Expert consensus on the clinical diagnosis and management of Congenital brachydactyly (2025 Edition)

Brachydactyly type E (BDE) is characterized by variable shortening of metacarpals or metatarsals, often involving phalanges. It may occur as an isolated anomaly or as part of congenital syndromes. With advancements in molecular diagnostic technologies, how genetic testing enhances the precise diagnosis of BDE remains unclear. Our aims were to establish an algorithm for molecular genetic diagnostics in Chinese children with BDE and to explore the phenotype-genotype correlations of Chinese patients with BDE. We reviewed left-hand wrist X-rays from children visiting Children's Hospital of Soochow University (Jun 2021-Dec 2023). From 60,650 films, 135 BDE cases were identified, and their comprehensive phenotypes were collected. Whole-exome sequencing (WES) with copy number variation (CNV) analysis was performed on 60 patients and their parents. Sanger sequencing was used to validate single nucleotide variants (SNV) and indels. Causative variants were found in 19 patients. SNVs and indels affecting 10 genes were identified in 15 patients, and CNVs in four. GNAS mutations were the leading cause (four cases), followed by EXT1 and ACAN defects. The diagnostic yield was 19.1% in patients with isolated brachydactyly; 75% in patients with brachydactyly combined with short stature; 77.8% in patients with brachydactyly combined with facial dysmorphism; 83.3% in patients with brachydactyly combined with intellectual disability. Through comprehensive evaluation of genotype-phenotype correlations, we propose a diagnostic algorithm for precise molecular diagnosis in Chinese children with BDE.

Brachydactyly (BD) is a type of hand/foot malformation caused by the abnormal shortening or missing phalanges and/or metacarpals/metatarsals. BD most often occurs as an isolated trait, but can also occur as part of complex malformation syndromes. According to the patterns of affected digits, isolated BD can be divided into five groups: BDA, BDB, BDC, BDD, and BDE with individual subtypes. As an important molecular disease family, the pathogenic genes and molecular mechanisms of most isolated BD forms and some complicated syndromes are elucidated. Although BDs are highly diversified in phenotypes, at the molecular levels these pathogenic genes mainly affect several important signaling pathways: Hedgehog, NOTCH, WNT and BMP. These pathways form a complex signaling network and play different roles in different stages of the digit and joint development, in which BMP signaling pathway occupies a central position. Based on the current classification of BDs, this review summarizes the latest progress in the pathogenesis of BDs and the signaling pathways involved. The purpose of this review is to explore the molecular mechanisms of digit formation, which will provide references for the clinical diagnosis of BD, and the understanding of molecular mechanism of human bone development.

Objective To analyze the disease constitution, accuracy of clinical and pathological diagnoses of skin biopsy samples in Peking Union Medical College Hospital. Methods A total of 29 987 patients subjected to skin biopsy were collected from Department of Dermatology, Peking Union Medical College Hospital from June 2010 to November 2018, and clinical and histopathological diagnoses of these skin biopsy samples were analyzed retrospectively. Results According to the results of histopathological diagnosis, confirmed diagnoses of these patients could be classified into 33 categories and 242 kinds. Common disease categories included epidermal tumors (2 931 cases, 9.77%) , connective tissue diseases (2 809 cases, 9.37%) , melanocytic tumors (2 078 cases, 6.93%) , erythematous scaly pustular dermatoses (1 376 cases, 4.59%) , lichenoid dermatoses (1 291cases, 4.31%) , allergic or eczematous skin diseases (1 282 cases, 4.28%) and infectious skin diseases (1 156 cases, 3.86%) . Common skin diseases included scleroderma (1 887 cases, 6.29%) , pigmented nevus (1 755 cases, 5.85%) , seborrheic keratosis (1 136 cases, 3.79%) , eczema (1 089 cases, 3.63%) , psoriasis (881 cases, 2.94%) , lichen planus (867 cases, 2.89%) , lupus erythematosus (638 cases, 2.13%) , pemphigus (549 cases, 1.83%) , and basal cell carcinoma (501 cases, 1.67%) . Poor consistency was observed between clinical diagnosis and histopathological diagnosis of lichen planus, bullous pemphigoid, granuloma annulare and hypereosinophilic dermatitis. Conclusions Common disease categories of the skin biopsy samples in Peking Union Medical College Hospital were epidermal tumors, connective tissue diseases, melanocytic tumors, erythematous scaly pustular dermatoses, lichenoid dermatoses, and allergic or eczematous skin diseases. Poor consistency was observed between clinical and pathological diagnosis in some skin diseases, and understanding of these diseases should be improved. Key words: Biopsy; Connective tissue diseases; Nevi and melanomas; Skin diseases, papulosquamous; Lichenoid eruptions; Skin diseases, eczematous

Citation:Zhang XL, Xiao Y. Sleep health service in China during the COVID-19 outbreak. J Clin Sleep Med. 2020;16(7):1221–1222.

Objective To investigate the prevalence and possible factors of hypouricemia in Peking Union Medical College Hospital. Methods A retrospective investigation. Serum uric acid, lipids, glucose and other chemistry tests were analyzed among 83176 outpatients (Male: 30795, Female: 52381), 15849 inpatients (Male: 7402, Female: 8447) and 24081 healthy subjects (Male: 11859, Female: 12222) in Peking Union Medical College Hospital from December 2015 to April 2016. Grouped by gender and age, the prevalence of hypouricemiawas analyzed in all subjects and the etiology and possible risk factors of hypouricemia were explored among all patients. Results The serum uric acid of outpatients, inpatients and healthy subjects were 286 (235-348)μmol/L, 282 (226-348)μmol/L and 298 (244-358)μmol/L, respectively. And the prevalence were 0.6%(499/83176), 2.5%(390/15849) and 0.2%(39/24081), respectively. The prevalence of hypouricemia ofwomen was significantly higher than that ofmen(outpatients: 0.7% vs 0.4%, P<0.001; inpatients: 2.8% vs 2.1%, P=0.004; healthy subjects: 0.30% vs 0.04%, P<0.001). After analyzing 507 hypouricemia patients, the top three clinical diagnoses that related with hypouricemia were kidney diseases, tumor and rheumatic diseases. Compared with the control group, the prevalence of hypouricemia in hypertriglyceridemia group and group with eGFR higher than 90 ml/(min·1.73 m2) were lower (OR: 0.33, 95% CI: 0.21-0.50; OR: 0.16, 95% CI: 0.09-0.29), and the prevalence of hypouricemia in hyperglycemia group was higher (OR: 1.62, 95% CI: 1.12-2.35). Conclusion The prevalence of hypouricemia of Chinese women was higher than that of men and may be related with TG, Glu and eGFR.(Chin J Lab Med, 2018, 41: 237-241) Key words: Kidney diseases; Uric acid; Prevalence; Risk factors

We identified and characterized a Chinese family with autosomal dominant Brachydactyly type B1 (BDB1). Linkage analysis revealed that the disease gene of the Chinese BDB1 family was linked to ROR2 locus. Mutational hot spot of ROR2 gene was amplified by polymerase chain reaction (PCR) and sequenced directly. A c.2265C>A heterozygous mutation was detected in all of the patients. This mutation led to the change of p.Y755X in protein level and a truncated ROR2 protein losing integrant domains was generated. The mutation was detected in all the patients, but not in all the normal individuals of this family and 50 normal controls. This paper for the first time reported a c.2265C>A mutation in ROR2 gene of a family with BDB1 in China, which enriches ROR2 gene mutation spectrum in Chinese with BDB1.

Background and Aims Congenital solitary kidney – one category of congenital anomalies of the kidney and urinary tract (CAKUT) may combine with other system malformations such as reproductive, cardiac, skeletal system, and so on. Our study analysed the clinical characteristics among congenital solitary kidney patients and their reproductive system malformations. And further work about probable pathogenic genes was explored. Method The information of CAKUT patients who were indicated by Doppler ultrasound was collected. The clinical and imaging features including reproductive system abnormalities were retrospectively reviewed in patients with congenital solitary kidney. In patients with Mayer-Rokitansky- Küster-Hauser (MRKH) syndrome, a disorder of congenital agenesis of uterus and vagina, whole exome sequencing was performed. Rare variants in CAKUT-related genes were analysed. Trio analysis was conducted to identify de novo mutations. Results We identified 209 patients with congenital solitary kidney from July 20, 2017 to July 19, 2020 among 1160 CAKUT patients in Peking Union Medical College Hospital. There were 152 females. The average age of congenital solitary kidney patients was 35.26±18.42 years when they were diagnosed. 53.2% showed different degrees of proteinuria and hematuria. Serum creatinine elevating was proved 13.1% and 40% in women and men separately. Among 81 females who also had a gynecological ultrasound report, 88.9% combined with genital malformation, oblique vaginal septum syndrome 48.7%, the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome 22.2%, malformed uterus 23.5%, vaginal atresia and other genital malformation 7%. Congenital heart disease, complete transposition of viscera, and scoliosis were also found in some patients with congenital solitary kidney. Furthermore, based on the whole exome data of 443 patients with MRKH syndrome, seven function-lost mutations were confirmed. And also two De nove mutations (NOTCH2 (NM_024408.3: c.703A&amp;gt;T(p.Thr235Ser), ESRRG (NM_001243512.1:c.-169-8delT)), one homozygous patients with parents heterozygous (NM_133433.3:c.8084C&amp;gt;T(p.Thr2695Me) were identified as possible pathogenic genes caused CAKUT. Conclusion We should be aware of reproductive system malformations in CAKUT patients. Whole exome sequencing may suggest common pathogenic genes between the two kinds of diseases.

Mutations in PTHLH (PTH-like hormone), cause brachydactyly type E (BDE) characterized by shortening of metacarpals, metatarsals and/or phalanges with short stature. In this report we describe three siblings and their mother with a novel heterozygous mutation c.25 T > C, p.Trp9Arg in exon 2 of the PTHLH gene. Beside the known clinical features of PTHLH mutations all had a delay in speech and language development, unknown if this is related to the mutation. Patients with PTHLH mutation may have a variable phenotypic presentation.

To improve understanding of the clinical characteristics and diagnosis of hypersensitivity pneumonitis (HP). We retrospectively analyzed the clinical data, including clinical symptoms, laboratory tests, exposure, pulmonary function tests, chest CT imaging and cytological classification of bronchoalveolar lavage (BAL) of 96 patients with HP from Jan 2001 to Jun 2011 in Peking Union Medical College Hospital. We divided the patients into 2 groups: a pathologically-confirmed group and a clinically-suspected group. There were 58 females and 41 males. The median age at the diagnosis was 53 years. The most common exposures were low-molecular-weight chemicals (42.7%) and animal proteins (37.5%). Common clinical symptoms included dyspnea on exertion (90.6%) and cough (76.0%). Pulmonary function test showed diffusion abnormality (73.5%) and restrictive ventilatory impairment (59.7%). Chest CT scan revealed patchy or diffuse bilateral ground-glass opacities (64.6%), centrilobular nodules (21.9%), and air trapping (15.6%). Reticulation (45.8%), traction bronchiectasis (21.9%) and honeycombing(9.4%) were present in chronic HP. BAL lymphocyte counts > 0.2 and CD4/CD8 < 0.9 were more commonly seen in patients with a disease course of less than 1 year. The pathologically-confirmed group and the clinically-suspected group shared many similar characteristics including age at diagnosis, gender, clinical manifestation, pulmonary function impairments and imaging findings, but significant differences existed in certain parameters. In the pathologically- confirmed group, the duration of disease was longer (24 months vs 6 months, Z = -2.492, P = 0.013) and clubbed fingers were more common (23.4% vs 8.2%, χ(2) = 4.227, P = 0.040). Diffusion abnormality was present in more patients of this group (90.7% vs 44.0%, χ(2) = 35.219, P < 0.01). By CT scan, reticulation, traction bronchiectasis and honeycombing (57.5% vs 26.5%, χ(2) = 9.434, P < 0.01) were more evident as compared to the clinically-suspected group. The value of transbronchial lung biopsy for diagnosing HP was limited, with a positive result of only 8.2%. Surgical lung biopsy was needed in uncertain cases. The diagnosis of HP was difficult. In some cases a clinical diagnosis can be made by combination of history of exposure, CT manifestations and cell classification of BAL. For atypical cases a multi-disciplinary approach including pathologists, radiologists and pulmonologists is needed.

Objective To screen the disease-causing genes in an autosomal dominant(AD)Weill-Marchesani syndrome (WMS) family from Henan province in China, and to analyze the relationship between genotypes and phenotypes of the AD WMS. Methods A family with suspected WMS was collected and studied in Henan Eye Hospital from September 2016 to July 2017.Clinical data and genomic DNA of the families were analyzed and genetic variations were screened by whole-exome sequencing (WES) The candidate genes related to ectopia lentis (FBN1, ADAMTSL2, ADAMTSL4, TGFBR2, CBS, ADAMTS10, ADAMTS17) were analyzed, and multiplex ligation dependent probe amplification (MLPA) was applied.Novel variants were further evaluated by sequencing 96 normal individuals.The previous reports with similar genetic characteristics were reviewed and the mutation types and clinical features were summarized.Written informed consent was obtained from the participants or their guardians before the collection of their venous blood and clinical data.Ethical approval was obtained from the Institutional Review Board of Henan Eye Institute. Results The suspicious mutation of the c. 5260G>A was detected in exon 42 of the FBN1 by WES in this family, which was predicted to be pathogenic and cosegregated with the disease; the clinical futures of the patients in the family included proportionate short stature, brachydactyly, joint stiffness, and the ocular problems included microspherophakia, moderate myopia, secondary glaucoma.Four mutations of FBN1 that related to WMS were reported in previous literature, and three of them were located in 41-42 exons and the others were the deletion of exons 9-11.All patients had typical clinical features of microspherophakia, short stature, brachydactyly, joint stiffness.In addition, thick skin was common, heart defects were occasional, protuberant abdomen and umbilical hernia were rarely reported. Conclusions The affected members in this family are in according with the clinical and genetic diagnosis of WMS.A novel mutation (c.5260G>A) in FBN1 is discovered, which increases the spectrum of WMS mutation.The 41-42 exons of the FBN1 are hotspot of mutation in WMS. Key words: Weill-Marchesani syndrome; FBN1 gene; Whole-exome sequencing; Phenotype

Objective To analyze the clinical characteristics of adult patients with autoinflammatory diseases (AUID) presenting as recurrent fever of unknown origin (FUO). Methods The clinical and genetic features of 51 adult patients with recurrent FUO, who were suspected of monogenic AUID admitted in adult AUID center Department of Rheumatology, Peking Union Medical College Hospital from April 2015 to March 2017, were prospectively studied. The clinical phenotypes were compared between patients with pathogenic gene mutations and diagnosed as monogenic AUID (gene-positive group), and those without pathogenic gene mutations (gene-negative group). Results Among 51 patients, there were 26 patients with positive monogenic mutations (51.0%); in addition 6 patients were diagnosed as periodic fever-aphthous stomatitis-pharyngitis-adenitis (PFAPA) syndrome. Finally 32 patients (63.0%) were diagnosed as AUID, including 11 cases of familial Mediterranean fever (34.4%), 5 cases of cryopyrin-associated periodic syndrome (15.6%), 5 cases of NLRP12-autoinflammtory disease (15.6%), 2 cases of Blau syndrome (6.3%), 2 cases of Yao syndrome (6.3%), 1 case of tumor necrosis factor-receptor associated periodic syndrome (3.1%), and 6 cases of PFAPA syndrome (18.8%). Among 25 gene-negative patients except 6 cases of PFAPA syndrome, 9 were diagnosed as other diseases, and the diagnosis of AUID was not confirmed in 10 cases (40.0%). Compared with gene-negative group, gene-positive group had more common childhood-onset (30.8% vs. 8.0%, P=0.041), longer disease duration (11.2±10.1 vs. 6.1±5.9, P=0.031), and more common abdominal pain/diarrhea (42.3% vs.12.0%, P=0.015). There were no significant differences in manifestations such as rash, arthralgia/arthritis, thoracic pain, eye inflammation and oral ulcers between two groups. One patient had family history of AUID, and finally diagnosed as Blau syndrome with NOD2 gene mutation. Conclusion AUID is one of the main causes of adult patients with recurrent FUO. Childhood-onset, long disease duration, abdominal pain/diarrhea, and family history of AUID are more common in patients with AUID pathogenic gene variations. Recognizing these symptom patterns can provide the clues, leading to the initiation of gene testing for patients with recurrent FUO. Adults patients with recurrent FUO suspected of AUID should be referred to specialist physicians in adult AUID center. Key words: Fever of unknown origin; Autoinflammatory diseases; Disease attributers

Rheumatic diseases, a typical kind of autoimmune disease, are often treated with glucocorticoids, immunosuppressants, biological agents, and small-molecule targeted drugs, which often leads to immune dysfunction in patients and increases the risk of activation of latent tuberculosis infection. To regulate the screening, diagnosis, and prophylactic treatment of latent tuberculosis infection in patients with rheumatic diseases, reduce the risk of developing active tuberculosis and improve the prognosis, Peking University Shenzhen Hospital, Shenzhen Third People's Hospital and Peking Union Medical College Hospital jointly organized domestic experts in the field of rheumatology and tuberculosis to establish the expert consensus on the diagnosis and treatment of latent tuberculosis infection in patients with rheumatic diseases. This consensus focuses on epidemiology, the importance of screening, screening methods, and prophylactic anti-tuberculosis treatment strategies for latent tuberculosis infection combined with rheumatic diseases.

Autoantibodies are important biomarkers of autoimmune diseases and crucial for disease diagnosis, differential diagnosis, and the evaluation of disease activity and prognosis. Specifying the requirement of quality control for detecting autoantibodies is essential for accurately reporting relevant results. In 2023, National Clinical Research Center for Dermatologic and Immunologic Diseases (Peking Union Medical College Hospital), Experimental Diagnosis Research Committee, Rheumatology and Immunology Physicians Committee of Chinese Medical Doctor Association, Autoantibodies Detection Committee, Chinese Rheumatism Data Center invited relevant clinical and laboratory experts to develop the current consensus based on the national standards, the industry guidelines, the national situation, and the experience of quality control regarding autoantibody detection. This consensus aims to standardize the quality control of autoantibody detection in relevant laboratories in China.

After the promulgation of the first edition of expert consensus on the application of chromosomal microarray analysis (CMA) technology in prenatal diagnosis in 2014, after 8 years of clinical and technical development, CMA technology has become a first-line diagnosis technology for fetal chromosome copy number deletion or duplication abnormalities, and is widely used in the field of prenatal diagnosis in China. However, with the development of the industry and the accumulation of experience in case diagnosis, the application of CMA technology in many important aspects of prenatal diagnosis, such as clinical diagnosis testimony, data analysis and genetic counseling before and after testing, needs to be further standardized and improved, so as to make the application of CMA technology more in line with clinical needs. The revision of the guideline was led by the National Prenatal Diagnostic Technical Expert Group, and several prenatal diagnostic institutions such as Peking Union Medical College Hospital were commissioned to write, discuss and revise the first draft, which was discussed and reviewed by all the experts of the National Prenatal Diagnostic Technical Expert Group, and was finally formed after extensive review and revision. This guideline is aimed at the important aspects of the application of CMA technology in prenatal diagnosis and clinical diagnosis, from the clinical application of evidence, test quality control, data analysis and interpretation, diagnosis report writing, genetic counseling before and after testing and other work specifications are elaborated and introduced in detail. It fully reflects the integrated experience, professional thinking and guidance of the current Chinese expert team on the prenatal diagnosis application of CMA technology. The compilation of the guideline for the application of CMA technology in prenatal diagnosis will strive to promote the standardization and advancement of prenatal diagnosis of fetal chromosome diseases in China.

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