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Introduction: Idiopathic hypothalamic dysfunction (IHD) is a rare syndrome with heterogeneous clinical symptoms. This study aimed to systematically review the clinical features and potential treatment of IHD based on our case series and literature. Methods: We analysed six recently diagnosed cases of IHD in Peking Union Medical College Hospital and conducted a systematic review of IHD case studies published before August 25, 2021, using the PubMed/Medline database. All 12 articles that met the definition of IHD and provided individual clinical data were reviewed. Results: Of the 19 cases reviewed (13 from the literature and 6 from our centre), the median age at onset was 6 years. Obesity/weight gain (n = 14, 73.7%) and electrolyte abnormalities (n = 14, 73.7%) were the most common hypothalamic physiological dysfunction, followed by autonomic dysregulation (n = 13, 68.4%) and adipsia (n = 13, 68.4%). The most common initial symptom of young patients was obesity/weight gain, whereas the initial symptoms of the three adult patients were hypothalamic amenorrhoea, delayed sexual development, and polydipsia. 11 (57.9%) patients had obesity, and three of our patients were diagnosed with metabolic syndrome in late adolescence or early adulthood. Three of our cases diagnosed with growth hormone deficiency received growth hormone therapy, which exerted positive effects on growth promotion and weight stabilization. Conclusion: Although obesity/weight gain was the most common symptom of IHD, uncommon initial symptoms such as electrolyte abnormalities and sexual disorders also require attention, especially in patients with late childhood- or adult-onset IHD. Consistent monitoring of metabolic profiles is recommended. Positive effects of growth hormone replacement therapy on growth and weight were observed, but more extensive cohort studies are required to confirm its efficacy and safety.

Hypothalamic dysfunction is characterized by complex aetiologies, multiple forms of onset and various clinical symptoms. This study aims to explore the clinical and metabolic characteristics of hypothalamic dysfunction in Chinese children and adolescents.This study is a single-centre, retrospective study that covers patients from 1989 to 2019.We included 40 children and adolescents with hypothalamic dysfunction from our medical centre in Beijing, China.Intracranial tumour (37.5%) was the most common aetiology of children and adolescents with hypothalamic dysfunction, especially germ cell tumours, hypopituitarism (82.5%), weight gain (72.5%) and central diabetes insipidus (70.0%) were the most common symptoms in these patients. Furthermore, serum alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase, uric acid, total cholesterol, triglycerides and low-density lipoprotein cholesterol was significantly higher in hypothalamic dysfunction patients than sex- and age-matched controls and sex, age and body mass index (BMI)-matched controls (all p 0.05). However, albumin and high-density lipoprotein cholesterol were lower (p 0.05). Moreover, 95% (38/40) of the patients had metabolic diseases. In addition, the incidence of dyslipidaemia and hyperuricemia in children and adolescents with hypothalamic dysfunction was significantly higher than both sex- and age-matched controls and sex-, age- and BMI-matched controls (both p 0.05) as well.Intracranial tumour was the most common aetiology in children and adolescents with hypothalamic dysfunction. In addition, these patients presented a worse metabolic profile on average than healthy patients.

The differential diagnosis of ACTH-dependent Cushing's disease (CS) is challenging. The gold standard approach bilateral inferior petrosal sinus sampling (BIPSS) is expensive and invasive, while other noninvasive tests, like the high-dose dexamethasone suppression test (HDDST), provide unsatisfactory diagnostic accuracy. This study aimed to find a new noninvasive practical approach with higher diagnostic accuracy to differently diagnose ACTH-dependent CS, which can be used in centers where BIPSS cannot be applied.264 Cushing's disease (CD) patients and 47 ectopic ACTH secretion syndrome (EAS) patients were analyzed in this single-center retrospective study (2011-2021). The multivariate logistic model was used to construct the scoring model.Female (adjusted OR 3.030, 95%CI 1.229-7.471), hypokalemia (0.209, 0.076-0.576), ACTH (0.988, 0.982-0.994), MRI pituitary lesion positive (8.671, 3.521-21.352), and HDDST positive (2.768, 1.139-6.726) have a strong association with the differential diagnosis of ACTH-dependent CS and were included in the final multivariable logistic regression model. A -14-to-14-point noninvasive scoring model was built on the model. The AUC of the noninvasive scoring model was 0.915 (95% CI 0.869-0.960), significantly higher than the AUC of HDDST (0.756, 95% CI 0.685-0.825, P = 0.004). The optimal cutoff of the model was ≥0 to diagnose CD. The sensitivity of the noninvasive scoring model was 91.3% (95% CI 87.3%-94.1%), and the specificity was 80.9% (95% CI 67.5%-89.6%). When the model's sensitivity was 100.0%, the cutoff was ≥ -10 with a specificity of 19.2%; when the model's specificity was 100.0%, the cutoff was ≥ 13 with a sensitivity of 22.7%.We developed a noninvasive scoring model to distinguish CD and EAS in ACTH-dependent CS patients with higher diagnostic utility than HDDST in the same cohort. The noninvasive scoring model might be applied in areas where BIPSS is unavailable, the CRH is hard to obtain, or the desmopressin stimulation is not widely applied. It also provided a triage tool for selecting patients that might benefit the most from a further BIPSS test.

To summary the clinical features of premenopausal women with functioning gonadotroph adenomas (FGAs) and preliminarily explore their molecular characterization.12 premenopausal females with FGAs in our center were retrospectively analyzed. Previously reported cases were also summarized. The patients were clinically divided into FSH- or LH-predominant types according to their preoperative serum FSH/LH ratio. The expressions of related genes in the tumor tissues of female FGAs, non-functioning gonadotroph adenomas (NFGAs), and silent corticotropin adenomas were evaluated by RT-qPCR.Of all the 12 patients with FGAs from our center, 11 (91.7%) were diagnosed as FSH-predominant type, and they all had menstrual disorders, including 9 with spontaneous ovarian hyperstimulation syndrome (sOHSS). Their hormonal profiles showed non-suppressed FSH (12.45 ± 7.34 IU/L) with hyperestrogenemia [median estradiol level 1353.0 pg/mL (636.0, 3535.0)]. The other patient (8.3%) with LH-predominant type mainly manifested with infertility and sustained elevated serum LH without FSH or estradiol increasing. 65 premenopausal FGAs patients were systematic reviewed. 60 patients (92.3%) were FSH-predominant type, including 86.7% presented with menstrual disorders, 16.7% reported infertility, and 98.2% (55/56) showed sOHSS. No sOHSS or hyperestrogenemia were found in the 5 patients (7.7%) with LH-predominant type. Pituitary imaging data revealed macroadenomas and microadenomas accounted for 89.2% and 10.8%, respectively. Of 63 patients (96.9%) who underwent pituitary adenoma resection, 77.8% had complete tumor resection and no recurrence at the last follow-up. The relative expressions of KISS1 mRNA were significantly higher in FGA group than in NFGA group (p = 0.018), and significantly positively correlated with the preoperative serum estradiol levels (p = 0.004).Different clinical features were observed in premenopausal women with FGAs of FSH- or LH-predominant types. The elevated KISS1 expression in tumor tissues might involve in the secretion function of FGAs.

The aim of the work was to explore the correlation between thyroid hormones and coronary atherosclerotic severity. This cross-sectional study included 340 euthyroid patients who underwent diagnostic coronary artery angiography (CAG). Gensini Score (GS) was applied to assess the severity of coronary atherosclerosis. Thyroid hormones and routine biochemical parameters were measured. The associations between thyroid hormones and coronary atherosclerosis severity were analyzed. Thyroid hormones levels or parameters were taken as both continuous variables and tertiles into analysis, and the lowest tertile was usually used as the reference (OR=1) for medium and highest tertiles. Free triiodothyronine (FT3) level was associated with GS≥22 (Median GS) in Model I adjusted for age and sex [Continuous: OR=0.46, 95% CI (0.23, 0.92), p=0.029; Tertile 3: OR=0.54, 95% CI (0.30, 0.97), p=0.038], and Model II adjusted for all known risk factors of coronary artery disease (CAD) [Continuous: OR=0.44, 95% CI (0.20, 0.95), p=0.036; Tertile 3: OR=0.49, 95% CI (0.25, 0.96), p=0.039]. Subjects with highest tertile of FT3 to free thyroxine (FT4) ratio (FT3/FT4 ratio) appeared to have the remarkably decreased risk of CAD in both Non-adjusted Model [OR=0.49, 95% CI (0.24, 0.98), p=0.044] and Model I [OR=0.45, 95% CI (0.22, 0.93), p=0.031]. Higher FT3 level within normal range was independently and negatively associated with severity of coronary atherosclerosis. Besides, FT3/FT4 ratio was remarkably correlated with the prevalence of CAD in euthyroid population.

ContextPatients with adult growth hormone deficiency (AGHD) are at increased risk of metabolic syndrome. Metabolic profiles in AGHD patients have been insufficiently evaluated.ObjectiveThis work aims to explore serum metabolite profiles by metabolomics analysis and assess potential metabolites associated with recombinant human growth hormone (rhGH) treatment.MethodsThirty-one AGHD patients and 31 healthy controls were enrolled. Untargeted ultra-performance liquid chromatography–coupled mass spectroscopy was conducted in all patients and controls at baseline and during 12 months of rhGH treatment in 11 AGHD patients. Data were processed by principal component analysis, variable importance in projection scoring, orthogonal partial least squares–discriminant analysis, and MetaboAnalyst 5.0. We further explored the associations between metabolites and clinical parameters.ResultsMetabolomics indicated a distinct metabolic pattern between AGHD patients and healthy controls. The perturbed pathways mainly include the biosynthesis of unsaturated fatty acids, sphingolipid metabolism, glycerophospholipid metabolism, fatty acid elongation, degradation, and biosynthesis. rhGH treatment increased the levels of specific glycerophospholipids compounds and reduced fatty acid ester compounds. Significant correlations existed between the 40 identified metabolites and insulin-like growth factor-1 SD score (IGF-1 SDS), body composition, and glucose and lipid metabolism plasma markers. During rhGH treatment, there was a statistically significant negative correlation between deoxycholic acid glycine conjugate and waist-to-hip ratio, while a statistically significant positive correlation existed between decanoylcarnitine and serum low-density lipoprotein levels.ConclusionAGHD patients have unique metabolomic profiles. rhGH treatment alters the serum levels of several fatty acid compounds/amino acids, which may contribute to the improvement of metabolic status in AGHD patients.

Purpose To retrospectively summarize the clinical features of acromegaly complicated with fulminant pituitary apoplexy and analyze the prognostic factors to guide early identification and timely treatment of such patients. Methods A retrospective analysis was carried out to summarize the clinical manifestations, hormone changes, imaging, treatment and follow-up of 10 patients with acromegaly complicated with fulminant pituitary apoplexy admitted to our hospital from February 2013 to September 2021. Results The mean age of the 10 patients (5 males and 5 females) at the time of pituitary apoplexy was 37.1 ±13.4 years old. There were 9 cases with sudden severe headache and 5 cases with visual impairment. All patients had pituitary macroadenomas, of which 6 cases with Knosp grade ≥ 3. The level of GH/IGF-1 hormone after pituitary apoplexy was lower compared with pre-apoplexy, and 1 patient reached biochemical remission spontaneously. 7 patients underwent transsphenoidal pituitary surgery after apoplexy and 1 patient was treated with long-acting somatostatin analog. The biochemical remission rate was 37.5% in 8 patients immediately after treatment and 50% at the last follow-up. Patients with Knosp grade ≥ 3 were less likely to achieve biochemical remission than those with Knosp grade < 3 (16.7% vs. 100%, p=0.048), and patients who achieved biochemical remission had a smaller maximum tumor diameter [20.1（20.1,28.0）mm vs. 44.0（44.0,60）mm，p=0.016]. Conclusion Acromegaly complicated with fulminant pituitary apoplexy remains a diagnostic and therapeutic challenge.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia type 1 (MED1) are two rare skeletal disorders caused by cartilage oligomeric matrix protein (COMP) variants. This study aims to analyze the genotype and phenotype of patients with COMP variants. Clinical information for 14 probands was collected; DNA was extracted from blood for COMP variant detection. Clinical manifestations and radiology scoring systems were established to evaluate the severity of each patient's condition. Serum COMP levels in PSACH patients and healthy subjects were measured. Thirty-nine patients were included, along with 12 PSACH probands and two MED1 probands. Disproportionate short stature, waddling gait, early-onset osteoarthritis and skeletal deformities were the most common features. The height Z-score of PSACH patients correlated negatively with age at evaluation (r = - 0.603, p = 0.01) and the clinical manifestation score (r = - 0.556, p = 0.039). Over 50% of the PSACH patients were overweight/obese. The median serum COMP level in PSACH patients was 16.75 ng/ml, which was significantly lower than that in healthy controls (98.53 ng/ml; p 0.001). The condition of MED1 patients was better than that of PSACH patients. Four novel variants of COMP were detected: c.874TC, c.1123_1134del, c.1531GA, and c.1576GT. Height Z-scores and serum COMP levels were significantly lower in patients carrying mutations located in calmodulin-like domains 6, 7, and 8. As the two phenotypes overlap to different degrees, PSACH and MED1 are suggested to combine to produce "spondyloepiphyseal dysplasia, COMP type". Clinical manifestations and radiology scoring systems, serum COMP levels and genotype are important for evaluating patient condition severity.

Adult growth hormone deficiency (AGHD) is associated with increased cardiovascular risks. The primary endpoint of this retrospective cohort study was to compare metabolic profile and echocardiographic parameters in childhood-onset (CO) and adulthood-onset (AO) AGHD patients. 26 patients with CO AGHD (19 males, 26.8±8.5 years) and 41 patients with AO AGHD (23 males, 35.1±6.8 years) were included. The standard deviation score of insulin-like growth factor-1 (IGF-1 SDS), metabolic profile, liver sonography and echocardiographic parameters were compared. The IGF-1 SDS were significantly lower in CO AGHD patients (p

To evaluate the prevalence of overweight/obesity and dyslipidemia in patients with intracranial germ cell tumor (iGCT), and to explore the risk factors of it.iGCT patients visiting Peking Union Medical College Hospital between Jan 2008 to Oct 2020 were included. The prevalence of overweight/obesity and dyslipidemia was calculated. Mixed-effects models were used to evaluate the relationship between BMI z-scores, concentration of lipid profiles and potential risk factors.One hundred and six patients were included. The median follow-up time was 27 (IQR 5-59) months. The number of patients diagnosed with overweight/obesity and dyslipidemia were 49 (46.2%) and 86 (81.1%) during visits. Higher BMI z-scores were associated with treatment (mean difference (MD) 0.51, 95%CI 0.31-0.72), surgical biopsies (MD 0.71, 95%CI 0.16-1.25), adrenal insufficiency (MD 0.37, 95%CI 0.07-0.68), hypothyroidism (MD 0.35, 95%CI 0.06-0.63), glucocorticoid supplementation (MD 0.64, 95%CI 0.40-0.87), and thyroxine supplementation (MD 0.48, 95%CI 0.24-0.72). Hypothalamus involvement was associated with increased TC (MD 0.52, 95%CI 0.06-0.98), TG (MD 0.36, 95%CI 0.01-0.72), LDL-C (MD 0.60, 95%CI 0.20-0.98), and decreased HDL-C (MD - 0.23, 95%CI - 0.44 to - 0.02). Higher TC (MD 0.53, 95%CI 0.26-0.80) and LDL-C (MD 0.39, 95%CI 0.17-0.62) were observed in patients after treatment. Glucocorticoid supplementation was associated with increased TC (MD 0.70, 95%CI 0.38-1.03), LDL-C (MD 0.51, 95%CI 0.24-0.78), and HDL-C (MD 0.25, 95%CI 0.09-0.40), while sex hormone supplementation was associated with decreased TC (MD - 0.74, 95%CI - 1.2 to - 0.29) and TG (MD - 0.47, 95%CI - 0.86 to - 0.08).Overweight/obesity and dyslipidemia were high prevalent in iGCT patients and should be screened during follow-ups.

OBJECTIVES The aims of this study were to analyze the continuous glucose monitoring (CGM) profiles of patients with insulinoma before and after treatment with endoscopic ultrasound-guided ethanol injection and assess the value of CGM in curative effect evaluating. METHODS We included 8 patients, and CGM was performed for 3 to 5 days before and after treatment. RESULTS The proportion of monitoring points at which the glucose level was lower than 3.9 mmol/L after treatment decreased in patient 5 (from 4% to 3%) and patient 8 (from 30% to 12%), whereas the proportion increased in patient 1 (from 1% to 16%), patient 3 (from 5% to 23%), and patient 7 (from 7% to 63%). There was no mean significant difference between CGM values (5.75 [standard deviation, 2.49] mmol/L) and self-monitoring of blood glucose values (5.76 [standard deviation, 2.32] mmol/L) (P > 0.05). Pearson correlation analysis showed positive correlation between CGM values and self-monitoring of blood glucose values (r = 0.88, P < 0.05). Clarke Error Grid Analysis showed that 91.5% of pairs were located in areas A and B. CONCLUSIONS Continuous glucose monitoring is useful for detecting hypoglycemia and evaluating curative effect, but the correction of fingertip blood glucose is necessary when the blood glucose is relatively low.

Background Functional gonadotroph adenomas (FGAs) are rare adenomas that most commonly secrete FSH. However, solitary LH-secreting pituitary adenomas are unusual. Case presentation A 30-year-old woman with elevated LH and normal FSH presented with inability to conceive. An MRI revealed an enlarged sella turcica and an intrasellar mass. Treatment with transsphenoidal resection led to normalization of LH and estradiol, as well as successful pregnancy. And we reviewed 6 cases of LH-secreting pituitary adenomas from 1981 to 2020. Conclusions Our case is unique because of the LH-secreting pituitary adenoma without FSH hypersecretion. This case indicates that pituitary adenoma should be considered when other diseases causing infertility have been excluded.

Dysfunction of adipose tissue could lead to insulin resistance, obesity and type 2 diabetes. Thus, our present study aimed to investigate metabolites alterations in white adipose tissue (WAT) of diabetic GK rats after IT surgery. Ten-week-old male diabetic GK rats were randomly subjected to IT and Sham-IT surgery. Six weeks later, the untargeted metabolomics in WAT of diabetic GK rats was performed. Differential metabolites were selected according to the coefficient of variation (CV) of quality control (QC) sample 1 and P

Context Extreme insulin resistance is caused by genetic defects intersecting with the insulin action pathway or by the insulin receptor antibodies. Insulin autoimmune syndrome (IAS) is not considered one of the causes of extreme insulin resistance. Objective This work aimed to expand the current knowledge of extreme insulin resistance and to propose the diagnostic criteria and management strategy of a novel type of extreme insulin resistance. Methods A patient with IAS never experienced hypoglycemia but had persistent hyperglycemia and extreme insulin resistance with treatment with 200 U of intravenous insulin per day. Immunoreactive insulin (IRI), free insulin, and total insulin were measured. The ratio of free insulin to total insulin (insulin-free ratio, IFR) was calculated. Results Extreme insulin resistance has not been reported to be caused by IAS. At admission, IRI and free insulin were undetectable in our patient; total insulin was more than 20 160 pmol/L; and the IFR was lower than 0.03% (control, 90.9%). After adding 500 U porcine insulin to the precipitate containing insulin antibodies, the IRI was still undetectable. Since the patient started glucocorticoid therapy, the free insulin has gradually increased to 11.16 pmol/L, his total insulin has decreased to 5040 pmol/L, and the IFR has increased to 18.26%. Intravenous insulin was stopped, with good glycemic control. Conclusion High-affinity insulin autoantibodies with a large capacity can induce a novel type of extreme insulin resistance characterized by extremely high total insulin and very low free insulin levels. The IFR can be used to evaluate therapeutic effects.

The benefits of growth hormone (GH) therapy in Prader-Willi syndrome (PWS) children are well established, but there is still considerable controversy regarding whether GH treatment can improve cognitive, motor, and behavioral development in PWS children. The objectives of this meta-analysis were to quantitatively evaluate the effects of GH on cognitive, motor function, and behavioral development in PWS children. Randomized controlled trials (RCTs) examining the effects of GH on cognitive, motor, and behavioral development in PWS children were identified by searching the MEDLINE, EMBASE, and Cochrane Library databases. Intervention effects were represented by Hedges’g and pooled to calculate effect sizes using a random-effects model. Ten relevant studies comprising data from 302 participants were finally included. We observed no significant difference in cognitive performance between the GH treatment group and the control group (p = 0.197). GH treatment was shown to remarkably improve motor development in PWS children compared with the control treatment (p

Context The natriuretic peptide receptor 2 gene (NPR2) is a causative gene of idiopathic short stature (ISS) with an incidence rate of 2% to 6%. The clinical characteristics of patients with NPR2 heterozygous mutations are atypical, and data on the efficacy of recombinant human growth hormone (rhGH) treatment in patients with NPR2 mutations are limited. Objectives This work reports 6 cases with NPR2 mutation and explores the characteristics of patients with an NPR2 mutation and their therapeutic response to rhGH. Design, Settings, and Patients Six Chinese short-stature patients in our hospital with NPR2 mutations by whole-exome sequencing were included. We also searched all previously published NPR2 mutation cases as of August 10, 2020, and information about their medical history, mutations, and rhGH treatment were recorded and summarized. Results The clinical characteristics of patients with an NPR2 heterozygous mutation mainly included short stature, facial anomalies, and skeletal dysplasia. Skeletal dysplasia mainly included brachydactyly (56.2%), shortened metacarpals or metatarsals (particularly fourth to fifth; 26.1%), and clinodactyly (21.7%). rhGH treatment significantly improved the height SD score (SDS) of patients with NPR2 heterozygous mutations (median, –2.1 vs –2.9, P < .001), especially in girls. The height SDS change correlated negatively with initial age of treatment (r = –0.477; P = .034), and height SDS change of patients with NPR2 heterozygous mutations in the carboxyl-terminal guanylyl cyclase catalytic domain was significantly higher than that of the extracellular ligand-binding region domain (median, 1.9 vs 0.6, P = .019). Conclusions ISS patients with skeletal deformities should be tested for an NPR2 mutation. rhGH treatment is beneficial for short-stature patients with NPR2 heterozygous mutations and needs further study.

Automated facial recognition technology based on deep learning has achieved high accuracy in diagnosing various endocrine diseases and genetic syndromes. This study attempts to establish a facial diagnostic system for Turner syndrome (TS) based on deep convolutional neural networks. Photographs of 207 TS patients and 1074 female controls were collected from July 2016 to April 2019. Finally, 170 patients diagnosed with TS and 1053 female controls were included. Deep convolutional neural networks were used to develop the facial diagnostic system. A prospective study, which included two TS patients and 35 controls, was conducted to test the efficacy in the real clinical setting. The average areas under the curve (AUCs) in three different scenarios were 0.9540 ± 0.0223, 0.9662 ± 0.0108 and 0.9557 ± 0.0119, separately. The average sensitivity and specificity of the prospective study were 96.7% and 97.0%, respectively. The facial diagnostic system achieved high accuracy. Prospective study results demonstrated the application value of this system, which is promising in the screening of Turner syndrome.

There are numerous reasons for short stature, including mutations in osteochondral development genes. ACAN, one such osteochondral development gene in which heterozygous mutations can cause short stature, has attracted attention from researchers in recent years. Therefore, we analyzed six cases of short stature with heterozygous ACAN mutations and performed a literature review.Clinical information and blood samples from 6 probands and their family members were collected after consent forms were signed. Gene mutations in the probands were detected by whole-exome sequencing. Then, we searched the literature, performed statistical analyses, and summarized the characteristics of all reported cases.We identified six novel mutations in ACAN: c.1411CT, c.1817CA, c.1762CT, c.2266GC, c.7469GA, and c.1733-1GA. In the literature, more than 200 affected individuals have been diagnosed genetically with a similar condition (height standard deviation scorelsqb;SDS] -3.14 ± 1.15). Among affected individuals receiving growth-promoting treatment, their height before and after treatment was SDS -2.92±1.07 versus SDS -2.14±1.23 (P.001). As of July 1, 2019, a total of 57 heterozygous ACAN mutations causing nonsyndromic short stature had been reported, including the six novel mutations found in our study. Approximately half of these mutations can lead to protein truncation.This study used clinical and genetic means to examine the relationship between the ACAN gene and short stature. To some extent, clear diagnosis is difficult, since most of these affected individuals' characteristics are not prominent. Growth-promoting therapies may be beneficial for increasing the height of affected patients.AI = aromatase inhibitor; ECM = extracellular matrix; GnRHa = gonadotropin-releasing hormone analogue; IQR = interquartile range; MIM = Mendelian Inheritance in Man; PGHD = partial growth hormone deficiency; rhGH = recombinant human growth hormone; SDS = standard deviation score; SGA = small for gestational age; SGHD = severe growth hormone deficiency.

Introduction: This study described a Chinese case of X-linked acrogigantism (X-LAG) and summarized the characteristics and treatment of all reported cases. Methods: Clinical materials and biological samples from a 5-year and 2-month-old female due to “growth acceleration for 4 years” were collected. Array comparative genomic hybrid (aCGH) and further verification were performed. All X-LAG cases from the PubMed and Web of Science databases were collected and summarized with available data. Results: The patient presented accelerating growth since 1 year, and her height reached 134.6 cm (+5.24 standard deviation score [SDS]) when she was 5-year and 2-month old. She also had coarsening facial features, snoring, and acral enlargement. Growth hormone (GH) was not suppressed by the glucose-GH inhibition test, and insulin-like growth factor 1 (IGF-1) and prolactin (PRL) levels were elevated. Pituitary MRI revealed a pituitary enlargement with a maximum diameter of 22.3 mm. Octreotide imaging indicated the presence of a pituitary adenoma. The tumor shrank slightly after 3 courses of somatostatin analog but without clinical or biochemical remissions, of which the GH nadir value was 9.4 ng/mL, and IGF-1 was elevated to 749 ng/mL. Therefore, she underwent transsphenoidal surgery. Immunohistochemistry showed GH-positive and PRL-positive cells in the pituitary adenoma. Xq26.3 microduplication of the patient’s germline DNA was identified by aCGH. Of all 35 reported cases, females accounted for 71.43%. There were 93.10% and 53.83% patients with hyperprolactinemia and hyperinsulinemia, respectively. Pathology showed that 75.00% of cases were adenomas. Ninety percent of cases had germline variants. The clinical and biochemical remission rates were 78.26% and 82.61%, respectively. However, the rate of complication occurrence during therapy reached 80%. Conclusion: It is important to recognize the possibility of X-LAG when a child under 2-year old presents overgrowth. Early diagnosis and treatment are of great importance for better treatment efficacy and clinical outcome.

Objective To summarize our experience in the treatment of pituitary somatotroph adenomas by fractionated intensity-modulated radiotherapy (IMRT), describe the treatment outcomes, and determine predictors. Methods and Materials Patients with pituitary somatotroph adenoma treated by IMRT in our institution from August 2009 to January 2019 were reviewed. A total of 113 patients (37 male) were included in this study. The median age was 33 years (range 12-67 years). A total of 112 patients had not achieved complete remission after surgery, and 1 patient was treated by radiotherapy (RT) alone because she refused to surgery. The median growth hormone level was 8.6 ng/mL (range 2-186 ng/mL) and the median insulin-like growth factor (IGF)-1 level was 732 ng/mL (range 314-1485 ng/mL) pre-RT. The radiation doses to clinical target volume were usually 50-56 Gy in 25 to 30 fractions and to gross tumor volume were 60.2 Gy in 28 fractions while simultaneous integrated boost-IMRT used. After RT, the patients were followed up with endocrine testing every 6 to 12 months and magnetic resonance imaging annually. Endocrine complete remission was defined as a normal sex- and age-adjusted IGF-1 level without any pituitary suppressive medications. The outcomes including endocrine remission and new hypopituitarism after RT were recorded. The median follow-up time was 36 months (range 6-105.5 months). Results The endocrine complete remission rates of IGF-1 at 1, 2, 3, and 5 years were 6%, 22.8%, 48.6%, and 74.3%, respectively. The median time to complete remission was 36.2 ± 3.8 months. The tumor control rate was 99% during the follow-up. The overall incidence of RT-induced hypopituitarism was 28.3% at the last follow-up. Univariate and multivariate analysis demonstrated that tumor sizes before RT, pre-RT IGF-1 level, and age significant predicted the endocrine remission. Conclusions IMRT is a highly effective treatment for pituitary somatotroph adenoma. Endocrine remission rate, tumor control rate, the median time to remission and hypopituitarism incidence are similar to stereotactic radiosurgery. Age and IGF-1 level before RT were significant predictive factors in endocrine remission.

Glypican4 (GPC4) is a novel adipokine associated with obesity and insulin resistance. GPC4 was cleaved by the glycosylphosphatidylinositol-specific phospholipase D (GPLD1) in an anchored site of the glycosylphosphatidylinositol, and then was released into the extracellular environment. Herein, we investigated the changes of serum GPC4 and GPLD1 levels in obese subjects with different glucose metabolism status and their relationship with adipose tissue insulin resistance index (Adipo-IR) in Chinese north populations. A total of 221 obese subjects and 37 normal controls (NC) were recruited in this study. Obese subjects were divided into normal insulin (NI) group, hyperinsulinemia (HI) group, impaired glucose tolerance (IGT) group, and type 2 diabetes mellitus (DM) group. Serum GPC4, GPLD1, and adiponectin were determined by commercially available ELISA kits. Serum GPC4 levels in the HI, IGT, and DM groups were significantly higher than those in the NC and NI groups (2.27 ± 0.58 ng/mL, 2.21 ± 0.60 ng/mL, 2.49 ± 0.67 ng/mL vs. 1.70 ± 0.33 ng/mL, 1.93 ± 0.34 ng/mL, P

Introduction To explore serum zinc-α2-glycoprotein (ZAG) and adiponectin in metabolically healthy non-obese (MHNO), metabolically healthy obesity (MHO), metabolically abnormal obesity (MAO) and metabolically abnormal diabetic obese (MADO) subjects and the relationship with metabolically phenotypes of obesity. Methods Two hundred twenty-five subjects including 32 with MHNO, 40 with MHO, 104 with MAO and 49 with MADO were enrolled. Baseline clinical data and biochemical variables were collected. Serum ZAG and adiponectin levels were measured by enzyme-linked immunosorbent assay (ELISA) kits. Metabolically healthy (

Context The tumor immune microenvironment is associated with clinical outcomes and immunotherapy responsiveness. Objective To investigate the intratumoral immune profile of pituitary adenomas (PAs) and its clinical relevance and to explore a novel immune classification for predicting immunotherapy responsiveness. Design, Patients, and Methods The transcriptomic data from 259 PAs and 20 normal pituitaries were included for analysis. The ImmuCellAI algorithm was used to estimate the abundance of 24 types of tumor-infiltrating immune cells (TIICs) and the expression of immune checkpoint molecules (ICMs). Results The distributions of TIICs differed between PAs and normal pituitaries and varied among PA subtypes. T cells dominated the immune microenvironment across all subtypes of PAs. The tumor size and patient age were correlated with the TIIC abundance, and the ubiquitin-specific protease 8 (USP8) mutation in corticotroph adenomas influenced the intratumoral TIIC distributions. Three immune clusters were identified across PAs based on the TIIC distributions. Each cluster of PAs showed unique features of ICM expression that were correlated with distinct pathways related to tumor development and progression. CTLA4/CD86 expression was upregulated in cluster 1, whereas programmed cell death protein 1/programmed cell death 1 ligand 2 (PD1/PD-L2) expression was upregulated in cluster 2. Clusters 1 and 2 exhibited a “hot” immune microenvironment and were predicted to exhibit higher immunotherapy responsiveness than cluster 3, which exhibited an overall “cold” immune microenvironment. Conclusions We summarized the immune profile of PAs and identified 3 novel immune clusters. These findings establish a foundation for further immune studies on PAs and provide new insights into immunotherapy strategies for PAs.

Objective Automatic diabetic retinopathy screening system based on neural networks has been used to detect diabetic retinopathy (DR). However, there is no quantitative synthesis of performance of these methods. We aimed to estimate the sensitivity and specificity of neural networks in DR grading. Methods Medline, Embase, IEEE Xplore, and Cochrane Library were searched up to 23 July 2019. Studies that evaluated performance of neural networks in detection of moderate or worse DR or diabetic macular edema using retinal fundus images with ophthalmologists’ judgment as reference standard were included. Two reviewers extracted data independently. Risk of bias of eligible studies was assessed using QUDAS-2 tool. Results Twenty-four studies involving 235 235 subjects were included. Quantitative random-effects meta-analysis using the Rutter and Gatsonis hierarchical summary receiver operating characteristics (HSROC) model revealed a pooled sensitivity of 91.9% (95% CI: 89.6% to 94.3%) and specificity of 91.3% (95% CI: 89.0% to 93.5%). Subgroup analyses and meta-regression did not provide any statistically significant findings for the heterogeneous diagnostic accuracy in studies with different image resolutions, sample sizes of training sets, architecture of convolutional neural networks, or diagnostic criteria. Conclusions State-of-the-art neural networks could effectively detect clinical significant DR. To further improve diagnostic accuracy of neural networks, researchers might need to develop new algorithms rather than simply enlarge sample sizes of training sets or optimize image quality.

Liraglutide has been approved for the treatment of obesity in the past few years. Both oxidative stress and leptin resistance are the critical drivers of obesity. The present study investigated the mechanism of liraglutide protection against obesity by ameliorating leptin resistance and oxidative stress. Male C57BL/6J mice were fed a high-fat diet (HFD) and subcutaneously injected with 200 μg/kg/d liraglutide for 20 weeks. Body weight, fat mass, serum levels of leptin, insulin, and superoxide dismutase (SOD) activities were measured. In addition, glucose and insulin tolerance tests were performed. The expressions of leptin, its signaling genes, and antioxidant enzymes were detected using RT-qPCR and western blot methods in liver and white adipose tissue (WAT) of mice. The results depicted that liraglutide treatment significantly slowed weight gain of body, reduced the fat mass, ameliorated glucose and lipid metabolism, and hepatic steatosis in HFD-fed obese mice. Further study demonstrated that liraglutide treatment resulted in decreased serum levels and the transcript levels of leptin as well as leptin signaling inhibitory regulators. However, it increased leptin receptor expression and the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) in WAT (p0.05). In addition, the antioxidant enzyme expression was elevated in both liver and WAT of liraglutide-treated mice (p0.05). In conclusion, liraglutide conspicuously prevented obesity and ameliorated glucose and lipid metabolism in obese mice through a novel mechanism that improves peripheral leptin resistance in WAT and enhance the antioxidant enzyme expression in both liver and WAT.

The aim of the work was to investigate the bone mineral density (BMD) in middle-aged male patients with both childhood-onset (CO) and adulthood-onset (AO) adult growth hormone deficiency (AGHD). In this retrospective cross-sectional study in a major medical center in China, dual X-ray absorptiometry was performed in 50 male AGHD patients (average age was 35.2±9.8 years) and 50 age- and BMI-matched non-athletic healthy men. BMD was compared between AGHD patients and controls. Compared with healthy controls, AGHD group had significantly decreased IGF-1 (p1

Aim To determine the antiobesity effect and safety of glucagon-like peptide-1 receptor agonist (GLP-1RA) including liraglutide, exenatide and semaglutide treatment in overweight/obese patients without diabetes. The random-effect model was used to pool data extracted from included literatures. The weighted mean difference (WMD), odds ratio and 95% confidence interval (CI) were used to present the meta-analysis results (PROSPERO registration number: CRD 42020173199). The sources of intertrial heterogeneity, bias and the robustness of results were evaluated by subgroup analysis, sensitivity analysis and regression analysis, respectively. A total of 24 RCTs were recruited in the present analysis which included 5867 patients. The results showed that the treatment of overweight/obese patients without diabetes with GLP-1RAs including liraglutide, exenatide and semaglutide significantly achieved greater weight loss than placebo [WMD=–5.39, 95% CI (–6.82, –3.96)] and metformin [WMD=–5.46, 95% CI (–5.87, –5.05)]. The subgroup analysis showed that semaglutide displayed the most obvious antiobesity effect in terms of weight loss, the reduction of body mass index (BMI) and waist circumference (WC). However, GLP-1RAs treatments had more gastrointestinal adverse events (such as nausea and vomiting) than placebo and Met. The subgroup analysis also represented that semaglutide displayed the lowest risk of gastrointestinal adverse events among three kinds of GLP-1RAs. Our meta-analysis demonstrated that GLP-1RA had a superior antiobesity effect than placebo/Met in overweight/obese patients without diabetes in terms of body weight, BMI, and WC, especially for semaglutide, which had more obvious antiobesity effect and lower GI adverse events than liraglutide and exenatide.

Background The relationship between maternal thyroid function and pregnancy outcomes remains controversial and the safe range of TSH is still unclear in women planning pregnancy. Methods This population-based cohort study enrolled Chinese women who became pregnant in 30 provinces from 2010 to 2012 from the National Free Preconception Checkups Project. The maternal TSH level within 6 months before pregnancy and different pregnancy outcomes were collected and analyzed using restricted cubic spline regression model for dose-response relationship and potential optimal cutoff values. Logistic regression was used to reveal the relationship between different TSH groups and the risk of adverse outcomes. Results Among 175 112 women, a J-shaped association was revealed between TSH and large for gestational age (LGA; P < 0.001). When TSH was lower than 1.27 or 0.91 mIU/L, lower TSH was associated with higher odds ratio of low birth weight (LBW; P = 0.003) or preterm delivery (P < 0.001). There was no significant association of preconception TSH with SGA, macrosomia, fetal anomalies, stillbirth, natural or induced abortion, and cesarean delivery. The range of TSH for odds ratio lower than 1.0 was within 0.91 to 1.82 mIU/L in dose-response association. Compared with TSH 0.91 to 1.82 mIU/L, TSH low (< 0.40 mIU/L and 0.40-0.90 mIU/L) and high (1.83-2.49 mIU/L, 2.50-3.99 mIU/L, and >4.00 mIU/L) were associated with higher risk of preterm delivery and LGA. There was no significant association between TSH groups and the risk of LBW except for TSH < 0.40 mIU/L. Conclusion Preconception TSH was associated with preterm delivery, LGA, and LBW. Preconception TSH had a bidirectional effect on LGA, indicating a potential mechanism regarding influence of TSH on birth weight. TSH within 0.91 to 1.82 mIU/L was the potential safe range for preconception women.

BackgroundThyrotropin-secreting adenoma (TSH-oma) is a very rare kind of functional pituitary adenoma, especially that which occurs in adolescents. However, its potential clinical and therapeutic characteristics are still unknown.ObjectivesThe study was aimed to summarize the clinical and therapeutic characteristics of patients with adolescent-onset TSH-oma.MethodsWe retrospectively analyzed six (4.1%) adolescent-onset TSH-oma cases from 148 patients who were diagnosed with TSH-oma at our hospital between January 2012 and October 2020. A literature review was performed on the PubMed online database, and 14 adolescent-onset TSH-oma cases were retrieved. Then, the characteristics of clinical manifestations, treatment outcomes, and follow-ups were analyzed and compared to the adult TSH-oma patients.ResultsAltogether, 20 adolescent-onset cases were included in this study having mean onset age of 13.4 ± 3.3 years. Males were found to be slightly predominant (M: F = 1.5:1) in our study. The median baseline levels of TSH, FT3, and FT4 in adolescent-onset cases were found to be 6.30 [interquartile range (IQR) 9.82] µIU/ml, 9.18 (IQR 11.61) pg/ml, and 3.22 (IQR 1.90) ng/dl, respectively, which were all significantly higher than the adult patients of our hospital. Also, the adolescent-onset cases showed more large tumor ratio (36.8% vs. 9.3%, p = 0.007) compared to the adult patients. Compared to the patients of all ages in the literature, the biochemical remission rate of SSAs (57.1%) and remission rate of TSS (38.9%) were found to be considerably lower in adolescent-onset patients, while the recurrence rate (44.4%) was found to be considerably higher.ConclusionsAdolescent-onset TSH-oma patients showed higher TSH and thyroid hormone levels, more large tumors, and worse treatment outcomes than adult cases. Hence, early diagnosis, multidisciplinary therapy, and close follow-up should be highlighted to improve the prognosis.

Background18q- syndrome is a rare chromosomal disease caused by the deletion of the long arm of chromosome 18. Some cases with 18q- syndrome can be combined with growth hormone deficiency (GHD), but data on the efficacy of recombinant human growth hormone (rhGH) treatment in 18q- syndrome are limited.MethodsHere, we report one case of 18q- syndrome successfully treated with long-term rhGH supplement. Previously reported cases in the literature are also reviewed to investigate the karyotype–phenotype relationship and their therapeutic response to rhGH.ResultsA 7.9-year-old girl was referred for evaluation for short stature. Physical exam revealed proportionally short stature with a height of 111.10 cm (−3.02 SD score (SDS)), low-set ears, a high-arched palate, a small jaw, webbed neck, widely spaced nipples, long and tapering fingers, and cubitus valgus. Thyroid function test indicated subclinical hypothyroidism. The peak value of growth hormone was 10.26 ng/ml in the levodopa provocation test. Insulin-like growth factor 1 (IGF-1) was 126 ng/ml (57–316 ng/ml). Other laboratory investigations, including complete blood cell count, liver and kidney function, gonadal function, serum adrenocorticotropin levels, and serum cortisol levels, were all within normal ranges. Karyotype analysis showed 46, XX, del (18) (q21). L-Thyroxine replacement and rhGH treatment were initiated and maintained in the following 7 years. At the age of 14.8, her height has reached 159.5 cm with a height SDS increase of 2.82 SDS (from −3.02 SDS to −0.20 SDS). No significant side effects were found during the treatment. The literature review indicated the average rhGH treatment duration of 16 patients was 5.9 ± 3.3 years, and the average height SDS significantly increased from −3.12 ± 0.94 SDS to −1.38 ± 1.29 SDS after the rhGH treatment (p < 0.0001).ConclusionThe main clinical manifestations of 18q- syndrome include characteristic appearance, intellectual disability, and abnormal genital development. The literature review suggested a significant height benefit for short stature with 18q- syndrome from long-term rhGH treatment.

Objectives This study aimed to compare the efficacy, safety and metabolic effects of once-weekly pegylated human growth hormone (PEG-rhGH) with daily rhGH in patients with growth hormone deficiency (GHD). Design 48 patients enrolled in this 12-month single-center, open-label, prospective, randomized controlled trial is allocated to PEG-rhGH 0.12 mg/kg/w and 0.20 mg/kg/w treatment. Besides, the control group allocated 23 patients treated with daily rhGH 0.28 mg/kg/w matched with sex, age, and baseline IGF-1 levels. The primary endpoint included height velocity (HV) and IGF-1 increase at the end of treatment. Other parameters associated with growth, metabolism and safety were also monitored. Results In terms of HV increase, the efficacy of PEG-rhGH dosed at 0.12 mg/kg/w and 0.20 mg/kg/w was comparable to that of daily rhGH dosed at 0.28 mg/kg/w after 3, 6 and 12 treatment (p>0.05). IGF-1 concentration and IGF-1 SDS were both elevated significantly at 3, 6 and 12 months (p=0.000) into normal range following PEG-rhGH treatment. BMI SDS elevated after PEG-rhGH treatment for 3, 6 and 12 months (p=0.000). HbA1c elevated after 3 and 12 months (p=0.009) and METS-IR elevated after 6 months (p=0.019) compared with baseline. The differences of other metabolic indexes (such as blood glucose, blood lipid, etc.) have no statistical significance (p>0.05). No severe adverse event was observed among the three groups. Conclusions The efficacy and safety were promising and comparable between once-weekly PEG-rhGH and daily rhGH injection within 12 months. The negative influence on glucose homeostasis needed attention and monitoring.

PurposeCushing’s disease (CD) is a rare disease that contributes to 70–80% hypercortisolemia, which presents similarities and differences between pediatric and adult patients, and even between male and female patients. However, the comparative study of CD between different age groups and different genders is still insufficient. The aim of the study is to make a systematic comparison to reveal the gender differences in children and adult patients of CD, helping clinicians to provide optimal treatment for different groups of patients.MethodsWe conducted a retrospective research consisting of 30 pediatric and 392 adult CD patients in a single center in Peking Union Medical College Hospital. All 422 patients showed symptoms related to hypercortisolism and received adenoma excision surgery in the department of neurosurgery between 2014 and 2020.ResultsFor the accuracy of diagnosis, the sensitivity of BIPSS at baseline in pediatric patients was lower than in adults (75 vs. 91%, P = 0.054) but increased greatly after desmopressin stimulation (94 vs. 95%). However, the accuracy of lateralization for BIPSS was not preferred for prediction. As for clinical manifestations, growth retardation, weight gain, hirsutism, and acne were more prevalent for children, while for adults, hypertension, osteopenia, glucometabolic disorder, easy bruising, hair loss, and weight loss were more frequently seen. As previously reported, we observed a significant difference between the male prevalence of pediatric and adult patients (50 vs. 17%, P < 0.001), which was possibly caused by the more severe and earlier onset of a series of symptoms. Gender-related comparison showed greater morbidity of nephrolithiasis, hypokalemia, hypertension, easy bruising, osteopenia, and striae for male patients, while irregular menses, hirsutism, and hair loss were more common for female patients. Further analysis showed that the secretory activity of the PA axis was higher for males, presenting as the more remarkable alteration of laboratory parameters and contributing to the more severe clinical manifestations. For patients treated with transsphenoidal pituitary surgery (TSS), the immediate prognosis could be predicted by operation history, invasiveness, Ki-67, and information provided by MRI, including tumor size and Knosp grading. However, we still lack methods to predict long-term prognosis.ConclusionsOur study is the first detailed and systematic comparison between pediatric and adult CD patients. Further exploration of the impact of CD on different genders reveals a more severe and probably an earlier-onset pattern of CD for male patients.

PurposeXanthomatous hypophysitis (XHP) is an extremely rare form of primary hypophysitis for which there is a lack of clinical experience. A comprehensive understanding of its clinical characteristics, diagnosis and treatment is needed.MethodsHere, we report a case study and conduct a systematic review of XHP. Thirty-six cases were included, and their clinical manifestations, endocrine assessment, imaging features, treatment and follow-up data were collected and analyzed.ResultsThe mean age at diagnosis was 39.1 years, and females were predominant (75.0%). The most common symptom was headache (68.6%), and 66.7% of female patients presented menstrual disorders. The most common pituitary dysfunction was growth hormone (GH) deficiency. More than half of patients exhibited central diabetes insipidus (CDI). The majority of patients had an imaging presentation of a cystic lesion with peripheral enhancement. Pituitary stalk thickening was observed in half of the patients. Total lesion resection was achieved in 57.1% of cases. The recurrence rate after partial resection and biopsy was significantly higher than that after total lesion resection (57.1% vs. 0.0%, P = 0.0147). The most common pituitary hormone abnormalities to resolve after surgery were hyperprolactinemia (100.0%) and GH deficiency (91.7%). The typical pathological feature was inflammatory infiltration of foamy histiocytes, which showed positivity for CD68.ConclusionDiagnosis of XHP is difficult when relying on clinical symptoms and imaging features. Therefore, surgical histopathology is necessary. Based on the available evidence, total lesion resection is recommended for treatment. However, the long-term prognosis for this rare disease remains unclear.

BackgroundMcCune-Albright syndrome is a rare disorder characterized by fibrous dysplasia, café au lait skin spots, and hyperfunctioning endocrinopathies. The coexistence of precocious puberty and growth hormone excess in McCune-Albright syndrome is rare. Both conditions can manifest as accelerated growth, and treatments can be more challenging for such patients. This study aimed to describe the clinical manifestations of combined GH excess and PP in the context of McCune-Albright syndrome and analyze the clinical features and treatments of these patients.MethodClinical data from 60 McCune-Albright syndrome patients from Peking Union Medical College Hospital were obtained. The demographic characteristics, growth hormone, insulin-like growth factor-1, prolactin, alkaline phosphatase, and sex hormone levels; growth velocity; and bone age data were obtained. The growth velocity Z-score, bone age over chronological age ratio, and predicted adult height Z-score were calculated before and after treatment. Published studies and case reports were systemically searched, and data on demographic, clinical, and biochemical characteristics and treatment outcomes were obtained.ResultsWe reviewed seven patients among 60 McCune-Albright syndrome patients at Peking Union Medical College Hospital (5 female) and 39 patients (25 female) from the published literature. Six of the seven patients from Peking Union Medical College Hospital and half of the patients from the published studies were pediatric patients. These patients had increased growth velocity Z-scores and bone age over chronological age ratios. After good control of both conditions, the growth velocity Z-score and bone age over chronological age ratio decreased significantly, and the predicted adult height Z-score increased. The final heights and predicted adult height Z-scores were not impaired in patients with gigantism. All the patients had craniofacial fibrous dysplasia associated with optic and otologic complications.ConclusionMcCune-Albright syndrome with growth hormone excess and precocious puberty is more common in girls. Patients have accelerated linear growth and advanced skeletal age, and early and good control of both conditions leads to a reduced growth velocity and stabilized bone age. The predicted adult and final heights are not negatively affected when growth hormone excess is diagnosed in pediatric patients.

BackgroundInsidious-onset acromegaly may easily be overlooked by non-specialists of acromegaly and cause diagnostic delay. This study aims to examine the association between diagnostic delay and advice from doctors before any confirmed diagnosis and subsequent comorbidities, and elicit patient-perceived reasons for misdiagnoses.MethodsAn online nationwide cross-sectional study was conducted through China Acromegaly Patient Association. Growth Hormone (GH) and Insulin-like Growth Factor 1 (IGF-1) levels at diagnosis and cancerous, endocrine-metabolic, musculoskeletal, cardiovascular, respiratory, and psychiatric comorbidities were reported by patients. The association between diagnostic delay and pre-diagnostic advice from doctors as well as subsequent comorbidities after diagnosis were examined.ResultsIn total, 447 valid responses were collected. Overall, 58.8% patients experienced misdiagnoses, and 22.6% had diagnostic delay. Before arriving at any diagnosis, patients without treatment (adjusted odds ratio [AOR]: 3.66, 95% confidence interval [CI]: 1.30-10.33) or receiving treatment to symptoms only (AOR: 7.05, 95%CI: 4.09-12.17) had greater chance of being misdiagnosed, and hence had diagnostic delay. Patients believed insufficient specialists, limited awareness of acromegaly of non-specialists and poor doctor-patient communications were major reasons of misdiagnosis. Diagnostic delay were associated with higher GH level at diagnosis and endocrine-metabolic, musculoskeletal and cardiovascular comorbidities (all PConclusionsSuboptimal pre-diagnostic advice for patients, reflecting limited awareness of acromegaly among non-specialists, may delay the diagnosis and increase comorbidities. Feedbacks on the patients’ final diagnosis from specialists to non-specialists should be considered, and doctor-patient communication and clinical decision-making process should be improved. Comorbidities should be screened and monitored particularly for patients with diagnostic delay.

Coronary artery disease (CAD), the leading cause of morbidity and mortality, has imposed huge health and economic burdens globally. Zinc-α2-glycoprotein (ZAG) is a novel adipokine. Increasing evidence suggests the close relationship between serum ZAG levels and various cardiometabolic risk factors. However, the relationship between serum ZAG levels and CAD is still not fully clarified. We conducted this study to evaluate serum ZAG levels and its association with cardiovascular risk factors. A total of 129 patients with CAD, 99 patients with noncoronary artery disease (NCAD), and 121 controls were recruited in this retrospective study. CAD (coronary artery stenosis ≥50%) or NCAD (coronary artery stenosis β = −0.328, P<0.001) after controlling other confounding factors. Further multivariate ordinary logistic regression analysis demonstrated that the risk of grouping at one level higher in subjects with the lowest tertile of ZAG levels was 2.28-fold higher than those with the highest tertile levels (OR = 3.281, 95% CI 1.782–6.038, P<0.001). The receiver-operating characteristic (ROC) curve analysis showed that serum ZAG could distinguish CAD patients (AUC = 0.706, 95% CI, 0.643–0.770, P<0.05), NCAD patients (AUC = 0.673, 95% CI, 0.602–0.743, P<0.05), and NCAD and CAD patients (AUC = 0.692, 95% CI, 0.633–0.750, P<0.05) from controls. In conclusion, serum ZAG levels were significantly decreased in NCAD/CAD patients. The decreased serum ZAG levels were independently associated with the presence of NCAD/CAD. ZAG might serve as a candidate diagnostic biomarker for NCAD/CAD.

Ectopic ACTH-secreting pituitary adenoma (EAPA) are a rare cause of Cushing’s disease. Due to the lack of consensus and experience in terms of the diagnosis and treatment of EAPAs, preoperative identification and optimal treatment remain challenging. To investigate the characteristics of EAPAs and offer some proposals for the diagnosis and management of this uncommon disease, the EAPA patients admitted to our center and all of the EAPA cases reported in the literature were reviewed. In a retrospective electronic medical chart review, 6 patients (0.39%) with EAPAs were identified from 1536 consecutive patients who were admitted to our hospital with a diagnosis of Cushing’s syndrome between January 2000 and August 2019. A literature review was performed on the online databases PubMed and EMBASE, and 52 cases conformed to the criteria. The data regarding biochemical tests, imaging examinations and follow-ups were analyzed. The mean age of patients with EAPAs was 37.7 years old, and an obvious female predominance (3.5: 1) was demonstrated. The most common location of EAPAs was the cavernous sinus (34.5%), followed by the sphenoid sinus (31.0%) and the suprasellar region (20.7%). No significant differences in the biochemical test results were found among tumors in different locations. Except for sex, no risk factors related to remission were found. Although no significant differences among different locations were found, the tumors in the cavernous sinus had a relatively higher rate of invisibility in terms of imaging and a higher non-remission rate than tumors in other locations. In patients with negative intrasellar findings, the uncommon disease of EAPA should be considered. Due to the endocrine similarity between intrasellar pituitary corticotrophin adenoma and EAPA, the preoperative identification of EAPA depends on a careful review of the imaging examinations. Locations such as the cavernous sinus, sphenoid sinus and suprasellar region should be considered first. Tumor resection is recommended when the diagnosis is confirmed.

Purpose A clinical case presenting secondary amenorrhea accompanied by an adrenal adenoma and hyperprogesteronemia is described in this study. Methods Selective catheterization and sampling of adrenal and ovarian veins were performed. Results The source of hyperprogesteronemia was located in the right adrenal gland. A progesterone-producing tumor in the right adrenal gland was diagnosed and removed. Twenty-six days after tumor resection, menstruation occurred. Conclusions Progesterone-producing tumors should be considered with the presence of an adrenal mass and hyperprogesteronemia. Combined adrenal and ovarian venous sampling may help to identify the source of progesterone secretion.

Background: Deep learning has the potential to assist the medical diagnostic process. We aimed to identify facial anomalies associated with endocrinal disorders using a deep-learning approach to facilitate the process of diagnosis and follow-up. Methods: We collected facial images of patients with hypercortisolism and acromegaly, and we augmented these images with additional negative samples from public databases. A model with a pretrained deep-learning network was constructed to automatically identify these hypersecretion statuses based on characteristic facial changes. We compared its performance to that of endocrine experts and further investigated key factors upon which the best performing model focused. Findings: The model achieved areas under the receiver operating characteristic curve of 0.9647 (Cushing’s syndrome) and 0.9556 (acromegaly), accuracies of 0.9593 (Cushing’s syndrome) and 0.9479 (acromegaly), and recalls of 0.7593 (Cushing’s syndrome) and 0.8089 (acromegaly). It performed better than any level of our endocrine experts. Furthermore, the regions of interest on the part of the machine were primarily the same as those upon which the humans focused. Interpretation: Our findings suggest that the deep-learning model learned the facial characters based merely on labeled data without learning prerequisite medical knowledge, and its performance was comparable with professional medical practitioners. The model has the potential to assist in the diagnosis and follow-up of these hypersecretion statuses.

PurposeThis study aimed to evaluate the bone turnover markers and bone microarchitecture parameters derived from high-resolution peripheral quantitative computed tomography (HR-pQCT) in active and controlled acromegaly patients.MethodsThis cross-sectional study involved 55 acromegaly patients from a tertiary hospital (23 males and 32 females, aged 45.0 ± 11.6 years). Firstly, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and markers for bone turnover were assessed. Next, we derived peripheral bone microstructure parameters and volumetric bone mineral density (vBMD) through HR-pQCT. These parameters were compared between acromegaly patients and 110 healthy controls, as well as between 27 active and 28 controlled acromegaly patients. Moreover, the relationship between GH/IGF-1 and bone microstructure parameters was analyzed through multiple linear regression.ResultsAs compared with healthy controls, acromegaly patients exhibited elevated cortical vBMD, reduced trabecular vBMD, and increased trabecular inhomogeneity in the distal radius and tibia. While controlled acromegaly patients had slower bone turnover, they did not necessarily have better bone microstructure relative to active patients in intergroup comparison. Nevertheless, multiple regression indicated that higher IGF-1 was associated with lower tibial stiffness and failure load. Additionally, males with higher IGF-1 typically had larger trabecular separation, lower trabecular number, and larger cortical pores in the radius. Moreover, patients with elevated GH typically had more porous cortical bone in the radius and fewer trabeculae in the tibia. However, the compromised bone strength in active patients was partially compensated by increased bone thickness. Furthermore, no significant linkage was observed between elevated GH/IGF-1 and the most important HR-pQCT parameters such as trabecular volumetric bone density.ConclusionAcromegaly adversely affected bone quality, even in controlled patients. As the deterioration in bone microstructure due to prolonged GH/IGF-1 exposure was not fully reversible, clinicians should be aware of the bone fragility of acromegaly patients even after they had achieved biochemical remission.

ContextTraditionally, low-dose dexamethasone suppression test (LDDST) was used to confirm the diagnosis of Cushing’s syndrome (CS), and high-dose dexamethasone suppression test (HDDST) was used to differentiate Cushing’s disease (CD) and ectopic adrenocorticotropin (ACTH) syndrome (EAS), but some studies suggested that HDDST might be replaced by LDDST. For the differential diagnosis of CS, dexamethasone suppression test was usually combined with other tests such as bilateral petrosal sinus sampling (BIPSS) and pituitary magnetic resonance imaging, but the optimal pathway to incorporate these tests is still controversial.ObjectivesTo develop an optimized pathway for the differential diagnosis of CD and EAS based on LDDST.Design and SettingSingle-center retrospective study (2011–2019).PatientsTwo hundred sixty-nine CD and 29 EAS patients with pathological diagnosis who underwent consecutive low- and high-dose DST.ResultsFor the differential diagnosis of CD and EAS, the area under curve (AUC) of LDDST using urine free cortisol (0.881) was higher than that using serum cortisol (0.685) (p < 0.001) in head-to-head comparison among a subgroup of 108 CD and 10 EAS. The AUC of LDDST (0.883) was higher than that of HDDST (0.834) among all the included patients. With the cutoff of ConclusionLDDST had similar value to HDDST in differentiating CD and EAS using the specific cutoff point. The pathway that combined LDDST and BIPSS could differentiate CD and EAS accurately.

PurposeCornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder, and cases caused by variants in SMC3 are infrequent. This article describes a case of CdLS related to a pathogenic variant in SMC3 and performs a literature review.MethodsWe collected clinical data and biological samples from a 12-year-old boy with “short stature for 11 years”. Gene variants in the proband were detected by whole-exome sequencing, and the variants in his parents were verified by Sanger sequencing. All SMC3-related CdLS patients from the PubMed and Web of Science databases were collected and summarized using the available data.ResultsA pathogenic variant in SMC3 in the proband, c.1942A>G, was identified. Neither of his parents carried the same variant. Twenty-eight patients were diagnosed with CdLS with variants in SMC3, including the cases in this study and those reported in the literature, where half of the variant types were missense, followed by 32% (9/28) with a deletion and 11% (3/28) with a duplication. All patients showed symptoms of verbal development delay and intellectual disability to different degrees, and 90% patients had long eyelashes while 89% patients had arched eyebrows.ConclusionThis study summarized different gene variants in SMC3 and the frequencies of the various clinical manifestations according to the reported literature. For CdLS caused by SMC3 variants, short stature and facial dysmorphic features are the two most important clinical clues. Definite diagnosis of this rare disease may be challenging clinically; thus, it is significant to use molecular diagnosis.

BackgroundBasal ganglia germ cell tumors (BGGCTs) represent an extremely rare subset of tumors about which little is known. Some patients suffer from tumor dissemination, such as sellar involvement. This study aimed to evaluate the independent prognostic risk factors of patients with BGGCTs with or without sellar involvement.MethodsSixteen patients were diagnosed with BGGCTs at Peking Union Medical College Hospital from January 2000 to December 2020. A literature review was performed on the online databases Medline and PubMed, and 76 cases in the 19 retrieved articles were identified at the same time. The data regarding biochemical tests, radiological examinations, and outcomes during follow-up were analyzed.ResultsOf 92 patients in this study, seven patients were clinically diagnosed as germinomas, with the remaining 85 patients receiving surgery. Fifty-two patients suffered from multifocal lesions or tumor dissemination. The patients with BGGCTs demonstrated a significant male predilection. The patients with delayed diagnosis more likely had cognitive disturbance (p = 0.028), mental disturbance (p = 0.047), and diabetes insipidus (p = 0.02). Multivariate analysis demonstrated that the independent poor prognostic risk factors of patients with BGGCTs were delayed diagnosis [odd ratio (OR) 2.33; 95% CI 1.02–5.31], focal radiotherapy (OR 4.00; 95% CI 1.69–9.49), and non-pure germinoma (OR 4.64; 95% CI 1.76–12.22).ConclusionsThe delayed diagnosis, focal radiotherapy, and non-pure germinoma were associated with a poorer prognosis for patients with BGGCTs with or without sellar involvement.

BackgroundPrimary pituitary lymphoma (PPL) is an extremely rare disease with poor prognosis. Although PPL has been shown to be different from classical primary central nervous system lymphoma because of the embryological origin of structures, individual and precise treatment of PPL remains unknown.MethodsA 61-year-old man and a 65-year-old woman both diagnosed with primary pituitary diffuse large B cell lymphoma underwent genetic analysis of cerebrospinal fluid and tumor tissue by next generation sequencing.ResultsIn the first case, partial remission was achieved following R²-MTX chemotherapy. In the other case with TP53 mutation and BCL6-LPP fusion, disease progressed although different chemotherapy regimens were given.ConclusionThe gene mutation of TP53 and BCL6 may be identified as a marker responsible for prognostic difference in patients with PPL. Genetic analysis may provide a novel approach for precise management and prognosis prediction.