Abstract Since 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. 1. Screening for HeFH should be performed only in children older than 2 years when HeFH has been identified or is suspected (based on a genetic test or clinical criteria) in one parent. 2. The diagnostic procedure includes, as a first step, the establishment of a clear diagnosis of HeFH in one of the parents. If this precondition is satisfied, a low-density-lipoprotein cholesterol (LDL-C) level above 3.5 mmol/L (135 mg/dL) in the suspected child is predictive for differentiating affected from non-affected children. 3. A low saturated fat and low cholesterol diet should be started after 2 years, under the supervision of a dietician or nutritionist. 4. The pharmacological treatment, using statins as first line drugs, should usually be started after 10 years if LDL-C levels remain above 5 mmol/L (190 mg/dL), or above 4 mmol/L (160 mg/dL) in the presence of a causative mutation, a family history of early cardiovascular disease or severe risk factors. The objective is to reduce LDL-C by at least 30% between 10 and 14 years and, thereafter, to reach LDL-C levels of less than 3.4 mmol/L (130 mg/dL). Conclusion : The aim of this consensus statement is to achieve more consistent management in the identification and treatment of children with HeFH in Belgium.
Summary
In 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 ≥ 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 treatment of brain tumors in childhood is frequently complicated by growth retardation with a high proportion of irradiation (Irr)-induced GH deficiency (GHD) resulting in reduced adult final ...height (AFH) even after GH therapy (GHT). In order to optimize future GHT protocols, more information on the factors influencing the growth response to GH in these children is needed. This retrospective study evaluated AFH and influencing auxological and treatment factors of a standardized daily biosynthetic GHT in childhood survivors of brain tumors with documented GHD after brain Irr.
From the Belgian GH Registry, 57 children survivors of a brain tumor outside the hypothalamo-pituitary area with available AFH were stratified into two groups depending on cranial (C-Irr; n=25) or craniospinal (CS-Irr; n=32) Irr.
In the C-Irr patients, results showed an AFH of -0.8 (-2.5, 1.4) SDS (median (range)) and in the CS-Irr patients, results showed a significantly (P<0.001) lower AFH of -1.8 (-4.2, 0.0) SDS. AFH SDS corrected for mid-parental height (MPH) in the C-Irr group was -0.5 (-2.2, 0.9) and -1.5 (-3.6, 0.0) SDS in the CS-Irr group. AFH was positively correlated with age at end of tumor therapy, height SDS at start GHT, height gain SDS first year GHT, and negatively correlated with CS-Irr.
GHT failed to restore adult height to MPH in nearly half of Irr-induced GHD patients for brain tumor, especially those receiving CS-Irr, irradiated at a younger age or shorter at start GHT.
Familial hypocalciuric hypercalcaemia (FHH) is clinically characterized by mild to moderate parathyroid hormone (PTH)-dependent hypercalcaemia, autosomal dominant pattern of inheritance, and normal ...to frankly reduced urinary calcium excretion in spite of a high serum calcium (clearance (Ca)/clearance (Cr)<0.01). FHH has a benign course and should be differentiated from primary hyperparathyroidism. It is usually caused by a heterozygous loss-of-function mutation in the calcium-sensing receptor gene (CASR).
We report the case of a 16-year-old patient with hypercalcaemia and a mixed family history of parathyroid adenoma and mild hypercalcaemia. Serum calcium was 14 mg/dl with a serum iPTH of 253 pg/ml.
A neck 99mTc-sesta MIBI tomoscintigraphy showed a definite hyperactivity in the left upper quadrant. A surgical four-gland exploration confirmed a single parathyroid adenoma. After surgical resection of a left superior parathyroid adenoma, the patient's hypercalcemia improved but did not normalize, returning to a level typical of FHH. An inactivating mutation in exon 4 of the CASR gene, predicting a p.Glu297Lys amino acid substitution was found.
Thus, this 16-year old patient presented with the association of FHH and a single parathyroid adenoma. The young age of the patient and the association of parathyroid adenoma and FHH in his grandmother argue for a causal link between CASR mutation and parathyroid adenoma in this family. This case contributes to illustrate the expanding clinical spectrum of CASR loss-of-function mutations.
Children born small for gestational age (SGA) are not only at risk for short stature, but also for neurodevelopmental and behavioral problems. In this study, we analyzed the effects of high-dose GH ...therapy on cognitive development and psychosocial functioning in 34 prepubertal (3-8 years) short SGA children, equally randomized into a GH-treated group (TRG) and an untreated group (UTRG).
At start and after 2 years, children underwent standardized tests measuring the intellectual abilities (Wechsler Preschool and Primary Scale of Intelligence-Revised, or Wechsler Intelligence Scale for Children-Revised); their parents completed a standardized questionnaire evaluating psychosocial functioning (Child Behavior Checklist; CBCL).
At start, total IQ scores were significantly (P < 0.05) lower in the SGA group than in the general population: 32% of the SGA patients had scores below 85. After 2 years, IQ scores remained unchanged in the TRG, but increased significantly (P < 0.05) in the UTRG. After exclusion of children with developmental problems, however, no significant changes in IQ scores occurred in the UTRG as well as the TRG. At baseline, 24% (8/34) children had problematic CBCL total problems scores, equally distributed among the two groups; no significant changes in the different subscale scores occurred after 2 years.
No beneficial effect of 2 years of GH therapy on cognitive and behavioral profile could be observed in a cohort of rather young short SGA children presenting a variable degree of developmental delay and behavioral problems. Subsequent follow-up could reveal potential long-term effects of GH therapy on development and behavior.
Achieving good metabolic control in people with type 1 diabetes (T1D) remains a challenge, despite the evolutions in diabetes technologies over the past decade. Here we investigate the evolution of ...metabolic control in people with T1D, where care is provided by specialized centers with access to technology, diabetes education, and regular follow-up.
Data were cross-sectionally collected between 2010 and 2018 from more than 100 centers in Belgium. The evolutions over time of hemoglobin A1C (HbA1c), low-density lipoprotein (LDL) cholesterol, and systolic blood pressure (SBP) were investigated, together with the evolutions of use of insulin pump (continuous subcutaneous insulin infusion CSII), continuous glucose monitoring (CGM), and lipid-lowering and antihypertensive drugs. Association of HbA1c with gender, age, diabetes duration, and technology use was analyzed on the most recent cohort.
The study population contained data from 89,834 people with T1D (age 1-80 years). Mean HbA1c decreased from 65 mmol/mol (8.1%) in 2010-2011 to 61 mmol/mol (7.7%) in 2017-2018 (
< 0.0001, adjusted for gender, age, diabetes duration, and technology use). Respectively, mean LDL cholesterol decreased from 2.45 mmol/L (94.6 mg/dL) to 2.29 mmol/L (88.5 mg/dL) (
< 0.0001, adjusted for gender, age, and diabetes duration), and mean SBP remained stable. CGM usage increased, whereas the use of CSII and lipid-lowering and antihypertensive drugs remained stable. Gender, age, diabetes duration, and technology use were independently associated with HbA1c.
Our real-world data show that metabolic and lipid control improved over time in a system where T1D care is organized through specialized multidisciplinary centers with emphasis on linking education to provision of technology, and its quality is monitored.
The mechanisms underlying the maintenance of normal to high rates of linear growth and plasma insulin-like growth factor I (IGF-I) levels in spite of a low growth hormone secretion in obese children ...remain unknown. Among the animal models of early-onset obesity, obese Zucker (FA/FA) rats (which are homozygous for an inactivating missense mutation in the leptin receptor) are particularly appropriate, because their linear growth shows this growth hormone independence.
To study the regulation of IGF-I synthesis in this model, we have established primary cultures of hepatocytes derived from 12-week-old Zucker male obese and lean rats. The rat IGF-I gene contains six exons, and alternative splicing generates different mRNAs, one of which (called IGF-1B) has been shown to be decreased by fasting. We report steady state mRNA levels for IGF-I (all transcripts) and for IGF-IB in hepatocytes after 3 days in culture, in freshly isolated hepatocytes, and in whole-liver tissue. RT-PCRs using primers specific for IGF-I or IGF-IB were performed with two different internal competitors for quantification.
In primary cultures of hepatocytes, the IGF-IB mRNA was increased by >50-fold (p = 0.01) in cells derived from obese animals as compared with cells from lean animals. However, these transcript levels were not significantly different when measured in freshly isolated hepatocytes or in whole-liver tissue.
Increased IGF-IB transcription could be an intrinsic characteristic of cultured hepatocytes harbouring leptin receptors that bear the FA mutation. However, the modulation of this characteristic by cell-cell interactions and by in vivo hormone and metabolic status remains to be studied.
Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes with onset in patients aged less than 25 years. It is a heterogeneous disorder due to heterozygous monogenic mutations with ...an autosomal dominant transmission. It could represent 2 to 5% of diabetes but is often under-diagnosed. We report three different cases of MODY, two without associated abnormalities and one with renal disorder. Mutations concern genes that are directly involved in the beta-cell function. In patients with non-syndromic diabetes, more than 99% of MODY result from mutations in hepatocyte nuclear factor-1-alpha (HNF-1-alpha ; formerly MODY 3), glucokinase (MODY 2), or HNF-4-alpha (MODY 1). The symptoms manifest slowly with the absence of obesity and ketosis in most cases. MODY is usually treated by diet, oral diabetes medications or insulin. Treatment and prognosis vary depending on the genetic mutation. Clinicians should keep in mind the possibility of MODY, especially in antibody-negative youth with familial diabetes. Making a diagnosis of MODY may have important implications for the guidance of appropriate treatment, prognosis and genetic counselling.
PDF
