"Poor accessibility to drugs" is the most problematic issue for patients with rare diseases in China. In recent years, China has issued a number of policies, such as prioritizing speeding up the evaluation for rare disease drugs, publishing national rare disease lists and giving priority to treatments for severe diseases like rare diseases during annual adjustments of National Medical Insurance Medicine Catalogue to improve the accessibility of rare disease drugs. From the outcome perspective, the evaluation of rare disease drugs takes 3 months shorter than ordinary drugs, basic research projects have been started and the number of rare disease drugs included in National Medical Insurance Medicine Catalogue has increased to 50. However, the policies' effects on new drug research and development, rare disease diagnosis and treatment as well as drug pricing are limited. It is recommended to learn the tilt policy of research and development for rare disease drugs from foreign countries and the mechanism of medical insurance funding and patient co-payments. Thus it is important to improve the availability, accessibility and affordability of rare diseases drugs based on the Chinese context.

In order to ascertain the current status of and challenges posed by the incidence and prevalence of rare diseases in China, this study teases out data on the incidence and prevalence of 121 rare diseases listed in China's First List of Rare Disease to provide rationales and references for the development and promotion of rare-disease-related policies. The National Health Commission of the People's Republic of China issued the Rare Disease Diagnosis and Treatment Guide (2019) (denoted here as China's Rare Disease Diagnosis and Treatment Guide), which cited data on the incidence/prevalence of 21 rare diseases (21 of 121 rare diseases, 17.36%). Data on 68 diseases (56.20%) were found in monographs, literature databases, and official websites. Data on the incidence/prevalence of 70 diseases were compiled, though no data were available for the 51 remaining diseases. There are published data on the incidence/prevalence of only 14 diseases at the national level. Sources of data on the incidence and prevalence of rare diseases mainly include cases counts from hospitals (40.56%), other sources of data (24.48%), screening (20.98%), cross-sectional studies (8.39%), and estimates from models (7.69%). Data on the incidence/prevalence of rare diseases in China are limited and typically lack accuracy, uniformity, and timeliness. Epidemiological data at the national level are greatly lacking, and data are not amenable to comparison. China recently initiated epidemiological studies of rare diseases at the national and regional level. The country will continue to promote, use, and update its list of common rare diseases, actively encourage the coding and registration of cases of rare diseases, and take actions to collect, share, and use that information.

Type I collagen is an important structural protein of bone, skin, tendon, ligament and other connective tissues. It is initially synthesized as a precursor form, procollagen, consisting of two identical pro-α1(I) and one proα2(I) chains, encoded by COL1A1 and COL1A2, respectively. The N- and C- terminal propeptides of procollagen are cleavage by N-proteinase and C-proteinase correspondingly, to form the central triple helix structure with Gly-X-Y repeat units. Mutations of COL1A1 and COL1A2 genes are associated with osteogenesis imperfecta, some types of Ehlers-Danlos syndrome, Caffey diseases, and osteogenesis imperfect/Ehlers-Danlos syndrome overlapping diseases. Clinical symptoms caused by different variations can be variable or similar, mild to lethal, and vice versa. We reviewed the relationship between clinical manifestations and type I collagen – related rare genetic disorders and their possible molecular mechanisms for different mutations and disorders.

Median arcuate ligament syndrome (MALS) refers to a clinical syndrome caused by compression of the median arcuate ligament due to the fibers of this ligament that connect the diaphragmatic crura on the two sides of the aortic foramina, forming the anterior edge of the aortic foramina. If MALS is suspected, invasive digital subtraction angiography and computed tomography angiography or magnetic resonance angiography (MRA) can be used to verify the location of the celiac trunk. A disrupted or increased blood flow in the proximal end of the celiac trunk can be detected with doppler ultrasound, indicating stenosis. Treatment needs to alleviate celiac trunk compression. A common procedure involves separation of the ligament fibers and other surrounding tissues around the beginning of the celiac trunk. This can be achieved by either laparotomy or laparoscopic surgery. Patient prognosis is good, with a cure rate of about 80%.

Osteoporosis represent one of main characteristics of Turner syndrome (TS), a rare diseases caused by aberrant deletion of X chromosomes, however, the underlying pathological mechanism remains unknown yet. In this study, we used pluripotent stem cells (iPSCs) derived from a Turner syndrome patient and a health control to induce functional osteoblasts and osteoclasts, in order to compare their difference in these two differentiation. We successfully produced functional osteoblasts and osteoclasts from iPSCs through embryoid bodies (EBs) and mesoderm stages, as demonstrated obvious mineralized nodules and multi-nuclear giant cells with positive tartrate-resistant acid phosphatase (TRAP) staining, and significant up-regulated differentiation marker genes. Interestingly, we found that there was no significant difference in phenotype and marker genes expression between osteoblasts from Turner syndrome and healthy control iPSCs. In contrast, Turner syndrome showed increased osteoclastogenesis compared to the healthy control indicating higher frequency of multi-nuclear TRAP staining cells and elevated osteoclast marker genes TRAP, MMP9, CA2, OSCAR. Therefore, our results suggest that the low bone density of Turner syndrome patients may be caused by aberrant osteoclast differentiation, and further investigation towards osteoclast function under Turner syndrome is deserved.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein first identified in low-metastatic human melanoma cell lines as a regulator of tumor growth. GPNMB is widely expressed in various tissues, where it is involved in cell differentiation, migration, inflammation/anti-inflammation, tissue regeneration, and neuroprotection. GPNMB is identified in microglia of adult rat brains, neurons and astrocytes of GPNMB transgenic (Tg) mouse brains, and motor neurons of amyotrophic lateral sclerosis (ALS) patients. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of either TYROBP (DAP12) or TREM2. TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Pathologically, the brains of NHD patients exhibit leukoencephalopathy, astrogliosis, accumulation of axonal spheroids, and remarkable activation of microglia predominantly in the white matter of frontal and temporal lobes and the basal ganglia. At present, molecular mechanisms responsible for development of leukoencephaolpathy in NHD brains remain totally unknown. Recent evidence indicates that disease-associated microglia (DAM) that cluster around amyloid plaques express high levels of GPNMB in Alzheimer's disease (AD) brains. Because microglia act as a key regulator of leukoencephalopathy in NHD brains, it is proposed that GPNMB expressed on microglia might play a protective role in progression of leukoencephalopathy possibly via active phagocytosis of myelin debris. In the present study using immunohistochemistry, we have attempted to clarify the expression of GPNMB in NHD brains, compared with AD brains. We found that microglia accumulating in the white matter express an intense GPNMB immunoreactivity in both NHD and AD brains, suggesting that the accumulation of GPNMB-immunoreactive microglia is a general phenomenon in neurodegenerative brains.

Circular RNAs (circRNAs) are recently characterized non-coding RNAs that have a closed continuous loop. CircRNAs might play important roles in the oncogenesis of several cancers. However, little is known about association between circRNAs and skin tumors. In this study, we tried to demonstrate the expression change of circ_0024169 in angiosarcoma, and to elucidate correlations between circ_0024169 expression in angiosarcoma tissues and clinical manifestation. RNA expression was evaluated by quantitative real-time PCR with TaqMan systems for circ_0024169 and linear isoform CUL5. Both relative circRNA levels (corrected for EEF1A1 levels) and circRNA levels/linear RNA expression ratio were evaluated. We found that both relative circ_0024169 levels and circ_0024169/CUL5 ratio was decreased in normal human dermal microvascular endothelial cells (HDMEC) and angiosarcoma cell line in vitro, compared to squamous cell carcinoma line. circ_0024169/CUL5 ratio was significantly reduced in angiosarcoma and pyogenic granuloma than other tumors in vivo, which were more evident than decreased relative circ_0024169 levels. On the other hand, relative circ_0024169 levels showed mild inverse correlation with the follow-up periods (duration between the first hospital visit and the last hospital visit/the date of death) of angiosarcoma patients. Taken together, circ_0024169/CUL5 ratio are likely to be useful as a diagnostic biomarker for vascular tumors, whereas circ_0024169 levels may have more potential as a prognostic marker of angiosarcoma. The future studies of the function of circRNAs may lead to the clarification of detailed mechanism of oncogenesis of angiosarcoma.

Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by repetitive episodes of transient hemiplegia. Although autonomic nervous system dysfunction is believed to be associated with AHC, there are no reports of heart rate variability (HRV) in patients with AHC. In the current study, we analyzed HRV in a 20-year-old female with this disorder. The frequency of paralytic attacks have decreased since the patient was a teenager, compared to when she was < ten years old; however, as a 20-year-old, she still experiences paralytic attacks several times per month to more than ten times per month. Thus far, she has only suffered paralytic attacks and no epileptic seizures. Using Sanger sequencing, Gly947Arg (2839G>A) in the sodium-potassium (Na⁺/K⁺)-ATPaseα3 subunit gene (ATP1A3) was confirmed from her blood sample. An elevated heart rate lasting one to two minutes and sometimes longer, was primarily observed at night while the patient was sleeping. Large fluctuations in HRV, including low- and high- frequency components, were primarily observed while the patient was sleeping but suppressed during paralytic attacks. These results confirm the presence of an autonomic nervous system disorder in AHC. Because large variation of the autonomic nervous function was observed at night, the pathophysiological function should be investigated for 24 hours.

Skull base pseudotumors, or tumefactive fibroinflammatory lesions (TFIL), are tumors characterized by local destruction with benign histopathology. Treatment includes surgery and steroids with varying degrees of symptom relief. A 45-year-old female presented with right otorrhea and middle ear effusion, which progressed to CN V3 pain/numbness, trismus, headache, and autophony. MRI showed a diffuse infiltrating mass in the right infratemporal region involving the trigeminal ganglion. Biopsy revealed benign fibromuscular and adipose tissue with lymphoplasmacytic infiltrate, giving a diagnosis of TFIL. Resection would be very difficult given tumor location. Initial treatment included an extended course of steroids without response, and interval disease progression. Two courses of rituximab 375 mg/m² weekly × 4 given 3 months apart were then completed with excellent tolerance. With sixteen months following induction, the patient reports minimal symptoms with radiographic findings confirming continued disease regression. Rituximab is a potential treatment option for patients with TFIL without response to steroids.

Titin (TTN) is a large gene with 363 exons that encodes a large abundant protein (longest known polypeptide in nature) that is expressed in cardiac and skeletal muscles. TTN has an important role in the sarcomere organization, assembly of muscles, transmission of the force at the Z-line, passive myocyte stiffness, and resting tension maintenance in the I-band region. Mutation in extreme C terminus of TTN, situated at the end of M-band of the TTN in chromosome 2q31, results in tibial muscular dystrophy (TMD), also called Udd Distal Myopathy, which is an autosomal dominant distal myopathy. In this article, we report a novel mutation in TTN gene in a Saudi patient with bilateral facial weakness and scapular winging. This report adds to the literature a heterozygous missense variant c.85652C>G, p.(Pro28551Arg) in TTN gene, which may be related to genes that cause the disease, but more case validation is needed. The novel mutation described in the present study widened the genetic spectrum of TTN-associated diseases, which may benefit studies addressing this disease in the future.

Hypogenesis or agenesis of right hepatic lobe is a rare abnormality and is generally associated with gallbladder and biliary tract abnormalities. Cases of biliary injury following cholecystectomy have been reported in patients with agenesis of right hepatic lobe because the anatomical anomalies complicate the surgical approach. We report a case of laparoscopic cholecystectomy in a patient with hypogenesis of right hepatic lobe. A 92-year-old male patient was admitted to our hospital with fever and right lower abdominal pain with suspected acute appendicitis. Abdominal computed tomography revealed gallstones with acute cholecystitis and hypogenesis of right hepatic lobe. He underwent laparoscopic cholecystectomy with the left semilateral decubitus position. The patient's postoperative course was uneventful. In conclusions, some patients with liver lobe hypoplasia do not present with the typical symptoms of acute cholecystitis due to dislocation of the gallbladder. The left semilateral decubitus position with modified placement of port sites is useful for laparoscopic cholecystectomy in patients with hypogenesis of right hepatic lobe.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility and blue sclerae, which are mainly caused by a mutation of the COL1A1 or COL1A2 genes that encode type I procollagen. Mutations in the splice site of type I collagen genes are one of the mutations that cause OI and usually lead to a mild or moderate OI phenotype. A heterozygous A to G point mutation in intron 9 at the -2 position of the splice receptor site of COL1A1 was identified in a family with type I or IV OI. Three affected individuals in four generations of one family all presented with several clinical symptoms. They all had pectus carinatum, flat feet, gray-blue sclerae, and normal stature, teeth, hearing, and vision. Forearm fractures, small joint dislocations, and muscle weakness were all present in the patient's father and grandmother, who presented with a moderate type IV phenotype. The 10-year-old proband with type I OI had suffered a fracture twice, but had no history of joint dislocation or skin hyperextensibility. Charting the family helped to identify clinical symptoms in patients with mutations at the N-terminal of type I collagen genes.

Goldston syndrome (GS) is a rare association of Dandy-Walker malformation (DWM) and cystic renal dysplasia with or without hepatic fibrosis. It is considered to be a milder variant of Meckel Gruber syndrome (MGS) and shares features with Miranda syndrome. We reported a 22 day old infant with DWM and autosomal recessive polycystic kidney disease (ARPKD) who presented with cholestasis and acholic stools. Ultrasonography and magnetic resonance cholangiopancreatography (MRCP) confirmed the diagnosis of congenital hepatic fibrosis (CHF). The child improved with supportive treatment. CHF is a rare condition which may present as a syndromic association.

In addition to difficulties with treatment and expenses, patients with rare diseases in China greatly lack social support. In around 2000, Chinese patients with rare diseases and their families began to organize a series of charitable activities such as medical aid, public education, and policy advocacy. After nearly 20 years, organizations for Chinese patients with rare diseases have progressed. Many problems still remain, including a relatively small number of organizations, a low level of specialization, a lack of stability, limited social influence, and limited access to social resources. In order to spur the development of Chinese rare disease patient organizations, public education needs to be enhanced, policy support is needed, teams need to be created, and communication and cooperation need to be enhanced.

Testicular germ cell tumors (TGCTs) are the most frequent solid malignant tumors in men 20-34 years of age and the most frequent cause of death from solid tumors in this age group. In addition, the incidence of these tumors has significantly increased over the last few decades. Testicular germ cell tumors are classified into seminoma and nonseminoma germ cell tumors (NSGCTs). NSGCTs can be further divided into embryonal carcinoma, Teratoma, yolk sac tumor, and choriocarcinoma. There are noteworthy differences about therapy and prognosis of seminomas and nonseminoma germ cell tumors, even though both share characteristics of the primordial germ cells (PGCs). Many discovered biomarkers including HMGA1, GPR30, Aurora-B, estrogen receptor β, and others have given further advantage to discriminate between histological subgroups and could represent useful molecular therapeutic targets.