testing for ZnT8A). Screening for IA-2A and ZnT8A alone allows identification of the majority of rapidly progressing prediabetic siblings and offspring regardless of age and is more cost-effective to select participants for intervention trials than conventional screening.

The aim of this study is to describe the growth, pubertal development, and gonadal function of a cohort of 30 sickle cell disease children who underwent bone marrow transplantation. They all received the standard pretransplant conditioning regimen of busulfan (14 or 16 mg/kg) and cyclophosphamide (200 mg/kg). Growth was normal both before and after transplant. Seven out of 10 girls had severe ovarian failure and requirement for estrogen replacement. Three out of 10 girls recovered some ovarian function posttransplant, with spontaneous pubertal development, menses, and 1 successful normal pregnancy. Follicle-stimulating hormone (FSH) serum levels were very high during spontaneous puberty and slowly normalized thereafter in these 3 patients. The 3 girls with ovarian function recovery differed from the 7 others by the lower busulphan dose of the conditioning regimen they received (14 rather than 16 mg/kg). All boys showed spontaneous pubertal development. However, most of them had small testis and elevated serum FSH levels, reflecting germinal epithelium damage. Testosterone level was low normal and luteinizing hormone elevated, reflecting Leydig cell insufficiency. In conclusion, 7/10 girls had complete gonadal failure and most of the boys had spontaneous puberty but germinal epithelial failure. Serum FSH levels showed important variations over time in the same patient.