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Introduction: Ectopic posterior pituitary (EPP) is a rare congenital abnormality, sometimes associated with other midline defects, such as pituitary stalk interruption syndrome (PSIS), in which thin or absent pituitary stalk and anterior pituitary hypoplasia are combined to EPP. Most cases are sporadic, with few reports of familial cases, and many congenital hypopituitarism (CH) cases remain unsolved. Objective: To search for candidate genes associated with this condition, we performed trio-based whole-exome sequencing (WES) on patients with EPP, including two familial cases. Methods: This study included subjects with EPP and PSIS diagnosed by a simple MRI protocol (FAST1.2). We performed two distinct analyses in the trio-based WES. We looked for previously described genes associated with pituitary development. Next, we investigated the whole exome for variants inherited in a pattern consistent with a monogenic etiology. Results: Ten families were evaluated; eight were composed of a child with EPP and healthy parents, one has two affected siblings, and one family has a son and mother with EPP. When analyzing the previously described candidate variants associated with pituitary development, we found variants in GLI2 and FGFR1 in three families. We also found six other variants of interest in three patients: KMT2A, GALR3, RTN4R, SEMA3A, NIPBL, and DSCAML1. Conclusion: The analysis allowed us to find previously reported and not reported GLI2 variants, all inherited from healthy parents, which reinforces the incomplete penetrance pattern of GLI2 variants in the development of EPP and draws attention to possible future functional studies of those variants that have a recurrent expression in CH. We also found novel FGFR1 and SEMA3A variants that suggest an oligogenic mechanism in PSIS and EPP, as seen in patients with hypogonadotropic hypogonadism. We report the first case of a patient with Wiedemann-Steiner syndrome and PSIS, suggesting that the KMT2A gene may be related to pituitary development. Furthermore, the trios' analysis allowed us to find five other variants of interest. Future investigations may clarify the roles of these variants in the etiology of EPP and PSIS.

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BACKGROUND: Pituitary apoplexy (PA) is characterized by acute hemorrhage or infarction of the pituitary gland. Management can be either conservative or surgical. Evidence favoring either is still limited to observational studies. This meta-analysis evaluates the effectiveness of both approaches on patient outcomes. METHODS: A systematic search was performed until February 2024. We included cohort studies of patients with PA. Patients were divided into 2 groups: a conservative management group and a surgery group, including early and late surgery. Outcomes of interest were assessed categorically using risk ratio (RR) and Mantel-Haenszel's random effects model. RESULTS: Of the 273 published articles, 15 cohort studies comprising 908 patients were included. There was no statistically significant difference between groups in recovery of ophthalmoplegia (RR=1.09, confidence interval [CI]=1.00-1.18, P=0.05), visual field (RR=1.09, CI=0.91-1.3, P=0.35), visual acuity (RR=1.05, CI=0.87-1.26, P=0.61), hypopituitarism (RR=1.37, CI=0.81-2.32, P=0.25), and tumor recurrence (RR=0.74, CI=0.34-1.61, P=0.45). This was similar for conservative management versus early surgery in recovery of visual field (RR=0.92, CI=0.62-1.37, P=0.68), visual acuity (RR=1.01, CI=0.81-1.26, P=0.93), and ophthalmoplegia (RR=0.92, CI=0.53-1.61, P=0.77). CONCLUSIONS: Both interventions provide comparable outcomes. These findings, though, are drawn from observational studies, and more severe cases typically undergo surgery. Larger studies are necessary to provide conclusive evidence.

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Hypopituitarism is a rare endocrine disorder characterized by insufficient hormone secretion from the pituitary gland. This condition leads to deficient production of one or more pituitary hormones, including growth hormone (GH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotropic hormone (ACTH), and antidiuretic hormone (ADH), also called arginine vasopressin (AVP). Symptoms vary widely and are often not, late recognized.Diagnosis typically involves a thorough clinical evaluation, hormone level assessments, and neuroimaging studies to identify underlying causes. Treatment aims to replace deficient hormones and address the underlying cause and related complications when possible. In this special issue we address diagnosis, comorbidities, and management of hypopituitarism. We hope that it will help healthcare professionals to manage their patients.

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Central hypothyroidism (CH) is characterized by decreased thyroid hormone production due to insufficient stimulation of an otherwise normal thyroid gland by TSH. In patients with established hypothalamic-pituitary disease, a low FT4 concentration is considered highly specific, although poorly sensitive, for the diagnosis of CH. That would be comparable to diagnosing primary hypothyroidism in patients at risk only when serum FT4 concentrations are below the reference range, missing all patients with subclinical primary hypothyroidism and preventing proper therapy in patients in which thyroxine replacement is clearly beneficial. Cardiac time intervals, especially the isovolumic contraction time (ICT), have been considered the gold standard of peripheral thyroid hormone action. Using Doppler echocardiography, we have previously shown a very high proportion of prolonged ICT in patients with hypothalamic-pituitary disease and serum FT4 levels indistinguishable from controls. As ICT decreased/normalized after thyroxine-induced increases in FT4 concentrations within the normal reference range, prolonged ICT was considered a bona fide diagnostic biomarker of subclinical CH. Those findings challenge the usual interpretation that FT4 concentrations in the mid-reference range exclude hypothyroidism in patients with hypothalamic-pituitary disease. Rather, subclinical central hypothyroidism, a state analogous to subclinical primary hypothyroidism, seems to be frequent in patients with hypothalamic-pituitary disease and normal FT4 levels. They also challenge the notion that thyroid function is usually the least or the last affected in acquired hypopituitarism. The relevance of Doppler echocardiography to correctly diagnose and monitor replacement therapy in both clinical and subclinical forms of CH should improve quality of life and decrease cardiovascular risk, as already demonstrated in patients with clinical and subclinical primary hypothyroidism.

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Pituitary hormone deficiency, hypopituitarism, is a dysfunction resulting from numerous etiologies, which can be complete or partial, and is therefore heterogeneous. This heterogeneity makes it difficult to interpret the results of scientific studies with these patients.Adequate treatment of etiologies and up-to-date hormone replacement have improved morbidity and mortality rates in patients with hypopituitarism. As GH replacement is not performed in a reasonable proportion of patients, especially in some countries, it is essential to understand the known consequences of GH replacement in each subgroup of patients with this heterogeneous dysfunction.In this review on hypopituitarism, we will address some particularities regarding insulin resistance, which is no longer common in these patients with hormone replacement therapy based on current guidelines, metabolic syndrome and its relationship with changes in BMI and body composition, and to vascular complications that need to be prevented taking into account the individual characteristics of each case to reduce mortality rates in these patients.

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ABSTRACT Objective: Congenital hypopituitarism (CH) is a rare disease characterized by one or more hormone deficiencies of the pituitary gland. To date, many genes have been associated with CH. In this study, we identified the allelic variant spectrum of 11 causative genes in Turkish patients with CH. Materials and methods: This study included 47 patients [21 girls (44.6%) and 26 boys (55.4%)] from 45 families. To identify the genetic etiology, we screened 11 candidate genes associated with CH using next-generation sequencing. To confirm and detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results: We identified 12 possible pathogenic variants in GHRHR, GH1, GLI2, PROP-1, POU1F1, and LHX4 in 11 patients (23.4%), of which six were novel variants: two in GHRHR, two in POU1F1, one in GLI2, and one in LHX4. In all patients, these variants were most frequently found in GLI2, followed by PROP-1 and GHRHR. Conclusion: Genetic causes were determined in only 23.4% of all patients with CH and 63% of molecularly diagnosed patients (7/11) from consanguineous families. Despite advances in genetics, we were unable to identify the genetic etiology of most patients with CH, suggesting the effect of unknown genes or environmental factors. More genetic studies are necessary to understand the etiology of CH.

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Presentamos el caso de una paciente con displasia septo-óptica (SOD), también conocida como síndrome de De Morsier, un desorden congénito raro. Se caracteriza por una combinación de alteraciones: hipoplasia del nervio óptico, disfunción hipofisaria y anormalidades de la línea media. Presentamos el caso de una paciente de 37 años con síndrome de De Morsier que consulta por infertilidad. Asocia hipopituitarismo, con déficit de hormona de crecimiento e hipogonadismo hipogonadotrófico, diagnosticada a los 11 años, en contexto de hipocrecimiento e impuberismo. También presenta complicaciones asociadas a estos déficits, como infertilidad, síndrome metabólico y compromiso óseo. Un diagnóstico y tratamiento temprano puede prevenir la morbimortalidad asociada a este síndrome, pero no así la infertilidad. Sin embargo, es posible lograr el embarazo mediante inducción de la ovulación.

The study presents the case of a patient with septo-optic dysplasia (SOD), also known as de Morsier syndrome, which is a rare congenital disorder. It is characterized by a combination of abnormalities, including optic nerve hypoplasia, pituitary dysfunction, and midline abnormalities. We present the case of a 37-year-old female patient with De Morsier syndrome, who seeks medical attention due to infertility. She presents with hypopituitarism, characterized by growth hormone deficiency and hypogonadotropic hypogonadism, diagnosed at the age of 11 in the context of short stature and delayed puberty. The patient also exhibits complications associated with these deficits, such as infertility, metabolic syndrome, and skeletal compromise. Early diagnosis and treatment can prevent morbidity and mortality associated with this syndrome, but unfortunately, infertility remains unaffected. Nevertheless, achieving pregnancy is possible through ovulation induction.

A síndrome de De Morsier, é uma doença congênita rara, caracterizada por uma combinação de alterações: hipoplasia do nervo óptico, disfunção hipofisária e anomalias da linha média. Apresentamos o caso de uma paciente de 37 anos com displasia septo-óptica (SOD), também conhecida como síndrome de De Morsier que consultou por infertilidade. Associado à SOD detectou-se hipopituitarismo, com deficiência de hormônio do crescimento e hipogonadismo hipogonadotrófico diagnosticado aos 11 anos de idade em um contexto de hipocrescimento e impuberdade. Foram observadas também complicações associadas a esses déficits como infertilidade, síndrome metabólica e envolvimento ósseo. O diagnóstico e tratamento precoces podem prevenir a morbimortalidade associada a esta síndrome, mas não a infertilidade. No entanto, a gravidez é possível através da indução da ovulação.

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Objective: Congenital hypopituitarism (CH) is a rare disease characterized by one or more hormone deficiencies of the pituitary gland. To date, many genes have been associated with CH. In this study, we identified the allelic variant spectrum of 11 causative genes in Turkish patients with CH. Materials and methods: This study included 47 patients [21 girls (44.6%) and 26 boys (55.4%)] from 45 families. To identify the genetic etiology, we screened 11 candidate genes associated with CH using next-generation sequencing. To confirm and detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results: We identified 12 possible pathogenic variants in GHRHR, GH1, GLI2, PROP-1, POU1F1, and LHX4 in 11 patients (23.4%), of which six were novel variants: two in GHRHR, two in POU1F1, one in GLI2, and one in LHX4. In all patients, these variants were most frequently found in GLI2, followed by PROP-1 and GHRHR. Conclusion: Genetic causes were determined in only 23.4% of all patients with CH and 63% of molecularly diagnosed patients (7/11) from consanguineous families. Despite advances in genetics, we were unable to identify the genetic etiology of most patients with CH, suggesting the effect of unknown genes or environmental factors. More genetic studies are necessary to understand the etiology of CH.

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INTRODUCTION: Pituitary incidentalomas (PIs) are lesions found incidentally in the pituitary on imaging performed for reasons unrelated to pituitary disease. METHODS: A cross-sectional, retrospective and descriptive study was carried out with the aim of analyzing the clinical and evolutionary characteristics of a population of patients with PIs in the city of Córdoba. RESULTS: A total of 67 patients were included, 67% female, with a median age at diagnosis of 44 years. Among the reasons that led to requesting the first image, chronic or recurrent headache was the most prevalent (34%). The median tumor size was 12 mm. Fifty-eight percent were macroincidentalomas. Men had significantly larger lesions (p = 0.04). At diagnosis, including both sexes, 30% showed extrasellar extension and 45% invasion of the cavernous sinuses. Neuro-ophthalmological compromise was detected in 21%. A positive correlation was found between age at diagnosis and tumor size (r= +0.31, p = 0.001). Ninety-one percent were non-functioning tumors and at presentation, 21% of patients had one or more hormonal deficiencies. Of the total, 26% required surgery. Most of those who continued without treatment showed no change in tumor size at the end of follow-up (median 42 months). CONCLUSION: We highlight the high frequency of macroincidentalomas in our series, with visual field defects and hypopituitarism being frequent at diagnosis. Although most non-operated PIs remained stable, there was a high frequency of clinically significant lesions.

Introducción: Los incidentalomas hipofisarios (IH) son lesiones halladas fortuitamente en la hipófisis mediante imágenes realizadas por motivos no relacionados con enfermedad hipofisaria. Métodos: Se realizó un estudio transversal, retrospectivo y descriptivo con el objetivo de analizar las características clínicas y evolutivas de una población de pacientes portadores de IH en la ciudad de Córdoba. Resultados: Se incluyeron 67 pacientes, 67% del sexo femenino, con una mediana de edad al diagnóstico de 44 años. Entre los motivos que llevaron a solicitar la primera imagen, la cefalea crónica o recurrente fue el más prevalente (34%). La mediana del tamaño tumoral fue de 12 mm. El 58% fueron macroincidentalomas. Los hombres tuvieron lesiones significativamente más grandes (p = 0.04). Al diagnóstico, considerando ambos sexos, el 30% evidenció extensión extraselar y el 45% invasión a senos cavernosos. Se detectó compromiso neurooftalmológico en el 21%. Se halló correlación positiva entre la edad al momento del diagnóstico y el tamaño tumoral (r = +0.31, p = 0.001). El 91% fueron tumores no funcionantes y en su presentación, el 21% de los pacientes presentaron una o más deficiencias hormonales. El 26% del total requirió cirugía. La mayoría de aquellos que continuaron sin tratamiento no evidenciaron cambios en el tamaño tumoral al final del seguimiento (mediana 42 meses). Conclusión: Destacamos la elevada frecuencia de macroincidentalomas en nuestra serie, siendo los defectos del campo visual y el hipopituitarismo frecuentes al diagnóstico. Si bien la mayoría de los IH no operados permanecieron estables, existió una alta frecuencia de lesiones clínicamente significativas.

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Resumen Introducción : Los incidentalomas hipofisarios (IH) son lesiones halladas fortuitamente en la hipófisis mediante imágenes realizadas por motivos no relacionados con enfermedad hipofisaria. Métodos : Se realizó un estudio transversal, retros pectivo y descriptivo con el objetivo de analizar las características clínicas y evolutivas de una población de pacientes portadores de IH en la ciudad de Córdoba. Resultados : Se incluyeron 67 pacientes, 67% del sexo femenino, con una mediana de edad al diagnóstico de 44 años. Entre los motivos que llevaron a solicitar la primera imagen, la cefalea crónica o recurrente fue el más prevalente (34%). La mediana del tamaño tumoral fue de 12 mm. El 58% fueron macroincidentalomas. Los hombres tuvieron lesiones significativamente más grandes (p = 0.04). Al diagnóstico, considerando ambos sexos, el 30% evidenció extensión extraselar y el 45% invasión a senos cavernosos. Se detectó compromi so neurooftalmológico en el 21%. Se halló correlación positiva entre la edad al momento del diagnóstico y el tamaño tumoral (r = +0.31, p = 0.001). El 91% fueron tumores no funcionantes y en su presentación, el 21% de los pacientes presentaron una o más deficiencias hormonales. El 26% del total requirió cirugía. La ma yoría de aquellos que continuaron sin tratamiento no evidenciaron cambios en el tamaño tumoral al final del seguimiento (mediana 42 meses). Conclusión : Destacamos la elevada frecuencia de macroincidentalomas en nuestra serie, siendo los de fectos del campo visual y el hipopituitarismo frecuentes al diagnóstico. Si bien la mayoría de los IH no operados permanecieron estables, existió una alta frecuencia de lesiones clínicamente significativas.

Abstract Introduction : Pituitary incidentalomas (PIs) are le sions found incidentally in the pituitary on imaging performed for reasons unrelated to pituitary disease. Methods : A cross-sectional, retrospective and descrip tive study was carried out with the aim of analyzing the clinical and evolutionary characteristics of a population of patients with PIs in the city of Córdoba. Results : A total of 67 patients were included, 67% fe male, with a median age at diagnosis of 44 years. Among the reasons that led to requesting the first image, chron ic or recurrent headache was the most prevalent (34%). The median tumor size was 12 mm. Fifty-eight percent were macroincidentalomas. Men had significantly larger lesions (p = 0.04). At diagnosis, including both sexes, 30% showed extrasellar extension and 45% invasion of the cavernous sinuses. Neuro-ophthalmological compromise was detected in 21%. A positive correlation was found between age at diagnosis and tumor size (r= +0.31, p = 0.001). Ninety-one percent were non-functioning tumors and at presentation, 21% of patients had one or more hormonal deficiencies. Of the total, 26% required surgery. Most of those who continued without treatment showed no change in tumor size at the end of follow-up (median 42 months). Conclusion : We highlight the high frequency of mac roincidentalomas in our series, with visual field defects and hypopituitarism being frequent at diagnosis. Al though most non-operated PIs remained stable, there was a high frequency of clinically significant lesions.