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1.
Orphanet J Rare Dis ; 18(1): 312, 2023 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-37805563

RESUMEN

BACKGROUND: Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care. OBJECTIVE: To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally. METHODS: An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD. RESULTS: As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing. CONCLUSIONS: To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored.


Asunto(s)
Enanismo , Síndrome de Laron , Humanos , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Calidad de Vida , Síndrome de Laron/diagnóstico , Síndrome de Laron/tratamiento farmacológico , Síndrome de Laron/genética , Enanismo/tratamiento farmacológico , Trastornos del Crecimiento
2.
BMC Endocr Disord ; 23(1): 155, 2023 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-37474955

RESUMEN

BACKGROUND: Human growth hormone (hGH) plays a crucial role in growth by binding to growth hormone receptor (GHR) in target cells. Binding of GH molecules to their cognate receptors triggers downstream signaling pathways leading to the transcription of several genes, including insulin-like growth factor (IGF)-1. Pathogenic variants in the GHR gene can result in structural and functional defects in the GHR protein, leading to Laron Syndrome (LS) with the primary clinical manifestation of short stature. So far, around 100 GHR variants have been reported, mostly biallelic, as causing LS. CASE PRESENTATION: We report on three siblings from an Iranian consanguineous family who presented with dwarfism. Whole-exome sequencing (WES) was performed on the proband, revealing a novel homozygous missense variant in the GHR gene (NM_000163.5; c.610 T > A, p.(Trp204Arg)) classified as a likely pathogenic variant according to the recommendation of the American College of Medical Genetics (ACMG). Co-segregation analysis was investigated using Sanger sequencing. CONCLUSIONS: To date, approximately 400-500 LS cases with GHR biallelic variants, out of them 10 patients originating from Iran, have been described in the literature. Given the high rate of consanguineous marriages in the Iranian population, the frequency of LS is expected to be higher, which might be explained by undiagnosed cases. Early diagnosis of LS is very important, as treatment is available for this condition.


Asunto(s)
Enanismo , Hormona de Crecimiento Humana , Síndrome de Laron , Humanos , Receptores de Somatotropina/genética , Receptores de Somatotropina/metabolismo , Síndrome de Laron/genética , Síndrome de Laron/tratamiento farmacológico , Irán , Consanguinidad , Linaje , Enanismo/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo
3.
Horm Res Paediatr ; 95(6): 619-630, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36446332

RESUMEN

The growth hormone (GH)-insulin-like growth factor (IGF) cascade is central to the regulation of growth and metabolism. This article focuses on the history of the components of the IGF system, with an emphasis on the peptide hormones, IGF-I and -II, their cell surface receptors, and the IGF binding proteins (IGFBPs) and IGFBP proteases that regulate the availability of the peptide hormones for interaction with their receptors in relevant target tissues. We describe landmark events in the evolution of the somatomedin hypothesis, including evidence that has become available from experiments at the molecular and cellular levels, whole animal and tissue-specific gene knockouts, studies of cancer epidemiology, identification of prismatic human cases, and short- and long-term clinical trials of IGF-I therapy in humans. In addition, this new evidence has expanded our clinical definition of GH insensitivity (GHI) beyond growth hormone receptor mutations (classic Laron syndrome) to include conditions that cause primary IGF deficiency by impacting post-receptor signal transduction, IGF production, IGF availability to interact with the IGF-I receptor (IGF-1R), and defects in the IGF-1R, itself. We also discuss the clinical aspects of IGFs, from their description as insulin-like activity, to the use of IGF-I in the diagnosis and treatment of GH deficiency, and to the use of recombinant human IGF-I for therapy of children with GHI.


Asunto(s)
Factor II del Crecimiento Similar a la Insulina , Factor I del Crecimiento Similar a la Insulina , Síndrome de Laron , Animales , Humanos , Factor I del Crecimiento Similar a la Insulina/deficiencia , Factor I del Crecimiento Similar a la Insulina/historia , Factor I del Crecimiento Similar a la Insulina/fisiología , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Síndrome de Laron/genética , Síndrome de Laron/historia , Síndrome de Laron/fisiopatología , Hormonas Peptídicas , Procesamiento Proteico-Postraduccional , Transducción de Señal , Somatomedinas/deficiencia , Somatomedinas/historia , Somatomedinas/fisiología , Factor II del Crecimiento Similar a la Insulina/deficiencia , Factor II del Crecimiento Similar a la Insulina/historia , Factor II del Crecimiento Similar a la Insulina/fisiología , Factor II del Crecimiento Similar a la Insulina/uso terapéutico
4.
Gene Ther ; 29(6): 346-356, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35105948

RESUMEN

The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The response is suboptimal and associated with progressive obesity. In this study, we treated 4-5-week-old Laron dwarf mice (GHR-/-) with an adeno-associated virus expressing murine GHR (AAV-GHR) injection at a dose of 4 × 1010 vector genome per mouse. Serum growth hormone (GH) levels decreased, and GH-responsive IGF1, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS) increased. There was a significant but limited increase in body weight and length, similar to the response to rhIGF1 treatment in LS patients. All the major organs increased in weight except the brain. Our study is the first to use gene therapy to treat GH-receptor deficiency. We propose that gene therapy with AAV-GHR may eventually be useful for the treatment of human LS.


Asunto(s)
Hormona del Crecimiento , Síndrome de Laron , Animales , Modelos Animales de Enfermedad , Terapia Genética , Hormona del Crecimiento/genética , Hormona del Crecimiento/uso terapéutico , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Síndrome de Laron/terapia , Ratones , Receptores de Somatotropina/genética , Receptores de Somatotropina/metabolismo , Receptores de Somatotropina/uso terapéutico
5.
Eur J Endocrinol ; 184(2): 267-276, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33434161

RESUMEN

OBJECTIVE: The European Increlex® Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin, Increlex®) therapy in patients with severe primary IGF1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS). DESIGN: Ongoing, open-label, observational registry (NCT00903110). METHODS: Children and adolescents receiving rhIGF1 therapy from 10 European countries were enrolled in 2008-2017 (n = 242). The treatment-naïve/prepubertal (NPP) cohort (n = 138) was divided into subgroups based on reported genetic diagnosis of LS (n = 21) or non-LS (n = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score (SDS) gain ≥ 0.3). Assessments included change in height and weight over 5 years and adverse events (AEs). RESULTS: Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years' treatment (P < 0.05). In the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P < 0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 years vs 7.00 years) at baseline and height SDS gain in year 1 (0.64 vs 0.70), although NPP-non-LS-responders were taller (P < 0.001) at baseline. BMI SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common. CONCLUSIONS: In most NPP children with SPIGFD, with or without LS, rhIGF1 therapy promotes linear growth. The safety profile was consistent with previous studies.


Asunto(s)
Trastornos del Crecimiento/tratamiento farmacológico , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Factor I del Crecimiento Similar a la Insulina/deficiencia , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Adolescente , Estatura , Peso Corporal/efectos de los fármacos , Niño , Femenino , Crecimiento/efectos de los fármacos , Humanos , Hipoglucemia/sangre , Hipoglucemia/inducido químicamente , Síndrome de Laron/genética , Estudios Longitudinales , Masculino , Seguridad del Paciente , Pubertad , Resultado del Tratamiento , Adulto Joven
6.
Growth Horm IGF Res ; 51: 22-26, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31982729

RESUMEN

The efficacy and safety of IGF-1 therapy in patients with severe primary IGF-I deficiency has been evaluated for more than two decades. Most of the therapeutic experience comes from treating the more severe IGF-I deficient patients, who usually present with a phenotype characteristic of growth hormone receptor deficiency or Laron syndrome. Although most of these patients do not experience enough catchup growth to bring their height into normal range, many individuals achieve an adult height significantly greater than what would have been predicted in the absence of IGF-1 therapy. In the last couple of years a few reports on the benefit of IGF-1 therapy for patients with milder types of IGF-I deficiency have also been published, with variable height outcomes. More short children with prior diagnosis of idiopathic short stature are now being diagnosed with specific molecular defects of the growth hormone/IGF-I axis. Because of this, the clinical spectrum of primary IGF-I deficiency is widening to include many patients with such a milder phenotype, creating a need for well-designed long-term clinical studies evaluating the growth response to growth promoting agents such as rhIGF-1 in these individuals.


Asunto(s)
Factor I del Crecimiento Similar a la Insulina/deficiencia , Síndrome de Laron/tratamiento farmacológico , Niño , Preescolar , Hormona de Crecimiento Humana/metabolismo , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Pruebas de Función Hipofisaria , Receptores de Somatotropina/genética , Proteínas Recombinantes , Índice de Severidad de la Enfermedad
7.
J Pediatr Endocrinol Metab ; 31(8): 895-902, 2018 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-29995632

RESUMEN

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.


Asunto(s)
Biomarcadores/sangre , Trastornos del Crecimiento/sangre , Pérdida Auditiva Sensorineural/sangre , Factor I del Crecimiento Similar a la Insulina/deficiencia , Síndrome de Laron/sangre , Proteínas Recombinantes/administración & dosificación , Adolescente , Adulto , Glucemia/análisis , Niño , Estudios de Seguimiento , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/patología , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Pérdida Auditiva Sensorineural/patología , Humanos , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/administración & dosificación , Factor I del Crecimiento Similar a la Insulina/análisis , Síndrome de Laron/tratamiento farmacológico , Síndrome de Laron/patología , Masculino , Pronóstico , Adulto Joven
8.
J Pediatr Endocrinol Metab ; 31(6): 675-679, 2018 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-29750649

RESUMEN

BACKGROUND: Laron syndrome (LS), which can be defined as primary growth hormone resistance or insensitivity, is a rare genetic disease inherited by an autosomal recessive trait. Although it is undistinguishable from growth hormone deficiency, LS has high levels of growth hormone, but insulin-like growth factor (IGF-1) cannot be synthesized. Mecasermin treatment is the only option for the patients who suffer from LS. This study aims to research cardiac findings of children with LS, who receive treatment with mecasermin. METHODS: The study enrolled five children four males and one female, 4 M/1 F with LS, two of whom were siblings with a mean age of 6.3±2.1 years, a body weight of 13.36±4.74 kg, a height of 88±8.7 cm, and a body mass index (BMI) of 16.47±3.35. Their demographic data were obtained from their family and files. The children received mecasermin via subcutaneous injection at 0.04-0.12 µg/kg doses twice per day. The duration of mecasermin treatment was 8-53 months. All of them were examined clinically by electrocardiogram and echocardiogram. RESULTS: Their cardiac examinations were normal, except for one case, who had systolic murmur at cardiac auscultation. Arrhythmia was not observed on their electrocardiograms. The echocardiograms did not show a significant congenital cardiac anomaly. Their cardiac measure and functions were within normal ranges. The echocardiogram of the child with the murmur showed mitral and tricuspid insufficiency. The Doppler images showed pulmonary hypertension findings. These findings were proven by angiography. The vasoreactivity test results of that patient were negative. No reason could be found for the observed pulmonary hypertension. We diagnosed this finding as a primary pulmonary hypertension and Bosentan therapy was started. CONCLUSIONS: In this study, we showed that cardiac findings were consistent with previous studies. To the best of our knowledge, the observed pulmonary hypertension in children with LS, who received treatment with or without mecasermin, is reported for first time in the literature.


Asunto(s)
Corazón/efectos de los fármacos , Corazón/diagnóstico por imagen , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Niño , Preescolar , Ecocardiografía , Femenino , Corazón/fisiopatología , Humanos , Lactante , Síndrome de Laron/complicaciones , Síndrome de Laron/diagnóstico , Masculino , Insuficiencia de la Válvula Mitral/complicaciones , Insuficiencia de la Válvula Mitral/diagnóstico
9.
Eur J Endocrinol ; 178(5): 481-489, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29500309

RESUMEN

BACKGROUND: Patients with homozygous intronic pseudoexon GH receptor (GHR) mutations (6Ψ) have growth hormone insensitivity (GHI) (growth failure, IGF1 deficiency and normal/elevated serum GH). We report 9 patients in addition to previously described 11 GHR 6Ψ patients and their responses to rhIGF1 therapy. METHODS: 20 patients (12 males, 11 families, mean age 4.0 ± 2.2 years) were diagnosed genetically in our centre. Phenotypic data and responses to rhIGF1 treatment were provided by referring clinicians. Continuous parametric variables were compared using Student t-test or ANOVA. RESULTS: 10/20 (50%) had typical facial features of GHI, 19/20 (95%) from consanguineous families and 18/20 (90%) of Pakistani origin. At diagnosis, mean height SDS: -4.1 ± 0.95, IGF1 SDS: -2.8 ± 1.4; IGFBP3 SDS: -3.0 ± 2.1 and mean basal and peak GH levels: 11.9 µg/L and 32.9 µg/L, respectively. 1/12 who had IGF1 generation test, responded (IGF1: 132-255 ng/mL). 15/20 (75%; 11M) received rhIGF1 (mean dose: 114 µg/kg twice daily, mean duration: 5.3 ± 2.5 years). Mean baseline height velocity of 4.7 ± 1.1 cm/year increased to 7.4 ± 1.8 cm/year (P = 0.001) during year 1 of therapy. Year 3 mean height SDS (-3.2 ± 1.0) was higher than pre-treatment height SDS (-4.3 ± 0.8) (P = 0.03). Mean cumulative increase in height SDS after year 5 was 1.4 ± 0.9. Difference between target height (TH) SDS and adult or latest height SDS was less than that of TH SDS and pre-treatment height SDS (2.1 ± 1.2 vs 3.0 ± 0.8; P = 0.02). CONCLUSION: In addition to phenotypic heterogeneity in the cohort, there was mismatch between clinical and biochemical features in individual patients with 6Ψ GHR mutations. rhIGF1 treatment improved height outcomes.


Asunto(s)
Trastornos del Crecimiento/prevención & control , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Mutación Puntual , Receptores de Somatotropina/agonistas , Receptores de Somatotropina/genética , Estatura/efectos de los fármacos , Niño , Preescolar , Consanguinidad , Resistencia a Medicamentos , Inglaterra , Salud de la Familia , Femenino , Trastornos del Crecimiento/etiología , Homocigoto , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Intrones , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Síndrome de Laron/fisiopatología , Masculino , Pakistán/etnología , Receptores de Somatotropina/metabolismo , Proteínas Recombinantes/uso terapéutico
10.
Growth Horm IGF Res ; 28: 62-5, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26822565

RESUMEN

Normal linear growth in humans requires GH and IGF-I. Diminished GH action resulting in reduced availability of IGF-I and IGF-binding proteins is the hallmarks of GH Insensitivity Syndromes (GHIS). The deficiencies are the perceived mechanisms for the growth failure of affected patients and the therapeutic targets for the restoration of normal growth. Early treatment attempts with pituitary-derived GH had limited effects in GHIS patients. Recombinant human insulin-like growth factor-I (rhIGF-I) treatment initially provides accelerated growth to GHIS children and provides substantial benefit. But, in general, catch up growth is less substantial with rhIGF-I treatment of GHIS than with rhGH treatment of GH Deficiency. Few classic GHIS patients have reached heights in the normal range (height SD score between -2.0 SD and +2.0 SD) with rhIGF-I monotherapy. A potential explanation is that while rhIGF-I treatment increases circulating concentrations of IGF-1 and IGFBP-3, such treatment reduces endogenous GH levels by negative feedback inhibition of pituitary GH release. In as much as both GH and IGF-I are required for good catch up growth, the loss of any residual GH signaling during IGF-I monotherapy in GHIS patients may attenuate possible catch up growth. Consistent with this explanation is the finding that, as predicted by the preclinical studies by Ross Clark, combination of rhGH & rhIGF-1 provides better growth responses than rhIGF-1 monotherapy in prepubertal children with short stature and low IGF-I levels despite normal stimulated GH responses. In the future, rhGH and rhIGF-I combination therapy can potentially improve growth outcomes over that seen with rhIGF-I monotherapy in all GHIS patients except in those with a total lack of functional GH signaling. Future alternative treatments for GHIS subjects may also include the use of post-growth hormone receptor signaling agonists which restore both GH signaling and IGF-I exposures or the addition of long-acting rhGH species to rhIGF-I. Additional etiologic factors for the growth failure in GHIS should be considered if the growth deficits of GHIS do not resolve with treatment.


Asunto(s)
Hormona de Crecimiento Humana/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Quimioterapia Combinada , Humanos , Proteínas Recombinantes/uso terapéutico
12.
Ophthalmic Genet ; 37(1): 53-8, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-25078475

RESUMEN

BACKGROUND: The purpose of this study was to assess retinal vascular characteristics of patients with Laron syndrome (LS) as a genetic model of IGF-I deficiency before and after rhIGF1/IGFBP3 treatment and to compare them with healthy controls. METHODS: A total of 28 subjects (11 LS, and 17 controls) were enrolled. Patients with LS received combined rhIGF1/rhIGFBP3 1-2 mg/kg/d in a single dose and digital fundus imaging was performed. The number of branching points and tortuosity of retinal vessels were studied. Pre- and post-treatment findings were compared with each other and with controls. RESULTS: The number of branching points was significantly lower in patients with LS in comparison to controls (12.73 ± 3.41, and 17.47 ± 5.82 respectively, p = 0.012). This difference persisted after treatment (12.09 ± 2.66 post-treatment LS versus controls, p = 0.017). Tortuosity indices of nasal arteries (NA) were significantly less in LS than that of controls (upper NA 1.07 ± 0.04 and 1.12 ± 0.06 respectively p = 0.022; lower NA 1.07 ± 0.03 and 1.13 ± 0.07 respectively, p = 0.004). This difference also persisted following treatment (p < 0.05). Remaining vessels did not differ in tortuosity index. There was no significant difference of tortuosity index and number of branching points before and after treatment in patients with LS. CONCLUSION: Retinal vascular development may be adversely affected in the setting of severe IGF-I deficiency confirming a major role for GH/IGF-I axis during retinal vascular development in humans antenatally. Resolution of IGF-I deficiency following birth using rhIGF1, however, may not reverse these changes, suggesting that IGF-I may be necessary but insufficient by itself for postnatal angiogenesis.


Asunto(s)
Trastornos del Crecimiento/fisiopatología , Hormona del Crecimiento/fisiología , Pérdida Auditiva Sensorineural/fisiopatología , Factor I del Crecimiento Similar a la Insulina/deficiencia , Factor I del Crecimiento Similar a la Insulina/fisiología , Síndrome de Laron/fisiopatología , Enfermedades de la Retina/fisiopatología , Vasos Retinianos/patología , Niño , Combinación de Medicamentos , Femenino , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/tratamiento farmacológico , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/tratamiento farmacológico , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/diagnóstico , Síndrome de Laron/tratamiento farmacológico , Masculino , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/tratamiento farmacológico , Agudeza Visual/fisiología
13.
Growth Horm IGF Res ; 28: 46-50, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26276451

RESUMEN

UNLABELLED: A growth hormone (GH) dependent substance responsible for sulfate uptake by costal cartilage of hypophysectomized rats, labeled sulfation factor, was reported in 1957. In 1962 the radioimmunoassay for GH was described. The clinical picture of severe GH deficiency but with high serum concentrations of GH was reported in 3 siblings in 1966 and followed by a 1968 report of 22 patients belonging to 14 consanguineous oriental Jewish families in Israel. Defective sulfation factor generation was demonstrated in 15 of these individuals and in a 1971 report; FFA response to IV GH and growth response to GH injections suggested competitive saturation of peripheral tissue receptors by an abnormal GH. However, studies published in 1973 demonstrated normal fractionation of their circulating GH, and normal binding of GH from 22 patients to various antisera used for radioimmunoassay. In 1976, the Israeli investigators reported that circulating GH from 7 patients reacted normally in the recently developed radioreceptor assay for GH. In 1984, using hepatic microsome pellets, they demonstrated that the defect was a failure of GH binding to receptors. Characterization of the human GH receptor (GHR) gene, reported in 1989, included the initial description of a genetic defect of the GHR in 2 of 9 Israeli patients. At about the same time began the identification in Ecuador of what was to become the largest population of GH insensitivity in the world, ~100 individuals, and the only substantial population with a common mutation of the GH receptor. Treatment studies with recombinant IGF-I began in 1990. Growth response was modest compared to that of GH treated GH deficient subjects. The spectrum of GH insensitivity has expanded beyond GH receptor deficiency to include postreceptor abnormalities: IGF-I gene mutation (1996); IGF-I receptor mutation (2003); signal transducer and activator of transcription 5b mutation (2003); and mutation of the GH-dependent acid labile subunit (2004). CONCLUSION: Rare conditions of GH insensitivity caused by GH receptor and postreceptor abnormalities have provided insights into the processes of growth, body composition, and metabolism.


Asunto(s)
Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/diagnóstico , Ecuador , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Síndrome de Laron/tratamiento farmacológico , Síndrome de Laron/genética , Síndrome de Laron/historia , Obesidad/inducido químicamente , Receptor IGF Tipo 1/genética , Receptores de Somatotropina/genética , Proteínas Recombinantes , Factor de Transcripción STAT5/genética
14.
Growth Horm IGF Res ; 28: 53-6, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26307357

RESUMEN

Clinical and laboratory investigations of dwarfed children newly Jewish immigrants from Yemen and Middle East and who resembled patients with isolated growth hormone deficiency were started by our group in 1958. In 1963 when we found that they have high serum levels of hGH, we knew that we had discovered a new disease of primary GH insensitivity. It was subsequently coined Laron Syndrome (LS, OMIM #262500). The etiopathogenesis was disclosed by 2 liver biopsies demonstrating a defect in the GH receptor. Subsequent investigations demonstrated deletions or mutations in the GHR gene. The defect lead to an inability of IGF-I generation, resulting in severe dwarfism, obesity, and other morphologic and biochemical pathologies due to IGF-I deficiency. With the biosynthesis of IGF-I in 1986, therapeutic trials started. Following closely our cohort of 69 patients with LS enabled us to study its features in untreated and IGF-I treated patients. This syndrome proved to be a unique model to investigate the effects of IGF-I dissociated from GH stimulation. In recent studies we found that homozygous patients for the GHR mutations are protected lifelong from developing malignancies, opening new directions of research.


Asunto(s)
Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Israel , Judíos , Síndrome de Laron/epidemiología , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Masculino , Persona de Mediana Edad , Medio Oriente , Neoplasias/epidemiología , Factores Protectores , Receptores de Somatotropina/genética , Adulto Joven
15.
Arq Bras Endocrinol Metabol ; 58(1): 23-9, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24728160

RESUMEN

OBJECTIVES: GH therapy is still controversial, except in severe GH deficiency (SGHD). The objective of this study was to compare the response to growth hormone (GH) therapy in children with partial GH insensitivity (PGHIS) and mild GH deficiency (MGHD) with those with SGHD. SUBJECTS AND METHODS: Fifteen PGHIS, 11 MGHD, and 19 SGHD subjects, followed up for more than one year in the Brazilian public care service, were evaluated regarding anthropometric and laboratory data at the beginning of treatment, after one year (1st year) on treatment, and at the last assessment (up to ten years in SGHD, up to four years in MGHD, and up to eight years in PGHIS). RESULTS: Initial height standard deviation score (SDS) in SGHD was lower than in MGHD and PGHIS. Although the increase in 1 st year height SDS in comparison to initial height SDS was not different among the groups, height-SDS after the first year of treatment remained lower in SGHD than in MGHD. There was no difference in height-SDS at the last assessment of the children among the three groups. GH therapy, in the entire period of observation, caused a trend towards lower increase in height SDS in PGHIS than SGHD but similar increases were observed in MGHD and SGHD. CONCLUSION: GH therapy increases height in PGHIS and produces similar height effects in MGHD and SGHD.


Asunto(s)
Hormona de Crecimiento Humana/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/análisis , Síndrome de Laron/tratamiento farmacológico , Adolescente , Determinación de la Edad por el Esqueleto , Análisis de Varianza , Estatura/efectos de los fármacos , Índice de Masa Corporal , Brasil , Niño , Hormona de Crecimiento Humana/sangre , Humanos , Mediciones Luminiscentes , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos
16.
Horm Res Paediatr ; 81(4): 258-65, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24642532

RESUMEN

BACKGROUND/AIM: Growth hormone insensitivity syndrome (GHIS) is a spectrum of disorders. Laron syndrome was the earliest discovered. Insulin-like growth factor 1 (IGF-1) therapy is used to improve growth. IGF-1 has diverse effects on the growth of body organs. We aim to assess the long-term effects of IGF-1 therapy in patients with GHIS particularly on adiposity and acral growth. METHODS: Six patients (5 with Laron syndrome and 1 with type 1A growth hormone deficiency) were followed for a mean (±SD) of 8.2 ± 1.8 years. Mean age at start of therapy was 7.6 ± 4.1 years. Anthropometric evaluation including growth of hand, foot, ear, and skin folds, and assessment of internal organ growth were done. RESULTS: Hand and foot sizes improved significantly, especially when treatment was initiated early. Prominent effects on adiposity were observed, reflected by increment in body mass index standard deviation score (SDS) and skin fold SDS. Mean height, height velocity, sitting height, and head circumference SDS improved with therapy. A significant increase in spleen and right kidney was appreciated. CONCLUSION: IGF-1 therapy improves growth in GHIS. The hand and foot sizes increase significantly with therapy, and can even normalize with early initiation of treatment. Ear length further improves with therapy. Other effects include increase in adiposity and internal organ growth.


Asunto(s)
Adiposidad/efectos de los fármacos , Estatura/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Adolescente , Niño , Preescolar , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Masculino , Proteínas Recombinantes/farmacología , Resultado del Tratamiento , Adulto Joven
17.
Obes Res Clin Pract ; 8(1): e55-62, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24548577

RESUMEN

OBJECTIVE: To evaluate changes in adiposity in congenital GH/IGF-1 deficient children during hGH or IGF-1 treatment. SUBJECTS AND METHODS: 27 children with congenital isolated growth hormone deficiency (cIGHD) treated with hGH for 2.5-€“15.2 years (mean 10.0 ± 3.4), 18 children with congenital multiple pituitary hormone deficiency (cMPHD), treated with hGH for 2.3-€“17.9 years (mean 6.1 ± 4.3), and 14 children with Laron syndrome (LS) treated with IGF-1 for 1.2-12 years (mean 5.5 ± 3.7) were studied. Changes in the degree of adiposity were evaluated by subscapular skinfold thickness (SSFT), before, during and up to 2 years after treatment. All the children had various degrees of obesity. RESULTS: During the pretreatment period, cIGHD patients showed little changes in SSFT (P = 0.45), cMPHD and LS patients showed an increase in SSFT (P = 0.01, P = 0.06 respectively). During the initial 0.6-1.1 years of hGH/IGF-1 treatment, the SSFT decreased in all 3 groups (P < 0.001), while during subsequent years a significant increase in SSFT (P < 0.001) was observed, in all types of patients, notably in females. Only the cIGHD patients demonstrated a significant correlation between the degree of SSFT decrease and height SDS gain (R = -ˆ’0.56, P = 0.002) in the first period of treatment. CONCLUSIONS: Short term replacement therapy of 0.6-€“1.1 years with either hGH or IGF-1, induced a reduction in subscapular subcutaneous fat whereas prolongation of therapy led to an increase in the subcutaneous fat.


Asunto(s)
Adiposidad , Enanismo Hipofisario/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Hipopituitarismo/tratamiento farmacológico , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/tratamiento farmacológico , Grasa Subcutánea/metabolismo , Adolescente , Niño , Preescolar , Enanismo Hipofisario/congénito , Enanismo Hipofisario/metabolismo , Femenino , Hormona de Crecimiento Humana/deficiencia , Humanos , Hipopituitarismo/congénito , Hipopituitarismo/metabolismo , Síndrome de Laron/metabolismo , Masculino , Hormonas Hipofisarias/deficiencia , Escápula , Factores Sexuales , Grosor de los Pliegues Cutáneos
18.
Arq. bras. endocrinol. metab ; 58(1): 23-29, 02/2014. tab
Artículo en Inglés | LILACS | ID: lil-705236

RESUMEN

Objectives: GH therapy is still controversial, except in severe GH deficiency (SGHD). The objective of this study was to compare the response to growth hormone (GH) therapy in children with partial GH insensitivity (PGHIS) and mild GH deficiency (MGHD) with those with SGHD.Subjects and methods: Fifteen PGHIS, 11 MGHD, and 19 SGHD subjects, followed up for more than one year in the Brazilian public care service, were evaluated regarding anthropometric and laboratory data at the beginning of treatment, after one year (1 st year) on treatment, and at the last assessment (up to ten years in SGHD, up to four years in MGHD, and up to eight years in PGHIS).Results: Initial height standard deviation score (SDS) in SGHD was lower than in MGHD and PGHIS. Although the increase in 1 st year height SDS in comparison to initial height SDS was not different among the groups, height-SDS after the first year of treatment remained lower in SGHD than in MGHD. There was no difference in height-SDS at the last assessment of the children among the three groups. GH therapy, in the entire period of observation, caused a trend towards lower increase in height SDS in PGHIS than SGHD but similar increases were observed in MGHD and SGHD.Conclusion: GH therapy increases height in PGHIS and produces similar height effects in MGHD and SGHD.


Objetivos: O tratamento com GH é ainda controverso, salvo na deficiência grave de GH (SGHD). O objetivo deste estudo foi comparar a resposta ao tratamento com GH em indivíduos com insensibilidade parcial ao GH (PGHIS) e na deficiência moderada do GH (MGHD) com SGHD.Sujeitos e métodos: Quinze pacientes com PGHIS, 11 com MGHD e 19 com SGHD, seguidos por mais de um ano no Sistema Único de Saúde, foram avaliados antropométrica e laboratorialmente, no início, com um ano de tratamento e na última avaliação (tempo máximo de dez anos na SGHD, quatro anos na MGHD e oito anos na PGHIS).Resultados: O escore de desvio-padrão (EDP) da estatura inicial foi menor nos indivíduos com SGHD do que naqueles com MGHD e PGHIS. Embora o aumento no EDP da estatura no primeiro ano em comparação com o inicial não fosse diferente entre os grupos, o EDP da altura no primeiro ano de tratamento permaneceu menor na SGHD que na MGHD. Não houve diferença no EDP da estatura na última avaliação entre os três grupos. O tratamento com GH, no período completo da observação, provocou uma tendência a menor aumento no EDP da estatura nos pacientes com PGHIS que naqueles com SGHD, entretanto aumentos semelhantes foram encontrados nos grupos MGHD e SGHD.Conclusão: O tratamento com GH aumentou a estatura nos indivíduos com PGHIS e produziu efeitos similares na estatura em MGHD e SGHD.


Asunto(s)
Adolescente , Niño , Humanos , Hormona de Crecimiento Humana/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/análisis , Síndrome de Laron/tratamiento farmacológico , Determinación de la Edad por el Esqueleto , Análisis de Varianza , Índice de Masa Corporal , Brasil , Estatura/efectos de los fármacos , Hormona de Crecimiento Humana/sangre , Mediciones Luminiscentes , Estudios Retrospectivos , Proteínas Recombinantes/uso terapéutico
19.
Horm Res Paediatr ; 80(6): 397-405, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24296660

RESUMEN

BACKGROUND/AIMS: Mutations in the human growth hormone receptor gene (GHR) are the most common cause of growth hormone insensitivity (GHI) syndrome and insulin-like growth factor (IGF-1) deficiency. The extracellular domain of GHR (encoded by exons 2-7 of the GHR gene) can be proteolytically cleaved to circulate as GH-binding protein (GHBP). METHODS: We evaluated the cause of classical GHI (Laron) phenotypes in 3 siblings. RESULTS: Two brothers (aged 16.5 and 14.9 years) and their half-brother (aged 11.3 years) presented with extreme short stature (height standard deviation score, SDS, of -7.05, -6.34 and -8.02, respectively). The parents were consanguineous and of normal stature. Serum GHBP levels of probands were undetectable and circulating IGF-1 and IGF-binding protein-3 were abnormally low, but GH concentrations were elevated. Molecular analysis of the GHR gene revealed homozygous deletion of exon 3, a common polymorphism, and a novel c.266+83G>T variant within intron 4 which generated a 5' donor splice site. Splicing events from this cryptic 5' donor site resulted in retention of 81 intronic nucleotides in the GHR mRNA. Long-term rhIGF-1 therapy combined with leuprolide depot increased height by +2 to +3 SDS. CONCLUSION: The c.266+83G>T is the second intronic GHR mutation identified that activates a cryptic 5' donor splice site. The abnormal splicing event led to early protein termination and undetectable serum GHBP concentrations. © 2013 S. Karger AG, Basel.


Asunto(s)
Síndrome de Laron/genética , Polimorfismo de Nucleótido Simple , Sitios de Empalme de ARN/genética , Receptores de Somatotropina/genética , Adolescente , Secuencia de Bases , Niño , Humanos , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Intrones/genética , Síndrome de Laron/tratamiento farmacológico , Masculino , Datos de Secuencia Molecular , Linaje , Índice de Severidad de la Enfermedad , Hermanos
20.
J Pediatr Endocrinol Metab ; 26(9-10): 955-8, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23729552

RESUMEN

There are different opinions concerning changes in glucose metabolism in patients with Laron syndrome. In this paper we discuss the treatment results of our patient with Laron syndrome who developed diabetes during late adolescence. A 19-year-old boy with Laron syndrome was referred to our clinic for follow-up. He had been diagnosed with Laron syndrome (LS) at 4 years old and rIGF-1 therapy was initiated. After 4 months the treatment was discontinued. At the age of 17, rIGF-1 therapy was restarted. A height gain of 8.8 cm. was observed during the 2-year treatment period. He was admitted to our hospital at the age of 19 years following discontinuation of the therapy. At that time, his height was 142 cm, and weight for height was 136%. His blood glucose was 85 mg/dL (4.72 mmol/L), insulin was 26.39 pmol/L, and HbA1c was 5.4%. At the age of 20, when he has not been receiving IGF-1 therapy for 1 year, his weight for height was 143 cm. Laboratory evaluation revealed that fasting blood glucose was 176 mg/dL (9.77 mmol/L), fasting insulin was 29.86 pmol/L, and HbA1c was 7.5%. Primary insulin therapy was then initiated. His parents both had a diagnosis of type 2 diabetes. Insulin therapy was switched to oral antidiabetic (OAD) therapy at the end of the second year because of a normal C-peptide level of 0.8 nmol/L under insulin therapy. After 6 months of OAD, HbA1c was 5.7%. The treatment was then switched to IGF-1 therapy, but his blood glucose profile was impaired and OAD therapy was restarted. In conclusion, we observed that genetic susceptibility and abdominal obesity caused type 2 diabetes in this patient. We believe that oral antidiabetic agents and life-style changes may be the appropriate approach when diabetes is developed in LS patients.


Asunto(s)
Diabetes Mellitus Tipo 2/etiología , Síndrome de Laron/fisiopatología , Obesidad Abdominal/fisiopatología , Adulto , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Susceptibilidad a Enfermedades , Monitoreo de Drogas , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Síndrome de Laron/complicaciones , Síndrome de Laron/tratamiento farmacológico , Masculino , Metformina/uso terapéutico , Obesidad Abdominal/complicaciones , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , Adulto Joven
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