MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature.

Autor:	Wit JM; Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands j.m.wit@lumc.nl., Oostdijk W; Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands., Losekoot M; Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands., van Duyvenvoorde HA; Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands., Ruivenkamp CA; Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands., Kant SG; Departments of PaediatricsClinical GeneticsLeiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
Jazyk:	angličtina
Zdroj:	European journal of endocrinology [Eur J Endocrinol] 2016 Apr; Vol. 174 (4), pp. R145-73. Date of Electronic Publication: 2015 Nov 17.
DOI:	10.1530/EJE-15-0937
Abstrakt:	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. (© 2016 European Society of Endocrinology.)
Databáze:	MEDLINE
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