Primordial dwarfism (PD) refers to a group of monogenic genetic disorders characterized by intrauterine growth restriction (IUGR) and severe, persistent postnatal growth retardation. These diseases have been associated with variants of multiple genes whose products are mainly involved in critical cellular biological processes such as maintenance of genomic stability, DNA damage repair, mRNA splicing regulation, and centrosome function. Variants of such genes can directly impair cell proliferation and developmental potential. With the widespread application of molecular genetic technologies such as high-throughput sequencing, significant progress has been made in the research of PD. This article focuses on the major subtypes of PD, including Seckel syndrome, Microcephalic osteodysplastic primordial dwarfism (MOPD) types I/III, MOPD type II, and Meier-Gorlin syndrome. It has systematically summarized the advances in their clinical phenotypic characteristics, pathogenic genes, and molecular mechanisms, with an aim to deepen the understanding of the essence of growth disorders associated with PD.
Humans ; Dwarfism/genetics* ; Microcephaly/genetics* ; Phenotype ; Fetal Growth Retardation/genetics* ; Osteochondrodysplasias/genetics* ; Growth Disorders ; Micrognathism ; Patella/abnormalities* ; Congenital Microtia

Distal vaginal agenesis (DVA) is a rare form of female genital tract malformation that presents as cryptomenorrhea. It results from the failure of the urogenital sinus to form the caudal portion of the vagina. Through a thorough history, physical examination and appropriate imaging studies, an accurate diagnosis is integral in selecting the correct intervention for the patient. This is a case of distal vaginal agenesis in a 10-year-old nulligravid, who presented with fecal retention from an abdominopelvic mass. The patient had no bowel movement for four days, and abdominal enlargement. On inspection, there was a 12.0cm x 10.0cm palpable abdominal mass. Inspection of the external genitalia, the introitus appeared concave, with no appreciable introital opening. On digital rectal examination, an anterior bulge was palpated 0.5 cm from the anal verge. A pull-through vaginoplasty was performed with an unremarkable post-operative course. The patient was discharged with a patent vagina and resolution of her gastrointestinal symptoms. On follow-up, the patient had monthly menstruation after surgery with no recurrence of her gastrointestinal symptoms.

OBJECTIVE: To explore the clinical features, genetic characteristics in a child with Miller-McKusick-Malvaux syndrome (3MS) type 1 caused by CUL7 gene variant. METHODS: A child diagnosed with 3MS type 1 at the Children's Hospital Affiliated to Zhengzhou University in February 2021 was selected as the subject of this study. Peripheral blood samples were collected from the child and her parents for genomic DNA extraction. Whole exome sequencing (WES) was performed on the child, and Sanger sequencing was used to validate the candidate variants and analyze their pathogenicity. A literature search was conducted using the keywords "3M syndrome" in the China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, and PubMed databases from inception to December 2024. The clinical data of Chinese children with 3MS reported in the literature were summarized. This study was approved by the Medical Ethics Committee of the Children's Hospital Affiliated to Zhengzhou University (Ethics No. 2024-K-020). RESULTS: The child was a 6-year-old and 2-month-old female with facial dysmorphism, skeletal abnormalities, and growth and developmental delay. WES revealed compound heterozygous variants in the CUL7 gene: c.2686G>T (p.E896*) and c.1200delT (p.R401Gfs66). Sanger sequencing confirmed that these two variants were inherited from the child's father and mother, respectively. According to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants, c.2686G>T (p.E896) was classified as a pathogenic (PVS1+PM2_Supporting+PM3), and c.1200delT (p.R401Gfs*66) was classified as a likely pathogenic (PVS1+PM2_Supporting). Based on the literature search strategy, 18 relevant articles were identified, including a total of 32 Chinese cases of 3MS, of which 8 were fetuses. A total of 32 Chinese 3MS cases were included in the literature review, of which 8 were fetuses. The majority of these cases carried variants in the CUL7 gene (20/32, 62.5%) and OBSL1 gene (12/32, 37.5%). The main clinical manifestations included intrauterine or postnatal growth and developmental delay (32/32, 100.0%), triangular facies (27/32, 84.3%), and skeletal abnormalities (21/32, 65.6%). CONCLUSION The compound heterozygous variants c.2686G>T (p.E896*) and c.1200delT (p.R401Gfs*66) in the CUL7 gene are likely the genetic cause of 3MS type 1 in the child. For children presenting with facial dysmorphism, skeletal abnormalities, and intrauterine or postnatal growth and developmental delay, 3MS should be considered as a differential diagnosis.
Humans ; Cullin Proteins/genetics* ; Female ; Child ; Limb Deformities, Congenital/genetics* ; Exome Sequencing ; Mutation ; Child, Preschool ; Dwarfism ; Muscle Hypotonia ; Spine/abnormalities*

OBJECTIVE: To explore the genetic characteristics of a fetus affected with Structural heart defects and renal anomalies syndrome (SHDRA). METHODS: A pedigree with SHDRA (fetus and the parents) who had visited the Affiliated Women and Children's Hospital of Ningbo University in April 2023 was selected as the study subject. Clinical data of the family were collected. A total of 10 mL of amniotic fluid cells from the fetus and 5 mL of peripheral blood samples from the parents were collected for genomic DNA extraction. Trio whole-exome sequencing (Trio-WES) was performed, and Sanger sequencing was used to validate candidate variants in the family. The identified variants were classified according to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as the "ACMG Guidelines). Relevant research literature on SHDRA in domestic and international databases were searched for literature review. This study was approved by the Affiliated Women and Children's Hospital of Ningbo University (Ethics No. EC2023-094). RESULTS: In this family, prenatal ultrasound at 18 weeks of gestation revealed left renal multicystic dysplasia in the fetus. After birth, the infant exhibited an ostium secundum atrial septal defect, patent ductus arteriosus, and left renal multicystic dysplasia. Trio-WES revealed that the fetus had carried c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) compound heterozygous variants in the TMEM260 gene, which were respectively inherited from its father and mother. According to the ACMG guidelines, the c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) variants were classified as pathogenic (PM2_Supporting+PVS1+PP4) and likely pathogenic (PM2_Supporting+PM4+PM3+PP4), respectively. According to the literature search strategy set for this study, a total of 6 literature was retrieved, involving 25 SHDRA patients from 20 families. Together with the patients in this study, there were 14 TMEM260 gene variants, most of which were frameshift variants (7 types) and had located in exons 3, 11 and 13. The main clinical features of SHDRA were congenital heart malformation, renal abnormality and neurodevelopmental abnormality, and there was a lack of genotype-phenotype correlation. CONCLUSION The c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) variants of the TMEM260 gene probably underlay the SHDRA in this family. Above finding has provided a basis for clinical diagnosis and genetic counseling for the family.
Humans ; Female ; Pedigree ; Membrane Proteins/genetics* ; Male ; Heart Defects, Congenital/genetics* ; Kidney/abnormalities* ; Pregnancy ; Adult ; Kidney Diseases/congenital* ; Exome Sequencing ; Mutation ; Genetic Testing

OBJECTIVE: To assess the diagnostic value of whole exome sequencing (WES) for fetuses undergone induced abortion due to structural abnormalities. METHODS: A retrospective analysis was carried out on 43 aborted fetuses with negative results for copy number variation (CNV) testing from January 2023 to June 2024 at Northwest Women's and Children's Hospital. Trio-WES was carried out on the tissues from the aborted fetuses. This study has been approved by the Ethics Committee of the Hospital (Ethics No. 21-036). RESULTS: Among the 43 abortic fetuses, WES has detected pathogenic variants in 15 cases, with a total of 9 pathogenic variants, 5 suspected pathogenic variants, and 5 variants of uncertain significance. No definite pathogenic variants were detected in the remaining 28 cases. CONCLUSION For fetuses with structural abnormalities and negative results from CNV testing, WES can increase the diagnostic rate and facilitate etiological diagnosis and genetic counseling.
Humans ; Female ; Exome Sequencing/methods* ; Pregnancy ; DNA Copy Number Variations/genetics* ; Retrospective Studies ; Adult ; Prenatal Diagnosis/methods* ; Abortion, Induced ; Fetus/abnormalities* ; Congenital Abnormalities/diagnosis* ; Genetic Testing ; Aborted Fetus/abnormalities*

Congenital musculoskeletal and limb deformities (CMLD) seriously affect the physical and mental health of patients, and pose great challenges to healthcare systems worldwide. We explored the specific situation and changes of incidence, prevalence, disability-adjusted life years rates, and mortality of CMLD in under-5 children from 1990 to 2021 in different groups, including different regions, periods, genders and socio-demographic indices (SDI), through corresponding analytical models. Overall, the global disease burden of CMLD in under-5 children has decreased from 1990 to 2021. The disease burden of CMLD in under-5 children varied significantly among different regions and countries, and there was a strong correlation between the corresponding burden of disease and the level of SDI. In addition, cross-country inequality analysis showed that while absolute inequalities in the disease burden of CMLD in under-5 children have improved, relative inequalities have worsened. It is essential to reduce the global health impact of CMLD by implementing targeted interventions to improve health care in underdeveloped areas.
Humans ; Global Burden of Disease/trends* ; Child, Preschool ; Global Health/statistics & numerical data* ; Infant ; Male ; Prevalence ; Limb Deformities, Congenital/mortality* ; Musculoskeletal Abnormalities/mortality* ; Female ; Disability-Adjusted Life Years ; Incidence ; Infant, Newborn ; Cost of Illness ; Socioeconomic Factors

Human cytomegalovirus (HCMV) poses a significant risk of neural damage during pregnancy. As the most prevalent intrauterine infectious agent in low- and middle-income countries, HCMV disrupts the development of neural stem cells, leading to fetal malformations and abnormal structural and physiological functions in the fetal brain. This review summarizes the current understanding of how HCMV infection dysregulates the Wnt signaling pathway to induce fetal malformations and discusses current management strategies.
Humans ; Cytomegalovirus Infections/virology* ; Wnt Signaling Pathway ; Pregnancy ; Female ; Cytomegalovirus/physiology* ; Pregnancy Complications, Infectious/virology* ; Congenital Abnormalities/virology* ; Animals

OBJECTIVE: To explore the corrective strategies and effectiveness of osteotomy surgery for severe lower limb deformities in hypophosphatemic rickets. METHODS: A retrospective analysis was conducted on 29 patients with severe lower limb deformities of hypophosphatemic rickets who underwent surgical treatment between February 2012 and August 2024. There were 9 males and 20 females. The age ranged from 13 to 53 years, with an average of 24.6 years. All patients were deformities of both lower limbs, presenting as 24 cases of O-shaped legs, 2 cases of wind-blown deformities, and 3 cases of X-shaped legs. Based on the full-length films of both lower limbs in the standing position before operation, the osteotomy planes of the femur, tibia, and fibula were designed. Among them, if both the same-sided thigh and leg were deformed, staged surgeries of both lower limbs were selected. If only the thigh or leg were deformed, simultaneous surgeries of both lower limbs were selected. The femur deformity was corrected immediately after osteotomy at the deformed plane; the osteotomy fragment was temporarily controlled with an external fixator, which was removed after perform internal fixation with a steel plate. After fibular osteotomy, the Ilizarov frame or Taylor frame was installed on the tibia and fibula. The threaded rods were removed and then tibial osteotomy was performed on the deformed plane. Patients using the Taylor frame did not undergo deformity correction during operation. The external fixators were adjusted starting 7 days after operation to correct the varus, valgus, and rotational deformities of the lower limb. Patients using the Ilizarov frame corrected the rotational deformity of the tibia during operation. The external fixator was adjusted starting 7 days after operation to correct the varus and valgus deformities of the lower limb. During the treatment period, the patient could walk with partial weight-bearing on the operated limb with crutches. The external fixator was removed after the bone healed. Before operation and at last follow-up, the medial proximal tibial angle (MPTA), lateral distal tibial angle (LDTA), posterior proximal tibial angle (PPTA), anterior distal tibial angle (ADTA), anatomic lateral distal femoral angle (aLDFA), posterior distal femoral angle (PDFA), and mechanical axis deviation (MAD), lower limb rotation, limb length discrepancy (LLD) were measured. The self-made scoring criteria were adopted to evaluate the degree of lower limb deformity of the patients. RESULTS: All operations were successfully completed, and no complications such as nerve or vascular injury occurred. The adjustment time of the external fixator of the lower limb after operation was 28-46 days, with an average of 37.4 days. The wearing time of the external fixator ranged from 134 to 398 days, with an average of 181.5 days. Mild pin tract infections occurred in 2 limbs. The osteofascial compartment syndrome occurred in 1 limb after operation. No complications related to orthopedic adjustment of the external fixator occurred in other patients. All patients were followed up 6-56 months, with an average of 28.2 months. At last follow-up, full-length films of both lower limbs in the standing position showed that the coronal mechanical axes of the lower limbs of all patients returned to the normal. At last follow-up, MPTA, LDTA, PPTA, aLDFA, PDFA, MAD, lower limb rotation, LLD, and the score of lower limb deformity significantly improved when compared with those before operation ( P<0.05). There was no significant difference in ADTA between pre- and post-operation ( P>0.05). The degree of lower limb deformity were rated as moderate in 2 cases and poor in 27 cases before operation and as excellent in 7 cases, good in 18 cases, and moderate in 4 cases at last follow-up, with an excellent and good rate of 86.2%. CONCLUSION For severe lower limb deformities in hypophosphatemic rickets, immediate correction of deformities with femoral osteotomy and internal plate fixation, as well as gradually correction of deformities with tibiofibular osteotomy and circular external fixation (Ilizarov frame or Taylor frame), have satisfactory therapeutic effects.
Humans ; Male ; Osteotomy/instrumentation* ; Female ; Adult ; Retrospective Studies ; Tibia/abnormalities* ; Adolescent ; Femur/abnormalities* ; Middle Aged ; Fibula/surgery* ; Rickets, Hypophosphatemic/complications* ; Young Adult ; Treatment Outcome ; External Fixators ; Bone Plates ; Lower Extremity Deformities, Congenital/etiology*

OBJECTIVE: To evaluate the functional and aesthetic evaluation of external fixator lengthening through plantar approach for fourth brachymetatarsia. METHODS: A retrospective analysis was conducted on 20 patients (23 feet) with fourth brachymetatarsia who met the selection criteria between January 2016 and January 2024, including 3 males and 17 females, with 8 left, 9 right, and 3 bilateral cases. The mean age was 24.7 years (range, 14-51 years). The preoperative metatarsal shortening length was (13.8±3.2) mm. The preoperative American Orthopaedic Foot and Ankle Society (AOFAS) forefoot score was 79.5±3.9, the visual analogue scale (VAS) score of appearance satisfaction was 1.7±0.8, and the appearance index (AI) score was 13.6±0.9. All patients underwent external fixator lengthening through plantar approach. The lengthening length of metatarsal bone, lengthening ratio, healing time, and healing index were recorded. Functional outcomes were assessed using the AOFAS forefoot score, VAS score of appearance satisfaction, and quality-of-life impact with AI questionnaire. RESULTS: All 20 patients were followed up 14-55 months with an average of 36.3 months. During the follow-up, complications occurred in 4 cases (17.4%), including 2 cases of metatarsophalangeal joint stiffness, which had no significant effect on the function and appearance. Delayed union of osteotomy occurred in 1 case (healed at 12 weeks after operation). Pin loosening occurred in 1 case and recovered after outpatient reinforcement. No complications related to plantar scar occurred. At last follow-up, the lengthening length of metatarsal bone was (13.9±3.1) mm, and the lengthening ratio was 25.8%±5.6%. All cases achieved bony union, with a mean healing time of (64.3±12.5) days and a healing index of (46.9±4.8) d/cm. At last follow-up, AOFAS score was 98.9±2.1, the VAS score of appearance satisfaction was 9.3±0.7, and the AI score was 0.6±0.8, which significantly improved when compared with those before operation ( t=27.398, P<0.001; t=32.994, P<0.001; t=56.135, P<0.001). CONCLUSION External fixator lengthening through plantar approach is a safe and effective technique for fourth brachymetatarsia, achieving satisfactory functional and aesthetic outcomes.
Humans ; Male ; Female ; Adult ; External Fixators ; Retrospective Studies ; Bone Lengthening/instrumentation* ; Middle Aged ; Metatarsal Bones/abnormalities* ; Adolescent ; Young Adult ; Treatment Outcome ; Patient Satisfaction ; Esthetics ; Osteotomy/methods* ; Foot Deformities, Congenital/surgery*

OBJECTIVES: To study the incidence and disease burden of congenital birth defects in children under five in China from 1990 to 2021 and to predict the incidence of congenital birth defects in this population from 2022 to 2036, providing a reference for the prevention of congenital birth defects in children. METHODS: Using the Global Burden of Disease Study 2021 (GBD 2021) database, the incidence and disability-adjusted life years (DALY) were employed to describe the disease burden. The Joinpoint regression model was used to analyze the trends in incidence and DALY rates of congenital birth defects in children under five. A grey prediction model GM(1,1) was applied to fit the trend of incidence rates of congenital birth defects in this age group and to predict the incidence from 2022 to 2036. RESULTS: In 2021, the incidence rate of congenital birth defects among children under five in China was 737.28 per 100 000. Among these, congenital musculoskeletal and limb deformities had the highest incidence rate at 307.15 per 100 000, followed by congenital heart defects (223.53 per 100 000), congenital urinary and genital tract malformations (74.99 per 100 000), and congenital gastrointestinal malformations (62.61 per 100 000). From 1990 to 2021, the incidence rate and DALY rate of congenital birth defects in children under five in China decreased at an average annual rate of 1.73% and 5.42%, respectively. The prediction analysis indicated a decreasing trend in the incidence of congenital birth defects among children under five in China from 2022 to 2036, with the incidence rate dropping from 892.36 per 100 000 in 2022 to 783.35 per 100 000 in 2036. CONCLUSIONS The incidence and disease burden of congenital birth defects in children under five in China showed a significant declining trend from 1990 to 2021. It is predicted that this incidence will continue to decrease until 2036.
Humans ; Congenital Abnormalities/epidemiology* ; China/epidemiology* ; Incidence ; Infant ; Infant, Newborn ; Child, Preschool ; Female ; Male ; Forecasting ; Disability-Adjusted Life Years