Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4 and POU1F1 genes

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.

Displasia septo-óptica (síndrome de De Morsier) con hipopituitarismo y sus múltiples complicaciones: reporte de un caso y revisión de literatura

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.

Características clínicas y evolutivas de adenomas hipofisarios incidentales: estudio multicéntrico retrospectivo / Clinical and evolutionary characteristics of incidental pituitary adenomas: retrospective multicenter study

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.

Does Postpartum Hypopituitarism Influence the Craniofacial Pattern? A Case-Control Study with Sheehan's Syndrome Patients

This study aimed to assess the craniofacial morphologic aspects of Sheehan's syndrome (SHS) patients.An observational study was performed with 19 women diagnosed with SHS and 19 controls matched by age and sex. Lateral cephalometric radiographs were obtained, and 30 linear and angular measurements were analyzed using the Radiocef Studio 2 software. The mean age of patients was 65.47 ± 10.19 years. The main findings were propositioned maxilla (52.63 %) and mandible (52.63 %) relative to the cranial base, mandibular prognathism in 73.68 %, deep growth pattern in 42.1 %, increased mandibular plane in 36.84 %, and reduction in anterior facial height. The SHS group showed statistically significant differences in SNB (p=0.026), N-Me (p=0.006), soft palate length (p=0.011), and Ena-Me (p<0.001) in comparison with controls. The standard deviation score analysis revealed altered values in relation to total maxillary and mandibular lengths. SHS showed altered craniofacial morphology, characterized by maxillo- mandibular prognathism, brachyfacial type, increased mandibular plane, and reduction in soft palate length. This study reports novel findings in SHS.

Este estudio tuvo como objetivo evaluar los aspectos morfológicos craneofaciales de los pacientes con síndrome de Sheehan (SHS). Se realizó un estudio observacional con 19 mujeres diagnosticadas con SHS y 19 controles asociados por edad y sexo. Se obtuvieron radiografías cefalométricas laterales y se analizaron 30 medidas lineales y angulares mediante el software Radiocef Studio 2. La edad media de los pacientes fue de 65,47 ± 10,19 años. Los principales hallazgos fueron proposición maxilar (52,63 %) y mandíbula (52,63 %) con respecto a la base del cráneo, prognatismo mandibular en 73,68 %, patrón de crecimiento profundo en 42,1 %, aumento del plano mandibular en 36,84 % y reducción de la altura facial anterior. El grupo SHS mostró diferencias estadísticamente significativas en SNB (p=0,026), N-Me (p=0,006), longitud del paladar blando (p=0,011) y Ena-Me (p<0,001) en comparación con los controles. El análisis de la puntuación de la desviación estándar reveló valores alterados en relación con las longitudes maxilares y mandibulares totales. El SHS mostró una morfología craneofacial alterada, caracterizada por prognatismo maxilomandibular, tipo braquifacial, aumento del plano mandibular y reducción de la longitud del velo del paladar. Este estudio informa hallazgos novedosos en SHS.

Características clínicas e histopatológicas de niños peruanos con craneofaringioma

Introducción: Los craneofaringiomas son tumores benignos, de los cuales hasta el 50% ocurren en niños. Sin embargo, no hay estudios en niños peruanos. Objetivo: describir las características clínicas e histopatológicas de niños con craneofaringioma hospitalizados en el Hospital Nacional Edgardo Rebagliati Martins entre agosto de 2019 y mayo de 2021. El estudio: El diseño es transversal y la fuente de los datos fueron las historias clínicas. Se recolectó información sobre el sexo, edad, cirugías y características relacionadas a la primera cirugía de resección tumoral. Hallazgos: Incluimos 12 pacientes. El 83.3% fueron varones, al momento del diagnóstico la mediana de edad fue de 6 años y predominaron los síntomas visuales, todos tuvieron deficiencias hormonales luego de la primera cirugía de resección. Conclusión: tres recibieron radioterapia, uno desarrolló transformación maligna y otro falleció. Es necesario realizar a futuro estudios prospectivos.

Introduction: Craniopharyngiomas are benign tumors, of which up to 50% occur in children. However, there are no studies in Peruvian children. Objective : to describe the clinical and histopathological characteristics of children with craniopharyngioma hospitalized at the Edgardo Rebagliati Martins National Hospital between August 2019 and May 2021. The study: The design is cross-sectional and the data source were medical records. Information on sex, age, surgeries and characteristics related to the first tumor resection surgery were collected. Findings: We included 12 patients. 83.3% were male, at the time of diagnosis the median age was 6 years and visual symptoms predominated, all had hormonal deficiencies after the first resection surgery. Conclusions: three received radiotherapy, one developed malignant transformation and one died. Future prospective studies are necessary.

Hypopituitarism in elderly � A case series

Hypopituitarism is found to be one of the under investigated disease in elderly as it produces non specific symptoms which can be easily attributed to ageing and related co morbidities. Unless the hypopituitarism is identified and proper therapy is instituted, the clinical consequences of the untreated patients will be fatal. Here we report three cases of hypopituitarism in elderly patients whose clinical presentation and etiology was completely different. The first patient was fifty year old lady who is a known asthmatic for the past thirty years on steroids and had iatrogenic Cushing抯. On tapering the steroids she developed hypotension and giddiness. On eliciting the history she was suspected to have Sheehan抯 syndrome and was confirmed with investigations. She was advised to continue the steroids with calcium supplements. The second patient is an 80 years old female who came with complaints of increased tiredness daily more in the morning while getting up and improves slowly in the afternoon time and getting tired again in the night. When she was examined she had hypotension of 90/50 mm of hg. She was evaluated for Partial hypopituitarism and investigation confirmed hypopituitarism and she was started on Hydrocortisone tablets and she improved. The third patient was a 65 year old lady who was diagnosed to have diabetes mellitus and hypothyroidism and was on oral hypoglycemic drugs and eltroxine supplementation respectively. She had multiple hypoglycemic symptoms unresolved in spite of tapering the oral hypoglycemic drugs and on evaluation found to have partial hypopituitarism and started on T. Hydrocortisone and she improved well. We report these three cases as hypopitiutarism has multifaceted clinical presentation and needs high level of suspicion to diagnose it in elderly

La meningoencefalitis bacteriana que era en realidad una apoplejía hipofisaria

Introducción: La apoplejía hipofisaria es un síndrome que se produce como consecuencia de una lesión isquémica o hemorrágica en la glándula pituitaria dando lugar a un déficit de hormonas hipofisarias. Se manifiesta en forma de deterioro neurológico con cefalea en trueno como síntoma prínceps, siendo la irritación meníngea una manifestación infrecuente. Métodos: Presentamos el caso de una mujer de 53 años con antecedente de madroadenoma productor de prolactina que comienza con cefalea, náuseas y deterioro de nivel de consciencia. Se detecta un hipopituitarismo incompleto con nivel de cortisol normal. El líquido cefalorraquídeo (LCR) es consistente con una pleocitosis aséptica sin respuesta a terapias antibióticas. Asocia paresia oculomotora y una RM craneal revela sangrado en el adenoma hipofisario con compromiso de seno cavernoso. Resultados: la sospecha inicial es una meningoencefalitis bacteriana por la fiebre, estupor y LCR con pleocitosis, si bien no se identifica microorganismo y no hay respuesta a antibióticos. El LCR de la apoplejía muestra una pleocitosis aséptica por irritación meníngea del espacio subaracnoideo por el sangrado y la necrosis de la glándula. El hipopituitarismo puede ser parcial o completo, siendo más frecuente el déficit selectivo. Especial atención merece el déficit de ACTH por la morbimortalidad que conlleva el fallo adrenal. La oftalmoparesia traduce implicación de seno cavernoso por incremento en la presión selar. Conclusiones: Destacamos la importancia de tener una sospecha diagnóstica de apoplejía ante un cuadro neurológico agudo para dirigir las investigaciones pertinentes con determinación hormonal y así iniciar una terapia sustitutiva temprana y una actitud neuroquirúrgica en caso de ser necesaria; precisando un manejo multidisciplinar.

Introduction: Pituitary apoplexy is a syndrome that occurs as a result of an ischemic or hemorrhagic lesion in the pituitary gland, leading to a deficiency of pituitary hormones. It manifests in the form of neurological deterioration with thunderclap headache as the main symptom, with meningeal irritation being an infrequent manifestation. Methods: We present the case of a 53-year-old woman with a history of prolactin-producing madroadenoma that began with headache, nausea and impaired level of consciousness. Incomplete hypopituitarism with normal cortisol level is detected. Cerebrospinal fluid (CSF) is consistent with an aseptic pleocytosis unresponsive to antibiotic therapy. It is associated with oculomotor paresis and a cranial MRI reveals bleeding in the pituitary adenoma with involvement of the cavernous sinus. Results: the initial suspicion is bacterial meningoencephalitis due to fever, stupor and CSF with pleocytosis, although no microorganism is identified and there is no response to antibiotics. CSF from stroke shows aseptic pleocytosis due to meningeal irritation of the subarachnoid space from bleeding and necrosis of the gland. Hypopituitarism can be partial or complete, selective deficiency being more frequent. ACTH deficiency deserves special attention due to the morbidity and mortality that adrenal failure entails. Ophthalmoparesis translates involvement of the cavernous sinus due to an increase in sellar pressure. Conclusions: We emphasize the importance of having a suspected diagnosis of apoplexy in case of an acute neurological condition, to direct the pertinent investigations with hormonal determination and thus initiate early replacement therapy and a neurosurgical approach if necessary; requiring a multidisciplinary management.

Crisis adrenal neonatal secundaria a hipoplasia hipofisaria / Neonatal Adrenal Crisis Secondary to Pituitary Hypoplasia

Introducción: La insuficiencia adrenal hipotálamo hipofisaria usualmente se manifiesta secundaria a tumores y, cuando resulta congénita se asocia, con frecuencia, con otras deficiencias hormonales. La crisis adrenal suele presentarse en su debut y puede resultar potencialmente mortal. Objetivo: Examinar el caso de una paciente con insuficiencia adrenal central que debutó con una crisis adrenal congénita. Presentación del caso: Recién nacida a término, padres no consanguíneos, hospitalizada a los 9 días de vida por clínica de una semana con múltiples episodios eméticos y apnea. Ingresó con deshidratación severa, hipotensa y estuporosa. Además, se encontró acidosis metabólica severa, hipoglucemia persistente, hiponatremia e insuficiencia prerrenal. Ante la no mejoría de su estado hemodinámico, a pesar del uso de cristaloides y vasopresores, finalmente mejoró con la administración de dosis altas de hidrocortisona. El diagnóstico de deficiencia de cortisol de origen central se realizó con un test dinámico de insulina y la resonancia magnética nuclear hipofisaria. Conclusiones: La crisis adrenal se debe tener presente como diagnóstico diferencial en episodios agudos con inestabilidad hemodinámica persistente e hipoglucemia de difícil manejo. Adicionalmente, hay que considerar que existen otras causas menos comunes de insuficiencia adrenal en neonatos como la hipoplasia hipofisaria(AU)

Introduction: Hypothalamic-pituitary adrenal insufficiency usually manifests secondary to tumors and, when congenital, is often associated with other hormonal deficiencies. Adrenal crisis usually occurs at its onset and can be life threatening. Objective: To review the case of a patient with central adrenal insufficiency who had an onset with a congenital adrenal crisis. Case presentation: Term newborn, non-consanguineous parents, hospitalized at 9 days of life for a week-long clinical presentation with multiple emetic episodes and apnea. She was admitted with severe dehydration, hypotensive and stuporous. In addition, severe metabolic acidosis, persistent hypoglycemia, hyponatremia and prerenal failure were found. Given the lack of improvement of her hemodynamic status, despite the use of crystalloids and vasopressors, she finally improved with the administration of high doses of hydrocortisone. The diagnosis of cortisol deficiency of central origin was made with a dynamic insulin test and pituitary nuclear magnetic resonance imaging. Conclusions: Adrenal crisis should be kept in mind as a differential diagnosis in acute episodes with persistent hemodynamic instability and difficult-to-manage hypoglycemia. Additionally, other less common causes of adrenal insufficiency in neonates, such as pituitary hypoplasia, should be considered(AU)

Clinical characteristics and risk factors for concurrent infection in adult patients with hypopituitarism / 中国医师杂志

Objective:To explore the clinical characteristics and risk factors of concurrent infection in adult patients with hypopituitarism (HP).Methods:Clinical data of patients diagnosed with HP in Fuyang People′s Hospital from October 2016 to August 2020 were collected. Patients were divided into infected group and non-infected group according to whether they were co-infected, and the differences in clinical characteristics between the two groups were compared. The risk factors of infection in HP patients were analyzed by binary logistic regression.Results:The top three clinical manifestations of 64 HP patients were decreased libido; lack of energy, fear of cold, and poor appetite; hyponatremia. Etiological analysis of 64 HP patients: 23 cases of Sheehan′s syndrome, 14 cases of postoperative brain tumors (pituitary adenoma, craniopharyngioma, meningioma), 8 cases of idiopathic, 7 cases of pituitary adenoma, 8 cases of pituitary volume and morphology changes, and 4 cases of empty sella turcica. 40.32%(25/62) of patients with adrenal axis dysfunction received glucocorticoid replacement therapy, with 80%(20/25) receiving prednisone and 20%(5/25) receiving hydrocortisone. The replacement dose was 2.5-25(6.77±3.90)mg of prednisone equivalent dose. 37.70%(23/61) of patients with low thyroid axis function received thyroid hormone replacement therapy, of which 52.17%(12/23) free thyroxine (FT4) levels were still lower than the lower normal limit. 20%(2/10) of males ≤60 years old and 5.56%(1/18) of females≤50 years old received hormone replacement therapy for patients with hypogonadism of the gonadal axis. Among 64 HP patients included, 29 were co-infected (infected group) and 35 were not co-infected (non infected group). There was no significant difference between the infected group and the non infected group in gender, etiology, number of pituitary axis involved, glucocorticoid replacement therapy dose, thyroid hormone replacement therapy dose, and sex hormone replacement therapy rate (all P>0.05). Compared with the non infected group, the infected group was older, had a longer course of disease, lower diastolic blood pressure (DBP) and albumin levels, with statistically significant difference (all P<0.05), while the other indicators showed no statistically significant difference (all P>0.05). The results of binary logistic regression analysis showed that age, course of disease, occupation, and albumin level were the influencing factors of HP complicated infection (all P<0.05). Conclusions:The most common cause of pituitary dysfunction in adults is Sheehan′s syndrome; Adult HP patients who are older, have a longer course of disease, work as farmers, and have hypoalbuminemia are more likely to develop concurrent infections.

A case of mitochondrial diabetes mellitus complicated with hypopituitarism and literature review / 中华内分泌代谢杂志

The clinical data of a patient with mitochondrial diabetes mellitus complicated with hypopituitarism were analyzed, the patient′s mitochondrial gene was detected by microarray capture high-throughput sequencing, and the related domestic and foreign literature was reviewed and analyzed. The results showed that the patient had m. 3243 A>G variant on MT-TL1 gene and the clinical features were consistent with mitochondrial diabetes mellitus and hypopituitarism.

Clinical features of hypopituitarism with nonalcoholic fatty liver disease after sellar tumor surgery in children / 临床肝胆病杂志

Objective To investigate the clinical features of hypopituitarism with nonalcoholic fatty liver disease (NAFLD) in children after sellar tumor surgery and the association between hypopitarism and NAFLD in children. Methods A retrospective analysis was performed for the clinical data of children with hypopituitarism and NAFLD after sellar tumor surgery who were followed up regularly in Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2017 to December 2021, and their clinical features were analyzed. Results There were 32 children with regular follow-up and complete clinical data after sellar tumor surgery, and 10 children (31.25%) developed NAFLD, among whom there were 5 boys and 5 girls. Among these 10 children, 9 had craniopharyngioma and underwent surgical treatment, and 1 had germinoma and underwent local radiotherapy. The 10 children had a median age of 8.4(6.29.8) years at the diagnosis of hypopituitarism and a median age of 11.9(8.7-12.6) years at the diagnosis of NAFLD. The median number of years from the diagnosis of hypopituitarism to the diagnosis of NAFLD was 2.0(1.4-4.0) years. At the diagnosis of NAFLD, all 10 children had obesity, and body mass index (BMI) was increased by 7.26±4.25 kg/m 2 on average since the diagnosis of hypopituitarism; the 10 children had a mean fasting blood glucose level of 4.67±0.55 mmol/L, a mean fasting insulin level of 25.40±5.93 μIU/ml, and a mean HOMA-IR index of 5.26±1.29. Among these 10 children, 9 had hypertriglyceridemia, and 1 had elevated triglyceride, with a mean level of 3.08±1.09 mmol/L; 6 children had hypercholesterolemia, with a mean level of 5.67±1.25 mmol/L; 8 children had high-density lipoprotein cholesterolemia, with a mean level of 3.97±1.27 mmol/L. After the diagnosis of NAFLD, 2 children were treated with recombinant human growth hormone and metformin and achieved reductions in BMI, HOMA-IR, and triglyceride after treatment, and total cholesterol and low-density lipoprotein cholesterol were reduced to the normal range. Conclusion Children may experience weight gain, hypopituitarism, insulin resistance, and dyslipidemia after sellar tumor surgery, which may lead to the onset of NAFLD. Weight management and active pituitary hormone replacement therapy are recommended for such children, as well as routine screening and management of fatty liver disease.

Occurrence of hypopituitarism after severe craniocerebral trauma and its predictors / 中华内分泌外科杂志

Objective:To investigate the occurrence and predictors of hypopituitarism after traumatic brain injury (TBI) .Methods:A prospective study was conducted on 185 patients with severe TBI in the Emergency Department of the First Hospital of Shanxi Medical University from Jan. 2020 to May. 2022, of whom 108 were male and 77 were female; age ranged from 18 to 79 years, mean (51.32±9.34) years. Pituitary function was assessed within 3-7 d after the onset of TBI, and the occurrence of hypopituitarism after severe TBI was counted. 41 cases in the hypopituitarism group, 26 males and 15 females, aged (52.76±9.83) years, were divided into the hypopituitarism group (hypopituitarism occurred) and the non-hypopituitarism group (hypopituitarism did not occur) according to whether hypopituitarism occurred. In the non-decompensated group, there were 144 cases, 82 males and 62 females, aged (50.91±9.27) years. The clinical data of the decompensated and non-decompensated groups were compared, and the factors influencing the occurrence of hypopituitarism were analysed, and a logistic prediction model was constructed based on the relevant influencing factors. The value of this model in predicting the occurrence of hypopituitarism after severe TBI was evaluated by using the receiver operating characteristic (ROC) curve.Results:The prevalence of hypopituitarism in the 185 patients with severe TBI in this study was 22.16%; the Glasgow coma scale (GCS) score on admission was lower in the decompensated group than in the non-decompensated group [ (6.36±1.04) vs (7.48±0.59) ], the percentage of hyperbaric oxygen therapy was lower than in the non-decompensated group (21.95% vs 49.31%) , the percentage of intracranial pressure (82.93% vs 49.31%) , midline displacement ≥5 mm (78.05% vs 29.86%) , skull base fracture (34.15% vs. 17.36%) , diffuse cerebral edema (19.51% vs 4.17%) , and serum brain derived neurophic factor (BDNF) . Brain derived neurophic factor (BDNF) was higher than that in the non-reduced group [ (6.35±1.29) ng/ml vs (4.51±1.06) ng/ml], and neuronal-specific enolase (NSE) was higher than that in the non-reduced group [ (33.06±5.42) μg/L vs (23.15±4.97) μg/L]. (4.97) μg/L]. Vascular epithelial growth factor (VEGF) was higher than that in the non-reduced group [ (312.07±24.35) pg/ml vs (226.80±20.96) pg/ml], tumor necrosis factor-α (TNF-α) was higher than that in the non-reduced group [ (281.24±38.91) ng/L vs (186.91) pg/ml], and tumor necrosis factor-α (TNF-α) was higher than that in the non-reduced group (186.55±35.72) ng/L (all P<0.05) . Increased intracranial pressure, midline displacement ≥5 mm, diffuse cerebral edema, serum BDNF, NSE, VEGF, and TNF-α levels were all independent risk factors for the development of hypopituitarism after severe TBI, with admission GCS score and hyperbaric oxygen therapy as protective factors ( P<0.05) ; a logistic prediction model was constructed based on the influencing factors as: Logit ( P) = 5.264-0.880×admission GCS score + 1.618×increased intracranial pressure + 1.941×midline displacement ≥5 mm + 1.289×diffuse cerebral edema+1.306×BDNF+1.426×NSE+1.781×VEGF+1.615×TNF-α-0.758×hyperbaric oxygen therapy; the model predicted the occurrence of severe TBI after the area under the curve (AUC) of hypopituitarism was 0.930 (95% CI 0.883-0.962) , with a predictive sensitivity and specificity of 90.24% and 89.19%, respectively. Conclusions:The incidence of hypopituitarism is higher after severe TBI. Increased intracranial pressure, midline displacement ≥5 mm, diffuse cerebral edema, serum BDNF, NSE, VEGF and TNF-α levels are all used as predictors of hypopituitarism.

Metastatic diffuse follicular variant papillary thyroid cancer without cervical lymph node metastasis presenting with symptoms related to hypopituitarism

ABSTRACT In this article, we present a case of diffuse follicular variant papillary thyroid carcinoma with pituitary metastasis, which is a rare cause of pituitary metastasis. The follicular variant of papillary thyroid carcinoma is an uncommon variant of papillary carcinoma. A 74-year-old male was presented with weakness, fatigue, and a decreased appetite. The patient was diagnosed with secondary adrenal and thyroid insufficiencies. Imaging revealed a pituitary mass with suprasellar extension, right cavernous sinus invasion, and optic chiasm compression. Thyroid ultrasonography revealed a nodule with a maximum size of 7.2cm in the right lobe. Cytological examination via fine-needle aspiration suggested papillary thyroid cancer. Total thyroidectomy with central and right lateral neck dissection confirmed the diagnosis of diffuse follicular variant of papillary thyroid carcinoma. Owing to visual field defects, the patient underwent transsphenoidal surgery. Histological and immunohistochemical evaluations confirmed pituitary metastasis from the papillary thyroid cancer. Radioactive iodine treatment and gamma knife radiotherapy of the pituitary gland were performed. The initiation of sorafenib treatment was deemed appropriate during the follow-up. A significant decrease in the thyroglobulin levels was observed after sorafenib treatment. Pituitary metastasis should be considered in patients diagnosed with hypopituitarism and pituitary lesions at initial evaluation. The presence of visual field defects may be an indication for neurosurgical intervention and guide both diagnosis and treatment. The management of papillary thyroid cancer and the role of treatment modalities in prognosis depend on the biological behavior of the tumor. Early diagnosis and multidisciplinary management are crucial for the treatment of these patients.

Diabetes insípida, panhipofisitis y silla turca vacía. Presentación de un caso / Diabetes insipidus, panhypophysitis, and empty sella turcica. Presentation of a case

RESUMEN La diabetes insípida central se produce por déficit de síntesis o secreción de hormona antidiurética. Es una entidad de muy baja prevalencia que se puede ver asociada a hipofisitis linfocítica y silla turca vacía. Sin embargo, el diagnóstico histopatológico solo se realiza cuando es necesaria la cirugía debido a un compromiso neurológico. Se presentó el caso de un paciente masculino de 41 años que acudió a consulta porque orinaba frecuentemente y bebía mucha agua. Se le realizó prueba de supresión de líquidos, seguida de prueba de la vasopresina, que fueron consistente con el diagnóstico de diabetes insípida central. La resonancia magnética de la hipófisis reveló silla turca vacía parcial y signos de infundíbulo-neurohipofisitis, coincidencia que ha sido escasamente reportada. En el seguimiento se evidenció hipogonadismo hipogonadotrópico y baja reserva adrenal. Se indicó tratamiento de reemplazo hormonal con desmopresina y testosterona, con lo cual el paciente ha mantenido buena calidad de vida. Se concluye que la diabetes insípida puede ser la primera manifestación de una panhipofisitis. La asociación de estas enfermedades con el síndrome de silla turca vacía es infrecuente, pero puede ser el curso natural de la enfermedad.

ABSTRACT Central diabetes insipidus is caused by a deficiency in the synthesis or secretion of antidiuretic hormone. It is a very low prevalence entity that can be seen associated with lymphocytic hypophysitis and empty sella turcica. However, histopathological diagnosis is only made when surgery is necessary due to neurological compromise. The case of a 41-year-old male patient who came to the clinic because he urinated frequently and drank a lot of water was presented. A fluid suppression test was performed, followed by a vasopressin test, the results of which were consistent with a diagnosis of central diabetes insipidus. Magnetic resonance imaging of the pituitary gland revealed partial empty sella turcica and signs of infundibulo-neurohypophysitis, a coincidence that has been rarely reported. In the follow-up, hypogonadotropic hypogonadism and low adrenal reserve were revealed. Hormone replacement treatment with desmopressin and testosterone was indicated, with which the patient has maintained a good quality of life. It is concluded that diabetes insipidus may be the first manifestation of panhypophysitis. The association of these diseases with the empty sella syndrome is rare, but it may be the natural course of the disease.

Pituitary apoplexy. An unusual cause of thunderclap headaches

A thunderclap headache (TCH) is defined as an excruciating headache which occurs abruptly like "thunder," reaches its maximum point in less than a minute, and should be considered a medical emergency. Below, we present the clinical case of a 49-year-old Colombian patient who developed a thunderclap headache as the initial sign of pituitary apoplexy. He progressed satisfactorily, with no evidence of sequelae, highlighting the early diagnosis of a potentially fatal entity. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2336).

La cefalea tipo trueno (CT) es considerada un dolor de cabeza intolerable, el cual se produce de forma abrupta como un "trueno", alcanza su punto máximo en menos de un minuto después de su aparición, y debe considerarse una emergencia médica. A continuación presentamos el caso clínico de un paciente colombiano, de 49 años quien presenta cefalea tipo trueno como manifestación inicial de apoplejía hipofisaria, con adecuada evolución y sin evidencia secuelar, resaltando el diagnóstico temprano en una entidad potencialmente mortal. (Acta Med Colomb 2022; 47. DOI:https://doi.org/10.36104/amc.2022.2336).

A DELAYED PRESENTATION OF POSTERIOR HYPOPITUITARISM FOLLOWING TRAUMATIC BRAIN INJURY – A CASE REPORT OF A 24 YEAR OLD ASIAN FEMALE.

Background: Cases of post traumatic hypopituitarism are rarely contemplated in the Indian subcontinent. However global literatures disclose that the incidence rate of hypopituitarism following traumatic brain injury is around 15-30%. Most hospitals do not routinely screen patients for pituitary dysfunction following traumatic brain injury due to the lack of proper protocol supporting the same. Hence large number of cases with varying pituitary abnormalities is procrastinated, which could have been otherwise bene?ted from early interventions. This case is a classic example of delayed exhibition of posterior hypopituitarism post traumatic brain injury, which has signi?cantly compromised the quality of life of the patient in later stage due to the failure of timely screening. Case Presentation:This is a case of 24 year old female who sustained a traumatic brain injury 3 years ago allegedly due to domestic abuse. The patient presented to the urology department with the complaints of polyuria, polydipsia, secondary amenorrhea, sleep disturbance and weight gain for 6-7 months. The patient was not under regular follow-up for the traumatic injury. On further evaluation, all the anterior pituitary hormones were found to be normal. We further investigated the case with biochemical investigations and an MRI of brain (plain and contrast) which showed a thickened enhancing pituitary stalk with absence of posterior pituitary bright spot with a normal anterior pituitary gland – suggestive of Central Diabetes Insipidus. Upon initiation with Desmopressin, the patient showed signi?cant symptomatic improvement. Conclusion:One of the most common complications of traumatic brain injury is hypopituitarism. Early screening for hypopituitarism in such cases will help us intervene early and improve the quality of life of the patients.

Embolia de líquido amniótico asociada a paro cardiorrespiratorio recuperado y síndrome de Sheehan / Amniotic fluid embolism associated with recovered cardiac arrest and postpartum Sheehan's syndrome

Resumen La embolia de líquido amniótico es una condición catastrófica propia del embarazo que ocurre típicamente durante el parto o justo posterior a este, cuyo sustrato fisiopatológico no ha sido aclarado por completo. Se ha estimado, según cifras de los Estados Unidos, que su incidencia rondaría 1 por cada 12.953 partos, y en el Reino Unido 1 por cada 50.000 partos; sin embargo, estas cifras pueden ser imprecisas debido a que no existen una referencia ni un consenso respecto a los criterios diagnósticos, además de que el cuadro clínico se puede confundir con otras emergencias obstétricas. Se presenta el caso de una paciente sin antecedentes mórbidos que presenta un cuadro de embolia de líquido amniótico no fatal, caracterizado por un estado fetal no tranquilizador durante la inducción del trabajo de parto, seguido de un paro cardiorrespiratorio durante la cesárea de urgencia y la rápida y catastrófica aparición de signos clínicos de una coagulopatía de consumo grave. Se describen además las complicaciones posoperatorias y su manejo, entre ellas un síndrome de Sheehan y la aparición de convulsiones tónico-clónicas generalizadas con alteración de neuroimágenes.

Abstract Amniotic fluid embolism is a catastrophic pregnancy condition that typically occurs during or inmediately after delivery, and whose pathophysiological background has not been fully clarified. According to US records the incidence of amniotic fluid embolism could been around 1 for every 12,953 births and in the United Kingdom 1 for every 50,000 births, however these numbers may be imprecise because there is no gold standard as well as no consensus regarding the diagnostic criteria, in addition that the clinical presentation can be misdiagnosis with other obstetric emergencies. We present the clinical case of a patient without a morbid history who presents with a non-fatal amniotic fluid embolism, characterized by an non-reassuring fetal status during labor induction, followed by cardiorespiratory arrest during emergency cesarean section and the rapid and catastrophic appearance of clinical signs of a severe consumptive coagulopathy. Postoperative complications and their management are also described, including Sheehans syndrome and the appearance of generalized tonic-clonic seizures with impaired neuroimaging.

Approach to the patient with pituitary metastases initially manifested as central diabetes insipidus / 中华内分泌代谢杂志

The data of 10 patients with pituitary metastases were retrospectively analyzed, including tumor origin, clinical features, imaging characteristics, diagnosis and differential diagnosis, treatment and prognosis. The results showed that the average age of 10 patients at the time of consultation was 62.0 years. Nine metastases were originated from lung cancer and one from breast cancer. All patients started with central diabetes insipidus, and some of them accompanied with hypopituitarism, as well as occupancy manifestations such as headache, blurred vision, etc. MRI showed abnormalities in the pituitary stalk and posterior pituitary, four of which showed characteristic " dumbbell-shaped" changes. Three patients with epidermal growth factor receptor(EGFR)-mutated lung adenocarcinoma revealed improvement in both primary lesion and pituitary metastases after targeted therapy.

Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases / 北京大学学报(医学版)

Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases SUMMARY Programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) have been widely used in lung cancer treatment, but their immune-related adverse events (irAEs) require intensive attention. Pituitary irAEs, including hypophysitis and hypopituitarism, are commonly induced by cytotoxic T lymphocyte antigen 4 inhibitors, but rarely by PD-1/PD-L1 inhibitors. Isolated adrenocorticotropic hormone(ACTH) deficiency (IAD) is a special subtype of pituitary irAEs, without any other pituitary hormone dysfunction, and with no enlargement of pituitary gland, either. Here, we described three patients with advanced lung cancer who developed IAD and other irAEs, after PD-1 inhibitor treatment. Case 1 was a 68-year-old male diagnosed with metastatic lung adenocarcinoma with high expression of PD-L1. He was treated with pembrolizumab monotherapy, and developed immune-related hepatitis, which was cured by high-dose methylprednisolone [0.5-1.0 mg/(kg·d)]. Eleven months later, the patient was diagnosed with primary gastric adenocarcinoma, and was treated with apatinib, in addition to pembrolizumab. After 17 doses of pembrolizumab, he developed severe nausea and asthenia, when methylprednisolone had been stopped for 10 months. His blood tests showed severe hyponatremia (121 mmol/L, reference 137-147 mmol/L, the same below), low levels of 8:00 a.m. cortisol (< 1 μg/dL, reference 5-25 μg/dL, the same below) and ACTH (2.2 ng/L, reference 7.2-63.3 ng/L, the same below), and normal thyroid function, sex hormone and prolactin. Meanwhile, both his lung cancer and gastric cancer remained under good control. Case 2 was a 66-year-old male with metastatic lung adenocarcinoma, who was treated with a new PD-1 inhibitor, HX008, combined with chemotherapy (clinical trial number: CTR20202387). After 5 months of treatment (7 doses in total), his cancer exhibited partial response, but his nausea and vomiting suddenly exacerbated, with mild dyspnea and weakness in his lower limbs. His blood tests showed mild hyponatremia (135 mmol/L), low levels of 8:00 a.m. cortisol (4.3 μg/dL) and ACTH (1.5 ng/L), and normal thyroid function. His thoracic computed tomography revealed moderate immune-related pneumonitis simultaneously. Case 3 was a 63-year-old male with locally advanced squamous cell carcinoma. He was treated with first-line sintilimab combined with chemotherapy, which resulted in partial response, with mild immune-related rash. His cancer progressed after 5 cycles of treatment, and sintilimab was discontinued. Six months later, he developed asymptomatic hypoadrenocorticism, with low level of cortisol (1.5 μg/dL) at 8:00 a.m. and unresponsive ACTH (8.0 ng/L). After being rechallenged with another PD-1 inhibitor, teslelizumab, combined with chemotherapy, he had pulmonary infection, persistent low-grade fever, moderate asthenia, and severe hyponatremia (116 mmol/L). Meanwhile, his blood levels of 8:00 a.m. cortisol and ACTH were 3.1 μg/dL and 7.2 ng/L, respectively, with normal thyroid function, sex hormone and prolactin. All of the three patients had no headache or visual disturbance. Their pituitary magnetic resonance image showed no pituitary enlargement or stalk thickening, and no dynamic changes. They were all on hormone replacement therapy (HRT) with prednisone (2.5-5.0 mg/d), and resumed the PD-1 inhibitor treatment when symptoms relieved. In particular, Case 2 started with high-dose prednisone [1 mg/(kg·d)] because of simultaneous immune-related pneumonitis, and then tapered it to the HRT dose. His cortisol and ACTH levels returned to and stayed normal. However, the other two patients' hypopituitarism did not recover. In summary, these cases demonstrated that the pituitary irAEs induced by PD-1 inhibitors could present as IAD, with a large time span of onset, non-specific clinical presentation, and different recovery patterns. Clinicians should monitor patients' pituitary hormone regularly, during and at least 6 months after PD-1 inhibitor treatment, especially in patients with good oncological response to the treatment.

Immune checkpoint inhibitors induced pituitary immune-related adverse events: diagnosis and management / 中华肿瘤杂志

Immune checkpoint inhibitors (ICIs) have been used in treating a wide variety of cancers, but they challenge clinicians with a series of special immune related adverse events (irAEs) resulting from activated immune system. Since June 2018, when the first programmed cell death 1 (PD-1) inhibitor, nivolumab, was approved by the National Medical Products Administration (NMPA), abundant experience has been accumulated in coping with irAEs from PD-1 and PD-1 ligand 1 (PD-L1) blockade therapies. In October 2021, the first CTLA-4 inhibitor, ipilimumab, which has a different spectrum of irAEs was also approved by NMPA. The discrepancy in clinical features of pituitary irAEs is obvious between these two types of ICIs. Pituitary irAEs include hypophysitis and hypopituitarism. In this review of latest literature, we have summarized the incidence, possible mechanisms, time of onset, clinical presentations, hormone test, pituitary imaging, treatment strategies and recovery patterns of pituitary irAEs. By referring to domestic and foreign clinical guidelines, we have proposed practical suggestions for screening, diagnosing and treating pituitary irAEs.