ABSTRACT
Background Recombinant human insulin-like growth factor 1 (rhIGF-I) has been approved as an orphan drug for the treatment of growth failure in children and adolescents with severe primary IGF-I deficiency (SPIGFD) with little pharmacokinetic data available. Therefore, sequential measurements of serum IGF-I, glucose, potassium, insulin and cortisol were performed in patients treated with rhIGF-I to evaluate their significance in safety and efficacy. Methods Repetitive blood samples were taken after meals before and 30, 60, 120, 180 and 360 min after rhIGF-I injections in two male patients with Laron syndrome at times of dose adjustments. Results Maximal IGF-I concentrations were observed 2 h after injections (495 ng/mL) and concentrations were still higher 6 h after injections than at baseline (303 ng/mL vs. 137 ng/mL). Thirteen percent of all and 33% of maximum IGF-I concentrations were greater than +2 standard deviation score (SDS) calculated for bone age (BA) (IGF-I SDS BA) rather than chronological age (CA) as BA was significantly delayed to CA by 3.2 years (p=0.0007). Height velocities correlated with individual maximum IGF-I SDS BA (ρ=0.735; p<0.0001). Serum insulin, cortisol and glucose did not correlate with IGF-I concentrations, but serum potassium showed a negative correlation (ρ=-0.364; p<0.0001) with IGF-I concentrations. Conclusions Sequential measurements of serum IGF-I, glucose and potassium in patients with Laron syndrome may aid in optimizing and individualizing rhIGF-I treatment. IGF-I concentrations should be referenced according to BA which better reflects the biological age. The inverse correlation of IGF-I and serum potassium concentrations after injections of rhIGF-I has not been reported before and warrants further consideration.
Subject(s)
Biomarkers/blood , Growth Disorders/blood , Hearing Loss, Sensorineural/blood , Insulin-Like Growth Factor I/deficiency , Laron Syndrome/blood , Recombinant Proteins/administration & dosage , Adolescent , Adult , Blood Glucose/analysis , Child , Follow-Up Studies , Growth Disorders/drug therapy , Growth Disorders/pathology , Hearing Loss, Sensorineural/drug therapy , Hearing Loss, Sensorineural/pathology , Humans , Insulin/blood , Insulin-Like Growth Factor I/administration & dosage , Insulin-Like Growth Factor I/analysis , Laron Syndrome/drug therapy , Laron Syndrome/pathology , Male , Prognosis , Young AdultABSTRACT
BACKGROUND/AIMS: Monogenic forms of growth hormone insensitivity (GHI) and its treatment with recombinant insulin-like growth factor-1 (rIGF-1) are both associated with glucose dysregulation. We used the information provided by continuous glucose monitoring systems (CGMS) for the clinical management of two children with monogenic GHI prior to the commencement of therapy as well as during the years when they received rIGF-1 treatment and continued to do so after the cessation of therapy. METHODS: We evaluated the extent of hyper- and hypoglycaemia with CGMS. RESULTS: In one patient, before treatment CGMS identified self-limiting nocturnal hypoglycaemia. Initiation of rIGF-1 treatment resulted in severe and persistent hypoglycaemia with an absence of spontaneous recovery. Corrective dietary measures were instituted. In a second patient, who had a poor growth response to rIGF-1 therapy, CGMS identified significant fluctuations in daytime glucose levels whilst on treatment with evidence of postprandial hyperglycaemia and both rebound and nocturnal hypoglycaemia. Given the lack of improved growth and the documented glucose dysregulation, treatment was stopped and repeat measurements with CGMS 1 month afterwards showed complete resolution. CONCLUSIONS: We have demonstrated that CGMS is an effective tool to assess glucose dysregulation in patients with GHI and alters clinical management.
Subject(s)
Glucose Metabolism Disorders/diagnosis , Laron Syndrome/blood , Laron Syndrome/complications , Monitoring, Physiologic/methods , Blood Glucose/analysis , Blood Glucose Self-Monitoring/statistics & numerical data , Child, Preschool , Consanguinity , Female , Glucose Metabolism Disorders/blood , Glucose Metabolism Disorders/complications , Humans , Hyperglycemia/blood , Hyperglycemia/complications , Hyperglycemia/diagnosis , Hypoglycemia/blood , Hypoglycemia/complications , Hypoglycemia/diagnosis , InfantABSTRACT
States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKO-HIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1, allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth.
Subject(s)
Bone Development , Bone and Bones/metabolism , Insulin-Like Growth Factor I/metabolism , Laron Syndrome/blood , Receptors, Somatotropin/metabolism , Animals , Bone and Bones/pathology , Disease Models, Animal , Female , Hormone Replacement Therapy , Humans , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/therapeutic use , Laron Syndrome/drug therapy , Laron Syndrome/genetics , Male , Mice , Mice, Mutant Strains , Receptors, Somatotropin/genetics , TransgenesABSTRACT
OBJECTIVE: To analyze clinical manifestations and gene mutations in a child with severe short stature, explore its molecular mechanism and further clarify the diagnostic procedure for short stature. METHOD: We observed clinical characteristics of a patient with short stature and did diagnostic examinations, assessed the function of GH-IGF-1 axis, and surveyed its family members.Genomic DNA was extracted from peripheral blood, GHR, IGFALS, STAT5b and GH1 gene were amplified by PCR for sequencing, including exons and splicing areas. RESULT: The patient presented symmetrical short stature (height -8.2 SDS) and facial features, and other congenital abnormalities.It displayed non-growth hormone deficiency. The baseline value of GH was 21 µg/L, and the peak was 57.9 µg/L. The value of IGF-1 was less than 25 µg/L, and the IGFBP-3 less than 50 µg/L. And IGF-1 generation test showed no response. There was no similar patients in the family members.Sequencing of GHR in the patient revealed a homozygous point mutation (c.Ivs6+1G>A), and her father and mother had the same heterozygous mutation. The same mutation was not identified for her sister.No other candidate gene was found. CONCLUSION: As the result of combined clinical characteristics and lab examinations, as well as gene detection, the case was diagnosed with Laron syndrome and GHR gene mutation is the molecular mechanism.We should explicit the etiological diagnosis for short stature, and avoid missed diagnosis and misdiagnosis.
Subject(s)
Growth Disorders/genetics , Laron Syndrome/genetics , Mutation , Receptors, Somatotropin/genetics , Base Sequence , Body Height , Child , DNA Mutational Analysis , Exons , Growth Disorders/blood , Growth Disorders/pathology , Human Growth Hormone/blood , Humans , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/analysis , Laron Syndrome/blood , Laron Syndrome/pathology , Male , Molecular Sequence Data , Pedigree , STAT5 Transcription Factor/geneticsABSTRACT
CONTEXT: Undetectable circulating growth hormone-binding protein (GHBP) can be indicative of a GH receptor (GHR) defect and cause GH insensitivity (GHI) syndrome. CASE REPORT: The proband, severely growth retarded from birth, had a height of 73 cm (-6 SDS) and weight of 10.5 kg (-2.5 SDS) at the age of 3.25 years; her consanguineous parents were normal statured. Basal serum GH measurement was high, >40 ng/ml, while serum insulin-like growth factor-I (IGF-I; 8.5 ng/ml; normal, 13-100), IGF-binding protein 3 (126 ng/ml; normal, 365-1,294), acid labile subunit (0.59 mg/l; normal, 5.6-16), and GHBP (120 pmol/l; normal, 431-1,892) concentrations were all markedly low. Recombinant IGF-I therapy improved height to -4.4 SDS after 2.5 years of treatment. RESULTS: GHR gene analysis revealed a homozygous c.784G>C transversion, the last nucleotide of exon 7; the parents were heterozygous for the mutation. Evaluation of GHR mRNA indicated c.784G>C was not a missense mutation but induced exon 7 excision, leading to a frame shift and predicted early protein termination. CONCLUSION: A novel homozygous GHRc.784G>C mutation, identified in a GHI patient, induced functional loss of the native intron 7 donor splice site, demonstrating, for the first time, the importance of exonic nucleotides at exon-intron junctions for normal GHR splicing.
Subject(s)
Exons/genetics , Laron Syndrome/genetics , Mutation/genetics , Receptors, Somatotropin/genetics , Female , Homozygote , Humans , Infant , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/therapeutic use , Introns/genetics , Laron Syndrome/blood , Laron Syndrome/drug therapy , Recombinant Proteins/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: Laron syndrome is caused by a mutation in the growth hormone (GH) receptor and manifests as insulin-like growth factor-I (IGF-I) deficiency, severe short stature, and early hypoglycemia. We report a case with postprandial hyperglycemia, an abnormality not reported previously. Postprandial hyperglycemia was due to chronic IGF-I deficiency, and was reversed by IGF-I replacement therapy. METHODS: A Moroccan girl referred for short stature at 7 years and 8 months of age had dwarfism [height, 78 cm (-9 SDs); weight, 10 kg (-4 SDs)], hypoglycemia, and truncal obesity. Her serum IGF-I level was very low, and her baseline serum GH level was elevated to 47 mIU/l. Molecular analysis showed a homozygous mutation in the GH receptor gene. RESULTS: Continuous glucose monitoring before treatment showed asymptomatic hypoglycemia with postprandial hyperglycemia (2.5 g/l, 13.75 mmol/l). Treatment with recombinant human IGF-I (mecasermin, Increlex®) was started. The blood glucose profile improved with 0.04 µg/kg/day and returned to normal with 0.12 µg/kg/day. CONCLUSION: Postprandial hyperglycemia is a metabolic consequence of chronic IGF-I deficiency. The beneficial effect of IGF-I replacement therapy may be ascribable to improved postprandial transfer of glucose.
Subject(s)
Hormone Replacement Therapy , Hyperglycemia/drug therapy , Insulin-Like Growth Factor I/therapeutic use , Laron Syndrome/drug therapy , Child , Female , Humans , Hyperglycemia/blood , Hyperglycemia/complications , Laron Syndrome/blood , Laron Syndrome/complications , Recombinant Proteins/therapeutic useABSTRACT
OBJECTIVE: The established causes of GH insensitivity include defects of the GH receptor and STAT5B. The latter condition is also characterized by severe immunodeficiency. A recent case with short stature, GH resistance, and immunodeficiency due to an IκB mutation suggests that the NF-κB pathway may interact with STAT5B signaling. DESIGN: Here, we present a case of a short child with several congenital anomalies as well as GH insensitivity and mild immunodeficiency associated with a mosaic de novo duplication of chromosome 17q21-25, suggesting that overexpression of one of the duplicated genes may be implicated in GH resistance. METHODS AND RESULTS: In vitro studies on blood lymphocytes showed disturbed signaling of the CD28 pathway, involving NF-κB and related proteins. Functional studies on cultured skin fibroblasts revealed that NF-κB activation, PI3K activity, and STAT5 phosphorylation in response to GH were suppressed, while the sensitivity to GH in terms of MAPK phosphorylation was increased. An in silico analysis of the duplicated genes showed that MAP3K3 and PRKCA are associated with the NF-κB pathway. Baseline MAP3K3 expression in T-cell blasts (TCBs) was normal, but PRKCA expression in TCBs and fibroblasts was significantly higher than that in control cells. CONCLUSIONS: We conclude that the 17q21-25 duplication is associated with GH insensitivity and disturbed STAT5B, PI3K, and NF-κB signaling, possibly due to PRKCA mRNA overexpression.
Subject(s)
CD28 Antigens/metabolism , Chromosome Duplication , Chromosomes, Human, Pair 17/genetics , Laron Syndrome/genetics , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , STAT5 Transcription Factor/metabolism , Cells, Cultured , Child, Preschool , Enzyme Activation , Female , Humans , Laron Syndrome/blood , Laron Syndrome/immunology , Mosaicism , STAT5 Transcription Factor/genetics , Signal Transduction/genetics , Signal Transduction/physiology , Transcriptional ActivationABSTRACT
The IGF1 generation test (IGFGT) is often used during the assessment of suspected GH insensitivity (GHI). We report the results of a survey undertaken in 2010 to determine the use of IGFGT amongst members of the European Society for Paediatric Endocrinology to evaluate suspected GHI. The literature surrounding the usefulness and limitations of IGFGT are reviewed, and recommendations provided for its use. Of 112 paediatric endocrinologists from 30 countries who responded to the survey, 91 (81%) reported that they had used the IGFGT in the previous 2 years; >10 IGFGT protocols were used. The IGFGT impacted treatment decisions for 97% of the respondents and was a prerequisite for recombinant human IGF1 treatment for 45% of respondents. From a literature review, sensitivity of the IGFGT was evaluated as 77-91% in molecularly proven cases of GHI; specificity was ≤97%, depending on the protocol. The positive predictive value of the IGFGT is likely to be low, as the frequency of normality is predictably higher than that of abnormality in GH signalling. Given the limitations of the IGFGT in the most severe cases of GHI syndrome (GHIS), the ability of the IGFGT to detect less severe GHIS is doubtful. In a pragmatic approach, the IGFGT may not be useful for the diagnosis of GHIS.
Subject(s)
Growth Disorders/diagnosis , Growth Disorders/physiopathology , Growth Hormone/physiology , Insulin-Like Growth Factor I/biosynthesis , Laron Syndrome/diagnosis , Laron Syndrome/physiopathology , Body Height/physiology , Child , Growth Disorders/blood , Growth Hormone/blood , Humans , Insulin-Like Growth Factor I/physiology , Laron Syndrome/blood , Predictive Value of Tests , Severity of Illness IndexABSTRACT
BACKGROUND: The role of growth hormone, insulin, and insulin-like growth factor-1 (IGF-1) in the development of acne is incompletely understood. OBJECTIVE: To study the effect of the absence of IGF-1 and its pharmacologic replacement on the occurrence of acne vulgaris. PATIENTS AND METHODS: Laron syndrome (LS) is characterized by congenital IGF-1 deficiency. The study group consisted of 21 patients with classical LS, who underwent puberty: 13 (8 male, 5 female) untreated and under regular follow-up until age 20?48 years; and 8 (2 male, 6 female) treated with IGF-1 (70-200 µg/kg/day), including 6 adults (2 male, treated at age 14.5-29 years and 4 female, treated at age 30-37 years) and 2 adolescents (2 female, treated at age 3.5-16 years). The medical files were reviewed for occurrence of acne and the corresponding sex hormone levels, and the findings were compared between the treated and untreated patients. RESULTS: Puberty was delayed in all untreated patients. Only one patient had slight acne at age 22 years, when he reached full puberty. Among the 2 IGF-1 treated male patients, none acquired acne. Among the 6 treated female patients, 3 had signs of hyperandrogenism (oligo-amenorrhea) and acne during IGF-1 over-dosage. On reduction of the IGF-1 dose (to 50 µg/kg/day) or cessation of treatment, the acne disappeared in all 3 patients. CONCLUSION: This study demonstrates for the first time that serum IGF-1 deficiency prevents the occurrence of acne. The findings suggest that an interaction between IGF-1 and androgens is necessary for the development of acne.
Subject(s)
Acne Vulgaris/etiology , Insulin-Like Growth Factor I/deficiency , Insulin-Like Growth Factor I/therapeutic use , Laron Syndrome/drug therapy , Acne Vulgaris/blood , Adolescent , Adult , Androstenedione/blood , Child , Child, Preschool , Female , Follicle Stimulating Hormone, Human/blood , Humans , Insulin/blood , Laron Syndrome/blood , Luteinizing Hormone/blood , Luteinizing Hormone/drug effects , Male , Testosterone/blood , Young AdultSubject(s)
Human Growth Hormone/analysis , Acromegaly/blood , Adult , Child , Humans , Laron Syndrome/bloodABSTRACT
Growth Hormone (GH) is a 22 kDa protein that has effects on growth and glucose and fat metabolisms. These effects are initiated by binding of growth hormone (GH) to growth hormone receptors (GHR) expressed in target cells. Mutations or deletions in the growth hormone receptor cause an autosomal disorder called Laron-type dwarfism (LS) characterized by high circulating levels of serum GH and low levels of insulin like growth factor-1 (IGF-1). We analyzed the GHR gene for genetic defect in seven patients identified as Laron type dwarfism. We identified two missense mutations (S40L and W104R), and four polymorphisms (S473S, L526I, G168G and exon 3 deletion). We are reporting a mutation (W104R) at exon 5 of GHR gene that is not previously reported, and it is a novel mutation.
Subject(s)
Laron Syndrome/genetics , Receptors, Somatotropin/genetics , Child , Child, Preschool , Female , Human Growth Hormone/blood , Humans , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/metabolism , Laron Syndrome/blood , Male , Mutation/genetics , Polymerase Chain Reaction , Polymorphism, Genetic/geneticsABSTRACT
We assessed the efficacy and safety of recombinant human insulin-like growth factor 1 (IGF-1) therapy over a period of 7.5 years in a child with severe IGF-1 deficiency. Recombinant human IGF-1 was administered subcutaneously in doses between 40 and 80 microg/kg once daily. Height velocity increased from 2 cm/year on average at baseline to 7.9 cm/year during the first year of treatment. In the following years, growth velocity was less but satisfactory during treatment, but decreased when therapy was stopped.
Subject(s)
DNA/genetics , Insulin-Like Growth Factor I/administration & dosage , Insulin-Like Growth Factor I/genetics , Laron Syndrome/drug therapy , Mutation , Recombinant Proteins/administration & dosage , Child , DNA Mutational Analysis , Follow-Up Studies , Humans , Injections, Subcutaneous , Insulin-Like Growth Factor I/deficiency , Laron Syndrome/blood , Laron Syndrome/genetics , Male , Time FactorsABSTRACT
OBJECTIVE: Patients with Laron syndrome (LS; primary GH insensitivity) caused by molecular defects of the GH receptor gene, are characterized by dwarfism, profound obesity, and hyperlipidemia. The aim of the current study was to evaluate adiponectin levels in LS, as obesity is known to be associated with low adiponectin. DESIGN AND METHODS: We studied nine untreated LS adult patients (5 males, 4 females) and six girls with LS receiving once-daily treatment by IGF1. Total and high molecular weight (HMW) adiponectin levels, adiponectin multimers distribution, and metabolic indices were analyzed in serum samples obtained during several years of follow-up. RESULTS: Adiponectin levels in the severely obese adult LS patients (percent body fat; females 61.0+/-2.5%, males 40.6+/-8.1%) were two- to three-fold higher than those reported for subjects of corresponding age, gender and degree of adiposity. Total adiponectin was significantly higher in females compared with males (21.4+/-3.5 vs 10.2+/-4.6 microg/ml, P<0.001). The elevated adiponectin in LS subjects was associated with an increased abundance of the HMW isoform, and positively correlated with body fat percentage (r=0.65, P=0.017) and leptin (r=0.65, P=0.012). There was no correlation between adiponectin levels (total and HMW) and the degree of insulin resistance in LS subjects or their blood lipids levels. Adiponectin was also high in young girls with LS (22.9+/-7.4 microg/ml) and did not change during long-term IGF1 replacement therapy. CONCLUSION: Adiponectin hypersecretion in LS, despite profound obesity, suggests that GH activity may negatively impact adiponectin secretion from adipocytes.
Subject(s)
Adiponectin/blood , Laron Syndrome/blood , Adolescent , Adult , Child, Preschool , Female , Humans , Insulin-Like Growth Factor I/therapeutic use , Laron Syndrome/complications , Laron Syndrome/drug therapy , Male , Middle Aged , Molecular Weight , Obesity/blood , Protein MultimerizationABSTRACT
BACKGROUND: To date, about sixty different mutations within GH receptor (GHR) gene have been described in patients with GH insensitivity syndrome (GHI). In this report, we described a novel nonsense mutation of GHR. METHODS: The patient was evaluated at the age of 6 yr, for short stature associated to clinical phenotype of GHI. GH, IGF-1, and GHBP levels were determined. The PCR products from exons 2-10 were sequenced. RESULTS: The patient had high GH (26 µg/L), low IGF-1 (22.5 ng/ml) and undetectable GHBP levels. The sequencing of GHR exon 5 disclosed adenine duplication at nucleotide 338 of GHR coding sequence (c.338dupA) in homozygous state. CONCLUSION: We described a novel mutation that causes a truncated GHR and a loss of receptor function due to the lack of amino acids comprising the transmembrane and intracellular regions of GHR protein, leading to GHI.
INTRODUÇÃO: Até o momento, aproximadamente 60 diferentes mutações envolvendo o gene do receptor do GH (GHR) foram descritas em pacientes com a síndrome de insensibilidade ao GH (GHI). Neste artigo, descrevemos uma nova mutação nonsense do GHR. MÉTODOS: O paciente foi avaliado aos 6 anos de idade para baixa estatura associada ao fenótipo clínico da GHI. Níveis de GH, IGF-1 e GHBP foram determinados. Os produtos de PCR dos éxons 2-10 foram seqüenciados. RESULTADOS: O paciente apresentou níveis elevados de GH (26 µg/L), baixos de IGF-1 (22.5 ng/ml) e indetectáveis de GHBP. O seqüenciamento do éxon 5 do GHR revelou uma duplicação da adenina no nucleotídeo 338 da sequência de codificação do GHR (c.338dupA) em homozigose. CONCLUSÃO: Descrevemos uma nova mutação que causa um GHR truncado e uma perda da função do receptor devido à perda de aminoácidos compreendendo as regiões transmembrana e intracelular do receptor, levando a GHI.
Subject(s)
Child , Humans , Male , Codon, Nonsense/genetics , Laron Syndrome/genetics , Membrane Proteins/genetics , Carrier Proteins/blood , Growth Hormone/blood , Homozygote , Insulin-Like Growth Factor I/analysis , Laron Syndrome/blood , Sequence Analysis, DNAABSTRACT
It is reported in this study the clinical, laboratory and genetic aspects of short stature investigation with emphasis to the diagnostic approach of growth hormone insensitivity (GHI). This patient in case presented typical clinical features of GHI and his laboratory findings at prepubertal age were typical of those observed in GHI patients (low IGF-1 and IGFBP-3 levels, with high basal and stimulated GH levels). However, during the puberty, he presented normal IGFBP-3 and IGF-1 levels that hindered the diagnosis. The molecular study disclosed a mutation in exon 7 of growth hormone receptor gene (S226I). The steps that demonstrated the causative effect of this mutation are shown here, and also a review of Brazilian GHI cases is given and new molecular defects in this field are discussed as well.
Subject(s)
Laron Syndrome/diagnosis , Adolescent , DNA Mutational Analysis , Exons/genetics , Human Growth Hormone/blood , Human Growth Hormone/genetics , Humans , Insulin-Like Growth Factor Binding Protein 3/blood , Insulin-Like Growth Factor I/analysis , Laron Syndrome/blood , Laron Syndrome/genetics , Male , Phenotype , Receptors, Somatotropin/geneticsABSTRACT
Neste artigo são descritos os aspectos clínicos, laboratoriais e genéticos da investigação da baixa estatura, dando ênfase para o diagnóstico da insensibilidade ao hormônio de crescimento (IGH). O paciente apresentado possuía características clínicas típicas de pacientes com IGH e em idade pré-púbere seus achados laboratoriais eram compatíveis com este diagnóstico (IGF-1 e IGFBP3 baixos, GH basal e pós-estímulo elevados). No entanto, quando avaliado durante a puberdade, as dosagens de IGF-1 e IGFBP-3 foram normais, dificultando o diagnóstico. O estudo molecular identificou mutação no exon 7 do gene do receptor do hormônio de crescimento (S226I). Discutiram-se os passos realizados para identificar a mutação e demonstrar que ela é responsável pelo fenótipo observado no paciente. Também será feita revisão dos casos de IGH descritos no Brasil e dos novos defeitos moleculares descritos nesta doença.
It is reported in this study the clinical, laboratory and genetic aspects of short stature investigation with emphasis to the diagnostic approach of growth hormone insensitivity (GHI). This patient in case presented typical clinical features of GHI and his laboratory findings at prepubertal age were typical of those observed in GHI patients (low IGF-1 and IGFBP-3 levels, with high basal and stimulated GH levels). However, during the puberty, he presented normal IGFBP-3 and IGF-1 levels that hindered the diagnosis. The molecular study disclosed a mutation in exon 7 of growth hormone receptor gene (S226I). The steps that demonstrated the causative effect of this mutation are shown here, and also a review of Brazilian GHI cases is given and new molecular defects in this field are discussed as well.
Subject(s)
Adolescent , Humans , Male , Laron Syndrome/diagnosis , DNA Mutational Analysis , Exons/genetics , Human Growth Hormone/blood , Human Growth Hormone/genetics , /blood , Insulin-Like Growth Factor I/analysis , Laron Syndrome/blood , Laron Syndrome/genetics , Phenotype , Receptors, Somatotropin/geneticsABSTRACT
Growth hormone (GH), secreted by the anterior pituitary into the circulation, binds to membrane receptors in target tissues to stimulate body growth; most of its effects is mediated by the insulin-like growth factor 1 (IGF-1). In addition to promoting growth, GH has important metabolic actions. The syndrome of GH insensitivity (GHI) was first identified in 1966 by Laron et al. in three children with clinical phenotype characteristic of growth hormone deficiency but associated with elevated serum concentration of GH. Direct evidence of a GH receptor (GHR) abnormality was provided in 1989. More recently, molecular abnormalities in the postreceptor signalling mechanism were found. Mutations of signal transducer and activator of transcription 5b (Stat5b) were reported in patients with growth retardation and primary immunodeficiency. Mutations of the tyrosin phosphatase Shp2 were identified in patients affected by Noonan syndrome characterized by short stature, cardiopathy and increased risk of leukaemia. The unmasking of the molecular bases for these defects will contribute greatly to our future understanding of both normal and aberrant growth. Moreover, this knowledge should bring insight on cancerogenesis or immunodeficiency caused by cytokines resistance.