
==== Front
J Clin Endocrinol Metab
J Clin Endocrinol Metab
jcem
The Journal of Clinical Endocrinology and Metabolism
0021-972X
1945-7197
Oxford University Press US

38888172
10.1210/clinem/dgae423
dgae423
Approach to the Patient
AcademicSubjects/MED00250
Approach to the Patient With Suspected Silver-Russell Syndrome
https://orcid.org/0009-0007-9941-3161
Kurup Uttara Centre for Endocrinology, William Harvey Research Institute (WHRI), Charterhouse Square, Barts and the London School of Medicine, London EC1M 6BQ, UK

https://orcid.org/0000-0002-3174-5051
Lim David B N Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK

https://orcid.org/0000-0003-1806-2990
Palau Helena Centre for Endocrinology, William Harvey Research Institute (WHRI), Charterhouse Square, Barts and the London School of Medicine, London EC1M 6BQ, UK

https://orcid.org/0000-0001-8051-3866
Maharaj Avinaash V Centre for Endocrinology, William Harvey Research Institute (WHRI), Charterhouse Square, Barts and the London School of Medicine, London EC1M 6BQ, UK

https://orcid.org/0000-0002-4769-2273
Ishida Miho Centre for Endocrinology, William Harvey Research Institute (WHRI), Charterhouse Square, Barts and the London School of Medicine, London EC1M 6BQ, UK

https://orcid.org/0000-0001-7560-6320
Davies Justin H Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK

https://orcid.org/0000-0002-9963-1931
Storr Helen L Centre for Endocrinology, William Harvey Research Institute (WHRI), Charterhouse Square, Barts and the London School of Medicine, London EC1M 6BQ, UK

Correspondence: Helen L. Storr, BSc, MBBS, PhD, Centre for Endocrinology, Queen Mary University London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK. Email: h.l.storr@qmul.ac.uk; or Justin H. Davies, MBBCh, MD, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK. Email: Justin.Davies@uhs.nhs.uk.
Uttara Kurup and David B. N. Lim equal contribution for first and last authorship.

Justin H. Davies and Helen L. Storr equal senior authorship.

10 2024
18 6 2024
18 6 2024
109 10 e1889e1901
15 3 2024
14 6 2024
03 7 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
2024
https://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.

Abstract

Silver-Russell syndrome (SRS) is a clinical diagnosis requiring the fulfillment of ≥ 4/6 Netchine-Harbison Clinical Scoring System (NH-CSS) criteria. A score of ≥ 4/6 NH-CSS (or ≥ 3/6 with strong clinical suspicion) warrants (epi)genetic confirmation, identifiable in ∼60% patients. The approach to the investigation and diagnosis of SRS is detailed in the only international consensus guidance, published in 2016. In the intervening years, the clinical, biochemical, and (epi)genetic characteristics of SRS have rapidly expanded, largely attributable to advancing molecular genetic techniques and a greater awareness of related disorders. The most common etiologies of SRS remain loss of methylation of chromosome 11p15 (11p15LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). Rarer causes of SRS include monogenic pathogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (PLAG1 and HMGA2) genes. Although the age-specific NH-CSS can identify more common molecular causes of SRS, its use in identifying monogenic causes is unclear. Preliminary data suggest that NH-CSS is poor at identifying many of these cases. Additionally, there has been increased recognition of conditions with phenotypes overlapping with SRS that may fulfill NH-CSS criteria but have distinct genetic etiologies and disease trajectories. This group of conditions is frequently overlooked and under-investigated, leading to no or delayed diagnosis. Like SRS, these conditions are multisystemic disorders requiring multidisciplinary care and tailored management strategies. Early identification is crucial to improve outcomes and reduce the major burden of the diagnostic odyssey for patients and families. This article aims to enable clinicians to identify key features of rarer causes of SRS and conditions with overlapping phenotypes, show a logical approach to the molecular investigation, and highlight the differences in clinical management strategies.

Silver-Russell syndrome
diagnosis
genetic
NH-CSS
NIHR 10.13039/501100000272 NIHR300098 MRC Population and Systems Research MR/X021173/1 Barts Charity Healthcare Professional Clinical Research Training Fellowship G-002779
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pmcCase 1

A 5-year-old girl with a history of intrauterine growth retardation (IUGR) (birth weight −3.8 SDS) had short stature (height −3.9 SDS), feeding difficulties (body mass index [BMI] −3.0 SDS) and microcephaly (occipito-frontal circumference [OFC] −4.9 SDS). Maternal height was reduced (−3.5 SDS) but paternal height was normal (−0.2 SDS). She scored ≥ 3 on the IGF1R clinical score (Table 1) (1) but had syndromic features not typical of insulin-like growth factor 1 receptor (IGF1R) defects, including triangular face, high-pitched voice, high-arched palate, and developmental delay (inattention and poor motor, writing, and reading skills). Investigations established normal female karyotype (46,XX) and short stature screen except for elevated serum insulin-like growth factor 1(IGF-1) levels (+4.4 SDS). Silver-Russell syndrome (SRS) was suspected, and she scored 3/6 Netchine-Harbison Clinical Scoring System (NH-CSS) criteria. What would you do next?

Table 1. IGF1R clinical scoring system ( 1 )

Criterion	Score	
Birth weight and/or birth length SDS below −1.0	1	
Height SDS at presentation below −2.5	1	
Head circumference SDS at presentation below −2.0	1	
IGF-1 SDS >0	1	
Total score	Score of ≥ 3 should warrant IGF1R gene analysis	

Case 2

A 4-year-old girl with short stature (height SDS −2.9) had a history of birth at 29 weeks’ gestation following IUGR (birth weight and length −1.4 and −2.2 SDS). At birth she had a prominent forehead, relative macrocephaly (head circumference [OFC] + 1.3 SDS) and no body asymmetry. During the neonatal period she was hypotonic and required nasogastric feeding. For the first year following nasogastric tube removal, she was slow to complete feeds. She did not cry during vaccinations, appearing to have a high pain threshold. Height and weight were persistently < 0.4th centile (< −2.7 SDS). Speech and language development was delayed. By 3 years she ate a varied diet and was persistently hungry. At 4 years, her BMI was elevated (+2.5 SDS). Investigations established normal female karyotype (46,XX) and short stature screen. She scored 4/6 on the NH-CSS, confirming a clinical diagnosis of SRS. Molecular testing did not reveal 11p15 hypomethylation or maternal uniparental disomy of chromosome 7. Recombinant growth hormone (rhGH) was commenced under the small for gestational age (SGA) license. What other diagnostic molecular testing should be considered at the same time?

Short Stature Secondary to Being Born Small for Gestational Age—Definition and Clinical Relevance

When assessing childhood short stature, a key consideration is a history of IUGR and/or born SGA (defined as a birth weight and/or length < −2 SDS). Children with short stature, secondary to being born SGA, comprise an extremely heterogeneous group with numerous underlying causes of both syndromic and nonsyndromic phenotypes. SRS and conditions that mimic SRS are increasingly recognized as an important cause of short stature secondary to being born SGA. It is critical to distinguish SRS from these other conditions. (Epi)genetic investigations can be key to stratification of these disorders and, in turn, a more tailored clinical management.

Silver-Russell Syndrome

SRS is characterized by pre- and postnatal growth restriction, dysmorphic features, and feeding difficulties. SRS occurs equally in male and female individuals and has an estimated incidence of 1 in 15 000 children (2). SRS can usually be distinguished from other causes of pre- and postnatal growth failure by the presence of SGA, relative macrocephaly (head circumference at birth of ≥ 1.5 SDS above birth and/or length SDS), prominent forehead, feeding difficulties, and body asymmetry.

SRS has a diverse phenotype (Tables 2 and 3), and some clinical characteristics are less apparent with increasing age, thus making a clinical diagnosis challenging in older people (31). The age-specific NH-CSS has the highest sensitivity and predictive value for making a clinical diagnosis of SRS (Table 2). Essential features of the NH-CSS are SGA at birth, postnatal growth failure by 2 years, asymmetry, feeding difficulties in the first 2 years of life, prominent forehead between 1 and 3 years, and relative macrocephaly at birth. A clinical diagnosis of SRS requires the fulfillment of ≥ 4/6 NH-CSS criteria, including relative macrocephaly and prominent forehead. (Epi)genetic testing is recommended for patients who score ≥ 4/6 (or ≥ 3/6 with strong clinical suspicion) (2).

Table 2. NH-CSS criteria for clinical Silver-Russell syndrome (SRS) diagnosis

Diagnostic features of SRS (NH-CSS criteria)	Clinical features associated with SRS but not specific to SRS	
Small for gestational age (birth weight and/or length ≥ 2 SDS below the mean for gestational age)	Triangular face
Fifth finger clinodactyly
Shoulder dimples
Micrognathia
Low muscle mass
Excessive sweating
Low-set and/or posteriorly rotated ears
Downturned mouth
High-pitched or squeaky voice
Prominent heels
Delayed closure of fontanelle
Male genital abnormalities
Speech delay
Irregular or crowded teeth
Motor delay
Syndactyly of toes
Hypoglycemia
Scoliosis and/or kyphosis	
Postnatal growth failure (length/height ≥ 2 SDS below the mean at 24 months)	
a Relative macrocephaly at birth (head circumference > 1.5 SDS above birth weight and/or length)	
a Frontal bossing or prominent forehead (forehead projecting beyond the facial plane on a side view as a toddler [1-3 years])	
Body asymmetry (limb length discrepancy ≥ 0.5 cm, or < 0.5 cm with ≥ 2 other asymmetric body parts)	
Feeding difficulties or body mass index ≤ 2 SD at 24 months or current use of a feeding tube or cyproheptadine for appetite stimulation	
a Major criteria for the clinical SRS diagnosis. SRS should be suspected in individuals who meet ≥ 4/6 clinical criteria. Those who meet at least 3 of the clinical criteria with a high suspicion need molecular testing to confirm the diagnosis (3).

Table 3. Comparison of clinical features in Silver-Russell syndrome patients with confirmed 11p15LOM, mUPD7, and monogenic causes

Clinical feature	(Epi)genetic cause of Silver-Russell syndrome	
11p15LOM	upd(7)mat	CDKN1C	IGF2	HMGA2	PLAG1	
NH-CSS % (n)	
Patients scoring ≥ 4/6	78% (61)	85% (17)	53% (9)	86% (18)	65% (11)	40% (4)	
Patients scoring 3/6	22% (17)	15% (3)	47% (8)	9% (2)	23% (4)	50% (5)	
Patients scoring < 3/6	NR	NR	NR	5% (1)	12% (2)	10% (1)	
SGA (birth weight and / or birth length)a	100% (35)	73% (11)	71% (12)	95% (20)	88% (15)	80% (8)	
Postnatal growth failureb	84% (173)	81% (47)	100% (17)	95% (20)	100% (17)	100% (10)	
Relative macrocephaly at birthc	99% (112)	85% (27)	59% (10)	81% (17)	29% (5)	20% (2)	
Protruding/prominent foreheadd	94% (126)	100% (27)	94% (16)	86% (18)	71% (12)	60% (6)	
Body asymmetrye	77% (226)	29% (62)	NR	29% (6)	6% (1)	NR	
Feeding difficulties and / or low BMIf	72% (173)	87% (47)	59% (10)	86% (18)	71% (12)	90% (9)	
SRS associated features % (n)	
Triangular face	99% (74)	50% (16)	76% (13)	86% (18)	65% (11)	70% (7)	
Delayed closure of fontanelle	44% (36)	36% (11)	6% (1)	5% (1)	NR	NR	
Low-set +/− posteriorly rotated ears	50% (140)	69% (48)	6% (1)	38% (8)	NR	NR	
Downturned mouth	57% (114)	26% (39)	NR	9% (2)	NR	NR	
Irregular/crowded teeth	29% (105)	39% (36)	6% (1)	5% (1)	6% (1)	20% (2)	
Micrognathia	75% (79)	26% (27)	NR	48% (10)	6% (1)	10% (1)	
Low muscle mass	67% (61)	47% (19)	NR	9% (2)	6% (1)	NR	
Fifth finger clinodactyly	81% (176)	56% (48)	6% (1)	71% (15)	24% (4)	30% (3)	
Syndactyly of toes	42% (141)	17% (48)	NR	19% (4)	6% (1)	NR	
Prominent heels	26% (35)	100% (12)	NR	NR	NR	NR	
Shoulder dimples	77% (35)	67% (12)	NR	5% (1)	NR	NR	
Scoliosis +/− kyphosis	10% (97)	16% (43)	NR	NR	NR	NR	
High-pitched / squeaky voice	39% (26)	71% (7)	NR	24% (5)	12% (2)	NR	
Excessive sweating	51% (70)	70% (27)	NR	NR	NR	NR	
Hypoglycemia	50% (43)	29% (17)	NR	NR	NR	NR	
Other features % (n)	
Motor delay	31% (141)	58% (36)	6% (1)	62% (13)	6% (1)	30% (3)	
Speech delay	32% (101)	64% (36)	NR	52% (11)	NR	30% (3)	
Intellectual disability / Learning difficulties	NR	NR	NR	5% (1)	NR	10% (1)	
Challenging behavior/inattention	6% (35)	58% (12)	6% (1)	NR	NR	NR	
Gastrointestinal manifestations / gastroesophageal reflux	14% (6)	10% (2)	NR	NR	12% (2)	10% (1)	
Diabetes	NR	NR	12% (2)	NR	6% (1)	10% (1)	
Delayed bone age	NR	NR	NR	24% (5)	18% (3)	NR	
Asthma	NR	NR	12% (2)	NR	NR	NR	
Cardiac abnormalities	13% (7)	NR	NR	43% (9)	NR	NR	
Cleft palate	7% (3)	NR	NR	29% (6)	NR	NR	
Male genital abnormalities	44% (63)	21% (14)	6% (1)	33% (7)	NR	NR	
Placental hypoplasia / small placenta	NR	NR	NR	17% (5)	NR	10% (1)	
References	(4-11)	(4-12)	(13-18)	(16, 17, 19-21)	(19, 22-27)	(17, 19, 28-30)	
Literature review of clinical features of SRS associated with confirmed 11p15LOM, mUPD7, and monogenic causes. N (%), number (and percentage of total) cases exhibiting the feature. Duplicate reporting of cases was not identified.

Abbreviations: 11p15LOM, loss of methylation of chromosome 11p15; CDK1N1C, Cyclin-dependent kinase inhibitor 1; HMGA2, high-mobility group AT-hook 2; IGF2, insulin-like growth factor 2; NH-CSS, Netchine-Harbison Clinical Scoring System; NR, not recorded; PLAG1, pleomorphic adenoma gene 1; SGA, small for gestational age; SRS, Silver-Russell syndrome; upd(7)mat, maternal uniparental disomy of chromosome 7.

NH-CSS criteria: aSGA, defined as birth weight/length ≤ −2 SDS for gestational age; bPostnatal growth failure, defined as height ≤ −2 SDS or height ≤ −2 SDS below mid-parental target height at 24 ± 1 months; cRelative macrocephaly at birth, defined as head circumference at birth ≥1.5 SDS above birth weight and/or length SDS; dProminent forehead, defined as forehead projecting beyond the facial plane on a side view as a toddler (1-3 years); eAsymmetry, defined as leg length discrepancy (LLD) of ≥ 0.5 cm or arm asymmetry or LLD < 0.5 cm with at least 2 other asymmetrical body parts (one non-face); fLow BMI, defined as body mass index ≤−2 SDS at 24 months or use of a feeding tube or cyproheptadine for appetite stimulation; microcephaly, occipito-frontal circumference (OFC) > 2 SD below the mean for age, sex, and ethnicity.

Etiology of SRS

A diagnosis of SRS can be based on an identifiable molecular defect (∼30%-60% of cases) or a clinical diagnosis using standard clinical criteria. Therefore, inconclusive genetic testing does not exclude SRS and occurs in a significant proportion (∼40%) of patients, classified as “clinical SRS” (32) (see later).

In ∼60% of clinically diagnosed SRS patients, an (epi)genetic cause is identified. SRS is molecularly heterogenous; the most common causes are loss of methylation of chromosome 11p15 (11p15LOM) (Fig. 1A) and maternal uniparental disomy of chromosome 7 (upd(7)mat), occurring in 30% to 60% and 5% to 10% of SRS cases, respectively. 11p15LOM results in reduced paternal IGF2 and increased maternal H19 expression, leading to growth restriction (Fig. 1A) (33). Rarer genetic causes of SRS include monogenic pathogenic variants in imprinted (CDKN1C and IGF2) and non-imprinted (PLAG1 and HMGA2) genes and copy number variants (CNV) (34, 35). Growth restriction observed in SRS due to monogenic variants result from: inhibition of cell proliferation due to maternally inherited gain-of-function CDKN1C defects (13), or reduction in IGF2 levels secondary to paternally inherited loss-of-function IGF2 defects, and pathogenic PLAG1 / HMGA2 gene variants (19) (Fig. 1A).

Figure 1. Proposed mechanisms in Silver-Russell syndrome (SRS) and Temple syndrome leading to growth restriction. A, Representation of the 11p15 region, showing the paternal and maternal telomeric H19/IGF2 IG-DMR (ICR1) and centromeric KCNQ1OT1 TSS-DMR (ICR2) imprinting control regions associated with SRS. A differentially paternally methylated region between the IGF2 and H19 genes regulates expression. Aberrant expression of genes (upstream or within the imprinting control region) controlling the IGF2 gene (paternally expressed fetal growth factor) and H19 (maternally expressed) expression leads to growth restriction. B, Representation of the 14q32 region implicated in Temple syndrome (TS14). TS14 can be caused by 3 mechanisms: maternal UPD leading to expression of only maternally expressed genes from both chromosomes, paternal loss of methylation of MEG3/DLK1 IG-DMR resulting in a maternal chromosome-like expression pattern, or deletion in the paternal chromosome resulting in absence of paternally expressed genes. Aberrant expression of these genes is associated with IGF2 downregulation, leading to growth restriction. Gray boxes indicate expressed genes; open boxes, silenced genes; black box, activating mutation (CDKN1C); X, pathogenic loss-of-function mutations (HMGA2, IGF2, PLAG1).

Common Molecular Causes of SRS

The frequency of associated clinical features in SRS subgroups (11p15LOM, upd(7)mat, and clinical SRS) and patients with SGA but not SRS, was extensively reviewed in the SRS consensus document (1). Genotype-phenotype studies indicate considerable overlap in the clinical phenotypes of SRS (epi)genotypes and are generally considered clinically indistinguishable. However, some features are more common in the molecular subgroups, and these are highlighted below.

Loss of methylation of chromosome 11p15

NH-CSS criteria are generally better at detecting SRS secondary to 11p15LOM compared to upd(7)mat (4, 5). Individuals exhibiting 11p15LOM typically have lower birth length and weight and a higher incidence of body asymmetry and congenital anomalies than upd(7)mat patients. Excessive catch-up weight gain leading to increased metabolic and cardiovascular risk is more frequent in 11p15LOM compared to upd(7)mat. Genital ambiguity is more frequent in patients with severe 11p15LOM and includes females with uterine and vaginal aplasia and cryptorchidism and hypospadias in male patients (5, 36, 37). Serum IGF-1 levels are significantly higher in 11p15LOM epimutation patients than in those with upd(7)mat (38).

Two imprinted domains on chromosome 11p15.5 play a crucial role in regulating intrauterine growth (32, 39) (Fig. 1A). The telomeric domain implicated in SRS is regulated by the paternally methylated imprinting control region H19/IGF2 IG-DMR (H19/IGF2 intergenic differentially methylated region). Hypomethylation of the H19/IGF2 IG-DMR results in reduced paternal Insulin-like Growth Factor 2 (IGF2) expression and increased maternal noncoding RNA H19 expression, leading to growth repression (40). Hypomethylation typically affects both IGF2 and H19, rarely affecting one of them exclusively. The likelihood of SRS recurrence in siblings or offspring of probands is low, except when there are CNVs in this region (32). Multiple DNA methylation abnormalities, collectively termed multi-locus imprinting disturbance (MLID), has been documented in up to 30% of individuals diagnosed with SRS (see below).

Maternal uniparental disomy of chromosome 7

Neurocognitive impairment is more prevalent among individuals with upd(7)mat in contrast to either 11p15LOM or clinical SRS patients. Furthermore, upd(7)mat is also associated with pervasive developmental disorders such as autism and learning disabilities (2).

The SRS phenotype associated with upd(7)mat is hypothesized to result from the altered expression of currently unknown growth gene(s). Pathogenic gene mutations were excluded in candidate regions 7p11.2-p13 (GRB10) and 7q31 (MEST/PEG1) (41). Overexpression of maternal growth limiting genes (MEST/PEG1) may be the primary cause of maternal uniparental disomy at chromosome 7q32 rather than reduced expression or deletion of paternal growth promoting gene(s) (40). The imprinting control region 7p12.1 (GRB10) has also been implicated in upd(7)mat. Hypomethylation can occur due to maternal isodisomy/heterodisomy, mosaicism, or segmental upd(7)mat. Isodisomy can lead to the expression of recessive conditions such as cystic fibrosis in upd(7)mat SRS (42). The risk of recurrence in siblings or offspring of probands is low, except in cases of microdeletions or microduplications (up to ∼50% recurrence based on parental carrier or affected status) (32).

Rarer (Monogenic) Causes of SRS

Monogenic causes of SRS can be challenging to diagnose since features not typically associated with SRS may be present and the clinical presentation may not fulfill the NH-CSS criteria. Molecular testing is therefore recommended in patients scoring ≥ 3/6 NH-CSS (2). Monogenic causes of SRS are rare and exhibit autosomal dominant inheritance (14). SRS due to monogenic defects have been identified in Cyclin-dependent kinase inhibitor 1C (maternally transmitted; CDKN1C), insulin-like growth factor 2 (paternally transmitted; IGF2), pleomorphic adenoma gene 1 (PLAG1), and high-mobility group AT-hook 3 (HMGA2) (Fig. 1A). Unlike IGF2 and CDKN1C, HMGA2 and PLAG1 are not imprinted and both male and female individuals have a 50% chance of transmitting the mutation (19, 28, 43).

Cyclin-dependent kinase inhibitor 1

Review of 17 reported CDKN1C gene defect cases with detailed clinical data revealed 47% did not fulfill the NH-CSS criteria (scoring 3/6) (Supplementary Table S1 (44)). Relative macrocephaly and prominent forehead were noted in 59% and 94% of cases, respectively. No cases had microcephaly (defined as OFC ≥ 2 SD below the mean for age, sex, and ethnicity). Postnatal growth failure was present in all cases and 71% of patients were born SGA. Feeding difficulties were frequent (59%) but none presented with body asymmetry. Other clinical features not typically associated with SRS included diabetes (12%), motor and/or speech delay (6%), challenging behavior and poor concentration (6%), and asthma (12%) (Table 3 and Supplementary Table S1) (13-18, 44, 45).

CDKN1C is a maternally expressed imprinted growth repressor gene located in the centromeric domain of chromosome 11p15) (Fig. 1A). CDKN1C imprinting is controlled by the imprinting control region KCNQ1OT1 TSS-DMR. CDKN1C is involved in cell proliferation inhibition through G1 cell cycle arrest. Gain-of-function mutations in this region lead to growth restriction observed in SRS and IMAGe Syndrome (13, 46). In contrast, loss-of-function CDKN1C mutations are associated with an overgrowth phenotype of Beckwith-Wiedemann syndrome. Monoallelic dominant mutations lead to increased stability of the CDKN1C protein and functional gain (15).

Gain-of-function mutations affecting the highly conserved 279th amino acid within analogous proliferating cell nuclear antigen (PCNA) domains of the CDKN1C gene have been reported in IMAGe syndrome and familial SRS (p.Arg279Pro, p.Arg279Ser, p.Arg279Leu) (15). CDKN1C c.843G>T (p.Arg281Leu) cases are also associated with early-onset adult diabetes (18).

Insulin-like growth factor 2

Of 21 patients harboring pathogenic IGF2 variants, 86% presented with high NH-CSS scores (≥ 4/6) (Supplementary Table S2 (44)). Most patients were born SGA (95%), had postnatal growth failure (95%), relative macrocephaly (81%), and prominent forehead (86%). There was also a high frequency of feeding issues (86%). There were no cases of microcephaly and body asymmetry was infrequent (29%). Interestingly, there was a high percentage of clinical features not typically associated with SRS, including developmental delay (speech/motor) (62%), male genital abnormalities (33%), cardiac anomalies (43%), cleft palate (29%), and intellectual disabilities (5%) (Table 3 and Supplementary Table S2) (16, 17, 19-21, 29, 44, 47-52). Biochemical analyses revealed higher serum IGF-1/IGFBP3, lower IGF2 levels, and a lower IGF2/IGF-1 ratio (47, 53).

IGF2, located on chromosome 11p15, is maternally imprinted (paternally transmitted) and biparentally expressed in the liver and brain (Fig. 1A). Unlike 11p15 LOM, IGF2 defects do not exhibit somatic mosaicism (47), which may explain the phenotypic differences described above. The reported SRS-causing IGF2 gene mutations are splice site (leading to exon skipping), nonsense or frameshift (leading to nonsense mediated mRNA decay) mutations (17). IGF2 binds to the insulin-like growth factor binding protein (IGFBP), preventing spontaneous degradation. IGF2 mutations that influence this essential binding promote instability and thus increased IGF2 clearance/reduced half-life, resulting in diminished placental and fetal cell growth. This is evidenced by placental hypoplasia (21, 47).

High-mobility group AT-hook 2

Review of 17 reported cases of SRS secondary to HMGA2 defects revealed that 35% scored ≥3/6 NH-CSS (Supplementary Table S3 (44)). Prominent forehead was a frequent feature (71%) but only 29% had relative macrocephaly. Interestingly, microcephaly was present in 29%. All cases had postnatal growth failure, 88% associated with being born SGA. Feeding difficulties were reported in 71% patients but body asymmetry was infrequent (6%) (Table 3 and Supplementary Table S3) (19, 22-27, 44).

HMGA2 gene expression reduces with advancing age, with highest expression identified in fetal tissues (22). HMGA2 and PLAG1 play independent and cumulative roles in the regulation of IGF2 in the HMGA2-PLAG1-IGF2 pathway (19). HMGA2 silencing initiates a reduction in PLAG1 and consequently a reduction in total IGF2 levels (Fig. 1A). PLAG1 binds to the IGF2 promoter P3, which is highly expressed in fetal tissue. Lower IGF2 promoter P3 levels are associated with HMGA2 silencing when compared to PLAG1 mutations, highlighting its independent role in IGF2 transcription. Heterozygous missense and nonsense mutations both within and outside the AT-hooks have been reported in SRS. The severity of phenotypic abnormalities is potentially determined by the number of residual functional AT-hooks (22).

Pleomorphic adenoma gene 1

Review of 10 SRS cases harboring PLAG1 gene mutations confirmed that 60% scored ≥ 3/6 NH-CSS (Supplementary Table S4 (44)). All had postnatal growth failure, associated with SGA at birth in 80% patients. Prominent forehead was present in 60%, but only 20% of patients had relative macrocephaly. Microcephaly was present in 30% of cases. No patient had body asymmetry, but feeding difficulties were common (90%). Other clinical features not typically associated with SRS included speech and/or motor delay (40%) and gastrointestinal manifestations (10%) (Table 3 and Supplementary Table S4) (17, 19, 28-30, 44).

Plag1−/− mice showed a reduction in overall weight at birth, continuing into adulthood, compared to Plag1+/+ mice. A similar phenotype was seen in paternal Igf2-deficient mice (43). Frameshift and nonsense PLAG1 mutations affect its DNA-binding ability and lead to reduced levels of IGF2 (Fig. 1A).

SRS secondary to copy number variations

CNVs account for ∼1% of SRS cases and more than 30 different pathogenic CNVs have been associated with SRS. Some of these patients do fulfill the NH-CSS criteria and receive a clinical SRS diagnosis. These cases generally have more severe developmental delay and/or intellectual disability than typically observed in SRS; however, the phenotype is dependent on CNV size, location, and parental origin (2, 54). Thus, the clinical management should be tailored to the specific phenotypic consequences of the CNV. The majority of the CNVs involve maternal duplications of H19/IGF2 IG-DMR and/or KCNQ1OT1 TSS-DMR (40, 55).

Clinical SRS

A “clinical SRS” diagnosis can be made based on clinical criteria using the NH-CSS, as the identification of a molecular defect is not required to make an SRS diagnosis. In approximately 40% of “clinical” SRS cases fulfilling the NH-CSS criteria, no molecular cause is identified, and in these cases, it is likely that there are currently undiscovered (epi)genetic causes. In clinical SRS cases, there is also the potential for a misdiagnosis of SRS when in fact it may be another distinct condition that has an overlapping phenotype with SRS (Fig. 2).

Figure 2. Flow chart for the investigation and diagnosis of Silver-Russell syndrome (SRS) and conditions with phenotypes overlapping with SRS.

Conditions With Phenotypes Overlapping With SRS

Several conditions have clinical features that “mimic” SRS and may fulfill the NH-CSS criteria but that have a genetic etiology and clinical course distinct from SRS. These conditions may be presumptively diagnosed as clinical SRS if standard (epi)genetic investigations for SRS are negative. They are under-recognized, overlooked, and under-investigated by clinicians managing short stature and can lead to delayed or no diagnosis and poorer outcomes.

Evidence is accumulating that these conditions require tailored management and alternative care strategies to SRS. This emphasizes the need to extend the molecular investigation of apparent clinical SRS to inform clinical management decisions. Critically, like SRS, these conditions are multisystemic disorders requiring multidisciplinary care. Table 4 provides a summary of the conditions which have phenotypes overlapping with SRS (2, 56, 57).

Table 4. Conditions with phenotypes overlapping with SRS ( 2, 56, 57)

Condition	Molecular mechanism	Possible clinical features overlapping with SRS	
Conditions associated with normocephaly or macrocephaly	
Temple syndrome	Disruption to 14q32 region of chromosome 14 due to:maternal uniparental disomy of chromosome 14 (30%-78% of cases),

paternal hypomethylation of the MEG3/DLK1 IG-DMR (12%-60% of cases), or (iii) paternal deletion of 14q32 (∼10%)

	IUGR and SGA
Postnatal growth failure
Short stature
Relative macrocephaly
Prominent forehead
Asymmetry
Feeding difficulties in infancy	
UPD(20)mat	Maternal uniparental disomy of chromosome 20	IUGR and SGA
Postnatal growth failure
Short stature
Relative macrocephaly
Prominent forehead
Feeding difficulties in infancy	
UPD(16)mat	Maternal uniparental disomy of chromosome 16	IUGR and SGA
Postnatal growth failure
Short stature
Relative macrocephaly
Prominent forehead
Feeding difficulties in infancy	
MLID	Variable	variable	
SHORT syndrome	Heterozygous PIK3R1 gene mutations (chromosome 5q13)	IUGR and SGA
Postnatal growth failure
Short stature
Triangular face
Prominent forehead	
Floating-Harbor syndrome	Heterozygous SRCAP gene mutations (chromosome 16p11)	IUGR and SGA
Postnatal growth failure
Short stature
Normocephaly
Triangular face
Fifth finger clinodactyly
Brachydactyly
Low-set ears
Speech and language delay
Male genital abnormalities (eg, hypospadias, crypto-orchidism)	
3-M syndrome	Homozygous CCDC8 gene mutations (chromosome 19q13) in 75% of cases; or
Homozygous or compound heterozygous OBSL1 gene mutations (chromosome 2q35) in 20% of cases; or
Homozygous CCDC8 gene mutations (chromosome 19q13) in 5% of cases	IUGR and SGA
Postnatal growth failure
Short stature
Relative macrocephaly
Prominent forehead
Triangular face
Fifth finger clinodactyly
Prominent heels	
Mulibrey nanism	Homozygous or compound TRIM37 gene heterozygous mutations (chromosome 17q22)	IUGR and SGA
Postnatal growth failure
Short stature
Relative macrocephaly
Prominent forehead
Triangular face
High-pitched voice	
IMAGe syndrome	Heterozygous CDKN1C gene mutations (chromosome 11p15)	IUGR and SGA
Postnatal growth failure
Short stature
Male genital abnormalities (eg, micropenis, hypospadias, crypto-orchidism)	
Conditions associated with microcephaly	
IGF1 gene defects	Homozygous or heterozygous mutation in IGF1 gene on chromosome 12q22	IUGR and SGA
Postnatal growth failure
Short stature
Developmental delay	
IGF1R gene defects	Heterozygous mutation in IGF1R gene on chromosome 15q26	IUGR and SGA
Postnatal growth failure
Short stature
Developmental delay	
Bloom syndrome	Homozygous or compound heterozygous RECQL3 gene mutations (chromosome 15q26)	IUGR and SGA
Postnatal growth failure
Short stature
Developmental delay
Triangular face
Micrognathia
Low-set ears
Feeding difficulties in infancy	
Nijmegen breakage syndrome	Homozygous or compound heterozygous RAD50 gene mutations (chromosome 5q31)	IUGR and SGA
Postnatal growth failure (mild)
Short stature
Developmental delay (mild)
Fifth finger clinodactyly
Syndactyly of toes	
MOPD II	Homozygous or compound heterozygous PCNT gene mutations (chromosome 21q22)	IUGR and SGA
Postnatal growth failure (mild)
Short stature
High-pitched voice
Micrognathia
Fifth finger clinodactyly
Scoliosis	
Meier-Gorlin syndrome	Homozygous or compound heterozygous ORC1 gene mutations (chromosome 1p32); or
Homozygous or compound heterozygous ORC4 gene mutations (chromosome 2q23); or
Homozygous or compound heterozygous ORC6 gene mutations (chromosome 16q11); or
Homozygous or compound heterozygous CDT1 gene mutations (chromosome 16q24); or
Homozygous CDC6 gene mutations (chromosome 17q21); or
Homozygous or compound heterozygous CDC45 gene mutations (chromosome 22q11); or
Compound heterozygous MCM5 gene mutations (chromosome 22q12)	IUGR and SGA
Postnatal growth failure
Short stature
Triangular face
Low-set ears
Micrognathia
Fifth finger clinodactyly
Delayed motor and/or speech development
Feeding difficulties in infancy
Male genital abnormalities (eg, micropenis, hypospadias, crypto-orchidism)
Scoliosis	
Abbreviations: IUGR, intrauterine growth restriction; SGA, small for gestational age; SRS, Silver-Russell syndrome.

Temple Syndrome

Temple syndrome (TS14) is caused by disruption to the 14q32 region of chromosome 14 due to: (i) maternal uniparental disomy of chromosome 14 (upd(14)mat) (30%-78% cases); (ii) paternal hypomethylation of the MEG3/DLK1 IG-DMR (12%-60% cases); or (iii) paternal deletion of 14q32 (∼10%) (Fig. 1B) (58-60).

The presenting phenotype of TS14 overlaps with SRS, Prader-Willi syndrome (PWS), and SGA-related short stature. Most patients with TS14 presenting in infancy have features of both SRS and PWS (50% cases). Approximately, 20% of cases have an SRS phenotype and may initially be labeled as clinical SRS, while 20% have a PWS phenotype and 10% a short stature SGA only phenotype (59, 61). The overlapping clinical features between these presenting phenotypes make clinical diagnosis challenging and features may become less prominent with increasing age. Body composition changes in children with TS14 (high fat mass and low lean mass) contrasts with that observed in SRS (low fat mass and low lean mass) and may help differentiate TS14 from SRS (61). If genetic testing is negative for infants with suspected SRS or PWS, investigation for TS14 should be considered.

Characteristic clinical features of TS14 include SGA (84%), postnatal growth failure and short stature (92%), relative macrocephaly (52%), prominent forehead (63%) at birth, asymmetry (23%), and feeding difficulties (63%) (59). Thus, some TS14 cases fulfill the NH-CSS. Other features include hypotonia (68%), developmental delay (19%), early-onset obesity and hyperphagia (11%), gonadotrophin-dependent precocious puberty (GDPP), high pain threshold, small hands and/or feet, and psycho-behavioral issues (59, 61).

Feeding difficulties in infancy are frequent and may require nasogastric tube placement, but usually less severe than observed in SRS (58, 61). In older children with TS14, reduced appetite is less problematic to manage compared to SRS. Absence of satiety may manifest from early childhood, but the hyperphagia is usually not as severe as PWS. The nutritional goals change with increasing age and calorie restriction to prevent excess weight gain may be required at an early age to reduce the likelihood of early-onset obesity. Like SRS, surveillance for ketotic hypoglycemia, scoliosis, and metabolic syndrome is needed (62).

GDPP is more prevalent in TS14 (86% of cases) compared to SRS, requiring monitoring from approximately 4 years of age (58, 60, 61). Unlike SRS, premature adrenarche is not a typical feature of TS14. GDPP is amenable to treatment with gonadotropin-releasing hormone analogue (GnRHa) therapy (63). The loss of function of DLK1, located within the 14q32.2 imprinting region, and which is involved in osteogenesis, adipogenesis, and regulation of hypothalamic satiety, is likely a contributory factor to GDPP and obesity (64-66).

Short stature is a frequent feature of TS14. Apparent growth hormone (GH) deficiency demonstrated through failed GH provocation testing, has been observed in up to 15% (n = 2/13) of TS14 cases (59). Some children who have TS14 without GH deficiency may be eligible for rhGH therapy under the SGA indication. Treatment with rhGH improves short-term linear growth and may optimize final height, although, data is limited (67, 68). Combined treatment with rhGH and GnRHa may further improve growth outcomes (59). Growth hormone treatment may also be beneficial for improving body composition.

TS14 secondary to a paternal deletion of 14q32 has been reported in association with thyroid dysfunction and papillary carcinoma at a young age (69). The deleted region in TS14 contains MEG3 (which is thought to result in tumor suppression) and may be implicated in the development of thyroid carcinoma (70). This genotype may require clinical, biochemical, and sonographic monitoring for thyroid disease.

Maternal Uniparental Disomy of Chromosome 20

Maternal uniparental disomy of chromosome 20 (upd(20)mat or Mulchandani-Bhoj-Conlin syndrome), may account for up to 5% of cases presenting with an SRS phenotype (71). Upd(20)mat has recently been recognized as an imprinting disorder with overlapping features of SRS such as being born SGA, postnatal growth failure, relative macrocephaly, prominent forehead, and feeding difficulties in early infancy (72-75). In contrast to SRS, limb asymmetry is an infrequent finding (73). Upd(20)mat may resemble TS14 since both have features of developmental delay, growth restriction and hypotonia (72). Advanced maternal age has been reported in association with upd(20)mat (71).

The GNAS locus is on chromosome 20q and may be maternally or paternally imprinted depending on the tissue site. In upd(20)mat there is loss of the paternally expressed allele of the GNAS locus. Deficiency in paternal GNAS gene products (including XLas and A/B), in combination with overexpression of maternally derived GSα resulting in hypersensitivity of Gsα-mediated hormone receptors, may account for problems with energy metabolism, feeding, and growth (71, 74-76). In contrast to upd(20)mat, paternal upd(20) leads to reduction in Gsα expression, leading to parathyroid hormone (PTH) resistance and pseudohypoparathyroidism type 1b (77, 78). Growth hormone deficiency has been reported in upd(20)mat patients (74). Hypercalcemia with low/low-normal PTH has been described in children with upd(20)mat (71), possibly due to Gsα overexpression leading to PTH-receptor hypersensitivity. Impaired inactivation of 1,25(OH)2D may also contribute to hypercalcemia as a CYP24A1 gene mutation was reported in one individual (79). Thyrotropin (TSH) receptor hypersensitivity may also feature (71). Thus, in addition to growth monitoring, individuals with upd(20)mat may require surveillance of calcium, TSH, free thyroxine (T4), and free triiodothyronine (T3) levels.

Maternal Uniparental Disomy of Chromosome 16

Maternal uniparental disomy of chromosome 16 (upd(16)mat) may give rise to an SRS-like phenotype and has been reported in up to 2.1% of individuals with a SRS phenotype of unknown etiology (12). The phenotype may be due to aberrant expression of the chromosome 16 imprinted genes, autosomal recessive mutations unmasked as a result of chromosome 16 isodisomy, mosaic trisomy 16, or placental insufficiency caused by trisomy 16 (12, 80). The overexpression of zinc-finger gene ZNF597 (paternally imprinted, ie, maternally expressed) situated on 16p13.3 may account for some features seen in upd(16)mat, in particular growth failure (12, 81).

Upd(16)mat individuals may exhibit IUGR and SGA, short stature, relative macrocephaly, and a prominent forehead. Other features include pregnancy-induced hypertension, clinodactyly, prematurity, congenital heart disease, hypospadias, and—like SRS—prenatal and postnatal growth failure and low BMI (12, 80). Compared to SRS, the frequency of SGA birth is lower, while the frequency of congenital heart disease is higher (12). Spontaneous catch-up growth to normal height was observed in one individual (81). Clinicians should consider genetic testing for upd(16)mat in patients with SRS-like phenotypes of unknown etiology who are born preterm and have congenital heart disease (12).

Multi-Locus Imprinting Disturbance

Up to 30% of SRS patients with hypomethylation of H19 TSS-DMR have multi-locus imprinting disturbance (MLID) (82). Generally, one single differential methylation region (DMR) is altered in a given imprinting disorder; however, MLID occurs in a proportion of patients, in whom DNA methylation abnormalities (most commonly loss of methylation) exist at multiple imprinted loci, ie, aberrant methylation of further imprinted loci in addition to the disease-specific ones (83, 84). Cis-acting genetic mutations are usually not seen in MLID (85). Endocrine-disrupting chemicals, parental metabolic and nutritional status, assisted reproductive techniques, and trans-acting variants influencing oocyte development (in the mother) or early epigenetic reprogramming, have been suggested as contributory factors in the pathogenesis (82-84, 86).

Phenotypic diversity exists in MLID patients, which means those who do not fulfill clinical criteria for molecular testing may remain undiagnosed. It is currently not standard practice to perform full epigenomic analysis in patients with molecular imprinting disorders; thus, cases of MLID will be undiagnosed (84). The clinical heterogeneity may be due to tissue-specific epigenotypes, and the involvement of multiple loci may influence phenotype severity (87-89). The major phenotypic traits may be related to the disease-specific loci with more severe methylation abnormality or the degree of tissue-specific mosaicism (89). In patients with SRS-MLID, growth failure and additional congenital anomalies are frequently observed (89). Additionally, MEST gene hypomethylation in SRS-MLID has been observed (87, 90, 91). As MLID-associated features can evolve with age, following the molecular diagnosis of an imprinting disorder investigation for MLID may be indicated to guide disease surveillance (3, 87).

An individual with a molecular diagnosis of TS14 and Beckwith-Wiedemann syndrome has been reported (84), as has an individual with a molecular diagnosis of both SRS and TS14 (92, 93). The contribution of each locus to the phenotype is unpredictable, and features of each condition may occur. The clinical diagnosis is challenging as the classical phenotype may not be evident, but making a diagnosis is important to enable tailored management considering the management principles for each condition.

Molecular Investigation of SRS

The molecular investigation of SRS must accommodate investigation for known causes of SRS as well as conditions that mimic SRS to help guide clinical management strategies (Fig. 2). The most common underlying molecular mechanisms underlying SRS are 11p15LOM and upd(7)mat. Numerous molecular changes at chromosome 11p15 (encompassing the paternally methylated imprinted control region H19/IGF2 IG-DMR) have been associated with SRS. Molecular testing measures DNA methylation of CpG dinucleotides at the H19/IGF2 IG-DMR27. The most common diagnostic test is methylation-specific multiplex ligation-mediated PCR amplification (MS-MLPA) which also enables copy number and DNA methylation analysis (94, 95). Negative molecular diagnosis on a blood sample could be explained by incomplete/low levels of H19/IGF2 IG-DMR hypomethylation. Additionally, methylation patterns vary between different tissues and cells (leucocytes, buccal swab, skin fibroblasts) (89, 91, 96). Upd(7)mat can be identified by microsatellite analysis. However, this cannot detect imprinting defects (epimutations) and requires DNA from at least one parent, so detection by MS-MLPA is usually employed. Recent recommendations suggest that patients with growth disturbance should receive first-line testing for TS14 simultaneously with SRS, when there are nonspecific or overlapping clinical features (97).

If 11p15, chromosome 7, and TS14 testing are negative, additional molecular testing should be considered. Over 30 different pathogenic CNVs have been associated with SRS, many involving the 11p15.5 region. Although CNVs can be detected by MS-MLPA, array analysis (comparative genomic hybridization [CGH] or single nucleotide polymorphism [SNP]) is useful for detailed assessment of the size and gene content of any CNV identified (40). Arrays will also detect regions of segmental isodisomy.

Monogenic causes (mutations in PLAG1, HMGA2, CDKN1C, and IGF2 genes) are rare but pose a higher recurrence risk (2, 19, 32). These genes should be included in next-generation sequencing testing approaches. In undiagnosed cases, analysis for conditions with phenotypes overlapping with SRS, such as TS14 (if not already tested as part of first-line investigations), upd(20)mat, upd(16)mat, and MLID, should be undertaken.

Whole-genome sequencing, which scrutinizes the entirety of the genome at single-base resolution can be employed as a single test. This method potentially facilitates the identification of numerous genetic aberrations, including pathogenic monogenic variants, uniparental disomies, and CNVs. Crucially, whole-genome sequencing methodologies might overlook methylation anomalies (16). Genome-wide methylation screening should also be considered where available to detect MLID, for example, EPIC array epigenome analysis which interrogates CpGs across the genome.

Back to the Patients

Case 1

Molecular testing did not reveal 11p15 hypomethylation or upd(7)mat. Given the atypical clinical phenotype of developmental delay and microcephaly in association with a 3/6 NH-CSS score, further molecular testing was initiated. Whole-exome sequencing excluded an IGF1R gene defect but identified a maternally inherited, heterozygous damaging HMGA2 gene variant, confirming a rare monogenic cause of SRS. The identification of a genetic cause for the patient's phenotype allowed an end to diagnostic testing, the initiation of active surveillance, and referral for genetic counseling.

Case 2

At 4.5 years, the patient developed recurrent early morning symptomatic hypoglycemia and investigations confirmed ketotic hypoglycemia. Weight gain continued and calorie restriction was required. As the clinical course was atypical for SRS, molecular investigations for conditions with phenotypes overlapping with SRS were instigated, revealing Temple syndrome (TS14) secondary to maternal uniparental disomy of chromosome 14. Diagnosis prompted active surveillance for precocious puberty and by the age of 5 years, she developed breast budding with biochemical evidence of GDPP (luteinizing hormone–releasing hormone test [U/L]: baseline LH 0.3, FSH 2.6; peak LH 33.6, FSH 17.8). GnRHa treatment was commenced, resulting in breast tissue regression and pubertal arrest.

Summary

SRS is clinically and molecularly heterogeneous and an underlying (epi)genetic cause is currently identifiable in ∼60% cases. Stratification of the molecular subtype is critical to guide appropriate clinical management. In recent years, there have been significant developments in this area that are relevant to clinical practice. Conditions with phenotypes overlapping with SRS which “mimic” SRS and fulfill NH-CSS criteria can be diagnosed as “clinical SRS” if standard (epi)genetic investigations are negative. However, these conditions require tailored management and differing care strategies to classical SRS cases.

Detailed molecular investigations, including next-generation sequencing approaches, are key in the diagnosis of rarer monogenic causes of SRS. It is notable that the NH-CSS is poor at identifying many of these cases missing 60% PLAG1, 47% CDKN1C, 35% HMGA2 and 14% IGF2 cases. Additionally, the presence of associated or atypical clinical features, including microcephaly (OFC > 2 SD below the mean for age, sex, and ethnicity) and learning difficulties, should not preclude clinicians from investigating for rarer causes of SRS. This emphasizes the need to extend the molecular investigation of apparent and atypical SRS to inform clinical management decisions and enhance outcomes for affected individuals.

Funding

National Institute for Health and Care Research (NIHR) Academy Advanced fellowship NIHR300098 awarded to H.L.S. Medical Research Council (MRC) Population and Systems Research Grant MR/X021173/1 awarded to J.H.D. Barts Charity Healthcare Professional Clinical Research Training Fellowship G-002779 awarded to U.K.

Disclosures

J.H.D. has received travel bursaries from Pfizer, Novo Nordisk, and Sandoz; H.L.S. has received consultancies from Pfizer, Novo Nordisk, Ipsen, Sandoz, and Merck and travel bursaries from Pfizer and Novo Nordisk. H.L.S. is an Editorial Board Member for The Journal of Clinical Endocrinology & Metabolism and played no role in the Journal's evaluation of the manuscript.

Data Availability

Original data generated and analyzed during this study are included in this published article and in a data repository listed in References (44).

Abbreviations

11p15LOM loss of methylation of chromosome 11p15

BMI body mass index

CDK1N1C Cyclin-dependent kinase inhibitor 1C

CNV copy number variant

DMR differential methylation region

GDPP gonadotrophin-dependent precocious puberty

GH growth hormone

GNRHa gonadotropin-releasing hormone analogue

HMGA2 high-mobility group AT-hook 2

IGF-1 insulin-like growth factor 1

IGF1R insulin-like growth factor 1 receptor

IGF2 insulin-like growth factor 2

IGFBP insulin-like growth factor binding protein

IUGR intrauterine growth restriction

MLID multi-locus imprinting disturbance

MS-MLPA methylation-specific multiplex ligation-mediated PCR amplification

NH-CSS Netchine-Harbison Clinical Scoring System

OFC occipito-frontal circumference

PLAG1 pleomorphic adenoma gene 1

PTH parathyroid hormone

PWS Prader-Willi syndrome

rHGH recombinant human growth hormone

SGA small for gestational age

SRS Silver-Russell syndrome

upd(7)mat maternal uniparental disomy of chromosome 7

upd(20)mat maternal uniparental disomy of chromosome 20

TS14 Temple syndrome
==== Refs
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