Laron syndrome: A tale of two siblings / Journal of the ASEAN Federation of Endocrine Societies

@#Primary growth hormone (GH) resistance or growth hormone insensitivity syndrome, also called Laron syndrome, is a hereditary disease caused by mutations in the GH receptor or in the post-receptor signaling pathway. This disorder is characterized by postnatal growth failure resembling GH deficiency. Differentiating the two conditions is necessary. We present the cases of two siblings, a 16-year-old female and a 9-year-old male, born from a consanguineous union. Both had normal birth weights with subsequent severe short stature and delayed teeth eruption, with no features suggestive of any systemic illness. Serum insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) were both low. Suspecting GH deficiency, provocative testing with clonidine was done revealing peak growth hormone >40 ng/mL in both patients. In view of low IGF1 and IGFBP3 and high GH on stimulation, IGF1 generation test was done for both siblings, with values supporting the diagnosis of GH insensitivity or Laron syndrome.

Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: evidence for a founder effect

ABSTRACT Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation.

Correlation of growth hormone receptor and its signal pathway defects with the phenotype: A study of 21 cases with growth hormone insensitivity syndrome / 中华内分泌代谢杂志

Objective To detect the relationship between the molecular defects and their phenotypes in children with growth hormone insensitivity syndrome (GHIS).Methods 21 patients defined as GHIS were enrolled in the study.4 candidate genes (GHR,IGFALS,JAK2,and STAT5B) were analyzed by genomic DNA sequence screening and clinical relevance analysis.Results The statistical descriptions of the patients were showed as an average height standard deviation (SDS)-4.33 ± 1.91 (-9.17 to-2.21),average serum peak values of GH (22.67 ±20.98) tg/L (11.33 to 104.21 μg/L),basal serum insulin-like growth factor-Ⅰ SDS-2.65 ± 0.53 (-3.57 to -1.79),insulin-like growth factor-binding protein 3 SDS-1.77 ± 1.64 (-4.13 to 0.96).Bone age of backward difference (chronological age-bone age) (43.10 ± 19.54) months (6 to 82 months).One of two children with severe growth failure and mid-face hypoplasia was found to a homozygote for G to A gene mutation in the intron 6 splice donor consensus sequences (IVS6 ds+ 1 G-A) in the GHR gene,causing its functional defect.3 cases with mild dwarf were found gene variations as novel finding:c.1097T＞C c.1098C＞T p.V366A pathogenic variant,c.1229C＞T p.S410L and nt1843707 A→G of 5' UTR region in the IGFALS gene.JAK2 and STAT5b genes mutations were not found.Conclusion Molecular pathology of GHIS is considered as involving the defects of GHR and its signal pathway.The mutation of intron 6 splice donor sequences in GHR gene has been reported which affect the function of GHR.The 3 novel type base variants in IGFALS gene,causing non severe dwarfism,might be suspected with pathogenic roles of GHIS.

Deficiência da STAT5B: uma nova síndrome de insensibilidade ao hormônio de crescimento associada a acometimento imunológico / STAT5B deficiency: a new growth hormone insensitivity syndrome associated to immunological dysfunction

Uma nova apresentação da insensibilidade ao hormônio de crescimento (IGH), causada por mutações em homozigose no gene STAT5B (transdutor de sinal e ativador de transcrição tipo 5B), foi caracterizada nos últimos anos. Sua particularidade é a associação com quadros de disfunção imunológica grave, sendo o mais característico a pneumonite intersticial linfocítica. A presença concomitante de doenças crônicas imunológicas pode fazer com que a baixa estatura seja erroneamente considerada uma consequência do quadro clínico, levando ao subdiagnóstico dessa forma de IGH. O objetivo desta revisão é divulgar o conhecimento atual sobre essa rara patologia, facilitando o reconhecimento de pacientes com IGH secundária a mutações no gene STAT5B em ambulatórios de endocrinologia e de outras especialidades.

A new presentation of growth hormone insensitivity (GHI) caused by homozygous mutations in STAT5B (signal transducer and activator of transcription 5B) gene has been characterized in the last years. Its particularity is the association with severe immune dysfunction, especially with lymphocytic interstitial pneumonitis. This may mislead physicians into considering short stature as secondary to chronic immunological disease and consequently into underdiagnosing this form of GHI. The objective of this review is to propagate current knowledge about this rare pathology, facilitating the diagnosis of patients with GHI due to STAT5B mutations in endocrinology and other specialties clinics.

Growth responses to growth hormone therapy in children with attenuated growth who showed normal growth hormone response to stimulation tests / 소아과

PURPOSE: The aim was to investigate the clinical characteristics and responses to growth hormone (GH) therapy in children with attenuated growth who showed normal GH responses to GH stimulation tests (GHST). METHODS: The study included 39 patients with height velocity (HV) of less than 4 cm/yr and normal GHST results. Clinical characteristics of patients were analyzed retrospectively. RESULTS: Eleven were born as small for gestational age (SGA) and 28 as appropriate for age (AGA). In the SGA group, the standard deviation score (SDS) of age and height measured at their first visit was significantly low. Sixteen patients were treated with GH and six of 23 without GH therapy were followed for 1 year after GHST. The mean (range) of HV was 7.7 (4.9 to 11.1) cm/yr in patients with GH therapy and 3.7 (2.7 to 4.5) cm/yr in those without GH therapy, which was statistically significant (P or =3 (P=0.023). CONCLUSION: In children with growth failure and normal GHST, HV increases significantly by short-term GH therapy. The assessment of long-term effects of GH therapy is necessary. Moreover, further studies should be considered to evaluate the GH-IGF-I axis due to the possibility of GH insensitivity syndrome.

Novel nonsense mutation (p. Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome / Nova mutação nonsense (p. Y113X) no gene do receptor do hormônio do crescimento em um paciente brasileiro com síndrome de Laron

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.

Investigação de baixa estatura: aspectos clínicos, laboratoriais e moleculares da insensibilidade ao hormônio de crescimento / Short stature investigation: clinical, laboratorial and genetic aspects concerning the trowth hormone insensitivity (GHI)

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.

Relationship between Onset of Malnutrition and Growth Hormone-Insulin-Like Growth Factor Axis in Children with Congenital Heart Disease / 实用儿科临床杂志

Objective To investigate the relationship between onset of malnutrition and growth hormone-insulin-like growth factor(GH-IGF) axis in children with congenital heart disease(CHD).Methods Fifty cases with CHD were divided into two groups,13 cases of cyanotic group and 37 cases of acyanotic group.And the acyanotic group was then subdivided into two groups,25 cases of heart failure group and 12 cases of without heart failure group,and 20 normal children were selected as control group.The nutritional status of these children were evaluated by detecting the serum total protein,serum protein,body height and weight.IGF-Ⅰ and insulin-like growth factor binding protein-3(IGFBP-3) and growth hormone binding protein(GHBP) were detected by immunoradiometric assay.Results The acute malnutrition ratio and chronic malnutrition ratio in the children with CHD were 62% and 28%,respectively.The acute malnutrition ratio was similar between cyanotic group and acyanotic group(P=0.105);the chronic malnutrition ratio significantly increased in cyanotic group than that in cyanotic group(P=0.006).The levels of serum IGF-Ⅰ and IGFBP-3 decreased in the patients with CHD,which significantly decreased in cyanotic group and heart failure group.The level of serum GHBP decreased in cyanotic group and heart failure group.Conclusions The levels of serum IGF-Ⅰ and IGFBP-3 in patients with CHD decrease,which are related to growth hormone receptor down regulated,that is one of the molecular mechanisms of growth hormone resistant or insensitivity,growth hormone counteract or insensitivity are one of the reasons of acute and chronic malnutrition in children with CHD.

Growth Hormone Receptor Mutation and Partial Growth Hormone Insensitivity in Children with Idiopathic Short Stature

PURPOSE: Children with idiopathic short stature(ISS) are classified on the basis of exclusion criteria. Short stature with normal or increased circulating growth hormone(GH) and low IGF-I levels indicates that partial growth hormone insensitivity(GHI) may play a role in ISS. The present study was performed to investigate whether partial GHI is observed in children with idiopathic short stature and whether partial GHI is related to growth hormone receptor(GHR) defect. METHODS: Twenty-five children with ISS were studied and 30 normal children were enrolled as control. Anthropometric measurement and IGF-I generation test were performed. The GHR gene was amplified by PCR, from leukocyte-derived DNA and sequenced directly. RESULTS: IGF-I level was increased after GH treatment, but there was no significant correlation between delta IGF-I and delta HTSDS, as well as between delta IGFBP-3 and delta HTSDS indicating partial GHI in children with ISS. When GHR genes were analyzed, polymorphism was observed. That is, adenine which is third base for 168 th amino acid was guanine. Furthermore this finding was observed in 100% of 55 children examined, which was a rather higher incidence compared to previous reports from other country. The first base of 526 th amino acid was either adenine or cytosine or heterozygous of adenine and cytosine, suggesting an occurrence of I526L variant. Deletions of one or two bases in flanking region of exon 3 and 8 were confirmed in Koreans, the same as it occurs in Japanese. There are differences in the sequences of human GHR gene among different ethnic populations. Wide variations of phenotype in ISS cannot clearly be explained by GHR gene alone. Variations or polymorphism of GHR genes remains to be functionally analysed. CONCLUSION: ISS might be due to the partial GHI which is resuls from mutation of GHR genes.

The role of endotoxin, TNF-? and IL-6 in inducing the growth hormone insensitivity / 肠外与肠内营养

Objectives:To investigate the role of endotoxin, TNF ? and IL 6 in inducing the growth hormone insensitivity at the receptor and post receptor levels. Methods:Spague Dawley rats were injected with endotoxin, TNF ?, and IL 6 respectively and were killed at different time points. The liver expressions of IGF 1, GHR and SOCS 3 mRNA were detected by RT PCR, the GH levels were measured by radioimmunoassay,and the levels of TNF ? and IL 6 were detected by ELISA. Results:Serum growth hormone levels at each time points after LPS iv injection did not have significant changes compared with control rats without iv injection of LPS, TNF ? and IL 6 levels were elevated rapidly after LPS injection, but TNF ? levels returned to normal quickly. The most remarkable down regulations for liver IGF 1 mRNA and GHR mRNA occurred at 12h and 8h respectively after LPS infusion. The liver SOCS 3 mRNA was weakly expressed in control rats. However, it was strongly up regulated after LPS injection and had a 7.84 times increase at 1h. The linear regression analysis had shown a positive correlation between IL 6 levels and liver SOCS 3 mRNA expressions. Liver GHR mRNA expression was obviously down regulated after TNF ? iv injection, but there was no effect on liver SOCS 3 mRNA expression. IL 6 up regulated the liver SOCS 3 mRNA expression, but it could not affect the liver GHR mRNA expression. Conclusions:The growth hormone insensitivity could be induced by LPS injection, which was associated with down regulated GHR mRNA expression at receptor level and up regulated SOCS 3 mRNA expression at post receptor level. The biological activities of LPS are mediated by TNF ? and IL 6 indirectly.And TNF ? and IL 6 exert their effects on the receptor and post receptor levels respectively, but the effect of TNF ? is of hysteresis.