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2023, 2(3): .  
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Current Status, Opportunities and Challenges of Rare Endocrine and Metabolic Diseases
WU Huixiao, LI Zongyue, XU Chao, ZHAO Jiajun
Abstract: The rare endocrine and metabolic diseases, due to their varieties, face many challenges in the study of clinical diagnosis, pathogenesis, and treatment. In the past a couple of years, the research on rare endocrine and metabolic diseases has been gradually improved. The diagnosis has made great progress. The research into molecular mechanism of rare endocrine and metabolic diseases has significantly advanced. The effort in exploring the breakthroughs and progress in therapeutic methods based on the pathogenesis of the diseases has also made. This article provides a brief overview of the current status of research into diagnosis, mechanism, and treatment of rare endocrine and metabolic diseases. In addition, the article points out the problems and challenges and proposes future possibilities. more>
2023, 2(3): 319-324.   doi: 10.12376/j.issn.2097-0501.2023.03.001
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Perspectives From Experts
Classification, Diagnosis and Management Status of Carbohydrate Metabolic Rare Disorders
HUANG Yumeng, LIU Ming
Abstract: Approximately 30%-40% of rare diseases are related to the endocrine and metabolic system, and abnormal metabolism of carbohydrate accounts for a significant proportion among others. Carbohydrate metabolic rare disorders often develop insidiously. The clinical symptoms of these disorders sometimes overlap with common diseases. Therefore, delayed diagnosis, misdiagnosis, and mismanagement happen often. The diagnosis and treatment of carbohydrate metabolic rare disorders is usually difficult in clinical practice. Efficient and practical screening models, identification of specific clinical features and biochemical changes, and genomic sequencing are critical to improve diagnostic efficiency. Most carbohydrate metabolic rare disorders are still lack in effective and targeted therapies. So, the symptomatic treatment is still main practice. The targeted medications and gene therapies based on precision diagnosis are directions for the diagnosis and management of rare disorders of carbohydrate metabolism in the future. In this paper, we classify the carbohydrate metabolic rare disorders based on their causes. We also discuss the current status and prospective of diagnosis and management of those diseases. more>
2023, 2(3): 325-330.   doi: 10.12376/j.issn.2097-0501.2023.03.002
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Perspectives From Experts
The Syndromes of Resistance to Thyroid Hormone Beta
WANG Huangman, SHAN Zhongyan, TENG Xiaochun
Abstract: The syndrome of resistance to thyroid hormone(RTH) is a rare syndrome caused by the mutation of thyroid hormone receptor (TR) gene, which reduces the sensitivity of target organs to thyroid hormone (TH) and leads to the dysfunction of TH. Thyroid hormone resistance syndrome β (RTHβ) is caused by the mutations in the THRB gene. The main characteristics of RTHβ are increased thyroxine (T4) in the circulating blood, normal or elevated levels of triiodothyronine(T3), paired with normal or high thyroid-stimulating hormone (TSH) concentration. Clinically, it is easy to misdiagnose RTHβ as hyperthyroidism, and give anti-thyroid drugs, radioactive 131I therapy or surgery, which then leads to the aggravation of TH resistance, so the correct diagnosis of the disease is critical. In this paper, the molecular mechanism, clinical characteristics, diagnosis and treatment of RTHβ are summarized. more>
2023, 2(3): 331-336.   doi: 10.12376/j.issn.2097-0501.2023.03.003
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Original Articles
Clinical Features and Mutation Analysis of Gordon Holmes Syndrome Associated with RNF216 Gene Mutation and a Literature Review
CHEN Meiping, YANG Hongbo, PAN Hui, FENG Feng, ZHU Yicheng, ZHU Huijuan
Abstract:   Objective  To summarize the clinical characteristics and RNF216 gene mutation of a patient with Gordon Holmes syndrome (GHS), and to improve the understanding of the genetic and clinica characteristics of this disease through literature review.  Methods  We collected the clinical data of the patient with GHS, extracted the DNA from 2 mL peripheral venous blood of the patient and his parents for whole exome gene detection, and then we analyzed the clinical and genetic characteristics of all previously reported patients with RNF216 gene mutation.  Results  The young male patient was short in stature at sixyearsold and was diagnosed growth hormone deficiency.He had no secondary sexual characteristics by the age of 15 and was diagnosed hypogonadal hypogonadism.After the age of 22, he gradually developed abnormal gait and had progressive decline in speech, motor, and cognitive functions.Whole exome sequencing revealed a homozygous, nonsense mutation c.1549C>T (p.R517*) in the RNF216 gene.His parents were consanguineous and were heterozygous carriers of the mutations with phenotypic normality.Combined with literature review and this case report results showed that a total of 21 patients of the disease in the world and among them 15 had pathogenic variants of RNF216 gene mutation.7 of the 15 had truncated mutations, 5 had missense mutations, and 1 synonym mutation, 1 splice mutation, and 1 deletion mutation respectively.RNF216 gene mutation can be seen in neurodegenerative diseases with multiple overlapping symptoms of GHS, Huntington-like disease, and 4H syndrome.The main clinical manifestations are hypogonadotropic hypogonadism and early-onset progressive neurological dysfunction in adolescence or early adulthood.The median age of onset of neurological symptoms is 28 years old, featuring cerebellar ataxia, dysarthria, and cognitive impairment, as well as imaging manifestations of extensive white matter lesions and cerebellar atrophy.  Conclusions  The mutation of RNF216 gene can cause GHS.Genetic testing is helpful to the diagnosis and treatment of rare diseases. more>
2023, 2(3): 337-345.   doi: 10.12376/j.issn.2097-0501.2023.03.004
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Original Articles
Clinical Characteristics and Diagnostic Experience of Adult Thyroid Langerhans Cell Histiocytosis with Diabetes Insipidus
WANG Qian, SUN Quanya, HE Min, ZHANG Shuo, XIANG Boni, LI Qiufan, WANG Yong, ZHANG Xialing, DING Tianling, YE Hongying
Abstract:   Objective  To analyze the clinical characteristics of thyroid LCH to enhance understanding of the disease.  Methods  We retrospectively studied the clinical data from six thyroid LCH patients who hospitalized in Huashan Hospital Affiliated to Fudan University from January 2015 to January 2022.We analyzed the ultrasound and 18F FDG-PET/CT imaging characteristics of thyroid LCH.  Results  The six patients diagnosed (2 males and 4 females) were between 18 and 58 years old.All patients had diabetes insipidus.MRI revealed thickened pituitary stalk.Two cases had central hypothyroidism, while four cases euthyroidism.Three cases tested positive for thyroid antibodies.Ultrasound showed thyroid nodules of TI-RADS 3 in three cases, TI-RADS 4 in two cases, and 1 with nodular goiter.Ultrasound showed that all sic cases indicated low echogenicity, 5 of which clear boundaries, 4 of which uneven echo distribution, 5 of which irregular shape, and noen has calcification.18F FDG-PET/CT indicated high uptake nodules with SUVmax values all above 10.4 cases were diagnosed by surgical excision and the other 2 by coarse-needle aspiration biopsy.When diagnosed, two cases had liver and thymus involvement respectively.One case had lung and bone involvement respectively.After treatment, 4 cases showed that nodular goiter shrank, while the other two with liver involvement progressed fast and no assessment made.  Conclusions  Thyroid LCH presented low echogenicity, clear boundaries, irregular shape, without calcification, and high uptake in 18F FDG-PET/CT.A definite diagnosis of pituitary stalk thicking accompanied by thyroid nodules, especially those with hypoechoic and irregular nodules, can be achieved by coarse-needle aspiration biopsy and langerin-specific pathological staining. more>
2023, 2(3): 346-352.   doi: 10.12376/j.issn.2097-0501.2023.03.005
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Original Articles
Clinical Characteristics of 5 Cases of Immune Checkpoint Inhibitor Induced Diabetes Mellitus
HAN Li, YU Jie, LIU Yiwen, FU Yong, PING Fan, LI Wei, ZHANG Huabing, XU Lingling, LI Yuxiu
Abstract:   Objective  By summarizing the clinical characteristics and follow-up outcomes of 5 patients with immune checkpoint inhibitor induced diabetes mellitus (ICI-DM) and reviewing the relevant literatures, the article aims at providing reference to clinicians in the diagnosis and treatment of the ICI-DM.  Methods  Clinical data of 5 patients with ICI-DM who were admitted to Peking Union Medical College Hospital from December 2018 to February 2023 and did retrospectively analyzed.  Results  Five patients with a mean age of (65±7)years received treatment by the programmed cell death 1 (PD-1) or its ligand inhibitor (PD-L1). The median time from the first immunotherapy to the discovery of elevated plasma glucose was 100 (43, 210)days, and the median cycle of immunotherapy was 7 (2.5, 10.5). The onset of the illness of all the 5 patients started with diabetic ketosis or ketoacidosis. At the onset, urine ketone bodies were positive, random plasma glucose was (36.36±15.89)mmol/L, glycosylated hemoglobin A1c (HbA1c)was (8.6%±0.66%), arterial blood pH was (7.28±0.16), and the median fasting C-peptide level was 0.09 (0.05, 0.32)μg/L. Five patients had an onset plasma glucose level of grade 3 or 4.Then, ICI treatment was discontinued in all patients and insulin therapy started. The daily dosage of insulin was (56±20)IU, supplemented with hypoglycemic drugs. After treatment, urine ketone body turned negative, pH value increased to normal range, and random plasma glucose decreased significantly (the median difference of random blood glucose before and after treatment was 21.30 mmol/L, P=0.043) showing that the treatment was effective. During the follow-up, all patients continued to use insulin. The PD-1 or PD-L1 inhibitors were restarted after hyperglycemia remission. The tumor condition was under control.  Conclusions  ICI-DM mainly occurs in patients who receive treatment with PD-1 or PD-L1 inhibitors usually with acute hyperglycemia whose laboratory tests indicate insulin secretion defects. Some patients had positive islet cell antibodies, glutamic acid decarboxylase antibodies and autoantibodies.Patients with positive autoantibodies needed early diagnosis and continuous insulin treatment. ICI treatment can be restarted after endocrinologists brought the blood glucose under control. more>
2023, 2(3): 353-358.   doi: 10.12376/j.issn.2097-0501.2023.03.006
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MDT on Rare Disease Cases
Rare Manifestations of Common Diseases: Middle-Aged Male Polyuria-Headache-Inflammatory Granulomatous Lesions
ZHAO Yuxing, DUAN Lian, LYU Wei, YAO Yong, YOU Hui, ZHANG Wen, MA Jin, MAO Xinxin, ZHU Huijuan
Abstract: A middle-aged man was presented with poor appetite, polyuria, polydrpsia, and headache. A sellar mass was found, along with total pituitary hypofunction and visual field defect. A biopsy of the lesion via the trans-sphenoidal approach showed inflammatory changes and granuloma formation. However, repeated cerebrospinal fluid and pathogenic examination of the pathological tissue showed no positive indications. The initial diagnosis considered autoimmune hypophysitis, and treatment of glucocorticoids combined with immunosuppressants was administered, which led to a temporary shrinkage of the lesion, but it gradually enlarged subsequently. After multidisciplinary discussion, a high possibility of pituitary tuberculosis infection was decided upon. After standardized anti-tuberculosis treatment was initiated, the lesion reduced noticeably and the patient′s condition improved. Pituitary tuberculosis infection is incredibly rare and extremely easy to misdiagnose. This case was diagnosed and treated in a timely and effective manner through a multidisciplinary approach, highlighting the importance of such an approach in dealing with rare diseases. more>
2023, 2(3): 359-364.   doi: 10.12376/j.issn.2097-0501.2023.03.007
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Guideline and Consensus
Expert Consensus on Bilateral Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing′s Syndrome (2023)
Chinese Medical Association Rare Diseases Branch, Hypothalamic and Pituitary Disease Group of China Alliance of Rare Diseases (CARD), Innovation Center of Pituitary Diseases, Peking Union Medical College Hospital
Abstract: Cushing′s syndrome(CS)is a clinical syndrome caused by a variety of causes, with main manifestations exhibited by central obesity, purple skin striae, hypertension, and diabetes. In patients with adrenocorticotropic hormone(ACTH)-dependent CS, the result of bilateral inferior petrosal sinus sampling(BIPSS)is the gold standard for determining the source of ACTH in the absence of routine imaging findings.However, the indications, contraindications, operating procedures, precautions and outcome judgments of BIPSS differ from one medical center to another, and there are currently no international and domestic clinical guidelines and expert consensus on BIPSS. In order to further improve the operation specifications of BIPSS in the diagnosis process of difficult CS, the Hypothalamic and Pituitary Disease Group of the China Alliance for Rare Diseases and the Innovation Center of Pituitary Diseases of Peking Union Medical College Hospital organized experts in endocrinology, interventional radiology, neurosurgery and laboratory in China to formulate this consensus. This consensus aims to provide standardized methodological guidance for the use of BIPSS in the differential diagnostic process of CS in clinical practice. more>
2023, 2(3): 365-376.   doi: 10.12376/j.issn.2097-0501.2023.03.008
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Guideline and Consensus
Clinical Practice Guideline for Adolescent & Adult Patients with Spinal Muscular Atrophy
Rare Disease Society of Chinese Research Hospital Association, China Alliance for Rare Diseases, Beijing Society of Rare Disease Clinical Care and Accessibility, China Expert Group for Clinical Practice Guideline for Adolescent & Adult Patients with Spinal Muscular Atrophy
Abstract: In recent years, spinal muscular atrophy (SMA) has made progress in multidisciplinary treatment and disease-modifying therapeutic drugs, so that the progress has significantly improved the survival and quality of life of the patients. However, no clinical practice guideline has developed for the management of SMA in adults and adolescents patients. Experts of multidisciplinary from a number of tertiary medical centers in China who specialize in the diagnosis and treatment of SMA have come to an agreement based on the evidence-based medicine. This guideline serves as instrumental reference for the standardized care of the Chinese SMA patients. more>
2023, 2(3): 377-397.   doi: 10.12376/j.issn.2097-0501.2023.03.009
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Images of Rare Diseases
Imaging Characteristics of 68Ga-DOTATATE PET/CT in Tumor-Induced Osteomalacia
ZHANG Yuwei, JING Hongli
Abstract: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumors secreting fibroblast growth factor 23 (FGF23) that promotes urinary phosphorus excretion. Thus, TIO is typically characterized by phosphoruria, hypophosphatemia, and osteomalacia. Diagnosis and localization of the tumor is often difficult due to its small size, slow growth and concealed location. Due to the high expression of somatostatin receptors in pathogenic tumors, nuclear medicine functional imaging, particularly somatostatin receptor imaging, is used for diagnosis and localization of culprit tumors with high sensitivity and specificity. Here we retrospectively analyze 25 cases in which 68Ga-DOTATATE PET/CT successfully localized and diagnosed TIO culprit tumors. The clinical features, pathological results and image characteristics of 68Ga-DOTATATE PET/CT imaging were analyzed and compared with other imaging diagnostic techniques. It was confirmed that 68Ga-DOTATATE PET/CT imaging was the preferred imaging technique for successful diagnosis and localization of TIO pathogenic tumors. more>
2023, 2(3): 398-405.   doi: 10.12376/j.issn.2097-0501.2023.03.010
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Spotlight on Orphan Drugs
Exploring the Accessibility by Using the Hydroxycobalamin Preparations of High Concentration in Treating Methylmalonic Acidemia
LI Ruohan, DU Liping, JIE Hengbo, MEI Dan
Abstract: Methylmalonic acidemia(MMA) is one of the common diseases in hereditary organic acid metabolism disorder. The disorder is mainly treated by using vitamin B12 which comes in various forms.The use of the methylcobalamin and adenosylcobalamin in China cannot meet the needs of children with MMA. Parenteral use of hydroxocobalamin of high concentration has significant advantages in the treatment of MMA. But, the accessibility to hydroxocobalamin is challenging now.Through the supervision and adjustment of hydroxocobalamin, we explored the strategy of using the drugs. Meanwhile, we are considering the oral use of the hydroxocobalamin as supplement to treatment. Solving the challenges of the hydrococobalamin is helpful to meet the treatment of MMA and to provide a new possibility for the use of medication for rare diseases. The improvement in policy and supervision measures will facilitate the development, involvement, and production of hydroxocobalamin, so that the patients will have a good chance of access to the treatment. more>
2023, 2(3): 406-413.   doi: 10.12376/j.issn.2097-0501.2023.03.011
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Spotlight on Orphan Drugs
Clinical Research Progress of the Non-Peptide Oral Somatostatin Receptor Ligand Paltusotine
LIU Yuke, TAN Huiwen
Abstract: The research and development of somatostatin analogues is a hot area in endocrinology and metabolism. The first generation octreotide, lanreotide and the second generation pareotide have been approved to be effective for the treatment of neuroendocrine tumors such as acromegaly. However, paltusotine, a somatostatin receptor ligand, is a novel non-peptide small molecule drug which can be administered orally and inhibits excessive secretion of growth hormone and insulin-like growth factor 1. This review summarizes the research progress of the pharmacokinetics, pharmacodynamics, clinical efficacy, telerability, and safety of paltusotine. more>
2023, 2(3): 414-419.   doi: 10.12376/j.issn.2097-0501.2023.03.012
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Case Reports
Irregular Menstruation-Hirsutism-Infertility: Clinical Management of Non-Classic Congenital Adrenal Hyperplasia
NIE Zhimei, DOU Jianxin, DU Jin, GU Weijun, LYU Zhaohui, DOU Jingtao, MU Yiming
Abstract: A 38-year-old female presented with irregular menstruation and hirsutism that started at age of 16 and diagnosed with polycystic ovary syndrome at age of 29 with elevated testosterone. When treated with ethinestradiol cyproterone tablets, her menstruation returned to normal and androgen levels was not changed. At age of 38 she was referred to the hospital with infertility, a diagnosis of nonclassical 21-hydroxylase deficiency was confirmed using 17-hydroxyprogesterone, dehydroepiandrosterone-sulfate, a cosyntropin-stimulation test and genetic test. This case suggested that nonclassical congenital adrenal hyperplasia should be considered when a patient is presented with oligomenorrhea, hirsutism with hyperandrogenemia and infertility. more>
2023, 2(3): 420-426.   doi: 10.12376/j.issn.2097-0501.2023.03.013
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