Familial short stature and intrauterine growth retardation associated with a novel mutation in the IGF-I receptor (IGF1R) gene.

CONTEXT: IGF-I is essential for normal human growth and mediates its effects through the IGF1R. IGF1R mutations have been associated with varying degrees of intrauterine and postnatal growth retardation. OBJECTIVE: To identify IGF1R gene mutations in a short-statured family with intrauterine growth retardation and microcephaly. METHODS: Direct DNA sequencing was used to identify IGF1R mutations. Multiplex ligation-dependent probe amplification analyses were performed for deletions and duplications of all IGF1R exons. Functional studies were conducted to assess mutation pathogenicity. RESULTS: A novel heterozygous IGF1R missense mutation in exon 7 (c.A1549T, p.Y487F) was identified in a short-statured girl with severe prenatal growth retardation and microcephaly. The same mutation was also identified in her mother, who presented prenatal and postnatal growth failure, and her short-statured maternal grandmother, both of whom exhibited microcephaly. The index case showed a partial response to rhGH. Functional studies performed in dermal fibroblasts from the index case and her mother showed normal IGF-I binding; however, IGF-I activation of intracellular signalling measured as AKT and extracellular signal-regulated kinase phosphorylation was markedly reduced, with patients' values being lower than those of her mother. IGF-I stimulation of DNA synthesis was significantly reduced compared with controls. CONCLUSION: Our results show a novel missense mutation in the IGF1R gene (c.A1549T, p.Y487F) associated with prenatal and postnatal growth failure and microcephaly in the context of familial short stature. The functional studies are in line with the inactivation of one copy of the IGF1R gene with variable expression within the same family.

Metabolic syndrome and endothelial dysfunction in a population born small for gestational age relationship to growth and Gh therapy.

UNLABELLED: Being born small for gestational age (SGA) and a rapid increase in weight during early childhood and infancy have been strongly linked to metabolic syndrome. A transversal study was conducted on 167 pre-pubertal and 102 pubertal subjects; auxological parameters, systolic and diastolic blood pressure, laboratory data, and carotid-wall thickness (CA-IMT) were measured. RESULTS: Patients born SGA with spontaneous catch-up growth have higher values of BMI, blood pressure, HOMA index, and CA-IMT than those treated with GH and the appropriate-for-gestational age (AGA) group. In conclusion, subjects born SGA are at high risk of developing chronic diseases, including obesity, hypertension, insulin resistant, and endothelial dysfunction, at an early age, mainly those with good catch-up growth compared with the receiving GH because of negative catch-up growth. Our data is compared with published results.

Evaluating the Usefulness and Ease of Use of a Next-Generation-Connected Drug Delivery Device for Growth Hormone Therapy: Qualitative Study of Health Care Professionals' Perceptions.

BACKGROUND: Digital solutions targeting children's health have become an increasingly important element in the provision of integrated health care. For the treatment of growth hormone deficiency (GHD), a unique connected device is available to facilitate the delivery of recombinant human growth hormone (r-hGH) by automating the daily injection process and collecting injection data such that accurate adherence information is available to health care professionals (HCPs), caregivers, and patients. The adoption of such digital solutions requires a good understanding of the perspectives of HCPs as key stakeholders because they leverage data collection and prescribe these solutions to their patients. OBJECTIVE: This study aimed to evaluate the third generation of the easypod device (EP3) for the delivery of r-hGH treatment from the HCP perspective, with a focus on perceived usefulness and ease of use. METHODS: A qualitative study was conducted, based on a participatory workshop conducted in Zaragoza, Spain, with 10 HCPs experienced in the management of pediatric GHD from 7 reference hospitals in Spain. Several activities were designed to promote discussion among participants about predefined topics based on the Technology Acceptance Model and the Unified Theory of Acceptance and Use of Technology to provide their perceptions about the new device. RESULTS: Participants reported 2 key advantages of EP3 over previous easypod generations: the touch screen interface and the real-time data transmission functionality. All participants (10/10, 100%) agreed that the new device should be part of a digital health ecosystem that provides complementary functionalities including data analysis. CONCLUSIONS: This study explored the perceived value of the EP3 autoinjector device for the treatment of GHD by HCPs. HCPs rated the new capabilities of the device as having substantial improvements and concluded that it was highly recommendable for clinical practice. EP3 will enhance decision-making and allow for more personalized care of patients receiving r-hGH.

Identification of miRNAs Involved in Foetal Growth Restriction Due to Maternal Smoking during Pregnancy.

INTRODUCTION: Smoking during pregnancy is associated with reduced foetal growth, amongst other effects. Epigenetic modification in the foetus and placenta during embryonic development as a result of changes in the function of miRNAs is one of the pathophysiological mechanisms responsible for this. This dysregulation may be due to environmental changes or toxins such as tobacco. OBJECTIVE: To study the impact of smoking during pregnancy and its role in intrauterine growth restriction via hypermethylated miRNAs. MATERIALS AND METHODS: The differences in methylation patterns for miRNAs in umbilical cord blood from low-birth-weight newborns of smoking mothers were compared with those from normal-weight newborns using MedIP-seq (StarArray). RESULTS: Seven hypermethylated miRNAs were identified in the epigenetic study of cord blood from low-birth-weight newborns of smoking mothers in our sample. The miRNAs found to be hypermethylated were: MIR7-1, MIR3918, MIR1244-1, MIR4721, MIR25, MIR93, MIR3656. CONCLUSION: Intrauterine exposure to tobacco induces hypermethylation-mediated miRNA silencing in low-birth-weight newborns by modifying the expression of factors involved in vascular development, growth, and adaptation to hypoxia.

Growth hormone and treatment outcomes: expert review of current clinical practice.

Although there are guidelines for treatment of short stature, open questions regarding optimal management of growth hormone therapy still exist. Experts attending six international meetings agree that successful therapy results in the patient attaining mid-parental height, and relies on correct diagnosis and early intervention. Experts advocate patient followup every 3-6 months, and that growth and adherence should be monitored at each visit. Growth response is variable, and an accepted definition of good/poor response is lacking. Combined with patient education and regular patient follow-up, a definition of treatment response could lead to improved treatment outcomes. Few experts use prediction models in clinical practice, but all agree that pharmacogenetics might improve prediction, enable early therapy modulation, and promote growth. Poor growth is often due to low adherence. Guidance on optimal management of growth hormone therapy is required, with focus on early diagnosis, dosing, treatment monitoring, adherence, and motivation.

Important Tools for Use by Pediatric Endocrinologists in the Assessment of Short Stature

Assessment and management of children with growth failure has improved greatly over recent years. However, there remains a strong potential for further improvements by using novel digital techniques. A panel of experts discussed developments in digitalization of a number of important tools used by pediatric endocrinologists at the third 360° European Meeting on Growth and Endocrine Disorders, funded by Merck KGaA, Germany, and this review is based on those discussions. It was reported that electronic monitoring and new algorithms have been devised that are providing more sensitive referral for short stature. In addition, computer programs have improved ways in which diagnoses are coded for use by various groups including healthcare providers and government health systems. Innovative cranial imaging techniques have been devised that are considered safer than using gadolinium contrast agents and are also more sensitive and accurate. Deep-learning neural networks are changing the way that bone age and bone health are assessed, which are more objective than standard methodologies. Models for prediction of growth response to growth hormone (GH) treatment are being improved by applying novel artificial intelligence methods that can identify non-linear and linear factors that relate to response, providing more accurate predictions. Determination and interpretation of insulin-like growth factor-1 (IGF-1) levels are becoming more standardized and consistent, for evaluation across different patient groups, and computer-learning models indicate that baseline IGF-1 standard deviation score is among the most important indicators of GH therapy response. While physicians involved in child growth and treatment of disorders resulting in growth failure need to be aware of, and keep abreast of, these latest developments, treatment decisions and management should continue to be based on clinical decisions. New digital technologies and advancements in the field should be aimed at improving clinical decisions, making greater standardization of assessment and facilitating patient-centered approaches.

Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations.

CONTEXT: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). OBJECTIVE: To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. METHODS: Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. RESULTS: Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ±â€…1.2 years in girls and 7.1 ±â€…1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ±â€…1.6 vs 1.6 ±â€…1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ±â€…1.8 vs 1.1 ±â€…1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. CONCLUSION: Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.

Content Analysis of Apps for Growth Monitoring and Growth Hormone Treatment: Systematic Search in the Android App Store.

BACKGROUND: The use of mobile apps for health is growing. This rapid growth in the number of health apps can make it hard to assess their quality and features. The increased demand for and availability of mobile health apps highlights the importance of regular publication of reviews to identify potential areas of unmet needs and concern. The focus of this review is mobile apps for monitoring growth for health care professionals, caregivers, and patients. Monitoring growth as a part of healthy physical development is important across different periods of childhood and adolescence. OBJECTIVE: The goal of this content analysis is to map and understand the types of apps that currently exist that are related to growth monitoring and growth hormone treatment. METHODS: A semiautomated search was undertaken using the app search engine 42Matters, complemented by a manual search for growth apps using the web search tool of Google Play (Android App Store). Apps were rated on their relevance to growth monitoring and categorized by independent raters. RESULTS: In total, 76 apps were rated relevant to growth monitoring or growth hormone treatment. The level of agreement was measured for the semiautomated search and was very high (Κ=0.97). The target audience for 87% of the apps (66/76) was patients and relatives, followed by health care professionals (11%; 8/76) and both (3%; 2/76). Apps in the category "growth tracking tools for children and babies" were retrieved most often (46%; 35/76) followed by "general baby care apps" (32%; 24/76), "nonpharmacological solutions for growth" (12%; 9/76) and "growth hormone-related" (11%; 8/76). Overall, 19/76 apps (25%) tracked a precise location. CONCLUSIONS: This study mapped the type of apps currently available for growth monitoring or growth hormone treatment that can be used as a foundation for more detailed evaluations of app quality. The popularity of care apps for children and growth monitoring apps should provide a great channel for potential intervention in childhood health in the future.

Growth and metabolic effects of long-term recombinant human growth hormone (rhGH) treatment in short children born small for gestational age: GH-RAST study.

Objectives To study the efficacy and influence on metabolism of recombinant human growth hormone (rhGH) treatment in short children born small for gestational age (SGA). Methods Retrospective, observational, multicenter study in 305 short children born SGA, treated with rhGH during a mean ± SD of 5.03 ± 1.73 years at a mean ± SD dose of 37 ± 8 µg/kg/day. Auxological and metabolic assessment including glucose and lipids profile were collected. Results Mean ± SD age at the start of treatment was 7.11 ± 2.78 years. Height and weight improved significantly until the end of treatment from mean -2.72 (CI95%: -2.81 to -2.63) standard deviation score (SDS) to -1.16 (CI95%: -1.44 to -0.88) SDS and from -1.62 (CI95%: -1.69 to -1.55) SDS to -0.94 (CI95%: -1.14 to -0.74) SDS respectively. Mean height gain was 1.27 (CI95%: 0.99-1.54) SDS. Prepubertal patients showed higher height gain than pubertal children (mean [CI95%] = 1.44 [CI95%: 1.14-1.74] vs. 0.73 [CI95%: 0.22-1.24], p=0.02). Height gain SDS during treatment negatively correlated with chronological age (CA) and bone age (BA) delay and positively correlated with duration of treatment, height gain during first year of treatment, years on prepubertal treatment and height SDS from target height (TH). Glucose, insulin, and triglycerides increased significantly but remained within the normal range. Total and LDL-cholesterol decreased significantly, and HDL-cholesterol remained unchanged. Conclusions rhGH treatment in short SGA children effectively normalized height in most of the patients and showed a safe metabolic profile. Children who benefit the most are those with greater height SDS distance from TH, BA delay, longer duration of treatment and prepubertal treatment initiation.

Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study.

BACKGROUND: Central precocious puberty (CPP) has been associated with loss-of-function mutations in 2 paternally expressed genes (MKRN3 and DLK1). Rare defects in the DLk1 were also associated with poor metabolic phenotype at adulthood. OBJECTIVE: Our aim was to investigate genetic and biochemical aspects of DLK1 in a Spanish cohort of children with CPP without MKRN3 mutations. PATIENTS: A large cohort of children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic deoxyribonucleic acid was obtained from 444 individuals (168 index cases) with CPP and their close relatives. Automatic sequencing of MKRN3 and DLK1 genes were performed. RESULTS: Five rare heterozygous mutations of MKRN3 were initially excluded in girls with familial CPP. A rare allelic deletion (c.401_404 + 8del) in the splice site junction of DLK1 was identified in a Spanish girl with sporadic CPP. Pubertal signs started at 5.7 years. Her metabolic profile was normal. Familial segregation analysis showed that the DLK1 deletion was de novo in the affected child. Serum DLK1 levels were undetectable (<0.4 ng/mL), indicating that the deletion led to complete lack of DLK1 production. Three others rare allelic variants of DLK1 were also identified (p.Asn134=; g.-222 C>A and g.-223 G>A) in 2 girls with CPP. However, both had normal DLK1 serum levels. CONCLUSION: Loss-of-function mutations of DLK1 represent a rare cause of CPP, reinforcing a significant role of this factor in human pubertal timing.

Children born small for gestational age: multidisciplinary approach.

The definition of a newborn SGA changes depending on which parameter is taken as reference. For the neonatologists who are the first to take care of these newborns the most used parameter in the past has been the weight that should be below the 10 centile for the reference standards. In the last years paediatric endocrinologists are more and more interested in the length of these newborns, a parameter more accurate to growth. This paper presents the last consensus statements regarding the definition of SGA newborns taken into consideration the length, the weight, both or them and even the head circumference.

Study of apoptosis and related proteins, CRH and hpGH in placentas of newborns small for gestational age (SGA).

UNLABELLED: The aim of this study is to quantify the expression of apoptotic genes and genes related to the development and growth in placentas of pregnancies with IUGR (intrauterine growth restriction) and normal placentas. We studied the expression of Bcl-2, Caspase3, hpGH (human placental growth hormone) and CRH (corticotropin releasing hormone) genes in normal and IUGR placentas. In addition we have demonstrated this expression by immunohistochemical techniques. MATERIAL AND METHODS: Placentas of newborns with intrauterine infections, complicated pregnancies, congenital malformations and birth asphyxia were excluded. RNA extraction and purification. Total RNA was extracted and cleansed from the lysate using RNA wiz (Ambion) and Qiagen Rneasy Mini (Qiagen). cDNA synthesis. This assay was performed using the Retroscript Kit, Ambion. RT-PCR was performed with the LightCycler System 2.0 (Roche Diagnostics) and the LightCycler FastStart DNA Master Plus SYBR Green I. An immunochemical study was performed using the Envision Plus Dako protocol. RESULTS: Bcl-2, hpGH and CRH are down regulated in the SGA group in comparison to the control group. Caspase3 is up regulated in the SGA group in comparison to the control group. We demonstrated that in placentas from pregnancies with IUGR, expression of Bcl-2is diminished and expression of caspase 3 is augmented compared to normal placentas.

Growth and growth hormone treatment in short stature children born small for gestational age.

Persistent short stature is one of the most frequent complications of being born small for gestational age (SGA) as almost 15% of such children have a low adult height. Additionally, individuals born SGA may have low lean body mass and increased central adiposity which put them at risk of long-term morbidity related to insulin resistance and metabolic disease. Onset of puberty appears at a normal age but comes relatively early for their actual height. There are studies that show that the pubertal growth spurt is moderately decreased in SGA and some girls may experience advanced pubarche and menarche. We have retrospectively analyzed 64 untreated SGA children and we have observed that adult height was lower than target height and positively correlated with maternal height, target height and height at onset of puberty; the tempo of puberty was very similar between SGA and controls but pubertal growth spurt was lower in SGA than in controls. The pathophysiology of postnatal growth failure is complex and different anomalies in the GH-IGF axis had been described. The effect of GH therapy on linear growth and adult height has been extensively studied in the last 15 years. In the short term, GH treatment produces an acceleration of growth with a significant increment of height which is dose dependent during the first 3-4 years. The long-term response is less dose dependent and the vast majority of short SGA children reach an adult height within normal standards and adequate for their target height. There is an important variation in the growth response of SGA children to GH indicating that SGA represents a heterogeneous condition in which response during the first year is the most important predictor of subsequent growth response. GH appears to be safe at the current doses employed but monitoring of IGF-I, IGFBP-3 and glucose metabolism is mandatory during therapy.

Psychomotor and intellectual development (Neurocognitive Function) of children born small for gestational age (SGA). Transversal and longitudinal study.

Although much is now known about the effects of intrauterine growth retardation (IUGR) on children born SGA with regard to anthropometric and biochemical parameters and their treatment, there are still many gaps associated with its impact on neurocognitive functions. In our experience published several years ago, IUGR has a negative effect on neurocognitive development, regardless of whether these children showed evidence of catch-up growth or not or of the socio-economic conditions that might contribute to the situation. We have now accumulated a large number of cases, many of whom have been followed longitudinally, some for up to 7 years, many having been treated with GH from the time when this therapy was first approved by the EMA. Apart from the cases mentioned, other confounding factors such as gestational age, Apgar score, neonatal comorbidity and the possible effects of GH treatment have also been included. In addition and using our own reference standards, we now present our experience, which confirms what we had already noted in the past, that IUGR is in itself a condition that often causes psychomotorintellectual impairment, may be extremely severe and tends to worsen. This negative impact of IUGR on neurocognitive development does not depend on how the child grows,spontaneous growth is better and when growth is not altered by GH therapy. Later studies will be able to confirm whether early treatment with GH throughout the 2nd year of life, or an early specific stimulation programme, or the sum of both, can improve the neurocognitive development of these children. IUGR prevention, acting on causal factors that are partly avoidable such as smoking, working conditions and stress during pregnancy (see the corresponding article in this supplement) proves once again to be the best way to stop this negative impact on the IQ of many children born SGA.

Short Stature Diagnosis and Referral.

The "360° GH in Europe" meeting, which examined various aspects of GH diseases, was held in Lisbon, Portugal, in June 2016. The Merck KGaA (Germany) funded meeting comprised three sessions entitled "Short Stature Diagnosis and Referral," "Optimizing Patient Management," and "Managing Transition." Each session had three speaker presentations, followed by a discussion period, and is reported as a manuscript, authored by the speakers. The first session examined current processes of diagnosis and referral by endocrine specialists for pediatric patients with short stature. Requirements for referral vary widely, by country and by patient characteristics such as age. A balance must be made to ensure eligible patients get referred while healthcare systems are not over-burdened by excessive referrals. Late referral and diagnosis of non-GH deficiency conditions can result in increased morbidity and mortality. The consequent delays in making a diagnosis may compromise the effectiveness of GH treatment. Algorithms for growth monitoring and evaluation of skeletal disproportions can improve identification of non-GH deficiency conditions. Performance and validation of guidelines for diagnosis of GH deficiency have not been sufficiently tested. Provocative tests for investigation of GH deficiency remain equivocal, with insufficient information on variations due to patient characteristics, and cutoff values for definition differ not only by country but also by the assay used. When referring and diagnosing causes of short stature in pediatric patients, clinicians need to rely on many factors, but the most essential is clinical experience.

[Study of Medullary Thyroid Carcinoma from a proband]. / Estudio de carcinoma medular de tiroides a partir de un caso índice.

Thyroid cancer is an uncommon type of cancer, accounting less than 1% of all cancers in adults, and 0.5-3% of all cancers in children. There are four different types: papillary carcinoma (80-90% of cases), follicular (5-10%), medullary (5%) and anaplastic cell (2-3%). Eighty per cent of cases of medullary thyroid cancer are sporadic, but 20% are associated with an inherited syndrome that is divided into three groups: multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. The inherited forms are caused by a disruption in the RET oncogene, which is located in the long arm of chromosome 10. A hereditary case of medullary thyroid carcinoma is presented. It was detected because of a familial genetic study. The purpose of the paper is emphasize the importance of the early diagnosis and the intervention of multidisciplinary teams of experts.

El carcinoma de tiroides es un tumor infrecuente; constituye menos del 1% de las neoplasias malignas en la población general y el 0,5%-3% en la edad pediátrica. Existen cuatro tipos: papilar (80%-90% de los casos), folicular (5%-10%), medular (5%) y anaplásico (2%-3%). En el tipo medular, el 80% son esporádicos, y un 20% se asocia a un síndrome hereditario que se divide, fundamentalmente, en tres grupos: neoplasia endócrina múltiple 1, neoplasia endócrina múltiple 2 y carcinoma medular de tiroides familiar. Las formas hereditarias se producen por una mutación en el protooncogén RET, localizado en el brazo largo del cromosoma 10. Se presenta un caso de carcinoma medular de tiroides detectado a raíz de un estudio genético familiar con el propósito de resaltar la importancia del diagnóstico precoz y la intervención de equipos multidisciplinares expertos en esta patología para su manejo y seguimiento.

Individualised vs fixed dose of oral 17ß-oestradiol for induction of puberty in girls with Turner syndrome: an open-randomised parallel trial.

CONTEXT: Oestrogen induction of pubertal changes in Turner girls may reinforce their psychological well-being and may also optimise final height; however, oestrogen type, dose, and route are not well established. OBJECTIVE: To induce normal pubertal development in Turner girls and ovarian insufficiency with oral 17ß-oestradiol (E(2)), either as individualised dose (ID) or as fixed dose (FD), and to determine whether growth is affected. DESIGN: Open-label randomised, parallel groups, multicentre clinical trial in 48 GH-treated Turner girls. Oral E(2) was given in tablets, either as an ID of 5-15 µg/kg per day during 2 years or as a FD of 0.2 mg daily during the first year followed by 0.5 mg daily during the second year. Main outcome measures were the event of attaining a Tanner breast staging ≥4 (primary), FSH, and auxological variables (secondary). RESULTS: Shorter median time to Tanner staging ≥ B4 in the FD group (733 days) compared with the ID group (818 days) (P=0.046). Higher proportion of girls with Tanner staging ≥ B4 (65%) in the FD group compared with the ID group (42%) (P=0.068). Bone age did not show inadequate acceleration and adult height prediction was maintained in both groups. No oestrogen-related adverse events were reported. CONCLUSIONS: Two-year treatment with oral E(2) can progressively induce normal pubertal development in Turner syndrome. Low-dose oral E(2) given as a FD produces a satisfactory pubertal development not inferior to ID. Treatment was well tolerated and did not interfere with the growth-promoting effect of GH.

Estudio de carcinoma medular de tiroides a partir de un caso índice / Study of Medullary Thyroid Carcinoma from a proband

El carcinoma de tiroides es un tumor infrecuente; constituye menos del 1% de las neoplasias malignas en la población general y el 0,5%-3% en la edad pediátrica. Existen cuatro tipos: papilar (80%-90% de los casos), folicular (5%-10%), medular (5%) y anaplásico (2%-3%). En el tipo medular, el 80% son esporádicos, y un 20% se asocia a un síndrome hereditario que se divide, fundamentalmente, en tres grupos: neoplasia endócrina múltiple 1, neoplasia endócrina múltiple 2 y carcinoma medular de tiroides familiar. Las formas hereditarias se producen por una mutación en el protooncogén RET, localizado en el brazo largo del cromosoma 10. Se presenta un caso de carcinoma medular de tiroides detectado a raíz de un estudio genético familiar con el propósito de resaltar la importancia del diagnóstico precoz y la intervención de equipos multidisciplinares expertos en esta patología para su manejo y seguimiento.

Thyroid cancer is an uncommon type of cancer, accounting less than 1% of all cancers in adults, and 0.5-3% of all cancers in children. There are four different types: papillary carcinoma (80-90% of cases), follicular (5-10%), medullary (5%) and anaplastic cell (2-3%). Eighty per cent of cases of medullary thyroid cancer are sporadic, but 20% are associated with an inherited syndrome that is divided into three groups: multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. The inherited forms are caused by a disruption in the RET oncogene, which is located in the long arm of chromosome 10. A hereditary case of medullary thyroid carcinoma is presented. It was detected because of a familial genetic study. The purpose of the paper is emphasize the importance of the early diagnosis and the intervention of multidisciplinary teams of experts.

Growth hormone does not alter CYP2A6 activity in growth hormone-deficient children.

A large number of metabolic alterations are increasingly being treated with growth hormone. Despite the fact that growth hormone is known to be the main regulator of several hepatic drug metabolizing enzymes in rodents, few studies deal with the effect of growth hormone on hepatic enzyme activities in human beings. The aim of this study was to determine the effects of growth hormone replacement therapy for 4 weeks on CYP2A6 activity in children, because changes in this enzyme activity may have important therapeutic and toxic consequences. A total of 31 growth hormone-deficient children (age range 4.1-13.1 years; mean age 9.88 +/- 2.89 years) participated. The genotypes of CYP2A6 gene, CYP2A6*1A, CYP2A6*1B, CYP2A6*4, CYP2A6*1x2 and CYP2A6*9, were determined by polymerase chain reaction. To assess the enzyme activity, we used caffeine as a probe drug at two points in time: before starting growth hormone therapy (Day 0) and after 4 weeks of growth hormone therapy (Day A). Caffeine and metabolite concentrations in urine were assayed by high-pressure liquid chromatography. The metabolite ratio 1,7-dimethilxanthine to 1,7-dimethylurate (17U/17X) served to indicate CYP2A6 activity. Median value and 95% confidence interval at baseline was 1.08 (0.98-1.24). The value after treatment was 1.08 (0.86-1.21). Data comparison between periods showed lack of statistically significant differences (P > 0.05). The relative change, measured by the ratio of medians and 90% confidence interval, was 1.02 (0.84-1.19). There were no significant differences when the ratio between genotype groups were compared. These results indicate that growth hormone replacement therapy of growth hormone-deficient children for 4 weeks does not modify the CYP2A6 activity and hence the efficacy or toxicity of the CYP2A6 substrate compounds.

Lack of effect of growth hormone replacement therapy on CYP1A2 and xanthine oxidase activities in growth hormone-deficient children.

BACKGROUND AND OBJECTIVES: The recombinant human growth hormone (rhGH) is being increasingly used for a number of metabolic alterations. GH is the main regulator of several hepatic drug metabolizing enzymes in rodents. In addition, GH could play a major role in defining the interface between pharmacogenetics and development. However, little is known about the effect of GH on the activity of hepatic enzymes in children. The aim of this study was to determine the effect of rhGH replacement therapy for 4 weeks on CYP1A2 and xanthine oxidase (XO) activities in children. METHODS: We used caffeine as a probe drug to assess the enzyme activities at two points in time: before starting GH treatment (day 0) and after 4 weeks on rhGH therapy (day A). A total of 31 GH-deficient children (age range: 4.1-13.1 years, mean age: 9.88+/-2.89 years) participated. Urinary concentrations of caffeine and metabolites were determined by high-performance liquid chromatography (HPLC) to calculate the metabolite ratios: (AFMU+1X+1U)/17U for CYP1A2 and 1U/(1X+1U) for XO. RESULTS: Four weeks of GH substitution did not importantly alter the markers of the enzyme activities measured in this study. Median values and 95% confidence intervals (CI) at baseline were 5.17 (3.87-5.59) for the CYP1A2 ratio and 0.62 (0.56-0.65) for the XO ratio. These values, after treatment, were 4.57 (3.90-5.97) for the CYP1A2 marker and 0.62 (0.59-0.67) for the XO ratio. Data comparison between periods showed lack of statistically significant differences (P>0.05). The relative changes measured by the ratios of medians and 90% CI were 1.14 (0.90-1.31) and 0.99 (0.94-1.06) for CYP1A2 and XO, respectively. CONCLUSIONS: The absence of significant changes in the markers of enzyme activities CYP1A2 and XO suggests that rhGH replacement therapy of GH-deficient children for 4 weeks could not noticeably modify the efficacy or toxicity of substrates of these metabolic enzymes.