OBJECTIVES: To study genotype-phenotype correlations in children with FGFR3 variants and to improve clinical recognition of related disorders. METHODS: Clinical data of 95 patients aged 0-18 years harboring FGFR3 variants, confirmed by whole‑exome sequencing at Shanghai Children's Medical Center from January 2012 to December 2023, were retrospectively reviewed. Detailed phenotypic characterization was performed for 22 patients with achondroplasia (ACH) and 10 with hypochondroplasia (HCH). RESULTS: Among the 95 patients, 52 (55%) had ACH, 24 (25%) had HCH, 9 (9%) had thanatophoric dysplasia, 3 (3%) had syndromic skeletal dysplasia, 2 (2%) had severe achondroplasia with developmental delay and acanthosis nigricans, and 5 (5%) remained unclassified. A previously unreported FGFR3 variant, c.1663G>T, was identified. All 22 ACH patients presented with disproportionate short stature accompanied by limb dysplasia, commonly with macrocephaly, a depressed nasal bridge, bowed legs, and frontal bossing; complications were present in 17 (77%). The 10 HCH patients predominantly exhibited disproportionate short stature with limb dysplasia and depressed nasal bridge. CONCLUSIONS ACH is the most frequent phenotype associated with FGFR3 variants, and missense variants constitute the predominant variant type. The degree of FGFR3 activation appears to correlate with the clinical severity of skeletal dysplasia.
Humans ; Receptor, Fibroblast Growth Factor, Type 3/genetics* ; Child ; Male ; Child, Preschool ; Female ; Infant ; Adolescent ; Dwarfism/genetics* ; Achondroplasia/genetics* ; Lordosis/genetics* ; Infant, Newborn ; Retrospective Studies ; Genetic Association Studies ; Bone and Bones/abnormalities* ; Phenotype ; Limb Deformities, Congenital

OBJECTIVE: To investigate the clinical and genetic characteristics of a patient with STISS syndrome due to variant of PSMD12 gene. METHODS: Clinical data and result of genetic testing of a patient who was admitted to Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine on October 4, 2020 were analyzed, together with a review of relevant literature. RESULTS: The patient was found to harbor a heterozygous c.601C>T (p.Arg201*) nonsense variant of the PSMD12 gene, which was unreported previously. Clinically, the height of the patient has differed significantly from reported in the literature. An extremely rare case of STISS syndrome due to variant of the PSMD12 gene has been diagnosed. CONCLUSION Whether the severely short stature is part of the clinical spectrum for PSMD12 gene variants needs to be further explored, and the efficacy and safety of growth hormone therapy has yet to be determined.
Child ; Humans ; China ; Dwarfism ; Genetic Testing ; Heterozygote ; Syndrome

OBJECTIVE: To analyze the genetic characteristics of a child with Meier-Gorlin syndrome (MGS) due to a homozygous variant of the ORC6 gene. METHODS: A child who was admitted to the Children's Hospital Affiliated to Soochow University on March 25, 2019 due to growth retardation was selected as the study subject. Clinical data of the child was collected. Whole exome sequencing was carried out for the child. Candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 8-year-and-3-month-old male, has featured short stature, small ears, bilateral cryptorchidism and patellar dysplasia. His parents were of first cousins. The child was found to harbor a homozygous c.712A>T (p.K238*) missense variant of the ORC6 gene, which may lead to premature termination of protein translation. Sanger sequencing confirmed that both of his parents were heterozygous carriers. Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was classified as pathogenic (PVS1_Moderate+PM2_Supporting+PM3+PP3+PP4). CONCLUSION The homozygous c.712A>T (p.K238*) variant probably underlay the MGS in this child.
Humans ; Infant ; Male ; Computational Biology ; Congenital Microtia/genetics* ; Dwarfism/genetics* ; Growth Disorders/genetics* ; Origin Recognition Complex/genetics*

OBJECTIVE: To explore the clinical and genetic characteristics of a boy with isolated maternal uniparental disomy of chromosome 20 [UPD(20)mat]. METHODS: A child who was admitted to the Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology on April 8,2021. was selected as the study subject. Phenotypic and endocrinological findings of the child were retrospectively analyzed. Whole exome sequencing (WES) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were carried out for detecting the UPD sequences and copy number variations. Both of his parents were verified by Sanger sequencing. Relevant literature was systematically reviewed. RESULTS: The child, a 3-year-and-8-month-old boy born to a 41-year-old mother by Cesarean delivery at 36⁺² gestational weeks due to oligohydramia, had a birth weight of 2 300 g and length of 46 cm. He was admitted to the NICU for feeding difficulties which had persisted despite of clinical management. At the age of 3.75, he had a height of 92.5 cm (< 3rd percentile; 25th ~ 50th percentile at 2.5 years) and a weight of 10.8 kg (< 3rd percentile; 50th percentile at 15 months). He had also presented with growth retardation, short stature, attention deficit and hyperactivity disorder (ADHD), mild mental retardation, and speech and language development disorders. He had simian creases in both hands but no additional dysmorphic signs, and his motor development was normal. Serum insulin, thyroid-stimulating hormone, and insulin growth factor binding protein 3 levels were within the normal ranges, though insulin growth factor-1 (IGF-1) was slightly decreased. Since that time he had continuously used atomoxetine hydrochloride capsules to control his ADHD. WES and MS-MLPA revealed the existence of UPD (20)mat. CONCLUSION The UPD(20)mat syndrome is characterized by feeding difficulties, growth retardation and short stature. The child in our case has been accompanied by ADHD and speech and language development disorders, which required long-term treatment. For women with advanced maternal age and suggestive phenotypes, genetic testing and counseling should be conducted.
Male ; Pregnancy ; Humans ; Child ; Female ; Infant ; Adult ; Chromosomes, Human, Pair 20 ; DNA Copy Number Variations ; Retrospective Studies ; Uniparental Disomy/genetics* ; Atomoxetine Hydrochloride ; Dwarfism ; Intercellular Signaling Peptides and Proteins ; Language Development Disorders ; Growth Disorders ; Insulins

Short stature is a common physical developmental abnormality in children. Without timely and accurate diagnosis, as well as early intervention, it can impose a heavy burden on the children and their families. There are numerous causes for short stature, and the diagnostic process essentially involves identifying its underlying causes. Based on a thorough understanding of the regular patterns of child physical development and the characteristics of individuals at high risk of short stature, a scientific definition of short stature needs to be established, along with standardized diagnostic and treatment protocols, to achieve early diagnosis or referral for short stature. Furthermore, it is necessary to enhance scientific awareness of short stature among parents and primary care pediatricians, in order to avoid over-treatment, missed diagnoses, and misdiagnoses arising from "misconceptions", and to improve the scientific assessment of short stature.
Humans ; Child ; Dwarfism/diagnosis* ; Child Development ; Parents ; Body Height ; Growth Disorders/etiology*

The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis is an essential component of the hypothalamic-pituitary growth hormone axis and plays a crucial role in childhood growth and development. Disruptions and abnormalities in the GH/IGF-1 signaling pathway and its pathways typically manifest as short stature in children. Children with short stature often undergo GH stimulation testing and IGF-1 level measurements to differentiate growth hormone deficiency (GHD) from other causes of growth delay. This article aims to analyze and elucidate the values of GH stimulation testing and IGF-1 measurement, providing reference for the diagnosis of GHD in children.
Child ; Humans ; Growth Hormone/metabolism* ; Insulin-Like Growth Factor I/metabolism* ; Insulin-Like Peptides ; Insulin-Like Growth Factor Binding Protein 3 ; Human Growth Hormone/metabolism* ; Dwarfism, Pituitary/diagnosis*

OBJECTIVE: To analyze the genetic etiology of a Chinese pedigree affected with short stature. METHODS: A child with familial short stature (FSS) who had presented at the Ningbo Women and Children's Hospital in July 2020 and his parents and paternal and maternal grandparents were selected as the study subject. Clinical data of the pedigree was collected, and the proband was subjected to routine growth and development assessment. Peripheral blood samples were collected. The proband was subjected to whole exome sequencing (WES), and the proband, his parents and grandparents were subjected to chromosomal microarray analysis (CMA). RESULTS: The height of the proband and his father was 87.7cm (-3 s) and 152 cm (-3.39 s) respectively. Both of them were found to harbor a 15q25.3-q26.1 microdeletion, which has encompassed the whole of the ACAN gene which is closely associated with short stature. The CMA results of his mother and grandparents were all negative, and above deletion has not been included in population database and related literature, and was rated as pathogenic based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). After 14 months of rhGH treatment, the height of the proband has increased to 98.5 cm (-2.07 s). CONCLUSION The 15q25.3-q26.1 microdeletion probably underlay the FSS, in this pedigree. Short-term rhGH treatment can effectively improve the height of the affected individuals.
Child ; Female ; Humans ; Male ; Aggrecans/genetics* ; Dwarfism/genetics* ; East Asian People ; Mutation ; Pedigree

OBJECTIVE: To analyze the clinical features of 3M syndrome and effect of growth hormone therapy. METHODS: Clinical data of four children diagnosed with 3M syndrome by whole exome sequencing at Hunan Children's Hospital from January 2014 to February 2022 were retrospectively analyzed, which included clinical manifestation, results of genetic testing and recombinant human growth hormone (rhGH) therapy. A literature review was also carried our for Chinese patients with 3M syndrome. RESULTS: The clinical manifestations of the 4 patients included severe growth retardation, facial dysmorphism and skeletal malformations. Two patients were found to harbor homozygous variants of CUL7 gene, namely c.4717C>T (p.R1573*) and c.967_993delinsCAGCTGG (p.S323Qfs*33). Two patients were found to harbor 3 heterozygous variants of the OBSL1 gene including c.1118G>A (p.W373*), c.458dupG (p.L154Pfs*1002) and c.690dupC (p.E231Rfs*23), among which c.967_993delinsCAGCTGG and c.1118G>A were unreported previously. Eighteen Chinese patients with 3M syndrome were identified through the literature review, including 11 cases (11/18, 61.1%) carrying CUL7 gene variants and 7 cases (7/18, 38.9%) carrying OBSL1 gene variants. The main clinical manifestations were in keeping with previously reported. Four patients were treated with growth hormone, 3 showed obvious growth acceleration, and no adverse reaction was noted. CONCLUSION 3M syndrome has a typical appearance and obvious short stature. To attain accurate diagnosis, genetic testing should be recommended for children with a stature of less than -3 SD and facial dysmorphism. The long-term efficacy of growth hormone therapy for patients with 3M syndrome remains to be observed.
Humans ; Child ; Retrospective Studies ; Dwarfism/genetics* ; Muscle Hypotonia/genetics* ; Growth Hormone/therapeutic use* ; Cytoskeletal Proteins/genetics*

OBJECTIVE: To analyze the clinical phenotype and genetic basis of a child with Alazami syndrome (AS). METHODS: A child who presented at Tianjin Children's Hospital on June 13, 2021 was selected as the study subject. The child was subjected to whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. RESULTS: WES revealed that the child has harbored two frameshifting variants of the LARP7 gene, namely c.429_430delAG (p.Arg143Serfs*17) and c.1056_1057delCT (p.Leu353Glufs*7), which were verified by Sanger sequencing to be respectively inherited from his father and mother. CONCLUSION The compound heterozygous variants of the LARP7 gene probably underlay the pathogenesis in this child.
Female ; Humans ; Dwarfism/genetics* ; Exome Sequencing ; Intellectual Disability/genetics* ; Microcephaly ; Mothers ; Mutation ; Male ; Child

OBJECTIVE: To explore the genetic basis of a Chinese pedigree affected with Dyggve-Melchior-Clausen syndrome. METHODS: Whole exome sequencing and Sanger sequencing were carried out to detect potential pathogenic variants associated with the syndrome. The function of candidate variant was verified by Western blotting. RESULTS: A novel homozygous variant, c.1222delG of the DYM gene was detected in the two affected siblings, for which both parents were heterozygous carriers. The variant has caused replacement of Asp by Met at amino acid 408 and generate a premature stop codon p.Asp408Metfs*10. Western blotting confirmed that the variant can result in degradation of the mutant DYM protein, suggesting that it is a loss of function variant. CONCLUSION The homozygous c.1222delG frameshift variant of the DYM probably underlay the Dyggve-Melchior-Clausen syndrome in the two affected siblings. Above findings has enabled clinical diagnosis and genetic counseling for the family.
China ; Dwarfism/genetics* ; Humans ; Intellectual Disability ; Osteochondrodysplasias/genetics* ; Pedigree