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.

Tuberculose chez les enfants de 0-14 ans: résistance primaire de Mycobacterium tuberculosis aux antituberculeux et variants génétiques à Kinshasa / Tuberculosis in children aged 0-14: primary resistance of Mycobacterium tuberculosis to antituberculosis drugs and genetic variants in Kinshasa

Dans les régions endémiques y compris la République Démocratique du Congo, les enfants sont susceptibles d'être exposés à la tuberculose (TB) par un contact dans l'entourage. L'absence de diagnostic peut avoir des conséquences dévastatrices. L'objectif de la présente étude était de déterminer la fréquence de TB, la résistance primaire des souches de Mycobacterium tuberculosis aux antituberculeux ainsi que des variants génétiques. Méthodes. Cette étude transversale et descriptive a été réalisée, entre juin 2011 et décembre 2017, à Kinshasa chez les enfants présumés TB. Les enfants ayant les signes évocateurs de TB figurant dans la tranche d'âge de 0-14 ans étaient inclus. Les échantillons ont été examinés par le Ziehl et mis en culture sur le milieu de Löwenstein-Jensens. Les souches étaient testées aux antituberculeux par la technique des proportions et typées par Spoligotyping. La comparaison des proportions a été faite à l'aide du test de chi-carré de Pearson. Résultats. Quarante-huit souches de Mycobacterium tuberculosis (15,4 %) ont été isolées. Dix souches (20,8%) étaient résistantes à au moins un antituberculeux plus fréquemment à l'INH. Le génotype LAM (66,7 %) et Haarlem (33,3%) était observé. Conclusion. La recherche active de TB infantile confirme qu'elle est relativement fréquente et est résistante à au moins un antituberculeux (surtout à l'INH).

Insensibilidad a la GH en pacientes con retraso de crecimiento (Participación del Dr. Juan Jorge Heinrich en la descripción de dos nuevas alteraciones genéticas) / Growth hormone (GH) insensitivity in patients with growth retardation (Dr. Juan Jorge Heinrich contribution to the characterization of two novel gene c altera ons)

Como homenaje a la actuación del Dr. Juan Jorge Heinrich en su carácter de docente, pediatra clínico e investigador, los autores del presente artículo consideran adecuada una revisión de su participación en el descubrimiento de dos nuevas patologías dentro del campo de la resistencia a la acción de la hormona de crecimiento. La primera es causada por una mutación en el gen que codifica para la STAT5b (transductor de señal y activador de transcripción 5b), proteína que participa en la transmisión intracelular de la señal de GH. La segunda es causada por una mutación en el gen que codifica para la subunidad ácido lábil (ALS), una proteína esencial para la formación de complejos ternarios con IGF-I e IGFBP-3, los que incrementan marcadamente la vida media del IGF-I en la circulación

In homage to Dr. Juan Jotge Heinrich actions as teacher, pediatrician, and researcher, we feel pertinent to remark his contributions to the discovery of two new pathologies within the field of resistance to the action of growth hormone. One is due to a mutation in the gene coding for a protein, STAT5b (signal transducer and activator of transcription 5b), involved in the intracellular chain of transmission of the growth hormone signal; the other due to a mutation in the gene coding for ALS (acid labile subunit) a protein essential for the ternary complex formation among IGF-I, IGFBP-3, and ALS, which markedly increases the half life of IGF-I in the circulation

Estudo da mutação da STAT5B em Criciúma-Santa Catarina: frequência e caracterização fenotípica de indivíduos heterozigotos / Study of STAT5B mutation in Criciúma - Santa Catarina: frequency and phenotypic characterization of heterozygous individuals

Mutações inativadoras em homozigose no gene do transdutor de sinal e ativador de transcrição 5B (STAT5B) causam insensibilidade ao hormônio de crescimento associada a disfunção imunológica grave que se manifesta na forma de infecções exacerbadas e de repetição, pneumonia intersticial linfocítica e outros eventos autoimunes. A caracterização do fenótipo destas mutações em heterozigose não foi realizada previamente. Dois pacientes descritos com mutação em homozigose na STAT5B (c.424_427del / p.L142RfsX19) são irmãos brasileiros naturais de Criciúma - Santa Catarina, sem consanguinidade conhecida na família. Houve também o relato de dois outros casos semelhantes na cidade, já falecidos, sugerindo que mutações na STAT5B pudessem ser relativamente frequentes nesta região. Os objetivos deste estudo foram investigar a frequência da mutação c.424_427del da STAT5B na população de Criciúma, avaliar a existência de efeito fundador e caracterizar o efeito da mutação c.424_427del da STAT5B em heterozigose sobre o fenótipo antropométrico e hormonal. Para investigar a frequência desta mutação em Criciúma, 1192 indivíduos da população foram genotipados. Foram identificados sete indivíduos heterozigotos, caracterizando uma frequência alélica mínima de 0,29% (intervalo de confiança 95%: 0,08 a 0,5%), significativamente mais alta que a frequência de outras variantes patogênicas da STAT5B descritas em bases de dados públicas. Utilizando-se o equilíbrio de Hardy-Weinberg, foi possível estimar a incidência de casos de homozigotos para o alelo mutado em um a cada 40 anos. No entanto, utilizando-se a maior frequência possível de acordo com o intervalo de confiança, esta incidência poderia atingir um a cada 13 anos. Além disso, foram estudados os pais dos dois casos relatados como semelhantes aos pacientes homozigotos para mutações na STAT5B e estes pais eram portadores da mutação c.424_427del da STAT5B em heterozigose. Para avaliar o efeito fundador, foram analisados dois...

Homozygous inactivating mutations in signal transducer and activator of transcription 5B gene (STAT5B) cause growth hormone insensitivity associated with signs of severe immune dysfunction, such as recurrent infections, lymphoid interstitial pneumonia and other autoimmune events. The phenotypic characterization of these mutations in heterozygous state has not been accomplished previously. Two patients with a homozygous STAT5B mutation (c.424_427del / p.L142RfsX19) are Brazilian brothers born in the city of Criciúma, Santa Catarina, and there is not known consanguinity in their family. Moreover, there was a report about two similar cases in this city, already deceased, suggesting that STAT5B mutations could be relatively frequent in this region. The objectives of this study were to evaluate the frequency of STAT5B c.424_427del mutation in Criciúma, to assess the existence of the founder effect and to characterize the effect of heterozygous STAT5B c.424_427del mutation on anthropometric and hormonal phenotypes. To evaluate the frequency of this mutation in Criciúma, 1192 individuals from the population were genotyped. Seven heterozygous individuals were identified, which characterized a minimum allele frequency of 0.29% (95% confidence interval: 0.08 to 0.5%), significantly higher than the frequency of other pathogenic variants described in public databases. By using the Hardy-Weinberg law, it was possible to estimate the incidence of cases of individuals homozygous for this mutation at one every 40 years. However, by using the highest possible frequency according to the confidence interval, this incidence could reach one every 13 years. Additionally, the parents of the two reported cases who were similar to patients with homozygous STAT5B mutations were genotyped and these parents were heterozygous for STAT5B c.424_427del mutation. To assess the founder effect, two markers near the mutation were analyzed in the two boys homozygous...

Comparison between the growth response to growth hormone (GH) therapy in children with partial GH insensitivity or mild GH deficiency / Comparação entre a resposta de crescimento ao tratamento com hormônio de crescimento (GH) em crianças com insensibilidade parcial ao GH ou deficiência de GH leve

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.

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.

Analysis of clinical manifestations and genetic mutations in a child with Laron syndrome / 中华儿科杂志

<p><b>OBJECTIVE</b>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.</p><p><b>METHOD</b>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.</p><p><b>RESULT</b>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.</p><p><b>CONCLUSION</b>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.</p>

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.

Baixa estatura por insensibilidade ao hormônio de crescimento / Short stature caused by growth hormone insensitivity

Objetivo: crianças portadoras de baixa estatura apresentam um grande número de opções diagnósticas. Muitas vezes não se consegue estabelecer o diagnóstico preciso...

Introduction: Tasks for diagnosing short stature in children has been challenged by a broad array of pathways. Precise diagnosis has been often unconspicuous...

Clinical features and growth hormone receptor gene mutations of patients with Laron syndrome from a Chinese family / 中国当代儿科杂志

Laron syndrome is an autosomal recessive disorder caused by defects of growth hormone receptor (GHR) gene. It is characterized by severe postnatal growth retardation and characteristic facial features as well as high circulating levels of growth hormone (GH) and low levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3). This report described the clinical features and GHR gene mutations in 2 siblings with Laron syndrome in a Chinese family. Their heights and weights were in the normal range at birth, but the growth was retarded after birth. When they presented to the clinic, the heights of the boy (8 years old) and his sister (11 years old) were 80.0 cm (-8.2 SDS) and 96.6 cm (-6.8 SDS) respectively. They had typical appearance features of Laron syndrome such as short stature and obesity, with protruding forehead, saddle nose, large eyes, sparse and thin silky hair and high-pitched voice. They had higher basal serum GH levels and lower serum levels of IGF-I, IGFBP-3 and growth hormone binding protein (GHBP) than normal controls. The peak serum GH level after colonidine and insulin stimulations in the boy was over 350 ng/mL. After one-year rhGH treatment, the boy's height increased from 80.0 cm to 83.3 cm. The gene mutation analysis revealed that two patients had same homozygous mutation of S65H (TCA -->CCA) in exon 4, which is a novel gene mutation. It was concluded that a definite diagnosis of Laron syndrome can be made based on characteristic appearance features and serum levels of GH, IGF-I, IGFBP-3 and GHBP. The S65H mutation might be the cause of Laron syndrome in the two patients.

High growth hormone levels in clinically short stature children

Growth Hormone [GH] is secreted from the anterior pituitary gland. It binds to receptors on the surface of target cells, stimulates production of Insulin-like growth factor-I [IGF-I] leading to growth of almost all tissues of the body capable of growing. Growth failure [height below 3rd centile] occurs in children who do not secrete sufficient amount of GH. In some children, however, short stature is present in the presence of high levels of GH in their blood and they also secrete normal to increased amounts of GH in response to stimulation tests when tested for possible deficiency of GH. This condition is known as GH resistance syndrome or Larons syndrome [LS]. All patients after a thorough clinical evaluation underwent GH evaluation protocol as follows. On arrival in the lab a blood sample was collected for basal GH level in each patient. Screening was performed by subjecting the patients to exercise stimulation test and/or L-dopa stimulation test. Patients with GH deficiency underwent insulin tolerance test [ITT] after one week for confirmation. All the basal and post-stimulation samples were analyzed for GH levels. A level below 10mIU/L indicated GH deficiency, between 10-20mIU/L as borderline and an adequate response was defined as a GH >20mIU/L. Patients with a basal GH level of >20mIU/L and/or a post-stimulation level of >40mIU/L were arbitrarily considered as having exaggerated GH levels. This article evaluates the high plasma growth hormone levels among clinically short stature children undergoing growth hormone stimulation tests. Two hundred ninty-three patients reported for GH evaluation. Twenty were excluded for various reasons. Thus 273 patients were included for GH evaluation out of which 66[24.2%] showed GH deficiency, 89[32.6%] were borderline while 118[43.2%] patients exhibited adequate response, with GH levels of >20mIU/L. A number of patients unexpectedly showed very high GH levels on screening tests. Out of 118 patients, 21 showed either very high basal levels of >20mIU/L and/or a much-exaggerated response to stimulation tests with levels more than about 40mIU/L. Close consanguinity was found in 67% of patients showing very high GH levels. Some children with idiopathic short stature may show high levels of GH during their evaluation for GH deficiency. We identified a considerable number of such patients. These patients require further investigations

Efeito fundador da mutação E180splice no gene do receptor de hormônio de crescimento identificada em pacientes brasileiros com insensibilidade ao GH / Founder effect of E180splice mutation in growth hormone receptor gene (GHR) identified in brazilian patients cith GH insensitivity

Estudamos o gene do receptor de hormônio de crescimento (GHR) de 6 pacientes com síndrome de Laron (SL) provenientes de 4 famílias distintas. Os exons 2 a 10 foram amplificados por pares de primers intrônicos. Os produtos de PCR foram seqüenciados diretamente. Os 6 pacientes possuíam no exon 6, codon 180, a troca GGA>GAA em homozigose. Esta mutação não altera o aminoácido traduzido, porém cria um novo sítio de splice que causa a deleção de 8 aminoácidos do domínio extracelular do GHR. Para avaliar um efeito fundador da mutação E180splice, os membros das 4 famílias foram genotipados para 4 regiões intragênicas polimórficas: a presença ou ausência do exon 3, dois polimorfismos de um único nucleotídeo presentes nos exons 6 e 10 e o sítio polimórfico no intron 9. Todos os pacientes apresentavam o mesmo haplótipo destas 4 regiões. A mutação E180splice foi descrita anteriormente em uma comunidade andina no sul do Equador descendente de espanhóis e também numa família judia de Israel. Nossas famílias compartilham o mesmo haplótipo do intron 9 observado nestes pacientes. Concluímos que a mutação E180splice é uma importante causa de IGH no Brasil e a presença do mesmo haplótipo em nossos pacientes, nos pacientes equatorianos e israelenses com a mutação E180splice é forte indício do efeito fundador desta mutação.