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MECHANISMS in ENDOCRINOLOGY: Novel Genetic Causes of Short Stature

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MECHANISMS in ENDOCRINOLOGY: Novel Genetic Causes of Short Stature J M Wit and others Genetics of short stature 174:4 R145–R173 Review MECHANISMS IN ENDOCRINOLOGY Novel genetic causes of short stature 1 1 2 2 Jan M Wit , Wilma Oostdijk , Monique Losekoot , Hermine A van Duyvenvoorde , Correspondence Claudia A L Ruivenkamp2 and Sarina G Kant2 should be addressed to J M Wit Departments of 1Paediatrics and 2Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Email The Netherlands [email protected] 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 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 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 European Journal of Endocrinology abnormalities, CNVs, and imprinting disorders. European Journal of Endocrinology (2016) 174, R145–R173 Introduction The fast technological development has caused a flood of stature. In the first decade of the 21st century, the genetic novel discoveries in genetic causes of congenital disorders, toolbox was expanded by whole genome single nucleotide including syndromic and non-syndromic forms of short polymorphism (SNP) array (1) and array-comparative Invited Author’s profile Professor Jan Maarten Wit is currently Professor Emeritus and honorary staff member of the Department of Paediatrics at Leiden University Medical Centre, The Netherlands. Trained as a paediatric endocrinologist, he served as an Associate Professor of Paediatric Endocrinology in Utrecht and Full Professor/Chairman of Paediatrics in Leiden. Most of his research has been focused on the diagnosis and management of growth disorders. Shortly after his PhD thesis (Responses to growth hormone therapy), he founded the Dutch Growth Hormone Advisory Group and the Dutch Growth Hormone Research Foundation’s bureau, instrumental in conducting numerous multicentre clinical trials on the efficacy and safety of growth hormone treatment. In Leiden, he led research projects on regulation of the epiphyseal growth plate and on referral criteria and diagnostic guidelines for short children, but the main subject focus over the last 10 years has been the elucidation of novel genetic causes of short and tall stature. www.eje-online.org Ñ 2016 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-15-0937 Printed in Great Britain Downloaded from Bioscientifica.com at 10/01/2021 04:38:46PM via free access Review J M Wit and others Genetics of short stature 174:4 R146 genomic hybridization (array-CGH) (2) for the detection including different clinical entities, previously defined as of microdeletions or microduplications (copy number separate conditions (‘allelic heterogeneity’). On the other variants (CNVs)), the former of which is also able to detect hand, one clinical disorder can be caused by mutations in uniparental disomy. In the second decade an even more different genes (‘locus heterogeneity’) (14). Furthermore, successful tool became available – whole exome sequen- mutations in some genes not only impair GP development cing (WES) – for the detection of gene variants as possible and/or function but also non-skeletal structures, causing causes of congenital disorders (3, 4, 5, 6), with a good associated congenital anomalies (syndromic short diagnostic yield in well-selected patients (6). In general, stature) (17). WES is performed in an index patient and his/her parents The last decades have taught us that with time the (a ‘trio’), and (if available) affected and non-affected clinical phenotype of genetic defects tends to become siblings, to limit the number of informative variants in more variable than initially assumed. The rapid increase the bioinformatic analysis. of the use of SNP arrays and WES in the coming years, and At the same time, information about genes associated the expected appearance of whole genome sequencing with linear growth was collected through non-clinical (WGS), RNA sequencing, and methylation assays, will research, in particular through genome-wide association certainly lead to the discovery of many more novel causes studies (GWAS) and animal and in vitro experiments on of short stature, as well as a further expansion of the epiphyseal growth plate (GP) function. GWAS have shown clinical phenotypes associated with genetic and epigenetic that common SNPs at over 400 loci contribute to variation variants. in normal adult stature, albeit with a small effect size per locus (7). Many of these genes, but also others, have Genetic defects of the GH–insulin-like appeared in gene expression studies in the various zones growth factor 1 axis of the GP (8, 9). For this review we chose to focus on discoveries made The GH––insulin-like growth factor 1 (IGF1) axis is an in the last 10 years (up to August 2015), against the important pathway in the regulation of linear growth, and background of earlier findings, as summarized in previous defects have been found in virtually all components of this reviews by our group (10, 11, 12, 13) and others (5, 14, 15, cascade. Tables 1 and 2 show conditions associated with 16, 17) (for search strategy see section at the end of the GH or IGF1 signalling, divided into three categories: i) GH article). The tables offer the formal names of the disorders deficiency (GHD); ii) GH insensitivity (GHI) and decreased and codes according to online Mendelian inheritance in expression or biologic activity of IGF1 or IGF2; and iii) European Journal of Endocrinology man (OMIM) (http://www.ncbi.nlm.nih.gov/omim), and IGF1 insensitivity. For various genes, a publicly available we aimed at providing the most recent relevant references. database has been established (www.growthgenetics.com) In line with a recent review paper (17), we structured (21), and clinicians and geneticists are encouraged to this review according to a diagnostic classification centred upload clinical and genetic data of additional cases. on the GP. In the GP, chondrocytes proliferate, hyper- trophy, and secrete cartilage extracellular matrix, under GH deficiency the influence of endocrine and paracrine factors. Thus, in this review successively hormones, paracrine factors, Table 1 shows the gene defects that have been associated matrix molecules, intracellular pathways, and fundamen- with GHD. Many of the proteins encoded by these tal cellular processes will be discussed, followed by CNVs genes are associated with GHD as part of combined and imprinting disorders. Because the GP is the structure pituitary hormone deficiency (CPHD), and function as where linear growth takes place, we prefer this patho- pituitary transcription factors (for detailed information on physiologic classification above the multiple reported associated clinical features and MRI appearances see (5, 22, alternative classifications, for example proportionate vs 23, 24)). A novel endocrine syndrome discovered by our disproportionate short stature; with or without micro- group, immunoglobulin superfamily member 1 (IGSF1) cephaly (18); prenatal vs postnatal onset of growth deficiency syndrome, is primarily characterized by central retardation (19); or growth hormone (GH) deficiency or hypothyroidism and macroorchidism, but can also insensitivity (20). present with hypoprolactinaemia and transient partial A complicating factor in the classification of mono- GHD (25, 26). The association of Netherton syndrome genic disorders is that a variety of mutations in one gene with GH and prolactin deficiency suggests that a defect of can result in a broad phenotypic spectrum, sometimes LEKT1 (encoded by SPINK5) may increase the degradation www.eje-online.org Downloaded from Bioscientifica.com at 10/01/2021 04:38:46PM via free access Review J M Wit and others Genetics of short stature 174:4 R147 Table 1 Causes of GHD. Disordera Gene(s) Clinical features Inheritance References GHD and potential for CPHD CPHD-1 (613038) POU1F1 GH, PRL, var. TSH def. AR, AD (5, 22, 23) CPHD-2 (262600) PROP1 GH, PRL, TSH, LH, FSH, var. ACTH def. AR (5, 22, 23) Pituitary can be enlarged.
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