Introduction: Among children born small for gestational age, 10–15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. Methods: Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <−2 SD for gestational age and life-minimum height <−2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. Results: The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. Conclusions: The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.

Approximately 5% of children are born small for gestational age (SGA) – with a birth weight and/or length below −2 SD compared to normative values for their gestational age [1]. The aetiology of SGA is heterogeneous (environmental, maternal, placental, and endogenous factors, including defined gene variants [2]). Up to 90% of SGA children develop catch-up growth during the first 2 years of life, while the remaining fail to catch up and are referred to as ‘small for gestational age – short stature’ (SGA-SS). These children are known to remain small throughout childhood and reach a substantially reduced adult body height [3, 4]. They are therefore indicated for treatment with growth hormone (GH) [1, 5, 6]. Nevertheless, the response to GH administration is variable among individual SGA-SS children, which may reflect the heterogeneous aetiology of their growth failure [7, 8].

In SGA-SS, several genetic mechanisms should be taken into consideration: imprinting disorders and abnormal methylation patterns such as Silver-Russell syndrome (SRS), Temple syndrome, IMAGe syndrome, and others [9‒11]. In addition, a long list of single gene conditions has been associated with the regulation of human growth and thus impact on final height, albeit not necessarily associated with prenatal growth restriction [12, 13]. Some of these genes regulate the structural development of the cerebral midline and pituitary and functional components of the GH-IGF-1 axis (hormones, their receptors, and post-receptor signalisation). Moreover, new genes have been discovered which code for important growth plate paracrine factors, proteins of cartilage extracellular matrix, components of intracellular regulating cascades, and proteins involved in fundamental intranuclear processes [2].

The elucidation of the genetic background of SGA-SS was initiated no more than 2 decades ago [2]. In some cases, a child might present with typical features, leading to targeted genetic testing. A typical example is the genetic diagnosis of SRS in individuals fulfilling the Netchine-Harbison clinical criteria [9]. However, most SGA-SS children present with no apparent syndromic features; therefore, genetic diagnosis is challenging.

New possibilities of genetic testing such as next-generation sequencing (NGS) allowed new advancements in discovering the genetic aetiology of short stature within the past decade [14]. Knowledge of the genetic basis of growth disorders in these children not only helps in better understanding the pathophysiology of growth but may have important consequences for their treatment and follow-up as well. The aim of this study was to decipher genetic aetiologies among a large single-centre cohort of SGA-SS children treated with GH and to stratify them according to molecular mechanisms leading to combined pre- and postnatal growth failure.

The study cohort was selected from 820 children treated with GH in our centre between May 2008 and December 2018 using a stepwise selection process as displayed in Figure 1. Other causes of growth failure were considered and appropriately evaluated before starting GH therapy. Extremely preterm children (gestational age <28 weeks) were excluded due to missing relevant normative values for their size at birth. After exclusion of children treated with GH for other causes (chronic kidney disease, acquired GH deficiency (GHD), Turner syndrome, Prader-Willi syndrome, and primary GHD born either appropriate for gestational age or SGA but with life-minimum height >−2.5 SD), 256 children with SGA-SS (birth weight or length <−2 SD and body height <−2.5 SD after 3 years of life) remained for further evaluation. Out of them, 176/256 (69%) families agreed to genetic testing; therefore, the child and both of his/her parents were enrolled in the study (Fig. 1). The clinical assessment of all children included measurements of weight (using an electronic scale) and height (mean of three measurements using a calibrated stadiometre to the nearest 1 mm). These results were converted to the SDS using age- and sex-specific normative values [15]. The height of the parents was either obtained during the patients’ visit using the same method or referred from their medical records. Birth parameters were obtained from medical records.

Fig. 1.

Flowchart of the study. GH, growth hormone; CKD, chronic kidney disease; GHD, growth hormone deficit; IGHD, idiopathic growth hormone deficit; AGA, appropriate for gestational age; MS-MLPA, methylation-specific multiplex ligation-dependent probe amplification; WES, whole-exome sequencing; SRS, Silver-Russell syndrome; VUS, variant of uncertain significance; LB, likely benign; B, benign; LP, likely pathogenic; P, pathogenic.

Fig. 1.

Flowchart of the study. GH, growth hormone; CKD, chronic kidney disease; GHD, growth hormone deficit; IGHD, idiopathic growth hormone deficit; AGA, appropriate for gestational age; MS-MLPA, methylation-specific multiplex ligation-dependent probe amplification; WES, whole-exome sequencing; SRS, Silver-Russell syndrome; VUS, variant of uncertain significance; LB, likely benign; B, benign; LP, likely pathogenic; P, pathogenic.

Close modal

The cohort included 93 males and 83 females. The median birth term was 39 weeks (interquartile range [IQR] 37; 40), median birth weight was 2,485 g (IQR 2,108; 2,788), and median birth length was 45 cm (IQR 43; 47). The median age at initiation of GH therapy was 4.95 years (IQR 3.13; 7.18), and the median life-minimum height SDS was −3.04 (IQR −3.49; −2.72).

All SGA-SS children underwent long-term GH treatment with a dosage of 35 μg/kg/day as suggested in the consensus from Clayton et al. [5]. If the child was also found to have GHD, the dose was in the range of 25–35 μg/kg/day in accordance with summary of product characteristics, and in the case of SHOX deficiency, 50 μg/kg/day as recommended in previous studies [16].

Genetic Testing

Genetic Testing Prior to the Study

All children with a clinical suspicion of a specific genetic disorder underwent genetic examination with an appropriate method (karyotype, FISH, MLPA, targeted Sanger sequencing) prior to the study. The remaining children were examined for SRS. After its’ exclusion, patients were examined by NGS methods.

Examination of SRS

Methylation-specific multiplex ligation-dependent Probe amplification (MS-MLPA) was done in all patients. MS-MLPA (probe mixes ME030 and ME032 examining regions of 11p15, 7q32, 7p12, and 14q32, respectively) and subsequent data analyses by software Coffalyser were performed according to the manufacturer’s instructions (MRC Holland, Amsterdam, The Netherlands).

Targeted NGS

Genomic DNA was extracted from peripheral blood using QIAmp DNA Blood Mini (Qiagen, Hilden, Germany) or from saliva (collected into Oragene OG-500) according to the manufacturer’s instructions (DNA Genotek, Ontario, Canada). DNA of patients without a verified genetic cause of their growth failure was analysed using a custom-targeted NGS panel of 398 genes with a known or potential association with growth [17] using SureSelect Custom Kit (Agilent Technologies, Santa Clara, CA, USA), and the indexed products were sequenced by synthesis on an Illumina MiSeq platform (San Diego, CA, USA) with ×100 average coverage. Altogether 6 DNA samples from probands underwent the whole-exome sequencing using SureSelect Human All Exon v6+UTR Kit (Agilent Technologies). The indexed products were sequenced by synthesis on an Illumina MiSeq or NextSeq platform (San Diego, CA, USA) with ×100 average coverage. Obtained sequences were annotated and mapped to reference genome followed by variant calling as described previously [17]. Detected variants were filtered using software Variant Annotation and Filter Tool [18] with filter settings described previously [17].

Evaluation of Genetic Findings

Confirmation of all variants of interest in the patient and segregation analyses in available family members were performed by direct Sanger sequencing [19]. Subsequently, variants were scored according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines [20] implemented in the VarSome software [21] as pathogenic (P), likely pathogenic (LP), benign (B), likely benign (LB), or as variants of uncertain significance (VUS). Consideration of co-segregation in the pathogenicity classification of variants (criterion PP1 in the ACMG guidelines) was applied based on recommendations by Jarvik and Browning [22].

Ethics Statement

This study protocol was reviewed and approved by the Institutional Ethics Committees of the 2nd Faculty of Medicine, Charles University in Prague, and University Hospital Motol, Czech Republic (date of approval: June 30, 2017; not numbered). Written informed consent was obtained from the parents/legal guardians of the patients for publication of the details of their medical cases and any accompanying images.

In total, the genetic diagnosis was elucidated in 74/176 (42%) children (Fig. 1). We confirmed pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development or GH secretion (LHX4, OTX2, PROKR2, PTCH1, POU1F, GHSR) and/or the GH-IGF-1 axis and IGF-2 axis (IGFALS, IGF1R, STAT3, HMGA2) in 12/74 (16%) patients. Two out of 74 children (3%) had P/LP gene variants affecting the thyroid axis (TRHR, THRA). P/LP gene variants affecting the growth plate were revealed in 31/74 (42%). Of these, 17/74 children had P/LP variants in genes responsible for components of the cartilaginous matrix (ACAN [in four], COL1A1, COL1A2, COL2A1, COL9A1, COL9A2, COL11A1, FLNB, MATN3), 7/74 had impaired paracrine regulation of chondrocytes (FGFR3, FGFR2, NPR2), and 7/74 had SHOX gene defects. In 12/74 children (16%), we revealed P/LP variants in genes involved in fundamental intracellular and intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SRS was diagnosed in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations were identified in 5/74 (7%) children.

Overall, in our cohort, 40 out of 74 patients (54%) had positive genetic findings and no dysmorphic features. Part of these results were published in our previous reports on children from families with vertical transmission of short stature (“familiar short stature”) [17] and/or in a paper summarising the effect of GH therapy in children with pathogenic NPR2 variants [23] and non-syndromic collagenopathies [24]. The principal clinical and growth data are summarised in Table 1. All the genetic findings are presented in Table 2. The single-gene conditions (and SRS) and their significance at three levels of growth regulation are displayed in Figure 2a–c.

Table 1.

Clinical findings in children born small for gestational age with persistent short stature (SGA-SS) with elucidated genetic diagnosis

Patient No.GenderGWBW, gBW (SDS)BL, cmBL (SDS)Father’s height (SDS)Mother’s_height (SDS)Age at start of GH therapy, yearsHeight (SDS) at start of GH therapyHeight (SDS) after 1 year of GH therapyHeight (SDS) after 3 years of GH therapyFinal height (SDS)IGF-1 (SDS) prior to therapyBA-CA, yearsPrimary diagnosis leading to GH treatmentBrain MRIDysmorphic features
37 1,860 −2.8 42 −3.8 −1.3 −2.7 6.3 −3.2 −2.0 −1.6 N/A 1.09 −1.2 GHD+SGA Normal No 
42 2,890 −2.1 50 −1.4 0.4 −3.9 4.1 −3.1 −2.4 −1.9 N/A −2.01 −0.4 GHD+SGA Normal No 
40 2,840 −1.9 47 −2.4 −1.7 −0.7 7.7 −2.7 −2.3 −1.6 −2.6 0.11 N/A GHD+SGA Normal No 
36 1,690 −3.0 37 −6.4 0.0 −0.5 3.2 −4.2 −3.3 −3.2 N/A N/A N/A SGA N/A Yes 
39 2,210 −2.9 44 −3.4 −1.5 0.1 3.5 −2.7 −2.0 −1.4 N/A 1.27 −1.5 SGA N/A No 
32 1,260 −1.9 38 −3.9 −1.6 −2.7 7.0 −3 −2.2 −1.7 N/A 0.02 −0.3 SGA N/A No 
39 2,480 −2.2 45 −2.8 −0.7 −0.4 7.4 −4.3 −4.0 −3.4 −2.8 −1.73 N/A SGA N/A No 
37 2,060 −2.5 44 −2.8 0.3 0.6 2.3 −3.8 −3.8 −2.7 N/A −5.37 N/A GHD+SGA Bilateral anophthalmia, agenesis of optic nerves, and chiasm Yes 
33 1,750 −1.1 41 −2.7 −0.6 0.4 1.1 −5.0 −3.1 −1.9 N/A −4.40 −1.1 GHD+SGA N/A No 
10 40 2,350 −2.9 48 −1.6 0.4 −1.2 13.5 −3.3 −2.3 −1.1 −1.0 −4.78 −1.4 GHD+SGA Rathke cleft cyst No 
11 30 1,120 −1.3 36 −4.0 0.4 0.4 2.8 −2.6 −1.9 −0.7 N/A −1.84 −1.8 GHD+SGA Normal No 
12 35 2,200 −1.1 44 −2.1 −0.03 −1.2 6.3 −2.5 N/A N/A N/A −2.74 −0.8 SGA N/A No 
13 40 2,750 −2.1 48 −1.9 −0.7 −0.8 7.1 −3.1 −2.6 −2.2 N/A −1.78 −2.3 GHD+SGA N/A No 
14 40 2,900 −1.8 47 −2.4 −2.9 −2.0 11.6 −3.7 −3.9 −2.9 −2.6 −3.22 −3.3 SGA N/A No 
15 39 2,850 −1.6 46 −2.2 −1.7 −2.9 5.7 −3.0 −2.7 −2.5 N/A 0.74 1.9 SGA N/A No 
16 38 2,670 −0.6 45 −2.7 0.7 −1.6 3.6 −2.5 −1.5 −1.0 −0.5 0.91 N/A SGA N/A No 
17 40 2,960 −1.3 46 −2.6 0.7 −1.2 4.4 −3.1 −2.4 −1.9 −3.6 1.19 0.1 SGA N/A No 
18 40 2,920 −1.8 45 −3.4 −3.6 −0.8 7.4 −3.3 −2.7 −2.1 −2.0 −3.10 0.5 SGA Normal No 
19 33 1,350 −2.1 38 −4.3 −2.4 −2.3 3.3 −2.7 −2.6 −2.1 −1.5 −1.51 0.2 SGA N/A No 
20 39 2,450 −2.4 46 −2.55 −2.3 −2.7 12.6 −2.7 −2.3 −2.7 −3.1 0.73 −0.3 SGA N/A No 
21 40 2,350 −2.9 46 −2.7 −1.0 −1.5 5.4 −3 −2.8 −1.9 N/A −1.35 −0.3 GHD+SGA Normal Yes 
22 40 2,520 −2.6 49 −1.4 −2.0 0.0 4.3 −2.5 −2.0 −1.9 −2.3 −0.64 −0.9 GHD+SGA N/A No 
23 39 2,270 −2.7 42 −4.4 −1.5 −3.4 5.7 −2.8 −2.1 −0.8 −2.7 0.49 −0.4 SGA N/A No 
24 39 2,450 −2.5 45 −3.1 −2.9 −1.3 12.0 −3.4 −2.7 −2.1 −2.2 −1.51 −1.6 SGA N/A No 
25 40 2,500 −2.5 43 −4.3 −2.2 −0.4 7.0 −3.1 −2.4 −2.1 N/A 0.93 −2.5 SGA N/A No 
26 39 2,660 −2.0 47 −2.1 −3.2 −1.5 6.0 −3.7 −3.2 −2.8 N/A −3.16 N/A SGA Cyst of cisterna magna No 
27 40 2,750 −2.1 48 −1.9 −1.3 −1.5 9.2 −2.7 −2.2 −1.4 N/A 0.34 −1.4 SGA N/A No 
28 40 2,400 −2.9 48 −1.9 −1.5 −1.2 10.2 −2.8 −2.0 −0.6 −1.5 −1.26 N/A GHD+SGA N/A Yes 
29 40 3,000 −1.3 45 −3.2 0.8 −1.5 6.4 −2.8 −2.2 −1.5 −2.1 −0.15 −0.2 SGA Normal No 
30 40 3,200 −1.0 47 −2.4 −3.2 0.8 1.5 −2.5 −1.8 −1.5 N/A −0.27 N/A SGA N/A No 
31 40 2,650 −2.3 47 −2.4 0.4 −2.3 9.1 −2.5 −1.6 −0.8 N/A 0.09 0.1 SGA N/A No 
32 41 3,190 −1.0 47 −2.4 −1.2 −1.2 7.1 −2.5 −1.6 0.1 N/A −0.90 −2.1 GHD+SGA Pituitary microadenoma No 
33 40 2,600 −2.3 45 −3.2 −1.1 −1.2 6.0 −2.9 −2.3 −1.4 N/A 0.32 N/A SGA Normal No 
34 41 2,880 −1.8 47 −2.4 0.8 −2.4 4.0 −2.9 −2.9 −1.9 N/A 0.15 N/A GHD+SGA Normal No 
35 39 2,710 −1.9 46 −2.6 N/A −1.8 3.3 −2.8 −2.4 −2.2 N/A −2.01 −0.4 GHD+SGA Normal No 
36 41 2,800 −2.0 48 −1.8 −2.4 −2.3 3.1 −3.6 −3.0 −2.5 N/A −6.04 N/A SGA N/A No 
37 40 2,630 −2.2 47 −2.1 −2.0 −1.3 3.4 −3.5 −2.7 −2.5 −2.7 −1.65 −0.3 SGA N/A No 
38 38 2,460 −2 44 −3.2 −1.5 −3.7 4.5 −3.5 −2.9 −2.5 N/A −2.48 N/A GHD+SGA Normal No 
39 39 2,490 −2.4 48 −1.6 −2.9 −1.2 1.5 −2.9 −2.9 −2.5 N/A −2.50 −0.8 SGA Normal Yes 
40 40 2,460 −2.8 49 −1.4 −0.5 0.4 2.2 −2.5 −1.1 −0.9 N/A −0.45 0.0 GHD+SGA Small pituitary Yes 
41 40 3,270 −0.9 46 −2.9 −0.46 0.43 1.9 −4 −3.0 −4.8 N/A −1.37 −0.5 GHD+SGA Small pituitary Yes 
42 39 2,444 −2.3 44 −3.4 −1.4 0.2 3.9 −2.9 −2.3 −2.5 N/A 0.88 N/A SGA N/A Yes 
43 35 2,050 −1.3 42 −2.9 0.8 −1.5 2.3 −3.9 −3.3 −2.9 N/A 0.12 N/A SGA N/A Yes 
44 42 2,800 −2.0 46 −3.1 −1.6 −1.5 5.2 −3.3 −3.0 −2.5 −3.0 −0.42 −0.8 GHD+SGA Normal No 
45 38 2,390 −2.2 N/A N/A −0.7 −0.4 2.1 −4.3 −3.5 −3.1 N/A <-2.5 N/A GHD+SGA Pachygyria, heterotopia of grey matter, thinning of corpus callosum Yes 
46 39 2,500 −2.2 46 −2.3 −2.3 −1.0 2.9 −3.4 −2.9 −2.0 −1.9 −1.26 N/A GHD+SGA Normal No 
47 40 3,350 −0.7 47 −2.4 −1.0 −1.6 4.2 −3.0 −2.2 −1.7 N/A −2.85 N/A GHD+SGA Normal No 
48 42 2,820 −2.0 48 −1.9 1.7 0.1 3.1 −3.7 −3.0 −3.1 −3.7 0.15 −1.9 SGA N/A Yes 
49 38 2,480 −1.8 45 −2.4 −1.2 −0.8 1.6 −3.4 −2.8 −2.0 N/A −0.37 N/A GHD+SGA Small pituitary, thin pituitary stalk Yes 
50 38 2,900 −1.0 45 −2.7 −1.5 −1.9 3.0 −3.6 −2.9 −2.4 N/A −1.60 N/A SGA N/A No 
51 40 2,790 −1.8 46 −2.7 0.8 −3.1 9.8 −3.0 −2.3 −1.8 −2.6 N/A −2.2 SHOX N/A Yes 
52 40 3,200 −1.0 47 −2.4 −3.2 −2.0 11.5 −2.9 −2.3 −2.1 −3.0 0.48 1.1 SHOX N/A Yes 
53 34 2,130 −0.5 43 −1.9 −1.7 −0.4 8.4 −2.8 −2.3 −1.7 N/A 0.67 −1.2 SHOX N/A Yes 
54 40 3,400 −0.3 44 −3.8 −2.9 −1.6 1.7 −2.5 −2.3 -1.8 N/A 0.45 N/A SHOX N/A Yes 
55 30 1,280 −0.8 38 −2.7 −1.9 −2.4 4.1 −3.8 −3.1 −2.2 N/A −2.47 N/A SHOX N/A Yes 
56 38 2,860 −1.1 43 −3.7 0.8 −3.5 5.4 −3.6 −3.7 −2.8 −3.8 −1.14 −0.8 SHOX N/A Yes 
57 40 2,500 −2.5 46 −2.7 −2.6 −2.0 7.5 −3.1 −2.7 −1.7 N/A N/A N/A SHOX N/A Yes 
58 37 2,090 −2.3 45 −2.1 −0.3 −0.7 2.9 −3.3 −2.8 −1.7 N/A N/A N/A SGA N/A Yes 
59 40 2,190 −3.3 42 −4.9 −0.6 −1.2 1.2 −3.5 −2.8 −2.8 N/A 0.53 N/A SGA N/A Yes 
60 34 1,345 −2.7 37 −5.5 0.0 0.7 2.2 −2.6 −2.3 −0.9 N/A −2.72 −1.1 GHD+SGA N/A No 
61 30 840 −2.2 N/A N/A −1.5 0.1 1.0 −5.3 −4.9 −4.2 N/A −1.89 N/A SGA N/A Yes 
62 38 1,750 −3.6 41 −4.5 0.0 1.4 0.8 −2.5 −1.6 −0.9 N/A 2.30 N/A SGA N/A Yes 
63 35 1,700 −2.3 38 −5.4 −1.0 −1.2 3.3 −3.4 −3.3 −3.2 N/A −1.17 −1.1 SGA N/A No 
64 38 1,700 −3.8 42 −3.9 −1.6 0.6 1.4 −4.2 −3.4 −2.9 N/A 0.71 −0.2 SGA N/A Yes 
65 37 2,100 −2.2 45 −2.1 1.4 0.0 1.5 −3.2 −3.0 −2.0 N/A −2.44 N/A SGA N/A Yes 
66 35 1,900 −1.8 42 −3.2 N/A N/A 1.0 −4.8 −3.7 −2.9 N/A −2.50 N/A SGA N/A Yes 
67 30 775 −2.4 N/A N/A 1.4 1.4 1.5 −4.2 −3.3 −2.6 −1.9 1.09 N/A SGA N/A Yes 
68 38 1,670 −3.8 39 −5.5 −0.6 0.4 2.3 −4.3 −3.5 −2.4 N/A 0.93 N/A SGA N/A Yes 
69 40 2,150 −3.5 43 −4.5 −0.7 −0.5 1.1 −3.0 −2.2 −1.7 N/A 0.02 N/A SGA N/A Yes 
70 33 1,210 −2.6 37 −4.9 −1.5 −0.5 4.1 −4.8 −2.3 −3.6 −4.7 0.88 N/A SGA Normal Yes 
71 33 1,645 −1.4 38 −4.4 −1.5 −1.8 2.8 −3.5 −3.4 −3.0 N/A 0.93 0.2 GHD+SGA Normal Yes 
72 42 2,950 −1.7 46 −3.1 0.5 1.1 7.5 −3.3 −1.8 −1.8 −1.6 0.23 −0.3 GHD+SGA Normal Yes 
73 40 3,350 −0.4 47 −2.1 0.0 −1.5 12.6 −4.1 −4.1 −3.3 −2.8 −1.51 −3.0 SGA Normal Yes 
74 41 2,720 −2.4 48 −2.2 −0.5 0.0 1.7 −3.7 −3.2 −3.1 −3.8 −2.45 −1.7 GHD+SGA Absent posterior pituitary, frontal atrophy Yes 
Patient No.GenderGWBW, gBW (SDS)BL, cmBL (SDS)Father’s height (SDS)Mother’s_height (SDS)Age at start of GH therapy, yearsHeight (SDS) at start of GH therapyHeight (SDS) after 1 year of GH therapyHeight (SDS) after 3 years of GH therapyFinal height (SDS)IGF-1 (SDS) prior to therapyBA-CA, yearsPrimary diagnosis leading to GH treatmentBrain MRIDysmorphic features
37 1,860 −2.8 42 −3.8 −1.3 −2.7 6.3 −3.2 −2.0 −1.6 N/A 1.09 −1.2 GHD+SGA Normal No 
42 2,890 −2.1 50 −1.4 0.4 −3.9 4.1 −3.1 −2.4 −1.9 N/A −2.01 −0.4 GHD+SGA Normal No 
40 2,840 −1.9 47 −2.4 −1.7 −0.7 7.7 −2.7 −2.3 −1.6 −2.6 0.11 N/A GHD+SGA Normal No 
36 1,690 −3.0 37 −6.4 0.0 −0.5 3.2 −4.2 −3.3 −3.2 N/A N/A N/A SGA N/A Yes 
39 2,210 −2.9 44 −3.4 −1.5 0.1 3.5 −2.7 −2.0 −1.4 N/A 1.27 −1.5 SGA N/A No 
32 1,260 −1.9 38 −3.9 −1.6 −2.7 7.0 −3 −2.2 −1.7 N/A 0.02 −0.3 SGA N/A No 
39 2,480 −2.2 45 −2.8 −0.7 −0.4 7.4 −4.3 −4.0 −3.4 −2.8 −1.73 N/A SGA N/A No 
37 2,060 −2.5 44 −2.8 0.3 0.6 2.3 −3.8 −3.8 −2.7 N/A −5.37 N/A GHD+SGA Bilateral anophthalmia, agenesis of optic nerves, and chiasm Yes 
33 1,750 −1.1 41 −2.7 −0.6 0.4 1.1 −5.0 −3.1 −1.9 N/A −4.40 −1.1 GHD+SGA N/A No 
10 40 2,350 −2.9 48 −1.6 0.4 −1.2 13.5 −3.3 −2.3 −1.1 −1.0 −4.78 −1.4 GHD+SGA Rathke cleft cyst No 
11 30 1,120 −1.3 36 −4.0 0.4 0.4 2.8 −2.6 −1.9 −0.7 N/A −1.84 −1.8 GHD+SGA Normal No 
12 35 2,200 −1.1 44 −2.1 −0.03 −1.2 6.3 −2.5 N/A N/A N/A −2.74 −0.8 SGA N/A No 
13 40 2,750 −2.1 48 −1.9 −0.7 −0.8 7.1 −3.1 −2.6 −2.2 N/A −1.78 −2.3 GHD+SGA N/A No 
14 40 2,900 −1.8 47 −2.4 −2.9 −2.0 11.6 −3.7 −3.9 −2.9 −2.6 −3.22 −3.3 SGA N/A No 
15 39 2,850 −1.6 46 −2.2 −1.7 −2.9 5.7 −3.0 −2.7 −2.5 N/A 0.74 1.9 SGA N/A No 
16 38 2,670 −0.6 45 −2.7 0.7 −1.6 3.6 −2.5 −1.5 −1.0 −0.5 0.91 N/A SGA N/A No 
17 40 2,960 −1.3 46 −2.6 0.7 −1.2 4.4 −3.1 −2.4 −1.9 −3.6 1.19 0.1 SGA N/A No 
18 40 2,920 −1.8 45 −3.4 −3.6 −0.8 7.4 −3.3 −2.7 −2.1 −2.0 −3.10 0.5 SGA Normal No 
19 33 1,350 −2.1 38 −4.3 −2.4 −2.3 3.3 −2.7 −2.6 −2.1 −1.5 −1.51 0.2 SGA N/A No 
20 39 2,450 −2.4 46 −2.55 −2.3 −2.7 12.6 −2.7 −2.3 −2.7 −3.1 0.73 −0.3 SGA N/A No 
21 40 2,350 −2.9 46 −2.7 −1.0 −1.5 5.4 −3 −2.8 −1.9 N/A −1.35 −0.3 GHD+SGA Normal Yes 
22 40 2,520 −2.6 49 −1.4 −2.0 0.0 4.3 −2.5 −2.0 −1.9 −2.3 −0.64 −0.9 GHD+SGA N/A No 
23 39 2,270 −2.7 42 −4.4 −1.5 −3.4 5.7 −2.8 −2.1 −0.8 −2.7 0.49 −0.4 SGA N/A No 
24 39 2,450 −2.5 45 −3.1 −2.9 −1.3 12.0 −3.4 −2.7 −2.1 −2.2 −1.51 −1.6 SGA N/A No 
25 40 2,500 −2.5 43 −4.3 −2.2 −0.4 7.0 −3.1 −2.4 −2.1 N/A 0.93 −2.5 SGA N/A No 
26 39 2,660 −2.0 47 −2.1 −3.2 −1.5 6.0 −3.7 −3.2 −2.8 N/A −3.16 N/A SGA Cyst of cisterna magna No 
27 40 2,750 −2.1 48 −1.9 −1.3 −1.5 9.2 −2.7 −2.2 −1.4 N/A 0.34 −1.4 SGA N/A No 
28 40 2,400 −2.9 48 −1.9 −1.5 −1.2 10.2 −2.8 −2.0 −0.6 −1.5 −1.26 N/A GHD+SGA N/A Yes 
29 40 3,000 −1.3 45 −3.2 0.8 −1.5 6.4 −2.8 −2.2 −1.5 −2.1 −0.15 −0.2 SGA Normal No 
30 40 3,200 −1.0 47 −2.4 −3.2 0.8 1.5 −2.5 −1.8 −1.5 N/A −0.27 N/A SGA N/A No 
31 40 2,650 −2.3 47 −2.4 0.4 −2.3 9.1 −2.5 −1.6 −0.8 N/A 0.09 0.1 SGA N/A No 
32 41 3,190 −1.0 47 −2.4 −1.2 −1.2 7.1 −2.5 −1.6 0.1 N/A −0.90 −2.1 GHD+SGA Pituitary microadenoma No 
33 40 2,600 −2.3 45 −3.2 −1.1 −1.2 6.0 −2.9 −2.3 −1.4 N/A 0.32 N/A SGA Normal No 
34 41 2,880 −1.8 47 −2.4 0.8 −2.4 4.0 −2.9 −2.9 −1.9 N/A 0.15 N/A GHD+SGA Normal No 
35 39 2,710 −1.9 46 −2.6 N/A −1.8 3.3 −2.8 −2.4 −2.2 N/A −2.01 −0.4 GHD+SGA Normal No 
36 41 2,800 −2.0 48 −1.8 −2.4 −2.3 3.1 −3.6 −3.0 −2.5 N/A −6.04 N/A SGA N/A No 
37 40 2,630 −2.2 47 −2.1 −2.0 −1.3 3.4 −3.5 −2.7 −2.5 −2.7 −1.65 −0.3 SGA N/A No 
38 38 2,460 −2 44 −3.2 −1.5 −3.7 4.5 −3.5 −2.9 −2.5 N/A −2.48 N/A GHD+SGA Normal No 
39 39 2,490 −2.4 48 −1.6 −2.9 −1.2 1.5 −2.9 −2.9 −2.5 N/A −2.50 −0.8 SGA Normal Yes 
40 40 2,460 −2.8 49 −1.4 −0.5 0.4 2.2 −2.5 −1.1 −0.9 N/A −0.45 0.0 GHD+SGA Small pituitary Yes 
41 40 3,270 −0.9 46 −2.9 −0.46 0.43 1.9 −4 −3.0 −4.8 N/A −1.37 −0.5 GHD+SGA Small pituitary Yes 
42 39 2,444 −2.3 44 −3.4 −1.4 0.2 3.9 −2.9 −2.3 −2.5 N/A 0.88 N/A SGA N/A Yes 
43 35 2,050 −1.3 42 −2.9 0.8 −1.5 2.3 −3.9 −3.3 −2.9 N/A 0.12 N/A SGA N/A Yes 
44 42 2,800 −2.0 46 −3.1 −1.6 −1.5 5.2 −3.3 −3.0 −2.5 −3.0 −0.42 −0.8 GHD+SGA Normal No 
45 38 2,390 −2.2 N/A N/A −0.7 −0.4 2.1 −4.3 −3.5 −3.1 N/A <-2.5 N/A GHD+SGA Pachygyria, heterotopia of grey matter, thinning of corpus callosum Yes 
46 39 2,500 −2.2 46 −2.3 −2.3 −1.0 2.9 −3.4 −2.9 −2.0 −1.9 −1.26 N/A GHD+SGA Normal No 
47 40 3,350 −0.7 47 −2.4 −1.0 −1.6 4.2 −3.0 −2.2 −1.7 N/A −2.85 N/A GHD+SGA Normal No 
48 42 2,820 −2.0 48 −1.9 1.7 0.1 3.1 −3.7 −3.0 −3.1 −3.7 0.15 −1.9 SGA N/A Yes 
49 38 2,480 −1.8 45 −2.4 −1.2 −0.8 1.6 −3.4 −2.8 −2.0 N/A −0.37 N/A GHD+SGA Small pituitary, thin pituitary stalk Yes 
50 38 2,900 −1.0 45 −2.7 −1.5 −1.9 3.0 −3.6 −2.9 −2.4 N/A −1.60 N/A SGA N/A No 
51 40 2,790 −1.8 46 −2.7 0.8 −3.1 9.8 −3.0 −2.3 −1.8 −2.6 N/A −2.2 SHOX N/A Yes 
52 40 3,200 −1.0 47 −2.4 −3.2 −2.0 11.5 −2.9 −2.3 −2.1 −3.0 0.48 1.1 SHOX N/A Yes 
53 34 2,130 −0.5 43 −1.9 −1.7 −0.4 8.4 −2.8 −2.3 −1.7 N/A 0.67 −1.2 SHOX N/A Yes 
54 40 3,400 −0.3 44 −3.8 −2.9 −1.6 1.7 −2.5 −2.3 -1.8 N/A 0.45 N/A SHOX N/A Yes 
55 30 1,280 −0.8 38 −2.7 −1.9 −2.4 4.1 −3.8 −3.1 −2.2 N/A −2.47 N/A SHOX N/A Yes 
56 38 2,860 −1.1 43 −3.7 0.8 −3.5 5.4 −3.6 −3.7 −2.8 −3.8 −1.14 −0.8 SHOX N/A Yes 
57 40 2,500 −2.5 46 −2.7 −2.6 −2.0 7.5 −3.1 −2.7 −1.7 N/A N/A N/A SHOX N/A Yes 
58 37 2,090 −2.3 45 −2.1 −0.3 −0.7 2.9 −3.3 −2.8 −1.7 N/A N/A N/A SGA N/A Yes 
59 40 2,190 −3.3 42 −4.9 −0.6 −1.2 1.2 −3.5 −2.8 −2.8 N/A 0.53 N/A SGA N/A Yes 
60 34 1,345 −2.7 37 −5.5 0.0 0.7 2.2 −2.6 −2.3 −0.9 N/A −2.72 −1.1 GHD+SGA N/A No 
61 30 840 −2.2 N/A N/A −1.5 0.1 1.0 −5.3 −4.9 −4.2 N/A −1.89 N/A SGA N/A Yes 
62 38 1,750 −3.6 41 −4.5 0.0 1.4 0.8 −2.5 −1.6 −0.9 N/A 2.30 N/A SGA N/A Yes 
63 35 1,700 −2.3 38 −5.4 −1.0 −1.2 3.3 −3.4 −3.3 −3.2 N/A −1.17 −1.1 SGA N/A No 
64 38 1,700 −3.8 42 −3.9 −1.6 0.6 1.4 −4.2 −3.4 −2.9 N/A 0.71 −0.2 SGA N/A Yes 
65 37 2,100 −2.2 45 −2.1 1.4 0.0 1.5 −3.2 −3.0 −2.0 N/A −2.44 N/A SGA N/A Yes 
66 35 1,900 −1.8 42 −3.2 N/A N/A 1.0 −4.8 −3.7 −2.9 N/A −2.50 N/A SGA N/A Yes 
67 30 775 −2.4 N/A N/A 1.4 1.4 1.5 −4.2 −3.3 −2.6 −1.9 1.09 N/A SGA N/A Yes 
68 38 1,670 −3.8 39 −5.5 −0.6 0.4 2.3 −4.3 −3.5 −2.4 N/A 0.93 N/A SGA N/A Yes 
69 40 2,150 −3.5 43 −4.5 −0.7 −0.5 1.1 −3.0 −2.2 −1.7 N/A 0.02 N/A SGA N/A Yes 
70 33 1,210 −2.6 37 −4.9 −1.5 −0.5 4.1 −4.8 −2.3 −3.6 −4.7 0.88 N/A SGA Normal Yes 
71 33 1,645 −1.4 38 −4.4 −1.5 −1.8 2.8 −3.5 −3.4 −3.0 N/A 0.93 0.2 GHD+SGA Normal Yes 
72 42 2,950 −1.7 46 −3.1 0.5 1.1 7.5 −3.3 −1.8 −1.8 −1.6 0.23 −0.3 GHD+SGA Normal Yes 
73 40 3,350 −0.4 47 −2.1 0.0 −1.5 12.6 −4.1 −4.1 −3.3 −2.8 −1.51 −3.0 SGA Normal Yes 
74 41 2,720 −2.4 48 −2.2 −0.5 0.0 1.7 −3.7 −3.2 −3.1 −3.8 −2.45 −1.7 GHD+SGA Absent posterior pituitary, frontal atrophy Yes 

BA-CA, difference between bone age and chronological age; BL (cm), birth length (cm); BW (g), birth weight (grams); GW, gestational week; GH, growth hormone; GHD, growth hormone deficiency; MRI, magnetic resonance imaging; N/A, not available; SDS, standard deviation score.

Table 2.

Genetic results in children born small for gestational age with persistent short stature (SGA-SS)

Patient No.GeneTranscript/karyotype variantReferenceProtein variantReferenceZygosityClassification*Previously published variantMAF
1a GHSR c.526G>A NM_198407.2 p.Gly176Arg NP_940799.1 Het LP [17] 
2a HMGA2 c.233C>T NM_003483.6 p.Arg75Trp NP_003474.1 Het LP [17] 
IGF1R c.2215C>T NM_000875.5 p.Arg739Trp NP_000866.1 Het LP [41] 
IGF1R del15q26.3    Het [42] 
IGF1R c.807C>G NM_000875.5 p.Tyr269Ter NP_000866.1 Het Novel 
6a IGFALS c.589C>T NM_004970.3 p.Arg197Cys NP_004961.1 Het LP [17] 
LHX4 del1q25.1q25.3    Het Novel 
8a OTX2 del14q22q23    Het [43] 
POU1F1 c.437T>G NM_000306.4 p.Leu146Ter NP_000297.1 Het Novel 
10 PROKR2 c.254G>A NM_144773.4 p.Arg85His NP_658986.1 Het [44] 0.00119 
11 PTCH1 c.3912G>T NM_000264.5 p.Arg1304Ser NP_000255.2 Het LP Novel 0.0000179 
12a STAT3 c.2144C>T NM_139276.3 p.Pro715Leu NP_644805.1 Het [45] 0.0000088 
13 THRA c.725T>C NM_003250.6 p.Leu242Pro NP_003241.2 Het Novel 
14a TRHR c.392T>C NM_003301.7 p.Ile131Thr NP_003292.1 Hom [46] 0.0000176 
15a ACAN c.916A>T NM_001135.4 p.Ser306Cys NP_001126.3 Het [47] 
16 ACAN c.7162T>A NM_001135.4 p.Glu2388Lys NP_001126.3 Het LP Novel 0.0000355 
17 ACAN c.4927delC NM_001135.4 p.Pro1643fs NP_001126.3 Het LP Novel 
18a ACAN c.1425delA NM_001135.4 p.Val478fs NP_001126.3 Het [47] 
19a COL11A1 c.475A>G NM_001854.4 p.Ile159Val NP_001845.3 Het LP [24] 
20a COL11A1 c.1543C>G NM_001854.4 p.Gln515Glu NP_001845.3 Het LP [17] 
21 COL1A1 c.4369G>A NM_000088.4 p.Asp1457Asn NP_000079.2 Het LP Novel 0.0000353 
22a COL1A2 c.577G>A NM_000089.4 p.Gly193Ser NP_000080.2 Het [17] 0.000008794 
23a COL2A1 c.410G>A NM_001844.5 p.Arg137His NP_001835.3 Het LP [48] 0.0001009 
24a COL2A1 c.3106C>G NM_001844.5 p.Arg1036Gly NP_001835.3 Het LP [17] 0.00006200 
25a COL2A1 c.3106C>G NM_001844.5 p.Arg1036Gly NP_001835.3 Het LP [17] 0.00006200 
26a COL2A1 c.2129C>T NM_001844.5 p.Pro710Leu NP_001835.3 Het LP [17] 0.000007776 
27 COL9A1 c.876+2T>A NM_001851.6   Het [49] 0.0001403 
28 COL9A2 c.1918C>T NM_001852.4 p.Arg640Ter NP_001843.1 Het [49] 0.00005501 
29 FLNB c.4388G>A NM_001457.4 p.Arg1463Gln NP_001448.2 Het LP Novel 0.00002760 
30 FLNB c.1599C>T NM_001457.4 p.Pro250Leu NP_001448.2 Het Novel 
31 MATN3 c.671G>A NM_002381.5 p.Arg224Gln NP_002372.1 Het LP Novel 0.0001716 
32 FGFR2 c.28C>G NM_000141.5 p.Leu10Val NP_000132.3 Het LP Novel 0.00002323 
33 FGFR3 c.1633C>T NM_000142.5 p.Arg545Cys NP_000133.1 Het LP Novel 0.000008856 
34a FGFR3 c.251C>T NM_000142.5 p.Ser84Leu NP_000133.1 Het LP [50] 
35 NPR2 c.2864G>C NM_003995.4 p.Arg955Thr NP_003986.2 Het LP Novel 
36a NPR2 c.1670G>A NM_003995.4 p.Arg557His NP_003986.2 Het LP [23] 0.00001759 
37a NPR2 c.1673T>C NM_003995.4 p.Ile558Thr NP_003986.2 Het [23] 0.00001759 
38a NPR2 c.1808G>C NM_003995.4 p.Ser603Thr NP_003986.2 Het LP [23] 
39 CDC42 c.191A>G NM_001791.4 p.Thr64Cys NP_001782.1 Het [51] 
40 KMT2D c.1967delT NM_003482.4 p.Leu656fs NP_003473.3 Het [52] 
41a LMNA c.433G>A NM_005572.4 p.Glu145Lys NP_005563.1 Het [53] 
42 NSD1 dup5q35.2q35.3    Het [54] 
43 PTPN11 c.236A>G NM_002834.5 p.Gln79Arg NP_002825.3 Het [55] 
44 PTPN11 c.802G>A NM_002834.5 p.Gly268Ser NP_002825.3 Het [56] 
45 SON c.2680C>T NM_138927.4 p.Gln894Ter NP_620305.3 Het Novel 
46 SOS1 c.2105A>G NM_005633.4 p.Tyr702Cys NP_005624.2 Het LP [57] 0.00001555 
47 SOS1 c.755T>C NM_005633.4 p.Ile252Thr NP_005624.2 Het LP [58] 0.00007039 
48 SRCAP c.7330C>T NM_006662.3 p.Arg2444Ter NP_006653.2 Het [59] 
49 TLK2 c.968+1G>A NM_006852.6   Het [60] 
50 SOX9 c.673G>A NM_000346.4 p.Gly225Ser NP_000337.1 Het LP Novel 0.00005492 
51 SHOX delXp22.3    Het [61] 
52 PPP2R3B dupXp22.33    Het Novel 
53 SHOX delXp22.3    Het [62] 
54 SHOX delXp22.3    Het [61] 
55 SHOX c.-10delG NM_000451.4   Het Novel 
56 PPP2R3B dupXp22.33    Het Novel 
57 SHOX delXp22.3    Het [61] 
58 UPD7    [62] 
59 Hypometh 11p15    [63] 
60 UPD7    [62] 
61 UPD7    [62] 
62 Hypometh 11p15    [63] 
63 Hypometh 11p15    [63] 
64 Hypometh 11p15    [63] 
65 UPD7    [62] 
66 UPD7    [62] 
67 Hypometh 11p15    [63] 
68 Hypometh 11p15    [63] 
69 Hypometh 11p15    [63] 
70 del17q24.2    Het N/A 
71 del1p31.1p31.3    Het [64] 
72 del22q11.2    Het N/A 
73 del6q24.3q25.1    Het [65] 
74 dupXq    N/A 
Patient No.GeneTranscript/karyotype variantReferenceProtein variantReferenceZygosityClassification*Previously published variantMAF
1a GHSR c.526G>A NM_198407.2 p.Gly176Arg NP_940799.1 Het LP [17] 
2a HMGA2 c.233C>T NM_003483.6 p.Arg75Trp NP_003474.1 Het LP [17] 
IGF1R c.2215C>T NM_000875.5 p.Arg739Trp NP_000866.1 Het LP [41] 
IGF1R del15q26.3    Het [42] 
IGF1R c.807C>G NM_000875.5 p.Tyr269Ter NP_000866.1 Het Novel 
6a IGFALS c.589C>T NM_004970.3 p.Arg197Cys NP_004961.1 Het LP [17] 
LHX4 del1q25.1q25.3    Het Novel 
8a OTX2 del14q22q23    Het [43] 
POU1F1 c.437T>G NM_000306.4 p.Leu146Ter NP_000297.1 Het Novel 
10 PROKR2 c.254G>A NM_144773.4 p.Arg85His NP_658986.1 Het [44] 0.00119 
11 PTCH1 c.3912G>T NM_000264.5 p.Arg1304Ser NP_000255.2 Het LP Novel 0.0000179 
12a STAT3 c.2144C>T NM_139276.3 p.Pro715Leu NP_644805.1 Het [45] 0.0000088 
13 THRA c.725T>C NM_003250.6 p.Leu242Pro NP_003241.2 Het Novel 
14a TRHR c.392T>C NM_003301.7 p.Ile131Thr NP_003292.1 Hom [46] 0.0000176 
15a ACAN c.916A>T NM_001135.4 p.Ser306Cys NP_001126.3 Het [47] 
16 ACAN c.7162T>A NM_001135.4 p.Glu2388Lys NP_001126.3 Het LP Novel 0.0000355 
17 ACAN c.4927delC NM_001135.4 p.Pro1643fs NP_001126.3 Het LP Novel 
18a ACAN c.1425delA NM_001135.4 p.Val478fs NP_001126.3 Het [47] 
19a COL11A1 c.475A>G NM_001854.4 p.Ile159Val NP_001845.3 Het LP [24] 
20a COL11A1 c.1543C>G NM_001854.4 p.Gln515Glu NP_001845.3 Het LP [17] 
21 COL1A1 c.4369G>A NM_000088.4 p.Asp1457Asn NP_000079.2 Het LP Novel 0.0000353 
22a COL1A2 c.577G>A NM_000089.4 p.Gly193Ser NP_000080.2 Het [17] 0.000008794 
23a COL2A1 c.410G>A NM_001844.5 p.Arg137His NP_001835.3 Het LP [48] 0.0001009 
24a COL2A1 c.3106C>G NM_001844.5 p.Arg1036Gly NP_001835.3 Het LP [17] 0.00006200 
25a COL2A1 c.3106C>G NM_001844.5 p.Arg1036Gly NP_001835.3 Het LP [17] 0.00006200 
26a COL2A1 c.2129C>T NM_001844.5 p.Pro710Leu NP_001835.3 Het LP [17] 0.000007776 
27 COL9A1 c.876+2T>A NM_001851.6   Het [49] 0.0001403 
28 COL9A2 c.1918C>T NM_001852.4 p.Arg640Ter NP_001843.1 Het [49] 0.00005501 
29 FLNB c.4388G>A NM_001457.4 p.Arg1463Gln NP_001448.2 Het LP Novel 0.00002760 
30 FLNB c.1599C>T NM_001457.4 p.Pro250Leu NP_001448.2 Het Novel 
31 MATN3 c.671G>A NM_002381.5 p.Arg224Gln NP_002372.1 Het LP Novel 0.0001716 
32 FGFR2 c.28C>G NM_000141.5 p.Leu10Val NP_000132.3 Het LP Novel 0.00002323 
33 FGFR3 c.1633C>T NM_000142.5 p.Arg545Cys NP_000133.1 Het LP Novel 0.000008856 
34a FGFR3 c.251C>T NM_000142.5 p.Ser84Leu NP_000133.1 Het LP [50] 
35 NPR2 c.2864G>C NM_003995.4 p.Arg955Thr NP_003986.2 Het LP Novel 
36a NPR2 c.1670G>A NM_003995.4 p.Arg557His NP_003986.2 Het LP [23] 0.00001759 
37a NPR2 c.1673T>C NM_003995.4 p.Ile558Thr NP_003986.2 Het [23] 0.00001759 
38a NPR2 c.1808G>C NM_003995.4 p.Ser603Thr NP_003986.2 Het LP [23] 
39 CDC42 c.191A>G NM_001791.4 p.Thr64Cys NP_001782.1 Het [51] 
40 KMT2D c.1967delT NM_003482.4 p.Leu656fs NP_003473.3 Het [52] 
41a LMNA c.433G>A NM_005572.4 p.Glu145Lys NP_005563.1 Het [53] 
42 NSD1 dup5q35.2q35.3    Het [54] 
43 PTPN11 c.236A>G NM_002834.5 p.Gln79Arg NP_002825.3 Het [55] 
44 PTPN11 c.802G>A NM_002834.5 p.Gly268Ser NP_002825.3 Het [56] 
45 SON c.2680C>T NM_138927.4 p.Gln894Ter NP_620305.3 Het Novel 
46 SOS1 c.2105A>G NM_005633.4 p.Tyr702Cys NP_005624.2 Het LP [57] 0.00001555 
47 SOS1 c.755T>C NM_005633.4 p.Ile252Thr NP_005624.2 Het LP [58] 0.00007039 
48 SRCAP c.7330C>T NM_006662.3 p.Arg2444Ter NP_006653.2 Het [59] 
49 TLK2 c.968+1G>A NM_006852.6   Het [60] 
50 SOX9 c.673G>A NM_000346.4 p.Gly225Ser NP_000337.1 Het LP Novel 0.00005492 
51 SHOX delXp22.3    Het [61] 
52 PPP2R3B dupXp22.33    Het Novel 
53 SHOX delXp22.3    Het [62] 
54 SHOX delXp22.3    Het [61] 
55 SHOX c.-10delG NM_000451.4   Het Novel 
56 PPP2R3B dupXp22.33    Het Novel 
57 SHOX delXp22.3    Het [61] 
58 UPD7    [62] 
59 Hypometh 11p15    [63] 
60 UPD7    [62] 
61 UPD7    [62] 
62 Hypometh 11p15    [63] 
63 Hypometh 11p15    [63] 
64 Hypometh 11p15    [63] 
65 UPD7    [62] 
66 UPD7    [62] 
67 Hypometh 11p15    [63] 
68 Hypometh 11p15    [63] 
69 Hypometh 11p15    [63] 
70 del17q24.2    Het N/A 
71 del1p31.1p31.3    Het [64] 
72 del22q11.2    Het N/A 
73 del6q24.3q25.1    Het [65] 
74 dupXq    N/A 

Het, heterozygous; Hom, homozygous; hypometh 11p15, hypomethylation 11p15; LP, likely pathogenic; MAF, minor allele frequency in the European, non-Finnish population in the gnomAD database; N/A, not available; P, pathogenic; UPD7, uniparental disomy of chromosome 7.

*Based on American College of Medical Genetics and Genomics (ACMG) standards and guidelines [20] implemented to the VarSome software [20] (on the date December 16, 2021).

aProbands who carried these variants have been reported previously in our studies.

Fig. 2.

Three levels of the genetic growth regulation in children born small for gestational age with persistent short stature (SGA-SS). The numbers in brackets in blue boxes show the numbers of patients identified with P/LP variants of the entire gene (if more than one). The numbers in closed circles refer to patient numbering in Table 1. a Genes involved in cerebral midline and pituitary development, and in the GH-IGF-1 and thyroid axes. b Genes encoding growth plate matrix components and elements of chondrocyte paracrine regulation. c Genes involved in intracellular signalling, in the stability of nuclear membrane, and in the fundamental intranuclear processes. A brief description of selected patients’ facial phenotypes: (8) OTX2: bilateral anophthalmia; (9) POU1F1: depressed nasal bridge and frontal bossing; (10) PROKR2: no apparent facial dysmorphism; (11) PTCH1: mild orbital hypotelorism, midface hypoplasia, and anteverted ears; (12) STAT3: no specific facial signs in a boy with severe immune dysregulation leading to early onset diabetes, hypothyroidism, cytopenia and lymphoproliferation, and short stature due to defective STAT3 signalling; (16) ACAN: mild facial dysmorphism similar to previously published cases; (30) FLNB: facial phenotype of atelosteogenesis type I – prominent forehead, depressed nasal bridge with a grooved tip, and micrognathia; (37) NPR2: the father and two daughters with vertical transmission of an NPR2 pathogenic variant, no facial phenotype; (40) KMT2D: Kabuki syndrome resembling the makeup in traditional Japanese theatre; (41) LMNA: gradually developing phenotype of Hutchinson-Gilford progeria syndrome; (43) PTPN11 and (47) SOS1: facial signs of Noonan syndrome; (48) SRCAP: typical face of Floating-Harbour syndrome. Image adapted from [25].

Fig. 2.

Three levels of the genetic growth regulation in children born small for gestational age with persistent short stature (SGA-SS). The numbers in brackets in blue boxes show the numbers of patients identified with P/LP variants of the entire gene (if more than one). The numbers in closed circles refer to patient numbering in Table 1. a Genes involved in cerebral midline and pituitary development, and in the GH-IGF-1 and thyroid axes. b Genes encoding growth plate matrix components and elements of chondrocyte paracrine regulation. c Genes involved in intracellular signalling, in the stability of nuclear membrane, and in the fundamental intranuclear processes. A brief description of selected patients’ facial phenotypes: (8) OTX2: bilateral anophthalmia; (9) POU1F1: depressed nasal bridge and frontal bossing; (10) PROKR2: no apparent facial dysmorphism; (11) PTCH1: mild orbital hypotelorism, midface hypoplasia, and anteverted ears; (12) STAT3: no specific facial signs in a boy with severe immune dysregulation leading to early onset diabetes, hypothyroidism, cytopenia and lymphoproliferation, and short stature due to defective STAT3 signalling; (16) ACAN: mild facial dysmorphism similar to previously published cases; (30) FLNB: facial phenotype of atelosteogenesis type I – prominent forehead, depressed nasal bridge with a grooved tip, and micrognathia; (37) NPR2: the father and two daughters with vertical transmission of an NPR2 pathogenic variant, no facial phenotype; (40) KMT2D: Kabuki syndrome resembling the makeup in traditional Japanese theatre; (41) LMNA: gradually developing phenotype of Hutchinson-Gilford progeria syndrome; (43) PTPN11 and (47) SOS1: facial signs of Noonan syndrome; (48) SRCAP: typical face of Floating-Harbour syndrome. Image adapted from [25].

Close modal

In our study, we examined a unique large single-centre cohort of SGA-SS children by NGS methods. We elucidated the genetic cause of growth disorder in 42% (74/176) of them. The results demonstrate a multifarious genetic landscape of SGA-SS and further contributed to the understanding of its aetiology.

Advances in genetic diagnostics led to better knowledge regarding the mechanisms causing short stature. Depending on the study cohort, NGS methods elucidated the aetiology of a growth disorder in 14.5–52% of cases [17, 26‒30]. Two of these studies focused on SGA-SS children. Freire et al. identified monogenic SGA-SS in 8/55 (15%) children with no apparent syndromic features. The aetiologies of their short stature were mostly primary growth plate disorders accompanied by the disruption of the RAS/MAPK signalling pathway [29]. Li et al. [26] demonstrated that including syndromic SGA-SS children can substantially increase the detection rate of genetic variants elucidating the aetiology of SGA-SS (17% in non-syndromic SGA-SS vs. 31% in syndromic SGA-SS). In our study, we have managed to find the genetic cause of SGA-SS in a higher number of children (42%), even in the case of non-syndromic SGA-SS (54%).

The aetiology of SGA-SS in our study cohort was rather heterogeneous. Not surprisingly, 42% of children with genetic aetiology elucidated carried a causal variant in the gene that is essential for correct growth plate function. This finding is in line with previous studies [26, 29] and corresponds with the new paradigm with the growth plate playing a key role in short stature pathogenesis [31]. As expected, other relatively frequent genetic diagnoses in our SGA-SS study cohort were causal variants in genes affecting fundamental intracellular processes including RASopathies which corresponds with the results of previous studies as well [26, 29].

Another condition typically associated with SGA-SS is SRS [9]. Not surprisingly, SRS was another frequent diagnosis in our study cohort (16% of cases with genetic aetiology elucidated). Importantly, SRS is diagnosed clinically using the Netchine-Harbison scoring system (NHS). Genetic examination may consequently provide useful confirmation of the clinical diagnosis [9]. In our study, we took a different approach – genetic examination of SRS was performed in all SGA-SS children. Surprisingly, we have genetically diagnosed SRS in 2 children who do not fulfil NHS criteria. Genetic examination of SRS can therefore be considered in all SGA-SS children, regardless of the presence of its typical clinical features.

In our study, we also had several less expected findings. GH is essential for normal growth, and children with GHD may have severe short stature [32]. However, GH is generally considered to affect mainly the postnatal phase of growth, and children with GHD should therefore be born with normal birth parameters [32]. In contrast with this concept, we have found causative genetic variants in genes affecting pituitary development or directly influencing GH production in 6/74 (8%) of SGA-SS children with genetic diagnosis in our study cohort. Some of them might have different causes of prenatal growth failure (e.g., patient no. 1 with LP GHSR variant whose mother suffered from HELLP syndrome during pregnancy); however, in other children, we found no additional explanation of prenatal growth impairment. On the other hand, other studies also have discovered genetic findings typical for GHD in SGA children [2]. We can speculate that GH might play a role in prenatal growth in some children or genetic variants found might affect growth on other levels besides affecting GH.

Another interesting result was the pathogenic variant found in the gene THRA encoding thyroid hormone receptor type A, which has also been previously associated with short stature [33]. In one patient, we diagnosed a homozygous variant in the gene TRHR, leading to central hypothyroidism. Since its first observation in 1997 [34], short stature has been recognised as one of the consistent features of central congenital hypothyroidism due to TRHR defects and their bi-allelic pathogenic variants. However, perinatal data were not displayed in patients published so far. Thus, we are adding the TRHR gene as a novel causative gene for SGA. These two findings in the thyroid axis increase the diagnostic yield by additional 3% and clearly show that pre- and postnatal growth is affected by the thyroid axis far beyond the classical hypothyroidism. The other variants found in our study were genes involved in the regulation of growth plates and other fundamental processes of intracellular signalling.

The clinical response to GH treatment has not been systematically studied in the sub-cohorts of SGA-SS with defined genetic aetiology, with the exception of children with SRS [35]. Thus, the currently available reports have their origin in retrospective analysis of children genetically diagnosed at a late stage of their therapy. The currently available data are scarce, as summarised in the latest consensus [36]. In our cohort, the long-term growth data are available only in a minority of children; therefore, we present short-time growth data following 1 year and 3 years of GH administration and, when available, final height SDS. Continuing the observation of the study cohort might bring important new data on the impact on the individual of the new genetic finding.

Some genetic studies in short stature tend to suffer from selection bias as the study population originates mostly from tertiary centres [26, 37, 38]. This questions the extrapolation of the genetic spectrum of growth disorders to the general population. The strength of our study is its population-based principle: all newborns in the Czech Republic have their birth weight and length measured and carefully recorded together with their gestational week. All children subsequently undergo regular, mandatory body height examinations that enable the identification of growth failure, an early referral to a paediatric endocrinologist, and the start of GH treatment if indicated. Our centre provides GH to about 30% of children in our country [39]; their selection depends mainly on their residence. Thus, our study should be relatively free of selection bias with the exception of those who neglected regular body height checkups (which is rare) or refused either GH therapy or genetic testing.

Our study had some limitations as well. Chromosomal analysis including microarrays was performed only in children whose phenotype led to the initial referral to the department of clinical genetics. Moreover, non-coding variants (with the exception of the disruption in exon-intron boundaries), epigenetic, and somatic changes were not captured by NGS. Finally, our study lacks the functional studies to help evaluate the pathogenicity of the discovered variants.

To conclude, our study elucidated the genetic aetiology of 42% of SGA-SS children from a genetically relatively homogenous, non-consanguineous population. The results demonstrate a complex aetiology of short stature affecting all the three key levels of growth regulation including the endocrine system, growth plate function, and fundamental processes of intracellular regulation and signalling. A conclusive genetic finding not only provides a clear explanation of the growth disorder but also enables focussing on possible associated hidden comorbidities and genetic consulting [40]. In our opinion, routine genetic testing may therefore become a standard of diagnostic care in resource-rich countries for all SGA-SS children after other causes of growth failure are ruled out.

We are grateful to the children and their parents for consenting to display the portrait photographs without covering their eyes, in favour to support the general medical knowledge and understanding.

This study protocol was reviewed and approved by the Institutional Ethics Committees of the 2nd Faculty of Medicine, Charles University in Prague, and University Hospital Motol, Czech Republic (date of approval: June 30, 2017; not numbered). Written informed consent was obtained from the parents/legal guardians of the patients for publication of the details of their medical cases and any accompanying images. The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Written informed consent was obtained from the participants’ parents/legal guardians to participate in the study.

The authors have no conflicts of interest to declare.

This study was supported by the Ministry of Health of the Czech Republic – conceptual development of research organisation (Grant No. NV18-07-00283), Motol University Hospital, Prague, Czech Republic (Grant No. 00064203), and Grant Agency of Charles University (Grant No. 4018120).

Prof. Dr. Jan Lebl and Dr. Ledjona Toni designed the study. Dr. Ledjona Toni, Dr. Lukas Plachy, and Prof. Dr. Jan Lebl wrote the manuscript. Dr. Petra Dusatkova did the NGS data analysis and coordinated the study. Prof. Dr. Zdenek Sumnik, Dr. Stanislava Kolouskova, Dr. Marta Snajderova, Dr. Barbora Obermannova, Dr. Stepanka Pruhova, and Prof. Dr. Jan Lebl referred patients and provided their clinical information. Dr. Petra Dusatkova, Dr. Lenka Elblova, and Dr. Shenali Anne Amaratunga provided insight on variant analysis. All authors contributed to the discussion and reviewed or edited the manuscript.

Additional Information

Based on the abstract that was granted the Henning-Andersen Prize at the 60th ESPE Annual Meeting, Rome, September 2022.

The datasets presented in this article are not readily available for ethical and legal reasons relating to the participants’ privacy rights. The raw sequencing data are available upon reasonable request to the corresponding author.

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