title: MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature.
abstract: The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFκB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in ∼3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.
authors.affiliation: Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands j.m.wit@lumc.nl.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wit
authors.affiliation: Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Wilma
authors.initials: W
authors.lastname: Oostdijk
authors.affiliation: Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Losekoot
authors.affiliation: Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Hermine A
authors.initials: HA
authors.lastname: van Duyvenvoorde
authors.affiliation: Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Claudia A L
authors.initials: CA
authors.lastname: Ruivenkamp
authors.affiliation: Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Sarina G
authors.initials: SG
authors.lastname: Kant
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D004393:Dwarfism, Pituitary / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000172:deficiency / Q000235:genetics; D006130:Growth Disorders / Q000235:genetics*; D019382:Human Growth Hormone / Q000172:deficiency / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000172:deficiency / Q000235:genetics; D044162:Parathyroid Hormone-Related Protein / Q000172:deficiency / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013577:Syndrome; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D019485:Bone Morphogenetic Proteins; D044162:Parathyroid Hormone-Related Protein; D019382:Human Growth Hormone; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1