Novel Genetic Causes of Short Stature

Home , Cockayne syndrome, Primordial dwarfism, Pseudohypoparathyroidism, Waardenburg syndrome

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 09/25/2021 11:53:36PM 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, hypertrophy, 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 09/25/2021 11:53:36PM 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. CPHD-3 (221750) LHX3 GH, TSH, LH, FSH, PRL def. Sensorineural hearing AR (5, 22, 23) loss, cervical abnormalities, short stiff neck CPHD-4 (262700) LHX4 GH, TSH, ACTH def. AD, AR (5, 22, 23) Septo-optic dysplasia (CPHD-5) HESX1 Optic nerve hypoplasia, pituitary hypoplasia, AR, AD (5, 22, 24) (182230) midline abnormalities of brain, absent corpus callosum and septum pellucidum CPHD-6 (613986) OTX2 TSH, GH, LH, FSH, var. ACTH and PRL def. AD (5, 22, 24) Axenfeld–Rieger syndrome type 1 PITX Coloboma, glaucoma, dental hypoplasia, AD (22) (180500) protuberant umbilicus, brain abnormalities, var. pituitary def. Optic nerve hypoplasia and SOX2 Var. GHD, hypogonadism, anophthalmia, AD (22, 24) abnormalities of the central developmental delay nervous system (206900) X-linked panhypopituitarism SOX3dupb GHD or CHPD, mental retardation XLR (5, 22, 24) (312000, 300123) Dopa-responsive dystonia due to SPR Diurnally fluctuating movement disorder, AR (237) sepiapterin reductase deficiency cognitive delay, neurologic dysfunction, (612716) GH and TSH def. Holoprosencephaly 9 (610829) GLI2 Holoprosencephaly, craniofacial abnormalities, AD (5, 22) polydactyly, single central incisor, partial agenesis corpus callosum (or hypopituitarism only) IGSF1 deficiency syndrome IGSF1 TSH, var. GH and PRL def.; macroorchidism XLR (26) (300888) Netherton syndrome (256500) SPINK5 Var. GH and PRL def. AR (27) Pallister–Hall syndrome (146510) GLI3 Hypothalamic hamartoma, central polydactyly, AD (5) visceral malformations FGF8 Holoprosencephaly, septo-optic dysplasia, AR (5, 24) Moebius syndrome European Journal of Endocrinology FGFR1 Hypoplasia pituitary, corpus callosum, ocular AD (5, 238) defects PROKR2 Var. hypopituitarism AD (238) HMGA2 Severe GHD, ectopic posterior pituitary AD (239, 240) GRP161 Pituitary stalk interruption syndrome, intellectual AR (241) disability, sparse hair in frontal area, hypo- telorism, broad nasal root, thick alae nasi, nail hypoplasia, short fifth finger, 2–3 toe syndactyly, hypopituitarism Isolated GHD or bioinactivity Isolated GHD, type IB (612781) GHRHR Low serum GH AR (240, 242) Isolated GHD, type 1A (262400) GH1 No serum GH, often anti-GH ab AR (240, 242) Isolated GHD, type IB (612781) GH1 Low serum GH AR (240, 242) Isolated GHD, type II (173100) GH1 Var. height deficit and pituitary size; other pituitary AD (240, 242) deficits can develop Isolated GHD, type III (307200) BTK, SOX3 GHD with agammaglobulinemia XLR (240, 242) Isolated partial GHD (615925) GHSR Var. serum GH and IGF1 AR, AD (39, 41) Kowarski syndrome (bioinactive GH1 high GH; def. of IGF1, IGFBP-3, and ALS AD (242) GH syndrome) (262650) Almstrom syndrome (203800) ALMS1 50% of cases are GHD AR (35) RNPC3 Severe GHD, hypoplasia anterior pituitary AR (33) IFT172 Functional GHD, retinopathy, metaphyseal AR (34) dysplasia, hypertension

AD, autosomal dominant; AR, autosomal recessive; def., deﬁciency; GHBP, growth hormone binding protein; GHD, growth hormone deﬁciency; IGF1, insulin-like growth factor 1; IGFBP-3, IGF binding protein-3; PRL, prolactin; var., variable; XLR, X-linked recessive. aName (number) according to OMIM. For clinical and radiological features of the various conditions, see (5, 22, 23, 24). bThis condition can also be caused by SOX3 polyalanine deletions and expansions.

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R148

Table 2 Causes of GH insensitivity or IGF insensitivity.

Disordera Gene(s) Clinical features Inheritance References

GH insensitivity Laron syndrome (262500) GHR Variable height deficit and GHBP, AR (AD) (46, 242) midfacial hypoplasia;[GH, YIGF1, IGFBP-3 and ALS GH insensitivity with immuno- STAT5B Midfacial hypoplasia, immuno- AR (55) deficiency (245590) deficiency; [GH and PRL; YIGF1, IGFBP-3 and ALS Multisystem, infantile-onset STAT3 (act) Associated with early-onset multi-organ AD (68, 69) autoimmune disease (615952) autoimmune disease X-linked severe combined IL2RG GH normal, low IGF1, non-responding XLR (243, 244) immunodeficiency (300400) to GH injections IGF1 deficiency (608747) IGF1 SGA, microcephaly, deafness; [GH and AR (13) IGFBP-3; variable IGF1 Severe growth restriction with IGF2 Y[/nl GH, IGFBP3; nl IGF1 Pat inheritance (82) distinctive facies (616489) ALS deficiency (615961) IGFALS Mild height deficit; GH?,YIGF1, IGFBP-3 AR (59) and ALS PAPP-A2 Microcephaly, skeletal abnormalities, AR (84) [GH, IGF1, IGFBP-3, and ALS Immunodeficiency 15 (615592) IKBKB Immunodeficiency; YIGF1 and IGFBP-3 AR, AD (65) IGF insensitivity Resistance to insulin-like growth IGF1R SGA, microcephaly; [/nl GH, IGF1, and AD, AR (85) factor 1 IGFBP-3

act, activating; AD, autosomal dominant; ALS, acid-labile subunit; AR, autosomal recessive; GH, growth hormone; GHBP, growth hormone binding protein; IGF1, insulinlike growth factor 1; IGFBP-3, insulin-like growth factor binding protein 3; SGA, small for gestational age; XLR, X-linked recessive. aName (number) according to OMIM.

of these hormones in pituitary cells by human tissue Isolated GHD can also be caused by biallelic mutations kallikreins before they enter the circulation (27). Other in RNPC3, which encodes a minor spliceosome protein causes of CPHD include mutations in GLI3, FGF8, FGFR1, required for U11/U12 small nuclear ribonucleoprotein PROKR2, HMGA2, and GRP161 (Table 1). (snRNP) formation and splicing of U12-type introns (33).

European Journal of Endocrinology Isolated GHD mutations in the genes encoding GH Compound heterozygosity for a gene encoding a protein (GH1) or GH releasing hormone receptor (GHRHR) can be important for ciliary function (IFT172)cancause found in up to 34% in familial cases (28). GH1 mutations functional GHD, pituitary hypoplasia, and ectopic pos- can either lead to classical GHD (types IA, IB, and II) or terior pituitary (34), and also Alstro¨m syndrome, caused bioinactive GH syndrome. While in the past the latter by a mutation of ALMS1 encoding a protein localized to diagnosis was used without good experimental evidence, the centrosomes and basal bodies of ciliated cells (35) is recent reports have shown that this is a real condition, associated with GHD. GHD has also been documented characterized by normal or even elevated circulating GH in a congenital malformation syndrome associated with a levels, and in some cases also associated with partial GHI paternal deletion of 6q24.2–q25.2 (36), complete general- (28, 29, 30). ized glucocorticoid resistance (37), and mitochondrial The most common cause of type IA GHD is a diseases (38). homozygous GH1 deletion; in most of such patients A still insufﬁciently deﬁned cause of GHD is a anti-GH antibodies develop with GH treatment. However, mutation of the gene encoding the Ghrelin receptor several other aberrations of GH1 have been described. The (GHSR) (reviewed in (39)). The variability of clinical less severe type IB GHD is caused by mutations of GH1 or phenotypes (GHD, idiopathic short stature (ISS) and GHRHR, and a dominant form of GHD (type II) is usually constitutional delay of growth and puberty (CDGP)) and caused by skipping of exon 3 resulting in production of a incomplete segregation of the mutations with the pheno- 17.5-kDa isoform of GH with a dominant negative effect type still cast doubt on the role of GHSR mutations in (28). The X-linked type III GHD is associated with causing short stature, although functional studies do agammaglobulinaemia, and has been associated with suggest that GHSR mutations may decrease GH secretion mutations in BTK (31) and SOX3 (32). (40, 41, 42), implying that GHSR mutations may

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R149

contribute to the genetic aetiology of children originally Homozygous deletions or missense mutations of considered ISS (41). IGF1 (encoding IGF1) resulting in a complete loss-of- function (70, 71) cause a severe prenatal and postnatal growth failure, developmental delay, microcephaly, and GHI and decreased expression or biologic activity of sensorineural deafness. Patients with a homozygous IGF1or IGF2 hypomorphic mutation (72) or specific heterozygous Table 2 shows the various syndromes presenting with mutations (73, 74) presented with less severe growth failure insensitivity to GH or IGF1. The first discovered cause and normal hearing (reviewed in (75)). Heterozygous of GHI was Laron syndrome, usually caused by a carriers of IGF1 mutations or deletions are w1 S.D. shorter homozygous mutation of the gene encoding the GH than non-carriers (71, 73, 74, 76). receptor (GHR) (43, 44, 45). Since then more than 70 With regard to IGF2, it is assumed that in most mutations in O300 cases have been found with mutations children with Silver–Russell syndrome the pre- and post- in extracellular, transmembrane, and intracellular parts of natal growth restriction is caused by deficient expression the GHR (46, 47). In most cases serum GH binding protein of the paternally expressed gene encoding IGF2 (IGF2) (77, (GHBP) is absent, except in cases with a mutation in the 78), usually through H19 hypomethylation. Such children intracellular or transmembrane part of the protein. While can have relatively high serum IGF1 and IGFBP-3, the classical form causes severe growth failure, there are suggesting partial IGF1 resistance (79, 80). In contrast, milder forms as well, for example caused by an intronic Silver–Russell syndrome patients carrying a maternal base change leading to the activation of a pseudoexon uniparental disomy of chromosome 7 (UPD7) usually sequence and insertion of 36 new amino acids within the present with low levels of IGF1 (79, 81). Very recently, the receptor extracellular domain (48, 49, 50) or by hetero- first family with a paternally inherited IGF2 mutation zygous GHR mutations causing a dominant negative effect and growth restriction was reported, indicating that (51, 52, 53). IGF2 not only is a mediator of intrauterine development In 2003 the first patient with a homozygous loss- but also contributes to postnatal growth (82).This of-function mutation of the gene encoding the main confirmed an earlier observation of a patient with a component of the intracellular GH signalling pathway paternally transmitted severe intrauterine growth retar- (STAT5B) was found (54), and since then ten patients have dation (IUGR) with a translocation breakpoint disrupting been reported in seven families (55).Mosthavean regulation of IGF2 (83). additional immunodeficiency and pulmonary fibrosis Another novel finding is that a homozygous mutation

European Journal of Endocrinology (56). Heterozygosity for a STAT5B mutation leads to a of the gene encoding the protease PAPPA-2 (PAPPA2)is slightly lower height (57). associated with mild short stature, presumably by insuffi- Another well-defined cause of GHI is a defect in cient availability of free IGF1 (84). IGFALS, encoding acid-labile subunit (ALS) which forms with IGF binding protein 3 (or 5) and IGF1 (or IGF2) a IGF1 insensitivity ternary complex in the circulation (58, 59). Children with ALS deficiency show a mild growth failure, delayed Numerous cases have been reported of heterozygous puberty, undetectable serum ALS, low serum IGF1, and mutations or deletions of the gene encoding the receptor even lower IGF binding protein 3 (IGFBP-3) (59), and for IGF1 (and IGF2) (IGF1R) (reviewed in (75, 85)). Clinical variable osteopenia and hyperinsulinism (60, 61, 62). features include prenatal growth failure persisting after Heterozygosity for IGFALS variants causes a one S.D. lower birth, microcephaly, and serum IGF1 in the upper half of, height (60, 62, 63) and may be responsible for a subset of or above, the normal range. On GH treatment serum IGF1 children previously considered having ISS (64). can become very high, which may probably be accepted GHI may also be caused by a mutation in the gene because of the decreased sensitivity. We estimate that encoding IkBa (IKBKB), presenting with short stature, IGF1R defects can be found in w3% of short children born GHI, severe immune deficiency and other features (65) or a small for gestational age (SGA) (86). A homozygous or PRKCA duplication, in a patient with a mosaic de novo compound heterozygous IGF1R mutation leads to a more duplication of 17q21–25 (66) (reviewed in (67)). Further- severe phenotype (87, 88, 89, 90).Intheory,IGF1 more, activating STAT3 mutations may be not only insensitivity may also be caused by mutations downstream associated with early-onset multi-organ autoimmune of the IGF receptor, or by defective microRNA regulation disease, but also with growth failure (68, 69). of IGF1 signalling (91).

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R150

Genetic defects affecting signalling of other be carried out, but also of sitting height and arm span, and hormones regulating GP function the same measurements should be performed in the parents. The length of upper and lower arms and legs, Congenital disorders of thyroid hormone signalling and hands and feet, should be at least visually assessed, include primary hypothyroidism (thyroid dysgenesis or and possibly measured and compared with normative dyshormonogenesis) and thyroid hormone resistance. charts (a relatively short upper arm and leg is called If undiagnosed, congenital hypothyroidism leads to very rhizomelia, in contrast to mesomelia if forearm and lower severe growth failure (92), but in most middle- and high- leg are relatively short). A series of skeletal radiographs income countries early detection by neonatal screening usually gives important clues for the diagnosis (15, 102, will prevent this, as well as the severe consequences for 103, 104). Most forms of skeletal dysplasia show short- mental development. Presently known genetic causes of limb dwarfism, in contrast to type I and II collageno- thyroid dysgenesis and dyshormonogenesis have recently pathies which are characterized by short-trunk dwarfism been reviewed (17, 93). (14). Because a comprehensive review of these conditions Children with thyroid hormone resistance caused by is beyond the scope of this article, only a few relatively mutations of THRB (encoding the beta form of the thyroid common conditions are discussed (Table 3). hormone receptor (TRb)) usually show normal growth, but in severe cases short stature has been observed (94). In contrast, all reported children with mutations in Fibroblast growth factor signalling THRA (encoding TRa) are short. Further clinical features Several fibroblast growth factors (FGFs) and their receptors include delayed mental and bone development, consti- play a role in the GP (9, 105). Best known is the FGF pation, and relatively low serum T and high serum T 4 3 receptor-3 (encoded by FGFR3), which acts as a negative levels (elevated T /T ratio) (95, 96). An opposite serum 3 4 regulator of GP chondrogenesis (106, 107). Consequently, thyroid hormone profile (elevated T and low-normal or 4 heterozygous activating mutations in FGFR3 impair bone slightly decreased T )isseeninahomozygousor 3 elongation and lead to a spectrum of disorders, reflecting compound heterozygous mutation of SECISBP2 (SBP2) the degree of activation of the FGFR3 mutation. The best (encoding an iodothyronine deiodinase), associated with known examples are thanatophoric dysplasia, achondro- short stature and responding to GH and T treatment (97). 3 plasia, and hypochondroplasia, each associated with It is well known that growth failure can be caused by different locations of the mutation. The clinical presen- excessive exposure to glucocorticoids, due to Cushing tation of hypochondroplasia is milder and more variable

European Journal of Endocrinology syndrome or pharmacological doses of corticosteroids. than achondroplasia and includes rhizomelic limb A discussion of newly discovered genetic causes of ACTH- shortening, limitation of elbow extension, brachydactyly, dependent and independent Cushing syndrome is outside relative macrocephaly, generalized laxity, and speciﬁc the scope of this paper (for recent ﬁndings, see (98, 99)). radiologic features (5, 108). We recently reported a novel Homozygous or compound heterozygous mutations of the activating FGFR3 mutation in a family with proportionate gene encoding the insulin receptor (INSR) cause Donohue short stature (109). syndrome (Leprechaunism) (100).

Bone morphogenetic protein signalling Genetic defects affecting paracrine factors Bone morphogenetic proteins (BMPs), also known as in the GP growth and differentiation factors (GDFs), belong to the Paracrine regulation plays a major role in the GP, and only transforming growth factor-beta (TGFb) superfamily of part of its complexity is presently understood. Most of the paracrine factors. The BMPs regulate a multitude of genetic defects of paracrine pathways result in some form processes in skeletal development, including spatial of skeletal dysplasia, of which 436 conditions, caused by regulation of proliferation and differentiation in the GP, defects in 364 genes, have been listed in the 2015 revision and a BMP signalling gradient across the GP may of the nosology of genetic skeletal disorders (101). contribute to the progressive differentiation of resting to Disproportionate short stature is one of the main features proliferative to hypertrophic chondrocytes (9). Inacti- of most of these conditions. Therefore, in the clinical vating mutations in the genes for several BMPs, their assessment of the short individual, not only accurate receptors, and antagonists cause various forms of skeletal measurements of height and head circumference have to dysplasias, particularly brachydactylies.

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R151

Table 3 Examples of genetic defects affecting paracrine factors in the growth plate.

Disordera Gene(s) Clinical features Inheritance References

FGF signaling Pfeiffer syndrome, acrocephalo- FGFR1, FGFR2 Craniosynostosis with characteristic AD (245) syndactyly, type V (101600) anomalies of the hands and feet (three types) Thanatophoric dysplasia type I FGFR3 (act) Severe short-limb dwarfism syndrome usually AD (9) (187600) lethal in the perinatal period Achondroplasia (100800) FGFR3 (act) Rhizomelic limb shortening, frontal bossing, AD (9) midface hypoplasia, exaggerated lumbar lordosis, limited elbow extension, genu varum, trident hand Hypochondroplasia (146000) FGFR3 (act) Short-limbed dwarfism, lumbar lordosis, AD (9, 108, 246) short and broad bones, caudal narrowing of interpediculate distance of lumbar spine Short stature FGFR3 (act) Relative macrocephaly for height AD (109) BMP signaling Brachydactyly A1 (112500) IHH, GDF5, Middle phalanges rudimentary or fused with AD (247) BMPR1B terminal phalanges, short proximal phalanges thumbs and big toes Brachydactyly A2 (112600) BMPR1B, BMP2, Malformations of middle phalanx of index AD (248) GDF5 finger, anomalies of second toe Brachydactyly C (113100) GDF5, CDMP1 Deformity of middle and proximal phalanges AD (249) (II, III), hypersegmentation of proximal phalanx WNT signaling Robinow syndrome (268310) ROR2, WNT5A Frontal bossing, hypertelorism, broad nose, AR, AD (112) short-limbed dwarfism, vertebral segmentation, genital hypoplasia Brachydactyly, Type B1 (113000) ROR2 Short middle phalanges, terminal phalanges AD (113) rudimentary or absent; deformed thumbs, big toes PTHrP-IHH pathway Brachydactyly, type E2 (613382) PTHLH Short stature and learning difficulties AD (116) Blomstrand chondro-dysplasia PTHR1 Short limbs, polyhydramnios, hydrops fetalis, AR (117) (215045) facial anoma-lies, increased bone density, European Journal of Endocrinology advanced skeletal maturation Jansen type of meta-physeal PTHR1 (act) Severe short stature, short bowed limbs, AD (118) chondrodys-plasia (156400) clinodactyly, prominent upper face, small mandible; hypercalcemia and hypophosphatemia Brachydactyly type A1 (112500) IHH, GDF5, Middle phalanges rudimentary or fused with AD (119) BMPR1B terminal phalanges. Short proximal phalanges of thumbs, big toes Acrocapitofemoral dysplasia IHH Variable short stature, short limbs with AR (119) (607778) brachydactyly, relatively large head circumference Albright hereditary osteodystrophy GNAS Pseudohypoparathyroidism, type Ia/c. Imprinted (228) (103580) Caused by loss of function of Gs-alpha isoform of GNAS on maternal allele. For further details see Table 8 Acrodysostosis 1 (101800) PRKAR1A Severe brachydactyly, facial dysostosis, nasal AD (121) hypoplasia, advanced bone age, obesity, resistance to multiple hormones CNP-NPR2 pathway Acromesomelic dysplasia, NPR2 Disproportionate shortening of middle AR (124) Maroteaux type (602875) segments (forearms and forelegs) and distal segments (hands and feet) (Dis)proportionate short stature NPR2 Moderate short stature, short forearms and AD (130) forelegs

AD, autosomal dominant; AR, autosomal recessive; act, activating. aName (number) according to OMIM.

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R152

WNT signalling children with achondroplasia. Binding of CNP to NPR2 stimulates the receptor guanylyl cyclase activity thereby The receptor tyrosine kinase-like orphan receptor 2 (RoR2) is increasing synthesis of cGMP, activating the type II cGMP- part of a conserved family of tyrosine kinase-like receptors dependent protein kinase (131), which in turn leads to that serve as receptors for noncanonical WNT ligands, inhibition of the MAPK pathway, thus antagonizing FGFR participating in developmental processes like cell move- signalling (132). In a mouse model of achondroplasia, ment and cell polarity (110, 111).Homozygousmutationsof CNP had beneﬁcial effects (133), and clinical trials with a ROR2 or heterozygous mutations of WNT5A cause Robinow long-acting CNP analogue are in progress in children with syndrome (112) and dominant ROR2 mutations cause achondroplasia. brachydactyly, Type B1 (113).

Genetic defects affecting cartilage PTHrP–IHH pathway extracellular matrix Parathyroid hormone related peptide (PTHrP) and Indian A unique characteristic of chondrocytes is that they Hedgehog (IHH) form a negative feedback loop within the secrete an extracellular matrix containing speciﬁc GP that regulates chondrocyte hypertrophy and prolifer- collagens, non-collagenous proteins and proteoglycans, ation (114, 115). Heterozygous loss-of-function mutations which are vital to normal GP function. This extracellular in PTHLH, encoding PTHrP, and inactivating and activat- matrix not only provides the compressible, resilient ing mutations in PTHR1 (encoding the parathyroid structural properties of cartilage, but also interacts with hormone receptor-1) cause various short stature syn- signalling molecules to regulate GP chondrogenesis (17). dromes (116, 117, 118), as well as inactivating and Mutations in several genes encoding matrix proteins activating mutations of IHH (119, 120). Heterozygous and proteoglycans have been shown to lead to growth missense mutations in PRKAR1A and PDE4D cause disorders (Table 4). Mutations in ACAN, encoding aggre- acrodysostosis 1 and 2 respectively, with or without can, show a gene-dose effect: homozygous mutations hormone resistance (121, 122). cause a severe skeletal dysplasia, spondyloepimetaphyseal dysplasia aggrecan type (134), while heterozygous CNP–NPR2 pathway mutations can present as a milder skeletal dysplasia, spondyloepiphyseal dysplasia type Kimberley, or as short One of the most interesting breakthroughs in the ﬁeld stature without evident radiographic skeletal dysplasia

European Journal of Endocrinology of growth genetics is the unravelling of the role of (135). This latter form is associated with an advanced bone C-natriuretic peptide (CNP, encoded by NPPC) and its age and early cessation of growth (17, 135). receptors in GP function. CNP is a local, positive regulator Some disorders, such as the genetically heterogeneous of GP function, and SNPs in NPPC and in the gene encoding brachyolmia, tend to affect the spine more than the long one of its receptors (NPR3) show a significant association bones, for example mutations in PAPSS2 encoding a with adult height in GWAS (123). Homozygous inactivat- sulphotransferase, required for sulphation of a variety of ing mutations of NPR2 (encoding the main CNP receptor) molecules, including cartilage glycosaminoglycans and cause a severe skeletal dysplasia, acromesomelic dysplasia, DHEA (136, 137). Maroteaux type (124). Initial observations that relatives heterozygous for NPR2 mutations of patients with acrome- Genetic defects of intracellular pathways somelic dysplasia are shorter than non-carriers (125), were confirmed by recent studies (126, 127, 128, 129). The Various intracellular pathways play a role in chondrocyte phenotype of heterozygous NPR2 mutations is similar to differentiation in the GP, and examples of disorders in that of patients with SHOX haploinsufficiency (Leri–Weill such pathways are listed in Table 5. syndrome), with short forearms and lower legs For the clinician, the relatively frequent aberrations of (mesomelia), except for the absence of Madelung deformity the gene encoding short stature homeobox (SHOX) (130). Heterozygous NPR2 mutations may explain 2–3% of (located at the tip of the X and Y chromosome, and cases with assumed ISS (129) and probably more if one of transmitted in a pseudoautosomal fashion) are most the parents has a similar phenotype. relevant. SHOX acts as a transcriptional activator and, Unravelling of the role of this pathway in linear like in NPR2 mutations, a gene-dose effect is apparent: growth has led to potential therapeutic consequences for homozygous or compound heterozygous inactivating

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R153

Table 4 Examples of genetic defects affecting cartilage extracellular matrix.

Disordera Gene(s) Clinical features Inheritance References

Acromicric dysplasia (102370) FBN1 Severe short stature, short hands and feet, AD (250, 251) joint limitations, skin thickening Geleophysic dysplasia-2 (614185) FBN1 Severe short stature, short hands and feet, AD (250, 251) joint limitations, skin thickening, heart involvement Brachyolmia type 4 with mild PAPSS2 Short trunk, normal intelligence and facies; AR (137, 252) epiphyseal and metaphyseal rectangular vertebral bodies with irregular changes (spondyloepimeta- endplates and narrow intervertebral discs, physeal dysplasia, Pakistani precocious calciﬁcation of rib cartilages, type) (612847) short femoral neck, mildly shortened metacarpals, and mild epiphyseal and metaphyseal changes of the tubular bones Hurler syndrome (607014) IDUA Skeletal deformities, corneal clouding, AR (253) hepatosplenomegaly, psychomotor delay Metaphyseal chondro-dysplasia, COL10A1 Short stature, widened growth plates, AD (254) Schmid type (156500) bowing of long bones Multiple epiphyseal dysplasia 1–6 COMP, COL9A2, Short-limbed dwarﬁsm, joint pain and AD (255) COL9A3, SLC26A2, stiffness and early onset osteoarthritis MATN3, COL9A1 Pseudoachondro-plasia (177170) COMP Disproportionate short stature, deformity of AD (256) lower limbs, brachydactyly, loose joints, ligamentous laxity, vertebral anomalies, osteoarthritis Spondyloepiphyseal dysplasia COL2A1 Multiple presentations AD (257) congenita (183900) Spondyloepimetaphy-seal ACAN Relative macrocephaly, severe midface AR (134) dysplasia aggrecan type hypoplasia, almost absent nasal cartilage, (612813) relative prognathism, slightly low-set, posteriorly rotated ears; short neck, barrel chest, mild lumbar lordosis; rhizomelia and mesomelia Spondyloepiphyseal dysplasia ACAN Proportionate short stature, stocky habitus, AD (258) type Kimberley (608361) progressive osteoarthropathy Short stature with advanced ACAN Advanced bone age, premature growth AD (135) bone age cessation European Journal of Endocrinology Weill–Marchesani syndrome ADAMTS10, FBN1 Spherophakia, lenticular myopia, ectopia AR (259) (613195, 608328) lentis, joint stiffness, brachydactyly

AD, autosomal dominant; AR, autosomal recessive. aName (number) according to OMIM.

SHOX mutations cause Langer mesomelic dysplasia, while arm span, forearm length, and presence of Madelung heterozygous mutations or deletions of SHOX cause a deformity. milder skeletal dysplasia, Leri–Weill dyschondrosteosis Heterozygous deletions of the downstream and (with the classic Madelung deformity of the wrist) or upstream enhancer of SHOX cause a similar phenotype as present clinically as ISS. It is assumed that most of the defects of SHOX itself (144, 145, 146, 147, 148, 149), and the growth failure characteristic for Turner syndrome is growth response to GH treatment is even better in children caused by heterozygous SHOX deletion. Body proportions carrying a deletion of the SHOX enhancer than in carriers are usually mildly affected (mesomelia) but can be within of a SHOX defect (150). The consequences of increased the normal range (138). Various clinical prediction rules copies of SHOX are less clear (146, 150, 151, 152, 153). have been proposed to select patients for testing (139, 140, A second intracellular pathway that plays a role in 141, 142), but the high variability of the clinical cellular proliferation and differentiation of GP chondro- presentation limits their predictive value (5). SHOX cytes is the Ras/MAPK signalling pathway, which inte- mutations account for 2–15% of individuals presenting grates signals from several growth factors including GH, with ISS (143). Since usually SHOX defects are transmitted FGFs, CNP, and EGF (154, 155). Activation of this pathway from one of the parents, physical examination of the results in a number of overlapping syndromes, called parents is essential, including height, sitting height, ‘rasopathies’, including Noonan,LEOPARD,Costello,

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R154

Table 5 Examples of genetic defects affecting intracellular pathways.

Disordera Gene(s) Clinical features Inheritance References SHOX aberrations Langer mesomelic dysplasia (249700) SHOX Severe limb aplasia or hypoplasia of AR (138) the ulna and fibula, and a thickened and curved radius and tibia Leri–Weill dyschon-drosteosis SHOX Mesomelia, Madelung wrist deform- AD (138, 149) (127300) ity, or mild body disproportion Rasopathies Noonan syndrome 1–8 PTPN11, KRAS, Facial dysmorphism, wide spectrum of AD (157, 260, 261) SOS1, RAF1, congenital heart defects NRAS, BRAF, RIT1 LEOPARD syndrome Multiple lentigines, electrocardio- AD (260) 1 (151100) PTPN11, graphic conduction abnormalities, 2 (611554) RAF1, ocular hypertelorism, pulmonic 3 (613707) BRAF stenosis, abnormal genitalia, sensorineural deafness Costello syndrome (218040) HRAS Coarse facies, distinctive hand posture AD (260) and appearance, feeding difficulty, failure to thrive, cardiac anomalies, developmental delay Cardio-facio-cutaneous syndrome BRAF, KRAS Distinctive facial appearance, heart AD (260) (115150) defects, mental retardation Neurofibromatosis-Noonan NF1 Features of both conditions AD (260) syndrome (601321) Neurofibromatosis type I (162200) NF1 Cafe-au-lait spots, Lisch nodules in AD (262) eye, fibroma-tous skin tumours; short in 13%; large head circumference in 24% Coffin–Lowry syndrome (303600) RPS6KA3 Mental retardation, skeletal XLR (261) malformations, hearing deficit, paroxysmal movement disorders Other syndromes Aarskog–Scott syndrome FGD1 Hypertelorism, shawl scrotum, XLR (263) (faciogenital dysplasia) (305400) brachydactyly Alstro¨ m syndrome (203800) ALMS1 Retinal photoreceptor degeneration, AR (35)

European Journal of Endocrinology sensorineural hearing imparment, obesity, insulin resistance Campomelic dysplasia (114290) SOX9 Congenital bowing and angulation of AD (264) long bones, other skeletal and extraskeletal defects Congenital disorders of glycosylation Multiple genes Multisystem disorders caused by AR (168) (O76) defects in biosynthesis of glyco- conjugates Kabuki syndrome 1 (147920) and 2 KMT2D, KDM6A Long palpebral fissures, eversion of AD (265) (300867) lateral third of the lower eyelids, broad and depressed nasal tip, large prominent earlobes, cleft or high- arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of vertebrae, hands, and hip joints, recurrent otitis media in infancy Kenny–Caffey syndrome type 1 TBCE, FAM111A Craniofacial anomalies, small hands AR (6, 266) (244460) and 2 (127000) and feet, hypocalcemia, hypopara- AD thyroidism, cortical thickening of long bones with medullary stenosis, delayed closure of anterior fonta- nel, eye abnormalities, transient hypocalcemia. Gene encodes tubulin-specific chaperone E.

AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive. aName (number) according to OMIM.

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R155

cardio-facio-cutaneous, and neurofibromatosis–Noonan Syndromes with (usually) normal head circumference syndrome, all characterized by postnatal growth failure CHARGE syndrome is caused by heterozygous mutations of varying degree (156, 157). Mutations in these genes can in CHD7 (169) or SEMA3E (170). CHD7 is a transcriptional also cause short stature without obvious clinical features regulator that binds to enhancer elements in the nucleo- (158). Inhibition of IGF1 release via GH-induced ERK plasm, and also functions as a positive regulator of rRNA hyperactivation or EGF-induced PI3K/AKT/GSK-3b stimu- biogenesis in the nucleolus (171). lation may contribute to short stature in patients with Patients diagnosed with Coffin–Siris syndrome have a PTPN11 mutations (159, 160). broad clinical variability, and at present mutations in six Genetic aberrations in several other intracellular genes have been reported, all encoding components of the pathways play a role in short stature syndromes. For SWI/SNF complex (172, 173). The gene associated with example, mutations in FGD1, encoding a guanine nucleo- Floating–Harbor syndrome (SRCAP) encodes a component tide exchange factor of the Rho/Rac family of small of SWI/SNF chromatin remodelling complexes (174, 175). GTP-binding proteins, cause the X-linked form of The KBG syndrome is caused by a heterozygous Aarskog–Scott syndrome (faciogenital dysplasia) (161), mutation in ANKRD11 (176), encoding a member of a although in only 18% of clinically suspected cases a family of ankyrin repeat-containing cofactors that mutation was found (162). FGD1 activates MAP3K mixed- lineage kinase 3 (MLK3), which regulates ERK and p38 interacts with p160 nuclear receptor coactivators and MAPK, which in turn phosphorylate and activate the inhibits ligand-dependent transcriptional activation (177). master regulator of osteoblast differentiation, RUNX2 Mulibrey nanism (referring to muscle, liver, brain and (163). FGD1 is involved in the regulation of the formation eye) is caused by homozygous mutations in TRIM37, and function of invadopodia and podosomes, which are which encodes a peroxisomal protein that mono-ubiqui- cellular structures devoted to degradation of the extra- tinates histone H2A, a chromatin modification associated cellular matrix in tumour and endothelial cells (164). with transcriptional repression (178). In contrast to a Inactivating mutations in SOX9 cause a severe skeletal promising short-term effect of GH treatment, the effect on dysplasia, campomelic dysplasia. The encoded protein adult height is modest (5 cm) (179). and its distant relatives SOX5 and SOX6 also activate the SHORT syndrome is caused by mutations in PIK3R1 genes for cartilage-specific extracellular matrix com- (p85-alpha). In addition to regulating PI3K function, ponents (165). p85-alpha and p85-beta regulate the function of XBP-1, Congenital disorders of glycosylation (CDG) are a a transcription factor that orchestrates the unfolded protein

European Journal of Endocrinology rapidly expanding family of genetic diseases due to defects response following endoplasmic reticulum stress (180). in the synthesis of the glycan moiety of glycoproteins and SOFT syndrome, caused by homozygous POC1A glycolipids and in their attachment to proteins and lipids. mutations, is associated with severe pre- and post-natal Most CDG are multisystem disorders, and many are short stature, symmetric shortening of long bones, associated with skeletal abnormalities, including short triangular facies, sparse hair, and short, thickened distal stature and microcephaly (166, 167, 168). phalanges (181, 182). Three-M syndrome is caused by defects in one of three genes: CUL7 (encoding a ubiquitin ligase) (183), OBSL1 (encoding a cytoskeletal adaptor) (184) or CCDC8 (encoding Genetic defects in fundamental cellular a protein possibly linked to CUL7 through the adaptor processes protein OBSL1) (185, 186). The products of these genes play Mutations in genes encoding proteins involved in a critical role in maintaining microtubule integrity with fundamental cellular processes can produce severe global defects leading to aberrant cell division (17, 187). growth deficiencies, termed primordial dwarfisms, which affect not just the GP but multiple other tissues and Microcephalic primordial dwarfism typically impair both pre- and post-natal growth (17). Several of these syndromes are associated with a normal Microcephalic primordial dwarfism is characterized head circumference, but many are microcephalic. In some by severe pre- and post-natal growth retardation accom- syndromes, DNA repair defects are prominent. Some panied by microcephaly (18). examples are presented in Tables 6 and 7, classified For Cornelia de Lange syndrome, five types have been according to head size and DNA repair. distinguished, and the same applies to Meier–Gorlin

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R156

Table 6 Examples of genetic defects in fundamental cellular processes.

Disordera Gene(s) Clinical features Inheritance References Syndromes with (usually) normal head circumference CHARGE syndrome CHD7, SEMA3E Choanal atresia, malformations of heart, AD (267) (214800) inner ear and retina Coffin–Siris syndrome SMARCB1, SMARCA4, Developmental delay, speech impairment, AD (172) (135900) SMARCA2, ARID1A, coarse facial features, hypertrichosis, ARID1B hypoplastic fifth fingernails or toenails, agenesis of the corpus callosum Floating–Harbor syndrome SRCAP Delayed bone age and speech, triangular face, AD (174, 175) (136140) deep-set eyes, long eyelashes, bulbous nose, wide columella, short philtrum, thin lips KBG syndrome (148050) ANKRD11 Macrodontia of upper central incisors, distinc- AD (176) tive craniofacial findings, skeletal anomalies, global developmental delay, seizures, intellectual disability Mulibrey nanism (253250) TRIM37 Progressive cardiomyopathy, characteristic facial AR (178) features, failure of sexual maturation, insulin resistance with DM2, increased risk for Wilms tumor SHORT syndrome (269880) PIK3R1 hyperextensibility of joints, inguinal hernia, AD (180) ocular depression, teething delay Short stature, onycho- POC1A Severely short long bones, peculiar facies AR (181, 182) dysplasia, facial dys- associated with paucity of hair, triangular morphism, hypotri-chosis facies, nail anomalies, short, thickened distal (SOFT, 614813) phalanges. Relative macrocephaly in childhood, microcephaly in adulthood Three-M syndrome 1 CUL7, OBSL1, CCDC8 Facial features, normal mental development, AR (183, 184, (273750), 2 (612921), long, slender tubular bones, reduced 185, 186) 3 (614205) anteroposterior diameter of vertebral bodies, delayed bone age Microcephalic primordial dwarfism Cornelia de Lange NIPBL, SMC1A, SMC3, Low anterior hairline, arched eyebrows, AD (190) syndrome 1–5 RAD21, HDAC8 synophrys, ante-verted nares, maxillary prognathism, long philtrum, thin lips, ‘carp’ European Journal of Endocrinology mouth, upper limb anomalies. Meier–Gorlin syndrome 1–5 ORC1, ORC4, ORC6, Bilateral microtia, and aplasia or hypoplasia of AR (192, 268) CDT1, CDC6 the patellae, normal intelligence MOPD I (210710) U4atac Neurologic abnormalities, including mental AR (5, 193) retardation, brain malformations, ocular/ auditory sensory deficits MOPD II (210720) PCNT Radiologic abnormalities, absent or mild mental AR (5, 194, 269) retardation in comparison to Seckel syndrome, truncal obesity, diabetes, moyamoya, small loose teeth Microcephaly and chorio- TUBGCP6, PLK4 Retinopathy. The gene encodes PLK4 kinase, AR (270) retinopathy, 1 (251270), a master regulator of centriole duplication. 2 (616171) Rett syndrome (312750) MECP2 Almost exclusively in females. Arrested XLD (271) development (6–18 months), loss of speech, stereotypic movements, microcephaly, seizures, mental retardation. Rubinstein–Taybi syndrome CREBBP, EP300 Mental retardation, broad thumbs and halluces, AD (272) 1 (180849), 2 (613684) dysmorphic facial features Seckel syndrome 1–8 ATR, RBBP8, CENPJ, Mental retardation, characteristic ‘bird-headed’ AR (5, 18, 195) CEP152, CEP63, NIN, facial appearance DNA2, ATRIP Short stature with micro- CRIPT Frontal bossing, high forehead, sparse hair and AR (273) cephaly and distinctive eyebrows, telecanthus, proptosis, anteverted facies (615789) nares, flat nasal bridge

AD, autosomal dominant; AR, autosomal recessive; DM2, diabetes mellitus type 2; MOPD, microcephalic osteodysplastic primordial dwarﬁsm; IUGR, intrauterine growth retardation; XLR, X-linked recessive. aName (number) according to OMIM.

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R157

Table 7 Examples of genetic defects in fundamental cellular processes: DNA repair defects.

Disordera Gene(s) Clinical features Inheritance References

Bloom syndrome (210900) RECQL3 Sun-sensitive, telangiectatic, hypo- and AR (274) hyperpigmented skin, predisposition to malignancy,chromosomal instability Cockayne syndrome A, B, XPG/CS ERCC8, ERCC6, ERCC5, Cutaneous photosensitivity, thin, dry hair, AR (272) (five types) ERCC3, ERCC4 progeroid appearance, pigmentary retinopathy, sensorineural hearing loss, dental caries Fanconi anemia (multiple types) FANCA and multiple Heterogeneous disorder causing genomic AR (275, 276) genes instability, abnormalities in major organ systems, bone marrow failure, high predisposition to cancer Hutchinson–Gilford progeria LMNA Low body weight, early loss of hair, lipo- AD (277) syndrome (176670) dystrophy, scleroderma, decreased joint mobility, osteolysis, facial features that resemble aged persons Hypomorphic PCNA mutation PCNA Hearing loss, premature aging, telangiecta- AR (278) sia, neurodegeneration, photosensitivity by nucleotide excision repair defect Immunoosseous dysplasia, SMARCAL1 Spondyloepiphyseal dysplasia, numerous AR (279) Schimke type (242900) lentigines, slowly progressive immune defect, immune-complex nephritis Natural killer cell and gluco- MCM4 Variant of familial glucocorticoid deficiency: AR (280, 281) corticoid deficiency with DNA hypocortisolemia, increased chromosomal repair defect (609981) breakage, NK cell deficiency Nijmegen breakage syndrome NBS1 Microcephaly, growth retardation, immuno- AR (282) (251260) deficiency, predisposition to cancer Ovarian dysgenesis 4 MCM9 Hypergonadotropic hypogonadism, genomic AR (283) instability Rothmund–Thomson syndrome RECQL4 Skin atrophy, telangiectasia, hyper- and AR (284) hypopigmentation, congenital skeletal abnormalities, premature aging X-linked mental retardation- ATRX Mental retardation, dysmorphic facies, XLR (285) hypotonic facies syndrome hypogonadism, deafness, renal anomalies, (309580) mild skeletal defects Defective nonhomologous end- LIG4, NHEJ1, ARTEMIS, Radiosensitive, severe combined immuno- AR (197, 198, European Journal of Endocrinology joining (NHEJ) DNA damage DNA-PKCs, XRCC4, deficiency 199, 273, repair PRKDC 286, 287)

AD, autosomal dominant; AR, autosomal recessive; DM2, diabetes mellitus type 2; IUGR, intrauterine growth retardation; XLR, X-linked recessive; MOPD, Microcephalic osteodysplastic primordial dwarﬁsm. aName (number) according to OMIM.

syndrome (188, 189, 190, 191, 192). Microcephalic osteo- gene encoding DNA helicase RecQ protein-like-3 (RECQL3). dysplastic primordial dwarﬁsm (MOPD) type I is caused by Cells of these patients show an increased frequency of mutations in RNU4ARAC, encoding a small nuclear RNA chromosomal breaks, and the elevation in the rate of sister that is part of the minor spliceosome and necessary for chromatid exchanges is used as a diagnostic test. Other proper splicing of U12-dependent introns (193). Mutations syndromes include Cockayne syndrome, Fanconi anaemia, in the gene encoding pericentrin (PCNT) cause MOPD type and Rothmund–Thomson syndrome. Fanconi anaemia is a II (5, 194). Seckel syndrome is caused by mutations in many clinically and genetically heterogeneous disorder that different genes encoding proteins involved in DNA damage causes genomic instability. Characteristic clinical features response or centrosomal function (reviewed in (5, 18, 195)). include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark is hypersen- DNA repair defects sitivity to DNA crosslinking agents and high frequency of Many syndromes associated with abnormal DNA repair chromosomal aberrations. present with short stature (Table 7). The best known An important pathway for the repair of DNA double- example is Bloom syndrome, caused by a mutation in the stranded breaks is non-homologous end-joining (196),

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R158

and mutations in several genes encoding proteins 2q35q36.2 deletion (212), and a possible role of dupli- involved in this process have been discovered in short cations of EPAS and RHOQ on chromosome 2p21 in severe individuals, including LIG4 and XRCC4 mutations short stature and delayed bone age (213). For Dubowitz (197, 198, 199). XRCC4 mutations are also associated syndrome, a presumed autosomal recessive disorder with hypergonadotrophic hypogonadism (199). characterized by microcephaly, developmental delay, growth failure, and a predisposition to allergies and eczema, no unifying genetic alteration has been identified, Chromosomal abnormalities, CNVs, and but in a subset of individuals diagnosed with this imprinting disorders associated with short syndrome deletions at 19q13 were found (214). Relatively stature frequent contiguous gene deletion (and occasionally Chromosomal abnormalities duplication) syndromes are listed in Table 8. Apart from these relatively well documented syn- Most guidelines on clinical workup of children with short dromes, there may be many more. Four recent studies stature advise to perform routine karyotyping in females (153, 215, 216, 217) showed that w10% of patients with ISS with unexplained short stature, to detect Turner syndrome. carry a disease-causing CNV, and in short children Indeed, it is very important to diagnose Turner syndrome, microdeletions (in contrast to microduplications) are given the comorbidities (partly potentially life-threaten- significantly more frequent than in controls (218).However, ing) and efficacy of GH treatment. However, the diagnostic for individual cases one often remains uncertain whether yield in females with isolated short stature is low (estimated their growth failure is due to the encountered CNV, and at 4% (200)), so that several clinicians have doubted if this which of the genes is responsible for it. Comparison with would be cost-effective (201, 202, 203, 204). In fact, even in previously reported patients and databases like DatabasE of the presence of clear guidelines for diagnostic studies in Chromosomal Imbalance and Phenotype in Humans using short children, karyotyping was only performed in w50% Ensembl Resources (DECIPHER; http://decipher.sanger.uk) of cases in a Dutch study (205). Potentially useful criteria for and European Cytogeneticists Association Register of a cost-effective selection of short girls for this expensive test Unbalanced Chromosome Aberrations (ECARUCA; http:// may include a large distance between height SDS and target www.ecaruca.net) may give hints for candidate genes. height SDS (e.g., O2 S.D.) (206), delayed puberty and any indication of physical stigmata. Deletions of the long arm of the Y chromosome, or X/XY mosaicisms in phenotypic Imprinting disorders and uniparental disomy

European Journal of Endocrinology females or males, are associated with short stature Examples of imprinting disorders are shown in Table 9. (207, 208, 209, 210).However,inshortmalesthe The best known example of a growth disorder associated diagnostic yield of karyotyping is low (3%) (200). with an imprinting disorder is the Silver–Russell syn- Besides numerical aberrations of sex chromosomes, drome, which is most commonly caused by hypomethyla- several other chromosome abnormalities associated with short stature are detectable with routine karyotyping, tion of an imprinting control region on the paternal allele e.g., Down syndrome (trisomy 21), Edwards syndrome of chromosome 11p15.5, controlling the methylation of (trisomy 18), Patau syndrome (trisomy 13), and trisomy 17 the IGF2 and H19 genes (219). However, also multilocus mosaicism (211). loss-of-methylation can occur (220, 221). Other genetic causes include uniparental (maternal) disomy of chromosome 7 (UPD7) (79) and a mutation in the paternally Copy number variants imprinted gene CDKN1C (222). CDKN1C mutations are As alluded to in the introduction, CNVs can be detected by also associated with the IMAGe syndrome, characterized array-CGH (2) or SNP arrays (1). With these methods, by intrauterine growth restriction, metaphyseal dysplasia, many new microdeletion and microduplication syn- congenital adrenal hypoplasia, and genital anomalies dromes have been identiﬁed, and several novel genes (223), and a syndrome of pre and postnatal growth failure associated with short stature as part of contiguous and early-onset diabetes mellitus (224). The clinical gene syndromes have been discovered. Examples include spectrum of Silver–Russell syndrome is considerably the observation that EPHA4 haploinsufﬁciency is broader than thought before, and lack of intrauterine responsible for short stature observed in children with growth restriction should not automatically result in Waardenburg syndrome caused by a chromosome exclusion from molecular testing (225).

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R159

Table 8 Examples of contiguous gene deletion or duplication syndromes associated with short stature.

Disordera Location Clinical features References Recurrent rearrangements of 1q21.1 1q21.1del Intellectual disability, autism spectrum disorder, (288) microcephaly, cardiac abnormalities, cataracts 2p16p22 microduplication syndrome 2p16p22dup Delayed bone age, facial dysmorphism. Role of (213) EPAS and RHOQ? Wolf–Hirschhorn syndrome (194190) 4p16.3del ‘Greek warrior helmet’, epicanthal folds, short (289, 290) philtrum, downturned corners of mouth, micrognathia, seizures. Mitochondrial defect by LETM1 haploinsufﬁciency Chromosome 4q21 deletion syndrome 4q21del Neonatal muscular hypotonia, severe psychomotor (291) (613509) retardation, severely delayed speech, broad forehead, frontal bossing, hypertelorism, short philtrum, downturned corners of mouth Cri-du-chat syndrome (123450) 5p15.2ter del High-pitched catlike cry, microcephaly, round face, (292) ocular hypertelorism, micrognathia, epicanthal folds, low-set ears, hypotonia, severe psychomotor retardation. CTNND2? Short stature, microce-phaly, speech 5q35.2q35.3dup Microcephaly, speech delay. Reciprocal to common (293) delay Sotos syndrome deletion (increased NSD1 function?) Williams–Beuren syndrome (194050) 7q11.23del Supravalvular aortic stenosis, intellectual disability, (294) distinctive facial features Trichorhinophalangeal syndrome, type II 8q21.11q24.13del Large, laterally protruding ears, bulbous nose, (295) (Langer–Giedion syndrome) (150230) elongated upper lip, sparse scalp hair, winged scapulae, multiple cartilaginous exostoses, redundant skin, intellectual disability. TRPS1, EXT1? WAGR syndrome (194072) 11p13del Aniridia, hemihypertrophy, Wilms tumor, (296) cryptorchidism. PAX6, WT1? 12q14 microdeletion syndrome 12q14del Developmental delay, osteopoikilosis. HMGA2? (297, 298) Chromosome 13q14 deletion syndrome 13q14del Retinoblastoma, mental impairment, high forehead, (299) (613884) prominent philtrum, anteverted earlobes Frias syndrome (609640) 14q22.1q22.3del Exophthalmia, palpebral ptosis, hypertelorism, short (300) square hands, small broad great toes. BMP4? Distal 14q duplication syndrome 14q32.2-qter Mild developmental delay, high forehead, hyper- (230) telorism, dysplastic ear helices, short philtrum, cupid

European Journal of Endocrinology bow upper lip, broad mouth, micrognathia Smith–Magenis syndrome (182290) 17p11.2del Brachycephaly, midface hypoplasia, prognathism, (301) hoarse voice, speech delay, hearing loss, psychomotor retardation, behavioral problems. RAI1? Can be associated with GHD Miller–Dieker lissencephaly syndrome 17p13.3del Lissencephaly, microcephaly, wrinkled skin over (302, 303) (247200) glabella and frontal suture, prominent occiput, narrow forehead, downward slanting palpebral ﬁssures, small nose and chin, cardiac malformations, hypoplastic male external genitalia, seizures. CRK? 17q21q25 duplication syndrome 17q2125dup Developmental delay, distal arthrogryposis. (66, 304) GH insensitivity, disturbed STAT5B, PI3K, and NF-kappaB signaling. Role of PRKCA mRNA overexpression? Chromosome 18p deletion syndrome 18p11del Intellectual disability, round face, dysplastic ears, wide (305) (146390) mouth, abnormalities of teeth, limbs, genitalia, brain, eyes, heart Chromosome 18q deletion syndrome 18q22.3q23del Congenital aural atresia, GHD, intellectual disability, (306, 307) (601808) reduced white-matter myelination, foot deformities Velocardiofacial syndrome (192430) 22q11.2del Highly variable phenotype. Central deletions: cardiac (308, 309) disorders, learning delays, dysmorphic facial features, hypernasal speech, velopalatal insufﬁciency, hypocalcemia, hypoparathyroidism, psychiatric disorders; role of TBX1? Distal: role of MAPK1?

GHD, growth hormone deﬁciency; WAGR syndrome, Wilms tumor, Aniridia, genitourinary anomalies, and mental retardation syndrome. aName (number) according to OMIM.

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R160

Table 9 Examples of imprinting disorders.

Disordera Genetics Clinical features References

Silver–Russell syndrome (180860) Hypomethylation of imprinting Severe IUGR, triangular shaped (79, 219, 220, 229, 310) control region on paternal face, broad forehead, body allele of 11p15.5 controling asymmetry, variety of minor methylation of IGF2 and H19 malformations Maternal UPD7 (SRS, 7p11.2) Silver–Russell syndrome or IMAGe Mutation in paternally imprinted IUGR, metaphyseal dysplasia, (222, 224) syndrome (614732) or IUGR C gene CDKN1C adrenal hypoplasia congenita, early-onset diabetes mellitus genital anomalies; or only Silver–Russell syndrome; or IUGR and early-adulthood- onset diabetes with normal adrenal function Prader–Willi syndrome (176270) Loss of expression of paternal Intellectual disability, seizures, (226) copies of imprinted genes poor gross and ﬁne motor (SNRPN, NDN), and others coordination, behavioral (15q11–q13) by deletion, problems, sleep disturbances, maternal UPD, imprinting high pain threshold center defect, or Robertsonian translocation Pseudohypoparathyroidism Heterozygous GNAS1 (20q13.32) Resistance to parathyroid (228) type 1a/c (103580) mutation inherited from hormone and other hormones mother Pseudohypoparathyroidism Both alleles have a paternal- Resistance to PTH is present with- type 1b (603233) speciﬁc imprinting pattern on out signs of Albright hereditary both parental alleles osteodystrophy Pseudopseudohypopara – Heterozygous GNAS1 mutation Albright hereditary osteodystro- thyroidism (612463) inherited from father phy without multiple hormone resistance, brachydactyly Temple syndrome (616222) Maternal UPD14 (14q32) Low birth weight, hypotonia, (153, 229) motor delay, feeding problems early in life, early puberty, reduced adult height, broad forehead, short nose with wide nasal tip, small hands and feet European Journal of Endocrinology IUGR, intrauterine growth retartdation. aName (number) according to OMIM.

Another well-known example is Prader–Willi syn- activate cAMP-dependent pathways via Gsa protein. The drome, a contiguous gene syndrome. There are three two main subtypes of PHP (types Ia and Ib) are caused by main genetic subtypes: a paternal chromosome 15q11q13 molecular alterations within or upstream of the imprinted deletion (65–75% of cases), a maternal UPD of chromo- GNAS gene, which encodes Gsa and other translated and some 15 (20–30% of cases), and an imprinting defect untranslated products. Patients who inherited a GNAS (1–3%). It is now thought that deletion of the paternal mutation from their father develop Albright hereditary copies of the imprinted genes SNRPN, NDN, and possibly osteodystrophy (AHO) without multiple hormone resist- others within the chromosome region 15q11q13, are ance (pseudopseudohypoparathyroidism), characterized responsible for the phenotype (226). GH secretion can be by brachydactyly and short stature. In contrast, patients low and GH treatment has positive effects on linear who inherited the mutation from their mother, addition- growth and body composition (227). ally develop resistance to PTH and other hormones Loss-of-function mutations of GNAS, coding for the (pseudohypoparathyroidism type 1a or 1c). This difference a-subunit of the Gs protein, is associated with a spectrum is caused by the tissue-speciﬁc imprinting of GNAS. of growth disorders (228). The term pseudohypopara- In pseudohypoparathyroidism type 1b only resistance to thyroidism indicates a group of heterogeneous disorders PTH is present without signs of AHO, due to an imprinting whose common feature is represented by impaired defect of GNAS with silencing of the maternal allele, signalling of various hormones (primarily PTH) that affecting mainly the renal tubules.

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R161

Besides UPD7, there is another UPD syndrome that is patients, since in the majority short stature is probably associated with short stature and various additional clinical of polygenic origin. If there is no strong suspicion on a features: maternal UPD14 (Temple syndrome) (229). This certain genetic diagnosis, or if initial testing showed no syndrome shares similarities with the distal 14q dupli- abnormality – while a monogenic disorder appears very cation phenotype (Table 8) (230). We showed that such likely – the clinician can either accept the diagnosis diagnoses can be found using SNP array technology in ‘apparent ISS’ or proceed on a hypothesis-free approach. children who had been considered ISS (153). To arrive at this decision, various considerations apply, There may be many more epigenetic disorders including the availability of DNA from other family associated with short stature. In a study on 79 patients members, informed consent, local infrastructure, and with suspected Silver–Russell syndrome or unexplained financial aspects. It is noteworthy that presently limited short stature/intrauterine growth restriction, 37% showed information is available about the sensitivity, specificity a methylation abnormality in eleven imprinted loci. The and cost-effectiveness of this approach, while it is commonest finding was a loss of methylation at H19, and important that the ethical aspects are properly dealt a gain of methylation at IGF2R was significantly more with, for example appropriate informed consent forms observed than in controls (231). Another example is the including information about handling incidental find- epigenetic control of several parts of the IGF1 signalling ings. For details we refer to recently published guidelines pathway. The IGF1 P2 promotor is an epigenetic quan- for diagnostic next-generation sequencing (235). titative trait locus (QTL), and methylation of a cluster of The hypothesis-free approach consists of two steps. six CGs located within the proximal part of this promoter First, an array-cGH or SNP array is carried out, to search for shows a strong negative association with serum IGF1 and CNVs and uniparental disomies (with SNP-arrays) (1). Even growth (232). In children with ISS CG-137 methylation in if no CNV is found, the results are useful for the analysis this promoter contributed 30% to the variance of the IGF1 of the second step, WES. For example, SNP arrays provide response to GH in an IGF1 generation test (233). information about homozygous regions, which can be used in the bioinformatic analyses of the WES data, particularly if a recessive condition is suspected. If a Diagnostic approach potentially causative gene variant is found, it should be In agreement with Dauber et al. (5), we believe that genetic confirmed by Sanger sequencing. After confirmation, testing to identify rare monogenic causes of short stature is cosegregation studies in affected and non-affected relatives important for various reasons: i) it can end the diagnostic should be performed, and if confirmatory, functional

European Journal of Endocrinology workup and the family’s uncertainty about the cause of studies are usually indicated to provide final proof. the condition; ii) it may alert the clinician to other However, we expect that in the coming years further medical comorbidities; iii) it is invaluable for genetic reduction of costs of next generation sequencing counselling; and iv) it may have implications for therapy technologies will render this step-wise approach super- (e.g., some conditions, such as Bloom syndrome, are fluous, so that WES will be used as a tool to identify contraindications for GH treatment (234)). With respect small mutations as well as CNVs and homozygous to the question of who should undergo genetic testing, the regions. The next step that the field will probably take clinician should take several factors into consideration is WGS which, in combination with RNA sequencing of that increase the likelihood of a monogenic cause of short the whole transcriptome and sequencing-based DNA stature (5). The severity of the growth failure, presence of methylation analysis of the whole genome, will provide additional abnormalities, presence of sibling or parent additional information. It will probably lead to further with similar features, and consanguinity may be the most novel insights in the causes of short stature, if the ability important indicators. to interpret sequence variants outside the exome can be The genetic evaluation of short stature is well improved. described in a recent review, which also presents a useful diagnostic algorithm (5) in a step-wise fashion. If a Conclusion particular genetic aetiology or syndrome is suspected, based on clinical features such as birth size, head In the past decade, many novel gene defects have been circumference, body proportions, and inheritance pattern, found in association with multiple clinical disorders a single gene-based test or gene panel is usually indicated. associated with short stature, which has enormously We estimate that this applies to a limited number of expanded the ability of clinicians to obtain a diagnosis

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R162

in their patients. A more widespread use of currently New England Journal of Medicine 2013 369 1502–1511. (doi:10.1056/ available genetic tools will certainly lead to a further NEJMoa1306555) 4 Biesecker LG & Green RC. Diagnostic clinical genome and exome increase of clinical syndromes associated with genetic sequencing. New England Journal of Medicine 2014 370 2418–2425. aberrations. We agree with Lu et al. (236) and Dauber et al. (doi:10.1056/NEJMra1312543) 5 Dauber A, Rosenfeld RG & Hirschhorn JN. Genetic evaluation of short (5) that clinical use of sequencing data may reduce the cost stature. Journal of Clinical Endocrinology and Metabolism 2014 99 3080– of care, result in more specific treatment guidelines and 3092. (doi:10.1210/jc.2014-1506) avoidance of costly diagnostic and therapeutic procedures, 6 Guo MH, Shen Y, Walvoord EC, Miller TC, Moon JE, Hirschhorn JN & Dauber A. Whole exome sequencing to identify genetic causes of short and reduce variance in diagnosis and treatment outcomes stature. Hormone Research in Pædiatrics 2014 82 44–52. (doi:10.1159/ between academic medical centres and community 000360857) hospitals and clinics. 7 Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, Chu AY, Estrada K, Luan J, Kutalik Z et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nature Genetics 2014 46 1173–1186. (doi:10.1038/ Declaration of interest ng.3097) J M Wit has served as consultant for Pfizer, Biopartners, OPKO, Versartis, 8 Lui JC, Nilsson O, Chan Y, Palmer CD, Andrade AC, Hirschhorn JN & Teva, Merck-Serono, and Ammonett and has received speaker’s honoraria Baron J. Synthesizing genome-wide association studies and expression from Pfizer, Versartis, Merck-Serono, Lilly and Sandoz. W Oostdijk received microarray reveals novel genes that act in the human growth plate to unrestricted grant support from Novo Nordisk, Ipsen and Ferring. The other modulate height. Human Molecular Genetics 2012 21 5193–5201. authors have nothing to disclose. (doi:10.1093/hmg/dds347) 9 Lui JC, Nilsson O & Baron J. Recent research on the growth plate: Recent insights into the regulation of the growth plate. Journal of Molecular Endocrinology 2014 53 T1–T9. (doi:10.1530/JME-14-0022) Funding 10 Kant SG, Wit JM & Breuning MH. Genetic analysis of short stature. This review did not receive any specific grant from any funding agency in Hormone Research 2003 60 157–165. (doi:10.1159/000073226) the public, commercial or not-for-profit sector. 11 Walenkamp MJ & Wit JM. Genetic disorders in the growth hormone– IGFI axis. Hormone Research 2006 66 221–230. (doi:10.1159/ 000095161) 12 Wit JM, Ranke MB & Kelnar CJH. ESPE classification of paediatric Search Strategy endocrine diagnoses. Hormone Research 2007 68 (Suppl 2) 1–120. The search strategy started with updating information on genetic causes of 13 Wit JM, Kiess W & Mullis P. Genetic evaluation of short stature. short stature described in previous reviews (10, 11, 13) and others (5, 14, 15, Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 16, 17), through OMIM and PubMed. Novel genetic causes were found with 1–17. (doi:10.1016/j.beem.2010.06.007) the following search strategy (courtesy J. Schoones, Leiden): 14 Mortier GR, Graham JM Jr & Rimoin DL. Short stature syndromes. In Growth Disorders, ch. 17, 2nd edn, pp 259–280. Eds CJH Kelnar, (("body size"[Majr] OR Body Size[ti] OR "body height"[Majr] OR body MO Savage, P Saenger & CT Cowell. London, UK: Hodder Arnold, 2007. height[Ti] OR "body height"[ti] OR (growth[ti] NOT ("growth factor"[ti] 15 Seaver LH & Irons M. ACMG practice guideline: genetic evaluation of European Journal of Endocrinology OR "growth factors"[ti]))) AND ("child"[MeSH Terms] OR child[Text Word] short stature. Genetics in Medicine 2009 11 465–470. (doi:10.1097/GIM. OR children[Text Word] OR "infant"[MeSH Terms] OR infant[Text Word] OR 0b013e3181a7e8f8) infants[Text Word] OR pediatric[tiab] OR paediatric[tiab]) NOT (obese 16 Durand C & Rappold GA. Height matters-from monogenic disorders OR obesity OR obes* OR mice[tiab] OR animal[tiab] OR animals[tiab] OR to normal variation. Nature Reviews. Endocrinology 2013 9 171–177. cattle[tiab] OR bovine[tiab] OR cows[tiab] OR pigs[tiab] OR birds[tiab] (doi:10.1038/nrendo.2012.251) OR fish[tiab] OR snakes[tiab] OR squirrels[tiab] OR cow[tiab] OR pig[tiab] 17 Baron J, Savendahl L, De Luca F, Dauber A, Phillip M, Wit JM & OR bird[tiab] OR fishes[tiab] OR snake[tiab] OR squirrel[tiab]) AND Nilsson O. Short and tall stature: a new paradigm emerges. english[la] AND ("genetics"[Subheading] OR "genetics"[tw] OR "genetics" Nature Reviews. Endocrinology 2015 11 735–746. (doi:10.1038/nrendo. [mesh] OR "Genetic Techniques"[mesh])) AND ("2005/01/01"[PDAT]: 2015.165) "3000/12/31"[PDAT]) NOT ("cell growth"[tw] OR "Cell Transformation, 18 Klingseisen A & Jackson AP. Mechanisms and pathways of growth Neoplastic"[mesh] OR "Cell Proliferation"[mesh] OR "Gene Expression failure in primordial dwarfism. Genes & development 2011 25 Regulation, Neoplastic"[mesh] OR "Cell Movement"[mesh]). 2011–2024. (doi:10.1101/gad.169037) 19 Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R & Rogol A. Management of the child born small for gestational age through to adulthood: a consensus statement of the International References Societies of Pediatric Endocrinology and the Growth Hormone Research Society. Journal of Clinical Endocrinology and Metabolism 2007 1 Gijsbers AC & Ruivenkamp CA. Molecular karyotyping: from 92 804–810. (doi:10.1210/jc.2006-2017) microscope to SNP arrays. Hormone Research in Pædiatrics 2011 76 20 Rosenfeld RG. The molecular basis of idiopathic short stature. 208–213. (doi:10.1159/000330406) Growth Hormone & IGF Research 2005 15 S3–S5. (doi:10.1016/j.ghir. 2 Kharbanda M, Tolmie J & Joss S. How to use. microarray comparative 2005.06.014) genomic hybridisation to investigate developmental disorders. 21 Rosenfeld RG & von Stein T. A database and website for molecular Archives of Disease in Childhood. Education and Practice Edition 2015 100 defects of the GH–IGF axis: www.growthgenetics.com. Hormone 24–29. (doi:10.1136/archdischild-2014-306022) Research in Pædiatrics 2013 80 443–448. (doi:10.1159/000355543) 3 Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, 22 Alatzoglou KS & Dattani MT. Genetic forms of hypopituitarism and Braxton A, Beuten J, Xia F, Niu Z et al. Clinical whole-exome their manifestation in the neonatal period. Early Human Development sequencing for the diagnosis of mendelian disorders. 2009 85 705–712. (doi:10.1016/j.earlhumdev.2009.08.057)

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R163

23 Pfaffle R & Klammt J. Pituitary transcription factors in the aetiology of 37 McMahon SK, Pretorius CJ, Ungerer JP, Salmon NJ, Conwell LS, combined pituitary hormone deficiency. Best Practice & Research. Pearen MA & Batch JA. Neonatal complete generalized glucocorticoid Clinical Endocrinology & Metabolism 2011 25 43–60. (doi:10.1016/j. resistance and growth hormone deficiency caused by a novel beem.2010.10.014) homozygous mutation in Helix 12 of the ligand binding domain 24 McCabe MJ, Alatzoglou KS & Dattani MT. Septo-optic dysplasia and of the glucocorticoid receptor gene (NR3C1). Journal of Clinical other midline defects: the role of transcription factors: HESX1 and Endocrinology and Metabolism 2010 95 297–302. (doi:10.1210/ beyond. Best Practice & Research. Clinical Endocrinology & Metabolism jc.2009-1003) 2011 25 115–124. (doi:10.1016/j.beem.2010.06.008) 38 Rocha V, Rocha D, Santos H & Marques JS. Growth hormone 25 Sun Y, Bak B, Schoenmakers N, van Trotsenburg AS, Oostdijk W, deficiency in a patient with mitochondrial disease. Journal of Pediatric Voshol P, Cambridge E, White JK, Le Tissier P, Gharavy SN et al. Endocrinology & Metabolism 2015 28 1003–1004. (doi:10.1515/jpem- Loss-of-function mutations in IGSF1 cause an X-linked syndrome of 2014-0315) central hypothyroidism and testicular enlargement. Nature Genetics 39 Wit JM, Oostdijk W & Losekoot M. Spectrum of insulin-like growth 2012 44 1375–1381. (doi:10.1038/ng.2453) factor deficiency. Endocrine Development 2012 23 30–41. (doi:10.1159/ 26 Joustra SD, Schoenmakers N, Persani L, Campi I, Bonomi M, Radetti G, 000341739) Beck-Peccoz P, Zhu H, Davis TM, Sun Y et al. The IGSF1 deficiency 40 Pantel J, Legendre M, Nivot S, Morisset S, Vie-Luton MP, Le Bouc Y, syndrome: characteristics of male and female patients. Journal of Epelbaum J & Amselem S. Recessive isolated growth hormone Clinical Endocrinology and Metabolism 2013 98 4942–4952. deficiency and mutations in the ghrelin receptor. Journal of Clinical (doi:10.1210/jc.2013-2743) Endocrinology and Metabolism 2009 94 4334–4341. (doi:10.1210/jc. 27 Aydin BK, Bas F, Tamay Z, Kilic G, Suleyman A, Bundak R, Saka N, 2009-1327) Ozkaya E, Guler N & Darendeliler F. Netherton syndrome associated 41 Inoue H, Kangawa N, Kinouchi A, Sakamoto Y, Kimura C, Horikawa R, with growth hormone deficiency. Pediatric Dermatology 2014 31 Shigematsu Y, Itakura M, Ogata T & Fujieda K. Identification and 90–94. (doi:10.1111/pde.12220) functional analysis of novel human growth hormone secretagogue 28 Alatzoglou KS, Turton JP, Kelberman D, Clayton PE, Mehta A, receptor (GHSR) gene mutations in Japanese subjects with short Buchanan C, Aylwin S, Crowne EC, Christesen HT, Hertel NT et al. stature. Journal of Clinical Endocrinology and Metabolism 2011 96 Expanding the spectrum of mutations in GH1 and GHRHR: genetic E373–E378. (doi:10.1210/jc.2010-1570) screening in a large cohort of patients with congenital isolated growth 42 Pugliese-Pires PN, Fortin JP, Arthur T, Latronico AC, Mendonca BB, hormone deficiency. Journal of Clinical Endocrinology and Metabolism Villares SM, Arnhold IJ, Kopin AS & Jorge AA. Novel inactivating 2009 94 3191–3199. (doi:10.1210/jc.2008-2783) mutations in the GH secretagogue receptor gene in patients with 29 Petkovic V, Godi M, Pandey AV, Lochmatter D, Buchanan CR, constitutional delay of growth and puberty. European Journal of Dattani MT, Eble A, Fluck CE & Mullis PE. Growth hormone (GH) Endocrinology/European Federation of Endocrine Societies 2011 165 deficiency type II: a novel GH-1 gene mutation (GH-R178H) affecting 233–241. (doi:10.1530/EJE-11-0168) secretion and action. Journal of Clinical Endocrinology and Metabolism 43 Laron Z, Pertzelan A & Mannheimer S. Genetic pituitary dwarfism 2010 95 731–739. (doi:10.1210/jc.2009-1247) with high serum concentation of growth hormone – a new inborn 30 Fritez N, Sobrier ML, Iraqi H, Vie-Luton MP, Netchine I, El Annas A, error of metabolism? Israel Journal of Medical Sciences 1966 2 152–155. Pantel J, Collot N, Rose S, Piterboth W et al. Molecular screening of a 44 Amselem S, Duquesnoy P, Attree O, Novelli G, Bousnina S, Postel- large cohort of Moroccan patients with congenital hypopituitarism. Vinay MC & Goossens M. Laron dwarfism and mutations of the Clinical Endocrinology 2015 82 876–884. (doi:10.1111/cen.12706) growth hormone-receptor gene. New England Journal of Medicine 1989 31 Duriez B, Duquesnoy P, Dastot F, Bougneres P, Amselem S & 321 989–995. (doi:10.1056/NEJM198910123211501) Goossens M. An exon-skipping mutation in the btk gene of a patient 45 Godowski PJ, Leung DW, Meacham LR, Galgani JP, Hellmiss R, Keret R, European Journal of Endocrinology with X-linked agammaglobulinemia and isolated growth hormone Rotwein PS, Parks JS, Laron Z & Wood WI. Characterization of the deficiency. FEBS Letters 1994 346 165–170. (doi:10.1016/0014-5793 human growth hormone receptor gene and demonstration of a partial (94)00457-9) gene deletion in two patients with Laron-type dwarfism. PNAS 1989 32 Burkitt Wright EM, Perveen R, Clayton PE, Hall CM, Costa T, 86 8083–8087. (doi:10.1073/pnas.86.20.8083) Procter AM, Giblin CA, Donnai D & Black GC. X-linked isolated 46 David A, Hwa V, Metherell LA, Netchine I, Camacho-Hubner C, growth hormone deficiency: expanding the phenotypic spectrum of Clark AJ, Rosenfeld RG & Savage MO. Evidence for a continuum of SOX3 polyalanine tract expansions. Clinical Dysmorphology 2009 18 genetic, phenotypic, and biochemical abnormalities in children with 218–221. (doi:10.1097/MCD.0b013e32832d06f0) growth hormone insensitivity. Endocrine Reviews 2011 32 472–497. 33 Argente J, Flores R, Gutierrez-Arumi A, Verma B, Martos-Moreno GA, (doi:10.1210/er.2010-0023) Cusco I, Oghabian A, Chowen JA, Frilander MJ & Perez-Jurado LA. 47 Kurtoglu S & Hatipoglu N. Growth hormone insensitivity: diagnostic Defective minor spliceosome mRNA processing results in isolated and therapeutic approaches. Journal of Endocrinological Investigation familial growth hormone deficiency. EMBO Molecular Medicine 2014 6 2015. In press. 299–306. (doi:10.1002/emmm.201303573) 48 Maamra M, Finidori J, Von Laue S, Simon S, Justice S, Webster J, 34 Lucas-Herald AK, Kinning E, Iida A, Wang Z, Miyake N, Ikegawa S, Dower S & Ross R. Studies with a growth hormone antagonist and McNeilly J & Ahmed SF. A case of functional growth hormone dual-fluorescent confocal microscopy demonstrate that the full- deficiency and early growth retardation in a child with IFT172 length human growth hormone receptor, but not the truncated mutations. Journal of Clinical Endocrinology and Metabolism 2015 100 isoform, is very rapidly internalized independent of Jak2-Stat5 1221–1224. (doi:10.1210/jc.2014-3852) signaling. Journal of Biological Chemistry 1999 274 14791–14798. 35 Romano S, Maffei P, Bettini V, Milan G, Favaretto F, Gardiman M, (doi:10.1074/jbc.274.21.14791) Marshall JD, Greggio NA, Pozzan GB, Collin GB et al. Alstrom 49 Metherell LA, Akker SA, Munroe PB, Rose SJ, Caulfield M, Savage MO, syndrome is associated with short stature and reduced GH reserve. Chew SL & Clark AJ. Pseudoexon activation as a novel mechanism for Clinical Endocrinology 2013 79 529–536. (doi:10.1111/cen.12180) disease resulting in atypical growth-hormone insensitivity. American 36 Stagi S, Lapi E, Pantaleo M, Carella M, Petracca A, De Crescenzo A, Journal of Human Genetics 2001 69 641–646. (doi:10.1086/323266) Zelante L, Riccio A & de Martino M. A new case of de novo 6q24.2-q25.2 50 David A, Camacho-Hubner C, Bhangoo A, Rose SJ, Miraki-Moud F, deletion on paternal chromosome 6 with growth hormone deficiency: Akker SA, Butler GE, Ten S, Clayton PE, Clark AJ et al. An intronic a twelve-year follow-up and literature review. BMC Medical Genetics growth hormone receptor mutation causing activation of a 2015 16 69. (doi:10.1186/s12881-015-0212-z) pseudoexon is associated with a broad spectrum of growth hormone

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R164

insensitivity phenotypes. Journal of Clinical Endocrinology and Journal of Clinical Endocrinology and Metabolism 2010 95 4184–4191. Metabolism 2007 92 655–659. (doi:10.1210/jc.2006-1527) (doi:10.1210/jc.2010-0489) 51 Ayling RM, Ross R, Towner P, Von Laue S, Finidori J, Moutoussamy S, 64 Domene HM, Scaglia PA, Martinez AS, Keselman AC, Karabatas LM, Buchanan CR, Clayton PE & Norman MR. A dominant-negative Pipman VR, Bengolea SV, Guida MC, Ropelato MG, Ballerini MG mutation of the growth hormone receptor causes familial short stature et al. Heterozygous IGFALS gene variants in idiopathic short stature (letter). Nature Genetics 1997 16 13–14. (doi:10.1038/ng0597-13) and normal children: impact on height and the IGF system. 52 Iida K, Takahashi Y, Kaji H, Nose O, Okimura Y, Abe H & Chihara K. Hormone Research in Pædiatrics 2013 80 413–423. (doi:10.1159/ Growth hormone (GH) insensitivity syndrome with high serum 000355412) GH-binding protein levels caused by a heterozygous splice site 65 Wu S, Walenkamp MJ, Lankester A, Bidlingmaier M, Wit JM & mutation of the GH receptor gene producing a lack of intracellular De Luca F. Growth hormone and insulin-like growth factor I domain. Journal of Clinical Endocrinology and Metabolism 1998 83 insensitivity of fibroblasts isolated from a patient with an IkBa 531–537. mutation. Journal of Clinical Endocrinology and Metabolism 2010 95 53 Aalbers AM, Chin D, Pratt KL, Little BM, Frank SJ, Hwa V & 1220–1228. (doi:10.1210/jc.2009-1662) Rosenfeld RG. Extreme elevation of serum growth hormone-binding 66 Mul D, Wu S, de Paus RA, Oostdijk W, Lankester AC, protein concentrations resulting from a novel heterozygous splice site Duyvenvoorde HA, Ruivenkamp CA, Losekoot M, Tol MJ, De Luca LF mutation of the growth hormone receptor gene. Hormone Research et al. A mosaic de novo duplication of 17q21-25 is associated with GH 2009 71 276–284. (doi:10.1159/000208801) insensitivity, disturbed in vitro CD28-mediated signaling, and 54 Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J, decreased STAT5B, PI3K, and NFkB activation. European Journal of Pratt KL, Bezrodnik L, Jasper H, Tepper A et al. Growth hormone Endocrinology/European Federation of Endocrine Societies 2012 166 insensitivity associated with a STAT5b mutation. New England 743–752. (doi:10.1530/EJE-11-0774) Journal of Medicine 2003 349 1139–1147. (doi:10.1056/ 67 Wit JM & De Luca F. Atypical defects resulting in growth hormone NEJMoa022926) insensitivity. Growth Hormone & IGF Research 2015. In press. 55 Hwa V, Nadeau K, Wit JM & Rosenfeld RG. STAT5b deficiency: 68 Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Lango AH, Lessons from STAT5b gene mutations. Best Practice & Research. De Franco E, McDonald TJ, Rajala H, Ramelius A, Barton J et al. Clinical Endocrinology & Metabolism 2011 25 61–75. (doi:10.1016/j. Activating germline mutations in STAT3 cause early-onset multi- beem.2010.09.003) organ autoimmune disease. Nature Genetics 2014 46 812–814. 56 Nadeau K, Hwa V & Rosenfeld RG. STAT5b deficiency: an unsuspected (doi:10.1038/ng.3040) cause of growth failure, immunodeficiency, and severe pulmonary 69 Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, disease. Journal of Pediatrics 2011 158 701–708. (doi:10.1016/j.jpeds. Lyons JJ, Engelhardt KR, Zhang Y, Topcagic N et al. Early-onset 2010.12.042) lymphoproliferation and autoimmunity caused by germline STAT3 57 Scalco RC, Hwa V, Domene H, Jasper HG, Belgorosky A, Marino R, gain-of-function mutations. Blood 2015 125 591–599. (doi:10.1182/ Pereira AM, Tonelli C, Wit JM, Rosenfeld RG et al. STAT5B mutations blood-2014-09-602763) in heterozygous state have negative impact on height: another clue in 70 Woods KA, Camacho-Hubner C, Savage MO & Clark AJ. Intrauterine human stature heritability. European Journal of Endocrinology 2015 173 growth retardation and postnatal growth failure associated with 291–296. (doi:10.1530/EJE-15-0398) deletion of the insulin-like growth factor I gene. New England 58 Domene HM, Bengolea SV, Martinez AS, Ropelato MS, Pennisi P, Journal of Medicine 1996 335 1363–1367. (doi:10.1056/ Scaglia P, Heinrich JJ & Jasper HG. Deficiency of the circulating NEJM199610313351805) insulin-like growth factor system associated with inactivation of the 71 Walenkamp MJ, Karperien M, Pereira AM, Hilhorst-Hofstee Y, acid-labile subunit gene. New England Journal of Medicine 2004 350 European Journal of Endocrinology van Doorn J, Chen JW, Mohan S, Denley A, Forbes B, 570–577. (doi:10.1056/NEJMoa013100) van Duyvenvoorde HA et al. Homozygous and heterozygous 59 Domene HM, Hwa V, Jasper HG & Rosenfeld RG. Acid-labile subunit expression of a novel insulin-like growth factor-I mutation. Journal of (ALS) deficiency. Best Practice & Research. Clinical Endocrinology & Clinical Endocrinology and Metabolism 2005 90 2855–2864. Metabolism 2011 25 101–113. (doi:10.1016/j.beem.2010.08.010) 60 van Duyvenvoorde HA, Kempers MJ, Twickler TB, van Doorn J, (doi:10.1210/jc.2004-1254) Gerver WJ, Noordam C, Losekoot M, Karperien M, Wit JM & 72 Netchine I, Azzi S, Houang M, Seurin D, Perin L, Ricort JM, Daubas C, Hermus AR. Homozygous and heterozygous expression of a novel Legay C, Mester J, Herich R et al. Partial primary deficiency of insulin- mutation of the acid-labile subunit. European Journal of like growth factor (IGF)-I activity associated with IGF1 mutation Endocrinology/European Federation of Endocrine Societies 2008 159 demonstrates its critical role in growth and brain development. 113–120. (doi:10.1530/EJE-08-0081) Journal of Clinical Endocrinology and Metabolism 2009 94 3913–3921. 61 Hess O, Khayat M, Hwa V, Heath KE, Teitler A, Hritan Y, Allon-Shalev S (doi:10.1210/jc.2009-0452) & Tenenbaum-Rakover Y. A novel mutation in IGFALS, c.380TOC 73 van Duyvenvoorde HA, van Setten PA, Walenkamp MJ, van Doorn J, (p.L127P), associated with short stature, delayed puberty, osteopenia Koenig J, Gauguin L, Oostdijk W, Ruivenkamp CA, Losekoot M, and hyperinsulinaemia in two siblings: insights into the roles of Wade JD et al. Short stature associated with a novel heterozygous insulin growth factor-1 (IGF1). Clinical Endocrinology 2013 79 mutation in the insulin-like growth factor 1 gene. Journal of Clinical 838–844. (doi:10.1111/cen.12200) Endocrinology and Metabolism 2010 95 E363–E367. (doi:10.1210/jc. 62 Hogler W, Martin DD, Crabtree N, Nightingale P, Tomlinson J, 2010-0511) Metherell L, Rosenfeld R, Hwa V, Rose S, Walker J et al. IGFALS gene 74 Fuqua JS, Derr M, Rosenfeld RG & Hwa V. Identification of a novel dosage effects on serum IGF-I and glucose metabolism, body heterozygous IGF1 splicing mutation in a large kindred with familial composition, bone growth in length and width, and the pharmaco- short stature. Hormone Research in Pædiatrics 2012 78 59–66. kinetics of recombinant human IGF-I administration. Journal of (doi:10.1159/000337249) Clinical Endocrinology and Metabolism 2014 99 E703–E712. 75 Walenkamp MJ, Losekoot M & Wit JM. Molecular IGF-1 and IGF-1 (doi:10.1210/jc.2013-3718) receptor defects: from genetics to clinical management. Endocrine 63 Fofanova-Gambetti OV, Hwa V, Wit JM, Domene HM, Argente J, Development 2013 24 128–137. (doi:10.1159/000342841) Bang P, Hogler W, Kirsch S, Pihoker C, Chiu HK et al. Impact of 76 Batey L, Moon JE, Yu Y, Wu B, Hirschhorn JN, Shen Y & Dauber A. heterozygosity for acid-labile subunit (IGFALS) gene mutations on A novel deletion of IGF1 in a patient with idiopathic short stature stature: results from the international acid-labile subunit consortium. provides insight Into IGF1 haploinsufficiency. Journal of Clinical

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R165

Endocrinology and Metabolism 2014 99 E153–E159. (doi:10.1210/jc. of the IGF1 receptor gene in a patient with severe pre- and postnatal 2013-3106) growth failure and congenital malformations. European Journal of 77 Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, Endocrinology/European Federation of Endocrine Societies 2013 168 Danton F, Thibaud N, Le MM, Burglen L et al. Epimutation of the K1–K7. (doi:10.1530/EJE-12-0701) telomeric imprinting center region on chromosome 11p15 in 90 Prontera P, Micale L, Verrotti A, Napolioni V, Stangoni G & Merla G. Silver–Russell syndrome. Nature Genetics 2005 37 1003–1007. A new homozygous IGF1R variant defines a clinically recognizable (doi:10.1038/ng1629) incomplete dominant form of SHORT syndrome. Human Mutation 78 Binder G, Seidel AK, Weber K, Haase M, Wollmann HA, Ranke MB & 2015 36 1043–1047. (doi:10.1002/humu.22853) Eggermann T. IGF-II serum levels are normal in children with 91 Jung HJ & Suh Y. Regulation of IGF1 signaling by microRNAs. Silver–Russell syndrome who frequently carry epimutations at the Frontiers in Genetics 2014 5 472. (doi:10.3389/fgene.2014.00472) IGF2 locus. Journal of Clinical Endocrinology and Metabolism 2006 91 92 Boersma B, Otten BJ, Stoelinga GB & Wit JM. Catch-up growth after 4709–4712. (doi:10.1210/jc.2006-1127) prolonged hypothyroidism. European Journal of Pediatrics 1996 155 79 Binder G, Seidel AK, Martin DD, Schweizer R, Schwarze CP, 362–367. (doi:10.1007/BF01955262) Wollmann HA, Eggermann T & Ranke MB. The endocrine phenotype 93 Kuhnen P, Turan S, Frohler S, Guran T, Abali S, Biebermann H, in Silver–Russell syndrome is defined by the underlying epigenetic Bereket A, Gruters A, Chen W & Krude H. Identification of alteration. Journal of Clinical Endocrinology and Metabolism 2008 93 PENDRIN (SLC26A4) mutations in patients with congenital 1402–1407. (doi:10.1210/jc.2007-1897) hypothyroidism and "apparent" thyroid dysgenesis. Journal of 80 Montenegro LR, Leal AC, Coutinho DC, Valassi HP, Nishi MY, Clinical Endocrinology and Metabolism 2014 99 E169–E176. (doi:10. Arnhold IJ, Mendonca BB & Jorge AA. Post-receptor IGF1 insensi- 1210/jc.2013-2619) tivity restricted to the MAPK pathway in a Silver–Russell syndrome 94 Phillips SA, Rotman-Pikielny P, Lazar J, Ando S, Hauser P, Skarulis MC, patient with hypomethylation at the imprinting control region on Brucker-Davis F & Yen PM. Extreme thyroid hormone resistance in a chromosome 11. European Journal of Endocrinology/European patient with a novel truncated TR mutant. Journal of Clinical Federation of Endocrine Societies 2012 166 543–550. (doi:10.1530/EJE- Endocrinology and Metabolism 2001 86 5142–5147. (doi:10.1210/jcem. 11-0964) 86.11.8051) 81 Iliev DI, Kannenberg K, Weber K & Binder G. IGF-I sensitivity in 95 Schoenmakers N, Moran C, Peeters RP, Visser T, Gurnell M & Silver–Russell syndrome with IGF2/H19 hypomethylation. Growth Chatterjee K. Resistance to thyroid hormone mediated by defective Hormone & IGF Research 2014 24 187–191. (doi:10.1016/j.ghir.2014. thyroid hormone receptor a. Biochimica et Biophysica Acta 2013 1830 06.005) 4004–4008. (doi:10.1016/j.bbagen.2013.03.018) 82 Begemann M, Zirn B, Santen G, Wirthgen E, Soellner L, Buttel HM, 96 van Mullem AA, Visser TJ & Peeters RP. Clinical consequences of Schweizer R, van Workum W, Binder G & Eggermann T. Paternally mutations in thyroid hormone receptor-a1. European Thyroid Journal inherited IGF2 mutation and growth restriction. New England 2014 3 17–24. (doi:10.1159/000360637) Journal of Medicine 2015 373 349–356. (doi:10.1056/NEJMoa1415227) 97 Hamajima T, Mushimoto Y, Kobayashi H, Saito Y & Onigata K. Novel 83 Murphy R, Baptista J, Holly J, Umpleby AM, Ellard S, Harries LW, compound heterozygous mutations in the SBP2 gene: characteristic Crolla J, Cundy T & Hattersley AT. Severe intrauterine growth clinical manifestations and the implications of GH and triiodo- retardation and atypical diabetes associated with a translocation thyronine in longitudinal bone growth and maturation. European breakpoint disrupting regulation of the insulin-like growth factor 2 Journal of Endocrinology/European Federation of Endocrine Societies 2012 gene. Journal of Clinical Endocrinology and Metabolism 2008 93 166 757–764. (doi:10.1530/EJE-11-0812) 4373–4380. (doi:10.1210/jc.2008-0819) 98 Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, 84 Munoz-Calvo MT, Barrios V, Pozo J, Martos-Moreno GA, Hawkings European Journal of Endocrinology Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y FG, Domene H, Jasper H, Yakar S, Conover CA, Kopchick.JE et al. et al. Mutations in the deubiquitinase gene USP8 cause Cushing’s A new syndrome of short stature, mild microcephaly, skeletal disease. Nature Genetics 2015 47 31–38. (doi:10.1038/ng.3166) abnormalities and high circulating IGF1, IGFBP3 and ALS associated 99 Beuschlein F, Fassnacht M, Assie G, Calebiro D, Stratakis CA, with a homozygous mutation in the gene for pregnancy-associated Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR et al. Constitutive plasma protein A2 (PAPP-A2, pappalysin2). Endocrine Society Meeting 2015. Abstract. activation of PKA catalytic subunit in adrenal Cushing’s syndrome. 85 Klammt J, Kiess W & Pfaffle R. IGF1R mutations as cause of SGA. New England Journal of Medicine 2014 370 1019–1028. (doi:10.1056/ Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 NEJMoa1310359) 191–206. (doi:10.1016/j.beem.2010.09.012) 100 Semple RK, Savage DB, Cochran EK, Gorden P & O’Rahilly S. 86 Ester WA, van Duyvenvoorde HA, de Wit CC, Broekman AJ, Genetic syndromes of severe insulin resistance. Endocrine Reviews 2011 Ruivenkamp CA, Govaerts LC, Wit JM, Hokken-Koelega AC & 32 498–514. (doi:10.1210/er.2010-0020) Losekoot M. Two short children born small for gestational age with 101 Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, insulin-like growth factor 1 receptor haploinsufficiency illustrate the Nishimura G, Sangiorgi L, Savarirayan R, Sillence D et al. Nosology and heterogeneity of its phenotype. Journal of Clinical Endocrinology and classification of genetic skeletal disorders: 2015 revision. American Metabolism 2009 94 4717–4727. (doi:10.1210/jc.2008-1502) Journal of Medical Genetics. Part A 2015 167 2869–2892. (doi:10.1002/ 87 Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, ajmg.a.37365) Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D et al. IGF-I receptor 102 Kant SG, Grote F, de Ru MH, Oostdijk W, Zonderland HM, mutations resulting in intrauterine and postnatal growth retardation. Breuning MH & Wit JM. Radiographic evaluation of children with New England Journal of Medicine 2003 349 2211–2222. (doi:10.1056/ growth disorders. Hormone Research 2007 68 310–315. (doi:10.1159/ NEJMoa010107) 000108399) 88 Fang P, Cho YH, Derr MA, Rosenfeld RG, Hwa V & Cowell CT. Severe 103 Veeramani AK, Higgins P, Butler S, Donaldson M, Dougan E, short stature caused by novel compound heterozygous mutations of Duncan R, Murday V & Ahmed SF. Diagnostic use of skeletal survey in the insulin-like growth factor 1 receptor (IGF1R). Journal of Clinical suspected skeletal dysplasia. Journal of Clinical Research in Pediatric Endocrinology and Metabolism 2012 97 E243–E247. (doi:10.1210/jc. Endocrinology 2009 1 270–274. (doi:10.4274/jcrpe.v1i6.270) 2011-2142) 104 Alanay Y & Lachman RS. A review of the principles of radiological 89 Gannage-Yared MH, Klammt J, Chouery E, Corbani S, Megarbane H, assessment of skeletal dysplasias. Journal of Clinical Research in Pediatric Abou GJ, Choucair N, Pfaffle R & Megarbane A. Homozygous mutation Endocrinology 2011 3 163–178. (doi:10.4274/jcrpe.463)

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R166

105 Grunwald T & De Luca F. Role of Fibroblast Growth Factor 21 (FGF21) 120 Klopocki E, Lohan S, Brancati F, Koll R, Brehm A, Seemann P, Dathe K, in the regulation of statural growth. Current Pediatric Reviews 2015 11 Stricker S, Hecht J, Bosse K et al. Copy-number variations involving the 98–105. (doi:10.2174/1573396311666150702105152) IHH locus are associated with syndactyly and craniosynostosis. 106 Foldynova-Trantirkova S, Wilcox WR & Krejci P. Sixteen years and American Journal of Human Genetics 2011 88 70–75. (doi:10.1016/j. counting: the current understanding of fibroblast growth factor ajhg.2010.11.006) receptor 3 (FGFR3) signaling in skeletal dysplasias. Human Mutation 121 Linglart A, Menguy C, Couvineau A, Auzan C, Gunes Y, Cancel M, 2012 33 29–41. (doi:10.1002/humu.21636) Motte E, Pinto G, Chanson P, Bougneres P et al. Recurrent PRKAR1A 107 Krejci P. The paradox of FGFR3 signaling in skeletal dysplasia: mutation in acrodysostosis with hormone resistance. New England why chondrocytes growth arrest while other cells over proliferate. Journal of Medicine 2011 364 2218–2226. (doi:10.1056/ Mutation Research. Reviews in Mutation Research 2014 759 40–48. NEJMoa1012717) (doi:10.1016/j.mrrev.2013.11.001) 122 Lindstrand A, Grigelioniene G, Nilsson D, Pettersson M, 108 Song SH, Balce GC, Agashe MV, Lee H, Hong SJ, Park YE, Kim SG & Hofmeister W, Anderlid BM, Kant SG, Ruivenkamp CA, Gustavsson P, Song HR. New proposed clinico-radiologic and molecular criteria in Valta H et al. Different mutations in PDE4D associated with hypochondroplasia: FGFR 3 gene mutations are not the only cause of developmental disorders with mirror phenotypes. Journal of Medical hypochondroplasia. American Journal of Medical Genetics. Part A 2012 Genetics 2014 51 45–54. (doi:10.1136/jmedgenet-2013-101937) 158A 2456–2462. (doi:10.1002/ajmg.a.35564) 123 Estrada K, Krawczak M, Schreiber S, van Duijn K, Stolk L, van Meurs JB, 109 Kant SG, Cervenkova I, Balek L, Trantirek L, Santen GW, de Vries MC, Liu F, Penninx BW, Smit JH, Vogelzangs N et al. A genome-wide van Duyvenvoorde HA, van der Wielen MJ, Verkerk AJ, association study of northwestern Europeans involves the C-type Uitterlinden AG et al. A novel variant of FGFR3 causes proportionate natriuretic peptide signaling pathway in the etiology of human short stature. European Journal of Endocrinology/European Federation of height variation. Human Molecular Genetics 2009 18 3516–3524. Endocrine Societies 2015 172 763–770. (doi:10.1530/EJE-14-0945) (doi:10.1093/hmg/ddp296) 110 Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, 124 Bartels CF, Bukulmez H, Padayatti P, Rhee DK, Ravenswaaij-Arts C, Suzuki K, Yamada G, Schwabe GC et al. The receptor tyrosine kinase Pauli RM, Mundlos S, Chitayat D, Shih LY, Al Gazali LI et al.Mutationsin Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. the transmembrane natriuretic peptide receptor NPR-B impair skeletal Genes to Cells: Devoted to Molecular & Cellular Mechanisms 2003 8 growth and cause acromesomelic dysplasia, type Maroteaux. American 645–654. (doi:10.1046/j.1365-2443.2003.00662.x) Journal of Human Genetics 2004 75 27–34. (doi:10.1086/422013) 111 Cerpa W, Latorre-Esteves E & Barria A. RoR2 functions as a 125 Olney RC, Bukulmez H, Bartels CF, Prickett TC, Espiner EA, Potter LR noncanonical Wnt receptor that regulates NMDAR-mediated synaptic & Warman ML. Heterozygous mutations in natriuretic peptide transmission. PNAS 2015 112 4797–4802. (doi:10.1073/pnas. receptor-B (NPR2) are associated with short stature. Journal of Clinical 1417053112) Endocrinology and Metabolism 2006 91 1229–1232. (doi:10.1210/jc. 112 Roifman M, Marcelis CL, Paton T, Marshall C, Silver R, Lohr JL, 2005-1949) Yntema HG, Venselaar H, Kayserili H, van Bon B et al. De novo WNT5A- 126 Vasques GA, Amano N, Docko AJ, Funari MF, Quedas EP, Nishi MY, associated autosomal dominant Robinow syndrome suggests speci- Arnhold IJ, Hasegawa T & Jorge AA. Heterozygous mutations in ficity of genotype and phenotype. Clinical Genetics 2015 87 34–41. natriuretic peptide receptor-B (NPR2) gene as a cause of short stature (doi:10.1111/cge.12401) in patients initially classified as idiopathic short stature. Journal of 113 Habib R, Amin-ud-din M & Ahmad W. A nonsense mutation in the Clinical Endocrinology and Metabolism 2013 98 E1636–E1644. gene ROR2 underlying autosomal dominant brachydactyly type B. (doi:10.1210/jc.2013-2142) Clinical Dysmorphology 2013 22 47–50. (doi:10.1097/MCD. 127 Amano N, Mukai T, Ito Y, Narumi S, Tanaka T, Yokoya S, Ogata T & European Journal of Endocrinology 0b013e32835c6c8c) Hasegawa T. Identification and functional characterization of two 114 van der Eerden BC, Karperien M, Gevers EF, Lowik CW & Wit JM. novel NPR2 mutations in Japanese patients with short stature. Expression of Indian hedgehog, parathyroid hormone-related protein, Journal of Clinical Endocrinology and Metabolism 2014 99 E713–E718. and their receptors in the postnatal growth plate of the rat: evidence (doi:10.1210/jc.2013-3525) for a locally acting growth restraining feedback loop after birth. 128 Vasques GA, Arnhold IJ & Jorge AA. Role of the natriuretic peptide Journal of Bone and Mineral Research 2000 15 1045–1055. (doi:10.1359/ system in normal growth and growth disorders. Hormone Research in jbmr.2000.15.6.1045) Pædiatrics 2014 82 222–229. (doi:10.1159/000365049) 115 Kronenberg HM. Developmental regulation of the growth plate. 129 Wang SR, Jacobsen CM, Carmichael H, Edmund AB, Robinson JW, Nature 2003 423 332–336. (doi:10.1038/nature01657) Olney RC, Miller TC, Moon JE, Mericq V, Potter LR et al. Heterozygous 116 Klopocki E, Hennig BP, Dathe K, Koll R, de Ravel T, Baten E, Blom E, mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of Gillerot Y, Weigel JF, Kruger G et al. Deletion and point mutations of short stature. Human Mutation 2015 36 474–481. (doi:10.1002/humu. PTHLH cause brachydactyly type E. American Journal of Human Genetics 22773) 2010 86 434–439. (doi:10.1016/j.ajhg.2010.01.023) 130 Hisado-Oliva A, Garre-Vazquez AI, Santaolalla-Caballero F, 117 Hoogendam J, Farih-Sips H, Wynaendts LC, Lowik CW, Wit JM & Belinchon A, Barreda-Bonis AC, Vasques GA, Ramirez J, Luzuriaga C, Karperien M. Novel mutations in the parathyroid hormone Carlone G, Gonzalez-Casado I et al. Heterozygous NPR2 mutations (PTH)/PTH-related peptide receptor type 1 causing Blomstrand cause disproportionate short stature, similar to Leri-Weill dyschon- osteochondrodysplasia types I and II. Journal of Clinical drosteosis. Journal of Clinical Endocrinology and Metabolism 2015 100 Endocrinology and Metabolism 2007 92 1088–1095. (doi:10.1210/jc. E1133–E1142. (doi:10.1210/jc.2015-1612) 2006-0300) 131 Teixeira CC, Agoston H & Beier F. Nitric oxide, C-type natriuretic 118 Schipani E, Kruse K & Juppner H. A constitutively active mutant peptide and cGMP as regulators of endochondral ossification. PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Developmental Biology 2008 319 171–178. (doi:10.1016/j.ydbio.2008. Science 1995 268 98–100. (doi:10.1126/science.7701349) 04.031) 119 Byrnes AM, Racacho L, Grimsey A, Hudgins L, Kwan AC, Sangalli M, 132 Krejci P, Masri B, Fontaine V, Mekikian PB, Weis M, Prats H & Kidd A, Yaron Y, Lau YL, Nikkel SM et al. Brachydactyly A-1 mutations Wilcox WR. Interaction of fibroblast growth factor and C-natriuretic restricted to the central region of the N-terminal active fragment of peptide signaling in regulation of chondrocyte proliferation and Indian Hedgehog. European Journal of Human Genetics 2009 17 extracellular matrix homeostasis. Journal of Cell Science 2005 118 1112–1120. (doi:10.1038/ejhg.2009.18) 5089–5100. (doi:10.1242/jcs.02618)

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R167

133 Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, dyschondrosteosis (LWD) and idiopathic short stature (ISS). Journal of Wendt DJ, Bell SM, Bullens S, Bunting S et al. Evaluation of the Clinical Endocrinology and Metabolism 2011 96 E404–E412. therapeutic potential of a CNP analog in a Fgfr3 mouse model (doi:10.1210/jc.2010-1689) recapitulating achondroplasia. American Journal of Human Genetics 147 Benito-Sanz S, Aza-Carmona M, Rodriguez-Estevez A, Rica- 2012 91 1108–1114. (doi:10.1016/j.ajhg.2012.10.014) Etxebarria I, Gracia R, Campos-Barros A & Heath KE. Identification of 134 Tompson SW, Merriman B, Funari VA, Fresquet M, Lachman RS, the first PAR1 deletion encompassing upstream SHOX enhancers in a Rimoin DL, Nelson SF, Briggs MD, Cohn DH & Krakow D. A recessive family with idiopathic short stature. European Journal of Human skeletal dysplasia, SEMD aggrecan type, results from a missense Genetics 2012 20 125–127. (doi:10.1038/ejhg.2011.210) mutation affecting the C-type lectin domain of aggrecan. American 148 Rosilio M, Huber-Lequesne C, Sapin H, Carel JC, Blum WF & Journal of Human Genetics 2009 84 72–79. (doi:10.1016/j.ajhg.2008. Cormier-Daire V. Genotypes and phenotypes of children with SHOX 12.001) deficiency in France. Journal of Clinical Endocrinology and Metabolism 135 Nilsson O, Guo MH, Dunbar N, Popovic J, Flynn D, Jacobsen C, Lui JC, 2012 97 E1257–E1265. (doi:10.1210/jc.2011-3460) Hirschhorn JN, Baron J & Dauber A. Short stature, accelerated bone 149 Kant SG, Broekman SJ, de Wit CC, Bos M, Scheltinga SA, Bakker E, maturation, and early growth cessation due to heterozygous aggrecan Oostdijk W, van der Kamp HJ, van Zwet EW, van der Hout AH et al. mutations. Journal of Clinical Endocrinology and Metabolism 2014 99 Phenotypic characterization of patients with deletions in the E1510–E1518. (doi:10.1210/jc.2014-1332) 30-flanking SHOX region. PeerJ 2013 1 e35. (doi:10.7717/peerj.35) 136 Ahmad M, Faiyaz Ul Haque M, Ahmad W, Abbas H, Haque S, 150 Donze SH, Meijer CR, Kant SG, Zandwijken GR, van der Hout AH, Krakow D, Rimoin DL, Lachman RS & Cohn DH. Distinct, autosomal van Spaendonk RM, van den Ouweland AM, Wit JM, Losekoot M & recessive form of spondyloepimetaphyseal dysplasia segregating in an Oostdijk W. The growth response to growth hormone treatment is inbred Pakistani kindred. American Journal of Medical Genetics 1998 78 greater in patients with SHOX enhancer deletions compared to SHOX ! 468–473. (doi:10.1002/(SICI)1096-8628(19980806)78:5 468::AID- defects. European Journal of Endocrinology 2015 173 611–621. O AJMG13 3.0.CO;2-D) (doi:10.1530/EJE-15-0451) 137 Oostdijk W, Idkowiak J, Mueller JW, House PJ, Taylor AE, 151 Iughetti L, Capone L, Elsedfy H, Bertorelli R, Predieri B, Bruzzi P, O’Reilly MW, Hughes BA, de Vries MC, Kant SG, Santen GW et al. Forabosco A & El Kholy M. Unexpected phenotype in a boy with PAPSS2 deficiency causes androgen excess via impaired DHEA trisomy of the SHOX gene. Journal of Pediatric Endocrinology & sulfation – in vitro and in vivo studies in a family harboring two novel Metabolism 2010 23 159–169. (doi:10.1515/JPEM.2010.23.1-2.159) PAPSS2 mutations. Journal of Clinical Endocrinology and Metabolism 152 Caliebe J, Broekman S, Boogaard M, Bosch CA, Ruivenkamp CA, 2015 100 E672–E680. (doi:10.1210/jc.2014-3556) Oostdijk W, Kant SG, Binder G, Ranke MB, Wit JM et al. IGF1, IGF1R 138 Malaquias AC, Scalco RC, Fontenele EG, Costalonga EF, Baldin AD, and SHOX mutation analysis in short children born small for Braz AF, Funari MF, Nishi MY, Guerra-Junior G, Mendonca BB et al. gestational age and short children with normal birth size (idiopathic The sitting height/height ratio for age in healthy and short individuals short stature). Hormone Research in Pædiatrics 2012 77 250–260. and its potential role in selecting short children for SHOX analysis. (doi:10.1159/000338341) Hormone Research in Pædiatrics 2013 80 449–456. (doi:10.1159/ 153 Wit JM, van Duyvenvoorde HA, van Klinken JB, Caliebe J, Bosch CA, 000355411) Lui JC, Gijsbers AC, Bakker E, Breuning MH, Oostdijk W et al. 139 Rappold GA, Fukami M, Niesler B, Schiller S, Zumkeller W, Copy number variants in short children born small for gestational age. Bettendorf M, Heinrich U, Vlachopapadoupoulou E, Reinehr T, Hormone Research in Pædiatrics 2014 82 310–318. (doi:10.1159/ Onigata K et al. Deletions of the homeobox gene SHOX (short stature 000367712) homeobox) are an important cause of growth failure in children with 154 Yasoda A, Komatsu Y, Chusho H, Miyazawa T, Ozasa A, Miura M, short stature. Journal of Clinical Endocrinology and Metabolism 2002 87 European Journal of Endocrinology Kurihara T, Rogi T, Tanaka S, Suda M et al. Overexpression of CNP in 1402–1406. (doi:10.1210/jcem.87.3.8328) chondrocytes rescues achondroplasia through a MAPK-dependent 140 Binder G, Ranke MB & Martin DD. Auxology is a valuable instrument pathway. Nature Medicine 2004 10 80–86. (doi:10.1038/nm971) for the clinical diagnosis of SHOX haploinsufficiency in school-age 155 Cseh B, Doma E & Baccarini M. "RAF" neighborhood: protein-protein children with unexplained short stature. Journal of Clinical FEBS Letters Endocrinology and Metabolism 2003 88 4891–4896. (doi:10.1210/jc. interaction in the Raf/Mek/Erk pathway. 2014 588 2003-030136) 2398–2406. (doi:10.1016/j.febslet.2014.06.025) 141 Jorge AA & Arnhold IJ. Anthropometric evaluation of children with 156 Lee BH, Kim JM, Jin HY, Kim GH, Choi JH & Yoo HW. Spectrum of SHOX mutations can be used as indication for genetic studies in mutations in Noonan syndrome and their correlation with pheno- children of short stature. Journal of Medical Genetics 2007 44 e90. types. Journal of Pediatrics 2011 159 1029–1035. (doi:10.1016/j.jpeds. 142 Jorge AA, Souza SC, Nishi MY, Billerbeck AE, Liborio DC, Kim CA, 2011.05.024) Arnhold IJ & Mendonca BB. SHOX mutations in idiopathic short 157 Roberts AE, Allanson JE, Tartaglia M & Gelb BD. Noonan syndrome. stature and Leri-Weill dyschondrosteosis: frequency and phenotypic Lancet 2013 381 333–342. (doi:10.1016/S0140-6736(12)61023-X) variability. Clinical Endocrinology 2007 66 130–135. 158 Wang SR, Carmichael H, Andrew SF, Miller TC, Moon JE, Derr MA, 143 Binder G. Short stature due to SHOX deficiency: genotype, Hwa V, Hirschhorn JN & Dauber A. Large-scale pooled next- phenotype, and therapy. Hormone Research in Pædiatrics 2011 75 generation sequencing of 1077 genes to identify genetic causes of 81–89. (doi:10.1159/000324105) short stature. Journal of Clinical Endocrinology and Metabolism 2013 98 144 Chen J, Wildhardt G, Zhong Z, Roth R, Weiss B, Steinberger D, E1428–E1437. (doi:10.1210/jc.2013-1534) Decker J, Blum WF & Rappold G. Enhancer deletions of the SHOX 159 De Rocca Serra-Nedelec A, Edouard T, Treguer K, Tajan M, Araki T, gene as a frequent cause of short stature: the essential role of a 250 kb Dance M, Mus M, Montagner A, Tauber M, Salles JP et al. Noonan downstream regulatory domain. Journal of Medical Genetics 2009 46 syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 834–839. (doi:10.1136/jmg.2009.067785) release via growth hormone-induced ERK hyperactivation, which 145 Huber C, Rosilio M, Munnich A & Cormier-Daire V. High incidence of contributes to short stature. PNAS 2012 109 4257–4262. (doi:10.1073/ SHOX anomalies in individuals with short stature. Journal of Medical pnas.1119803109) Genetics 2006 43 735–739. (doi:10.1136/jmg.2006.040998) 160 Edouard T, Combier JP, Nedelec A, Bel-Vialar S, Metrich M, Conte- 146 Benito-Sanz S, Barroso E, Heine-Suner D, Hisado-Oliva A, Romanelli V, Auriol F, Lyonnet S, Parfait B, Tauber M, Salles JP et al. Functional Rosell J, Aragones A, Caimari M, Argente J, Ross JL et al. Clinical and effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on molecular evaluation of SHOX/PAR1 duplications in Leri-Weill epidermal growth factor-induced phosphoinositide

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R168

3-kinase/AKT/glycogen synthase kinase 3b signaling. Molecular and 175 Nikkel SM, Dauber A, de Munnik S, Connolly M, Hood RL, Cellular Biology 2010 30 2498–2507. (doi:10.1128/MCB.00646-09) Caluseriu O, Hurst J, Kini U, Nowaczyk MJ, Afenjar A et al. The 161 Pasteris NG, Cadle A, Logie LJ, Porteous ME, Schwartz CE, phenotype of Floating–Harbor syndrome: clinical characterization of Stevenson RE, Glover TW, Wilroy RS & Gorski JL. Isolation and 52 individuals with mutations in exon 34 of SRCAP. Orphanet characterization of the faciogenital dysplasia (Aarskog–Scott Journal of Rare Diseases 2013 8 63. (doi:10.1186/1750-1172-8-63) syndrome) gene: a putative Rho/Rac guanine nucleotide exchange 176 Sirmaci A, Spiliopoulos M, Brancati F, Powell E, Duman D, Abrams A, factor. Cell 1994 79 669–678. (doi:10.1016/0092-8674(94)90552-5) Bademci G, Agolini E, Guo S, Konuk B et al. Mutations in ANKRD11 162 Orrico A, Galli L, Faivre L, Clayton-Smith J, Azzarello-Burri SM, cause KBG syndrome, characterized by intellectual disability, skeletal Hertz JM, Jacquemont S, Taurisano R, Arroyo Carrera I, Tarantino E malformations, and macrodontia. American Journal of Human Genetics et al. Aarskog–Scott syndrome: clinical update and report of nine 2011 89 289–294. (doi:10.1016/j.ajhg.2011.06.007) novel mutations of the FGD1 gene. American Journal of Medical 177 Zhang A, Yeung PL, Li CW, Tsai SC, Dinh GK, Wu X, Li H & Chen JD. Genetics. Part A 2010 152A 313–318. (doi:10.1002/ajmg.a.33199) Identification of a novel family of ankyrin repeats containing 163 Zou W, Greenblatt MB, Shim JH, Kant S, Zhai B, Lotinun S, Brady N, cofactors for p160 nuclear receptor coactivators. Journal of Biological Hu DZ, Gygi SP, Baron R et al. MLK3 regulates bone development Chemistry 2004 279 33799–33805. (doi:10.1074/jbc.M403997200) downstream of the faciogenital dysplasia protein FGD1 in mice. 178 Bhatnagar S, Gazin C, Chamberlain L, Ou J, Zhu X, Tushir JS, Journal of Clinical Investigation 2011 121 4383–4392. (doi:10.1172/ Virbasius CM, Lin L, Zhu LJ, Wajapeyee N et al. TRIM37 is a new JCI59041) histone H2A ubiquitin ligase and breast cancer oncoprotein. Nature 164 Genot E, Daubon T, Sorrentino V & Buccione R. FGD1 as a central 2014 516 116–120. (doi:10.1038/nature13955) regulator of extracellular matrix remodelling – lessons from 179 Karlberg N, Jalanko H & Lipsanen-Nyman M. Growth and growth faciogenital dysplasia. Journal of Cell Science 2012 125 3265–3270. hormone therapy in subjects with mulibrey nanism. Pediatrics 2007 (doi:10.1242/jcs.093419) 120 e102–e111. (doi:10.1542/peds.2006-2686) 165 Akiyama H & Lefebvre V. Unraveling the transcriptional regulatory 180 Park SW, Zhou Y, Lee J, Lu A, Sun C, Chung J, Ueki K & Ozcan U. The machinery in chondrogenesis. Journal of Bone and Mineral Metabolism regulatory subunits of PI3K, p85a and p85b, interact with XBP-1 and 2011 29 390–395. (doi:10.1007/s00774-011-0273-9) increase its nuclear translocation. Nature Medicine 2010 16 429–437. 166 Coman D, Irving M, Kannu P, Jaeken J & Savarirayan R. The skeletal (doi:10.1038/nm.2099) manifestations of the congenital disorders of glycosylation. Clinical 181 Sarig O, Nahum S, Rapaport D, Ishida-Yamamoto A, Fuchs-Telem D, Genetics 2008 73 507–515. (doi:10.1111/j.1399-0004.2008.01015.x) Qiaoli L, Cohen-Katsenelson K, Spiegel R, Nousbeck J, Israeli S et al. 167 Morava E, Zeevaert R, Korsch E, Huijben K, Wopereis S, Matthijs G, Short stature, onychodysplasia, facial dysmorphism, and Keymolen K, Lefeber DJ, De Meirleir L & Wevers RA. A common hypotrichosis syndrome is caused by a POC1A mutation. American mutation in the COG7 gene with a consistent phenotype including Journal of Human Genetics 2012 91 337–342. (doi:10.1016/j.ajhg.2012. microcephaly, adducted thumbs, growth retardation, VSD and 06.003) episodes of hyperthermia. European Journal of Human Genetics 2007 15 182 Barraza-Garcia J, Ivan Rivera-Pedroza C, Salamanca L, Belinchon A, 638–645. (doi:10.1038/sj.ejhg.5201813) Lopez-Gonzalez V, Sentchordi-Montane L, Del PA, Santos-Simarro F, 168 Scott K, Gadomski T, Kozicz T & Morava E. Congenital disorders of Campos-Barros A, Lapunzina P et al. Two novel POC1A mutations in glycosylation: new defects and still counting. Journal of Inherited the Primordial dwarfism, SOFT syndrome: clinical homogeneity but Metabolic Disease 2014 37 609–617. (doi:10.1007/s10545-014-9720-9) also unreported malformations. American Journal of Medical Genetics 169 Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, 2016 170 210–216. (doi:10.1002/ajmg.a.37393) Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC et al. 183 Huber C, Dias-Santagata D, Glaser A, O’Sullivan J, Brauner R, Wu K, European Journal of Endocrinology Mutations in a new member of the chromodomain gene family cause Xu X, Pearce K, Wang R, Uzielli ML et al. Identification of mutations CHARGE syndrome. Nature Genetics 2004 36 955–957. (doi:10.1038/ in CUL7 in 3-M syndrome. Nature Genetics 2005 37 1119–1124. ng1407) (doi:10.1038/ng1628) 170 Martin DM, Sheldon S & Gorski JL. CHARGE association with choanal 184 Hanson D, Murray PG, Sud A, Temtamy SA, Aglan M, Superti-Furga A, atresia and inner ear hypoplasia in a child with a de novo chromosome Holder SE, Urquhart J, Hilton E, Manson FD et al. The primordial translocation t(2;7)(p14;q21.11). American Journal of Medical Genetics growth disorder 3-M syndrome connects ubiquitination to the 2001 99 115–119. (doi:10.1002/1096-8628(2000)9999:999!00::AID- cytoskeletal adaptor OBSL1. American Journal of Human Genetics 2009 AJMG1126O3.0.CO;2-8) 84 801–806. (doi:10.1016/j.ajhg.2009.04.021) 171 Zentner GE, Hurd EA, Schnetz MP, Handoko L, Wang C, Wang Z, 185 Hanson D, Murray PG, O’Sullivan J, Urquhart J, Daly S, Bhaskar SS, Wei C, Tesar PJ, Hatzoglou M, Martin DM et al. CHD7 functions in the Biesecker LG, Skae M, Smith C, Cole T et al. Exome sequencing nucleolus as a positive regulator of ribosomal RNA biogenesis. Human identifies CCDC8 mutations in 3-M syndrome, suggesting that Molecular Genetics 2010 19 3491–3501. (doi:10.1093/hmg/ddq265) CCDC8 contributes in a pathway with CUL7 and OBSL1 to control 172 Santen GW, Aten E, Sun Y, Almomani R, Gilissen C, Nielsen M, human growth. American Journal of Human Genetics 2011 89 148–153. Kant SG, Snoeck IN, Peeters EA, Hilhorst-Hofstee Y et al. Mutations (doi:10.1016/j.ajhg.2011.05.028) in SWI/SNF chromatin remodeling complex gene ARID1B cause 186 Clayton PE, Hanson D, Magee L, Murray PG, Saunders E, Abu- Coffin–Siris syndrome. Nature Genetics 2012 44 379–380. Amero SN, Moore GE & Black GC. Exploring the spectrum of 3-M (doi:10.1038/ng.2217) syndrome, a primordial short stature disorder of disrupted 173 Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, ubiquitination. Clinical Endocrinology 2012 77 335–342. (doi:10.1111/ Kaname T, Naritomi K, Kawame H, Wakui K et al. Mutations j.1365-2265.2012.04428.x) affecting components of the SWI/SNF complex cause 187 Yan J, Yan F, Li Z, Sinnott B, Cappell KM, Yu Y, Mo J, Duncan JA, Coffin–Siris syndrome. Nature Genetics 2012 44 376–378. (doi:10. Chen X, Cormier-Daire V et al. The 3M complex maintains 1038/ng.2219) microtubule and genome integrity. Molecular Cell 2014 54 791–804. 174 Hood RL, Lines MA, Nikkel SM, Schwartzentruber J, Beaulieu C, (doi:10.1016/j.molcel.2014.03.047) Nowaczyk MJ, Allanson J, Kim CA, Wieczorek D, Moilanen JS et al. 188 Bicknell LS, Bongers EM, Leitch A, Brown S, Schoots J, Harley ME, Mutations in SRCAP, encoding SNF2-related CREBBP activator Aftimos S, Al-Aama JY, Bober M, Brown PA et al. Mutations in the protein, cause Floating–Harbor syndrome. American Journal of Human pre-replication complex cause Meier–Gorlin syndrome. Nature Genetics 2012 90 308–313. (doi:10.1016/j.ajhg.2011.12.001) Genetics 2011 43 356–359. (doi:10.1038/ng.775)

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R169

189 Guernsey DL, Matsuoka M, Jiang H, Evans S, Macgillivray C, 206 Grote FK, Van Dommelen P, Oostdijk W, De Muinck Keizer- Nightingale M, Perry S, Ferguson M, LeBlanc M, Paquette J et al. Schrama SM, Verkerk PH, Wit JM & Van Buuren S. Developing Mutations in origin recognition complex gene ORC4 cause evidence-based guidelines for referral for short stature. Archives of Meier–Gorlin syndrome. Nature Genetics 2011 43 360–364. Disease in Childhood 2008 93 212–217. (doi:10.1136/adc.2007.120188) (doi:10.1038/ng.777) 207 Kirsch S, Weiss B, Schon K & Rappold GA. The definition of the Y 190 Boyle MI, Jespersgaard C, Brondum-Nielsen K, Bisgaard AM & chromosome growth-control gene (GCY) critical region: relevance of Tumer Z. Cornelia de Lange syndrome. Clinical Genetics 2015 88 1–12. terminal and interstitial deletions. Journal of Pediatric Endocrinology & (doi:10.1111/cge.12499) Metabolism 2002 15 (Suppl 5) 1295–1300. 191 de Munnik SA, Otten BJ, Schoots J, Bicknell LS, Aftimos S, Al-Aama JY, 208 Richter-Unruh A, Knauer-Fischer S, Kaspers S, Albrecht B, van Bever Y, Bober MB, Borm GF, Clayton-Smith J et al. Meier–Gorlin Gillessen-Kaesbach G & Hauffa BP. Short stature in children with an syndrome: growth and secondary sexual development of a micro- apparently normal male phenotype can be caused by 45,X/46,XY cephalic primordial dwarfism disorder. American Journal of Medical mosaicism and is susceptible to growth hormone treatment. Genetics. Part A 2012 158A 2733–2742. (doi:10.1002/ajmg.a.35681) European Journal of Pediatrics 2004 163 251–256. (doi:10.1007/s00431- 192 Barbelanne M & Tsang WY. Molecular and cellular basis of autosomal 004-1406-0) recessive primary microcephaly. BioMed Research International 2014 209 Tosson H, Rose SR & Gartner LA. Children with 45,X/46,XY karyotype 2014 547986. (doi:10.1155/2014/547986) from birth to adult height. Hormone Research in Pædiatrics 2010 74 193 He H, Liyanarachchi S, Akagi K, Nagy R, Li J, Dietrich RC, Li W, 190–200. (doi:10.1159/000281468) Sebastian N, Wen B, Xin B et al. Mutations in U4atac snRNA, 210 Lindhardt JM, Hagen CP, Rajpert-De ME, Kjaergaard S, Petersen BL, a component of the minor spliceosome, in the developmental disorder Skakkebaek NE, Main KM & Juul A. 45,X/46,XY mosaicism: MOPD I. Science 2011 332 238–240. (doi:10.1126/science.1200587) phenotypic characteristics, growth, and reproductive function – 194 Rauch A, Thiel CT, Schindler D, Wick U, Crow YJ, Ekici AB, a retrospective longitudinal study. Journal of Clinical Endocrinology van Essen AJ, Goecke TO, Al-Gazali L, Chrzanowska KH et al. and Metabolism 2012 97 E1540–E1549. (doi:10.1210/jc.2012-1388) Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. 211 Utermann B, Riegel M, Leistritz D, Karall T, Wisser J, Meisner L, Science 2008 319 816–819. (doi:10.1126/science.1151174) Fauth C, Baldinger R, Johnson J, Erdel M et al. Pre- and postnatal 195 Ogi T, Walker S, Stiff T, Hobson E, Limsirichaikul S, Carpenter G, findings in trisomy 17 mosaicism. American Journal of Medical Genetics. Prescott K, Suri M, Byrd PJ, Matsuse M et al. Identification of the first Part A 2006 140 1628–1636. (doi:10.1002/ajmg.a.31319) ATRIP-deficient patient and novel mutations in ATR define a clinical 212 Li C, Chen R, Fan X, Luo J, Qian J, Wang J, Xie B, Shen Y & Chen S. spectrum for ATR-ATRIP Seckel Syndrome. PLoS Genetics 2012 8 EPHA4 haploinsufficiency is responsible for the short stature of a e1002945. (doi:10.1371/journal.pgen.1002945) patient with 2q35-q36.2 deletion and Waardenburg syndrome. 196 Davis AJ & Chen DJ. DNA double strand break repair via non- BMC Medical Genetics 2015 16 23. (doi:10.1186/s12881-015-0165-2) homologous end-joining. Translational Cancer Research 2013 2 213 Blassnig-Ezeh A, Bandelier C, Fruhmesser A, Revencu N, Krabichler B, 130–143. Beauloye V, Ravoet M, Fauth C, Zschocke J, Simma B et al. Severe 197 Murray JE, Bicknell LS, Yigit G, Duker AL, van Kogelenberg M, growth retardation, delayed bone age, and facial dysmorphism in two Haghayegh S, Wieczorek D, Kayserili H, Albert MH, Wise CA et al. patients with microduplications in 2p16/p22. American Journal of Extreme growth failure is a common presentation of ligase IV deficiency. Medical Genetics. Part A 2013 161A 3176–3181. (doi:10.1002/ajmg.a. Human Mutation 2014 35 76–85. (doi:10.1002/humu.22461) 36176) 198 Murray JE, van der Burg M, IJspeert H, Carroll P, Wu Q, Ochi T, 214 Urquhart JE, Williams SG, Bhaskar SS, Bowers N, Clayton-Smith J & Leitch A, Miller ES, Kysela B, Jawad A et al. Mutations in the NHEJ Newman WG. Deletion of 19q13 reveals clinical overlap with European Journal of Endocrinology component XRCC4 cause primordial dwarfism. American Journal of Dubowitz syndrome. Journal of Human Genetics 2015 60 781–785. Human Genetics 2015 96 412–424. (doi:10.1016/j.ajhg.2015.01.013) (doi:10.1038/jhg.2015.111) 199 de Bruin C, Mericq V, Andrew SF, van Duyvenvoorde HA, Verkaik NS, 215 Zahnleiter D, Uebe S, Ekici AB, Hoyer J, Wiesener A, Wieczorek D, Losekoot M, Porollo A, Garcia H, Kuang Y, Hanson D et al. An XRCC4 Kunstmann E, Reis A, Doerr HG, Rauch A et al. Rare copy number splice mutation associated with severe short stature, gonadal failure, variants are a common cause of short stature. PLoS Genetics 2013 9 and early-onset metabolic syndrome. Journal of Clinical Endocrinology e1003365. (doi:10.1371/journal.pgen.1003365) and Metabolism 2015 100 E789–E798. (doi:10.1210/jc.2015-1098) 216 van Duyvenvoorde HA, Lui JC, Kant SG, Oostdijk W, Gijsbers AC, 200 Moreno-Garcia M, Fernandez-Martinez FJ & Barreiro ME. Chromo- Hoffer MJ, Karperien M, Walenkamp MJ, Noordam C, Voorhoeve PG somal anomalies in patients with short stature. Pediatrics International et al. Copy number variants in patients with short stature. European 2005 47 546–549. (doi:10.1111/j.1442-200x.2005.02120.x) Journal of Human Genetics 2014 22 602–609. (doi:10.1038/ejhg.2013.203) 201 Eggert P, Pankau R & Oldigs HD. How necessary is a chromosomal 217 Canton AP, Costa SS, Rodrigues TC, Bertola DR, Malaquias AC, analysis in growth-retarded girls? Clinical Genetics 1990 37 351–354. Correa FA, Arnhold IJ, Rosenberg C & Jorge AA. Genome-wide (doi:10.1111/j.1399-0004.1990.tb03518.x) screening of copy number variants in children born small for 202 Savendahl L & Davenport ML. Delayed diagnoses of Turner’s gestational age reveals several candidate genes involved in growth syndrome: proposed guidelines for change. Journal of Pediatrics 2000 pathways. European Journal of Endocrinology/European Federation of 137 455–459. (doi:10.1067/mpd.2000.107390) Endocrine Societies 2014 171 253–262. (doi:10.1530/EJE-14-0232) 203 Partsch CJ, Raffenberg U & Sippell WG. Screening for Turner’s syndrome 218 Dauber A, Yu Y, Turchin MC, Chiang CW, Meng YA, Demerath EW, by chromosome analysis of all girls with short stature. Journal of Pediatrics Patel SR, Rich SS, Rotter JI, Schreiner PJ et al. Genome-wide association of 2002 140 140–141. (doi:10.1067/mpd.2002.119172) copy-number variation reveals an association between short stature and 204 Massa GG, Verlinde V & Heinrichs C. Screening for Turner’s syndrome the presence of low-frequency genomic deletions. American Journal of by chromosome analysis of all girls with short stature. Journal of Human Genetics 2011 89 751–759. (doi:10.1016/j.ajhg.2011.10.014) Pediatrics 2002 140 141–142. (doi:10.1067/mpd.2002.119173) 219 Netchine I, Rossignol S, Dufourg MN, Azzi S, Rousseau A, Perin L, 205 Grote FK, Oostdijk W, De Muinck Keizer-Schrama SM, Van Houang M, Steunou V, Esteva B, Thibaud N et al. 11p15 imprinting Dommelen P, Van Buuren S, Dekker FW, Ketel AG, Moll HA & Wit JM. center region 1 loss of methylation is a common and specific cause of The diagnostic work up of growth failure in secondary health care; typical Russell–Silver syndrome: clinical scoring system and epi- an evaluation of consensus guidelines. BMC Pediatrics 2008 8 21. genetic-phenotypic correlations. Journal of Clinical Endocrinology and (doi:10.1186/1471-2431-8-21) Metabolism 2007 92 3148–3154. (doi:10.1210/jc.2007-0354)

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R170

220 Azzi S, Rossignol S, Steunou V, Sas T, Thibaud N, Danton F, Le Jule M, 235 Matthijs G, Souche E, Alders M, Corveleyn A, Eck S, Feenstra I, Race V, Heinrichs C, Cabrol S, Gicquel C et al. Multilocus methylation analysis Sistermans E, Sturm M, Weiss M et al. Guidelines for diagnostic next- in a large cohort of 11p15-related foetal growth disorders (Russell generation sequencing. European Journal of Human Genetics 2016 24 Silver and Beckwith Wiedemann syndromes) reveals simultaneous 2–5. (doi:10.1038/ejhg.2015.226) loss of methylation at paternal and maternal imprinted loci. Human 236 Lu JT, Campeau PM & Lee BH. Genotype–phenotype correlation – Molecular Genetics 2009 18 4724–4733. (doi:10.1093/hmg/ddp435) promiscuity in the era of next-generation sequencing. New 221 Wakeling EL. Silver–Russell syndrome. Archives of Disease in Childhood England Journal of Medicine 2014 371 593–596. (doi:10.1056/ 2011 96 1156–1161. (doi:10.1136/adc.2010.190165) NEJMp1400788) 222 Brioude F, Oliver-Petit I, Blaise A, Praz F, Rossignol S, Le Jule M, 237 Zielonka M, Makhseed N, Blau N, Bettendorf M, Hoffmann GF & Thibaud N, Faussat AM, Tauber M, Le Bouc Y et al. CDKN1C mutation Opladen T. Dopamine-responsive growth-hormone deficiency and affecting the PCNA-binding domain as a cause of familial Russell– central hypothyroidism in sepiapterin reductase deficiency. In: JIMD Silver syndrome. Journal of Medical Genetics 2013 50 823–830. Reports vol 24 pp 109–113. Eds: J Zschocke, M Baumgartner, EMorava, (doi:10.1136/jmedgenet-2013-101691) M Patterson, S Rahman and V Peters Springer Verlag: Heidelberg 223 Arboleda VA, Lee H, Parnaik R, Fleming A, Banerjee A, Ferraz-de-Souza B, 2015. (doi:10.1007/8904_2015_450) Delot EC, Rodriguez-Fernandez IA, Braslavsky D, Bergada I et al. 238 Correa FA, Trarbach EB, Tusset C, Latronico AC, Montenegro LR, Mutations in the PCNA-binding domain of CDKN1C cause IMAGe Carvalho LR, Franca MM, Otto AP, Costalonga EF, Brito VN et al. syndrome. Nature Genetics 2012 44 788–792. (doi:10.1038/ng.2275) FGFR1 and PROKR2 rare variants found in patients with combined 224 Kerns SL, Guevara-Aguirre J, Andrew S, Geng J, Guevara C, Guevara- pituitary hormone deficiencies. Endocrine Connections 2015 4 100–107. Aguirre M, Guo M, Oddoux C, Shen Y, Zurita A et al. A novel variant in (doi:10.1530/EC-15-0015) CDKN1C is associated with intrauterine growth restriction, short 239 Gorbenko del BD, de Graaff LC, Posthouwer D, Visser TJ & Hokken- stature, and early-adulthood-onset diabetes. Journal of Clinical Koelega AC. Isolated GH deficiency: mutation screening and copy Endocrinology and Metabolism 2014 99 E2117–E2122. (doi:10.1210/jc. number analysis of HMGA2 and CDK6 genes. European Journal of 2014-1949) Endocrinology/European Federation of Endocrine Societies 2011 165 225 Eggermann T, Gonzalez D, Spengler S, Arslan-Kirchner M, Binder G & 537–544. (doi:10.1530/EJE-11-0478) Schonherr N. Broad clinical spectrum in Silver–Russell syndrome and 240 Alatzoglou KS, Webb EA, Le Tissier P & Dattani MT. Isolated growth consequences for genetic testing in growth retardation. Pediatrics 2009 hormone deficiency (GHD) in childhood and adolescence: 123 e929–e931. (doi:10.1542/peds.2008-3228) recent advances. Endocrine Reviews 2014 35 376–432. (doi:10.1210/er. 226 Angulo MA, Butler MG & Cataletto ME. Prader–Willi syndrome: 2013-1067) a review of clinical, genetic, and endocrine findings. Journal of 241 Karaca E, Buyukkaya R, Pehlivan D, Charng WL, Yaykasli KO, Endocrinological Investigation 2015 38 1249–1263. (doi:10.1007/ Bayram Y, Gambin T, Withers M, Atik MM, Arslanoglu I et al. s40618-015-0312-9) Whole-exome sequencing identifies homozygous GPR161 mutation 227 Bakker NE, Kuppens RJ, Siemensma EP, Tummers-de Lind van in a family with pituitary stalk interruption syndrome. Journal of Wijngaarden RF, Festen DA, Bindels-de Heus GC, Bocca G, Haring DA, Clinical Endocrinology and Metabolism 2015 100 E140–E147. Hoorweg-Nijman JJ, Houdijk EC et al. Eight years of growth hormone (doi:10.1210/jc.2014-1984) treatment in children with Prader–Willi syndrome: maintaining the 242 Mullis PE. Genetics of GHRH, GHRH-receptor, GH and GH-receptor: positive effects. Journal of Clinical Endocrinology and Metabolism 2013 Its impact on pharmacogenetics. Best Practice & Research. Clinical 98 4013–4022. (doi:10.1210/jc.2013-2012) Endocrinology & Metabolism 2011 25 25–41. (doi:10.1016/j.beem.2010. 228 Turan S & Bastepe M. GNAS spectrum of disorders. Current Osteoporosis 06.006) European Journal of Endocrinology Reports 2015 13 146–158. (doi:10.1007/s11914-015-0268-x) 243 Ursini MV, Gaetaniello L, Ambrosio R, Matrecano E, Apicella AJ, 229 Hoffmann K & Heller R. Uniparental disomies 7 and 14. Best Practice & Salerno MC & Pignata C. Atypical X-linked SCID phenotype Research. Clinical Endocrinology & Metabolism 2011 25 77–100. associated with growth hormone hyporesponsiveness. Clinical and (doi:10.1016/j.beem.2010.09.004) Experimental Immunology 2002 129 502–509. (doi:10.1046/j.1365- 230 Thiel CT, Dorr HG, Trautmann U, Hoyer J, Hofmann K, Kraus C, 2249.2002.01823.x) Ekici AB, Reis A & Rauch A. A de novo 7.6Mb tandem duplication of 244 Adriani M, Garbi C, Amodio G, Russo I, Giovannini M, Amorosi S, 14q32.2-qter associated with primordial short stature with neuro- Matrecano E, Cosentini E, Candotti F & Pignata C. Functional secretory growth hormone dysfunction, distinct facial anomalies and interaction of common gamma-chain and growth hormone receptor mild developmental delay. European Journal of Medical Genetics 2008 signaling apparatus. Journal of Immunology 2006 177 6889–6895. 51 362–367. (doi:10.1016/j.ejmg.2008.03.001) (doi:10.4049/jimmunol.177.10.6889) 231 Turner CL, Mackay DM, Callaway JL, Docherty LE, Poole RL, Bullman H, 245 Flottmann R, Knaus A, Zemojtel T, Robinson PN, Mundlos S, Lever M, Castle BM, Kivuva EC, Turnpenny PD et al.Methylation Horn D & Spielmann M. FGFR2 mutation in a patient without analysis of 79 patients with growth restriction reveals novel patterns of typical features of Pfeiffer syndrome – the emerging role of methylation change at imprinted loci. European Journal of Human combined NGS and phenotype based strategies. European Genetics 2010 18 648–655. (doi:10.1038/ejhg.2009.246) Journal of Medical Genetics 2015 58 376–380. (doi:10.1016/j.ejmg. 232 Ouni M, Gunes Y, Belot MP, Castell AL, Fradin D & Bougneres P. 2015.05.007) The IGF1 P2 promoter is an epigenetic QTL for circulating IGF1 and 246 Heuertz S, Le Merrer M, Zabel B, Wright M, Legeai-Mallet L, Cormier- human growth. Clinical Epigenetics 2015 7 22. (doi:10.1186/s13148- Daire V, Gibbs L & Bonaventure J. Novel FGFR3 mutations creating 015-0062-8) cysteine residues in the extracellular domain of the receptor cause 233 Ouni M, Castell AL, Linglart A & Bougneres P. Genetic and epigenetic achondroplasia or severe forms of hypochondroplasia. European modulation of growth hormone sensitivity studied with the IGF1 Journal of Human Genetics 2006 14 1240–1247. (doi:10.1038/sj.ejhg. generation test. Journal of Clinical Endocrinology and Metabolism 2015 5201700) 100 E919–E925. (doi:10.1210/jc.2015-1413) 247 Racacho L, Byrnes AM, MacDonald H, Dranse HJ, Nikkel SM, 234 Renes JS, Willemsen RH, Wagner A, Finken MJ & Hokken-Koelega AC. Allanson J, Rosser E, Underhill TM & Bulman DE. Two novel Bloom syndrome in short children born small for gestational age: a disease-causing variants in BMPR1B are associated with brachydactyly challenging diagnosis. Journal of Clinical Endocrinology and Metabolism type A1. European Journal of Human Genetics 2015 23 1640–1645. 2013 98 3932–3938. (doi:10.1210/jc.2013-2491) (doi:10.1038/ejhg.2015.38)

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R171

248 Liu X, Gao L, Zhao A, Zhang R, Ji B, Wang L, Zheng Y, Zeng B, branch point variant in Aarskog–Scott syndrome. Human Mutation Valenzuela RK, He L et al. Identification of duplication downstream 2013 34 430–434. (doi:10.1002/humu.22252) of BMP2 in a Chinese family with brachydactyly type A2 (BDA2). 264 Mattos EP, Sanseverino MT, Magalhaes JA, Leite JC, Felix TM, PLoS ONE 2014 9 e94201. (doi:10.1371/journal.pone.0094201) Todeschini LA, Cavalcanti DP & Schuler-Faccini L. Clinical and 249 Al-Qattan MM, Al-Motairi MI & Al Balwi MA. Two novel homozygous molecular characterization of a Brazilian cohort of campomelic missense mutations in the GDF5 gene cause brachydactyly type C. dysplasia patients, and identification of seven new SOX9 mutations. American Journal of Medical Genetics. Part A 2015 167 1621–1626. Genetics and Molecular Biology 2015 38 14–20. (doi:10.1590/S1415- (doi:10.1002/ajmg.a.37040) 475738120140147) 250 Le GC, Mahaut C, Wang LW, Allali S, Abhyankar A, Jensen S, 265 Dentici ML, Di PA, Lepri FR, Gnazzo M, Lombardi MH, Auriti C, Zylberberg L, Collod-Beroud G, Bonnet D, Alanay Y et al. Mutations in Petrocchi S, Pisaneschi E, Bellacchio E, Capolino R et al. Kabuki the TGFb binding-protein-like domain 5 of FBN1 are responsible for syndrome: clinical and molecular diagnosis in the first year of life. acromicric and geleophysic dysplasias. American Journal of Human Archives of Disease in Childhood 2015 100 158–164. (doi:10.1136/ Genetics 2011 89 7–14. (doi:10.1016/j.ajhg.2011.05.012) archdischild-2013-305858) 251 Cain SA, McGovern A, Baldwin AK, Baldock C & Kielty CM. Fibrillin-1 266 Isojima T, Doi K, Mitsui J, Oda Y, Tokuhiro E, Yasoda A, Yorifuji T, mutations causing Weill–Marchesani syndrome and acromicric and Horikawa R, Yoshimura J, Ishiura H et al. A recurrent de novo geleophysic dysplasias disrupt heparan sulfate interactions. PLoS ONE FAM111A mutation causes Kenny–Caffey syndrome type 2. 2012 7 e48634. (doi:10.1371/journal.pone.0048634) Journal of Bone and Mineral Research 2014 29 992–998. (doi:10.1002/ 252 Miyake N, Elcioglu NH, Iida A, Isguven P, Dai J, Murakami N, jbmr.2091) Takamura K, Cho TJ, Kim OH, Hasegawa T et al. PAPSS2 mutations 267 Dorr HG, Madeja J & Junghans C. Spontaneous postnatal growth is cause autosomal recessive brachyolmia. Journal of Medical Genetics reduced in children with CHARGE syndrome. Acta Paediatrica 2015 2012 49 533–538. (doi:10.1136/jmedgenet-2012-101039) 104 e314–e318. (doi:10.1111/apa.12980) 253 Gardner CJ, Robinson N, Meadows T, Wynn R, Will A, Mercer J, 268 de Munnik SA, Hoefsloot EH, Roukema J, Schoots J, Knoers NV, Church HJ, Tylee K, Wraith JE & Clayton PE. Growth, final height and Brunner HG, Jackson AP & Bongers EM. Meier–Gorlin syndrome. endocrine sequelae in a UK population of patients with Hurler Orphanet Journal of Rare Diseases 2015 10 114. (doi:10.1186/s13023- syndrome (MPS1H). Journal of Inherited Metabolic Disease 2011 34 015-0322-x) 489–497. (doi:10.1007/s10545-010-9262-8) 269 Griffith E, Walker S, Martin CA, Vagnarelli P, Stiff T, Vernay B, 254 Makitie O, Susic M, Ward L, Barclay C, Glorieux FH & Cole WG. Al Sanna N, Saggar A, Hamel B, Earnshaw WC et al. Mutations in Schmid type of metaphyseal chondrodysplasia and COL10A1 pericentrin cause Seckel syndrome with defective ATR-dependent mutations – findings in 10 patients. American Journal of Medical DNA damage signaling. Nature Genetics 2008 40 232–236. Genetics. Part A 2005 137A 241–248. (doi:10.1002/ajmg.a.30855) (doi:10.1038/ng.2007.80) 255 Briggs MD, Brock J, Ramsden SC & Bell PA. Genotype to phenotype 270 Martin CA, Ahmad I, Klingseisen A, Hussain MS, Bicknell LS, Leitch A, correlations in cartilage oligomeric matrix protein associated chon- Nurnberg G, Toliat MR, Murray JE, Hunt D et al. Mutations in PLK4, drodysplasias. European Journal of Human Genetics 2014 22 1278–1282. encoding a master regulator of centriole biogenesis, cause micro- (doi:10.1038/ejhg.2014.30) cephaly, growth failure and retinopathy. Nature Genetics 2014 46 256 Posey KL, Alcorn JL & Hecht JT. Pseudoachondroplasia/COMP – 1283–1292. (doi:10.1038/ng.3122) translating from the bench to the bedside. Matrix Biology 2014 37 271 Tarquinio DC, Motil KJ, Hou W, Lee HS, Glaze DG, Skinner SA, 167–173. (doi:10.1016/j.matbio.2014.05.006) Neul JL, Annese F, McNair L, Barrish JO et al. Growth failure and 257 Terhal PA, Nievelstein RJ, Verver EJ, Topsakal V, van Dommelen P, outcome in Rett syndrome: specific growth references. Neurology 2012 Hoornaert K, Le MM, Zankl A, Simon ME, Smithson SF et al. A study of 79 1653–1661. (doi:10.1212/WNL.0b013e31826e9a70) European Journal of Endocrinology the clinical and radiological features in a cohort of 93 patients with a 272 Seltzer LE & Paciorkowski AR. Genetic disorders associated with COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or postnatal microcephaly. American Journal of Medical Genetics. Part C, a related phenotype. American Journal of Medical Genetics. Part A 2015 Seminars in Medical Genetics 2014 166C 140–155. (doi:10.1002/ajmg.c. 167A 461–475. (doi:10.1002/ajmg.a.36922) 31400) 258 Gleghorn L, Ramesar R, Beighton P & Wallis G. A mutation in the 273 Shaheen R, Faqeih E, Ansari S, Abdel-Salam G, Al-Hassnan ZN, variable repeat region of the aggrecan gene (AGC1) causes a form of Al-Shidi T, Alomar R, Sogaty S & Alkuraya FS. Genomic analysis of spondyloepiphyseal dysplasia associated with severe, premature primordial dwarfism reveals novel disease genes. Genome Research osteoarthritis. American Journal of Human Genetics 2005 77 484–490. 2014 24 291–299. (doi:10.1101/gr.160572.113) (doi:10.1086/444401) 274 Arora H, Chacon AH, Choudhary S, McLeod MP, Meshkov L, Nouri K 259 Morales J, Al-Sharif L, Khalil DS, Shinwari JM, Bavi P, Al-Mahrouqi RA, & Izakovic J. Bloom syndrome. International Journal of Dermatology Al-Rajhi A, Alkuraya FS, Meyer BF & Al Tassan N. Homozygous mutations 2014 53 798–802. (doi:10.1111/ijd.12408) in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, 275 Petryk A, Kanakatti SR, Giri N, Hollenberg AN, Rutter MM, Nathan B, glaucoma, spherophakia, and short stature. American Journal of Human Lodish M, Alter BP, Stratakis CA & Rose SR. Endocrine disorders in Genetics 2009 85 558–568. (doi:10.1016/j.ajhg.2009.09.011) Fanconi anemia: recommendations for screening and treatment. 260 Bezniakow N, Gos M & Obersztyn E. The RASopathies as an example Journal of Clinical Endocrinology and Metabolism 2015 100 803–811. of RAS/MAPK pathway disturbances – clinical presentation and (doi:10.1210/jc.2014-4357) molecular pathogenesis of selected syndromes. Developmental Period 276 Manandhar M, Boulware KS & Wood RD. The ERCC1 and ERCC4 Medicine 2014 18 285–296. (XPF) genes and gene products. Gene 2015 569 153–161. (doi:10.1016/ 261 Chen PC, Yin J, Yu HW, Yuan T, Fernandez M, Yung CK, Trinh QM, j.gene.2015.06.026) Peltekova VD, Reid JG, Tworog-Dube E et al. Next-generation 277 Gonzalo S & Kreienkamp R. DNA repair defects and genome instability sequencing identifies rare variants associated with Noonan syndrome. in Hutchinson-Gilford Progeria Syndrome. Current Opinion in Cell PNAS 2014 111 11473–11478. (doi:10.1073/pnas.1324128111) Biology 2015 34 75–83. (doi:10.1016/j.ceb.2015.05.007) 262 Szudek J, Birch P & Friedman JM. Growth in North American white 278 Baple EL, Chambers H, Cross HE, Fawcett H, Nakazawa Y, Chioza BA, children with neurofibromatosis 1 (NF1). Journal of Medical Genetics Harlalka GV, Mansour S, Sreekantan-Nair A, Patton MA et al. 2000 37 933–938. (doi:10.1136/jmg.37.12.933) Hypomorphic PCNA mutation underlies a human DNA repair 263 Aten E, Sun Y, Almomani R, Santen GW, Messemaker T, Maas SM, disorder. Journal of Clinical Investigation 2014 124 3137–3146. Breuning MH & den Dunnen JT. Exome sequencing identifies a (doi:10.1172/JCI74593)

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R172

279 Morimoto M, Yu Z, Stenzel P, Clewing JM, Najafian B, Mayfield C, partial duplication of CTNND2. American Journal of Medical Genetics. Hendson G, Weinkauf JG, Gormley AK, Parham DM et al. Reduced Part A 2014 164A 1761–1764. (doi:10.1002/ajmg.a.36494) elastogenesis: a clue to the arteriosclerosis and emphysematous 293 Franco LM, de Ravel T, Graham BH, Frenkel SM, Van Driessche J, changes in Schimke immuno-osseous dysplasia? Orphanet Journal of Stankiewicz P, Lupski JR, Vermeesch JR & Cheung SW. A syndrome of Rare Diseases 2012 7 70. (doi:10.1186/1750-1172-7-70) short stature, microcephaly and speech delay is associated with 280 Hughes CR, Guasti L, Meimaridou E, Chuang CH, Schimenti JC, duplications reciprocal to the common Sotos syndrome deletion. King PJ, Costigan C, Clark AJ & Metherell LA. MCM4 mutation causes European Journal of Human Genetics 2010 18 258–261. (doi:10.1038/ adrenal failure, short stature, and natural killer cell deficiency in ejhg.2009.164) humans. Journal of Clinical Investigation 2012 122 814–820. 294 Honjo RS, Dutra RL, Furusawa EA, Zanardo EA, Costa LS, (doi:10.1172/JCI60224) Kulikowski LD, Bertola DR & Kim CA. Williams–Beuren Syndrome: 281 Gineau L, Cognet C, Kara N, Lach FP, Dunne J, Veturi U, Picard C, a clinical study of 55 Brazilian patients and the diagnostic use of Trouillet C, Eidenschenk C, Aoufouchi S et al. Partial MCM4 MLPA. BioMed Research International 2015 2015 903175. (doi:10.1155/ deficiency in patients with growth retardation, adrenal insufficiency, 2015/903175) and natural killer cell deficiency. Journal of Clinical Investigation 2012 295 Maas SM, Shaw AC, Bikker H, Ludecke HJ, van der Tuin K, Badura- 122 821–832. (doi:10.1172/JCI61014) Stronka M, Belligni E, Biamino E, Bonati MT, Carvalho DR et al. 282 Chrzanowska KH, Gregorek H, Dembowska-Baginska B, Kalina MA & Phenotype and genotype in 103 patients with tricho-rhino-phalan- Digweed M. Nijmegen breakage syndrome (NBS). Orphanet Journal of geal syndrome. European Journal of Medical Genetics 2015 58 279–292. Rare Diseases 2012 7 13. (doi:10.1186/1750-1172-7-13) (doi:10.1016/j.ejmg.2015.03.002) 283 Wood-Trageser MA, Gurbuz F, Yatsenko SA, Jeffries EP, Kotan LD, 296 Adams DJ & Clark DA. Common genetic and epigenetic syndromes. Surti U, Ketterer DM, Matic J, Chipkin J, Jiang H et al. MCM9 Pediatric Clinics of North America 2015 62 411–426. (doi:10.1016/j.pcl. mutations are associated with ovarian failure, short stature, and 2014.11.005) chromosomal instability. American Journal of Human Genetics 2014 95 297 Buysse K, Reardon W, Mehta L, Costa T, Fagerstrom C, Kingsbury DJ, et al 754–762. (doi:10.1016/j.ajhg.2014.11.002) Anadiotis G, McGillivray BC, Hellemans J, de Leeuw N . The 12q14 microdeletion syndrome: additional patients and further evidence 284 Smeets MF, DeLuca E, Wall M, Quach JM, Chalk AM, Deans AJ, that HMGA2 is an important genetic determinant for human height. Heierhorst J, Purton LE, Izon DJ & Walkley CR. The Rothmund– European Journal of Medical Genetics 2009 52 101–107. (doi:10.1016/j. Thomson syndrome helicase RECQL4 is essential for hematopoiesis. ejmg.2009.03.001) Journal of Clinical Investigation 2014 124 3551–3565. (doi:10.1172/ 298 Alyaqoub F, Pyatt RE, Bailes A, Brock A, Deeg C, McKinney A, JCI75334) Astbury C, Reshmi S, Shane KP, Thrush DL et al. 12q14 microdeletion 285 Gibbons RJ & Higgs DR. Molecular-clinical spectrum of the ATR-X associated with HMGA2 gene disruption and growth restriction. syndrome. American Journal of Medical Genetics 2000 97 204–212. (doi:10. American Journal of Medical Genetics. Part A 2012 158A 2925–2930. 1002/1096-8628(200023)97:3!204::AID-AJMG1038O3.0.CO;2-X) (doi:10.1002/ajmg.a.35610) 286 Woodbine L, Gennery AR & Jeggo PA. The clinical impact of 299 Mitter D, Ullmann R, Muradyan A, Klein-Hitpass L, Kanber D, deficiency in DNA non-homologous end-joining. DNA Repair 2014 16 Ounap K, Kaulisch M & Lohmann D. Genotype–phenotype corre- 84–96. (doi:10.1016/j.dnarep.2014.02.011) lations in patients with retinoblastoma and interstitial 13q deletions. 287 Mathieu AL, Verronese E, Rice GI, Fouyssac F, Bertrand Y, Picard C, European Journal of Human Genetics 2011 19 947–958. (doi:10.1038/ Chansel M, Walter JE, Notarangelo LD, Butte MJ et al. PRKDC ejhg.2011.58) mutations associated with immunodeficiency, granuloma, and 300 Martinez-Fernandez ML, Bermejo-Sanchez E, Fernandez B, autoimmune regulator-dependent autoimmunity. Journal of Allergy MacDonald A, Fernandez-Toral J & Martinez-Frias ML. Haploinsuffi- European Journal of Endocrinology and Clinical Immunology 2015 135 1578–1588. (doi:10.1016/j.jaci. ciency of BMP4 gene may be the underlying cause of Frias syndrome. 2015.01.040) American Journal of Medical Genetics. Part A 2014 164A 338–345. 288 Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, (doi:10.1002/ajmg.a.36224) Maloney VK, Crolla JA, Baralle D et al. Recurrent rearrangements of 301 Dubourg C, Bonnet-Brilhault F, Toutain A, Mignot C, Jacquette A, New England chromosome 1q21.1 and variable pediatric phenotypes. Dieux A, Gerard M, Beaumont-Epinette MP, Julia S, Isidor B et al. Journal of Medicine 2008 359 1685–1699. (doi:10.1056/ Identification of nine new RAI1-truncating mutations in Smith– NEJMoa0805384) Magenis syndrome patients without 17p11.2 deletions. Molecular 289 Maas NM, Van Buggenhout G, Hannes F, Thienpont B, Sanlaville D, Syndromology 2014 5 57–64. (doi:10.1159/000357359) Kok K, Midro A, Andrieux J, Anderlid BM, Schoumans J et al. 302 Yu YR, You LR, Yan YT, Chen CM et al. Role of OVCA1/DPH1 Genotype–phenotype correlation in 21 patients with Wolf–Hirsch- in craniofacial abnormalities of Miller–Dieker syndrome. horn syndrome using high resolution array comparative genome Human Molecular Genetics 2014 23 5579–5596. (doi:10.1093/hmg/ hybridisation (CGH). Journal of Medical Genetics 2008 45 71–80. ddu273) (doi:10.1136/jmg.2007.052910) 303 Ostergaard JR, Graakjaer J, Brandt C & Birkebaek NH. Further 290 Hart L, Rauch A, Carr AM, Vermeesch JR & O’Driscoll M. LETM1 delineation of 17p13.3 microdeletion involving CRK. The effect of haploinsufficiency causes mitochondrial defects in cells from humans growth hormone treatment. European Journal of Medical Genetics 2012 with Wolf–Hirschhorn syndrome: implications for dissecting the 55 22–26. (doi:10.1016/j.ejmg.2011.09.004) underlying pathomechanisms in this condition. Disease Models & 304 Lukusa T & Fryns JP. Pure de novo 17q25.3 micro duplication Mechanisms 2014 7 535–545. (doi:10.1242/dmm.014464) characterized by micro array CGH in a dysmorphic infant with growth 291 Bonnet C, Andrieux J, Beri-Dexheimer M, Leheup B, Boute O, retardation, developmental delay and distal arthrogryposis. Manouvrier S, Delobel B, Copin H, Receveur A, Mathieu M et al. Genetic Counseling 2010 21 25–34. Microdeletion at chromosome 4q21 defines a new emerging syn- 305 Wester U, Bondeson ML, Edeby C & Anneren G. Clinical and drome with marked growth restriction, mental retardation and absent molecular characterization of individuals with 18p deletion: a or severely delayed speech. Journal of Medical Genetics 2010 47 genotype–phenotype correlation. American Journal of Medical Genetics. 377–384. (doi:10.1136/jmg.2009.071902) Part A 2006 140 1164–1171. (doi:10.1002/ajmg.a.31260) 292 Sardina JM, Walters AR, Singh KE, Owen RX & Kimonis VE. 306 Feenstra I, Vissers LE, Pennings RJ, Nillessen W, Pfundt R, Kunst HP, Amelioration of the typical cognitive phenotype in a patient with the Admiraal RJ, Veltman JA, van Ravenswaaij-Arts CM, Brunner HG et al. 5pter deletion associated with Cri-du-chat syndrome in addition to a Disruption of teashirt zinc finger homeobox 1 is associated with

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access Review J M Wit and others Genetics of short stature 174:4 R173

congenital aural atresia in humans. American Journal of Human Genetics Journal of Medical Genetics. Part A 2014 164A 2707–2723. (doi:10.1002/ 2011 89 813–819. (doi:10.1016/j.ajhg.2011.11.008) ajmg.a.36711) 307 Cody JD, Hasi M, Soileau B, Heard P, Carter E, Sebold C, 309 Hacihamdioglu B, Hacihamdioglu D & Delil K. 22q11 deletion O’Donnell L, Perry B, Stratton RF & Hale DE. Establishing a syndrome: current perspective. Application of Clinical Genetics 2015 8 reference group for distal 18q-: clinical description and molecular 123–132. (doi:10.2147/TACG.S82105) basis. Human Genetics 2014 133 199–209. (doi:10.1007/s00439- 310 Penaherrera MS, Weindler S, Van Allen MI, Yong SL, Metzger DL, 013-1364-6) McGillivray B, Boerkoel C, Langlois S & Robinson WP. Methylation 308 Rump P, de Leeuw N, van Essen AJ, Verschuuren-Bemelmans CC, proﬁling in individuals with Russell–Silver syndrome. American Veenstra-Knol HE, Swinkels ME, Oostdijk W, Ruivenkamp C, Journal of Medical Genetics. Part A 2010 152A 347–355. (doi:10.1002/ Reardon W, de Munnik S et al. Central 22q11.2 deletions. American ajmg.a.33204)

Received 18 September 2015 Revised version received 2 November 2015 Accepted 16 November 2015 European Journal of Endocrinology

www.eje-online.org

Downloaded from Bioscientifica.com at 09/25/2021 11:53:36PM via free access