MINI REVIEW published: 06 September 2019 doi: 10.3389/fendo.2019.00602 Genetics of Growth Disorders—Which Patients Require Genetic Testing? Jesús Argente 1*, Katrina Tatton-Brown 2 , Dagmar Lehwalder 3 and Roland Pfäffle 4* 1 Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III and IMDEA Institute, Madrid, Spain, 2 Institute of Cancer Research, St George’s University Hospital NHS Foundation Trust, London and St George’s University of London, London, United Kingdom, 3 Global Medical Affairs, Merck Healthcare KGaA, Darmstadt, Germany, 4 Department of Pediatrics, University of Leipzig, Leipzig, Germany The second 360◦ European Meeting on Growth Hormone Disorders, held in Barcelona, Spain, in June 2017, included a session entitled Pragmatism vs. Curiosity in Genetic Edited by: Diagnosis of Growth Disorders, which examined current concepts of genetics and growth Tsutomu Ogata, in the clinical setting, in terms of both growth failure and overgrowth. For patients Hamamatsu University School of with short stature, multiple genes have been identified that result in GH deficiency, Medicine, Japan which may be isolated or associated with additional pituitary hormone deficiencies, or Reviewed by: Lorenzo Iughetti, in growth hormone resistance, primary insulin-like growth factor (IGF) acid-labile subunit University of Modena and Reggio deficiency, IGF-I deficiency, IGF-II deficiency, IGF-I resistance, and primary PAPP-A2 Emilia, Italy Youn Hee Jee, deficiency. While genetic causes of short stature were previously thought to primarily be Eunice Kennedy Shriver National associated with the GH–IGF-I axis, it is now established that multiple genetic anomalies Institute of Child Health and Human not associated with the GH–IGF-I axis can result in short stature. A number of genetic Development (NICHD), United States anomalies have also been shown to be associated with overgrowth, some of which *Correspondence: Jesús Argente involve the GH–IGF-I axis. In patients with overgrowth in combination with an intellectual jesus.argente@fundacionendo.org disability, two predominant gene families, the epigenetic regulator genes, and PI3K/AKT Roland Pfäffle Roland.Pfaeffle@ pathway genes, have now been identified. Specific processes should be followed for medizin.uni-leipzig.de decisions on which patients require genetic testing and which genes should be examined for anomalies. The decision to carry out genetic testing should be directed by the clinical Specialty section: This article was submitted to process, not merely for research purposes. The intention of genetic testing should be to Pediatric Endocrinology, direct the clinical options for management of the growth disorder. a section of the journal Frontiers in Endocrinology Keywords: growth hormone, genetics, short stature, overgrowth, diagnosis Received: 05 February 2019 Accepted: 19 August 2019 Published: 06 September 2019 INTRODUCTION Citation: Human linear growth continues from the embryonic stage through to adolescence and early Argente J, Tatton-Brown K, adulthood. During the fetal stage it is mainly controlled by insulin and growth factors and is Lehwalder D and Pfäffle R (2019) Genetics of Growth Disorders—Which affected by maternal health, nutrition and placental function; growth failure at this stage results in a Patients Require Genetic Testing? baby being born small for gestational age. During childhood, the hypothalamic-pituitary control of Front. Endocrinol. 10:602. the synthesis and release of growth hormone (GH), and the effects of the GH–insulin-like growth doi: 10.3389/fendo.2019.00602 factor (IGF)-I axis on tissues throughout the body, becomes increasingly important in determining Frontiers in Endocrinology | www.frontiersin.org 1 September 2019 | Volume 10 | Article 602 Argente et al. Genetics of Growth Disorders height growth. The synthesis and release of gonadotropins by with specific phenotypes linked with short stature. Development the pituitary, and the increases in sex steroid, GH and IGF- of both pragmatic and research aspects have been carried out I concentrations, become significant throughout puberty, and over time, and new genetic associations are being found as the pubertal growth spurt continues until near-adult height is the technologies become more sensitive, cheaper and more reached. However, normal skeletal growth and development widely applied. depends on multiple factors and can be affected by numerous genetic anomalies, including many that are not associated with The GH–IGF-I Axis the GH–IGF-I axis. If abnormal growth in either direction occurs Growth can be affected at various different developmental stages during the pediatric period, children frequently require referral and at different points and facets of the GH–IGF-I axis. The to an endocrine specialist for assessment and diagnosis. genetic alterations initially identified as being associated with While there are clearly environmental influences on height, growth disorders are shown in Figure 1. Genetic disorders may which may relate to the worldwide increase in average height cause defects in pituitary development during the embryonic through the twentieth century, genetic differences have a major stage, which most frequently results in multiple pituitary influence on height variation (1, 2). Height, which is one of hormone deficiencies. There may also be abnormalities within the most heritable phenotypes in humans, shows a binomial the pituitary gland or in hypothalamic signaling, which affect distribution, with abnormalities involving both growth failure GH synthesis and release by the pituitary. Finally, there may be and overgrowth. It is a polygenic trait, and studies in multiple defects in the actions of GH and IGF-I through abnormalities of cohorts of twins have identified ∼700 common variants that receptors in target tissues, causing resistance to the effects of GH captured ∼60% of heritability (1–5). For 83 identified height- or IGF-I. These defects are usually associated with intrauterine associated coding variants with minor allele frequencies, effects growth retardation. of up to 2 cm per allele were observed, which was more than 10- times the average effect of common variants (4). Results from GH Deficiency such genome-wide association studies have indicated several new Isolated GH deficiency or inactivity is a major cause of growth genetic candidates, although the loci of the variants involved failure, and multiple genetic abnormalities have been shown over in height are not randomly distributed; examination of genes time using whole genome sequencing approaches (Table 1). In enriched for these loci are implicated in novel pathways involved many familial cases, there are defects in, or deletions of, the gene in growth, some of which contribute to various syndromes of coding for GH (GH1) or the GH-releasing hormone receptor abnormal skeletal growth (3, 6). (GHRHR), which lead to either classical GH deficiency or GH While such studies indicate genes with biological relevance, that is biologically inactive (9, 10); in cases where GH is inactive, genetic testing of children with abnormal growth should not as in Kowarski syndrome, the apparent serum concentration just involve research to identify gene anomalies associated of GH may be normal or even slightly elevated (11). The with growth defects, but should also provide pragmatic aspects condition may also be associated with other syndromic effects, to determine the diagnostic causes. The following report is such as ciliopathies including Alström syndrome, where genetic based upon presentations from a meeting, funded by Merck abnormalities are associated with functional GH deficiency Healthcare Global Medical Affairs, that aimed to examine the (12). Ciliopathies are often associated with skeletal problems, various genetic causes of growth disorders and the treatment short stature and nephronophthisis, as seen with IFT172 options. A report from the session on adherence and personalized mutations that cause short-rib thoracic dysplasia (13). While GH treatment in the management of growth disorders will be there are few data on GH status with ciliopathies, a case of published separately. functional GH deficiency, with low IGF-I, that responded to GH treatment has been described in a patient with an IFT172 mutation (14). GENETIC TESTING FOR FACTORS Biallelic mutations in RNPC3 have also been associated with ASSOCIATED WITH SHORT STATURE familial isolated GH deficiency with hypoplasia of the anterior pituitary (15). The gene encodes a structural component of Multiple genetic anomalies have been shown to be associated the nuclear ribonucleoprotein complex that acts as a minor with growth failure and short stature. The short stature may spliceosome in the removal of specific introns for a number be either proportionate or disproportionate, severe or mild, of genes. The mutations were identified as being in the RNA and have pre-natal and/or post-natal origin (7, 8). While recognition motif of the protein, which binds to U12 and GH treatment has been approved for use in a number acts as a bridge between U12 small nuclear RNA and U11 of different conditions, growth response varies greatly, both small nuclear RNA of the intron recognition complex. The between conditions and within conditions, and it is important to growth failure was post-natal and proportionate, with only understand the genetic background to the condition in order to mild microcephaly, anterior pituitary hypoplasia, and normal help predict the response to treatments. psychomotor development. GH treatment of these patients was Genetic testing may, therefore, be carried out for practical effective, despite severe short stature and late initiation of reasons to determine the diagnosis and treatment options treatment (16). in patients with growth failure; however, research is also Patients with isolated GH deficiency are reported to develop necessary to identify genetic abnormalities that are associated combined pituitary hormone deficiency in about 5–45% of cases Frontiers in Endocrinology | www.frontiersin.org 2 September 2019 | Volume 10 | Article 602 Argente et al. Genetics of Growth Disorders FIGURE 1 | Genetic defects within the hypothalamo-pituitary axis. (17, 18). For cases of combined pituitary hormone deficiencies, with growth failure are in PROP1, which was reported in a the genetics appear to be more complicated and the genetic literature analysis to occur in 6.7% of worldwide sporadic cases etiology is frequently unidentified (Table 2). Genetic defects may of combined pituitary hormone deficiency and 11.2% when occur sporadically, with no family history, or may be familial; familial cases were included (21). Mutations of PROP1 cause the they may be dominant where a defect in only one allele is significant clinical feature of pituitary enlargement in some cases, associated with the condition, recessive where abnormalities of particularly in childhood and adolescence (22), that sometimes both alleles produce the effect, or X-linked where the defect helps in the diagnosis. Defects in genes for other transcription comes from an unaffected mother and generally affects only factors involved in pituitary development are associated with males (19). Reported frequencies of genetic mutations in patients other syndromic features. For defects in PITX, SOX2, SOX3, and with combined pituitary hormone deficiencies varies greatly SPR, short stature is the predominant phenotype, while for others between countries and ethnic groups (20). For PROP1, POU1F1, (shown in the shaded area of Table 2) there is a more severe and HESX1, mutation frequencies are <10% in patients with neurological phenotype, and GH deficiency may or may not be sporadic combined pituitary hormone deficiency in Western present as one part of the syndrome. Europe, although much higher in Eastern Europe. Despite the Using a candidate-gene approach to identify mutations in low prevalence in Western Europe, testing for mutations of these more than 900 patients with short stature due to GH deficiency, genes is routinely carried out as part of the work-up for such gene defects could be identified in only about 10% of cases patients (20). (23). Mutations were identified more frequently in patients with Anomalies of the classic transcription factor genes cause combined pituitary hormone deficiencies (14.7%) than in those very specific profiles of hormone deficiencies due to abnormal with isolated GH deficiency (6.5%). In patients with combined pituitary development; the most prevalent defects in patients pituitary hormone deficiencies, the most frequently identified Frontiers in Endocrinology | www.frontiersin.org 3 September 2019 | Volume 10 | Article 602 Argente et al. Genetics of Growth Disorders TABLE 1 | Genetic abnormalities associated with isolated GH deficiency (GHD) or bio-inactivity. Disorder Phenotype Gene/locus Gene/locus Location Clinical features Inheritance Syndromic MIM MIM Isolated GHD, type 1A 262400 139250 GH1 17q23.3 No serum GH, often anti-GH antibodies AR Isolated GHD, type IB 612781 139250 GH1 17q23.3 Low serum GH AR Isolated GHD, type II 173100 139250 GH1 17q23.3 Variable height deficit and pituitary size; AD other pituitary deficits can develop Isolated GHD, type III 307200 300300 BTK Xq22.1 GHD with agammaglobulinemia XLR Isolated GHD, type IV 612781 139191 GHRHR 7p14.3 Low serum GH AR Isolated GHD, type V 618160 618016 RNPC3 1p21.1 Severe GHD, hypoplasia anterior AR pituitary Isolated partial GHD 615925 601898 GHSR 3q26.31 Variable serum GH and IGF-I AR, AD Kowarski syndrome 262650 139250 GH1 17q23.3 Elevated GH; deficiency of IGF-I, AD (bio-inactive GH IGFBP-3 and acid-labile subunit syndrome) Alström syndrome 203800 606844 ALMS1 2p13.1 50% of cases are GH-deficient AR Yes Short-rib thoracic 615630 607386 IFT172 2p23.3 Functional GHD, retinopathy, AR Yes dysplasia 10 with or metaphyseal dysplasia, hypertension without polydactyly AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive; MIM, Mendelian inheritance in man coding (https://www.ncbi.nlm.nih.gov/omim); modified from Wit et al. (9). mutations were in PROP1 (11.6% of patients), followed by LHX3 through changes in binding proteins, free IGF-I concentrations; (1.2%), whereas the gene mutations in patients with isolated therefore, it is important to determine which methodologies GH deficiency were most frequently found in GH1 (4.8%), should be used in the diagnosis. It is often not easy to and GHRHR (1.1%). However, the proportion of patients with identify from the phenotype which genes should be examined, identified defects is increasing over time as more genetic variants because serum levels of GH and IGFs may be decreased, are investigated. normal or increased in patients with the same genetic defect. Genetic abnormalities also had an effect on clinical outcomes Classic examples of GH resistance are due to mutations following GH treatment (23). For 24 patients with an identified in the GH receptor (GHR) gene, and a large number of mutation and who reached near-adult height, the height standard missense and splice mutations and deletions in GHR have deviation score (SDS) at start of GH treatment was −4.1, been identified in patients with short stature (24). Mutations compared with a baseline height SDS of −2.9 in 191 patients in GHR are most generally associated with Laron syndrome, without an identified mutation. The mean near-adult height SDS in which patients also have very low IGF-I levels (9, 11, 25). was −0.7 in those with a mutation vs. −0.9 in those without, and Mutations have also been reported in the signal transducer the respective mean gain in height SDS at near-adult height was and activator of transcription gene, STAT5B, which is part 3.4 vs. 2.0, which was significantly different (p < 0.001). Thus, of the signaling cascade of the GH receptor; in addition to those with an identified mutation are likely to be shorter at the growth failure, clinical features of these patients frequently start of GH therapy and have a better response to GH treatment. involve immunodeficiency and pulmonary fibrosis (24, 26), For specific gene mutations, patients with a defect in GH1 (n = 4) although some missense mutations of STAT5B have recently had an initial height SDS of −4.2 and a height SDS gain of 3.4 to been reported to not cause severe immune and pulmonary reach a near-adult height SDS of −0.8. On average, these patients problems (27). remained slightly shorter than normal height. For patients with More recently, defects in PAPP-A2 have been identified a PROP1 mutation, initial height SDS was −3.6, with a gain of in children with progressive post-natal growth failure 3.6 to reach height SDS 0.0 at near-adult height, and thus were from two unrelated families (28, 29). The gene encodes normal height. pregnancy-associated plasma protein (PAPP)-A2, which is a metalloproteinase that cleaves insulin-like growth factor binding GH Resistance and IGF-I Deficiency protein (IGFBP)-3 and IGFBP-5. Serum concentrations of total The genetic abnormalities causing GH resistance or IGF- IGF-I, IGF-II, IGFBP-3, acid-labile subunit, and insulin were all I deficiency/insensitivity (Table 3) are mainly associated with increased in these patients; however, free IGF-I concentrations intrauterine growth retardation and being born small for were very low, resulting in lack of negative feedback on GH gestational age. The concept of GH resistance and IGF-I synthesis and release. X-radiography of the fibulae, tibiae, deficiency is becoming more complex and cannot now be and femurs showed that the long bones were very thin; bone considered as a single clinical entity, but is a continuum density was low, with abnormal trabecular structure, and mild to of genetic, phenotypic, and biochemical abnormalities (24). moderate microcephaly was observed. After 1 year of treatment Genetic variants influence both total IGF-I concentrations and, with recombinant human IGF-I, two Spanish patients showed Frontiers in Endocrinology | www.frontiersin.org 4 September 2019 | Volume 10 | Article 602 Argente et al. Genetics of Growth Disorders TABLE 2 | Genetic abnormalities associated with combined pituitary hormone deficiencies (CPHD). Disorder MIM Gene Clinical features Inheritance Syndromic CPHD-1 613038 POU1F1 GH, prolactin, variable TSH deficiencies AR, AD CPHD-2 262600 PROP1 GH, prolactin, TSH, LH, FSH, variable ACTH AR deficiencies; pituitary can be enlarged CPHD-3 221750 LHX3 GH, prolactin, TSH, LH, FSH deficiencies; AR Yes sensineural hearing loss; cervical abnormalities; short stiff neck CPHD-4 262700 LHX4 GH, TSH, ACTH deficiencies AD, AR (CPHD-5) Septo–optic 182230 HESX1 Optic nerve hypoplasia, pituitary hypoplasia, AR, AD Yes dysplasia midline abnormalities of brain, absent corpus callosum, and septum pellucidum CPHD-6 613986 OTX2 TSH, GH, LH, FSH, variable ACTH, and AR, AD prolactin deficiencies Axenfeld–Rieger syndrome 180500 PITX2 Coloboma, glaucoma, dental hypoplasia, AD Yes type 1 protuberant umbilicus, brain abnormalities, variable pituitary deficiencies Optic nerve hypoplasia and 206900 SOX2 Variable GHD, hypogonadism, anophthalmia, AR Yes CNS abnormalities developmental delay X-linked panhypopituitarism 312000, SOX3 dup GHD or CPHD, mental retardation XLR Yes 300123 Dopa-responsive dystonia 612716 SPR Diurnally fluctuating movement disorder, AR Yes due to sepiapterin reductase cognitive delay, neurologic dysfunction, GH, deficiency and TSH deficiencies Holoprosencephaly 610829 GLI2 Holoprosencephaly, craniofacial abnormalities, AD Yes polydactyly, single central incisor, partial agenesis corpus callosum (or hypopituitarism only) Pallister–Hall syndrome 146510 GLI3 Hypothalamic hamartoma, central polydactyly, AD Yes visceral malformations IGSF1deficiency syndrome 300888 IGSF1 Hypothyroidism, TSH, variable GH, and XLR Yes prolactin deficiencies; macroorchidism Netherton syndrome 256500 SPINK5 Variable GH and prolactin deficiency AR Yes 600483 FGF8 Holoprosencephaly, septo-optic dysplasia, AR Yes Moebius syndrome 136350 FGFR1 Hypoplasia pituitary, corpus callosum, ocular AD Yes defects 607123 PROKR2 Variable hypopituitarism AD Yes 600698 HMGA2 Severe GHD, ectopic posterior pituitary AD 612250 GPR161 Pituitary stalk interruption syndrome, AR Yes intellectual disability, sparse hair in frontal area, hypotelorism, broad nasal root, thick alae nasi, nail hypoplasia, short fifth finger, 2–3 toe syndactyly, hypopituitarism AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive; MIM, Mendelian inheritance in man coding (https://www.ncbi.nlm.nih.gov/omim); shaded rows indicate conditions with a neurological phenotype where GH deficiency is variable; modified from Wit et al. (9). a good response of growth velocity, height gain, and trabecular are rare in humans, with only about 9 cases reported (34, 35), bone score (30, 31). A report has recently been published on the although both homozygous and heterozygous mutations, and history and clinical implications of defects in PAPP-A2 in human heterozygous deletions have been identified in patients with growth (32). The specific degradation of IGFBP-3 and IGFBP-5 short stature (9, 36, 37); however, homozygous carriers generally by the active metalloproteinase results in release of free IGF-I, have more severe growth failure than those with heterozygous and it has been demonstrated that the identified mutations in defects. Homozygous IGF1 defects that result in complete loss of the PAPP-A2 gene, producing inactive PAPP-A2, cause increased functional IGF-I are associated with extreme growth failure, both binding of IGF-I and low bioactivity, with consequent reduced pre-natal and post-natal, together with sensorineural deafness, skeletal growth (33). microcephaly and mental retardation (34–38). Identified defects resulting in GH resistance also include More recently, IGF2 abnormalities have been detected in a mutations in the IGF1 and IGF2 genes. Abnormalities of IGF1 number of patients; the clinical data indicated that IGF-II affects Frontiers in Endocrinology | www.frontiersin.org 5 September 2019 | Volume 10 | Article 602 Frontiers in Endocrinology | www.frontiersin.org Argente et al. TABLE 3 | Genetic abnormalities associated with GH resistance and IGF-I insensitivity. Syndrome Phenotype Gene Inheritance Clinical characteristics Laboratory findings MIM GH GHBP Prolactin IGF-I IGFBP-3 and ALS GH Resistance Laron syndrome 262500 GHR AR (AD) Variable height deficit, mid-facial hypoplasia GH insensitivity with immunodeficiency 245590 STAT5B AR Mid-facial hypoplasia, immunodeficiency Multisystem, infantile-onset autoimmune disease 615952 STAT3 activating AD Associated with early-onset multi-organ autoimmune disease X-linked severe combined immunodeficiency 300400 IL2RG XLR Non-responding to GH injections IGF-I deficiency 608747 IGF1 AR Born small for gestational age, microcephaly, deafness Severe growth restriction with distinctive facies 616489 IGF2 Patient inheritance Short stature, facial anomalies Acid labile subunit deficiency 615961 IGFALS AR Mild height deficit Primary protease deficiency Not yet defined PAPP-A2 AR Moderate microcephaly, skeletal abnormalities Immunodeficiency 15 615592 IKBKB AR, AD Immunodeficiency IGF insensitivity Resistance to IGF-I 270450 IGF1R AD, AR SGA, microcephaly 6 AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive; MIM, Mendelian inheritance in man coding (https://www.ncbi.nlm.nih.gov/omim); arrows for laboratory findings indicate increase, decrease or no change, with more than one type of arrow indicating variability; modified from Wit et al. (9). September 2019 | Volume 10 | Article 602 Genetics of Growth Disorders Argente et al. Genetics of Growth Disorders FIGURE 2 | Proposed algorithm for screening patients for IGF-related genetic abnormalities. both pre-natal and post-natal growth and the genetic defects concentration is generally high and above normal during GH are associated with clinical features of Silver–Russell syndrome treatment, although this may be considered acceptable owing to (39). While IGF2 defects have only recently been identified, it is the reduced sensitivity. possible that they may be more common than initially suspected. As a result of these studies of patients with GH resistance, Imprinting disorders, with hypomethylation of genetic control an algorithm was designed to try to predict which patients regions, may result in down-regulation of IGF2 expression by the should have genetic screening for mutations (Figure 2). This paternal allele and are involved in short stature due to both pre- is difficult because of the inconsistent patterns of clinical and natal and post-natal growth failure in Silver-Russell syndrome laboratory features (Table 3). For patients with intrauterine and Temple syndrome (40). A clinical scoring system has been growth retardation, possibly with microcephaly, and who have derived for Silver-Russell syndrome, and a consensus guideline sporadic occurrence of psychomotor retardation and deafness, stated that first line molecular testing should include analysis it may be worthwhile to look for mutations in IGF1; however, of methylation of the H19/IGF2 domain of the 11p15 region genotyping is somewhat ambiguous in these patients. Patients in patients with a high likelihood of the syndrome (41). The with familial occurrence of short stature related to being born guideline also concluded that GH treatment improved body small for gestational age who have high IGF-I should be checked composition and linear growth in these patients. for abnormalities of IGF1R. A recent study has suggested a Defects in IGF1R that result in resistance to the effects of clinical score for selecting patients for genetic testing of IGF1R IGF-I have been described in a number of patients who had defects, and indicated that testing should be carried out for intrauterine growth retardation and failure of catch-up growth children born small for gestational age, with low birth weight (9, 42, 43). The defects can occur in the external domain, and/or length, and who remained short, had microcephaly and the internal domain or in the transmembrane domain of the had IGF-I SDS >0 at presentation (47). Patients with low receptor. The condition is associated with microcephaly and serum IGF-II concentration and clinical features of Silver–Russell psychomotor retardation in some, but not all, cases and there syndrome, although not necessarily full Silver–Russell syndrome, may be other clinical pathologies, such as impaired glucose should be examined for defects in IGF2 (48). tolerance, dysmorphic features, and cardiac abnormalities, but In patients shown to have severe primary IGF-I deficiency, the pattern is inconsistent (42, 44); patients with homozygous recombinant human IGF-I appears to be effective and has mutations may show stronger syndromic features compared with been approved for use (7, 49). IGF-I has also been tested heterozygous carriers (45). Recently, a case was described with in combination with GH in patients with reduced IGF-I both a deletion of IGF1R and a duplication of the paternal IGF2 concentrations and GH sufficiency (50). Combined GH and region, resulting in appropriate pre-natal growth but retardation IGF-I treatment has also been suggested for patients with of post-natal growth, indicating the key role of IGF-II in fetal GH insufficiency plus IGF-I deficiency due to heterozygous growth and the more important role of the GH–IGF-I axis in dominant-negative GHR variants (51). However, IGF-I treatment post-natal growth (46). In children with IGF1R defects, IGF-I has not been approved for use in such cases, and the specific Frontiers in Endocrinology | www.frontiersin.org 7 September 2019 | Volume 10 | Article 602 Argente et al. Genetics of Growth Disorders clinical conditions in which GH, IGF-I, or the combination of radiological characteristics, including rhizomelic short stature these, may be effective need to be identified; genetic testing with short limbs and short fingers, limited elbow extension, should help to determine which treatment approach may be small chest, macrocephaly, and flattened mid-facial features useful to improve linear growth (7, 52). (56). GH treatment is not an approved treatment, except in For 51 patients born small for gestational age and with failure Japan, but increases growth velocity over the first few years. of catch-up growth, treatment with GH resulted in a median gain Very few studies have followed patients to adult height, but the in height SDS of 0.64 in the first year; for nine patients born small long-term effect appears to be limited (58). The Indian hedgehog for gestational age and without catch-up growth due to genetic paracrine system also controls chondrocyte proliferation and defects that resulted in dysfunctional IGF-I receptors, the median differentiation and defects can result in short stature (57, 59). first year height SDS response was 0.24 (Pfäffle R, unpublished Autosomal dominant mutations in the IHH gene result in data). The difference between the overall cohort and the patients mild skeletal dysplasias with brachydactyly, but patients may with abnormal IGF1R was significant (p = 0.013). However, the be diagnosed as born small for gestational age or as idiopathic GH dose given to the patients with dysfunctional IGF-I receptors short stature with defects only identified through whole exome was kept slightly lower than the dose for the patients born small sequencing, and the growth failure appeared to be improved by for gestational age because of concerns of excessive serum IGF- GH in the short-term (59). I concentration, which could have partially accounted for the Aggrecan is a key component of the cartilage extracellular difference. A variable response to GH treatment of children with matrix of the growth plate and articular surfaces. Abnormalities IGF1R deletions or mutations was seen in other studies, with in the ACAN gene, which encodes the proteoglycan, results GH in most, though not all, having a beneficial effect (44). The in proportionate or mildly disproportionate short stature, response in children with an IGF1R defect was suggested to be generally with advanced bone aging and premature growth less than the response seen in short children born SGA due to cessation (60, 61). ACAN defects are a common cause of other causes, although adult height gain was similar and may be idiopathic short stature and born small for gestational age; related to duration of treatment (47). While GH treatment for homozygous abnormalities result in severe skeletal dysplasia children born small for gestational age and without spontaneous while heterozygous defects cause milder skeletal dysplasia (61, catch-up growth is indicated to be initiated only at age 4 years 62). A clinical scoring system has been proposed to identify or above, starting GH treatment at a very young age (<4 years) children likely to have an ACAN mutation, although there is a in such children has been described to be more effective than in variable spectrum of phenotypes (63). GH treatment has been those who were older at GH initiation (53), at least during 3 years reported to be effective, but very few studies have been carried of therapy. out (62, 63). Patients with anomalies of the short stature homeobox- containing (SHOX) gene also show a wide spectrum of Genetic Anomalies Not Associated With phenotypes, from Leri-Weill dischondrosteosis, with mesomelia the GH–IGF-I Axis and Madelung deformity, to non-specific short stature (64). Genome wide association studies and next-generation SHOX deficiency is one of the most common genetic defects sequencing have indicated a large number of new genes associated with short stature in humans. In patients with associated with short stature, although in many cases the exact idiopathic short stature, the prevalence of anomalies in the SHOX mechanism remains unknown (54). Until relatively recently, gene or its regulatory elements, including deletions, duplications it was thought that linear growth in childhood was primarily and insertions, has been reported to range from about 6 to 22%, influenced by the GH–IGF-I axis and that abnormal growth due with increasing prevalence reported as genetic tests have become to genetic causes were related to defects in that system. However, more accurate (65). The severity of the condition does not appear it has recently been suggested that rather than focusing on the to relate to specific gene anomalies, and individuals within a GH–IGF-I axis, genetic studies should be more concerned with family could have the same defect but different phenotype (65, the biology of the growth plate (55). Cases reported as idiopathic 66); however, SHOX deletions or mutations are more associated short stature may be due to genetic disorders previously only with Leri-Weill syndrome whereas enhancer region defects are considered to be associated with skeletal dysplasias. more likely to be associated with less severe features of idiopathic Hypochondroplasia and achondroplasia are the most short stature (67). SHOX protein expressed by the gene is a common skeletal dysplasias that cause short stature and are transcription factor that regulates the expression of various other associated with abnormalities of the FGFR3 gene (56, 57). genes in the growth plate, including ACAN and FGFR3; while the Fibroblast growth factor receptor 3 negatively regulates mechanism has not been completely elucidated, SHOX protein chondrogenesis and mutations in the gene result in increased influences chondrocyte proliferation, hypertrophy, maturation, activity, which disrupts normal functioning of the proliferation and apoptosis, thus regulating long bone growth (65, 68). zone of the growth plates and impairs bone elongation. While The SHOX gene is located in the pseudoautosomal region heritability is autosomal dominant, the majority of cases and normal physiology requires two copies of the gene, with arise from spontaneous mutations and ∼80% of cases are haploinsufficiency occurring when only one functioning copy born to parents of average height. Diagnosis is generally at of the gene is present. Short stature due to SHOX deficiency birth or in early infancy. No formal diagnostic criteria have is, therefore, a frequent occurrence in children with Turner been published although there are well-defined clinical and syndrome, with all or part of one X-chromosome missing. Frontiers in Endocrinology | www.frontiersin.org 8 September 2019 | Volume 10 | Article 602 Argente et al. Genetics of Growth Disorders A need for screening of SHOX gene defects may be predicted organomegaly, abdominal wall defects, neonatal hypoglycemia, from abnormal limb-to-trunk ratios, x-radiography and family and predisposition to embryonic tumors (77). Because of the history, and predictive algorithms have been proposed (64, 65). increased risk of tumors associated with the condition, a Where clinical features are severe, deletions are seen in about consensus meeting devised a scoring system based on both 80 to 90% and genetic evaluations should include chromosomal cardinal and suggestive clinical features of the syndrome. This microarray analysis or SNP array analysis; for patients with less allowed identification of patients requiring molecular testing severe characteristics, exome sequencing is used more frequently and provided a flowchart for analysis of gain of methylation (64, 65). GH treatment of children with SHOX deficiency is an within the 11p15 genetic region and copy number variation (78). approved indication and is effective in improving adult height by The guidelines also provided recommendations for management 7 to 10 cm (65, 69). of various complications, including overgrowth that continues SHOX gene anomalies are found in ∼70% of children beyond childhood, although that occurs in only 43 to 65% with Leri-Weill dischondrosteosis (68). However, similar of patients. phenotypic features, including short stature but without Overgrowth, with either gigantism occurring before Madelung deformity, occur with defects in the natriuretic epiphyseal growth plate fusion or acromegaly due to excessive peptide receptor-B gene, NPR2. NPR-B is the receptor for skeletal growth at any time, can be caused by a number of genetic C-type natriuretic peptide, which is a regulator of chondrocyte defects that result in benign adenomas, with excess GH and differentiation and hypertrophy in the growth plates, and may be IGF-I synthesis and release. Gigantism and acromegaly are rare one of the genes activated by SHOX proteins (65). NPR2 defects in children, although pediatric cases have aggressive features; have been identified in about 2 to 6% of cases of idiopathic identified genetic conditions include, amongst others, familial short stature (70, 71). Biallelic loss of function mutations cause isolated pituitary adenoma and the more recently described Maroteaux-type acromesomelic dysplasia, while heterozygous X-linked acrogigantism (X-LAG), which have been reviewed mutations result in less severe short stature (70, 71). Therefore, recently and an algorithm for genetic testing and counseling patients may have severe skeletal dysplasia or non-specific proposed (79, 80). Because such diagnoses are generally made skeletal abnormalities, but phenotype characteristics of patients at a young age and there is frequently resistance to medical with NPR2 gene defects are currently not well established (72), therapy, analysis of the genetic basis is needed to predict and patients with short stature due to NPR2 defects may only therapeutic options. The most common condition is familial be detected where a relative has acromesomelic dysplasia (71). isolated pituitary adenoma, which is usually diagnosed in Very few patients with NPR2 defects have currently been treated childhood or adolescence, requires at least two cases of pituitary off-label with GH, but increased growth appeared to be modest adenomas in the family and the tumor is large and invasive and further studies would be required to demonstrate long-term (81). Inactivating mutations or deletions of the aryl hydrocarbon efficacy (70, 72). receptor-interacting protein gene, AIP, predispose patients to the condition and are the most frequently identified genetic cause of pituitary gigantism (82). Prevalence of AIP mutations in cases GENETIC FACTORS ASSOCIATED WITH of sporadic pituitary adenomas is reported to be ∼4%, but may OVERGROWTH be up to 20% in children and adolescents with gigantism and/or macroadenomas (83). Although no genetic defects are found in a Overgrowth With No Associated majority of patients with familial isolated pituitary adenoma (84), Intellectual Problems a recent study found novel variants of the MEN1 gene in some By contrast to gene defects that cause short stature, alternative cases where no defects in AIP were observed (85). Patients with defects in the same genes can result in overgrowth. Gain-of- sporadic pituitary adenomas and identified AIP mutations have function mutations in NPR2 have been identified in a number been mainly young males, with median age of emergence at 17.5 of patients with skeletal overgrowth, with associated features years, the tumor tends to be larger than in patients without AIP of scoliosis and macrodactyly, with markedly large big toes mutations and tumors were more often resistant to somatostatin (71, 73, 74). The ligand for the receptor is C-type natriuretic analogs and required surgical intervention (80, 82, 83). peptide (CNP) and overproduction due to translocation of the X-LAG syndrome is very rare, but is the most frequently NPPC gene also caused tall stature with macrodactyly and skeletal identified cause of gigantism in pre-pubertal patients, with dysplasia (75, 76). The mechanism of excess skeletal growth due diagnosis generally before the age of 3 years (80, 86). The to increased activation of the CNP/NRPB system was reported to condition is characterized by increased linear growth and weight be through overproduction of cyclic guanosine monophosphate that can be seen before 12 months of age, although gestational within the growth plate chondrocytes (73, 74, 76). size may be normal; patients often have increased appetite and Beckwith-Wiedemann syndrome is one of the most common hunger and most identified cases also had hyperprolactinemia overgrowth conditions and is the converse of Silver-Russell (82, 86). Because of the very early onset of overgrowth, adult syndrome, due to molecular anomalies in the chromosome 11p15 height may be greatly increased at >4.5 SDS (87, 88). Both GH imprinting region (47, 77, 78). Duplications of the imprinting and IGF-I are markedly elevated, but GH releasing hormone is region is associated with over-expression of the IGF2 gene and also elevated and the adenomas remain sensitive suggesting that patients are reported to have both pre-natal and post-natal therapeutic antagonists of the GH releasing hormone receptor overgrowth, with associated anomalies including macroglossia, could reduce the excess GH secretion (87, 89). The condition is Frontiers in Endocrinology | www.frontiersin.org 9 September 2019 | Volume 10 | Article 602 Argente et al. Genetics of Growth Disorders TABLE 4 | Genetic abnormalities identified among 710 patients with OGID syndromes. Gene family Proportion of total Associated condition MIM Inheritance Variant gene patients Epigenetic regulator genes NSD1 240 cases, 34% Sotos syndrome 117550 AD EZH2 34 cases, 4.8% Weaver syndrome 277590 AD DNMT3A 18 cases, 2.5% Tatton-Brown–Rahman syndrome 615879 AD CHD8 12 cases, 1/7% Autism susceptibility 615032 AD HIST1H1E 5 cases, 0.7% Rahman syndrome 617537 AD EED 2 cases, 0.3% Cohen Gibson syndrome 617561 AD PI3K/mTOR pathway genes PTEN 16 cases, 2.3% PTEN hamartoma tumor syndrome 158350 AD PPP2R5D 3 cases, 0.4% Mental retardation 616355 AD MTOR 2 cases, 0.3% Smith-Kingsman syndrome 616638 AD AKT3 1 case, 0.1% Megalencephaly-polymicrogyria-polydactyl-hydrocephalus syndrome 2 615937 AD PIK3CA 1 case, 0.1% PIK3CA-related overgrowth syndrome Multiple Unknown Undetermined pathway genes NFIX 14 cases, 2.0% Marshall-Smith syndrome 602535 AD BRWD3 7 cases, 1.0% X-linked mental retardation 300659 XLR GPC3 2 cases, 0.3% Simpson-Golabi-Behmel syndrome 312870 XLR AD, autosomal dominant; XLR, X-linked recessive; MIM, Mendelian inheritance in man coding (http://www.omim.org); adapted from information in Tatton-Brown et al. (91). linked to a germline micro-duplication of chromosome Xq26.3 the introduction of next-generation sequencing technologies and is associated with the GPR101 gene (86–88). A number that permit the examination of thousands of genes in a single of mutations in GPR101 have also been identified in patients experiment, the genetic cause of many OGID syndromes has with sporadic acromegaly (86, 90). GPR101 encodes a G-protein been determined. A gene discovery study of patients with OGID coupled receptor, the function of which has not currently syndromes, reported in 2017, included 710 participants and been fully elucidated, that is predominantly expressed in the identified 14 different genes among 50% of affected individuals hypothalamus and fetal pituitary glands, and it may have a role (93). Children with overgrowth phenotypes without intellectual in pituitary ontogenesis (86, 87, 90). The disorder is X-linked, disability were excluded from the study. Two key OGID gene arising spontaneously in most cases; because index cases are families were identified: the epigenetic gene regulator family (six generally female and more than 70% of cases are female, it has genes, 44% of the overall patients) and the PI3K/mTOR pathway been suggested that affected hemizygous male embryos may be gene family (five genes, 6% of the overall patients); in addition, less viable, although familial cases from mother to son have been variants in three genes involved in, as yet, undetermined reported (79, 82, 87). X-LAG syndrome does not have any specific pathways were identified (Table 4). association with intellectual disability. However, a chromosome The proteins encoded by genes involved in epigenetic Xq26 microduplication was found in a 4-year old boy referred regulation were (1) histone methyltransferases targeting specific for examination for X-LAG (91). The genetic duplications are lysine residues of histone tails (NSD1, EED, EZH2), (2) a detected using array comparative genome hybridization (82, 87); DNA methyltransferase (DNMT3A), and (3) genes involved in this is normally clinical grade analysis, where duplications may chromatin remodeling (CHD8) and stabilization of higher-order be smaller than the assay resolution, and when assayed by chromatin structures (HIST1H1E). high definition molecular cytogenetics the duplication did not Of the OGID genes identified in the study, NSD1 was the most include the GPR101 gene (91). The patient did not show the frequently mutated (240 children, 34% overall). Nuclear receptor phenotype of gigantism or GH excess and the study showed binding SET domain protein 1 (NSD1) catalyzes the methylation the importance of the correct genetic assay and provided of lysine residue 36 of histone H3 (H3K36) and, to a lesser degree, supporting evidence for GPR101 being the gene involved lysine residue 20 of histone H4 (H4K20), a methylation mark in X-LAG. primarily associated with transcriptional activation (94). NSD1 variants cause Sotos syndrome (MIM 117550), associated with Overgrowth With Intellectual Disability increased growth, an intellectual disability and a characteristic Overgrowth-intellectual disability (OGID) syndromes are a facial appearance with a broad forehead, down-slanting palpebral family of genetic disorders characterized by excessive growth fissures, long thin face, tall chin, malar flushing and sparse fronto- (height and/or head circumference ≥2 SD above the mean temporal hair (95, 96). compared with the age-related peer group) in combination EZH2 and EED encode components of the polycomb with an intellectual disability (92). Over the last decade, since repressor complex 2 (PRC2), which catalyzes the methylation of Frontiers in Endocrinology | www.frontiersin.org 10 September 2019 | Volume 10 | Article 602 Argente et al. Genetics of Growth Disorders histone 3 at lysine 27 (H3K27) associated with transcriptional investigation frequently involves genetic analysis. Genome-wide repression (97). Pathogenic variants within EZH2 and EED cause studies have identified ∼700 common associated variants with very similar OGID phenotypes; respectively, Weaver syndrome effects on height and 83 minor allele variants that had effects (MIM 277590) and Cohen Gibson syndrome (MIM 617561), on growth of up to 2 cm per allele. Many genes have effects characterized by tall stature, variable intellectual disability and on the GH–IGF-I axis, and new genes are constantly being characteristic facial appearance of “stuck-on” chin, horizontal added to the list. Research is fundamental to increase knowledge skin crease, and hypertelorism (96, 98, 99). of the genes and mechanisms involved in the pathophysiology DNMT3A pathogenic variants cause Tatton-Brown–Rahman of different diseases. However, in the clinical setting, genetic overgrowth syndrome (TBRS; MIM 615879) (100). Children studies are required to progress from phenotype, auxology, with TBRS characteristically have variable intellectual disability, and hormone measurements to more precise genetic diagnoses autism spectrum disorders and increased growth (93, 100– and treatments. 102). A range of different medical issues are additionally New technologies, such as whole exome sequencing and whole associated with TBRS, including hypermobility of joints, obesity, genome sequencing, are increasing the speed, precision and kyphoscoliosis, and congenital cardiac anomalies (100). availability of genetic diagnoses, with decreasing costs (108– HIST1H1E encodes the linker histone H1.4, and recently five 110). Some areas of the genome have limited capture by whole unrelated probands were identified with de novo heterozygous exome sequencing, making it difficult to go from a diagnosis frameshift variants (protein truncated variants, PTVs) that were based on phenotype and medical background to proof from clustered in a 12 base-pair region of the carboxy-terminal domain genotype. Therefore, next-generation sequencing techniques, (93). Histone H1.4 is one of the 11 histones that mediate such as targeting exome sequencing, are being developed, to formation of chromatin structures that regulate gene expression. target specific collections of candidate genes with the use of It is hypothesized that the clustered PTVs all generate the same chromosomal microarrays to detect copy number variations open-reading frame, with the shorter mutant protein associated (16, 111). Such techniques can be directed to make a specific with a reduced net positive charge compared to the wild type, diagnosis, while whole exome and whole genome sequencing thereby disrupting normal binding to negatively-charged DNA may be more useful for research purposes to identify new genetic (93, 103). Patients with HIST1H1E pathogenic variants have a variations associated with specific conditions: identifying the variable intellectual disability and a characteristic appearance of genes involved in combined pituitary hormone deficiency may high hairline and frontal bossing. be more useful as a scientific interest to provide new insights With regard to the PI3K/mTOR pathway genes, PTEN into pathogenesis and novel treatment strategies; identifying the pathogenic variants have been an established cause of genes involved in Turner syndrome will be more useful from a PTEN hamartoma tumor syndrome (PHTS; MIM 158350), diagnostic point of view, when appropriate genetic counseling also known for many years as Bannayan-Riley-Ruvalcaba and treatment monitoring can be carried out; and detecting the syndrome in childhood (92, 96). The encoded PTEN protein genes involved in GH resistance could be useful for both scientific is a negative regulator of the PI3K/mTOR pathway, and research and for identifying potential clinical consequences. affected children are macrocephalic, and may have an While short stature is a frequent cause of referral to a pediatric intellectual disability and autistic spectrum disorder. In endocrinologist, screening for tall stature is generally considered addition, they have a predisposition to develop cancers in a lower priority. However, it is important to identify pathological adulthood (Cowden syndrome) (104). PIK3CA pathogenic causes of gigantism and overgrowth, particularly because certain variants are primarily associated with macrocephaly and genetic conditions may be resistant to medical therapy or asymmetric growth, which may be progressive (92, 96). predispose to tumors. With regard to the OGID syndromes, Treatment with drugs that block the PI3K/mTOR pathway, while there is considerable phenotypic overlap between many such as sirolimus and everolimus that are already in use as of the individual conditions, patients with epigenetic regulator anti-cancer agents, have been shown in vitro and in animal gene variants more frequently have tall stature in association models to be effective in reducing the progressive overgrowth with macrocephaly, whereas those with PI3K/mTOR pathway and may potentially improve cognition (93, 105, 106). gene variants more usually have isolated macrocephaly. Research Such treatments in humans have shown varying success into the genetic basis of these syndromes provides a background in reducing the regional overgrowth, although the side- understanding of the normal regulation and development of effect profile, most notably the increased infection rate, is growth. On a practical basis, knowledge of the genotype in significant [(106, 107), and ClinicalTrials.gov: NCT02991807 patients with OGID syndromes and in patients with growth and NCT00971789]. failure is likely to be increasingly useful for pharmacogenomics and gene-directed therapies. CONCLUSIONS AUTHOR CONTRIBUTIONS Human height follows a binomial distribution; however, individuals that lie at the extremes of the distribution may All authors critically revised the current work for important potentially have problems that require investigation. Height is a intellectual content and gave final approval of the version of highly heritable classic polygenic trait and, therefore, part of any the publication to be published. All authors have agreed to Frontiers in Endocrinology | www.frontiersin.org 11 September 2019 | Volume 10 | Article 602 Argente et al. Genetics of Growth Disorders be accountable for all aspects of the work in ensuring that to the authors for authoring this publication and no questions related to the accuracy or integrity of any part of it are compensation will be provided for the time they spend on appropriately investigated and resolved. the publication development. FUNDING ACKNOWLEDGMENTS The 2nd 360◦ European Meeting on Growth Hormone Medical writing assistance was provided by Peter Bates, Disorders was funded by Merck Healthcare KGaA, Darmstadt, Cambridge Medical Writing Services, UK, funded by Merck Germany. No payment has been offered or will be offered Healthcare KGaA, Darmstadt, Germany. REFERENCES 16. Martos-Moreno GÁ, Travieso-Suárez L, Pozo-Román J, Muñoz- Calvo MT, Chowen JA, Frilander MJ, et al. Response to growth 1. Silventoinen K, Sammalisto S, Perola M, Boomsma DI, Cornes BK, Davis C, hormone in patients with RNPC3 mutations. EMBO Mol Med. (2018) et al. 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