RETRACTED ARTICLE: Fatal factitious Cushing\ud syndrome (Münchhausen’s syndrome) in a patient with macroprolactinoma and silent\ud corticotrophinoma: case report and literature review

Abstract\ud Münchhausen’s syndrome (MS) is a chronic factitious disorder\ud characterized by the intentional production of clinical symptoms without external\ud incentive. One type of MS is factitious Cushing syndrome, an extremely rare clinical\ud situation in which the diagnosis is challenging mainly due to interference of the\ud exogenous medication in cortisol immunoassays. We described a 26-year-old woman who\ud was originally diagnosed with a macroprolactinoma and during follow-up developed\ud clinical and laboratorial hypercortisolism. A transsphenoidal surgery was performed\ud and immunohistochemistry revealed positive and diffuse staining for both hormones.\ud Four years later, her hypercortisolism recurred and the confirmation of factitious\ud Cushing syndrome was delayed due to conflicting laboratorial results.\ud There are few cases in the literature of factitious Cushing syndrome,\ud and only one had a fatal outcome. The diagnosis of this condition is complex and\ud includes cyclic Cushing syndrome in the differential diagnosis. These patients have\ud high morbidity and increased mortality risk and are likely to have other psychiatric\ud disorders. Prednisone was identified as the culprit in the majority of the\ud cases.We would like to thank Dr. Wagner Farid Gattaz and Dr. Jose Gallucci Neto,\ud from the Psychiatric Division, for providing assistance during hospitalization.\ud This work was partially supported by grants from Conselho Nacional de\ud Desenvolvimento Científico e Tecnológico – CNPq (301339/2008-9 to B.B.M.)

Molecular investigation of patients with tall stature

A altura é uma característica humana com alta herdabilidade e a maioria das patologias que ocorrem durante a infância levam a um prejuízo do crescimento. Desta forma, a alta estatura é uma condição clínica em que é esperado uma maior influência genética após a exclusão de fatores hormonais relacionados aos eixos GH/IGF-1 e gonadotrófico. Poucos estudos avaliaram a etiologia do distúrbio de crescimento de pacientes altos, e apenas um fez uma investigação genética sistemática em pacientes com déficit intelectual e alta estatura e/ou macrocefalia, com uma taxa de diagnóstico de 50%. Baseado neste contexto, o presente estudo teve como objetivo principal a investigação genética sistemática de uma coorte de pacientes com alta estatura, sindrômicos e não sindrômicos, através da análise de cariótipo (convencional ou molecular) e do sequenciamento paralelo em larga escala de múltiplos genes através de painel customizado e/ou exoma. Foram avaliados prospectivamente 42 pacientes com alta estatura após a exclusão de causas hormonais, sendo 12 não sindrômicos e 30 sindrômicos. Dos pacientes não sindrômicos, todos realizaram cariótipo, sendo identificado em um paciente duas cópias do cromossomo Y (47, XYY). No restante destes pacientes, foi realizado sequenciamento exômico sem identificação de variantes patogênicas. Entre os pacientes sindrômicos, o cariótipo convencional identificou um rearranjo cromossômico levando a uma trissomia do gene SHOX, e o cariótipo molecular encontrou uma microdeleção no cromossomo 9q22.3, além da confirmação de dois pacientes com síndrome de Beckwith-Wiedemann por MLPA. Os demais pacientes sindrômicos foram avaliados por painel e/ou exoma, sendo encontradas 9 variantes patogênicas ou provavelmente patogênicas (FBN1 = 3, NSD1 = 2, NFIX = 1, SUZ12 = 1, CHD8 = 1 e MC4R = 1). A taxa de diagnóstico combinandose todas as técnicas utilizadas foi de 33,3% (14/42 pacientes), sendo superior nos pacientes sindrômicos (43,3%, 13/30) que nos não sindrômicos (8,3%, 1/12). Assim, pode-se concluir neste estudo que uma abordagem de investigação genética sistemática é eficaz em estabelecer o diagnóstico definitivo em pacientes sindrômicos com alta estatura e deve ser recomendada neste subgrupo, independentemente de haver ou não uma hipótese diagnóstica inicial baseada nos achados clínicos. Além disso, o presente estudo ajudou a estabelecer o gene SUZ12 como uma causa rara de síndrome de Weaver, uma doença que cursa com alta estatura e déficit intelectualStature is a human trait with high herdability, and most of the pathologies that affects childhood lead to a growth impairment. Therefore, tall stature is a clinical condition in which is expected a higher genetic influence after ruling out hormonal alterations in GH/IGF-1 and gonadotrophic axis. Few studies have assessed the etiology of the growth disorder in tall patients, and only one report has made a systematic genetic evaluation of patients with intellectual disability and tall stature and/or macrocephaly, with a diagnostic rate of 50%. Based on this context, the aim of this study was to systematically perform a genetic investigation in a cohort of tall patients, both syndromic and non-syndromic, using the conventional and molecular karyotypes and multigene sequencing analysis (targeted panel and/or whole exome sequencing). We evaluated 42 patients with tall stature, 30 syndromic and 12 non-syndromic, after the exclusion of a hormonal etiology. Among non-syndromic patients, karyotype was performed in all of them, with the identification of a patient harboring two copies of chromosome Y. In the remaining non-syndromic patients, whole exome sequencing was performed, without pathogenic findings. Among syndromic patients, conventional karyotype identified a chromosomal abnormality leading to a SHOX gene trisomy, molecular karyotype diagnosed a microdeletion in chromosome 9q22.3 and MLPA confirmed two cases of Beckwith-Wiedemann syndrome. The remaining syndromic patients were evaluated with targeted panel and/or whole exome sequencing, and we found nine pathogenic or likely pathogenic variants (FBN1 = 3, NSD1 = 2, NFIX = 1, SUZ12 = 1, CHD8 = 1 e MC4R = 1). The diagnostic rate with all techniques combined was 33.3% (14/42 patients), and it was superior in syndromic (43.3%, 13/30) than in non-syndromic patients (8.3%, 1/12). Therefore, we concluded that a systematic genetic approach is efficient to establish the etiology of the growth disorder in syndromic patients with tall stature and should be recommended in this subgroup, independently of having an initial clinical suspicion. Further, this study helped to establish SUZ12 as a rare cause of Weaver syndrome, a disorder that causes tall stature and intellectual disabilit

Molecular investigation of patients with tall stature

A altura é uma característica humana com alta herdabilidade e a maioria das patologias que ocorrem durante a infância levam a um prejuízo do crescimento. Desta forma, a alta estatura é uma condição clínica em que é esperado uma maior influência genética após a exclusão de fatores hormonais relacionados aos eixos GH/IGF-1 e gonadotrófico. Poucos estudos avaliaram a etiologia do distúrbio de crescimento de pacientes altos, e apenas um fez uma investigação genética sistemática em pacientes com déficit intelectual e alta estatura e/ou macrocefalia, com uma taxa de diagnóstico de 50%. Baseado neste contexto, o presente estudo teve como objetivo principal a investigação genética sistemática de uma coorte de pacientes com alta estatura, sindrômicos e não sindrômicos, através da análise de cariótipo (convencional ou molecular) e do sequenciamento paralelo em larga escala de múltiplos genes através de painel customizado e/ou exoma. Foram avaliados prospectivamente 42 pacientes com alta estatura após a exclusão de causas hormonais, sendo 12 não sindrômicos e 30 sindrômicos. Dos pacientes não sindrômicos, todos realizaram cariótipo, sendo identificado em um paciente duas cópias do cromossomo Y (47, XYY). No restante destes pacientes, foi realizado sequenciamento exômico sem identificação de variantes patogênicas. Entre os pacientes sindrômicos, o cariótipo convencional identificou um rearranjo cromossômico levando a uma trissomia do gene SHOX, e o cariótipo molecular encontrou uma microdeleção no cromossomo 9q22.3, além da confirmação de dois pacientes com síndrome de Beckwith-Wiedemann por MLPA. Os demais pacientes sindrômicos foram avaliados por painel e/ou exoma, sendo encontradas 9 variantes patogênicas ou provavelmente patogênicas (FBN1 = 3, NSD1 = 2, NFIX = 1, SUZ12 = 1, CHD8 = 1 e MC4R = 1). A taxa de diagnóstico combinandose todas as técnicas utilizadas foi de 33,3% (14/42 pacientes), sendo superior nos pacientes sindrômicos (43,3%, 13/30) que nos não sindrômicos (8,3%, 1/12). Assim, pode-se concluir neste estudo que uma abordagem de investigação genética sistemática é eficaz em estabelecer o diagnóstico definitivo em pacientes sindrômicos com alta estatura e deve ser recomendada neste subgrupo, independentemente de haver ou não uma hipótese diagnóstica inicial baseada nos achados clínicos. Além disso, o presente estudo ajudou a estabelecer o gene SUZ12 como uma causa rara de síndrome de Weaver, uma doença que cursa com alta estatura e déficit intelectualStature is a human trait with high herdability, and most of the pathologies that affects childhood lead to a growth impairment. Therefore, tall stature is a clinical condition in which is expected a higher genetic influence after ruling out hormonal alterations in GH/IGF-1 and gonadotrophic axis. Few studies have assessed the etiology of the growth disorder in tall patients, and only one report has made a systematic genetic evaluation of patients with intellectual disability and tall stature and/or macrocephaly, with a diagnostic rate of 50%. Based on this context, the aim of this study was to systematically perform a genetic investigation in a cohort of tall patients, both syndromic and non-syndromic, using the conventional and molecular karyotypes and multigene sequencing analysis (targeted panel and/or whole exome sequencing). We evaluated 42 patients with tall stature, 30 syndromic and 12 non-syndromic, after the exclusion of a hormonal etiology. Among non-syndromic patients, karyotype was performed in all of them, with the identification of a patient harboring two copies of chromosome Y. In the remaining non-syndromic patients, whole exome sequencing was performed, without pathogenic findings. Among syndromic patients, conventional karyotype identified a chromosomal abnormality leading to a SHOX gene trisomy, molecular karyotype diagnosed a microdeletion in chromosome 9q22.3 and MLPA confirmed two cases of Beckwith-Wiedemann syndrome. The remaining syndromic patients were evaluated with targeted panel and/or whole exome sequencing, and we found nine pathogenic or likely pathogenic variants (FBN1 = 3, NSD1 = 2, NFIX = 1, SUZ12 = 1, CHD8 = 1 e MC4R = 1). The diagnostic rate with all techniques combined was 33.3% (14/42 patients), and it was superior in syndromic (43.3%, 13/30) than in non-syndromic patients (8.3%, 1/12). Therefore, we concluded that a systematic genetic approach is efficient to establish the etiology of the growth disorder in syndromic patients with tall stature and should be recommended in this subgroup, independently of having an initial clinical suspicion. Further, this study helped to establish SUZ12 as a rare cause of Weaver syndrome, a disorder that causes tall stature and intellectual disabilit

Triple A Syndrome: Preliminary Response to the Antioxidant N-Acetylcysteine Treatment in a Child

Introduction: Triple A syndrome (AAAS) is a rare autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency, autonomic dysfunction, and progressive neurodegeneration. Increased oxidative stress, demonstrated in patients’ fibroblasts in vitro, may be a central disease mechanism. N-acetylcysteine protects renal function in patients with kidney injuries associated with increased oxidative stress and improves viability of AAAS-knockdown adrenal cells in vitro. Patient and Results: A boy diagnosed with AAAS presented with short stature and increased oxidative stress in vivo assessed by increased thiobarbituric acid reactive substances (TBARS), which are markers of lipid peroxidation, and by the susceptibility of LDL to oxidation and the capacity of HDL to prevent it. A homozygous missense germline mutation (c.523G>T, p.Val175Phe) in AAAS was identified. N-acetylcysteine (600 mg orally, twice daily) decreased oxidative stress but did not change the patient’s growth pattern. Conclusions: An increase in oxidative stress is reported for the first time in vivo in an AAAS patient. N-acetylcysteine was capable of decreasing TBARS levels, reducing the susceptibility of LDL to oxidation and improving the antioxidant role of HDL. The longterm effect of antioxidant treatment should be evaluated to determine the real benefit for the prevention of the degenerative process in AAAS