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 NFkB 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 T 3 /T 4 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 w3% 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.

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

“…clinically distinguishable bone malformations or hormonal abnormalities, accumulating evidence suggests that such mutations can occasionally result in non-specific short stature, referred to as idiopathic short stature (ISS) [1][2][3]. For example, SHOX abnormalities account for 1-17% of ISS cases [4,5].…”

“…effects of these variants remained uncertain, because mutations in GHRHR, GHR, and IGFALS are known to lead to short stature primarily in an autosomal recessive manner [1][2][3].…”

“…Short stature is partly ascribed to monogenic mutations that cause skeletal dysplasia or endocrinological defects in the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis [1][2][3]. Known causative genes for skeletal dysplasia include ACAN, FGFR3, NPR2, and SHOX, and those for abnormalities in the GH-IGF1 axis include GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R [1][2][3].…”

“…Known causative genes for skeletal dysplasia include ACAN, FGFR3, NPR2, and SHOX, and those for abnormalities in the GH-IGF1 axis include GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R [1][2][3]. Although mutations in these genes usually lead to short stature with hormonal abnormalities such as GH deficiency (i.e., peak GH level ≤ 6 ng/mL after provocation), pubertal disorders, or thyroid diseases; (iii) chronic illnesses or environmental conditions that may affect growth; (iv) skeletal malformations and/or dysmorphic features; or (v) cytogenetically detectable chromosomal abnormalities.…”

A SHOX géndeletio előfordulása idiopáthiás alacsonynövésben. Multicentrikus tanulmány

“…Utóbbi kórkép markáns tünete az úgynevezett Madelung-deformitás. A Turner-szindró-mára jellemző kromoszómaeltérés miatt a SHOX-deficientia a betegek csaknem 100%-ában kimutatható [1,4,10,11]. A SHOX gén homozigóta eltérése a Langerszindrómát (LS) eredményezi, amely egy rendkívül ritka és súlyos tünetegyüttes, jelentős növekedési elmaradással és az ulna, illetve fibula hypo-és/vagy aplasiájával társul.…”