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1.
Endocr Connect ; 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33543731

RESUMO

The terms idiopathic short stature (ISS) and small for gestational age (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term SGA was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms SGA and ISS as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.

2.
Am J Hum Genet ; 108(1): 115-133, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33308444

RESUMO

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.


Assuntos
Osso e Ossos/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Deficiências do Desenvolvimento/metabolismo , Osteogênese/fisiologia , Transdução de Sinais/fisiologia , Animais , Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células HEK293 , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL
3.
Acta Paediatr ; 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33118654

RESUMO

AIM: To develop a guideline for preventive child healthcare professionals in order to improve early detection of pathological disorders associated with short stature (or growth faltering) or tall stature (or accelerated growth). METHODS: We updated the previous Dutch guideline for short stature in children aged 0-9 years and extended it to adolescents (10-17 years), and added a guideline for tall stature, based on literature and input from an expert committee. Specificities were calculated in a cohort of healthy Dutch children aged 0-9 years (n = 970). We investigated the impact of a late onset of puberty on height standard deviation score based on the Dutch growth charts. RESULTS: Growth parameters of the guideline include height, the distance between height and target height and change of height over time. Other parameters include diagnostic clues from medical history and physical examination, for example behavioural problems, precocious or delayed puberty, body disproportion and dysmorphic features. CONCLUSION: Preventive child healthcare professionals now have an updated guideline for referring short or tall children to specialist care. Further research is needed on the diagnostic yield after referral and specificity at field level.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33006554

RESUMO

Assessment and management of children with growth failure has improved greatly over recent years. However, there remains a strong potential for further improvements by use of 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, and computer programs have improved ways in which diagnoses are coded for use by various groups such as 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 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 IGF-I levels are becoming more standardized and consistent, for evaluation across different patient groups, and computer-learning models indicate that baseline IGF-I SDS 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 making clinical decisions more efficient and consider patient-centered approaches. Keywords: Short stature, height monitoring, bone age, cranial imaging, growth hormone treatment, prediction models.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33045800

RESUMO

Our objective is to further expand the spectrum of clinical characteristics of the IGSF1 deficiency syndrome in affected males, which so far includes congenital central hypothyroidism, disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index, decreased attentional control and a variable proportion of prolactin deficiency, transient partial growth hormone deficiency in childhood and increased growth hormone secretion in adulthood. We present a family in which the proband was diagnosed with central hypothyroidism (CeH) and low serum prolactin. Severe weight gain started at 2 years, up to a BMI of 42.3 at 13.9 years. Testicular enlargement (5-6 ml, 3.8-4.3 SDS) started at 3 years. A pathogenic variant was found in the IGSF1 gene: c.3411_3412del, p.(Tyr1137*). His brother was referred for short stature at age 13 years and was diagnosed with CeH, normal serum prolactin and IGF-1, and disharmonious puberty. In the four male relatives (the proband's brother and three cousins) who carried the variant (one adult), FT4 was below the lower limit of the reference range in two, and just above this limit in the other two cases. Three were overweight or obese, adolescents had disharmonious pubertal development and the adult had profound macroorchidism. In conclusion, male hemizygous carriers of a pathogenic IGSF1 variant can present with FT4 levels above the lower limit of the reference range, and severe early onset obesity or premature testicular growth are part of the phenotypic spectrum.

6.
Artigo em Inglês | MEDLINE | ID: mdl-32936765

RESUMO

BACKGROUND/AIMS: We hypothesized that modelling catch-up growth (CUG) as developed for coeliac disease (CD), might also fit CUG in adequately treated children with juvenile hypothyroidism (JHT) or growth hormone deficiency (GHD). METHODS: We used a monomolecular function for all available prepubertal data on height SDS minus target height SDS (adjHSDS) in children with JHT (n=20) and GHD (n=18) on a conventional (CoD) or high GH dose (HD), based either on a national height reference with an age cut-off of 10 (girls) and 12 (boys) years (Model 1) or prepubertal height reference values, if age(0) was ≥3, with no upper age limit (Model 2). RESULTS: The models could be fitted in 83-90% of cases; in other cases the HSDS decreased after several measurements which violates the assumption of an irreversible growth process. In JHT, the rate constant (k) and adjHSDS(0) were lower than in CD (p=0.02), but adjHSDS(end) was similar. In GHD (model 1), k was lower than for CD (p=0.004) but similar to JHT, while adjHSDS(0) and adjHSDS(end) were similar to CD and JHT. Thus, the shape of CUG is similar for children with JHT and GHD, while children with CD had less growth deficit at start and a faster CUG. The differences in CUG parameters between GH dose subgroups did not reach statistical significance. CONCLUSION: Modelling CUG of prepubertal children with JHT and GHD can be used for assessing the adequacy of CUG and the influence of clinical treatment modalities on its speed and magnitude.

7.
Mol Cell Endocrinol ; 518: 111035, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32941924

RESUMO

The insulin-like growth factor (IGF) system comprises two ligands, IGF-I and IGF-II, that regulate multiple physiological processes, including mammalian development, metabolism and growth, through the type 1 IGF receptor (IGF-1R). The growth hormone (GH)-IGF-I axis is the major regulator of longitudinal growth. IGF-II is expressed in many tissues, notably the placenta, to regulate human pre- and post-natal growth and development. This review provides a brief introduction to the IGF system and summarizes findings from reports arising from recent larger genomic sequencing studies of human genetic mutations in IGF1 and IGF2 and genes of proteins regulating IGF action, namely the IGF-1R, IGF-1R signaling pathway components and the IGF binding proteins (IGFBPs). A perspective on the effect of homozygous mutations on structure and function of the IGFs and IGF-1R is also given and this is related to the effects on growth.

8.
Horm Res Paediatr ; 93(3): 164-172, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32575104

RESUMO

BACKGROUND/OBJECTIVES: In the clinical assessment of a short or tall child, estimating body disproportion is useful to assess the likelihood of a primary growth disorder, e.g., skeletal dysplasia. Our objectives were (1) to use data from the Maastricht study on healthy children (2-17 years) to calculate relative arm span (AS) for height (H) to serve as age references for clinical purposes; (2) to assess its age and sex dependency; and (3) to investigate relative AS adjustment for age and sex in individuals with ACAN haploinsufficiency. METHODS: The Maastricht study data (2,595 Caucasian children, 52% boys, 48% girls) were re-analysed to produce reference tables and graphs for age and sex of AS - H and AS/H. Published information on AS/H in Europeans was used as reference data for adults. Relative AS from 33 patients with ACAN haploinsufficiency were plotted against reference data and expressed as standard deviation score (SDS) for age and sex. RESULTS: Mean AS - H from 2 to 17 years increased from -1.2 to +1.5 cm in boys and from -4.8 to +1.6 cm in girls. Mean AS/H increased from 0.9848 to 1.0155 in boys and from 0.9468 to 1.0028 in girls. Mean AS/H in patients with ACAN haploinsufficiency was approximately 1.0, 1.5 and 0.5 SDS in young children, adolescents and 20- to 50-year-olds, respectively, and normal thereafter. CONCLUSIONS: These reference charts can be used for 2- to 17-year-old children/adolescents. Carriers of ACAN haploinsufficiency have an elevated mean AS/H in childhood and adolescence and a slightly elevated ratio till 50 years.

9.
Hum Genet ; 139(11): 1471-1483, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32583022

RESUMO

Human growth is a complex trait determined by genetic factors in combination with external stimuli, including environment, nutrition and hormonal status. In the past, several genome-wide association studies (GWAS) have collectively identified hundreds of genetic variants having a putative effect on determining adult height in different worldwide populations. Theoretically, a valuable approach to better understand the mechanisms of complex traits as adult height is to study a population exhibiting extreme stature phenotypes, such as African Baka Pygmies. After phenotypic characterization, we sequenced the whole exomes of a cohort of Baka Pygmies and their non-Pygmies Bantu neighbors to highlight genetic variants associated with the reduced stature. Whole exome data analysis revealed 29 single nucleotide polymorphisms (SNPs) significantly associated with the reduced height in the Baka group. Among these variants, we focused on SNP rs7629425, located in the 5'-UTR of the Hyaluronidase-2 (HYAL2) gene. The frequency of the alternative allele was significantly increased compared to African and non-African populations. In vitro luciferase assay showed significant differences in transcription modulation by rs7629425 C/T alleles. In conclusion, our results suggested that the HYAL2 gene variants may play a role in the etiology of short stature in Baka Pygmies population.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Moléculas de Adesão Celular/genética , Proteínas Ligadas por GPI/genética , Transtornos do Crescimento/genética , Hialuronoglucosaminidase/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Estatura/genética , Exoma/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino
11.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31650157

RESUMO

CONTEXT: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. OBJECTIVE: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. PATIENTS, DESIGN, AND SETTING: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. MAIN OUTCOME MEASURES: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. RESULTS: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. CONCLUSIONS: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.


Assuntos
Imunoglobulinas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas de Membrana/fisiologia , Neurossecreção/fisiologia , Somatotrofos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Hormônio do Crescimento/biossíntese , Humanos , Imunoglobulinas/deficiência , Fator de Crescimento Insulin-Like I/análise , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Masculino , Proteínas de Membrana/deficiência , Camundongos , Pessoa de Meia-Idade
12.
J Clin Res Pediatr Endocrinol ; 12(2): 130-139, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31842524

RESUMO

The serum insulin-like growth factor-I (IGF-I) concentration is commonly used as a screening tool for growth hormone deficiency (GHD), but there is no consensus on the cut-off limit of IGF-I standard deviation score (SDS) to perform GH stimulation tests for confirmation or exclusion of GHD. We argue that the cut-off limit is dependent on the clinical pre-test likelihood of GHD and propose a diagnostic strategy in which the cut-off limit varies between zero to -2 SDS.

13.
Horm Res Paediatr ; 92(1): 1-14, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31514194

RESUMO

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.


Assuntos
Transtornos do Crescimento , Hormônio do Crescimento Humano , Criança , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Transtornos do Crescimento/terapia , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Humanos
14.
Horm Res Paediatr ; 91(5): 293-310, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31302655

RESUMO

Tall stature and/or accelerated growth (TS/AG) in a child can be the result of a primary or secondary growth disorder, but more frequently no cause can be found (idiopathic TS). The conditions with the most important therapeutic implications are Klinefelter syndrome, Marfan syndrome and secondary growth disorders such as precocious puberty, hyperthyroidism and growth hormone excess. We propose a diagnostic flow chart offering a systematic approach to evaluate children referred for TS/AG to the general paediatrician. Based on the incidence, prevalence and clinical features of medical conditions associated with TS/AG, we identified relevant clues for primary and secondary growth disorders that may be obtained from the medical history, physical evaluation, growth analysis and additional laboratory and genetic testing. In addition to obtaining a diagnosis, a further goal is to predict adult height based on growth pattern, pubertal development and skeletal maturation. We speculate that an improved diagnostic approach in addition to expanding use of genetic testing may increase the diagnostic yield and lower the age at diagnosis of children with a pathologic cause of TS/AG.


Assuntos
Acromegalia/diagnóstico , Transtornos do Crescimento/diagnóstico , Puberdade Precoce/diagnóstico , Acromegalia/etiologia , Criança , Pré-Escolar , Feminino , Transtornos do Crescimento/etiologia , Humanos , Hipertireoidismo/complicações , Hipertireoidismo/diagnóstico , Síndrome de Klinefelter/complicações , Síndrome de Klinefelter/diagnóstico , Masculino , Síndrome de Marfan/complicações , Síndrome de Marfan/diagnóstico , Puberdade Precoce/etiologia
15.
J Clin Res Pediatr Endocrinol ; 11(4): 329-340, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31284701

RESUMO

It is over sixty years since the first administration of human growth hormone (GH) to children with GH deficiency, and over thirty years since recombinant human GH has been available for treatment of GH deficiency and a wider range of non-GH deficiency disorders. From a diagnostic perspective, genetic analysis, using single gene or Sanger sequencing and more recently next generation or whole exome sequencing, has brought advances in the diagnosis of specific causes of short stature, which has enabled therapy to be targeted more accurately. Genetic discoveries have ranged from defects of pituitary development and GH action to abnormalities in intracellular mechanisms, paracrine regulation and cartilage matrix formation. The strategy of GH therapy using standard doses has evolved to individualised GH dosing, depending on diagnosis and predictors of growth response. Evidence of efficacy of GH in GH deficiency, Turner syndrome and short children born small for gestational age is reviewed. The importance of critical assessment of growth response is discussed, together with the recognition and management of a poor or unsatisfactory growth response and the organisational issues related to prevention, detection and intervention regarding suboptimal adherence to GH therapy.


Assuntos
Desenvolvimento do Adolescente/efeitos dos fármacos , Estatura/efeitos dos fármacos , Desenvolvimento Infantil/efeitos dos fármacos , Transtornos do Crescimento/tratamento farmacológico , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/administração & dosagem , Adolescente , Fatores Etários , Estatura/genética , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Transtornos do Crescimento/genética , Transtornos do Crescimento/fisiopatologia , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino , Fatores de Tempo , Resultado do Tratamento
16.
Horm Res Paediatr ; 91(4): 223-240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31195397

RESUMO

Based on a recent Dutch national guideline, we propose a structured stepwise diagnostic approach for children with growth failure (short stature and/or growth faltering), aiming at high sensitivity for pathologic causes at acceptable specificity. The first step is a detailed clinical assessment, aiming at obtaining relevant clinical clues from the medical history (including family history), physical examination (emphasising head circumference, body proportions and dysmorphic features) and assessment of the growth curve. The second step consists of screening: a radiograph of the hand and wrist (for bone age and assessment of anatomical abnormalities suggestive for a skeletal dysplasia) and laboratory tests aiming at detecting disorders that can present as isolated short stature (anaemia, growth hormone deficiency, hypothyroidism, coeliac disease, renal failure, metabolic bone diseases, renal tubular acidosis, inflammatory bowel disease, Turner syndrome [TS]). We advise molecular array analysis rather than conventional karyotyping for short girls because this detects not only TS but also copy number variants and uniparental isodisomy, increasing diagnostic yield at a lower cost. Third, in case of diagnostic clues for primary growth disorders, further specific testing for candidate genes or a hypothesis-free approach is indicated; suspicion of a secondary growth disorder warrants adequate further targeted testing.


Assuntos
Determinação da Idade pelo Esqueleto , Variações do Número de Cópias de DNA , Insuficiência de Crescimento , Hormônio do Crescimento Humano , Cariotipagem , Dissomia Uniparental , Criança , Pré-Escolar , Insuficiência de Crescimento/sangue , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino
18.
J Clin Res Pediatr Endocrinol ; 11(3): 293-300, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30859796

RESUMO

Objective: Insulin like growth factors-1 (IGF-1) is essential for normal in utero and postnatal human growth. It mediates its effects through the IGF-1 receptor (IGF1R), a widely expressed cell surface tyrosine kinase receptor. The aim of the study was to analyze pre- and post-natal growth, clinical features and laboratory findings in a small for gestational age (SGA) girl in whom discordant postnatal growth persisted and her appropriate for gestational age (AGA) brother. Methods: A girl born with a low weight and length [-2.3 and -2.4 standard deviation (SD) score (SDS), respectively] but borderline low head circumference (-1.6 SD) presented with a height of -1.7 SDS, in contrast to a normal height twin brother (0.0 SDS). IGF-1 resistance was suspected because of elevated serum IGF-1 levels. Results: Sequencing revealed the presence of a previously described pathogenic heterozygous mutation (p.Glu1050Lys) in the SGA girl which was not present in the parents nor in the AGA twin brother. Conclusion: The pathogenic IGF1R mutation in this girl led to intrauterine growth retardation followed by partial postnatal catch-up growth. Height in mid-childhood was in the lower half of the reference range, but still 1.7 SD shorter than her twin brother.


Assuntos
Insuficiência de Crescimento/patologia , Retardo do Crescimento Fetal/patologia , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Mutação , Receptor IGF Tipo 1/genética , Estatura , Insuficiência de Crescimento/sangue , Insuficiência de Crescimento/genética , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/genética , Idade Gestacional , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/sangue , Fator de Crescimento Insulin-Like I/análise , Masculino , Prognóstico , Gêmeos Dizigóticos
19.
J Clin Endocrinol Metab ; 104(8): 3157-3171, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30848790

RESUMO

CONTEXT: The phenotype and response to GH treatment of children with an IGF1R defect is insufficiently known. OBJECTIVE: To develop a clinical score for selecting children with short stature for genetic testing and evaluate the efficacy of treatment. DESIGN AND SETTING: Case series with an IGF1R defect identified in a university genetic laboratory. PATIENTS AND INTERVENTIONS: Of all patients with sufficient clinical data, 18 had (likely) pathogenic mutations (group 1) and 7 had 15q deletions including IGF1R (group 2); 19 patients were treated with GH. MAIN OUTCOME MEASURES: Phenotype and response to GH treatment. RESULTS: In groups 1 and 2, mean (range) birth weight, length, and head circumference (HC) SD scores (SDSs) were -2.1 (-3.7 to -0.4), -2.7 (-5.0 to -1.0), and -1.6 (-3.0 to 0.0), respectively. At presentation, height, HC, and serum IGF-1 SDSs were -3.0 (-5.5 to -1.7), -2.5 (-4.2 to -0.5), and +1.2 (-1.3 to 3.2), respectively. Feeding problems were reported in 15 of 19 patients. A clinical score with 76% sensitivity is proposed. After 3 years of GH treatment [1.1 (0.2) mg/m2/d] height gain in groups 1 (n = 12) and 2 (n = 7) was 0.9 SDS and 1.3 SDS (at a mean IGF-1 of 3.5 SDS), less than reported for small for gestational age (1.8 SDS). CONCLUSION: A clinical score encompassing birth weight and/or length, short stature, microcephaly, and IGF-1 is useful for selecting patients for IGF1R analysis. Feeding problems are common and the growth response to GH treatment is moderate.


Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Mutação , Receptor IGF Tipo 1/genética , Adolescente , Adulto , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Fator de Crescimento Insulin-Like I/análise , Masculino , Fenótipo , Estudos Retrospectivos , Adulto Jovem
20.
J Clin Res Pediatr Endocrinol ; 11(4): 426-431, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-30678423

RESUMO

Isolated growth hormone (GH) deficiency (IGHD) type 2 is a rare autosomal dominant disorder characterized by severe short stature with low GH level. Timely diagnosis is important for optimal results of recombinant human GH (rhGH) treatment and detection of additional pituitary deficiencies in affected relatives. A male child presented at the age of one year with severe, proportionate short stature [-4.9 standard deviation score (SDS)] and with a normal body mass index (-1.1 SDS). Physical examination revealed frontal bossing, midfacial hypoplasia, normal external genitalia and no dysmorphic features. Paternal and maternal heights were -6.1 and -1.9 SDS. Serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 were undetectable and the peak GH concentration by clonidine stimulation test was extremely low (0.18 ng/mL). Brain magnetic resonance imaging showed anterior pituitary hypoplasia. Genetic analysis identified a novel heterozygous mutation (c.291+2T>G) expected to lead to splicing out exon 3 of GH1. rhGH from age 2.4 years led to appropriate catch-up. In conclusion, we identified a novel GH1 gene mutation in an infant with classical IGHD type 2 presentation.


Assuntos
Estatura/genética , Nanismo Hipofisário/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/genética , Mutação , Fatores Etários , Estatura/efeitos dos fármacos , Desenvolvimento Infantil , Pré-Escolar , Nanismo Hipofisário/sangue , Nanismo Hipofisário/diagnóstico , Nanismo Hipofisário/tratamento farmacológico , Predisposição Genética para Doença , Transtornos do Crescimento/sangue , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/tratamento farmacológico , Hereditariedade , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Resultado do Tratamento
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