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*

OBJECTIVE: To explore the clinical and genetic characteristics of a fetus with Melnick-Needles syndrome (MNS). METHODS: A fetus with MNS diagnosed at Ningbo Women and Children's Hospital in November 2020 was selected as the study subject. Clinical data was collected. Pathogenic variant was screened by using trio-whole exome sequencing (trio-WES). Candidate variant was verified by Sanger sequencing. RESULTS: Prenatal ultrasonography of the fetus had shown multiple anomalies including intrauterine growth retardation, bilateral femur curvature, omphalocele, single umbilical artery, and oligohydramnios. Trio-WES revealed that the fetus has harbored hemizygous c.3562G>A (p.A1188T) missense variant of the FLNA gene. Sanger sequencing confirmed that the variant was maternally derived, whilst its father was of a wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS4+PM2_Supporting+PP3+PP4). CONCLUSION The hemizygous c.3562G>A (p.A1188T) variant of the FLNA gene probably underlay the structural abnormalities in this fetus. Genetic testing can facilitate accurate diagnosis of MNS and provide a basis for genetic counseling for this family.
Child ; Female ; Humans ; Pregnancy ; Abnormalities, Multiple/genetics* ; Fetal Growth Retardation ; Fetus ; Filamins/genetics* ; Genetic Counseling ; Mutation ; Osteochondrodysplasias

OBJECTIVE: To explore the genetic basis for a Chinese pedigree with 6q26q27 microduplication and 15q26.3 microdeletion. METHODS: A fetus with a 6q26q27 microduplication and a 15q26.3 microdeletion diagnosed at the First Affiliated Hospital of Wenzhou Medical University in January 2021 and members of its pedigree were selected as the study subject. Clinical data of the fetus was collected. The fetus and its parents were analyzed by G-banding karyotyping and chromosomal microarray analysis (CMA), and its maternal grandparents were also subjected to G-banding karyotype analysis. RESULTS: Prenatal ultrasound had indicated intrauterine growth retardation of the fetus, though no karyotypic abnormality was found with the amniotic fluid sample and blood samples from its pedigree members. CMA revealed that the fetus has carried a 6.6 Mb microduplication in 6q26q27 and a 1.9 Mb microdeletion in 15q26.3, and his mother also carried a 6.49 duplication and a 1.867 deletion in the same region. No anomaly was found with its father. CONCLUSION The 6q26q27 microduplication and 15q26.3 microdeletion probably underlay the intrauterine growth retardation in this fetus.
Female ; Humans ; Pregnancy ; East Asian People ; Fetal Growth Retardation/genetics* ; Karyotype ; Pedigree ; Prenatal Diagnosis ; Sequence Deletion ; Chromosome Duplication

OBJECTIVE: To carry out genetic analysis for a fetus with confined placental mosaicism (CPM) for trisomy 2 (T2) in conjunct with fetal uniparental disomy (UPD). METHODS: Amniocentesis and chromosomal karyotyping was carried out for a pregnant woman with a high risk for chromosome 2 anomalies indicated by non-invasive prenatal testing (NIPT). Single nucleotide polymorphism array (SNP-array) and trio-whole exome sequencing (Trio-WES) were carried out. Ultrasonography was used to closely monitor the fetal growth. Multifocal sampling of the placenta was performed after delivery for copy number variation sequencing (CNV-seq). RESULTS: The fetus was found to have a normal chromosomal karyotype. SNP-array has revealed multiple regions with loss of heterozygosity (LOH) on chromosome 2. Trio-WES confirmed the presence of maternal UPD for chromosome 2. Ultrasonography has revealed intrauterine growth restriction and oligohydramnios. Intrauterine fetal demise had occurred at 23⁺⁴ weeks of gestation. Pathological examination had failed to find salient visceral abnormality. The placenta was proved to contain complete T2 by CNV-seq. CONCLUSION T2 CPM can cause false positive result for NIPT and may be complicated with fetal UPD, leading to adverse obstetric outcomes such as intrauterine growth restriction, oligohydramnios and intrauterine fetal demise.
Female ; Humans ; Pregnancy ; Amniocentesis ; Chromosomes, Human, Pair 2/genetics* ; DNA Copy Number Variations ; Fetal Death ; Fetal Growth Retardation/genetics* ; Fetus ; Mosaicism ; Oligohydramnios ; Placenta ; Trisomy/genetics* ; Uniparental Disomy/genetics*

Dyskeratosis Congenita/genetics* ; Enterocolitis/genetics* ; Fetal Growth Retardation ; Humans ; Intellectual Disability/genetics* ; Microcephaly/genetics*

OBJECTIVE: To investigate the clinical features of fetuses with Wolf-Hirschhorn syndrome(WHS) and explore the diagnostic methods and prenatal ultrasound characteristics and provide evidence for prenatal genetic counseling. METHODS: We retrospectively analyzed 5 cases of WHS fetuses diagnosed from March 2016 to February 2020, and analyzed the results of chromosomal karyotype analysis and chromosomal microarray analysis (CMA) of the fetuses. RESULTS: Five cases of WHS were detected by CMA, four cases were detected by karyotype analysis. Prenatal ultrasound revealed 4 abnormalities, of which 3 had intrauterine growth restriction, and only 1 had abnormalities of the maxillofacial region. The sequence of the fragments was 4p16.3p16.1 with a loss of 6.5 Mb, 4p16.3p15.32 with a loss of 15.6 Mb combined with 2p25.3 increased by 906kb, 4p16.3p15.31 with a loss of 20.4 Mb, 4p16.p15.1 with a loss of 35 Mb and 4p16.3p14 with a loss of 37 Mb. CONCLUSION Fetal growth restriction may be one of the early manifestations of WHS. Absence of fetal facial abnormality by prenatal ultrasound screening cannot exclude WHS. Karyotype analysis may miss the diagnosis of WHS, while combined CMA techniques can improve the diagnostic accuracy.
Chromosomes, Human, Pair 4/genetics* ; Female ; Fetal Growth Retardation/genetics* ; Humans ; Karyotyping ; Pregnancy ; Prenatal Diagnosis ; Retrospective Studies ; Wolf-Hirschhorn Syndrome/genetics*