Toni Torresani

European best practice guidelines for cystic fibrosis neonatal screening

There is wide agreement on the benefits of NBS for CF in terms of lowered disease severity, decreased burden of care, and reduced costs. Risks are mainly associated with disclosure of carrier status and diagnostic uncertainty. When starting a NBS programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. However, given the wide geographic, ethnic, and economic variations, complete harmonisation of protocols is not appropriate. There is little evidence to support the use of IRT alone as a second tier, without involving DNA mutation analysis. However, if IRT/DNA testing does not lead to the desired specificity/sensitivity ratio in a population, a screening programme based on IRT/IRT may be used. Sweat chloride concentration remains the gold standard for discriminating between NBS false and true positives, but age-related changes in sweat chloride should be taken into account. CF phenotypes associated with less severe disease often have intermediate or normal sweat chloride concentrations. Programmes should include arrangements for counselling and management of infants where the diagnosis is not clear-cut. All newborns identified by NBS should be managed according to internationally accepted guidelines. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes. Clear explanation to families of the process of screening and of implications of normal and abnormal results is central to the success of CF NBS programmes. Effective communication is especially important when parents are told that their child is affected or is a carrier. When establishing a NBS programme for CF, attention should be given to ensuring timely and appropriate processing of results, to minimise potential stress for families.

European Society for Paediatric Endocrinology Consensus Guidelines on Screening, Diagnosis, and Management of Congenital Hypothyroidism

Objective: The aim was to formulate practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). Evidence: A systematic literature search was conducted to identify key articles relating to the screening, diagnosis, and management of CH. The evidence-based guidelines were developed with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Consensus Process: Thirty-two participants drawn from the European Society for Paediatric Endocrinology and five other major scientific societies in the field of pediatric endocrinology were allocated to working groups with assigned topics and specific questions. Each group searched the literature, evaluated the evidence, and developed a draft document. These papers were debated and finalized by each group before presentation to the full assembly for further discussion and agreement. Recommendations: The recommendations include: worldwide neonatal screening, approaches to assess the cause (including genotyping) and the severity of the disorder, the immediate initiation of appropriate L-T4 supplementation and frequent monitoring to ensure dose adjustments to keep thyroid hormone levels in the target ranges, a trial of treatment in patients suspected of transient CH, regular assessments of developmental and neurosensory functions, consulting health professionals as appropriate, and education about CH. The harmonization of diagnosis, management, and routine health surveillance would not only optimize patient outcomes, but should also facilitate epidemiological studies of the disorder. Individuals with CH require monitoring throughout their lives, particularly during early childhood and pregnancy.

Increasing the iodine concentration in the Swiss iodized salt program markedly improved iodine status in pregnant women and children: a 5-y prospective national study

BACKGROUND Many industrialized countries struggle to maintain adequate iodine intake because of changes in dietary habits and the food supply. In Switzerland, because of declining iodine intakes in children and pregnant women, the iodine concentration in table salt was increased from 15 to 20 mg/kg. OBJECTIVE We evaluated Swiss iodine nutrition after the 1999 increase in the salt iodine concentration. DESIGN In 1999 and 2004, a 3-stage probability proportionate-to-size cluster sampling was done to obtain a representative national sample of primary schoolchildren and pregnant women. Urine and household salt were collected for iodine measurement. The frequency of elevated thyrotropin concentrations found in the newborn screening program was evaluated before and after the increase. RESULTS In 1999, median urinary iodine (UI) concentrations among children (n = 610) and pregnant women (n = 511) were 115 microg/L (range: 5-413 microg/L) and 138 microg/L (range: 5-1881 microg/L), respectively, which indicated marginal iodine status. In 2004, median UI concentrations among children (n = 386) and pregnant women (n = 279) were 141 microg/L (range: 0-516 microg/L) and 249 microg/L (range: 8-995 microg/L), respectively (P < 0.01). Newborn thyrotropin concentrations >5 mU/L decreased from 2.9% in 1992-1998 (n = 259 035) to 1.7% in 1999-2004 (n = 218 665) (P < 0.0001). CONCLUSIONS A 25% increase in iodine concentration in iodized table salt markedly improved iodine status in Switzerland, which showed the value of monitoring and adjusting iodine concentrations in national salt programs. The frequency of newborn thyrotropin concentrations >5 mU/L appears to be a sensitive indicator of iodine nutrition during pregnancy.

Clinical Practice Guideline: European Society for Paediatric Endocrinology Consensus Guidelines on Screening, Diagnosis, and Management of Congenital Hypothyroidism

Objective: The aim was to formulate practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). Evidence: A systematic literature search was conducted to identify key articles relating to the screening, diagnosis, and management of CH. The evidence-based guidelines were developed with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Consensus Process: Thirty-two participants drawn from the European Society for Paediatric Endocrinology and five other major scientific societies in the field of pediatric endocrinology were allocated to working groups with assigned topics and specific questions. Each group searched the literature, evaluated the evidence, and developed a draft document. These papers were debated and finalized by each group before presentation to the full assembly for further discussion and agreement. Recommendations: The recommendations include: worldwide neonatal screening, approaches to assess the cause (including genotyping) and the severity of the disorder, the immediate initiation of appropriate L-T4 supplementation and frequent monitoring to ensure dose adjustments to keep thyroid hormone levels in the target ranges, a trial of treatment in patients suspected of transient CH, regular assessments of developmental and neurosensory functions, consulting health professionals as appropriate, and education about CH. The harmonization of diagnosis, management, and routine health surveillance would not only optimize patient outcomes, but should also facilitate epidemiological studies of the disorder. Individuals with CH require monitoring throughout their lives, particularly during early childhood and pregnancy.

Treatment with human growth hormone in patients with Prader-Labhart-Willi syndrome reduces body fat and increases muscle mass and physical performance.

Twelve children with documented Prader-Labhart-Willi syndrome were treated with human growth hormone (24 U/m2/week) during 1 year. The children were divided into three groups: group 1: overweight and prepubertal (n = 6, age 3.8–7.0 years); group 2: underweight and prepubertal (n = 3, age 0.6–4.1 years); group 3: pubertal (n = 3, age 9.2–14.6 years). In group 1, height increased from -1.7 SD to -0.6 SD, while weight decreased from 1.1 SD to 0.4 SD, with a dramatic drop in weight for height from 3.8 SD to 1.2 SD. Hand length increased from -1.5 SD to -0.4 SD and foot length from -2.5 SD to -1.4 SD. Body fat, measured by dual X-ray energy absorptiometry, dropped by a third, whereas muscle mass increased by a fourth. Physical capability (Wingate test) improved considerably. The children were reported to be much more active and capable. In group 2, similar changes were seen, but weight for height increased, probably because muscle mass increase exceeded fat mass decrease. Changes in group 3 were similar as in group 1, even though far less distinct.ConclusionGrowth hormone treatment in Prader-Labhart-Willi syndrome led to dramatic changes: distinct increase in growth velocity, height and muscle mass, as well as an improvement in physical performance. Fat mass and weight for height decreased in the initially overweight children, and weight for height increased in underweight children.

Low insulin, IGF-I and IGFBP-3 levels in children with Prader-Labhart-Willi syndrome

Abstract It is well established that insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and insulin are low in growth hormone deficiency, but due to their dependence on nutrition, they are elevated in healthy obese children. As the presence of growth hormone deficiency in Prader-Labhart-Willi syndrome (PWS) is still controversial, we studied insulin, IGF-I and IGFBP-3 levels in 19 children with PWS (age range 0.5–14.6 years). Serum concentrations of insulin (SDS: −0.7±0.9, P=0.01) and IGF-I (SDS: −0.7±0.8,P=0.002) were low, but IGFBP-3 (SDS: −0.3±1.2, P=0.2) was normal compared to normal weight age-matched children. Since children with PWS are typically obese, insulin, IGF-I and IGFBP-3 levels should be compared to normal obese children who present increased levels of these hormones. In comparison to data of healthy obese children reported in the literature, not only IGF-I, but also IGFBP-3 levels are low and fasting insulin levels even very low, suggesting a growth hormone deficiency.

Epidemiology of Type I diabetes mellitus in Switzerland: steep rise in incidence in under 5 year old children in the past decade

Aims/hypothesis. In this nationwide prospective study we wanted to verify the trend of increasing diabetes incidence data from our earlier retrospective analysis of the military registry of Swiss men. Subjects and methods. The data collection of newly diagnosed children in Switzerland at an age younger than 15 years started in 1991. The countrywide survey used a small questionnaire which was sent back to the study centre. The questionnaire was anonymous and contained: hospital of diagnosis, initials, sex, birth date, date of diagnosis, residence, country of citizenship, and responsible physician. General data on the population were taken from publications of the Swiss Federal Statistical Office. Results. A total of 941 children below the age of 15 years with newly diagnosed Type I (insulin-dependent) diabetes mellitus were collected (434 girls, 507 boys). The incidence in children aged 0 to 14 years rose significantly between 1991 and 1999 with a yearly average increase of 5.1 %. In the age group 0 to 4 years a more than four-fold increase in incidence from 2.4/100 000 per year to 10.5/100 000 per year (p = 0.0002) was recorded, whereas the age-specific incidence in the 5 to 9-year-old and 10 to 14-year-old children did not change during the data collection period. The incidence was significantly higher in boys than in girls, whereas no difference was found between rural and urban populations. Conclusion/interpretation. The incidence of Type I diabetes is rising in children living in Switzerland but only the youngest age group of under 5 years of age is affected showing a large annual average increase of 23.8 %. [Diabetologia (2001) 44: 286–289]

Children With Congenital Hypothyroidism: Long-Term Intellectual Outcome After Early High-Dose Treatment

We aim to determine long-term intellectual outcome of adolescents with early high-dose treated congenital hypothyroidism (CH). Sixty-three prospectively followed children with CH were assessed at age of 14 y with the Wechsler Intelligence Scale for Children-Revised and compared with 175 healthy controls. Median age at onset of treatment was 9 d (range 5–18 d) and median starting dose of levothyroxine (L-T4) was 14.7 μg/kg/d (range 9.9–23.6 μg/kg/d). Full-scale intelligence quotient (IQ) was significantly lower than in controls after adjustment for socioeconomic status (SES) and gender (101.7 versus 111.4; p < 0.0001). Children with athyreosis had a lower performance IQ than those with dysgenesis (adjusted difference 7.6 IQ scores, p < 0.05). Lower initial thyroxine (T4) levels correlated with poorer IQ (r = 0.27, p = 0.04). Lower SES was associated with poorer IQ, in particular in children with CH (interaction, p = 0.03). Treatment during childhood was not related to IQ at age 14 y. Adolescents with CH manifest IQ deficits when compared with their peers despite early high-dose treatment and optimal substitution therapy throughout childhood. Those adolescents with athyreosis and lower SES are at particular risk for adverse outcome. Therefore, early detection of intellectual deficits is mandatory in children with CH.

Interest of growth hormone-releasing hormone administration for improvement of ovarian responsiveness to gonadotropins in poor responder women *

OBJECTIVE We have investigated the beneficial effect of a somatotroph axis stimulation on ovarian response to gonadotropin. DESIGN Growth hormone-releasing hormone (GH-RH) was administered in a prospective study in women undergoing an in vitro fertilization protocol. PATIENTS Twelve patients were selected for their poor ovarian response to previous stimulations using gonadotropin-releasing hormone analog (GnRH-a) and human menopausal gonadotropins (hMG). INTERVENTIONS Five hundred micrograms of GH-RH1-29 were administered two times daily concomitantly with GnRH-a and hMG from day 2 of the cycle to the time of ovulation. MAIN OUTCOME MEASURES Stimulation of somatotroph axis was appreciated by measuring over-night urinary growth hormone (GH) output, plasma GH, and insulin-like growth factor I (IGF-I) and follicular fluid (FF) IGF-I. The effects of GH-RH administration on ovarian function were determined by plasma estradiol levels and follicular data. RESULTS Administration of GH-RH was associated with a significant improvement of urinary (P less than 0.025) and plasma (P less than 0.001) GH concentrations and of the hormonal response to hMG (P less than 0.01). Levels of IGF-I followed a biphasic plasma variation, and a slight increase in recruited follicles, retrieved oocytes, and FF IGF-I content was also observed. CONCLUSIONS Activation of the somatotroph axis by GH-RH enhances the hormonal ovarian response to hMG and may be an adjunctive therapy to improve follicular maturation.

Monitoring the adequacy of salt iodization in Switzerland: a national study of school children and pregnant women

Background: Several countries with long-standing salt iodization programs, including Switzerland, have recently reported declining and/or low urinary iodine (UI) levels in their populations. In Switzerland, in response to studies indicating low UI levels in children and pregnant women, the salt iodine level was increased in 1998 from 15 to 20 mg/kg.Objective: Our objective was to evaluate iodine nutrition in a national sample of Swiss school children and pregnant women 8–16 months after the increase in the salt iodine level.Design: A 3-stage probability proportionate to size cluster sampling method was used to obtain a representative national sample of 600 children aged 6–12 y and 600 pregnant women. We then measured UI in both groups, thyrotropin (TSH) in pregnant women and thyroid volume by ultrasound to determine goiter prevalence in school children.Results: The median UI (range) of the children and pregnant women was 115 μg/l (5–413) and 138 μg/l (5–1881), respectively. The median blood TSH concentration (range) of pregnant women was 0.6 mU/l (0.2–2.1). Based on the current WHO/ICCIDD normative data for thyroid volume, none of the children were goitrous, using either age/sex-specific or BSA/sex-specific cutoffs.Conclusions: The iodine status of the Swiss population is once again adequate, illustrating the value of periodic monitoring and prudent adjustments to the iodine level in salt. This approach could serve as a model for countries struggling to maintain dietary iodine intake in the face of shifting dietary habits and changes in the food supply.Sponsorship: Swiss Foundation for Nutrition Research, Zürich, Switzerland; Foundation for Micronutrients in Medicine, Rapperswil, Switzerland; and Swiss Federal Institute of Technology in Zürich, Switzerland.European Journal of Clinical Nutrition (2001) 55, 162–166