A novel heterozygous STAT5B variant in a patient with short stature and partial growth hormone insensitivity (GHI).

BACKGROUND: The most frequent monogenic causes of growth hormone insensitivity (GHI) include defects in genes encoding the GH receptor itself (GHR), the signal transducer and activator of transcription (STAT5B), the insulin like-growth factor type I (IGF1) and the acid-labile subunit (IGFALS). GHI is characterized by a continuum of mild to severe post-natal growth failure. OBJECTIVE: To characterize the molecular defect in a patient with short stature and partial GHI. PATIENT AND METHODS: The boy was born at term adequate for gestational age from non-consanguineous normal-stature parents. At 2.2 years, he presented proportionate short stature (height -2.77 SDS), wide forehead and normal mental development. Whole-exome analysis and functional characterization (site-directed mutagenesis, dual luciferase reporter assay, immunofluorescence and western immunoblot) were performed. RESULTS: Biochemical and endocrinological evaluation revealed partial GH insensitivity with normal stimulated GH peak (7.8 ng/mL), undetectable IGF1 and low IGFBP3 levels. Two heterozygous variants in the GH-signaling pathway were found: a novel heterozygous STAT5B variant (c.1896G>T, p.K632N) and a hypomorphic IGFALS variant (c.1642C>T, p.R548W). Functional in vitro characterization demonstrated that p.K632N-STAT5b is an inactivating variant that impairs STAT5b activity through abolished phosphorylation. Remarkably, the patient's immunological evaluation displayed only a mild hypogammaglobulinemia, while a major characteristic of STAT5b deficient patients is severe immunodeficiency. CONCLUSIONS: We reported a novel pathogenic inactivating STAT5b variant, which may be associated with partial GH insensitivity and can present without severe immunological complications in heterozygous state. Our results contribute to expand the spectrum of phenotypes associated to GHI.

Long-Term Follow-Up of Anterior Pituitary Deficiency after Aneurysmal Subarachnoid Hemorrhage: Prospective Cohort.

OBJECTIVE: The aim of this study was to evaluate the prevalence of hypopituitarism in the acute stage after aneurysmal subarachnoid hemorrhage (SAH) as well at the chronic stage, at least 1 year after bleeding, to assess its implications and correlation with clinical features of the studied population. PATIENTS AND METHODS: This was a prospective cohort study that evaluated patients admitted between December 2009 and May 2011 with a diagnosis of SAH secondary to cerebral aneurysm rupture. Clinical and endocrine assessment was performed during the acute stage after hospital admission and before treatment at a mean of 7.5 days (SD ± 3.8) following SAH, and also at the follow-up visit at a mean of 25.5 months (range: 12-55 months) after the bleeding. RESULTS: Out of the 119 patients initially assessed, 92 were enrolled for acute stage, 82 underwent hormonal levels analysis, and 68 (82.9%) were followed up in both acute and chronic phases. The mean age and median age were lower among patients with dysfunction in the acute phase compared to those without dysfunction (P < .05). The prevalence of dysfunction in the acute phase was higher among patients with hydrocephalus on admission computed tomography (57.9%) than among those without it (P < .05). At chronic phase, there was an association between dysfunction and Hunt & Hess scale score greater than 2 (P < .05). CONCLUSIONS: We believe that there is not enough literature evidence to incorporate routine endocrinological evaluation for patient victims of SAH, but we should always keep this differential diagnosis in mind when conducting long-term assessments of this population.

Reappraisal of serum insulin-like growth factor-I (IGF-1) measurement in the detection of isolated and combined growth hormone deficiency (GHD) during the transition period / Reavaliação da dosagem sérica do fator de crescimento insulina-símile-1 (IGF-1) para o diagnóstico da deficiência isolada e combinada de hormônio de crescimento no período de transição

OBJECTIVE: To evaluate the accuracy of serum IGF-1 in the detection of isolated (IGHD) or combined growth hormone deficiency (CGHD) at the transition phase. SUBJECTS AND METHODS: Forty nine patients with GHD during childhood [16 with IGHD (10 men) and 33 with CGHD (24 men); age 23.2 ± 3.5 yrs.] were submitted to an insulin tolerance test (ITT) with a GH peak < 5 µg/L used for the diagnosis of GHD at the transition phase. Pituitary function and IGF-1 measurements were evaluated in the basal sample of the ITT. Transition patients were reclassified as GH-sufficient (SGH; n = 12), IGHD (n = 7), or CGHD (n = 30). RESULTS: Five (31%) patients with IGHD and 32 (97%) with CGHD at childhood persisted with GHD at retesting. One patient with IGHD was reclassified as CGHD, whereas 3 patients with CGHD were reclassified as IGHD. Mean GH peak was 0.2 ± 0.3 µg/L in the CGHD, 1.3 ± 1.5 µg/L in the IGHD, and 18.1 ± 13.1 µg/L in the SGH group. Serum IGF-1 level was significantly higher in the SGH (272 ± 107 ng/mL) compared to IGHD (100.2 ± 110) and CGHD (48.7 ± 32.8) (p < 0.01). All patients reclassified as CGHD, 86% reclassified as IGHD, and 8.3% reclassified as SGH had low IGF-1 level, resulting in 97.3% sensitivity and 91.6% specificity in the detection of GHD at the transition period; the cutoff value of 110 ng/mL showed 94.5% sensitivity and 100% specificity. Mean IGF-1 values did not differ in IGHD or CGHD associated with one, two, three, or four additional pituitary deficiencies. CONCLUSION: IGF-1 measurement is accurate to replace ITT as initial diagnostic test for IGHD and CGHD detection at the transition phase.

OBJETIVO: Avaliar a acurácia da dosagem sérica de IGF-1 no diagnóstico da deficiência de hormônio de crescimento isolada (DGHI) ou combinada (DGHC) na fase de transição. SUJEITOS E MÉTODOS: Quarenta e nove pacientes com DGH na infância [16 DGHI (10 homens) e 33 DGHC (24 homens); idade 23,2 ± 3,5 anos] realizaram teste de tolerância à insulina (TTI), com pico de GH < 5 µg/L considerado diagnóstico de DGH na transição. Função hipofisária e níveis de IGF-1 foram determinados na amostra basal do TTI e os pacientes foram reclassificados em GH suficientes (SGH; n = 12), DGHI (n = 7) ou DGHC (n = 30). RESULTADOS: Cinco (31%) pacientes com DGHI e 32 (97%) com DGHC na infância persistiram com DGH no reteste. Um paciente com DGHI foi reclassificado como DGHC e três com DGHC como DGHI. Os picos médios de GH foram 0,2 ± 0,3 µg/L (DGHC), 1,3 ± 1,5 µg/L (DGHI) e 18,1 ± 13,1 µg/L (SGH). O nível médio de IGF-1 foi maior no grupo SGH (272 ± 107 ng/mL) comparado com DGHI (100,2 ± 110) e DGHC (48,7 ± 32,8) (p < 0,01). IGF-1 baixo foi observado em todos os pacientes reclassificados como DGHC, 86% dos DGHI e 8,3% dos SGH, resultando em sensibilidade de 97,3% e especificidade de 91,6% para detecção de DGH na transição; valor de corte de 110 ng/mL mostrou 94,5% sensibilidade e 100% especificidade. O nível médio de IGF-1 foi similar nos pacientes com DGHI ou DGHC com uma, duas, três ou quatro deficiências hipofisárias associadas. CONCLUSÃO: A dosagem sérica de IGF-1 mostrou-se acurada para substituir o TTI na detecção tanto de DGHI como DGHC na transição.

Pituitary deficiency after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage puts patients at high risk for the development of pituitary insufficiency. We evaluated the incidence of pituitary dysfunction in these patients and its correlation with clinical outcome. METHODS: Pituitary function was tested in 66 consecutive patients in the first 15 days after aneurysmal subarachnoid hemorrhage. The following were measured in all patients: thyroid-stimulating hormone, free thyroxine, triiodothyronine, luteinizing hormone, follicle-stimulating hormone, total testosterone (in males), estradiol (in females), prolactin, serum cortisol, plasma adrenocorticotropic hormone, growth hormone and insulin growth factor. RESULTS: The endocrine assessment was made at a mean of 7.4 days (standard deviation ±6.6) after subarachnoid hemorrhage. Forty-four (66.7%) female and 22 (33.3%) male patients were evaluated. Thirty-nine patients (59.1%) had some type of pituitary dysfunction. Follicle-stimulating hormone/luteinizing hormone deficiency was the most frequent disorder (34.8%), followed by growth hormone/insulin growth factor (28.7%), adrenocorticotropic hormone (18.1%) and thyroid-stimulating hormone (9%). Seventeen (25.7%) patients showed deficiencies in more than one axis. A greater incidence of hormone deficiency was observed in patients with a Glasgow Coma Scale score ≤13 (t test, p=0.008), Hunt-Hess grade ≥4 (t test, p<0.001), or Fisher grade 4 (t test, p=0.039). Hormone deficiency was not significantly associated (p>0.05) with increased hospitalization or clinical outcome. CONCLUSION: Pituitary dysfunction was identified in a substantial portion of patients with previous aneurysmal subarachnoid hemorrhage, but no association was found between this dysfunction and poor clinical outcome.

Pituitary deficiency after aneurysmal subarachnoid hemorrhage

OBJECTIVE: Aneurysmal subarachnoid hemorrhage puts patients at high risk for the development of pituitary insufficiency. We evaluated the incidence of pituitary dysfunction in these patients and its correlation with clinical outcome. METHODS: Pituitary function was tested in 66 consecutive patients in the first 15 days after aneurysmal subarachnoid hemorrhage. The following were measured in all patients: thyroid-stimulating hormone, free thyroxine, triiodothyronine, luteinizing hormone, follicle-stimulating hormone, total testosterone (in males), estradiol (in females), prolactin, serum cortisol, plasma adrenocorticotropic hormone, growth hormone and insulin growth factor. RESULTS: The endocrine assessment was made at a mean of 7.4 days (standard deviation ±6.6) after subarachnoid hemorrhage. Forty-four (66.7%) female and 22 (33.3%) male patients were evaluated. Thirty-nine patients (59.1%) had some type of pituitary dysfunction. Follicle-stimulating hormone/luteinizing hormone deficiency was the most frequent disorder (34.8%), followed by growth hormone/insulin growth factor (28.7%), adrenocorticotropic hormone (18.1%) and thyroid-stimulating hormone (9%). Seventeen (25.7%) patients showed deficiencies in more than one axis. A greater incidence of hormone deficiency was observed in patients with a Glasgow Coma Scale score ≤13 (t test, p = 0.008), Hunt-Hess grade ≥4 (t test, p<0.001), or Fisher grade 4 (t test, p = 0.039). Hormone deficiency was not significantly associated (p>0.05) with increased hospitalization or clinical outcome. CONCLUSION: Pituitary dysfunction was identified in a substantial portion of patients with previous aneurysmal subarachnoid hemorrhage, but no association was found between this dysfunction and poor clinical outcome. .

Reappraisal of serum insulin-like growth factor-I (IGF-1) measurement in the detection of isolated and combined growth hormone deficiency (GHD) during the transition period.

OBJECTIVE: To evaluate the accuracy of serum IGF-1 in the detection of isolated (IGHD) or combined growth hormone deficiency (CGHD) at the transition phase. SUBJECTS AND METHODS: Forty nine patients with GHD during childhood [16 with IGHD (10 men) and 33 with CGHD (24 men); age 23.2 ± 3.5 yrs.] were submitted to an insulin tolerance test (ITT) with a GH peak < 5 µg/L used for the diagnosis of GHD at the transition phase. Pituitary function and IGF-1 measurements were evaluated in the basal sample of the ITT. Transition patients were reclassified as GH-sufficient (SGH; n = 12), IGHD (n = 7), or CGHD (n = 30). RESULTS: Five (31%) patients with IGHD and 32 (97%) with CGHD at childhood persisted with GHD at retesting. One patient with IGHD was reclassified as CGHD, whereas 3 patients with CGHD were reclassified as IGHD. Mean GH peak was 0.2 ± 0.3 µg/L in the CGHD, 1.3 ± 1.5 µg/L in the IGHD, and 18.1 ± 13.1 µg/L in the SGH group. Serum IGF-1 level was significantly higher in the SGH (272 ± 107 ng/mL) compared to IGHD (100.2 ± 110) and CGHD (48.7 ± 32.8) (p < 0.01). All patients reclassified as CGHD, 86% reclassified as IGHD, and 8.3% reclassified as SGH had low IGF-1 level, resulting in 97.3% sensitivity and 91.6% specificity in the detection of GHD at the transition period; the cutoff value of 110 ng/mL showed 94.5% sensitivity and 100% specificity. Mean IGF-1 values did not differ in IGHD or CGHD associated with one, two, three, or four additional pituitary deficiencies. CONCLUSION: IGF-1 measurement is accurate to replace ITT as initial diagnostic test for IGHD and CGHD detection at the transition phase.

Reproducibility and performance of one or two samples of salivary cortisol in the diagnosis of Cushing's syndrome using an automated immunoassay system.

The purpose of this article is to evaluate the variability and reproducibility of late night salivary cortisol (LNSC) using electrochemiluminescence immunoassay (ECLIA) and compare the accuracy of one or two samples in diagnosis of Cushing's syndrome (CS). We prospectively included 64 healthy volunteers (HV), 35 patients with clinically suspected CS (S), and 26 patients with confirmed CS. Nine patients in the CS group had 24-h urinary free cortisol (UFC) less than two times the upper limit of normal (mild CS). UFC and two consecutive LNSC (LNSC1, LNSC2) were collected at home. All patients in the S group had normal UFC and low-dose dexamethasone suppression test. No differences were found between the HV and S groups in UFC, LNSC1, and LNSC2. Intra-individual variability between the two samples of LNSC was 22% in HV (1.6-91%), 32% in the S group (1.6-144%), and 51% (1.6-156%) in the CS group. Variability was higher in CS patients than those in the HV (P < 0.001) and S groups (P = 0.05). The AUC of LNSC1 was 0.945 (IC 95% 0.880-1.004); when considering the highest LNSC, the AUC was 0.980 (IC 95% 0.954-1.007) (P < 0.01). We found 23% of discordant LNSC in the S group and 11% in the CS group. Three patients with CS had only one elevated LNSC, all of them with mild CS. Our results suggest that LNSC is variable, and reproducibility is affected in both CS and S patients. We found significant improvements in the diagnostic accuracy of the LNSC measurement by obtaining two samples.

The effect of identifying macroprolactinemia on health-care utilization and costs in patients with elevated serum prolactin levels.

OBJECTIVES: The routine screening for macroprolactin of all hyperprolactinemic patients may avoid unnecessary imaging procedures and medication prescription. The study described the frequency and types of tests requested after a diagnosis of high serum prolactin concentration, and assessed whether the diagnosis of macroprolactinemia resulted in lower downstream utilization and costs compared with hyperprolactinemic patients. METHODS: A cost analysis was conducted using a decision tree to model the health-care utilization of the two groups. The database of the Fleury Medicina e Saúde provided the tests and medication of patients with a prolactin value >or=30 microg/L for a period of 6 months. RESULTS: Six hundred fifty-four of 1793 patients (36.5%) had hyperprolactinemia because of macroprolactin. The average number of tests per individual was higher (P = 0.001) in the patients with true hyperprolactinemia (3.07) than in patients with macroprolactinemia (2.51).The average cost in the hyperprolactinemic group (R$425 or euro 162) was significantly higher (P < 0.001) than the macroprolactinemic group (R$340 or euro 130), an incremental cost 25% higher. CONCLUSION: The macroprolactin screening did not completely avoid inappropriate clinical investigation or associated health-care costs. Our results demonstrate the importance of proper medical education and knowledge diffusion of the meaning of macroprolactinemia.

[Evaluating diagnosis methods on childhood GH (DGH) deficiency: IGFs, IGFBPs, releasing tests, GH rhythm and image exams]. / Avaliação dos métodos diagnósticos para deficiência de GH (DGH) na infância: IGFs, IGFBPs, testes de liberação, ritmo de GH e exames de imagem.

The diagnostic approach to growth hormone deficiency (GHD) in children with short stature (SS) is controversial. Here we review the available methodology and present prospective data obtained in a cohort of patients with SS suggesting the use of screening test followed by the confirmation test. Thus, the children with SS should be submitted to clinical and laboratorial evaluation to exclude of chronic and genetic diseases. In addition patients with height<3 percentile or growth velocity-1 SD, the growth velocity should have observed and GH/IGF-1 axis re-evaluated if the growth pattern is not satisfactory.

Avaliação dos métodos diagnósticos para deficiência de GH (DGH) na infância: IGFs, IGFBPs, testes de liberação, ritmo de GH e exames de imagem: [revisão] / Evaluating diagnosis methods on childhood GH (DGH) deficiency: IGFs, IGFBPs, releasing tests, GH rhythm and image exams: [review]

O emprego das diversas metodologias diagnósticas da deficiência de hormônio de crescimento (DGH) em crianças é controverso. Neste artigo serão analisadas estas alternativas revisando a literatura e apresentando dados prospectivos obtidos pelos autores, sugerindo que a DGH seja diagnosticada empregando-se testes de triagem seguidos de testes de confirmação. Assim, recomenda-se que crianças com baixa estatura sejam avaliadas clínica e laboratorialmente para exclusão de doenças crônicas e genéticas. Naquelas com estatura < 3º percentil ou velocidade de crescimento (VC) < percentil 25, dosar IGF-1 como triagem. Se IGF-1 < -1 desvio-padrão (DP), a DGH deve ser confirmada pela ausência de resposta do hormônio de crescimento (GH) a dois testes de estímulo (pico < 5 mcg/L). Em paciente com fatores de risco, IGF-1 < -1 DP e um teste não-responsivo também é diagnóstico de DGH. As crianças com IGF-1 > -1 DP, devem ter a VC acompanhada e, se alterada, pode-se indicar reavaliação do eixo GH/IGF-1 excluindo ou confirmando a DGH.

The diagnostic approach to growth hormone deficiency (GHD) in children with short stature (SS) is controversial. Here we review the available methodology and present prospective data obtained in a cohort of patients with SS suggesting the use of screening test followed by the confirmation test. Thus, the children with SS should be submitted to clinical and laboratorial evaluation to exclude of chronic and genetic diseases. In addition patients with height < 3 percentil or growth velocity < percentil 25, IGF-1 levels should be measured. If the IGF1 levels < -1 standard deviation (SD) compared to the age, GHD should be confirmed by two GH-stimulations tests (peak < 5 mcg/L). In risk factor patients, IGF-1 < -1 SD and one non-responsible GH-test, the GHD was confirmed. Children with IGF-1 > -1 SD, the growth velocity should have observed and GH/IGF-1 axis re-evaluated if the growth pattern is not satisfactory.

Growth hormone deficiency in children.

The foundation for the diagnosis of growth hormone (GH) deficiency in childhood must be auxology, that is, the comparison of the child's growth pattern to that of established norms for gender and ethnicity. It is only in those growing considerably more slowly than average that testing for GHD makes sense. Assessment of laboratory tests, whether static, for example, the measurement of growth factors or their binding proteins, or dynamic, for example, secretagogue-stimulated GH secretion is confirmatory. One must be cognizant of the assay used to determine GH, for there may be a 3-fold difference in the concentration of GH among commercially-available assays. Controversy still exists concerning the measurement of spontaneous GH release and whether sex-steroid priming is appropriate in prepubertal children. Imaging analysis may prove helpful in some children with congenital GHD or to detect a space-occupying lesion in the area of the hypothalamus and pituitary. The final diagnosis is based on multiple parameters and occasionally on a therapeutic trial of GH therapy to determine if there is a significant acceleration of growth velocity.

Differential diagnosis of Cushing's syndrome: [review]

The differential diagnosis of Cushing's syndrome requires careful multidisciplinary interaction with a number of specialities, co-ordinated through endocrine centres with good experience of this condition. It is essential that the diagnosis of Cushing's syndrome be fully established before differential diagnosis is attempted. The endocrinologist needs to be aware of the pitfalls and advantages of the tests in use. We discuss the approach to the differential diagnosis of this challenging condition.

O diagnóstico diferencial da síndrome de Cushing requer uma interação multidisciplinar cuidadosa entre várias especialidades, coordenadas através de centros de endocrinologia com boa experiência nessa condição. É essencial que o diagnóstico da síndrome de Cushing seja estabelecido antes da tentativa de diagnóstico diferencial. O endocrinologista precisa estar atento às possíveis falhas e vantagens dos testes empregados. Nós discutiremos a abordagem do diagnóstico diferencial nessa condição desafiadora.

Pitfalls in the diagnosis of Cushing's syndrome: [review]

Among endocrine disorders, Cushing's syndrome (CS) is certainly one of the most challenging to endocrinologists due to the difficulties that often appear during investigation. The diagnosis of CS involves two steps: confirmation of hypercortisolism and determination of its etiology. Biochemical confirmation of the hypercortisolaemic state must be established before any attempt at differential diagnosis. Failure to do so will result in misdiagnosis, inappropriate treatment, and poor management. It should also be kept in mind that hypercortisolism may occur in some patients with depression, alcoholism, anorexia nervosa, generalized resistance to glucocorticoids, and in late pregnancy. Moreover, exogenous or iatrogenic hypercortisolism should always be excluded. The three most useful tests to confirm hypercortisolism are the measurement of 24-h urinary free cortisol levels, low-dose dexamethasone-suppression tests, and determination of midnight serum cortisol or late-night salivary cortisol. However, none of these tests is perfect, each one has different sensitivities and specificities, and several are usually needed to provide a better diagnostic accuracy. The greatest challenge in the investigation of CS involves the differentiation between Cushing's disease and ectopic ACTH syndrome. This task requires the measurement of plasma ACTH levels, non-invasive dynamic tests (high-dose dexamethasone suppression test and stimulation tests with CRH or desmopressin), and imaging studies. None of these tests had 100 percent specificity and their use in combination is usually necessary. Bilateral inferior petrosal sinus sampling is mainly indicated when non-invasive tests do not allow a diagnostic definition. In the present paper, the most important pitfalls in the investigation of CS are reviewed.

Entre as doenças endócrinas, a síndrome de Cushing (SC) é certamente uma das mais desafiadoras para o endocrinologista, devido às dificuldades que comumente surgem durante a investigação. O diagnóstico de SC envolve dois passos: a confirmação do hipercortisolismo e a determinação de sua etiologia. A confirmação bioquímica do excesso de cortisol precisa ser estabelecida antes de qualquer tentativa de diagnóstico diferencial; caso contrário, poderá resultar em diagnóstico incorreto, tratamento impróprio e manejo insuficiente. Deve também ser lembrado que hipercortisolismo pode ocorrer em certos pacientes com depressão, alcoolismo, anorexia nervosa, resistência generalizada aos glicocorticóides e no final da gravidez. Além disso, hipercortisolismo exógeno ou iatrogênico deverá ser sempre excluído. Os três testes mais úteis para a confirmação do hipercortisolismo são: a medida do cortisol livre em urina de 24 h, os testes de supressão com dexametasona (TSD) em doses baixas e a determinação do cortisol sérico à meia-noite ou do cortisol salivar no final da noite. Contudo, nenhum deles é perfeito, cada um com sua sensibilidade e especificidade, sendo vários deles usualmente necessários para fornecer uma melhor acurácia diagnóstica. O maior desafio na investigação da SC envolve a diferenciação entre a doença de Cushing e a síndrome do ACTH ectópico. Esta tarefa requer a medida dos níveis plasmáticos de ACTH, testes dinâmicos não-invasivos (TSD com doses altas e testes de estímulo com CRH ou desmopressina) e estudos de imagem. Nenhum desses testes tem 100 por cento de especificidade e muitas vezes é necessário seu uso combinado. Amostragem venosa do seio petroso inferior está indicada principalmente quando os testes não-invasivos não permitem uma definição diagnóstica. Neste artigo, revisaremos as mais importantes armadilhas na investigação da SC.

Estados de pseudo-Cushing: [revisão] / Pseudo-Cushing states: [review]

Síndromes de pseudo-Cushing são um grupo heterogêneo de doenças, incluindo alcoolismo, anorexia nervosa, obesidade visceral e depressão, que compartilham muitas das características clínicas e bioquímicas da síndrome de Cushing. Os mecanismos responsáveis para a gênese da síndrome de pseudo-Cushing são fracamente compreendidos. Tem sido sugerido que o hipercortisolismo da síndrome de pseudo-Cushing pode ser resultante do aumento da secreção do hormônio liberador de corticotrofina (CRH) hipotalâmico no contexto de um eixo hipotálamo-hipofisário-adrenal que, de outra maneira, está normalmente constituído. A sobreposição substancial entre as características clínicas e laboratoriais entre muitos pacientes com síndrome de Cushing e aqueles com síndrome de pseudo-Cushing pode tornar o diagnóstico diferencial difícil. Distinguir entre síndrome de pseudo-Cushing e síndrome de Cushing verdadeira é crítico para se prevenir o tratamento desnecessário e potencialmente prejudicial de tais pacientes. Esta breve revisão sumariza os principais eventos patofisiológicos das síndromes de pseudo-Cushing e fornece uma estratégia útil para o seu diagnóstico diferencial.

Pseudo-Cushing syndromes are a heterogeneous group of disorders, including alcoholism, anorexia nervosa, visceral obesity, and depression, which share many of the clinical and biochemical features of Cushing's syndrome. The mechanisms responsible for the genesis of pseudo-Cushing's syndrome are poorly understood. It has been suggested that hypercortisolism of pseudo-Cushing syndrome may be the result of increased hypothalamic corticotrophin-releasing hormone (CRH) secretion in the context of a hypothalamic-pituitary-adrenal axis that is otherwise normally constituted. The substantial overlap in clinical and biochemical features among several patients with Cushing syndrome and those with pseudo-Cushing syndromes can make the differential diagnosis difficult. Distinguishing between pseudo-Cushing's syndrome and true Cushing's syndrome is critical for preventing the unnecessary and potentially harmful treatment of such patients. This brief review summarizes the main pathophysiological events of pseudo-Cushing syndromes and provides a useful strategy for differential diagnosis.

Differential diagnosis of Cushing's syndrome.

The differential diagnosis of Cushing's syndrome requires careful multidisciplinary interaction with a number of specialities, co-ordinated through endocrine centres with good experience of this condition. It is essential that the diagnosis of Cushing's syndrome be fully established before differential diagnosis is attempted. The endocrinologist needs to be aware of the pitfalls and advantages of the tests in use. We discuss the approach to the differential diagnosis of this challenging condition.

Pitfalls in the diagnosis of Cushing's syndrome.

Among endocrine disorders, Cushing's syndrome (CS) is certainly one of the most challenging to endocrinologists due to the difficulties that often appear during investigation. The diagnosis of CS involves two steps: confirmation of hypercortisolism and determination of its etiology. Biochemical confirmation of the hypercortisolaemic state must be established before any attempt at differential diagnosis. Failure to do so will result in misdiagnosis, inappropriate treatment, and poor management. It should also be kept in mind that hypercortisolism may occur in some patients with depression, alcoholism, anorexia nervosa, generalized resistance to glucocorticoids, and in late pregnancy. Moreover, exogenous or iatrogenic hypercortisolism should always be excluded. The three most useful tests to confirm hypercortisolism are the measurement of 24-h urinary free cortisol levels, low-dose dexamethasone-suppression tests, and determination of midnight serum cortisol or late-night salivary cortisol. However, none of these tests is perfect, each one has different sensitivities and specificities, and several are usually needed to provide a better diagnostic accuracy. The greatest challenge in the investigation of CS involves the differentiation between Cushing's disease and ectopic ACTH syndrome. This task requires the measurement of plasma ACTH levels, non-invasive dynamic tests (high-dose dexamethasone suppression test and stimulation tests with CRH or desmopressin), and imaging studies. None of these tests had 100% specificity and their use in combination is usually necessary. Bilateral inferior petrosal sinus sampling is mainly indicated when non-invasive tests do not allow a diagnostic definition. In the present paper, the most important pitfalls in the investigation of CS are reviewed.

[Pseudo-Cushing states]. / Estados de pseudo-Cushing.

Pseudo-Cushing syndromes are a heterogeneous group of disorders, including alcoholism, anorexia nervosa, visceral obesity, and depression, which share many of the clinical and biochemical features of Cushing's syndrome. The mechanisms responsible for the genesis of pseudo-Cushing's syndrome are poorly understood. It has been suggested that hypercortisolism of pseudo-Cushing syndrome may be the result of increased hypothalamic corticotrophin-releasing hormone (CRH) secretion in the context of a hypothalamic-pituitary-adrenal axis that is otherwise normally constituted. The substantial overlap in clinical and biochemical features among several patients with Cushing syndrome and those with pseudo-Cushing syndromes can make the differential diagnosis difficult. Distinguishing between pseudo-Cushing's syndrome and true Cushing's syndrome is critical for preventing the unnecessary and potentially harmful treatment of such patients. This brief review summarizes the main pathophysiological events of pseudo-Cushing syndromes and provides a useful strategy for differential diagnosis.

Final height in patients with idiopathic short stature and high growth hormone responses to stimulation tests.

UNLABELLED: Children with idiopathic short stature (ISS) may have normal or increased growth hormone (GH) responses to provocation tests and achieve a final height (FH) below -2.0 standard deviation score (SDS) if untreated. FH of subjects with high stimulated GH levels has not been studied in detail. AIM: It was the aim of this study to analyse FH in ISS patients with high GH peak responses to the provocation test. PATIENTS AND METHODS: We studied 16 patients (9 pre-pubertal) with ISS and a GH peak >or=40 mU/l to insulin-induced hypoglycaemia. The patients were recalled at age 19.7 +/- 2.5 years for measurement of FH when blood samples were obtained for serum insulin-like growth factor (IGF)-I, IGF binding protein 3, acid-labile subunit and GH binding protein measurements. GH bioactivity was determined using the Nb2 bioassay. RESULTS: FH was -3.1 +/- 1.0 SDS, being significantly lower than target height (TH). At FH, IGF-I levels were within -1.5 and +1.5 SDS for age and sex in 10 patients and higher than +1.5 SDS in 6 patients. IGF binding protein 3, acid-labile subunit, GH binding protein levels and GH bioactivity values were normal. SUMMARY: These data suggest that patients with ISS and high GH levels during a GH stimulation test may have a more compromised FH. The association of severe ISS with a peak GH >40 mU/l might suggest a degree of insensitivity for the GH-IGF-I axis.