Beckwith-Wiedemann syndrome mimicking the classical form of congenital adrenal hyperplasia in newborn screening.

Beckwith-Wiedemann syndrome (BWS) is a common genetic congenital disease characterized by somatic overgrowth and its broad clinical spectrum includes pre- and post-natal macrosomia, macroglossia, visceromegaly, increased risk of neonatal hypoglycemia, and development of embryonic tumors. BWS occurs due to genetic/epigenetic changes involving growth-regulating genes, located on region 11p15, with an important genotype-phenotype correlation. Congenital adrenal hyperplasia (CAH) comprises a spectrum of autosomal recessive diseases presenting a variety of clinical manifestations due to a deficiency in one of the enzymes involved in cortisol secretion. Early diagnosis based on newborn screening prevents the adrenal crisis and early infant death. However, high 17-hydroxyprogesterone (17-OHP) levels can occur in newborns or premature infants without CAH, in situations of stress due to maternal or neonatal factors. Here, we report new cases of false-positive diagnosis of 21-hydroxylase deficiency during newborn screening - two girls and one boy with BWS. Methylation-specific multiplex ligation-dependent probe amplification revealed a gain of methylation in the H19 differentially methylated region. Notably, all three cases showed a complete normalization of biochemical changes, highlighting the transient nature of these hormonal findings that imitate the classical form of CAH. This report sheds light on a new cause of false-positive 21-hydroxylase deficiency diagnosis during newborn screening: Beckwith-Wiedemann syndrome.

Impact of the reduction in TSH cutoff level to 6 mIU/L in neonatal screening for congenital hypothyroidism in Santa Catarina: final results.

OBJECTIVE: To assess the implications of changing the cutoff level of TSH from 10 to 6 mIU/L. METHODS: The study population was constituted by 74.123 children screened for congenital hypothyroidism by the National Screening Program in Santa Catarina, from March 2011 to February 2012. The cutoff of TSH was 6 mIU/L. If TSH between 6-10 mIU/L, the newborn was recalled for a second TSH measurement on filter paper. If TSH > 6 mIU/L in the second sample, the child was sent for medical evaluation. In children with normal topic thyroid, levothyroxine was suspended for 1 month at the age of 3 years for identification of the etiology and evaluation of the need to continue treatment. RESULTS: Among the children screened, 435 were recalled for presenting TSH between 6 and 10 mIU/L in the first sample, 28 remained TSH > 6 mIU/L in the second sample. Among these, 11 had a final diagnosis of dyshormonogenesis, two of ectopic thyroid, two of thyroid hypoplasia and one of transient hypothyroidism. Ten children presented normal TSH levels on the first medical evaluation and two lost follow-up. CONCLUSION: A decrease in the TSH cutoff level from 10 to 6 mIU/L in a neonatal screening program for congenital hypothyroidism reduced the number of false-negative results, increasing the sensitivity of the test, but increased the number of false-positive results and recalls. Since a TSH cutoff level of 6 mIU/L detects thyroid function abnormalities requiring treatment, the adoption of this cutoff level is justified.

Impact of the reduction in TSH cutoff level to 6 mIU/L in neonatal screening for congenital hypothyroidism in Santa Catarina: final results

ABSTRACT Oubjective: To assess the implications of changing the cutoff level of TSH from 10 to 6 mIU/L. Subjects and methods: The study population was constituted by 74.123 children screened for congenital hypothyroidism by the National Screening Program in Santa Catarina, from March 2011 to February 2012. The cutoff of TSH was 6 mIU/L. If TSH between 6-10 mIU/L, the newborn was recalled for a second TSH measurement on filter paper. If TSH > 6 mIU/L in the second sample, the child was sent for medical evaluation. In children with normal topic thyroid, levothyroxine was suspended for 1 month at the age of 3 years for identification of the etiology and evaluation of the need to continue treatment. Results: Among the children screened, 435 were recalled for presenting TSH between 6 and 10 mIU/L in the first sample, 28 remained TSH > 6 mIU/L in the second sample. Among these, 11 had a final diagnosis of dyshormonogenesis, two of ectopic thyroid, two of thyroid hypoplasia and one of transient hypothyroidism. Ten children presented normal TSH levels on the first medical evaluation and two lost follow-up. Conclusion: A decrease in the TSH cutoff level from 10 to 6 mIU/L in a neonatal screening program for congenital hypothyroidism reduced the number of false-negative results, increasing the sensitivity of the test, but increased the number of false-positive results and recalls. Since a TSH cutoff level of 6 mIU/L detects thyroid function abnormalities requiring treatment, the adoption of this cutoff level is justified.

Ten-year evaluation of a Neonatal Screening Program for congenital adrenal hyperplasia.

OBJECTIVE: Evaluate the Neonatal Screening Program (NSP) for congenital adrenal hyperplasia (CAH) of the Department of Health of the State of Santa Catarina (Secretaria de Estado da Saúde de Santa Catarina, SES/SC), and provide information to improve the program. SUBJECTS AND METHODS: Descriptive, retrospective study of 748,395 children screened between January 2001 and December 2010. We analyzed the coverage of the NSP-SES/SC prevalence of CAH, child's age when the first sample for 17-hydroxyprogesterone (17OHP) measurement was collected, levels of 17OHP, mean age at treatment onset and main clinical manifestations. RESULTS: The NSP-SES/SC covered 89% of the live newborns in the State. It diagnosed 50 cases of CAH, yielding an incidence of 1:14,967. Mean age at collection of the first sample was 7.3 days and mean level of 17OHP was 152.9 ng/mL. The most frequent manifestations were virilized genitalia with nonpalpable gonads, clitoromegaly and genital hyperpigmentation. In three girls, the genre established at birth was incorrect. The salt-wasting form was present in 74% of the cases. There was no occurrence of shock or death. Mean age at treatment onset in the salt-wasting form was 17.4 days compared with 54.9 days in those without the salt-wasting form of the disease. All children were treated with hydrocortisone, and those with salt-wasting CAH were also treated with fludrocortisone. CONCLUSIONS: The incidence of CAH was 1 case to 14,967 live newborns. Collection of the first sample occurred outside the recommended time, resulting in delays in treatment onset.

Ten-year evaluation of a Neonatal Screening Program for Congenital Adrenal Hyperplasia / Avaliação de dez anos de um Programa de Triagem Neonatal para Hiperplasia Adrenal Congênita

Objective Evaluate the Neonatal Screening Program (NSP) for congenital adrenal hyperplasia (CAH) of the Department of Health of the State of Santa Catarina (Secretaria de Estado da Saúde de Santa Catarina, SES/SC), and provide information to improve the program. Subjects and methods Descriptive, retrospective study of 748,395 children screened between January 2001 and December 2010. We analyzed the coverage of the NSP-SES/SC prevalence of CAH, child’s age when the first sample for 17-hydroxyprogesterone (17OHP) measurement was collected, levels of 17OHP, mean age at treatment onset and main clinical manifestations. Results The NSP-SES/SC covered 89% of the live newborns in the State. It diagnosed 50 cases of CAH, yielding an incidence of 1:14,967. Mean age at collection of the first sample was 7.3 days and mean level of 17OHP was 152.9 ng/mL. The most frequent manifestations were virilized genitalia with nonpalpable gonads, clitoromegaly and genital hyperpigmentation. In three girls, the genre established at birth was incorrect. The salt-wasting form was present in 74% of the cases. There was no occurrence of shock or death. Mean age at treatment onset in the salt-wasting form was 17.4 days compared with 54.9 days in those without the salt-wasting form of the disease. All children were treated with hydrocortisone, and those with salt-wasting CAH were also treated with fludrocortisone. Conclusions The incidence of CAH was 1 case to 14,967 live newborns. Collection of the first sample occurred outside the recommended time, resulting in delays in treatment onset. .

Objetivo Avaliar o Programa de Triagem Neonatal da Secretaria de Estado da Saúde de Santa Catarina (PTN-SES/SC) em relação à hiperplasia adrenal congênita (HAC) e fornecer subsídios que possibilitem seu aperfeiçoamento. Sujeitos e métodos Estudo descritivo e retrospectivo de 748.395 crianças triadas no período de janeiro de 2001 a dezembro de 2010, sendo analisados a cobertura do PTN-SES/SC, a prevalência da HAC, a idade na coleta da primeira amostra para 17-hidroxiprogesterona (17OHP), os níveis de 17OHP, a idade média de início de tratamento e as principais manifestações clínicas. Resultados A cobertura do PTN-SES/SC foi de 89% dos recém-nascidos vivos no Estado. Foram diagnosticados 50 casos de HAC, com incidência de 1:14.967. A média de idade na coleta da primeira amostra foi de 7,3 dias e a de 17OHP, de 152,9 ng/mL. As manifestações mais frequentes foram genitália virilizada sem gônadas palpáveis, clitoromegalia e hiperpigmentação genital. Em três meninas ocorreu erro no estabelecimento de gênero ao nascimento. A forma perdedora de sal foi encontrada em 74% dos casos. Nenhum caso de choque ou óbito foi verificado. A média de idade no início do tratamento nos perdedores de sal foi de 17,4 dias e nos não perdedores, de 54,9 dias. Todas as crianças foram tratadas com hidrocortisona e, nos casos com a forma perdedora de sal, associou-se fludrocortisona. Conclusões A incidência de HAC foi de 1 caso para 14.967 recém-nascidos vivos. A coleta da primeira amostra ainda ocorreu fora do tempo preconizado, acarretando atraso no início do tratamento. .

Programa de Triagem Neonatal para hipotireoidismo congênito de Santa Catarina, Brasil: avaliação etiológica no primeiro atendimento / Newborn Screening Program for congenital hypothyroidism of the State of Santa Catarina, Brazil: etiological investigation in the first visit

OBJETIVO: Avaliar a etiologia, no primeiro atendimento, dos casos de hipotireoidismo congênito primário (HCP) identificados pelo Programa de Triagem Neonatal de Santa Catarina entre julho de 2007 e junho de 2009. SUJEITOS E MÉTODOS: Estudo prospectivo com 45 pacientes com HCP confirmado. Para o diagnóstico etiológico, eram realizados na primeira consulta: anamnese, exames físico e complementares (TSH, tiroxina livre, tireoglobulina, idade óssea, ultrassonografia de tireoide). RESULTADOS: Estabeleceu-se o diagnóstico etiológico na primeira consulta em 53,33%. Disgenesia representou 51,11%, sendo 20% hipoplasia, 13,3% atireose e 17,7% ectopia; e 2,2% foram diagnosticados com disormoniogênese. Hérnia umbilical foi o sinal mais prevalente (48,89%) e 20% não apresentaram manifestação clínica. Aqueles com disgenesia apresentaram diferença significativa (p < 0,05) pela via de parto cesária, idade óssea atrasada e TSH sérico muito elevado. CONCLUSÕES: A abordagem diagnóstica realizada no primeiro atendimento determina a etiologia do HCP em 53,3% dos casos. A metade dos pacientes apresenta disgenesia tireoidiana. Arq Bras Endocrinol Metab. 2012;56(9):627-32.

OBJECTIVE: To evaluate the etiology of primary congenital hypothyroidism (PCH) identified in the Newborn Screening Program from the state of Santa Catarina, Brazil, from July 2007 to June 2009 in the first visit. SUBJECTS AND METHODS: A prospective study was performed in 45 patients with PCH. For the etiological diagnosis, history, physical examination, and additional tests (TSH, free thyroxine, thyroglobulin, bone age assessment, thyroid ultrasound) were carried out in the first visit. RESULTS: The etiology was established in the first visit in 53.3% of cases. Thyroid dysgenesis represented 51.11% of the cases, from which 20% showed hypoplastic thyroid, 13.3% showed athyreosis, and 17.7% showed ectopic glands; 2.2% were diagnosed with dyshormonogenesis. Umbilical hernia was the most prevalent sign (48.89%) and 20% had no clinical manifestations. Patients with dysgenesis showed significant differences (p < 0.05) in terms of cesarean section delivery, delayed bone age, and very high serum TSH. CONCLUSIONS: The diagnostic approach used at first visit for PCH patients may determine the etiology in 53.3% of cases. Half of patients had thyroid dysgenesis. Arq Bras Endocrinol Metab. 2012;56(9):627-32.

[Newborn Screening Program for congenital hypothyroidism of the State of Santa Catarina, Brazil: etiological investigation in the first visit]. / Programa de Triagem Neonatal para hipotireoidismo congênito de Santa Catarina, Brasil: avaliação etiológica no primeiro atendimento.

OBJECTIVE: To evaluate the etiology of primary congenital hypothyroidism (PCH) identified in the Newborn Screening Program from the state of Santa Catarina, Brazil, from July 2007 to June 2009 in the first visit. SUBJECTS AND METHODS: A prospective study was performed in 45 patients with PCH. For the etiological diagnosis, history, physical examination, and additional tests (TSH, free thyroxine, thyroglobulin, bone age assessment, thyroid ultrasound) were carried out in the first visit. RESULTS: The etiology was established in the first visit in 53.3% of cases. Thyroid dysgenesis represented 51.11% of the cases, from which 20% showed hypoplastic thyroid, 13.3% showed athyreosis, and 17.7% showed ectopic glands; 2.2% were diagnosed with dyshormonogenesis. Umbilical hernia was the most prevalent sign (48.89%) and 20% had no clinical manifestations. Patients with dysgenesis showed significant differences (p < 0.05) in terms of cesarean section delivery, delayed bone age, and very high serum TSH. CONCLUSIONS: The diagnostic approach used at first visit for PCH patients may determine the etiology in 53.3% of cases. Half of patients had thyroid dysgenesis.

A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings.

BACKGROUND: GH insensitivity (GHI) syndrome caused by STAT5B mutations was recently reported, and it is characterized by extreme short stature and immune dysfunction. Treatment with recombinant human IGF1 (rhIGF1) is approved for patients with GHI, but the growth response to this therapy in patients with STAT5B mutations has not been reported. OBJECTIVES: To report the clinical features, molecular findings, and the short-term growth response to rhIGF1 therapy in patients with STAT5B mutation. SUBJECTS AND METHODS: Hormonal and immunological evaluations were performed in two male siblings with GHI associated with atopic eczema, interstitial lung disease, and thrombocytopenic purpura. STAT5B genes were directly sequenced. The younger sibling was treated with rhIGF1 at a dose of 110 microg/kg BID. RESULTS: Both siblings had laboratory findings compatible with GHI associated with hyperprolactinemia. Lymphopenia and reduced number of natural killer cells without immunoglobulin abnormalities were observed. STAT5B sequence revealed a homozygous frameshift mutation (p.L142fsX161) in both siblings. The younger sibling (9.9 years of age) was treated with rhIGF1 at appropriate dosage, and he did not present any significant change in his growth velocity (from 2.3 to 3.0 cm/year after 1.5 years of therapy). The presence of a chronic illness could possibly be responsible for the poor result of rhIGF1 treatment. Further studies in patients with STAT5B defects are necessary to define the response to rhIGF1 treatment in this disorder. CONCLUSION: GHI associated with immune dysfunction, especially interstitial lung disease, and hyperprolactinemia is strongly suggestive of a mutation in STAT5B in both sexes.

Altura final em criancas com puberdade precoce central: a experiência de um serviço de referência / Final Height in Children with Central Precocious Puberty the experience of a Specialized Center The Experience of a Specialized Center

Introdução: A puberdade precoce central ocorre principalmente devido a ativação precoce do eixo hipotalâmico-hipofisário-gonadal e conseqüentemente ao aumento do hormônios gonadotróficos. A prematura ativação desse eixo não envolve apenas mudanças físicas precoces da puberdade, mas também aceleração do crescimento linear e aceleração da maturação óssea, que leva a fusão das epífises ósseas de maneira prematura e à diminuição da altura final. Objetivo: Identificar a altura final de pacientes que apresentaram Puberdade Precoce Central atendidos no Serviço de Endocrinologia Pediátrica do Hospital Infantil Joana de Gusmão. Métodos: Foram avaliados os registros de pacientes que haviam atingido a AF no período de 1997-2007. As variáveis analisadas foram: sexo, idade cronológica, idade óssea, idade ao diagnóstico, idade ao atingir a altura final, tempo de tratamento até altura final, tempo de acompanhamento até a altura final, tratamento utilizado, altura no início e término do tratamento, altura predita pelo método de Bayley – Pinneau, altura-alvo e altura final ( transformada em escore z). Resultados: Foram incluídos 56 pacientes, 96,4 % do sexo feminino e 90,75 % dos pacientes apresentavam PPC idiopática. Os pacientes masculinos foram tratados com análogo do hormônio liberador de gonadotrofinas por 2,7 anos em média, enquanto que as pacientes femininas foram tratadas durante 3,1 anos. A altura final foi alcançada aos 15,1 anos nos meninos e 14,2 anos nas meninas.Conclusões: A média de altura final foi 171,25 cm no sexo masculino e 160,77 cm no sexo feminino. O escore-z de AF foi de -0,55 desvios padrão da média nos meninos e 0,04 desvios padrão da média nas meninas. A diferença entre altura final e altura alvo foi de -5,25 cm nos meninos e 2,4 cm nas meninas.

Background: Central precocious puberty is mainly due to the precocious activation of hypothalamic-pituitary-gonadal axis leading to an increase of gonadotropic hormones. The premature activation of this axis it involves not only early physical changes of puberty, but also linear growth acceleration and acceleration of bone maturation, which leads to early epiphyseal fusion and short adult height. Objective: To identify final height in central precocious puberty patients treated at Pediatric Endocrinology Service of Hospital Infantil Joana de Gusmão. Methods: The study evaluated the registration of patients that had reached the final height between 1997-2007. Data included sex, chronological age, bone age, age at diagnosis, age at final height, duration of treatment, duration of accompaniment from the start of treatment to final height, treatment used, height at the start and at the end of treatment, predicted height by Bayley – Pinneau method, target height and final height (these are transformed in z-score). Results: Fifty six patients were involved. 96,4 % were female sex and 90,75 % had idiopathic central precocious puberty. The males were treated with Gonadotropin Releasing Hormone Analogue by 2,7 years and females were treated by 3,1 years. Final height was reached at 15,1 years in boys and 14,2 years in girls. Conclusions: Final height average was 171,25 cm in males and 160,77 cm in females. The z-score of final height was -0,55 standard deviation of average in boys and 0,04 standard deviation of average in girls. The difference between final height and target height were -5,25 cm in boys and 2,4 cm in girls.

Resultados preliminares de um programa de detecçäo precoce para o hipotireoidismo congênito / Congenital hypothyroidism screening program: preliminary results

Objetivo: Os autores têm por objetivo relatar os primeiros resultados do programa de detecçäo precoce de hipotireoidismo congênito (HC), realizado no período de julho de 1993 a dezembro de 1994 no estado de Santa Catarina. Métodos: Foram estudados todos os lactentes triados para HC pelo Laboratório Central de Saúde do Estado de Santa Catarina (LACEN), no período de julho de 1993 a dezembro de 1994. Foi coletada uma amostra de sangue em papel filtro para dosagem de TSH por imunofluorometria, em triplicata. na persistência de valores de TSH acima dos de corte, após a reconvocaçäo, os pacientes foram encaminhados para avaliaçäo especializada....