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

Introduction: Primary hyperparathyroidism (PHPT) is a common disorder that typically leads to increased bone turnover and reduced bone mineral density (BMD). Osteopetrosis, in contrast, is a rare, inherited disorder of defective osteoclast function, resulting in diffusely sclerotic but structurally fragile bones. The coexistence of both conditions is rare and can significantly alter the expected skeletal phenotype of PHPT. Case: We report a 77-year-old female with a previous history of resected ovarian carcinoma in remission, chronic iron deficiency anemia, and hypothyroidism. During a hospital admission for a lacunar infarct, an incidental finding of sclerotic skull lesions on computed tomography (CT) brain prompted further investigation. She had no history of fractures, hearing impairment, or family history of parathyroid or bone disorders. Biochemistry revealed parathyroid-dependent hypercalcemia with normal renal function. Bone turnover markers showed a normal resorption marker (BCTx) but an elevated formation marker (P1NP), with a mildly raised alkaline phosphatase. A sestamibi scan localized a probable left upper parathyroid adenoma, despite a negative neck ultrasound. Skeletal survey unexpectedly revealed widespread osteosclerosis of the skull, spine, and long bones, with a markedly elevated BMD on densitometry. Review of prior imaging confirmed that these sclerotic changes predated her current presentation, having been present on CTs from over a decade ago. Recurrent malignancy was excluded with repeat imaging and tumor markers. A diagnosis of PHPT secondary to parathyroid adenoma, coexisting with underlying, previously unrecognized osteopetrosis, was made. The patient declined both recommended parathyroidectomy and genetic studies. Conclusion This case demonstrates a rare coexistence of two pathologies with opposing effects on bone metabolism. The underlying osteopetrosis, characterized by defective osteoclasts, likely rendered the patient’s osteoclasts resistant to the catabolic effects of elevated PTH. This resulted in an atypically normal bone resorption marker and an unexpectedly high BMD, despite the diagnosis of PHPT.
Bone Density' ; Hyperparathyroidism ; Primary Osteopetrosis

OBJECTIVES: To study the clinical and genetic characteristics of osteopetrosis (OPT) in children. METHODS: A retrospective analysis was performed on the clinical data of 14 children with OPT. Whole-exome sequencing was used to detect pathogenic genes, and clinical phenotypes and genotypic features were summarized. RESULTS: Among the 14 children (10 males and 4 females), the median age at diagnosis was 8 months. Clinical manifestations included systemic osteosclerosis (14 cases, 100%), anemia (12 cases, 86%), infections (10 cases, 71%), thrombocytopenia (9 cases, 64%), hepatosplenomegaly (8 cases, 57%), and developmental delay (5 cases, 36%). Malignant osteopetrosis (MOP) cases had lower platelet counts, creatine kinase isoenzyme, and serum calcium levels, but higher white blood cell counts, lactate dehydrogenase, and alkaline phosphatase levels compared to non-MOP cases (P<0.05). Genetic testing identified 15 variants in 12 patients, including 8 variants in the CLCN7 gene (53%), 6 in the TCIRG1 gene (40%), and 1 in the TNFRSF11A gene (7%). Three novel CLCN7 variants were identified: c.2351G>C, c.1215-43C>T, and c.1534G>A. All four patients with TCIRG1 variants exhibited MOP clinical phenotypes. Of the seven patients with CLCN7 variants, 4 presented with intermediate OPT, 2 with benign OPT, and 1 with MOP. CONCLUSIONS Clinical phenotypes of OPT in children are heterogeneous, predominantly involving CLCN7 and TCIRG1 gene variants, with a correlation between clinical phenotypes and genotypes.
Humans ; Osteopetrosis/genetics* ; Male ; Female ; Infant ; Child, Preschool ; Retrospective Studies ; Vacuolar Proton-Translocating ATPases/genetics* ; Child ; Chloride Channels/genetics* ; Mutation ; Receptor Activator of Nuclear Factor-kappa B

OBJECTIVE: To explore the clinical characteristics and genetic etiology of a child with Osteopathia striata with cranial sclerosis (OSCS) due to variant of AMER1 gene. METHODS: A child presented at the Affiliated Children's Hospital of Zhengzhou University in July 2024 due to growth and development retardation was selected as the study subject. A retrospective study was conducted to collect the child's clinical data. Peripheral blood samples (2 mL each) were collected from the child and her parents, and genomic DNA was extracted for whole exome sequencing (WES). Sanger sequencing was used for the verification of candidate variants. The pathogenicity of variant was rated according to the guidelines from American College of Medical Genetics and Genomics (ACMG). The study has been approved by the Medical Ethics Committee of the Children's Hospital Affiliated to Zhengzhou University (Ethics No.: 2024-108-001). RESULTS: The patient, a 4-year-and-10-month-old girl, presented with global developmental delay, short stature, cleft palate, distinct facial features, and hearing impairment. WES revealed that she has harbored a heterozygous c.790_794dup (p.Cys265Trpfs*19) variant of the AMER1 gene, which was not detected in either parent. Based on the guidelines from ACMG, the gene variant was classified as pathogenic (PVS1 + PS2 + PM2_supporting). As the result of a non-triplet base insertion in the coding region of the AMER1 gene, it has converted a codon originally encoding an amino acid into a stop codon, and led to a truncated protein, causing severe alteration and dysfunction of the protein. CONCLUSION The child was diagnosed with OSCS for clinical features such as global developmental delay, short stature, cleft palate, distinctive facial features, and hearing impairment, for which the de novo heterozygous frameshift variant AMER1: c.790_794dup (p.Cys265Trpfs*19) may be accountable. Above finding has expanded the mutational spectrum of OSCS and provided a basis for genetic counseling and prenatal diagnosis for the family.
Humans ; Female ; Child, Preschool ; Osteosclerosis/genetics* ; Adaptor Proteins, Signal Transducing/genetics* ; Mutation ; Exome Sequencing ; Retrospective Studies ; Tumor Suppressor Proteins

OBJECTIVE: To analyze the clinical characteristics of a patient with Short rib-polydactyly syndrome type 6 (SRTD6) with long-term misdiagnosis, and improve its clinical recognition by reviewing the relevant literature. METHODS: A patient presented at the Children's Hospital Affiliated to Zhejiang University School of Medicine on August 19, 2024 for the discovery of liver dysfunction for 13 years and vision loss for 9 years was selected as the study subject. Her medical history, clinical data, laboratory findings and results of imaging examination were collected. High-throughput sequencing was carried out, and candidate variants were verified by Sanger sequencing. This study was approved by the Ethics Committee of the Hospital (Ethics No.: 2021-IRB-292). RESULTS: The patient had long-term unexplained liver dysfunction, vision loss, and growth delay. Blood acylcarnitine and urinary organic acid analysis have failed to found any abnormality. Previous genetic testing revealed a homozygous c.203A>C (p.Glu68Ala) missense variant in the ETFDH gene, leading to a misdiagnosis of various acyl-CoA dehydrogenase deficiencies. However, treatment with high-dose vitamin B₂ showed a poor effect. Physical examination revealed small hands, short and stubby fingers, and a narrow chest. Medical imaging showed shortened bilateral ribs, a narrowed chest, and short, thick metacarpals. High-throughput sequencing has detected a pathogenic homozygous c.1957C>T (p.R653*) nonsense variant in the NEK1 gene, confirming the diagnosis of SRTD6. CONCLUSION SRTD6 is characterized by rib and sternum dysplasia as the primary skeletal deformities, which is often accompanied by multi-organ impairment. Genetic testing can facilitate the precise diagnosis.
Humans ; Female ; Diagnostic Errors ; Short Rib-Polydactyly Syndrome/diagnosis* ; High-Throughput Nucleotide Sequencing

OBJECTIVE: To explore the prenatal features and genetic etiology of a fetus with Short-rib cage dysplasia (SRTD) due to variants of DYNC2H1 gene. METHODS: A pregnant women presented at Xinxiang Central Hospital in June 2020 for abnormal prenatal ultrasound findings was selected as the study subject. With informed consent obtained, amniotic fluid sample was extracted from the woman, and clinical data of the fetus were collected. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing. This study was approved by the Medical Ethics Committee of Xinxiang Central Hospital [Ethics No.: 2025-214-01(K)]. RESULTS: At 25⁺⁶ weeks gestation, genetic testing revealed that the fetus has harbored compound heterozygous variants of the DYNC2H1 gene, namely c.10585C>T (p.Arg3529Ter) and c.8954T>G (p.Val2985Gly), which were derived from its father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.10585C>T (p.Arg3529Ter) and c.8954T>G (p.Val2985Gly) variants were classified as pathogenic (PVS1+PM2_supporting+PM3+PP5) and likely pathogenic (PM1+PM2_supporting+PM3+PP3), respectively. Bioinformatics analysis suggested that both variants may affect the 3D structure of the DYNC2H1 protein. CONCLUSION The compound heterozygous variants of c.10585C>T (p.Arg3529Ter) and c.8954T>G (p.Val2985Gly) of the DYNC2H1 gene probably underlay the pathogenesis of SRTD in the fetus. Above findings had facilitated prenatal diagnosis and genetic counseling for the couple.
Humans ; Female ; Pregnancy ; Cytoplasmic Dyneins/chemistry* ; Prenatal Diagnosis ; Adult ; Short Rib-Polydactyly Syndrome/diagnostic imaging* ; Mutation ; Exome Sequencing ; Fetus/abnormalities* ; Ultrasonography, Prenatal

OBJECTIVE: To explore the clinical phenotypes and genetic diagnosis of 2 sporadic cases for cleidocranial dysplasia. METHODS: The clinical data of two cases of CCD admitted to the Third Affiliated Hospital of Zhengzhou University on December 16, 2021 and December 9, 2021 were analyzed retrospectively, and the whole exome sequencing (WES), chromosome microarray analysis and copy number variation sequencing were performed. RESULTS: The main ultrasonographic findings of the fetus had included poorly calcified skull bones, budging of parieto-occipital area, compression and deformation of skull, and loss of nasal bone. The infant's clinical phenotypes included delayed closure of anterior fontanelle, recurrent respiratory tract infection, growth retardation, and clavicular hypoplasia. By WES analysis, the fetus was found to harbor a heterozygous c.911_914delinsTTT variant of the RUNX2 gene, whilst the infant was found to harbor a heterozygous c.1008delT variant of the RUNX2 gene. Both variants were verified by Sanger sequencing to have occurred de novo. CONCLUSION For sporadic cases featuring cleidocranial dysplasia, prenatal ultrasonography is particularly important. Hypoplastic clavicle, skull calcification and nasal bone absence are the main features. Diagnosis should also be suspected for infants featuring growth retardation, recurrent respiratory tract infections and clavicular dysplasia. The identification of the c.911_914delinsTTT and c.1008delT variants of the RUNX2 gene has facilitated genetic counseling and prenatal diagnosis, and also expanded the mutational spectrum of the RUNX2 gene.
Female ; Humans ; Pregnancy ; Cleidocranial Dysplasia/genetics* ; Core Binding Factor Alpha 1 Subunit ; DNA Copy Number Variations ; Growth Disorders ; Retrospective Studies

Humans ; East Asian People ; Genetic Profile ; Mutation ; Osteochondrodysplasias/genetics*

Humans ; Female ; Tibet ; Kashin-Beck Disease/epidemiology* ; China ; Metabolomics

OBJECTIVE: To investigate the effectiveness of sequential plate internal fixation in the correction of Madelung deformity after ulnar osteotomy and shortening. METHODS: The clinical data of 13 patients with Madelung deformity admitted between September 2015 and July 2021 were retrospectively analyzed. There were 5 males and 8 females with an average age of 18.3 years ranging from 17 to 23 years. The disease duration ranged from 12 to 24 months, with an average of 17 months. Three cases had a clear history of trauma. All patients had external radial deviation deformity and limited movement of the ulnar deviation, and the ulnar impact pain was significant during ulnar deviation movement; 9 patients had limited wrist joint supination movement, and the supination movement was normal. In the first stage, ulnar osteotomy and shortening combined with external fixator were used to correct wrist deformity in 13 patients. After operation, bone transfer was performed 6 times per day, with adjustments made every 4 hours, which was 1 mm per day. After the osteotomy was in place, the ulnar plate internal fixation was performed to reconstruct the ulnar stability in the second stage. The Cooney wrist joint score was used to assess the pain, function, range of motion, flexion and extension range of motion, and grip strength of the wrist joint before operation and before the removal of internal fixator. The subjective feeling and appearance satisfaction of patients were recorded. RESULTS: After the second-stage operation, all the 13 patients were followed up 10-22 months, with an average of 15 months. The deformity of wrist joint disappeared after operation, and the flexion, extension, and ulnar deviation were basically normal. There was no complication such as ulnar impingement sign, nonunion or infection. Wrist function, pain, and range of motion were significantly improved after operation, except for 1 patient who had no significant improvement in rotation and pain. The ulnar internal fixator was removed at 10-18 months after the second-stage operation. The scores of pain, function, range of motion, flexion and extension range of motion, and grip strength in the Cooney wrist score before removal of internal fixator significantly improved when compared with those before operation ( P<0.05). Subjective and appearance satisfaction of patients were excellent in 9 cases, good in 3 cases, and fair in 1 case. CONCLUSION Ulnar osteotomy and shortening with sequential plate internal fixation for correction of Madelung deformity, with mild postoperative pain, can effectively avoid bone nonunion, improve wrist joint function, and have significant effectiveness.
Male ; Female ; Humans ; Adolescent ; Retrospective Studies ; Ulna/surgery* ; Osteochondrodysplasias ; Radius Fractures/surgery* ; Wrist Joint/surgery* ; Osteotomy ; Range of Motion, Articular ; Treatment Outcome