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

OBJECTIVE: To analyze the phenotype and genotype of a neonate with Osteo-oto-hepato-enteric syndrome (O2HE) and review the literature. METHODS: A female neonate diagnosed with O2HE syndrome on December 13, 2024 at the First Affiliated Hospital of Zhengzhou University was selected as the study subject, and her clinical characteristics were analyzed, and pathogenic variants were explored by whole exome sequencing (WES). This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2025-KY-1038). RESULTS: The proband, a female infant, was delivered by Cesarean section at 36⁺¹ weeks of gestation. Five days after birth, she had developed severe diarrhea, mild cholestasis, sensorineural hearing loss, and growth retardation. WES revealed that she has harbored novel compound heterozygous variants c.512delA (p.Lys171Serfs*64) and c.698C>A (p.Thr233Asn) of the UNC45A gene, which were inherited from her mother and father, respectively. A total of 8 English papers were retrieved, which involved 16 patients from 14 families. Combined with our case, the 17 patients included 13 (76.5%) females and 4 (23.5%) males. Four patients (23.5%) had consanguineous parents. One case was excluded from further genetic analysis due to co-morbidity with other genetic variants. The primary clinical features included diarrhea (87.5%), cholestasis (81.3%), sensorineural hearing loss (31.3%), bone fragility (37.5%), and developmental delay (50.0%). Bi-allelic compound heterozygous mutations were identified in 12 patients (75.0%), and homozygous variants in 4 (25.0%). These included missense, nonsense, frameshift and deletional variants. The c.710T>C (p.Leu237Pro) variant was identified for 5 times, 3 of which were in homozygote forms. CONCLUSION O2HE syndrome should be suspected in cases with diarrhea, cholestasis, and hearing abnormalities during early postnatal period. Genetic testing facilitate early identification, genetic diagnosis and treatment.
Humans ; Female ; Infant, Newborn ; Male ; Mutation ; Hearing Loss, Sensorineural/genetics* ; Diarrhea, Infantile/genetics* ; Exome Sequencing ; Phenotype ; Fetal Growth Retardation ; Hair Diseases ; Facies

OBJECTIVE: To explore the clinical features and genetic etiology of a child with Hoyeraal-Hreidarsson syndrome (HHS). METHODS: A child with HHS diagnosed at the Affiliated Hospital of Jining Medical University due to "developmental delay and anaemia" on April 27, 2024 was selected as the study subject. Clinical data of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members. Whole-exome sequencing was carried out, and candidate variant was verified by Sanger sequencing of his family members and bioinformatics analysis using CASAVA v1.8.2. The pathogenicity of the candidate variant was rated according to the Standards and Guidelines for the Interpretation of Sequence Variants released by the American College of Medical Genetics and Genomics (ACMG). Relevant literature on HHS cases reported in China was reviewed to analyze the clinical and genetic characteristics. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2024-10-C003). RESULTS: The child, a 7-month-old boy, had mainly manifested with growth retardation, developmental delay, microcephaly, cerebellar hypoplasia, immunodeficiency and bone marrow failure. Routine blood test indicated pancytopenia. The immunological workup showed reduction of B cells, NK cells and immunoglobulins. Cranial MRI demonstrated the volume of bilateral cerebellar hemispheres and brainstem and corpus callosum was small. Whole-exome sequencing revealed that he has harbored a hemizygous c.103_105del (p.Glu35del) variant of the DKC1 gene. Sanger sequencing showed that his mother and two sisters have carried the same variant. Based on the ACMG guidelines, the variant was predicted to be likely pathogenic (PM1+PM4+PS4_Supporting+PM2_Supporting). Four relevant literature were retrieved, which has involved 8 HHS cases. Together with the patient from this study, they have consisted of 8 males and 1 females. The most common symptoms of the 9 patients were blood system abnormalities and developmental delay. All patients had shown cerebellar dysplasia and anemia/erythrocytopenia. Among them, 3 cases have harbored TINF2 gene variants, and 6 cases had harbored DKC1 gene variants. The c.103_105del variant has not been reported in China previously. CONCLUSION The hemizygous c.103_105del (p.Glu35del) variant of the DKC1 gene probably underlay the disease in this child. Above finding has expanded the mutational and phenotypic spectra of the DKC1 gene, and has facilitated early diagnosis of HHS in this child.
Humans ; Infant ; Male ; Cell Cycle Proteins/genetics* ; Dyskeratosis Congenita/genetics* ; Exome Sequencing ; Fetal Growth Retardation/genetics* ; Intellectual Disability/genetics* ; Microcephaly/genetics* ; Mutation ; Nuclear Proteins/genetics* ; X-Linked Intellectual Disability/genetics*

OBJECTIVE: To carry out pathological and genetic analyses on a fetus with intrauterine growth restriction and death during second trimester after induced abortion. METHODS: A fetus undergone induced abortion due to intrauterine growth restriction and death during second trimester at the the Seventh Affiliated Hospital of Sun Yat-Sen University in 2024 was selected as the study subject. Clinical data of the pregnancy were collected. DNA was extracted from tissues from the aborted fetus and peripheral blood samples from its parents. Chromosomal microarray analysis and whole exome sequencing were carried out. Candidate variants were verified by Sanger sequencing. Following abortion, routine autopsy and pathological analysis were conducted. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: KY-2025-334-01). RESULTS: The aborted fetus was a male and harbored compound heterozygous nonsense variants of the TH gene (c.457C>T/p.Arg153* and c.694C>T/p.Gln232*), for which both parents were heterozygous carriers. Autopsy and pathological analysis revealed that the fetus had pathological features including loose arrangement of myocardial fibers and congestion in the liver. CONCLUSION Biallelic null variants of the TH gene may cause heart failure by affecting the development of cardiovascular system, which in turn may lead to intrauterine death. This study has provided new clues for the molecular diagnosis of stillbirth and recurrent pregnancy loss.
Humans ; Female ; Pregnancy ; Male ; Heterozygote ; Codon, Nonsense/genetics* ; Fetal Growth Retardation/pathology* ; Adult ; Stillbirth/genetics*

MIRAGE syndrome is a rare autosomal dominant disorder caused by gain-of-function mutations of the SAMD9 gene. Its typical clinical manifestations include myelodysplasia, intrauterine growth restriction, adrenal hypoplasia, genital abnormalities, and enteropathy. The gain-of-function toxicity of the SAMD9 gene and subsequent somatic revertant mutations have been identified as the core molecular mechanisms underlying the multi-system phenotypes and clonal hematopoietic evolution in this disease. The specific genotypic background and tissue-specific distribution of somatic revertant mutations collectively constitute the genetic basis for its significant clinical heterogeneity. In recent years, important breakthroughs have been made in research on the pathogenesis, phenotypic expansion, molecular diagnosis, and targeted therapy of the MIRAGE syndrome. This article has systematically reviewed the latest progress made in the research on the etiology, clinical manifestations, diagnosis, and treatment of this disease.
Humans ; Mutation ; Fetal Growth Retardation/therapy* ; Myelodysplastic Syndromes/therapy* ; Intracellular Signaling Peptides and Proteins/genetics*

Chorangiosis is a placental vascular abnormality characterized by excessive capillarization in terminal chorionic villi, often associated with chronic placental hypoxia. It is observed in 5%–7% of placentas from neonates admitted to neonatal intensive care units and correlates with adverse maternal and fetal outcomes. We report a case of a chorangiosis of the placenta revealed in an 18-year-old primigravida who presented with moderate anemia, fetal growth restriction, oligohydramnios, and underwent elective cesarean section at 36 + 5 weeks. Chorangiosis has been linked to adverse outcomes, including stillbirth and maternal morbidity. This case highlights the importance of considering chorangiosis in the differential diagnosis of placental lesions with atypical ultrasound features. Early recognition, close fetal surveillance, and timely delivery are crucial for optimizing perinatal outcomes in such scenarios.
Chorangioma ; Hemangioma ; Fetal Growth Retardation ; Hypoxia

Objective: The objective of this study was to evaluate and compare the global cardiac sphericity index (GCSI) of appropriate for gestational age (AGA) fetuses, small for gestational age (SGA) fetuses, and growth-restricted fetuses scanned at term in a government tertiary hospital, maternal high risk (MHR) and to determine the association between the GCSI of these three groups of fetuses and their neonatal outcomes. Methodology: The study prospectively evaluated and compared the GCSI of AGA, SGA, and growth-restricted fetuses. Pregnant women at term seen at the outpatient department and scanned at the MHR clinic then eventually delivered in the same hospital from March to May 2022 were included in this study. Results: GCSIs were measured with 147 fetuses (106 AGA, 38 SGA, and 3 growth‑restricted fetuses). The result indicated that the GCSI of AGA fetuses was higher than that of the SGA and growth‑restricted fetuses. This study found that there is a significantly higher frequency of abnormal GSCI among SGA and growth‑restricted fetuses. This study also found that there is no statistically significant correlation between the GCSI measurements of these three groups of fetuses and their neonatal outcomes. Conclusions Abnormal GCSIs were found in fetuses with an estimated fetal weight <10th percentile (more specifically in growth‑restricted fetuses than in those who are just SGA) as compared with AGA fetuses. However, the correlation between an abnormal GCSI in any of these three groups of fetuses and their neonatal outcomes needs further investigation.
Fetal Growth Retardation

The incidence of perinatal disease and perinatal mortality in small for gestational age infants increased significantly. This group of people is prone to a variety of long-term metabolic diseases and cardiovascular diseases, and is also prone to growth retardation and neurodevelopmental delay, which will seriously affect the long-term quality of life of children. The article studies the neurodevelopmental outcomes of small-for-gestational-age infants. By reviewing and sorting out previous literature, the neurodevelopmental disorders of small-for-gestational-age infants are analyzed according to five aspects: intellectual development, motor development, language development, sensory development, and mental illness. The classification and summary were carried out, and the influencing factors of neurodevelopmental disorders of SGA were also evaluated, so as to provide reference for promoting the improvement of neurodevelopmental outcomes of small-for-gestational-age infants.
Infant, Newborn ; Pregnancy ; Female ; Child ; Infant ; Humans ; Gestational Age ; Quality of Life ; Infant, Small for Gestational Age ; Fetal Growth Retardation/epidemiology*

Objective: To retrospectively analyze the clinical data of different types of selective intrauterine growth restriction (sIUGR) pregnant women under expectant management, including the natural evolution, typing conversion and perinatal outcomes. Methods: The clinical data of 153 pregnant women with sIUGR under expected treatment in Women's Hospital, Zhejiang University School of Medicine from January 2014 to December 2018 were collected. Maternal characteristics including maternal age, gravidity, parity, method of conception, pregnancy complication, gestational age at delivery, indication for delivery, birth weight, the rate of intrauterine and neonatal death and neonatal outcomes were recorded. Pregnant women with sIUGR were divided into three types according to end-diastolic umbilical artery flow Doppler ultrasonography, and the differences of typing conversion and perinatal outcomes of sIUGR pregnant women based on the first diagnosis were compared. Results: (1) Clinical characteristics and pregnancy outcomes: among 153 pregnant women with sIUGR, 100 cases (65.3%) were diagnosed with type Ⅰ, 35 cases (22.9%) with type Ⅱ, and 18 cases (11.8%) with type Ⅲ. There were no significant differences in age, conception mode, pregnancy complications, first diagnosis gestational age, characteristics of umbilical cord insertion, delivery indications, fetal intrauterine mortality and neonatal mortality among three types of sIUGR pregnant women (all P>0.05). The average gestational age at delivery of type Ⅰ sIUGR was (33.5±1.9) weeks, which was significantly later than those of type Ⅱ and Ⅲ [(31.3±1.8), (31.2±1.1) weeks, P<0.001]. The percentage disordance in estimated fetal weight (EFW) of type Ⅰ sIUGR was significantly lower than those of type Ⅱ and type Ⅲ (P<0.001). The incidence rate of neonatal intensive care unit (NICU) admission, cerebral leukomalacia and respiratory complications of both fetus and necrotizing enterocolitis of large fetus in type Ⅰ were significantly lower than those in type Ⅱ and type Ⅲ (all P<0.05). (2) Typing conversion: in 100 cases of type Ⅰ sIUGR, 18 cases progressed to type Ⅱ and 10 cases progressed to type Ⅲ. Compared with 72 stable type Ⅰ sIUGR, those with progressed type Ⅰ sIUGR had higher incidence of NICU admission and lung disease in both fetuses, and cerebral leukomalacia and necrotizing enterocolitis in large fetus (all P<0.05). The proportion of inconsistent cord insertion was significantly higher in those type Ⅰ progressed to type Ⅲ (6/10) than in those with stable type Ⅰ (19.4%, 14/72) and type Ⅰ progressed to type Ⅱ sIUGR [0 (0/18), P=0.001]. Four cases of type Ⅱ sIUGR reversed to type Ⅰ and 6 cases reversed to type Ⅲ. Compared with type Ⅱ reversed to type Ⅰ sIUGR, those stable type Ⅱ and type Ⅱ reversed to type Ⅲ sIUGR had a higher incidence of NICU admission in large fetus (P<0.05). Two cases of type Ⅲ sIUGR reversed to type Ⅰ and 6 cases progressed to type Ⅱ. There were no significant differences in fetal serious complications in type Ⅲ sIUGR with or without doppler changes (all P>0.05). Conclusions: The different types of sIUGR could convert to each other. The frequency of ultrasound examinations should be increased for patients with the type Ⅰ sIUGR, especially when the percentage discordance in EFW is substantial or with discordant cord insersion.
Pregnancy ; Female ; Infant, Newborn ; Humans ; Fetal Growth Retardation/epidemiology* ; Pregnancy Outcome ; Retrospective Studies ; Enterocolitis, Necrotizing ; Twins, Monozygotic ; Umbilical Arteries/diagnostic imaging* ; Gestational Age ; Ultrasonography, Prenatal/methods* ; Pregnancy, Twin

Objective: To analyze the ultrasonic manifestations, clinical features, high risk factors and key points of pregnancy management in prenatal diagnosis of umbilical artery thrombosis (UAT). Methods: The data of 31 pregnant women of UAT diagnosed by prenatal ultrasonography and confirmed after birth from July 2017 to July 2022 at the Women's Hospital, Zhejiang University School of Medicine were retrospectively analyzed, including the maternal characteristics, pregnancy outcomes and fetal complications. In addition, the baseline data and pregnancy outcomes were compared in 21 patients who continued pregnancy after diagnosis of UAT. Of the 21 UAT cases that continued pregnancy, 10 cases were treated with low molecular weight heparin (LMWH; LMWH treatment group), while the other 11 patients had expectant treatment(expectant treatment group). Results: The age of the 31 pregnant women was (30.2±4.7) years, of which 5 cases (16%,5/31) were advanced age pregnant women. The gestational age at diagnosis was (32.9±4.0) weeks, and the gestational age at termination of pregnancy was (35.6±2.9) weeks. In 31 fetuses with UAT, 15 cases (48%) had fetal distress, 11 cases (35%) had fetal growth restriction, and 3 cases (10%) had intrauterine stillbirth. There were 28 cases of live births, including 26 cases by cesarean section and 2 cases by vaginal delivery. There were also 3 stillbirths, all delivered vaginally. Four neonates had mild asphyxia and two newborns had severe asphyxia. Among the 31 cases, 10 cases were terminated immediately after diagnosis, the gestational age at diagnosis was (35.9±2.9) weeks. Another 21 pregnancies continued, and their gestational age at diagnosis was (31.4±3.7) weeks. The median prolonged gestational age in LMWH treatment group was 7.9 weeks (4.6-9.4 weeks), and all were live births. The median prolonged gestational age in the expectant treatment group was 0.6 weeks (0.0-1.0 weeks), and 2 cases were stillbirths. There was a statistically significant difference in prolonged gestational age (P=0.002). Conclusions: Ultrasound is the preferred method for prenatal detection of UAT. Clinicians need to be vigilant for UAT when a newly identified single umbilical artery is detected by ultrasound in the second or third trimesters. The decision to continue or terminate the pregnancy depends on the gestational age and the condition of fetus. Attention should be paid to fetal movements as the pregnancy continues. The treatment of LMWH as soon as possible after diagnosis of UAT may improve the pregnancy outcome.
Pregnancy ; Infant, Newborn ; Female ; Humans ; Adult ; Infant ; Stillbirth ; Cesarean Section ; Umbilical Arteries/diagnostic imaging* ; Asphyxia ; Retrospective Studies ; Heparin, Low-Molecular-Weight/therapeutic use* ; Pregnancy Outcome ; Fetal Growth Retardation/therapy* ; Ultrasonography, Prenatal/methods* ; Gestational Age