Achondroplasia (ACH) is a common skeletal dysplasia in children, primarily caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. These mutations disrupt the process of endochondral ossification in different types of bones, including long bones of the limbs and vertebrae. Children with ACH typically present with short stature and may experience severe multi-system complications. The diagnosis of ACH is based on typical clinical manifestations, imaging features, and genetic testing results. Treatment options mainly include pharmacological interventions and surgical procedures aimed at improving height, as well as symptomatic management for associated complications. This article discusses both prenatal and clinical diagnostic approaches for ACH, as well as treatment strategies focused on enhancing height, aiming to deepen the understanding of this condition.
Humans ; Achondroplasia/therapy* ; Child ; Body Height ; Early Diagnosis ; Receptor, Fibroblast Growth Factor, Type 3/genetics*

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

OBJECTIVES: To study the clinical features and fibroblast growth factor receptor 3 (FGFR3) gene mutations of children with achondroplasia (ACH) through an analysis of 17 cases. METHODS: A retrospective analysis was performed on the clinical data and FGFR3 gene detection results of 17 children with ACH who were diagnosed from January 2009 to October 2021. RESULTS: Of the 17 children with ACH, common clinical manifestations included disproportionate short stature (100%, 17/17), macrocephaly (100%, 17/17), trident hand (82%, 14/17), and genu varum (88%, 15/17). The common imaging findings were rhizomelic shortening of the long bones (100%, 17/17) and narrowing of the lumbar intervertebral space (88%, 15/17). Major complications included skeletal dysplasia (100%, 17/17), middle ear dysfunction (82%, 14/17), motor/language developmental delay (88%, 15/17), chronic pain (59%, 10/17), sleep apnea (53%, 9/17), obesity (41%, 7/17), foramen magnum stenosis (35%, 6/17), and hydrocephalus (24%, 4/17). All 17 children (100%) had FGFR3 mutations, among whom 13 had c.1138G>A hotspot mutations of the FGFR3 gene, 2 had c.1138G>C mutations of the FGFR3 gene, and 2 had unreported mutations, with c.1252C>T mutations of the FGFR3 gene in one child and c.445+2_445+5delTAGG mutations of the FGFR3 gene in the other child. CONCLUSIONS This study identifies the unreported mutation sites of the FGFR3 gene, which extends the gene mutation spectrum of ACH. ACH is a progressive disease requiring lifelong management through multidisciplinary collaboration.
Achondroplasia/genetics* ; Child ; Humans ; Mutation ; Osteochondrodysplasias/genetics* ; Receptor, Fibroblast Growth Factor, Type 3/genetics* ; Retrospective Studies

The Diagnostic Genetics Subcommittee of Korean Association of External Quality Assessment Service conducted two trials in 2015 based on cytogenetics and molecular genetics surveys. A total of 43 laboratories participated in the chromosome surveys, 31 laboratories participated in the fluorescence in situ hybridization surveys, and 133 laboratories participated in the molecular genetics surveys. All except one laboratory showed acceptable results in the cytogenetics surveys. The molecular genetics surveys included the following tests: Mycobacterium tuberculosis detection, hepatitis B and C virus detection and quantification, human papilloma virus genotyping, gene rearrangement tests for leukaemias and lymphomas, genetic tests for JAK2, FMS-like tyrosine kinase 3, nucleophosmin, cancer-associated genes (KRAS, EGFR, KIT, and BRAF), hereditary breast and ovarian cancer genes (BRCA1 and BRCA2), Li-Fraumeni syndrome (TP53), Wilson disease (ATP7B), achondroplasia (FGFR3), hearing loss and deafness (GJB2 ), multiple endocrine neoplasia 2 (RET), Huntington disease, spinocerebellar ataxia, spinal and bulbar muscular atrophy, mitochondrial encephalopathy with lactic acidosis and stroke like episodes, myoclonic epilepsy ragged red fibre, Leber hereditary optic neuropathy, Prader-Willi/Angelman syndrome, Duchenne muscular dystrophy, spinal muscular atrophy, fragile X syndrome (FMR1), apolipoprotein E genotyping, methylenetetrahydrofolate reductase genotyping, ABO genotyping, cytochrome P450 2C9 genotyping, cytochrome P450 2C19 genotyping, and DNA sequencing analysis. The molecular genetics surveys showed excellent results for most of the participants. The external quality assessment program for genetics analysis in 2015 proved to be helpful for continuous education and the evaluation of quality improvement.
Achondroplasia ; Acidosis, Lactic ; Apolipoproteins ; Breast ; Cytochrome P-450 Enzyme System ; Cytogenetics ; Deafness ; Education ; Epilepsies, Myoclonic ; Fluorescence ; fms-Like Tyrosine Kinase 3 ; Fragile X Syndrome ; Gene Rearrangement ; Genetics* ; Hearing Loss ; Hepatitis B ; Hepatolenticular Degeneration ; Humans ; Huntington Disease ; In Situ Hybridization ; Korea* ; Li-Fraumeni Syndrome ; Lymphoma ; Methylenetetrahydrofolate Reductase (NADPH2) ; Molecular Biology ; Multiple Endocrine Neoplasia ; Muscular Atrophy, Spinal ; Muscular Disorders, Atrophic ; Muscular Dystrophy, Duchenne ; Mycobacterium tuberculosis ; Optic Atrophy, Hereditary, Leber ; Ovarian Neoplasms ; Papilloma ; Quality Improvement ; Sequence Analysis, DNA ; Spinocerebellar Ataxias ; Stroke

Quality control for genetic tests has become more important as testing volume and clinical demands have increased dramatically. The diagnostic genetics subcommittee of Korean Association of External Quality Assessment Service conducted two trials in 2014 based on cytogenetics and molecular genetics surveys. A total of 44 laboratories participated in the chromosome surveys, 33 laboratories participated in the fl uorescence in situ hybridization (FISH) surveys, and 130 laboratories participated in the molecular genetics surveys as a part of these trials. All laboratories showed acceptable results in the chromosome and FISH surveys. The molecular genetics surveys included various tests: Mycobacterium tuberculosis detection, hepatitis B and C virus detection and quantification, human papilloma virus genotyping, gene rearrangement tests for leukaemia and lymphomas, genetic tests for JAK2, FMS-like tyrosine kinase 3, nucleophosmin, cancer-associated genes (KRAS, EGFR, KIT, and BRAF), hereditary breast and ovarian cancer genes (BRCA1 and BRCA2), Li-Fraumeni syndrome (TP53), Wilson disease (ATP7B), achondroplasia (FGFR3), Huntington disease, spinocerebellar ataxia, spinal and bulbar muscular atrophy, mitochondrial encephalopathy with lactic acidosis and stroke like episodes, myoclonic epilepsy ragged red fibre, Prader-Willi/Angelman syndrome, Duchenne muscular dystrophy, spinal muscular atrophy, fragile X syndrome, nonsyndromic hearing loss and deafness (GJB2), multiple endocrine neoplasia 2 (RET), Leber hereditary optic neuropathy (major mutation), apolipoprotein E genotyping, methylenetetrahydrofolate reductase genotyping, ABO genotyping, and DNA sequencing analysis. Molecular genetic surveys showed excellent results for most of the participants. The external quality assessment program for genetic analysis in 2014 proved to be helpful for continuous education and the evaluation of quality improvement.
Achondroplasia ; Acidosis, Lactic ; Apolipoproteins ; Breast ; Cytogenetics ; Deafness ; Education ; Epilepsies, Myoclonic ; fms-Like Tyrosine Kinase 3 ; Fragile X Syndrome ; Gene Rearrangement ; Genetics* ; Hearing Loss ; Hepatitis B ; Hepatolenticular Degeneration ; Humans ; Huntington Disease ; In Situ Hybridization ; Korea ; Li-Fraumeni Syndrome ; Lymphoma ; Methylenetetrahydrofolate Reductase (NADPH2) ; Molecular Biology ; Molecular Diagnostic Techniques ; Multiple Endocrine Neoplasia ; Muscular Atrophy, Spinal ; Muscular Disorders, Atrophic ; Muscular Dystrophy, Duchenne ; Mycobacterium tuberculosis ; Optic Atrophy, Hereditary, Leber ; Ovarian Neoplasms ; Papilloma ; Quality Assurance, Health Care ; Quality Control ; Quality Improvement ; Sequence Analysis, DNA ; Spinocerebellar Ataxias ; Stroke

Quality control for genetic tests has become more important as the test volume and clinical demands increase dramatically. The diagnostic genetics subcommittee of the Korean Association of Quality Assurance for Clinical Laboratories performed two trials for cytogenetics and molecular genetics surveys in 2013. A total of 43 laboratories participated in the cytogenetic surveys, 30 laboratories participated in the fluorescent in situ hybridization surveys, and 122 laboratories participated in the molecular genetics surveys in 2013. Almost all of them showed acceptable results. However, some laboratories had unacceptable results for karyotype nomenclature, detection of complex cytogenetic abnormalities in hematologic neoplasms and constitutional anomalies. The molecular genetics surveys included various tests: Mycobacterium tuberculosis detection, hepatitis B and C virus detection and quantification, human papilloma virus genotyping, gene rearrangement tests for leukaemia and lymphomas, genetic tests for JAK2, fms-related tyrosine kinase 3, Nucleophosmin, cancer-associated genes (KRAS, EGFR and BRAF), hereditary breast and ovarian cancer genes (BRCA1 and BRCA2), Li-Fraumeni syndrome (TP53), Wilson disease (ATP7B), achondroplasia (FGFR3), Huntington disease, spinocerebellar ataxia, spinal and bulbar muscular atrophy, mitochondrial encephalopathy with lactic acidosis and stroke like episodes, myoclonic epilepsy associated with ragged-red fibers, Prader-Willi/Angelman syndrome, Duchenne muscular dystrophy, spinal muscular atrophy, Fragile X syndrome, non-syndromic hearing loss and deafness (GJB2), apolipoprotein E genotyping, methylenetetrahydrofolate reductase genotyping, ABO genotyping and DNA sequence analysis. Molecular genetic surveys showed excellent results for most of the participants. The external quality assessment program for genetic analysis in 2013 was proved to be helpful for continuous education and evaluation of quality improvement.
Achondroplasia ; Acidosis, Lactic ; Apolipoproteins ; Breast ; Chromosome Aberrations ; Cytogenetics ; Deafness ; Education ; Fragile X Syndrome ; Gene Rearrangement ; Genetics* ; Hearing Loss ; Hematologic Neoplasms ; Hepatitis B ; Hepatolenticular Degeneration ; Humans ; Huntington Disease ; In Situ Hybridization, Fluorescence ; Karyotype ; Korea ; Li-Fraumeni Syndrome ; Lymphoma ; MERRF Syndrome ; Methylenetetrahydrofolate Reductase (NADPH2) ; Molecular Biology ; Muscular Atrophy, Spinal ; Muscular Disorders, Atrophic ; Muscular Dystrophy, Duchenne ; Mycobacterium tuberculosis ; Ovarian Neoplasms ; Papilloma ; Protein-Tyrosine Kinases ; Quality Control ; Quality Improvement ; Sequence Analysis, DNA ; Spinocerebellar Ataxias ; Stroke

This study aimed to report the clinical characteristics and COMP gene mutation of a family with pseudoachondroplasia (PSACH), a relatively rare spinal and epiphyseal dysplasia that is inherited as an autosomal dominant trait. Clinical information on a 5-year-2-month-old PSACH child and his parents was collected and analyzed. Diagnosis was confirmed by PCR amplification and direct sequencing of all the 19 exons and their flanking sequences of COMP gene, and the mutation was further ascertained by cloning analysis of exon 10. The child presented with short and stubby fingers, bow leg, short limb dwarfism and metaphysic broadening in long bone as well as lumbar lordosis. A mutation c.1048_1116del (p.Asn350_Asp372del) in exon 10, inherited from his father who did not demonstrate any phenotypic feature of PSACH, was detected in the child. PSACH was diagnosed definitively by means of COMP mutation analysis, on the basis of the child's clinical and imaging features. The non-penetrance phenomenon of COMP mutation was described for the first time in PSACH.
Achondroplasia ; genetics ; Cartilage Oligomeric Matrix Protein ; genetics ; Child, Preschool ; Cloning, Molecular ; Humans ; Male ; Mutation

OBJECTIVETo analyze the clinical manifestations, bone X-ray findings and genetic analysis results of three short-limb inherited short stature diseases: achondroplasia (ACH), hypochondroplasia (HCH) and pseudoachondroplasia (PSACH).

METHODSThe clinical manifestations, bone X-ray findings, and genetic analysis results of 10 children with genetically confirmed short-limb inherited short stature diseases, including 4 cases of ACH 3 cases of HCH, and 3 cases of PSACH, were analyzed.

RESULTSThe 10 patients had a mean body height of -3.69±1.79 SD, a mean sitting height/standing height ratio of 0.65±0.03, and a mean finger spacing/body height ratio of 0.93±0.04. Four ACH cases and 3 PSACH cases showed typical bone X-ray findings; one HCH case showed a smaller sciatic notch, and another HCH case showed no widening of interpedicular distance. G380R mutation in FGFR3 gene was detected in 3 of 4 ACH cases, and Y278C mutation in the other ACH case, N540K mutation in FGFR3 gene was detected in 3 HCH cases, and heterozygous mutations in COMP gene were detected in 3 PSACH cases.

CONCLUSIONSChildren with ACH and PSACH have severer short stature and skeletal deformities than children with HCH, who have mild, atypical clinical manifestations. Bone X-ray and genetic analysis are helpful for the diagnosis and differential diagnosis of the three diseases. The mutational hotspots in two genes are involved in the three diseases, which is conducive to clinical genetic diagnosis.

Achondroplasia ; diagnostic imaging ; genetics ; Bone and Bones ; abnormalities ; diagnostic imaging ; Child ; Child, Preschool ; Dwarfism ; diagnostic imaging ; genetics ; Female ; Humans ; Limb Deformities, Congenital ; diagnostic imaging ; genetics ; Lordosis ; diagnostic imaging ; genetics ; Male ; Mutation ; Radiography ; Receptor, Fibroblast Growth Factor, Type 3 ; genetics

This paper summarizes the clinical features, causative genes and treatment progress of patients with rickets-like genetic diseases, including X-linked hypophosphatemic rickets (XLH), hypophosphatasia, achondroplasia, vitamin D-dependent rickets, pycnodysostosis and ectodermal dysplasia, who visited the pediatric or child health clinic due to the symptoms of rickets, including bow legs, delayed closure of the anterior fontanelle, and sparse hair. Children with XLH usually go to hospital for bow legs and short stature, and biochemical evaluation reveals significantly low serum phosphorus so it is easily diagnosed. This disease is treated using phosphate mixture and 1,25(OH)2D3, which is different from the treatment of nutritional vitamin D deficiency rickets. Hypophosphatasia is characterized by a significant decrease in serum alkaline phosphatase, as well as normal serum calcium and phosphorus. The disease is caused by mutations in TNSALP gene. Patients with achondroplasia show short-limbed dwarfism and special face in addition to bow legs, but with normal serum calcium, phosphorus and alkaline phosphatase. Bone X-ray and FGFR3 gene test contribute to the diagnosis. Vitamin D-dependent rickets is an autosomal recessive disease, and active vitamin D supplement is effective in treatment of the disease. Patients with pycnodysostosis may be first seen at hospital because of large anterior fontanelle; in addition, they also show obtuse mandibular angle, dental abnormalities and dysplastic nails, which are caused by mutations in TSK gene. Children with ectodermal dysplasia may see a doctor for sparse hair, and they are easily misdiagnosed with nutritional vitamin D deficiency rickets. Ectodermal dysplasia is related to EDA, EDAR, EDARADD and WNT 10A genes.
Achondroplasia ; genetics ; therapy ; Ectodermal Dysplasia ; genetics ; therapy ; Familial Hypophosphatemic Rickets ; genetics ; therapy ; Humans ; Hypophosphatasia ; genetics ; therapy ; Pycnodysostosis ; genetics ; therapy

OBJECTIVETo diagnose achondroplasia prenatally by FGFR3 gene detection.

METHODSSeventy-eight fetuses affected by short-limb dysplasias were recruited. Umbilical blood sampling was employed to obtain fetal blood for karyotyping and FGFR3 gene detection. Genomic DNA was extracted, and the exon 10 of the FGFR3 gene was amplified. PCR amplicons were analyzed by DNA sequencing and restriction fragment length polymorphism with Bfm I. The FGFR3 exon 10 from the parents of the positive fetuses was screened by the same method.

RESULTSIn 78 fetuses affected with short-limb dysplasias, 8 cases had G1138A heterozygotic mutation and normal karyotype, and were diagnosed as achondroplasia. The other 70 fetuses had normal nucleotide at nucleotide 1138 in exon 10 of FGFR3, therefore were excluded from achondroplasia. Only one father in parents of the 8 achondroplasia fetuses also had the G1138A mutation.

CONCLUSIONAchondroplasia could be diagnosed prenatally in the fetuses affected with short-limb dysplasias by using PCR-RFLP and DNA sequencing of the exon 10 of the FGFR3 gene.

Achondroplasia ; diagnosis ; genetics ; DNA Mutational Analysis ; Female ; Humans ; Male ; Polymorphism, Restriction Fragment Length ; Pregnancy ; Prenatal Diagnosis ; methods ; Receptor, Fibroblast Growth Factor, Type 3 ; genetics