RESUMEN
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.
Asunto(s)
Hipopituitarismo , Humanos , Hipopituitarismo/terapia , Hipopituitarismo/diagnósticoRESUMEN
Hypopituitarism, or the failure to secrete hormones produced by the anterior pituitary (adenohypophysis) and/or to release hormones from the posterior pituitary (neurohypophysis), can be congenital or acquired. When more than one pituitary hormone axis is impaired, the condition is known as combined pituitary hormone deficiency (CPHD). The deficiency may be primarily due to a hypothalamic or to a pituitary disorder, or concomitantly both, and has a negative impact on target organ function. This review focuses on the pathophysiology, diagnosis and management of anterior pituitary hormone deficiency in the pediatric age. Congenital hypopituitarism is generally due to genetic disorders and requires early medical attention. Exposure to toxicants or intrauterine infections should also be considered as potential etiologies. The molecular mechanisms underlying the fetal development of the hypothalamus and the pituitary are well characterized, and variants in the genes involved therein may explain the pathophysiology of congenital hypopituitarism: mutations in the genes expressed in the earliest stages are usually associated with syndromic forms whereas variants in genes involved in later stages of pituitary development result in non-syndromic forms with more specific hormone deficiencies. Tumors or lesions of the (peri)sellar region, cranial radiation therapy, traumatic brain injury and, more rarely, other inflammatory or infectious lesions represent the etiologies of acquired hypopituitarism. Hormone replacement is the general strategy, with critical periods of postnatal life requiring specific attention.
Asunto(s)
Hipopituitarismo , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/terapia , Niño , Hormonas Adenohipofisarias/deficiencia , Hormonas Adenohipofisarias/metabolismoRESUMEN
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.
Asunto(s)
Hipopituitarismo , Femenino , Humanos , Masculino , Alelos , Hipopituitarismo/diagnóstico , Hipopituitarismo/genética , Mutación , Proteínas Nucleares/genética , Factor de Transcripción Pit-1/genética , Factores de Transcripción/genética , Proteína Gli2 con Dedos de Zinc/genéticaRESUMEN
INTRODUCTION: Primary hypophysitis (PH) is a rare disease that represents a challenge among differential diagnosis and management. Our aim was to describe clinical characteristics, diagnostic criteria and different treatment outcomes in patients with PH. Multicentric, retrospective study. Clinical presentation, endocrine function, magnetic resonance imaging findings, visual field defects at diagnosis and treatment outcomes were recorded. METHODS: Twenty-eight patients (23 women), with PH were included. Median age: 37. RESULTS: The most frequent symptoms: headache: 68%, polyuria-polydipsia: 50% and visual disturbances: 48%. At diagnosis, anterior pituitary deficiency was present in 71%, being hypogonadotrophic hypogonadism the most frequent manifestation. The radiological findings: symmetric lesion: 78.5%, homogeneous enhancement: 78.5% and pituitary stalk thickening: 70%. Association with pregnancy or puerperium was found in 4/23 women (17%). Fourteen patients did not receive any treatment ("wait and see" group), 8 underwent surgery for mass reduction or resection and 6 were treated with immunosuppression therapy. Among 15 patients with histopathological diagnosis, 9 were lymphocytic hypophysitis, 5 IgG4 related hypophysitis and 1 xanthomatous hypophysitis. Thirteen were diagnosed by established clinical criteria. Mass reduction was observed in 43% of "wait and see group" patients, 62.5% of operated patients and 50% with immunosuppression therapy. Compressive symptoms showed improvement in the 3 groups, with modest effect on anterior pituitary function, diabetes insipidus did not resolve in any patients. DISCUSSION: In patients without severe compressive symptoms, we adopted a "wait and see" approach. In patients with uncertain diagnosis of PH or severe compressive symptoms, transsphenoidal surgery was the best option.
Introducción: La hipofisitis es una enfermedad infrecuente que plantea un desafío en el diagnóstico y tratamiento. El objetivo de este estudio multicéntrico y retrospectivo fue describir: a) características de pacientes con hipofisitis primaria (HP), b) métodos diagnósticos, y c) tratamientos realizados. Además, evaluar: a) presentación clínica, b) bioquímica, c) radiológica, d) oftalmológica al diagnóstico y evolución según el tratamiento recibido. Métodos: Estudio retrospectivo donde se estudiaron 28 pacientes (23 mujeres/5 varones) con HP, edad promedio de 38±11.1 años. Resultados. Los síntomas fueron: cefalea: 68%, poliuria- polidipsia: 50% y alteraciones visuales: 48%. El examen de laboratorio inicial informó disfunción adenohipofisaria en 71% de los pacientes, siendo el eje gonadal el más afectado. Los hallazgos radiológicos más frecuentes fueron: lesión simétrica:78.5%, aumento homogéneo post contraste: 78.5% y engrosamiento de tallo:70%. En 4/23 mujeres (17%) se relacionó con embarazos o puerperio La conducta inicial fue expectante (CE) en 14 pacientes, cirugía de resección/descompresión en 8 y tratamiento con inmunosupresores en 6. Quince pacientes tuvieron confirmación histológica, 9 resultaron hipofisitis linfocitaria, 5 hipofisitis por IgG4 y una xantomatosa. Trece fueron diagnosticados por criterios clínicos establecidos. El tamaño de la lesión disminuyó en 43% de pacientes con CE, 62.5% con cirugía y 50% con inmunosupresores. Los síntomas compresivos mejoraron en los 3 grupos, con escaso efecto sobre la función adenohipofisaria, sin resolución de la diabetes insípida. Discusión: En pacientes sin síntomas compresivos adoptamos CE. En aquellos pacientes sin certeza diagnóstica o con síntomas compresivos graves, se optó por cirugía transesfenoidal.
Asunto(s)
Hipofisitis Autoinmune , Hipofisitis , Hipopituitarismo , Embarazo , Humanos , Femenino , Adulto , Estudios Retrospectivos , Hipofisitis/diagnóstico , Hipofisitis/terapia , Hipofisitis/patología , Hipófisis/patología , Hipopituitarismo/diagnóstico , Hipofisitis Autoinmune/diagnóstico , Hipofisitis Autoinmune/terapia , Hipofisitis Autoinmune/patología , Imagen por Resonancia MagnéticaRESUMEN
Objective: Isolated childhood growth hormone deficiency (GHD) can persist into adulthood, and re-testing at the transition period is needed to determine whether continued growth hormone therapy is indicated. Here, our objective was to identify predictors of permanent GHD. Design: Retrospective single-centre study of patients with childhood-onset GHD who were re-tested after adult height attainment. Methods: Auxological, clinical, laboratory, and MRI data throughout follow-up were collected. Results: We included 101 patients. At GH treatment initiation, age was 8.1 ± 0.4 years, height -2.25 ± 0.8, and BMI -0.27 ± 0.1 SDS. The 29 (28.7%) patients with persistent GHD had lower height SDS (-2.57 ± 0.1 vs. -2.11 ± 0.1, p<0.001) and mean GH peaks (8.4 ± 1.0 vs.13.2 ± 0.5 mIU/L, p<0.001) at GHD diagnosis; at adult height, they had lower IGF1 (232 ± 19.9 vs. 331 ± 9.1 ng/mL, p<0.001) and higher BMI SDS (-0.15 ± 0.27 vs. -0.73 ± 0.13, p<0.005). By multivariate analysis, the best predictive model included height and BMI SDS, both GH peaks, and MRI findings at diagnosis. Patients with height at diagnosis <-3 SDS had a 7.7 (95% IC 1.4-43.1, p=0.02) fold higher risk of persistent GHD after adjustment on BMI SDS. An abnormal pituitary region by MRI was the strongest single predictor (7.2 times, 95% CI 2.7-19.8) and after multivariate analysis adjustment for GH peaks and height SDS at diagnosis, the risk increased to 10.6 (1.8 - 61.3) times. Conclusions: Height <-3 SDS at GHD diagnosis and pituitary MRI abnormalities should lead to a high index of suspicion for persistent GHD.
Asunto(s)
Enanismo Hipofisario , Hormona de Crecimiento Humana , Hipopituitarismo , Adulto , Niño , Humanos , Enanismo Hipofisario/diagnóstico , Enanismo Hipofisario/tratamiento farmacológico , Hormona de Crecimiento Humana/deficiencia , Hipopituitarismo/diagnóstico , Hipopituitarismo/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
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.
Asunto(s)
Adenoma , Hipopituitarismo , Neoplasias Hipofisarias , Masculino , Humanos , Femenino , Adulto , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/epidemiología , Estudios Retrospectivos , Estudios Transversales , Adenoma/diagnóstico , Hipopituitarismo/diagnósticoRESUMEN
Abnormal hypothalamic/posterior pituitary development appears to be a major determinant of pituitary stalk interruption syndrome (PSIS). The observation of familial cases and associated congenital abnormalities suggests a genetic basis. Single-gene mutations explain less than 5% of the cases, and whole exome sequencing has shown heterogeneous results. The present study aimed to assess copy number variation (CNV) using array-based comparative genomic hybridization (aCGH) in patients with non-syndromic PSIS and comprehensively review data from the literature on CNV analysis in congenital hypopituitarism (CH) patients. Twenty-one patients with sporadic CH from our outpatient clinics presented with ectopic posterior pituitary (EPP) and no central nervous system abnormalities on magnetic resonance image (MRI) or any other malformations on physical examination at presentation were enrolled in the study. aCGH using a whole-genome customized 400K oligonucleotide platform was performed in our patients. For the literature review, we searched for case reports of patients with CH and CNV detected by either karyotype or aCGH reported in PubMed up to November 2021. Thirty-five distinct rare CNVs were observed in 18 patients (86%) and two of them (6%) were classified as pathogenic: one deletion of 1.8 Mb in chromosome 17 (17q12) and one deletion of 15 Mb in chromosome 18 (18p11.32p11.21), each one in a distinct patient. In the literature review, 67 pathogenic CNVs were published in 83 patients with CH, including the present study. Most of these patients had EPP (78% out of the 45 evaluated by sellar MRI) and were syndromic (70%). The most frequently affected chromosomes were X, 18, 20 and 1. Our study has found that CNV can be a mechanism of genetic abnormality in non-syndromic patients with CH and EPP. In future studies, one or more genes in those CNVs, both pathogenic and variant of uncertain significance, may be considered as good candidate genes.
Asunto(s)
Hipopituitarismo , Enfermedades de la Hipófisis , Humanos , Variaciones en el Número de Copia de ADN/genética , Hibridación Genómica Comparativa/métodos , Enfermedades de la Hipófisis/genética , Hipopituitarismo/genética , Hipopituitarismo/diagnóstico , Hipopituitarismo/patología , Síndrome , Hipófisis/diagnóstico por imagen , Hipófisis/patologíaRESUMEN
The deficiency of two or more pituitary hormones is called multiple pituitary hormone deficiencies (MPHD). Its prevalence is estimated to be about 1/8,000 worldwide. OBJECTIVE: To present the diagnosis processes, clinical findings, and long-term follow-up of patients with MPHD. PATIENTS AND METHOD: Between 1999 and 2015, patients diagnosed with MPHD were evaluated. Clinical presentation, anthropometry, imaging studies, and clinical evolution were analyzed. Hormone status was evaluated, including growth hormone (GH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone/luteinizing hormone (FSH/LH), and prolactin (PRL). Data were assessed using the student's t-test and the Mann-Whitney U test. Spearman's correlation was used for correlations. A p-value < 0.05 was considered statistically significant. RESULTS: Forty-five patients were included; 55.6% were male, the mean age at presentation was 5.6 ± 3.9 (0-14.4) years, and the median bone age was 3.5 ± 2.3 (0.5-11) years. At admission, GH deficiency was found in 88.9% of the cases, TSH deficiency in 77.8%, ACTH deficiency in 33.3%, FSH/LH deficiency in 22.2%, and PRL deficiency in 17.8%. During the follow-up, 62% of the cases added other hormone deficiencies. The mean follow-up period was 9.18 ± 3.6 (3.02-17.2) years. CONCLUSION: Patients with MPHD have very different clinical presentations, with GH and TSH deficiency being the most common in this study. Additional hormonal deficiencies can occur even years after the initial diagnosis and our results demonstrate that genetic height potential is achieved with GH treatment.
Asunto(s)
Hormona de Crecimiento Humana , Hipopituitarismo , Hipotiroidismo , Humanos , Masculino , Lactante , Preescolar , Femenino , Estudios de Seguimiento , Hormonas Hipofisarias , Hipopituitarismo/diagnóstico , Hipopituitarismo/tratamiento farmacológico , Hipopituitarismo/epidemiología , Hormona de Crecimiento Humana/uso terapéutico , Hormona del Crecimiento , Hormona Adrenocorticotrópica , Hormona Folículo Estimulante , Hipotiroidismo/tratamiento farmacológicoRESUMEN
Importance: The Zika virus infects progenitor neuron cells, disrupts cerebral development, and, in mice, drives hypothalamic defects. Patients with microcephaly caused by congenital Zika infection present with midline cerebral defects, which may result in hypopituitarism. Objective: To analyze postnatal growth and the presence of clinical and biochemical features associated with hypopituitarism in children with congenital Zika infections. Design, Setting, and Participants: In this prospective cohort study at 2 public referral hospitals in Bahia, Brazil, specializing in the treatment of congenital Zika infection, clinical data and growth parameters of 65 patients with the infection were evaluated. Data were analyzed from April 2017 through July 2018. Exposure: Congenital Zika infection. Main Outcomes and Measures: Length, weight, and head circumference were measured at birth and during follow up (ie, at 27 months of life) for each patient. Basal levels of free thyroxine, thyrotropin, cortisol, corticotropin, prolactin, insulin-like growth factor 1, insulin-like growth factor binding protein 3, urine and plasma osmolality, electrolytes, glucose, and insulin were evaluated at the age of 26 months to 28 months. All patients underwent central nervous system computed tomography scans and ophthalmic and otoacoustic evaluations at the time of this investigation or had done so previously. Results: Among 65 patients (38 [58.4%] male; median [interquartile range] age at enrollment, 27 [26-28] months), 61 patients presented with severe brain defects (93.8%), including corpus callosum agenesis or hypoplasia (ie, midline brain defects; 25 patients [38.5%]) and optic nerve atrophy (38 patients [58.5%]). Most patients presented with severe neurodevelopmental delay (62 of 64 patients [96.9%]). Past or present clinical signs of hypopituitarism were rare, occurring in 3 patients (4.6%). Severe microcephaly, compared with mild or moderate microcephaly, was associated with a shorter length by median (interquartile range) z score at birth (-1.9 [-2.5 to -1.0] vs -0.3 [-1.0 to 0]; P < .001), but this difference did not persist at 27 months (-1.6 [-2.3 to -0.3] vs -2.9 [-4.0 to -1.2]; P = .06). Growth hormone deficiency or hypothyroidism were not observed in any patients, and glucose and insulin levels were within reference ranges for all patients. Low cortisol levels (ie, below 3.9 µg/dL) were observed in 4 patients (6.2%). These 4 patients presented with low (ie, below 7.2 pg/mL) or inappropriately low (ie, below 30 pg/mL) corticotropin levels. Low corticotropin levels (ie, below 7.2 pg/mL) were observed in 6 patients (9.2%). Diabetes insipidus was evaluated in 21 patients; it was confirmed in 1 patient (4.8%) and suggested in 3 patients (14.3%). Conclusions and Relevance: This study found that congenital Zika infection with microcephaly was associated with midline brain defects and optic nerve atrophy. Children with congenital Zika infections presented with prenatal growth impairments with a lack of postnatal catch-up, as shown by persistent short length from birth until 27 months; these impairments were not associated with growth hormone deficiency. Patients also presented with severe developmental delay that was not associated with hypothyroidism, while central adrenal insufficiency and diabetes insipidus occurred in some patients.
Asunto(s)
Hipopituitarismo/virología , Microcefalia/virología , Infección por el Virus Zika/complicaciones , Brasil , Preescolar , Femenino , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/etiología , Hipopituitarismo/patología , Masculino , Microcefalia/diagnóstico por imagen , Microcefalia/etiología , Microcefalia/patología , Neuroimagen , Tomografía Computarizada por Rayos X , Infección por el Virus Zika/diagnóstico por imagen , Infección por el Virus Zika/patologíaRESUMEN
Hypopituitarism after moderate or severe traumatic brain injury (TBI) is usually underdiagnosed and therefore undertreated. Its course can be divided in an acute phase during the first 14 days after TBI with 50 to 80% risk of hypopituitarism, and a chronic phase, beginning three months after the event, with a prevalence of hypopituitarism that ranges from 2 to 70%. Its pathophysiology has been addressed in several studies, suggesting that a vascular injury to the pituitary tissue is the most important mechanism during the acute phase, and an autoimmune one during chronic stages. In the acute phase, there are difficulties to correctly interpret pituitary axes. Hence, we propose a simple and cost-effective algorithm to detect and treat a potential hypothalamic-pituitary-adrenal axis impairment and alterations of sodium homeostasis, both of which can be life-threatening. In the chronic phase, post-concussion syndrome is the most important differential diagnosis. Given the high prevalence of hypopituitarism, we suggest that all pituitary axes should be assessed in all patients with moderate to severe TBI, between 3 to 6 months after the event, and then repeated at 12 months after trauma by a specialized team in pituitary disease.
Asunto(s)
Humanos , Enfermedades de la Hipófisis , Lesiones Traumáticas del Encéfalo , Hipopituitarismo , Sistema Hipófiso-Suprarrenal , Lesiones Traumáticas del Encéfalo/complicaciones , Hipopituitarismo/diagnóstico , Hipopituitarismo/etiología , Sistema Hipotálamo-HipofisarioRESUMEN
Hypopituitarism after moderate or severe traumatic brain injury (TBI) is usually underdiagnosed and therefore undertreated. Its course can be divided in an acute phase during the first 14 days after TBI with 50 to 80% risk of hypopituitarism, and a chronic phase, beginning three months after the event, with a prevalence of hypopituitarism that ranges from 2 to 70%. Its pathophysiology has been addressed in several studies, suggesting that a vascular injury to the pituitary tissue is the most important mechanism during the acute phase, and an autoimmune one during chronic stages. In the acute phase, there are difficulties to correctly interpret pituitary axes. Hence, we propose a simple and cost-effective algorithm to detect and treat a potential hypothalamic-pituitary-adrenal axis impairment and alterations of sodium homeostasis, both of which can be life-threatening. In the chronic phase, post-concussion syndrome is the most important differential diagnosis. Given the high prevalence of hypopituitarism, we suggest that all pituitary axes should be assessed in all patients with moderate to severe TBI, between 3 to 6 months after the event, and then repeated at 12 months after trauma by a specialized team in pituitary disease.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Hipopituitarismo , Enfermedades de la Hipófisis , Lesiones Traumáticas del Encéfalo/complicaciones , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/etiología , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-SuprarrenalAsunto(s)
Técnicas de Diagnóstico Endocrino , Enanismo Hipofisario/diagnóstico , Hormona de Crecimiento Humana/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2 , Determinación de la Edad por el Esqueleto , Andrógenos , Arginina , Niño , Preescolar , Clonidina , Enanismo Hipofisario/metabolismo , Estrógenos , Etinilestradiol , Fármacos Gastrointestinales , Glucagón , Hormona de Crecimiento Humana/deficiencia , Humanos , Hipoglucemia , Hipoglucemiantes , Hipopituitarismo/diagnóstico , Hipopituitarismo/metabolismo , Insulina , Pruebas de Función Hipofisaria , TestosteronaRESUMEN
INTRODUCTION: The diagnosis of growth hormone deficiency (GHD) is difficult to determine, and could be associated with severe complications, especially in the neonatal period. The stimulation test of growth hormone (GH) secretion is considered the gold standard for diagnosis, but it has methodological complications and is associated with adverse effects. Neonates present physiological increased secretion of GH, representing a diagnostic window. OBJECTIVE: To evaluate if the dried blood spot on filter paper obtained in the neonatal period, as part of a neonatal screening for con genital hypothyroidism and phenylketonuria, allows differentiating patients with GHD from those who do not have it. PATIENTS AND METHOD: Study of cases and controls by measuring the GH concen tration in dried blood spot on filter paper obtained in the neonatal period, comparing controls with GHD with cases with discarded deficiency. The sample was extracted from the filter paper, obtaining two 0.125 inch discs per each patient from the center of the blood spot on the paper, for a highly sen sitive ELISA assay for human GH based on the use of polyclonal antibodies against 22 kDa recom binant human GH. RESULTS: Seven cases of GHD and ten controls were obtained. The median GH concentration of the dried blood spot in the cases is 2.0 ng/ml (Interquartile range 3.6 ng/ml) and 2.05 ng/ml (Interquartile range 2.0 ng/ml) in the controls, Mann-Whitney U test 30.5 (p = 0.68). The two cases with multiple pituitary-hormone deficiency (MPHD) present concentrations lower than 1 ng/ml. CONCLUSION: The dried blood spot sample did not differentiate GHD patients from control cases, although MPHD cases present much lower concentrations compared to isolated growth hor mone deficiency (IGHD).
Asunto(s)
Pruebas con Sangre Seca , Trastornos del Crecimiento/diagnóstico , Hormona de Crecimiento Humana/deficiencia , Hipopituitarismo/diagnóstico , Tamizaje Neonatal , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Preescolar , Enanismo Hipofisario/sangre , Enanismo Hipofisario/diagnóstico , Femenino , Trastornos del Crecimiento/sangre , Trastornos del Crecimiento/etiología , Hormona de Crecimiento Humana/sangre , Humanos , Hipopituitarismo/sangre , Hipopituitarismo/complicaciones , Lactante , Recién Nacido , MasculinoRESUMEN
The first description of patients with combined pituitary hormone deficiencies (CPHD) caused by PROP1 mutations was made 20 years ago. Here we updated the clinical and genetic characteristics of patients with PROP1 mutations and summarized the phenotypes of 14 patients with 7 different pathogenic PROP1 mutations followed at the Hospital das Clínicas of the University of Sao Paulo. In addition to deficiencies in GH, TSH, PRL and gonadotropins some patients develop late ACTH deficiency. Therefore, patients with PROP1 mutations require permanent surveillance. On magnetic resonance imaging, the pituitary stalk is normal, and the posterior lobe is in the normal position. The anterior lobe in patients with PROP1 mutations is usually hypoplastic but may be normal or even enlarged. Bi-allelic PROP1 mutations are currently the most frequently recognized genetic cause of CPHD worldwide. PROP1 defects occur more frequently among offspring of consanguineous parents and familial cases, but they also occur in sporadic cases, especially in countries in which the prevalence of PROP1 mutations is relatively high. We classified all reported PROP1 variants described to date according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines: 29 were pathogenic, 2 were likely pathogenic, and 2 were of unknown significance. An expansion of the phenotype of patients with PROP1 mutations was observed since the first description 20 years ago: variable anterior pituitary size, different pathogenic mutations, and late development of ACTH deficiency. PROP1 mutations are the most common cause of autosomal recessive CPHD with a topic posterior pituitary lobe. Arch Endocrinol Metab. 2019;63(2):167-74.
Asunto(s)
Proteínas de Homeodominio/genética , Hipopituitarismo/genética , Mutación/genética , Femenino , Humanos , Hipopituitarismo/diagnóstico , Masculino , Fenotipo , Displasia Septo-Óptica/genéticaRESUMEN
INTRODUCCIÓN: El diagnóstico de deficiencia de hormona de crecimiento (DHC) es difícil de establecer, y se puede asociar a serias complicaciones, especialmente en el período neonatal. La prueba de estímulo de secreción de hormona de crecimiento (HC) se considera de elección para el diagnóstico, pero presenta complicaciones metodológicas y se asocia a efectos adversos. Los neonatos presentan aumento de la secreción de HC de forma fisiológica, siendo una ventana diagnóstica. OBJETIVO: Evaluar si la muestra de sangre en papel filtro tomada en el período neonatal, en contexto del tamizaje neonatal de hipotiroidismo congénito y fenilcetonuria, permite diferenciar pacientes con DHC, de los que no la presentan. PACIENTES Y MÉTODO: Estudio de casos y controles mediante determinación de concentración de HC en sangre de papel filtro extraída en período neonatal, comparando controles con DHC con casos con deficiencia descartada. Se realizó extracción de la muestra del papel filtro, obteniendo dos discos de 0,125 pulgada por cada uno de los pacientes desde el centro de la mancha de sangre del papel, para un ELISA de HC humana altamente sensible basado en el uso de anticuerpos policlonales dirigidos contra la HC humana recombinante de 22kDa de peso molecular. RESULTADOS: Se obtuvo un total de 7 casos de DHC y 10 controles. La mediana de concentración de HC de papel filtro en los casos es 2,0 ng/ml (Rango intercuartil 3,6 ng/ml) y controles 2,05 ng/mL (RIC 2,0 ng/ml), U de Mann-Withney 30,5 (p = 0,68). Los dos casos con deficiencia de hormonas hipofisarias múltiples (DHHM) presentan concentraciones menores a 1 ng/ml. CONCLUSIÓN: La muestra de papel filtro no permitió diferenciar a los pacientes con DHC de los casos controles, aunque los casos con DHHM presentaron concentraciones mucho menores, en comparación a la deficiencia de hormona de crecimiento aislada (DHCA).
INTRODUCTION: The diagnosis of growth hormone deficiency (GHD) is difficult to determine, and could be associated with severe complications, especially in the neonatal period. The stimulation test of growth hormone (GH) secretion is considered the gold standard for diagnosis, but it has methodological complications and is associated with adverse effects. Neonates present physiological increased secretion of GH, representing a diagnostic window. OBJECTIVE: To evaluate if the dried blood spot on filter paper obtained in the neonatal period, as part of a neonatal screening for con genital hypothyroidism and phenylketonuria, allows differentiating patients with GHD from those who do not have it. PATIENTS AND METHOD: Study of cases and controls by measuring the GH concen tration in dried blood spot on filter paper obtained in the neonatal period, comparing controls with GHD with cases with discarded deficiency. The sample was extracted from the filter paper, obtaining two 0.125 inch discs per each patient from the center of the blood spot on the paper, for a highly sen sitive ELISA assay for human GH based on the use of polyclonal antibodies against 22 kDa recom binant human GH. RESULTS: Seven cases of GHD and ten controls were obtained. The median GH concentration of the dried blood spot in the cases is 2.0 ng/ml (Interquartile range 3.6 ng/ml) and 2.05 ng/ml (Interquartile range 2.0 ng/ml) in the controls, Mann-Whitney U test 30.5 (p = 0.68). The two cases with multiple pituitary-hormone deficiency (MPHD) present concentrations lower than 1 ng/ml. CONCLUSION: The dried blood spot sample did not differentiate GHD patients from control cases, although MPHD cases present much lower concentrations compared to isolated growth hor mone deficiency (IGHD).
Asunto(s)
Humanos , Masculino , Femenino , Recién Nacido , Lactante , Preescolar , Niño , Tamizaje Neonatal , Hormona de Crecimiento Humana/deficiencia , Pruebas con Sangre Seca , Trastornos del Crecimiento/diagnóstico , Hipopituitarismo/diagnóstico , Biomarcadores/sangre , Estudios de Casos y Controles , Hormona de Crecimiento Humana/sangre , Enanismo Hipofisario/diagnóstico , Enanismo Hipofisario/sangre , Trastornos del Crecimiento/etiología , Trastornos del Crecimiento/sangre , Hipopituitarismo/complicaciones , Hipopituitarismo/sangreRESUMEN
IgG4-related disease (IgG4-RD) is a recently described systemic entity of unknown origin. It predominantly affects older men and has distinctive histopathologic features as storiform fibrosis, obliterative phlebitis, dense lymphoplasmacytic infiltrate with immunostaining for IgG4, and it may be associated with elevated serum levels of IgG4. Although any organ can be affected, pituitary gland is rarely involved. We describe the case of a 36-year-old man who presented with headaches, impaired vision, panhypopituitarism with diabetes insipidus and an infiltrative lesion mainly of infundibulum and pituitary. We arrived at diagnosis of IgG4-RD by pituitary biopsy. A successful response to treatment with immunosuppressive doses of corticosteroids was achieved.
Asunto(s)
Hipopituitarismo/etiología , Enfermedad Relacionada con Inmunoglobulina G4/complicaciones , Escotoma/etiología , Adulto , Biopsia , Humanos , Hipopituitarismo/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Imagen por Resonancia Magnética , Masculino , Escotoma/diagnósticoRESUMEN
La enfermedad relacionada a IgG4 (IgG4-RD) constituye una entidad sistémica recientemente descrita, de causa desconocida. Afecta predominantemente a hombres mayores y presenta características histopatológicas distintivas, como fibrosis estoriforme, flebitis obliterante y denso infiltrado linfoplasmocitario con inmunomarcación para IgG4, pudiendo estar asociada a elevación sérica de dicha inmunoglobulina. Si bien cualquier órgano puede estar afectado, el compromiso de la hipófisis es infrecuente. Describimos el caso de un hombre de 36 años que se presentó con cefaleas, alteración del campo visual, panhipopituitarismo, diabetes insípida y una imagen que mostraba una lesión infiltrativa infundíbulo-panhipofisaria extendida. Arribamos al diagnóstico de IgG4-RD a través de biopsia hipofisaria. La respuesta al tratamiento con dosis inmunosupresoras de corticoides fue exitosa.
IgG4-related disease (IgG4-RD) is a recently described systemic entity of unknown origin. It predominantly affects older men and has distinctive histopathologic features as storiform fibrosis, obliterative phlebitis, dense lymphoplasmacytic infiltrate with immunostaining for IgG4, and it may be associated with elevated serum levels of IgG4. Although any organ can be affected, pituitary gland is rarely involved. We describe the case of a 36-year-old man who presented with headaches, impaired vision, panhypopituitarism with diabetes insipidus and an infiltrative lesion mainly of infundibulum and pituitary. We arrived at diagnosis of IgG4-RD by pituitary biopsy. A successful response to treatment with immunosuppressive doses of corticosteroids was achieved.
Asunto(s)
Humanos , Masculino , Adulto , Escotoma/etiología , Enfermedad Relacionada con Inmunoglobulina G4/complicaciones , Hipopituitarismo/etiología , Escotoma/diagnóstico , Biopsia , Imagen por Resonancia Magnética , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Hipopituitarismo/diagnósticoRESUMEN
El síndrome de interrupción del tallo pituitario (PSIS) se caracteriza por la demostración neurorradiológica de un tallo pituitario ausente, interrumpido o hipoplásico, adenohipófisis aplásica/hipoplásica o neurohipófisis ectópica. Este síndrome se ha relacionado con formas severas de hipopituitarismo congénito (HPC), asociado a múltiples deficiencias de hormonas pituitarias (MPHD). Evaluamos a pacientes con HPC y PSIS, analizando los signos y los síntomas neonatales al diagnóstico, relacionándolos con las deficiencias hormonales pituitarias y signos neurorradiológicos presentes. Estudiamos retrospectivamente a 80 pacientes asistidos en el Hospital de Niños de Córdoba, con diagnóstico de HPC, de los cuales 42 (52%) presentaron PSIS; 22 mujeres y 20 varones, EC: 5 días-9,5 años. El 62% presentó MPHD y el 38% insuficiencia somatotrófica aislada (IGHD). El análisis de las variables perinatales demostró antecedentes de parto natural en el 52% (11/21) de las MPHD vs. 13% (2/15) de las IGHD. Cuatro pacientes, 2 con MPHD y 2 con IGHD presentaban antecedentes obstétricos consistentes en presentación podálica y transversa respectivamente, todos ellos resueltos mediante operación cesárea. Los signos y los síntomas perinatales fueron hipo- glucemia: 61% en MPHD vs. 19% en IGHD, p: 0,0105; ictericia: 38% en MPHD vs. 25% en IGHD; micropene: 77% en MPHD y colestasis: 19% en MPHD. Convulsiones neonatales se presentaron en el 75% de los niños con MPHD e hipoglucemia. EC media de consulta: 2,1 años en MPHD (30% en el período neonatal, 70% antes de 2 años) y 3,6 años en IGHD (44% en menores de 2 años). Los pacientes con MPHD presentaban: tallo no visible 81% (n: 21/26) vs. tallo hipoplásico: 19% (n: 5/26), p: 0,0001; en IGHD 56% (n: 9/16) vs. 44% (n: 7/16), p: 0,5067, respectivamente. El 100% de los neonatos con HPC tenían tallo pituitario ausente. Concluimos que la demostración de PSIS en niños con HPC proporciona información valiosa como predictor de la severidad fenotípica, la presencia de MPHD y de la respuesta al tratamiento. La baja frecuencia de antecedentes obstétricos posicionales potencialmente distócicos, como parte de los mecanismos fisiopatogénicos responsables de PSIS, indicaría la necesidad de analizar la importancia de posibles factores genéticos y epigenéticos involucrados. El diagnóstico precoz de HPC debe sospecharse en presencia de signos y síntomas clínicos, tales como hipoglucemia, colestasis, micropene y defectos asociados en la línea media facial. La resonancia magnética cerebral debe formar parte de los estudios complementarios en pacientes con esta presunción diagnóstica, especialmente a edades tempranas. El reconocimiento tardío de esta entidad puede aumentar la morbilidad y la mortalidad con efectos potenciales deletéreos y permanentes.
Pituitary stalk interruption syndrome (PSIS) is characterised by the combination of an interrupted or thin pituitary stalk, absent or ectopic posterior pituitary, and anterior pituitary hypoplasia. It is manifested as isolated (IGHD) or combined pituitary hormone deficiencies (CPHD) of variable degrees and timing of onset, with a wide spectrum of clinical phenotypes. PSIS may be an isolated morphological abnormality or be part of a syndrome. A retrospective evaluation is presented of clinical signs and symptoms present at early life stages, as well as an analysis of their relationship with hormone laboratory tests and diagnostic imaging in children with congenital hypopituitarism (CHP), and PSIS. This study was performed in a single centre on a sample of 42 children out of a total of 80 CHP patients, with a chronological age range between 5 days and 9.5 years from a database analysed over a period of 26 years. The study included 26/42 (62%) with CPHD and 16/42 (38%) with IGHD. The analysis of perinatal variables showed a natural delivery in 52% (11/21) of CPHD vs 13% (2/15) of IGHD. Four patients, two with CPHD and two IGHD had breech and transverse presentation respectively. All of them were resolved by caesarean section. The perinatal histories showed hypoglycaemia (61% CPHD vs 19% IGHD, P=.0105), jaundice (38% CPHDvs25% IGHD), micropenis (75%CPHD), hypoglycaemic seizures (75% CPHD), and cholestasis (19% CPHD). The mean CA of consulting for CPHD patients was 2.1 years, 30% in neonatal period and 70% before 2 years. The mean chronical age (CA) was 3.6 years in IGHD patients, with 44% of them less than 2 years. MRI showed that 81% of CPHD patients had absence of pituitary stalk vs 19% with thin pituitary stalk (P=.0001); Patients with IGHD presented 56% absence of pituitary stalk vs 44% with thin pituitary stalk (P=.5067). All (100%) of the patients diagnosed in the neonatal stage had absent pituitary stalk. The characterisation of GH deficient patients by presence and type of hypothalamic-pituitary imaging abnormality provides valuable information as a predictor of phenotypic severity, treatment response, and the potential to develop additional hormonal deficiencies. We conclude that demonstrating PSIS in children with HPC provides valuable information as a predictor of phenotypic severity, presence of MPHD, and response to treatment. The low frequency of potentially dysfunctional positional obstetric history, as part of the pathophysiological mechanisms responsible for PSIS, would indicate the need to analyse the importance of possible genetic and epigenetic factors involved. Early diagnosis of HPC should be suspected in the presence of clinical signs and symptoms, such as hypoglycaemia, cholestasis, micropenis, and associated facial midline defects. MRI should be part of complementary studies in patients with this diagnostic suspicion, especially at an early age. Late recognition of this entity may increase morbidity and mortality with potential permanent deleterious effects.