Delphi consensus on the diagnosis and treatment of patients with short stature in Spain: GROW-SENS study.

PURPOSE: To identify consensus aspects related to the diagnosis, monitoring, and treatment of short stature in children to promote excellence in clinical practice. METHODS: Delphi consensus organised in three rounds completed by 36 paediatric endocrinologists. The questionnaire consisted of 26 topics grouped into: (1) diagnosis; (2) monitoring of the small-for-gestational-age (SGA) patient; (3) growth hormone treatment; and (4) treatment adherence. For each topic, different questions or statements were proposed. RESULTS: After three rounds, consensus was reached on 16 of the 26 topics. The main agreements were: (1) diagnosis tests considered as a priority in Primary Care were complete blood count, biochemistry, thyroid profile, and coeliac disease screening. The genetic test with the greatest diagnostic value was karyotyping. The main criterion for initiating a diagnostic study was prediction of adult stature 2 standard deviations below the target height; (2) the main criterion for initiating treatment in SGA patients was the previous growth pattern and mean parental stature; (3) the main criterion for response to treatment was a significant increase in growth velocity and the most important parameter to monitor adverse events was carbohydrate metabolism; (4) the main attitude towards non-responding patients is to check their treatment adherence with recording devices. The most important criterion for choosing the delivery device was its technical characteristics. CONCLUSIONS: This study shows the different degrees of consensus among paediatric endocrinologists in Spain concerning the diagnosis and treatment of short stature, which enables the identification of research areas to optimise the management of such patients.

Cost-effectiveness of somatrogon in the Spanish pediatric population with growth hormone deficiency.

OBJECTIVE: To analyze the cost-effectiveness of weekly somatrogon compared to daily growth hormones (GH-d) in the pediatric population of Spain with growth hormone deficiency (GHD). METHODS: Markov model with two states (patients with or without GH-d or somatrogon treatment) in prepubertal children (3 to 11 years and 3 to 12 years in girls and boys, respectively) with GHD in isolation or as part of multiple pituitary hormone deficiency and without previous treatment, from the perspective of the National Health System. The simulation of the economic model ends at the age of 18. The costs of hormones and monitoring were obtained from Spanish sources. The utilities were obtained from the literature. Spanish clinical experts validated the assumptions of the model. RESULTS: In the deterministic analysis, somatrogon would be cost-effective, compared to GH-d, with a cost per QALY (quality-adjusted life year) gained of €19,259 and a clinically relevant QALY gain (0.336). This result was confirmed in deterministic sensitivity analyses. According to the probabilistic analysis, somatrogon would be the dominant treatment, with a 61% probability of a willingness to pay of €25,000 per QALY gained. CONCLUSION: Compared to GH-d, somatrogon is cost-effective in the Spanish pediatric population with GHD.

[Study of bone mass in Turner syndrome]. / Estudio de la masa ósea en el síndrome de Turner.

OBJECTIVES: To evaluate bone mass in patients with Turner syndrome by measuring metacarpal cortical thickness and bone diameter before and after treatment with oxandrolone, growth hormone (GH) and estrogens. PATIENTS AND METHODS: We studied 42 girls with Turner syndrome divided into the following groups: group I: 31 patients aged between 3 and 15 years who were not treated before the study; group II: 15 patients treated with GH at start ages of between 5.2-14.8 years; group III: 17 patients treated with oxandrolone at start ages of between 5.3 and 15.2 years; group IV: 17 patients treated with estrogens and divided in different subgroups: IVa: seven patients treated with GH and estrogens at start ages of between 6.1 and 12.9 years; IVb: five patients treated with oxandrolone and estrogens at start ages of between 13.4 and 17.4 years, and IVc: five patients treated with oxandrolone, GH and estrogens at start ages of between 10.3 and 16.1 years. Bone mass was evaluated by a radiogrammetric method that measures the cortical thickness and bone diameter of three metacarpal bones with a magnifying glass. The results are expressed in SD according to Spanish longitudinal reference standards (Andrea Prader Center of Growth and Development) from 0.5 to 9 years of age and to Swiss standards from the age of 10 years onwards. Statistical significance was set at p < 0.05. RESULTS: Group I (spontaneous development): cortical development was below the mean and was significantly diminished at the ages of 9, 13 and 14 years; bone diameter was decreased in relation to controls throughout the study period; group II (impact of GH treatment): cortical thickness showed a nonsignificant increase of 0.6 SD from baseline to years 3-4 of treatment and diameter increased by 0.5 SD from baseline to year 4 of treatment; group III (impact of oxandrolone): cortical thickness increased from -0.8 SD before treatment to 0.0 SD at years 2 and 3 of treatment; bone diameter increased from -1.5 SD at baseline to -1 SD at 3 years of treatment; group IV (impact of treatment with estrogens); IVa: cortical thickness and bone diameter increased; IVb: cortical thickness increased but bone diameter was unchanged; IVc: both cortical thickness and bone diameter increased. CONCLUSIONS: The results of this study show that cortical thickness and bone diameter are decreased in untreated girls with Turner syndrome; cortical thickness was significantly decreased at the ages of 9, 13 and 14 years, while bone diameter was diminished at all ages, suggesting the presence of osteopenia in these patients. GH treatment produced a nonsignificant increase in cortical thickness and bone diameter. Oxandrolone treatment showed a positive effect on bone mass during the first few years of therapy. Because of the small number of patients, conclusions cannot be reached on the effectiveness of estrogens.

[Study of bone mass in patients with growth hormone deficiency]. / Estudio de la masa ósea en el déficit de hormona de crecimiento.

OBJECTIVES: To evaluate bone mineral density by radiogrametric study of metacarpal bone diameter and cortical thickness in patients with growth hormone deficiency (GHD) before and during treatment with growth hormone (GH). PATIENTS AND METHODS: We studied 92 children with GHD (60 boys and 32 girls) divided into two groups: group I: 66 previously untreated patients (42 boys and 24 girls) aged between 3 and 14 years old; group II: 66 patients (42 girls and 24 boys) treated with GH and with a mean age of 10.2 +/- 3.1 years at treatment onset. Bone mass was studied indirectly by radiogrametry; the bone diameter and cortical thickness of the 2nd-3rd and 4th metacarpal bones were measured with a magnifying glass. As reference standards we used the Spanish longitudinal growth and development study (Andrea Prader Center, Zaragoza) in children aged between 0.5 and 9 years and the Swiss longitudinal standards in children aged 10 years of age and older. Statistical significance was set at p < 0.05. RESULTS: Group I (spontaneous evolution): cortical thickness values were below the mean with statistically significant differences al 11, 12 and 13 years of age in girls and at 12, 13 and 14 years in boys. Bone diameter was diminished compared with controls in all the study periods and was significantly reduced at 8, 9, 10 and 11 years of age in girls and at 8, 10, 11, 12, 13 and 14 years in boys. Group II: (effect of GH treatment): cortical regression analysis showed a sharp increase in the first year of treatment with a subsequent moderate increase, which was statistically significant. Bone diameter showed a similar pattern with a significant increase which was more pronounced in the first period. CONCLUSIONS: Children with GHD have decreased bone mass before initiation of treatment and therefore show deficient acquisition of peak bone mass, which in normal conditions occurs during in the first 4-5 years of life and during adolescence. GH replacement therapy leads to recovery of bone mass, which is more pronounced in the first year of treatment and prevents the progressive reduction that appears in untreated patients. Therefore, GH treatment plays an important role in peak bone mass acquisition in children with GHD.

[Type 1 polyglandular autoimmune syndrome associated with C322fsx372 mutation]. / Síndrome poliglandular autoinmune tipo 1 y mutación C322fsX372.

Polyglandular autoimmune syndromes are rare diseases based on autoimmune mechanisms in which endocrine and non-endocrine disorders coexist. In type 1 the characteristic manifestations are chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. A case is presented of a patient with typical clinical sequence, along with other changes, and in whom a mutation in homozygosis, C322fsX372, was detected after performing a molecular analysis of autoimmunity regulator gene (AIRE). Inheritance is autosomal recessive, associated with mutations in the AIRE gene, which encodes a protein involved in autoimmunity and immunodeficiency. For diagnosis, At least two of the three major clinical manifestations are required for a diagnosis. However, only one of them is necessary in the study of relatives of affected patients. These syndromes must be diagnosed early, given their high morbidity and mortality. Every manifestation needs to be treated, in order to maintain the quality of life.

[Autosomal dominant osteopetrosis: a presentation of 3 cases and a new gene mutation]. / Osteopetrosis autosómica dominante: a propósito de 3 casos y una mutación.

Osteopetrosis (OP) is a congenital bone disease which is caused by a functional disorder in osteoclasts with inability for normal bone resorption, leading to increased bone mineral density and bone sclerosis. It can be classified into different groups according to their clinical and their genetic characteristics: autosomal recessive with several subtypes (OPTB) or autosomal dominant type 1 or 2 (OPTA1-2). There is a wide clinical variability of the disease, from asymptomatic to lethal in the first months of life, with variable expressivity in the family members. Diagnosis is mainly clinical with genetic confirmation of the OP, and treatment is symptomatic. Three cases of OP are presented, with the discovery of a new gene mutation in LRP5 which caused OPTA1 in one of them.

[Congenital adrenal hyperplasia due to lack of 17α-hydroxylase: a report of a new mutation in the gene CYP17A1]. / Hiperplasia suprarrenal congénita debida a deficiencia de 17α-hidroxilasa: a propósito de una nueva mutación en el gen CYP17A1.

P450c17 enzyme catalyses two different reactions: the 17α-hydroxylation of progesterone and pregnenolone, and segmenting the carbon 17-20 binding from the 17,20lyase producing adrenal androgens. This enzyme is coded by the CYP17A1 gene. The case is presented of a 14 year old patient with delayed pubertal development and a high blood pressure for height and age. 46,XX karyotype. Hormonal studies highlighted hypergonadotropic hypogonadism, adrenal insufficiency and mineralocorticoid excess. Subsequent genetic studies showed a homozygous mutation in the CYP17A1 gene (c.753+G>A), not previously described, which is responsible for the pathophysiology of 17α-hydroxylase deficiency. This entity is a rare form of congenital adrenal hyperplasia. The disease often goes unnoticed until adolescence or early adult life, and should be suspected in 46,XY individuals with ambiguous genitalia or 46,XX with delayed puberty associated with hypertension and/or hypokalaemia.

[Cleft palate and cleft lip. Clinical review]. / Fisura palatina y labio leporino. Revisión clínica.

UNLABELLED: The aim of this study is to do an analytical study of cleft palate and cleft lip in our hospital. PATIENTS AND METHODS: 85 clinical charts of patients attended in our hospital born between 1976 and 2001 in Aragon and Rioja were reviewed. We studied the incidence of oral cleft, associated malformations and morbidity, familial antecedents and perinatal data, phonatory disfunctions, serose otitis, growth failure and psychiatry problems. RESULTS: The mean incidence was 0.5/1000 newborns. 41.5% presented associated malformations and 19.3% were associated with a specific syndrome, being more frequent in patients affected of cleft palate and cleft lip (50%) than patients with only cleft palate (41.2%) or only cleft lip (8.8%). The most frequent malformations were: facial defects (50%), skeletal (33%), congenital cardiopathies (33%). 19% were born prematurely. The percentage of serose otitis that required control at hospital was 37.3%. 34.2% presented phonatory problems. There was a high incidence of growth failure and psychiatry problems. CONCLUSION: Oral clefts represent a complex clinical condition with a high percentage of medical complications that require a multidisciplinary treatment. The high incidence of congenital defects associated with this condition demand an exhaustive screening in the newborns affected.

[Different expression of the Asn264LysfsX35 mutation of the GNAS gene in a family with pseudohypoparathyroidism.]. / Diferente expresividad de la mutacion Asn264LysfsX35 del gen GNAS en una familia afecta de pseudohipoparatiroidismo.

Pseudohypoparathyroidism (PHP) is a heterogeneous group of endocrine diseases characterised by hypocalcaemia, hyperphosphataemia and resistance to PTH. There are different forms of PHP. PHP-Ia is the most frequent form and shows multi-hormonal resistance, GNAS (Gs(α)) mutations and signs of Albright́s hereditary osteodystrophy (AHO). PseudoPHP (PPHP) have isolated AHO without hormonal resistance and it is also caused by GNAS mutations. We present a family that share the same inactivating GNAS mutation (Asn264LysfsX35); the mother being affected with PPHP and the two daughters with PHP-Ia. We discuss the different clinical phenotypes and the dominant mode of inheritance with genetic imprinting where the phenotype of the offspring depends on the sex of the parent affected.

[Dog bites in children. Epidemiologic and clinical study of 144 cases]. / Mordeduras de perro en la infancia. Estudio epidemiológico y clínico de 144 casos.

We have done a prospective study of 144 cases of dog bites in children between 1 and 13 years of age that were attended at the Emergency Department of the "Miguel Servet" Children's Hospital of Zaragoza over a period of 30 months. The average child is an 8 year old boy who is bitten at 4 p.m. in the lower limbs by a dog belonging to either the family, a neighbor, or to some friends. The dog of unknown breed and the German shepherd are those most frequently involved (39.5% and 22.2%, respectively). There is a low incidence of infection (4.8%). The attacks were provoked by petting in 52.7%; therefore, we recommend not to get close to the animals even if they are known. In our area, 83.3% of the children are correctly vaccinated. Finally, we compare our results with other studies and we suggest that it is of great interest to establish measures in order to reduce the incidence of dog bites.

[Reference values of FSH, LH, total testosterone, free testosterone, 17-beta-estradiol and SHBG in healthy children in Zaragoza]. / Valores de referencia de FSH, LH, testosterona total, testosterona libre, 17-beta-estradiol y SHBG en niños sanos zaragozanos.

OBJECTIVE: Our purpose was to estimate reference values for basal serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, free testosterone, 17-beta-estradiol (E2) and sex steroid binding globulin (SHBG) in healthy children of Zaragoza. PATIENTS AND METHODS: The reference population consisted of healthy children between 0 and 14 years of age with normal weight and height and living in the metropolitan area of Zaragoza (Spain). It was a transversal study. Basal serum concentrations of FSH, LH and SHBG were measured by immunoradiometric assay. Basal serum concentrations of total testosterone, free testosterone and E2 were analyzed by radioimmunoassay. Reference values and ranges were estimated according to the recommendations of the International Federation of Clinical Chemistry. RESULTS: Reference values have been classified by age, sex and pubertal stage. Serum concentrations of FSH, LH, total testosterone, free testosterone and E2 increase during the first six months, remain low in infancy and rise during puberty. All of these concentrations showed marked differences according to sex. Serum SHBG levels are influenced by age and during puberty by sex. CONCLUSIONS: Differences in reference values for gonadotrophins, sex steroids and SHBG during infancy, childhood and adolescence makes it necessary for every population to establish their own reference values according to age, sex and pubertal stage.

[Reference values for IGF-I, IGFBP-1, IGFBP-3 and osteocalcin in healthy children in Zaragoza]. / Valores de referencia de IGF-I, IGFBP-1, IGFBP-3 y osteocalcina en niños sanos zaragozanos.

OBJECTIVE: Our aim was to estimate reference values for basal serum concentrations of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-1, IGFBP-3 and osteocalcin in healthy children of Zaragoza. PATIENTS AND METHODS: The reference population consisted of healthy children between 0 and 14 years of age with normal weight and height and living in the metropolitan area of Zaragoza (Spain). It was a transversal study. Immunoradiometric assays were used to determine basal serum IGF-I, IGFBP-1, IGFBP-3 and osteocalcin concentrations. Reference values and ranges were estimated according to the recommendations of the International Federation of Clinical Chemistry. RESULTS: Reference values have been classified according to age, sex and pubertal stage. IGF-I, IGFBP-1, IGFBP-3 and osteocalcin concentrations differ during the pubertal period according to age. There are differences in IGF-I, IGFBP-3 and osteocalcin levels between prepuberty and puberty and differences in IGF-I and osteocalcin levels among the pubertal stages. Sex did not influence IGF-I or IGFBP-1 concentrations and there were punctual differences in IGFBP-3 and osteocalcin levels between girls and boys. CONCLUSIONS: Sincere there are differences in IGF-I, IGFBP-1, IGFBP-3 and osteocalcin reference values according to age, sex, pubertal stage and immunoassays, it is necessary to establish the reference values for each population and laboratory in accordance with these parameters.

[Reference values for thyroid hormones, thyrotropin and thyroglobulin in healthy children of Zaragoza]. / Valores de referencia de hormonas tiroideas, tirotropina y tiroglobulina en niños sanos zaragozanos.

OBJECTIVE: The purpose of this study was to estimate the basal serum concentration reference values for total T3 (T3), total T4 (T4), free T4 (FT4), thyrotropin (TSH) and thyroglobulin (Tg) in healthy children of Zaragoza. PATIENTS AND METHODS: Healthy children aged 0 to 14, with normal weight and height, living in the metropolitan area of Zaragoza (Spain) were the reference population of this transversal study. Basal serum concentrations of T3, T4 and FT4 were measured by radioimmunoassay and of TSH and Tg by immunoradiometric assay. Reference values and ranges were estimated according to the recommendations of the International Federation of Clinical Chemistry. RESULTS: Reference values have been classified according to age, sex and pubertal stage. There are differences in T3, T4, FT4 TSH and Tg concentrations during the prepubertal period according to age, but not to sex, and between the prepubertal period and puberty. Sex and Tanner stage influence T3 and T4 concentrations during puberty. CONCLUSIONS: Since there are differences in T3, T4, FT4, TSH and Tg reference values according to age, sex, pubertal stage and immunoassays, it is necessary to establish reference values for every population and laboratory in accordance with these parameters.

[Hormonal reference values for adrenocortical function in healthy children from Zaragoza]. / Valores de referencia hormonales de función corticosuprarrenal en niños sanos zaragozanos.

OBJECTIVE: Estimation of reference values for basal serum concentrations of adrenocorticotropic hormone (ACTH), cortisol, 11-deoxycortisol, 17-OH-progesterone (17-OHP), plasma renin activity (PRA), aldosterone, -4-androstendione ( 4A) and dehydroepiandrosterone sulphate (DHA-S) in healthy children from Zaragoza. METHODS: Reference population were healthy children aged 0 to 14, with normal weight and height, living in the metropolitan area of Zaragoza (Spain). It is a transversal study. Reference values and ranges for ACTH, cortisol, 11-deoxycortisol, 17-OHP, PRA, aldosterone, 4A and DHA-S were estimated, and changes in concentrations were analyzed in relation to age, sex and puberal stage. RESULTS: Reference values have been classified by puberal stage and age in eleven groups for every sex: Tanner I (umbilical cordon, 3 days, 4-30 days, 1-6 months, 6 months-4 years, 4-7 years, 7-10 years, 10-14 years), Tanner II, Tanner III and Tanner IV-V. Sex did not influence ACTH, cortisol, 17-OHP and PRA concentrations, and there are punctual differences in 11-deoxycortisol, aldosterone, 4A and DHA-S levels. 17-OHP, 11-deoxycortisol and aldosterone concentrations significantly decreased from birth to 6 months-4 years and subsequently kept steady. The maximal concentration of ACTH, and ARP in blood cord significantly decreased until the period 6 months-4 years, and subsequent differences among different age groups, and between prepuberal and puberal groups are scarce. The highest concentration of 4A and DHA-S were observed in blood cord and third day of life, decreased until the lowest level in 6 months-4 years and progressively increased with age in prepuberty, and between prepuberty and puberty. The lowest concentration of cortisol was detected in 4-30 days, increased until 6 months-4 years and kept steady along the prepuberty and puberty. CONCLUSION: It is necessary that every population establish own reference values for ACTH, cortisol, 11-deoxycortisol, 17-OHP, PRA, aldosterone, 4A and DHA-S during infancy, childhood and adolescence, according to age, sex and puberal stage.

[Accidents in childhood: apropos of 14,301 cases treated in the course of one year]. / Accidentes en la infancia: a propósito de los 14.301 casos atendidos durante 1 año.

The present study aims: to revise all the cases of paediatric accidents attended at a Emergency Service of a tertiary Hospital; to analyze the epidemiological variables; and to try to draw conclusions in view of prevention. In order to achieve that, the 14.301 accidents attended during 1989 have been collected. The relation between little boys and little girls is 58.2:41.8. The average age is 7.12 years, though the mode has been 2 years. A larger number of accidents occur during non holiday. 44.3% of cases are attended between 18 and 23 hours. 89% of the accidents are, first of all, traumatisms and/or wounds; secondly, those which are produced by strange bodies (4.4%). In 51.9% of cases no complementary trial was carried out. Only 2.9% of cases were admitted to hospital, whereas 104% requires observation, and the rest returns home. The variables in the admitted patients are also analyzed, and a brief exposition of results for each of the 6 diagnostic groups is made.