Silver-Russell Syndrome (including the Silver-Russell-like phenotype)

Literature and regulatory information updated: 6 October 2026.

Silver-Russell syndrome (Russell-Silver syndrome; Silver-Russell dwarfism), an imprinting growth disorder associated with loss of methylation of H19/IGF2:IG-DMR at 11p15.5 or maternal uniparental disomy of chromosome 7, and growth restriction conditions with an overlapping phenotype (variants in IGF2, CDKN1C, HMGA2 and PLAG1, upd(20)mat and Temple syndrome)

0. Initial Reference Table

1. Introduction

Silver-Russell syndrome (SRS) is a genomic imprinting disorder characterised by growth restriction of prenatal onset without postnatal catch-up, with relative preservation of head growth, a prominent forehead in early childhood, body asymmetry and feeding difficulties that dominate the first years of life [1, 4]. Almost all patients are born small for gestational age (SGA, small for gestational age), defined as birth weight and/or length below −2 standard deviations (SD) for gestational age, but SRS differs from the heterogeneous group of SGA children through a distinctive pattern of features and specific management problems, including fasting hypoglycaemia, early and aggressive adrenarche, relatively early and rapid puberty and insulin resistance [3].

The condition was described independently by Silver and colleagues in 1953 and by Russell in 1954 [13]. Silver, Kiyasu, George and Deamer published the “syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins” in Pediatrics, and Silver emphasised skeletal asymmetry as a feature of the condition [13, 14]. Russell described five children in the Proceedings of the Royal Society of Medicine with “intra-uterine dwarfism” recognisable at birth, with craniofacial dysostosis and disproportionately short arms; asymmetry was a variable finding in his patients [13, 15]. The combined designation, with the eponyms reversed in the United States (“Russell-Silver”), persisted, and the 2026 consensus retains both forms as synonyms [1].

The first molecular cause identified was maternal uniparental disomy of chromosome 7. In 1995, Kotzot and colleagues studied 35 patients with SRS or primordial growth retardation and their parents using polymorphic markers and identified upd(7)mat in four, three with isodisomy and one with heterodisomy, proposing the existence of one or more maternally imprinted genes on chromosome 7 [16]. In 2005, Gicquel and colleagues in Paris described demethylation of the telomeric imprinting control region ICR1 at 11p15 in several patients with typical SRS, associated with biallelic H19 expression and reduced IGF2 [17]. In 2007, the same group analysed 127 SGA children, of whom 58 had SRS; 37 of these (63.8%) had partial loss of ICR1 methylation and three (5.2%) upd(7)mat, with no alteration in the 69 SGA children without SRS, and proposed the clinical scoring system that would lead to the current Netchine-Harbison system [18].

Prospective validation of this system by Azzi and colleagues in 2015 led to its adoption in the first international consensus, published online in September 2016 and in Nature Reviews Endocrinology in 2017 on behalf of COST Action BM1208, the European Society for Paediatric Endocrinology (ESPE), the Pediatric Endocrine Society (PES), the Asian Pacific Paediatric Endocrine Society (APPES) and the Sociedad Latino-Americana de Endocrinología Pediátrica (SLEP), with 41 participants from 16 countries [3, 19]. That document defined SRS as a primarily clinical diagnosis, allowing a diagnosis of “clinical SRS” with negative molecular testing [3]. On 23 September 2026, the second international consensus, developed by 39 experts from 11 countries with representatives of six international paediatric endocrinology societies, reversed this principle: the diagnosis of SRS becomes molecular, restricted to upd(7)mat and H19/IGF2:IG-DMR LoM, and patients with a typical presentation but negative testing become “suspected SRS” [1]. The change arose from the increasing number of alternative diagnoses identified by next-generation sequencing in patients meeting the previous clinical criteria [1].

SRS is the model imprinting growth disorder and the mirror image of Beckwith-Wiedemann syndrome (BWS) in the same 11p15 domain: loss of ICR1 methylation on the paternal allele reduces IGF2 expression and restricts growth, whereas gain of ICR1 methylation on the maternal allele or paternal disomy of 11p15 increases IGF2 expression and produces overgrowth [4, 20]. The following text brings together molecularly defined SRS, “suspected SRS” and conditions with a Silver-Russell-like phenotype that the 2026 consensus directs to the same management pathway, and addresses Temple syndrome (upd(14)mat) as the principal differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1 Genomic imprinting and imprinting disorders

Genomic imprinting is the mechanism whereby certain genes are silenced on the maternal or paternal homologue, so that only one allele is expressed according to parental origin; the mark results mainly from DNA methylation established during gametogenesis, is maintained in virtually all tissues throughout life and is erased and reset in germ cells for transmission to offspring [21]. Approximately 30 imprinting centres are recognised, controlling parent-of-origin-dependent expression of neighbouring genes with roles in growth, development, metabolism and behaviour [21]. Imprinting disorders feature disturbed growth from fetal life, overgrowth or restriction, with possible poor feeding, altered timing of puberty and risk of metabolic syndrome in adulthood, and may result from variants in the expressed genes, deletions or duplications, uniparental disomy (UPD) or epigenetic errors at imprinting centres, with or without an underlying genetic cause; imprinting errors may be mosaic and cause body asymmetry [21]. As a rule, purely epigenetic errors are reset in the next generation and UPD is a reproductive accident with a recurrence risk similar to that in the population, whereas coding variants and copy number alterations may be inherited and cause disease or not according to the sex of the transmitting parent [21]. The Oxford Desk Reference table of imprinted genes associates SRS with GRB10 (7p21, maternally expressed in the book’s terminology), PEG1/MEST (7q32.2, paternally expressed) and the H19/IGF2 domain at 11p15.5 [21].

2.2 The 11p15.5 domain and H19/IGF2:IG-DMR loss of methylation

The 11p15.5 region contains two imprinted domains. The telomeric domain includes the maternally expressed non-coding RNA H19 and the paternally expressed growth factor IGF2; its imprinting is controlled by the imprinting control region methylated on the paternal allele, designated H19/IGF2:IG-DMR in current nomenclature (intergenic differentially methylated region, formerly IC1, ICR1 or H19 DMR) [1, 3]. The centromeric domain includes the maternally expressed cell cycle inhibitor CDKN1C (p57KIP2), and its imprinting is controlled by the region methylated on the maternal allele KCNQ1OT1:TSS-DMR (formerly IC2, ICR2, LIT1 or KvDMR1) [3]. H19/IGF2:IG-DMR contains repetitive blocks and seven binding sites for the zinc-finger protein CTCF; enhancers distal to H19 are shared by H19 and IGF2. On the unmethylated maternal allele, CTCF binds to the DMR and acts as an insulator, blocking interaction of the IGF2 promoter with the enhancers and allowing H19 expression; on the methylated paternal allele, CTCF does not bind, the IGF2 promoter accesses the enhancers and IGF2 is expressed [1]. Loss of DMR methylation on the paternal allele makes it functionally “maternal”, with biallelic H19 expression and biallelic IGF2 silencing, restricting growth [4, 17].

IGF2 is the principal fetal growth factor: early embryonic growth depends mainly on IGF1 and IGF2, fetal and neonatal growth on IGF1 and later childhood growth on growth hormone (GH) and IGF1 [22]. 11p15 LoM is usually a postzygotic event and therefore mosaic; low levels of mosaicism may escape detection in blood and be detected in buccal mucosa or fibroblasts [1, 4]. Approximately 1% of patients with ICR1 hypomethylation have a small deletion near the ICR1 boundaries on the paternal allele, with a high recurrence risk, and a small number have selective hypomethylation of H19 alone or IGF2 alone [4]. Less frequently, maternal duplications involving the centromeric domain, alone or together with the telomeric domain, cause growth restriction through increased CDKN1C expression; smaller copy number variants require cautious classification because of the region’s complex regulation [1]. Four patients with SRS and upd(11)mat have been described, three whole-chromosome and one segmental, all mosaic, in whom overexpression of maternally expressed H19 and CDKN1C explains the phenotype [1]. The frequency attributed to 11p15 LoM varies between sources: 35–67% in GeneReviews, 30–60% in the first consensus and 40–60% in the European Molecular Genetics Quality Network (EMQN) laboratory recommendations, differences reflecting inclusion criteria, methods and cohort era [3, 4, 10].

2.3 Chromosome 7

upd(7)mat is found in 7–10% of patients with SRS according to GeneReviews and in 4–10% according to EMQN; it may involve isodisomy or heterodisomy, be whole or segmental (for example 7q31-qter or 7q11.2-qter), and be mosaic, including mosaicism with trisomy 7 [4, 10]. Most cases result from trisomy rescue, so advanced maternal age is the only known predisposing factor; two cases of upd(7)mat secondary to a familial chromosomal translocation have been described [10]. The phenotype is attributed to altered expression of one or more imprinted genes on chromosome 7, the main candidates being GRB10 (7p12.1) and MEST (7q32) [1]. Deletions of 7q32.2 including the paternal MEST allele have been described, among them a 79 kb deletion inherited from the father, and a de novo maternal duplication of 7p11.2-p13 that included GRB10 [4]. In December 2025, Vimercati and colleagues described two siblings with a clinical diagnosis of SRS carrying a 109 kb deletion including PEG10 and SGCE, inherited from their unaffected father, with reduced PEG10 expression and increased CDKN1C expression, proposing PEG10 as an SRS gene through a gain-of-function effect on CDKN1C; this concerns a single family [23]. Isodisomy may unmask autosomal recessive diseases through homozygosity for maternal pathogenic variants, such as cystic fibrosis, even when only the mother is heterozygous; the French PNDS also cites, among the reports, congenital chloride diarrhoea (through segmental upd(7)mat of 7q) and Pendred syndrome associated with SRS [11]. The myoclonus-dystonia observed in some patients with upd(7)mat is attributed to altered expression of SGCE (7q21), a paternally expressed gene [1, 3]. Verbal dyspraxia in upd(7)mat has been associated with absent paternal FOXP2 expression [1].

2.4 Genes of the HMGA2–PLAG1–IGF2 pathway and CDKN1C

In addition to methylation alterations, point variants have been identified in four genes. IGF2 loss-of-function variants cause disease only when transmitted by the father, consistent with maternal imprinting of the gene: in 2015, Begemann and colleagues described a multigenerational family with four affected individuals, all through paternal transmission, carrying the nonsense variant historically described as c.191C>A (p.Ser64Ter) in NM_001127598.2 (historical numbering, = NM_000612.6:c.23C>A p.(Ser8Ter)) [6, 24]. Maternally transmitted CDKN1C gain-of-function variants located in the PCNA-binding domain cause familial SRS; in 2013, Brioude and colleagues identified the variant historically designated c.836G>T (p.Arg279Leu), which corresponds to NM_000076.2:c.836G>T p.(Arg279Leu), in a family with SRS without signs of IMAGe syndrome, always transmitted by the mother, whereas substitution of the same amino acid p.Arg279Pro had been associated with IMAGe syndrome [25]. In the familial CDKN1C-related SRS cases described up to the GeneReviews revision, all variants were maternal substitutions of arginine 279 [4]. HMGA2 (12q14.3) and PLAG1 (8q12.1) are not imprinted and act upstream of IGF2: HMGA2 regulates PLAG1, whose main transcriptional target is IGF2, and haploinsufficiency of any node in the axis reduces IGF2 signalling [1, 4]. Described alterations include HMGA2 deletions, including a 7.3 kb deletion containing exons 1 and 2, loss-of-function variants and a homozygous NM_003483.6:c.239C>T p.(Pro80Leu) variant in two siblings born to first cousins, and, in PLAG1, a 77 kb deletion including PLAG1 and CHCHD7 and the variants NM_002655.3:c.551del p.(Lys184SerfsTer45) (published as c.551delA), in a three-generation family with five affected individuals, and NM_002655.3:c.131del p.(Asn44ThrfsTer6) [4].

The 2026 consensus introduced a conceptual distinction: although PLAG1 and HMGA2 appear in OMIM under the SRS designation and most patients score ≥4 on the Netchine-Harbison system, experts consider them distinct conditions because neither is consistently associated with relative macrocephaly and postnatal head circumference is often below −2 SD; for IGF2 and CDKN1C, phenotypic information was considered insufficient for inclusion within the molecular definition of SRS [1]. Patients with these variants, as well as those with upd(20)mat and Temple syndrome, should nevertheless follow the SRS management pathway [1].

2.5 Variant nomenclature and reference transcripts

The CDKN1C and IGF2 variants most commonly cited in the literature use transcripts that are not the current MANE (Matched Annotation from NCBI and EMBL-EBI) Select transcripts, so historical numbering differs from standardised numbering. Conversion was performed in VariantValidator (GRCh38) and confirmed in ClinVar records [6, 26, 27]. The table summarises the correspondence.

The difference of 11 amino acid positions in CDKN1C and 56 in IGF2 results solely from the reference transcript used; a report using the MANE transcript may not be recognised as the literature’s “p.Arg279 variant” if the correspondence is not given [26]. In ClinVar records, the condition name is assigned by the submitter and does not replace phenotypic correlation: the same CDKN1C c.803G>T variant described in familial SRS appears associated with BWS by the submitter [25, 27].

2.6 Multilocus imprinting disturbance

Some patients with 11p15 LoM have methylation alterations at other imprinted loci, termed multilocus imprinting disturbance (MLID, multi-locus imprinting disturbance). The estimated frequency has varied with methods and era: 15–38% in the first consensus, 7–10% in EMQN and approximately 5% in the 2026 consensus, which refers to the 2024 joint statement on MLID [1, 3, 10, 28]. In a series of 11 patients with SRS and MLID, the loci most frequently involved beyond ICR1 were ICR2 and MEST, and when both 11p15 DMRs showed LoM the phenotype depended on the more affected locus [4]. In some families, particularly with a maternal history of recurrent pregnancy loss or molar pregnancy, variants occur in maternal-effect genes encoding proteins of the subcortical maternal complex (NLRP2, NLRP5, NLRP7, PADI6 and KHDC3L); 20–30% of mothers of children with MLID and significant reproductive problems may carry biallelic or compound heterozygous variants in these genes [4].

2.7 Systemic pathophysiology

Reduced IGF2 impairs placental and fetal growth, and relative preservation of head growth produces the characteristic disproportion between head and body, with relative macrocephaly at birth [1]. Low muscle and liver mass, a disproportionately large brain for body size and feeding difficulties explain susceptibility to fasting hypoglycaemia, particularly before 5 years, with poor glycogen reserves and limited gluconeogenic capacity [3]. Children with 11p15 LoM have significantly higher IGF1 levels than those with upd(7)mat or other SGA children, as well as elevated IGFBP3, suggesting a degree of IGF1 resistance; this resistance, together with low muscle mass, is thought to contribute to greater metabolic risk in the 11p15 subtype [1, 4]. Abnormal body composition, with low lean mass and relatively high fat mass, persists into adulthood even with a normal body mass index (BMI) [1, 29].

3. Clinical Spectrum and Manifestations by System

3.1 Growth

Abnormal growth is the earliest manifestation. Most children are born with weight and/or length ≤−2 SD; although growth velocity may lie within the normal range, significant catch-up rarely occurs, and at 2 years most remain ≤−2 SD in length unless their parents are tall [4]. The typical newborn has a length SD score below the weight SD score; after birth, poor appetite, feeding difficulties and gastrointestinal problems cause weight to fall below length, and progressive malnutrition may add a calorie-related length deficit [3]. Except for limb asymmetry, restriction is proportionate and head growth is normal [4]. Mean untreated adult height is approximately −3.1 ± 1.4 SD; in two European series of untreated adults, height ranged from −3.7 to −3.5 SD in men and from −4.2 to −2.5 SD in women [4]. Smith reports final height up to approximately 5 feet (152 cm) [13]. Most children clinically diagnosed with SRS who showed catch-up growth in later childhood had other conditions [4]. Specific European growth charts and North American MAGIC Foundation charts with Wollmann’s data superimposed are available [4].

3.2 Face, skull and oral cavity

The face is small and triangular, with a prominent forehead, delayed anterior fontanelle closure, downturned corners of the mouth, facial asymmetry, blue sclerae in early childhood, low-set and posteriorly rotated ears and micrognathia [13]. The head appears large relative to the small face and, together with wide fontanelles, may falsely suggest hydrocephalus [13]. A prominent forehead is assessed in profile between 1 and 3 years and may disappear at older ages; the face becomes less characteristic with age, and adults appear less atypical than children [4, 7, 13]. The oral cavity shows micrognathia, a high-arched palate, microdontia, irregular and crowded teeth, delayed dental eruption, absent permanent teeth, blunt condyles and crossbite in patients with facial asymmetry; overbite and crowding are the most common orofacial manifestations [1, 4, 7]. Cleft palate or a bifid uvula, frequently associated with a submucous cleft, occurred in 7% of patients with 11p15 methylation defects and in none with upd(7)mat; velopharyngeal insufficiency is relatively common in 11p15 LoM [3, 4]. Pierre Robin sequence requires monitoring for obstructive apnoea [4].

3.3 Limbs, skeleton and asymmetry

Limb asymmetry results from hypoplasia or hemihypoplasia, with reduced growth on the affected side, and may involve the arms, legs or both; it has been described in 68% of patients (limbs and/or face) [4]. 5th-finger clinodactyly and brachydactyly are among the most frequent skeletal abnormalities; others include syndactyly of the 2nd and 3rd toes, camptodactyly, radial hypoplasia, limited elbow supination, Sprengel deformity, hip dysplasia and clubfoot [4, 13]. Scoliosis was described in 9–36% of patients in the first consensus and in 14–36% in the second, and may relate to lower limb discrepancy and/or hypotonia; in one series, 21% had scoliosis or kyphosis and 18% required surgical correction [1, 3, 4].

3.4 Feeding, gastrointestinal system and body composition

Feeding difficulties occur in 84–100% of patients (or BMI ≤−2 SD at 24 months, or use of a feeding tube or cyproheptadine) and include weak sucking, absence of hunger, gastro-oesophageal reflux and food aversion; Smith reports a frequency of 86% [4, 13]. Functional or structural gastrointestinal problems occur in 70–90% of patients; in a large series, 77% had feeding disorders and/or malnutrition and 55% severe gastro-oesophageal reflux, sometimes presenting atypically without vomiting, which may cause persistent vomiting beyond the first year; constipation is common particularly after 2 years [1, 4]. Reflux oesophagitis should be suspected in the presence of oral aversion or aspiration, and intestinal malrotation has been described [4]. Children have little subcutaneous fat and low muscle mass (56%), and are light for their length or height [3, 4]. Most school-aged children eat normally [13].

3.5 Hypoglycaemia and sweating

Fasting hypoglycaemia is frequent in young children: approximately 27% in the first consensus, 24–29% in GeneReviews and 24.3% (25 of 103) in the molecularly confirmed patients compiled by the second consensus (21.7% in 11p15 LoM and 29.0% in upd(7)mat), with spontaneous asymptomatic nocturnal episodes [1, 3, 4]. It is typically ketotic; Smith places the period of greatest susceptibility between approximately 10 months and 2–3 years, and recommends frequent meals and glucose provision during illness from 6 months to 3 years [13]. Contributing factors include reduced calorie intake, low body mass and, in some children, GH deficiency; most have symptoms, but some episodes are asymptomatic [4]. Excessive sweating, particularly of the head and upper trunk in early childhood, occurs with or without hypoglycaemia in up to 67% of patients [4, 13]. Severe non-ketotic hypoglycaemia or hypoglycaemia unrelated to fasting is atypical and should be investigated [1].

3.6 Endocrinology: adrenarche, puberty and metabolism

Bone age is delayed in early childhood and subsequently advances rapidly, usually from 8–9 years, sometimes earlier, particularly in children who have been unintentionally overfed [1, 3]. Adrenarche may be early and aggressive, particularly in 11p15 LoM, and is associated with weight gain [1, 3]. Central puberty begins within the normal range but at its early end (8–13 years in girls and 9–14 in boys), and early in relation to height; in a Dutch study, puberty began at 10.2 years in girls with SRS versus 11.2 in SGA girls without SRS, and at 11.4 versus 12.0 years in boys, with a greater loss of height SD between pubertal onset and final height [3]. Unpublished data cited by the first consensus indicate a mean onset of central puberty at 9.1 years in girls with SRS and, in upd(7)mat, at 8.5 years in girls and 9.5 in boys [3]. Elevated oestradiol levels have been described in boys with SRS several years before puberty, and some men with 11p15 LoM have small testes and low inhibin B [1]. The French PNDS attributes this finding to probable Sertoli cell insufficiency and draws a practical consequence from it: a boy may be in progressing central puberty with a still small testicular volume, a situation that may persist into adulthood, so the diagnosis of puberty should be confirmed biochemically and not by testicular volume alone [11]. Insulin resistance may be atypical and difficult to detect in the fasting prepubertal child, becoming more classical at puberty [3]. Classical GH deficiency is neither frequent nor relevant as a cause of short stature in SRS [3].

3.7 Neurodevelopment

Motor and language delay are common, the former related to reduced muscle mass and relative macrocephaly [1]. In GeneReviews, global delay occurs in 20–65% and speech delay in 39–50% [4]. In a large cohort, developmental delay, mostly mild, occurred in 34%, more frequently in upd(7)mat than in 11p15 methylation defects (65% versus 20%) [4]. Verbal dyspraxia and learning difficulties, usually mild, are concentrated in upd(7)mat, in which verbal comprehension, perceptual reasoning, working memory and processing speed may be impaired; autism spectrum disorder is more frequent in upd(7)mat than in 11p15 LoM (28% versus 5%) [1]. In a study of executive functions in adolescents and adults, mean intelligence quotient was 101.75 in 11p15 LoM and 101.00 in upd(7)mat, similar to controls [4]. In a survey of adults, 64.5% reported motor delay and 38.7% language delay; 21.2% had received special educational support according to GeneReviews (the abstract of the original study reports 9 of 33, approximately 27%) and 40% of those older than 21 years had completed a university degree [4, 30]. Myoclonus-dystonia should be sought in upd(7)mat [1].

3.8 Other congenital anomalies

Congenital anomalies occur in a minority and are more frequent in 11p15 LoM [1]. In boys, genital anomalies (hypospadias, cryptorchidism, micropenis) affect approximately 40%; Mayer-Rokitansky-Küster-Hauser syndrome, with hypoplasia or aplasia of the uterus and upper vagina, has been described in girls [3, 4]. Renal anomalies (horseshoe kidney, renal dysplasia) occur in approximately 10%, particularly in upd(7)mat according to GeneReviews, and congenital heart defects in approximately 9% (ventricular septal defect, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot, total anomalous pulmonary venous return) [4]. Other occasional abnormalities include metopic craniosynostosis, iris coloboma, inguinal hernia, posterior urethral valves, café-au-lait macules, refractive errors, strabismus and tortuous retinal vessels [13]. Otitis media is frequent in preschool children and sleep-disordered breathing has been documented in more than 70% of patients, mostly mild and not worsened by GH [1]. Isolated neoplasms have been described (craniopharyngioma, seminoma, hepatocellular carcinoma, Wilms tumour) [13], but neither the first nor second consensus includes cancer surveillance in SRS [1, 3].

3.9 Frequency of features by molecular subtype

Source: supplementary table 1 of the 2026 consensus, with numbers of patients assessed in brackets; denominators derive from heterogeneous hospital series and do not represent population prevalences [1]. Values are reproduced as published; in some rows (triangular face, speech delay, male genital anomalies), the percentage or denominator in the total column does not match the combination of the two subtype columns. In a compilation of 610 patients with H19/IGF2:IG-DMR LoM, 95.7% of the 368 assessed (352) had a score ≥4 and asymmetry was present in 79.1% (453/573); among 203 patients with upd(7)mat, 92.8% of the 139 assessed (129) scored ≥4 and asymmetry occurred in 26.2% (48/183) [1]. In the same survey, mean birth weight was −3.1 SD in LoM and −2.4 SD in upd(7)mat [1]. A Taiwanese series with LoM and upd(7)mat recorded asymmetry in 76% versus 50%, a triangular face in 89% versus 50%, clinodactyly in 68% versus 20% and genital anomalies in 19% versus 0% [4]. Annex 4 of the 2021 French PNDS presents a table of the same kind, without denominators, with values close to these in most rows but not identical: triangular face in 93.9% of the total (98.7% in 11p15 LoM and 50.0% in upd(7)mat), fifth-finger clinodactyly in 74.6% (80.7% and 56.3%), male genital anomalies in 40.0% (44.4% and 21.4%), language delay in 39.7% of the total and scoliosis in 17.6% of the total; it adds a row for pervasive developmental disorder (the French designation for the autism spectrum), present in 18.0% of the total, 5.7% in 11p15 LoM and 58.3% in upd(7)mat [11]. This last value is much higher than the 28% attributed to upd(7)mat by the 2026 consensus; the difference reflects smaller and earlier series and should not be read as a population frequency [1, 11].

3.10 Evolution through life stages

The Brazilian book Síndromes Genéticas: Reconhecer para Tratar summarises the age-related presentation: intrauterine growth restriction prenatally; in childhood, relative macrocephaly, growth retardation, micrognathia, feeding difficulty, 5th-finger clinodactyly, a prominent forehead, body asymmetry, speech and motor delay, hypotonia, a triangular face, low-set ears and downturned corners of the mouth; in adolescence, early puberty and adrenarche and short stature; and, in adults, short stature [7]. Growth, weight and appearance tend to improve throughout childhood and particularly during adolescence [13].

4. Clinical Recognition and Warning Signs

SRS should be considered in any newborn or infant who is small for gestational age and has a proportionately large head, particularly with a prominent forehead, body asymmetry and lack of interest in feeding [1, 22]. The Oxford Desk Reference describes head circumference as proportionately large but usually between the 3rd and 25th centiles, a triangular face with a downturned mouth, asymmetry as a key diagnostic sign and children as “notoriously difficult feeders”, with excessive sweating reported by parents [22]. History should include a three-generation pedigree with parents’ and siblings’ heights and birth weights and consanguinity, gestational age at ultrasound detection of growth restriction, amniotic fluid volume (oligohydramnios in placental insufficiency, polyhydramnios in cardiofaciocutaneous, Costello and Bartter syndromes), birth measurements and growth curve [22]. Examination should measure weight, length and head circumference accurately, compare limb length and circumference (aligning thumbs and feet), seek café-au-lait macules, blue sclerae and 5th-finger clinodactyly, and note telangiectases, acanthosis nigricans, lax skin, perioral polyps or coarse features, which suggest other diagnoses [22]. Before 3 years, children may have mild motor delay owing to disproportion between head size and body strength [22].

Several features shift suspicion towards other diagnoses: relative microcephaly (head circumference SD score below those for height and weight), marked global developmental delay or intellectual disability without an explanation such as documented hypoglycaemia, absence of severe feeding difficulties, additional congenital anomalies or atypical dysmorphism, disproportionate short stature (skeletal dysplasia), a photosensitive rash or recurrent bronchopulmonary infections (chromosomal instability), a family history of growth retardation or consanguinity [3, 4]. The 2026 consensus adds the following clues: height below −2 SD in a parent, head circumference below −2 SD (IGF1R, PLAG1, HMGA2, upd(20)mat, chromosomal instability), neonatal hypotonia with small hands and feet, rapid weight gain and early puberty (Temple syndrome) and adrenal insufficiency (IMAGe and MIRAGE syndromes) [1].

In a child with an established diagnosis, clinical warning signs are ketonuria or hypoglycaemia during fasting, fever or intercurrent illness, weight faltering, persistent vomiting, a rapidly rising weight curve during tube feeding, adrenarche with advancing bone age, onset of central puberty and emergence of scoliosis before or during GH treatment [1]. In adults with a historical SRS diagnosis, clinical scoring is hindered by missing early data, and the consensus recommends seeking profile photographs between 1 and 3 years and birth and 2-year measurements [1, 3].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Netchine-Harbison clinical scoring system

The Netchine-Harbison clinical scoring system (NH-CSS, Netchine-Harbison clinical scoring system) assigns one point to each of six criteria and was the only system developed using prospective data; in the validation cohort, it had 98% sensitivity and the highest negative predictive value (89%) among the systems compared, but only 36% specificity [3, 19]. Relative macrocephaly at birth and a prominent forehead are the two criteria that best distinguish SRS from SGA children without SRS [1, 3].

Source: table 1 of the 2017 and 2026 consensuses [1, 3]. The system can only be fully scored from 2 years [1].

5.2 Evolution of the criteria: 2017 and 2026

In the 2017 algorithm (visual reading of figure 1), a score ≥4/6, or 3/6 with persistent clinical suspicion, led to testing for 11p15 and upd(7)mat; a positive result confirmed SRS; with a negative result, relative microcephaly directed assessment to the table of differential diagnoses with microcephaly, and its absence to the table with normocephaly or macrocephaly, followed, if no differential diagnosis was confirmed, by analysis of copy number variants and/or 14q32 and then upd(16)mat, upd(20)mat, CDKN1C and IGF2, and another tissue; if all were negative, a score ≥5/6, or 4/6 with relative macrocephaly and a prominent forehead, allowed a diagnosis of “clinical SRS” [3]. Testing was not recommended with a score below 3/6, because no patient with fewer than three criteria had a molecular diagnosis in the Azzi cohort, but the 3/6 threshold was justified because one of the nine patients with three criteria had upd(7)mat [3].

The 2026 algorithm (visual reading of figure 1) starts from suggestive clinical features guided by NH-CSS and performs simultaneous methylation testing of 11p15, chromosome 7 and 14q32. MEG3 LoM confirms Temple syndrome; ICR1 LoM or upd(7)mat confirms SRS and requires definition of the molecular defect for the final report; unusual findings (MLID, copy number variants) require individualised management; a negative result leads to testing for single nucleotide variants, copy number variants and UPD, which may reveal IGF2, CDKN1C, HMGA2, PLAG1 or upd(20)mat (SRS management pathway) or another confirmed differential diagnosis; if all are negative and the patient meets “suspected SRS” criteria, the diagnosis remains under regular review and follows the SRS management pathway [1]. The figure notes indicate that scores ≥4 have a high likelihood of positive testing, scores ≤2 are rarely positive, and with 3 points testing should be considered if suspicion is strong, particularly with incomplete scoring (under 2 years, adolescents, adults) or signs of Temple syndrome; if mosaicism is suspected, testing another tissue may be considered [1].

The 2021 French PNDS, prepared by the Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement (CRMERCD) and published by the HAS in November 2021, adopts the 2017 algorithm and makes three points explicit in the notes to its decision tree (annex 3) [11]. First, testing for copy number variants should be performed at the outset, before methylation, if the child has global developmental delay, intellectual disability or relative microcephaly. Second, isolated intrauterine growth restriction without postnatal catch-up does not justify testing: in the series cited, neither 11p15 LoM nor upd(7)mat was found in this situation, although patients with upd(7)mat or aged under 2 years may score only 3/6. Third, with negative tests, “clinical SRS” requires ≥5/6 or 4/6 with relative macrocephaly and a prominent forehead, unless catch-up in height has occurred before 2 years. In first-line laboratory testing the PNDS retains only 11p15 and upd(7)mat, leaving 14q32, copy number variants, upd(16)mat and upd(20)mat, CDKN1C, IGF2 and the study of another tissue for second line [11]. There are two divergences from the 2026 consensus: the latter places 14q32 methylation in first line and replaces “clinical SRS” with “suspected SRS”, under regular review [1]. The French category therefore corresponds to the 2017 definition, and a patient with that label should be reassessed in the light of the 2026 classification.

The rationale for the change was the yield of alternative diagnoses: in a series of 39 children with clinical or suspected SRS at a tertiary centre in São Paulo, 43.5% had 11p15 LoM, 5.1% upd(7)mat, 5.1% maternal 11p15 duplications and 7.7% IGF2 or HMGA2 alterations, but others had upd(14)mat, upd(20)mat, copy number variants and variants in IGF1R, BLM, YY1, NAA15 and ZNF292 [31]. In an Italian group of 132 patients with NH-CSS ≥4 without an (epi)genetic alteration, 9.1% had pathogenic variants, 3% in IGF2, PLAG1 and HMGA2 and 3% in IGF1R, the IGF1 resistance gene [5].

5.3 Laboratory methods and their limitations

Methylation analysis should robustly measure methylation of DMR CpG dinucleotides; methods include bisulphite techniques and enzymatic methods such as MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification) or Southern blot (the latter mainly historical) [3, 4]. MS-MLPA is the most widely used test (more than 80% of laboratories in the 2014 EMQN pilot scheme), conserves DNA and can assess methylation and copy number in parallel [10]. The 11p15.5 kit includes more than 20 probes for the region, ten methylation-sensitive (four for H19/IGF2:IG-DMR and four for KCNQ1OT1:TSS-DMR), reducing the risk of false results from single nucleotide polymorphisms; the opposing methylation pattern of the two DMRs allows epimutations, UPD and copy number variants to be distinguished [10]. The chromosome 7 and 14 kit identifies upd(7)mat but does not distinguish UPD from epimutation without additional testing, and includes 14q32 and 6q loci allowing detection of Temple syndrome alterations and some MLID patterns [10]. The French PNDS requires quantitative analysis of H19/IGF2:IG-DMR methylation in an experienced molecular biology laboratory; at the time it was written, only the Armand Trousseau Hospital laboratory (Paris) performed this analysis in France [11].

The main limitations are mosaicism, the nature of the tests and interpretation of findings. H19/IGF2:IG-DMR hypomethylation is frequently incomplete and low levels may escape detection; the pattern may differ between leucocytes, buccal mucosa and fibroblasts, explaining some negative blood results [3, 10]. Microsatellite (STR) analysis requires DNA from at least one parent, does not detect epimutations and may not distinguish mosaic UPD from deletions or duplications; non-paternity should be considered [3, 10]. Single nucleotide polymorphism microarray detects upd(7)mat only when isodisomy is present, corresponding to 28.8% of upd(7)mat (2–3% of all patients with SRS); heterodisomy requires comparison with the parents [4]. Sequencing detects single nucleotide variants and small insertions or deletions, but not whole-exon deletions and duplications, which require targeted methods [4]. Methylation interpretation should consider copy number, because a duplication altering parental dosage changes the methylation pattern [4]. A negative result does not exclude SRS, and approximately 40% of patients with at least four Netchine-Harbison criteria had non-diagnostic conventional testing [1, 4].

5.4 Laboratory report content

The 2026 consensus recommends that reports follow international standards, describe the result and all analysed DMRs accurately (positive and negative), specify loci and associated disorders when methylation patterns are unusual, indicate whether additional testing is required, mention that mosaicism cannot be excluded for certain subtypes when 11p15, 7 and 14q32 are normal, state that a negative result does not exclude SRS and describe recurrence risk as accurately as possible (recommendation 4.9, A+++) [1]. With ICR1 LoM or gain of methylation of GRB10 and MEST, the molecular subtype (UPD, copy number variant or epimutation) must be defined; with upd(14)mat, the report should mention the risk of a translocation involving chromosome 14 [1]. Tested region nomenclature should be consistent; for sequence variants, the report should indicate gene, transcript with version, HGVS nomenclature, zygosity, classification according to the five-class ACMG/AMP system and parental origin when determined, because parental origin alters clinical significance in this disease [1, 4].

5.5 Other investigations

Wrist radiography for bone age is useful, but delayed bone age is non-specific in children with growth restriction of various causes, and disproportionate short stature should prompt a skeletal survey to exclude dysplasia [4, 32]. Growth hormone measurement by fasting stimulation tests is contraindicated owing to hypoglycaemia risk, and the 2026 consensus advises against stimulation tests because GH deficiency is not a feature of SRS [1, 4]. Baseline IGF1 is usually in or above the upper quartile of the reference range, particularly in 11p15 LoM, so normal or elevated IGF1 does not rule out the diagnosis [1]. In a patient with suspected overlapping osteogenesis imperfecta (growth restriction of prenatal onset, relative macrocephaly, a wide fontanelle, blue sclerae and asymmetry), a skeletal survey and possible COL1A1/COL1A2 testing are recommended [3]. In 11p15 LoM, the 2026 consensus suggests considering cardiac and renal ultrasound at diagnosis [1]. In a hypotonic infant with growth retardation, the Oxford Desk Reference suggests considering Prader-Willi methylation testing, and the 2026 consensus recommends 14q32 testing in patients with a Prader-Willi presentation and normal 15q11.2 methylation [1, 22].

6. Differential Diagnosis

The list of causes of prenatal and postnatal growth restriction is extensive, and distinction has therapeutic consequences: GH should be used only cautiously, after discussion with the haemato-oncology team, in chromosomal instability disorders such as Bloom syndrome, and precipitation of insulin resistance and type 2 diabetes during GH treatment has been described in SHORT syndrome [1, 3]. The first consensus organised differential diagnoses by relative head circumference, an organisation retained by the second through referral to those tables and reproduced by the French PNDS in its annex 5 [1, 3, 11]. The PNDS summarises the atypical signs that should prompt a search for another diagnosis: relative microcephaly (head circumference in SD lower than birth weight and length), global developmental delay or intellectual disability, additional congenital anomalies, facial dysmorphism and complete absence of feeding difficulties; GH deficiency is the frequent differential to exclude before maintaining a clinical diagnosis with negative molecular testing [11].

6.1 Temple syndrome

Temple syndrome (TS14) results from loss of expression of the paternally expressed genes at the 14q32 locus (DLK1 and RTL1) through upd(14)mat (approximately 50–60%), an epimutation with hypomethylation of paternal MEG3/DLK1:IG-DMR and MEG3:TSS-DMR (30–40%) or a paternal 14q32 deletion including DLK1 (approximately 10%) [9]. It shares SGA birth (82%), relative macrocephaly (approximately half), early feeding difficulties, growth failure and clinodactyly with SRS, but asymmetry is rare (16%) and additional features include neonatal hypotonia (81%), small hands and feet (77%), rapid weight gain with truncal obesity and high fat mass from 4–6 years, early puberty (86%, on average at 7 years) and early cardiometabolic risk, with type 2 diabetes from 9 years in 13% [9]. Facial features differ from SRS and become less marked with age [9]. Many patients score ≥4 on NH-CSS (57.3% of the 82 assessed for this parameter, among 139 patients with upd(14)mat compiled by the 2026 consensus), which is why 14q32 methylation became first-line testing [1]. The 2021 French PNDS, based on smaller earlier series, reported more than 70% of patients with Temple syndrome having NH-CSS ≥4/6; the broader compilation of the 2026 consensus gives a lower value [1, 11]. The same PNDS calls for the reference centre's opinion in the rare causes due to paternal 14q32 deletion and attributes to them an increased risk of thyroid carcinoma [11]; the GeneReviews chapter on Temple syndrome (2026) describes two patients with a paternal 14q32 deletion, thyroid dysfunction and papillary thyroid carcinoma, but considers the data insufficient to assert an association, and recommends annual thyroid function testing or as clinically indicated [9]. In SRS series before 2017, Temple syndrome was found in 1 of 127, 2 of 85 and 1 of 26 patients [3]. upd(14)mat may arise from a Robertsonian translocation involving 14, for which the UPD risk after prenatal diagnosis of a non-homologous balanced Robertsonian translocation was estimated at 0.65% (2 of 315 cases); an isochromosome or homologous translocation involving 14 entails a 100% UPD risk [33]. Distinction is clinical and molecular, and the 2026 consensus recommends managing Temple syndrome through the SRS pathway until specific guidelines exist, with early puberty surveillance every 6 months from approximately 4 years and annual bone age assessment from 5 [1].

6.2 Differential diagnoses with relative microcephaly

Source: table 3 of the first consensus [3]; AR, autosomal recessive; AD, autosomal dominant; ID, intellectual disability. GeneReviews adds Fanconi anaemia (café-au-lait macules, thumb hypoplasia, radial anomalies, chromosomal breaks), Warsaw syndrome (DDX11; deafness, chromosomal breaks) and, in the chromosomal disorders table, diploid/triploid mixoploidy (asymmetry, global delay and microcephaly) and upd(20)mat or a 20q13.2 deletion with loss of paternal GNAS (without relative macrocephaly or asymmetry, with hypotonia) [4]. Mixoploidy may require fibroblast culture because the triploid cell line may disappear from leucocytes, and the degree of asymmetry does not correspond to the proportion of triploid cells [34]. Fetal alcohol syndrome shares SGA birth, growth failure and clinodactyly, but adds microcephaly, a hypoplastic philtrum, short palpebral fissures and alcohol exposure [4, 22]. The Oxford Desk Reference also mentions Dubowitz syndrome and Donohue (leprechaunism, with very high insulin) and Johanson-Blizzard syndromes [22].

6.3 Differential diagnoses with normocephaly or relative macrocephaly

The differential diagnosis tables reproduce data from the cited sources and are not exhaustive [1]. 3M syndrome has previously been mistaken for autosomal recessive SRS in families with variants in its genes, and heel abnormalities are the most useful distinguishing sign [37]. In osteodysplastic primordial dwarfism type II, normal head circumference and asymmetry in SRS help separate the two conditions [38]. The Brazilian book also includes an IGF1 variant or deletion in its differential diagnosis table (short stature, a triangular face, micrognathia and clinodactyly, with cognitive impairment in some cases) [7].

6.4 Beckwith-Wiedemann syndrome and isolated asymmetry

BWS is the “mirror-image” differential diagnosis rather than a true clinical differential: it is an overgrowth syndrome with macroglossia, abdominal wall defects, hemihyperplasia and embryonal tumour risk, associated with KCNQ1OT1:TSS-DMR loss of methylation (approximately 50%), paternal 11p15 disomy (approximately 20%), H19/IGF2:IG-DMR gain of methylation (5–10%) and maternally transmitted CDKN1C loss-of-function variants (5–10%) [20]. Duplication of the entire 11p15.5 region produces SRS if maternal and BWS if paternal, so both phenotypes may coexist within a family [10]. Isolated hemihypoplasia may result from somatic mosaicism for paternal ICR1 LoM; patients with asymmetry and LoM without growth restriction score below 3/6 and do not receive an SRS diagnosis [3, 4]. For hemihypotrophy, the Oxford Desk Reference recommends a karyotype with a search for mosaicism and a genomic array at the highest resolution available and, if there is developmental delay (particularly with syndactyly or hypomelanosis of Ito) and a normal blood karyotype, chromosome studies on a skin biopsy; in facial asymmetry, hemiatrophy is less frequent than hyperplasia and should prompt consideration of mosaicism for monogenic and chromosomal disorders and, in older children, of Parry-Romberg progressive hemifacial atrophy [39, 40]. In isolated hemihypertrophy, approximately 20% have an 11p15 alteration like that of BWS, and in Hoyme's multicentre study (1998) embryonal tumours occurred in 9 of 168 patients (5.9%) [39].

7. Treatments and Risk Management Strategies

7.1 Organisation of care

There is no curative therapy or therapy targeting the imprinting defect; treatment is supportive and multidisciplinary [4]. The 2026 consensus recommends care in a reference centre in coordination with a multidisciplinary team led by the paediatric endocrinologist and comprising a gastroenterologist, dietitian, endocrine nurse, clinical geneticist, craniofacial team, otorhinolaryngologist, sleep medicine specialist, orthopaedic surgeon, neurologist, urologist, feeding therapist, speech and language therapist, physiotherapist and psychologist, the use of a case manager and/or patient association, routine information on associations and adaptation to each country’s resources (recommendations 5.1–5.5, A+++) [1]. The Brazilian book describes each specialty’s aims (early developmental stimulation, speech and language therapy, psychology, dentistry, endocrinology, orthopaedics and nutrition) [7]. In low-resource settings, the consensus proposes using NH-CSS to guide suspicion, seeking first-line methylation testing at reference laboratories, managing according to SGA guidelines when first-line testing is negative without atypical signs, prioritising malnutrition prevention, recommending exclusive breastfeeding in the first 6 months, considering a trial of cyproheptadine and, if GH is unavailable or not reimbursed, considering aromatase inhibitors in boys and/or GnRH analogues in both sexes to protect against rapid bone age advancement [1].

Organisation in France (2021 PNDS). The PNDS describes a broader team than that of the consensus, including the attending physician, the neonatologist, the social worker, the occupational therapist (ergotherapist), the psychomotor therapist, the physiotherapist, the visceral surgeon, the stoma therapist, the anaesthetist and the emergency physician [11]. It assigns two roles to the attending physician: ensuring that the patient obtains diagnostic confirmation and a follow-up plan at a specialist centre, and being the first point of contact for complications, in coordination with the reference team. Opinions from the reference centre are required for several decisions: GH before 4 years, enteral nutrition, combination with GnRHa and the exceptional use of aromatase inhibitors [11]. On the social level, SRS justifies, from diagnosis, 100% coverage by health insurance as an off-list long-term condition (affection de longue durée). School adjustments involve an individualised reception plan (projet d'accueil individualisé, PAI), focused mainly on the frequency and quality of meals and snacks, and, when necessary, a support worker for pupils with disabilities (AESH), requested from the Maison Départementale des Personnes Handicapées (MDPH) with a medical certificate; the MDPH may also recognise the disability and fund non-reimbursed orthopaedic insoles [11]. Psychomotor therapy is not reimbursed outside early medico-social action centres and medico-psycho-pedagogical centres, but may be covered by the Allocation d'Éducation de l'Enfant Handicapé [11]. The PNDS does not contraindicate sport or nursery attendance and recommends socialisation with children of the same age rather than the same height; it also recommends informing school staff about the signs of hypoglycaemia and dehydration and offering a psychology consultation at the time of diagnosis [11]. Drugs used outside the marketing authorisation (those flagged in the PNDS: cyproheptadine, growth hormone and combination with GnRHa) follow French rules: the patient must be informed, the prescription must state the off-label use and the justification must be recorded in the medical record (annex 9) [11]. These administrative rules are specific to France and do not transfer to Portugal or Brazil.

7.2 Nutrition and gastrointestinal management

Nutritional goals change throughout life. In the first 3 months, nutritional repletion is recommended with awareness of the risks of rapid weight catch-up; after 3 months, monitoring excessive weight gain is essential to avoid overnutrition and subsequent metabolic risk (recommendation 6.2, A+++) [1]. Because muscle mass is low, usual BMI targets are excessive; centres use a Waterlow index of 75–85%, weight-for-length between −2 and −1 SD in the first year and BMI between −2 and −1 SD after the first year [1]. Expert-suggested targets are a weight/height ratio of 75–85% of the 50th centile before 2 years or BMI above −2 SD after 2 years; after 4 years, a lower BMI may suffice in 11p15 LoM with very low muscle mass and asymmetry, and a higher BMI may be acceptable in upd(7)mat with near-normal muscle mass [1]. For children aged 2–4 years preparing for GH, the first consensus indicated weight at 75–85% of the 50th centile weight for height and/or BMI of 12–14 kg/m², BMI of 11–12 kg/m² in LoM with very low muscle mass and 14–15 kg/m² in upd(7)mat, and noted that weight below 70% of ideal compromises growth velocity despite GH; weight above 90% of ideal may rapidly increase fat mass [1, 3]. The French PNDS retains these 2017 targets (75–85% of ideal weight for height and/or BMI of 12–14 kg/m² from 2 to 4 years; after 4 years, 11–12 kg/m² in 11p15 LoM and 14–15 kg/m² in upd(7)mat). It defines ideal weight for height as the mean weight for the age at which the child's height would correspond to the mean, according to Waterlow, and recommends regular follow-up by a dietitian trained in the condition [11]. The divergence from 2026 is one of wording rather than substance: the second consensus expresses the targets in SD (weight-for-length or BMI between −2 and −1 SD) and adds the target for the first year [1].

Nasogastric or gastrostomy tube feeding should be avoided in children able to eat with adequate repletion; in extreme cases, particularly with hypoglycaemia, gastrostomy with or without fundoplication or a low-profile transgastric jejunostomy may be considered as a last resort, avoiding excessive weight gain (recommendations 6.3–6.4, A+++) [1]. Oromotor and sensory problems should be diagnosed and treated with a feeding and speech and language therapist, dysmotility (reflux, slow gastric emptying, constipation) screened early by history and, if indicated, objective investigations, and malrotation excluded in patients with severe refractory feeding failure (recommendations 6.5–6.7, A+++) [1]. When reflux is suspected, GeneReviews recommends assessment for oesophagitis with video swallowing studies, gastric emptying studies, pH monitoring and endoscopy [4]. The French PNDS limits enteral nutrition beyond the neonatal period to fewer than 10% of patients, those with severe and persistent undernutrition, almost always due to severe anorexia. It considers it unjustified, and metabolically harmful, in a child who eats spontaneously and for whom enriching or splitting meals is sufficient, and requires the reference centre's opinion before starting it [11].

Gastro-oesophageal reflux and constipation. The PNDS reports reflux in 55% of patients, often severe and with atypical presentation (persistent vomiting after 1 year, persistent reflux in childhood, silent reflux), sometimes associated with slow gastric emptying or anatomical anomalies. It calls for systematic screening by history and/or pH monitoring and treatment with a proton pump inhibitor, usually effective, because controlling reflux improves intake [11]. For constipation, frequent after 2 years and aggravating food refusal, it recommends fibre and hydration and, if necessary, an osmotic laxative of the macrogol type [11]. Neither the PNDS nor the consensuses give specific doses for SRS; the following doses are extrapolated from general paediatric guidelines, which are not directed at children with syndromes. The 2018 joint NASPGHAN/ESPGHAN guideline on reflux proposes omeprazole 1–4 mg/kg/day (maximum 40 mg/day, derived from the adult dose), noting that oesophagitis healing in paediatric trials occurred with 1–1.7 mg/kg/day, and courses of 4–8 weeks for typical symptoms, with reassessment [41]. The 2026 ESPGHAN/NASPGHAN guideline on functional constipation, which excludes organic constipation, indicates polyethylene glycol (macrogol 3350/4000, with or without electrolytes) at 1–1.5 g/kg/day for a maximum of 6 days for disimpaction and at 0.4–0.8 g/kg/day for maintenance, in one or several doses [42].

Cyproheptadine. The 2026 consensus now allows a trial of cyproheptadine as an appetite stimulant in children with weight faltering and lack of interest in feeding, before or during GH, to be stopped after 3 months at the maximum dose if there is no response or excessive BMI gain (recommendation 6.8, A++); the first consensus considered studies necessary before recommending it [1, 3]. According to the consensus supplement, it may be started after 18 months, at 0.25 to 0.4 mg/kg/day in two doses approximately 30 minutes before breakfast and the evening meal, introduced gradually: in the first week 50% of the evening dose, in the second 100% of the evening dose, in the third add 50% of the morning dose and in the fourth 100% of both; efficacy is assessed every 3 months through weight gain and calorie intake, and treatment is interrupted temporarily during fever or acute infection; initial drowsiness or irritability may occur [1]. In a French retrospective study of 23 children with weight faltering treated with cyproheptadine alone, 91% improved their weight by at least +0.5 SD and 52% by at least +1 SD, with weight/height ratio improving from 74.9% to 79.3% at 3 months [43]. The French PNDS, which predates the second consensus, already allowed cyproheptadine under the usual prescribing rules (progressive dose increase and suspension during acute illness or fever), as off-label use, but gave no dose; the reference dose is that of the 2026 consensus supplement [1, 11]. This use is off-label: the US cyproheptadine label indicates it for allergic conditions, calculates the paediatric dose at approximately 0.25 mg/kg/day, with a maximum of 12 mg/day from 2 to 6 years and 16 mg/day from 7 to 14 years and, in adults, 0.5 mg/kg/day, contraindicates it in newborns, premature infants and breastfeeding mothers and states that safety and efficacy below 2 years are not established; adverse effects include sedation, dizziness, paradoxical excitation, dry mouth and urinary retention [44].

7.3 Prevention and treatment of hypoglycaemia

The 2026 consensus recommends teaching parents to recognise hypoglycaemia, measure urine ketones and determine their child’s overnight “safe fasting time” when well, prevent hypoglycaemia using complex carbohydrates and avoid fasting outside a controlled setting; monitoring ketonuria at home; providing an illness emergency plan; agreeing prompt admission and intravenous dextrose with the local paediatrician and emergency department; admitting early with ketonuria or hypoglycaemia and withholding discharge until metabolic stability and adequate feeding; promoting all vaccinations in the national programme; avoiding glucagon because of limited glycogen stores and gluconeogenic capacity; and, in severe fasting hypoglycaemia without another cause and unresponsive to alternatives, considering early initiation of daily GH (recommendations 7.1–7.8) [1]. Nocturnal hypoglycaemia is prevented by adding high-molecular-weight glucose polymer (infants under 10 months) or uncooked cornstarch (older infants) to the last feed, with attention to oral hygiene; before discharge, absence of ketonuria should be verified after at least 12 hours of feeding without intravenous support [1]. Children with a history of hypoglycaemia without an adequate ketotic response require formal fasting tests [1]. GeneReviews recommends feeding intervals no longer than 4 hours in infants and ketone monitoring when a child begins sleeping through the night, during intense physical activity or illness [4].

Source: supplementary figure 1 of the 2026 consensus, which does not define a maximum dose for the boluses [1].

The French PNDS adds details on pathophysiology and management. Low reserves are probably compounded by a small liver volume, and relative macrocephaly increases glucose requirements; hypoglycaemia may have neurocognitive consequences. Dipstick ketonuria is used to anticipate risk during fasting, physical activity or acute illness and to determine, on occasion, the safe fasting time [11]. Any situation that reduces intake (fasting, febrile illness, vomiting, diarrhoea) exposes the child to hypoglycaemia and dehydration. The PNDS recommends infusing glucose solution at the slightest sign of hypoglycaemia, without waiting for it to occur: the infusion should start as soon as intake falls by more than 50%. A period of bowel rest may be needed before resuming oral or enteral feeding, because of dysmotility [11]. The protocol in annex 7, which allows replacement by a local protocol, differs in some values from the consensus plan:

Source: annex 7 of the PNDS [11]. Neither source gives a maximum dose for the boluses. Where they differ (10% glucose 2 or 3 ml/kg; crystalloid 10 or 20 ml/kg), the international reference is the 2026 consensus, and the French protocol is a national alternative explicitly replaceable by local protocols [1, 11].

Emergency card. The PNDS recommends giving all patients, with or without an identified molecular cause, an emergency card, obtained from the reference centre and updated regularly (annex 8) [11]. The bilingual template lists three risks, each with its cause. Growth restriction with normal head circumference entails a risk of hypoglycaemia. Chronic undernutrition entails a risk of rapid dehydration. Micrognathia and maxillary hypoplasia entail difficult intubation. It requests priority in the paediatric emergency department and monitoring in any acute situation with a risk of hypoglycaemia or dehydration (fever, vomiting, food refusal), with immediate infusion of glucose solution if there is ketonuria or dehydration. It states that glucagon is useless and that the patient must never be left fasting without an intravenous infusion [11].

7.4 Surgery and anaesthesia

Elective surgery should be deferred until the child is adequately nourished; SRS problems should be reviewed in advance with the anaesthetist and surgeon; admission the previous evening should be considered to start intravenous dextrose as soon as fasting begins; the patient should be first on the operating list; blood glucose should be monitored with intravenous 5% dextrose during and after surgery, without discharge while ketonuria persists or the patient cannot maintain oral or enteral intake; the intraoperative temperature protocol should match size rather than age; and postoperative malnutrition risk should be anticipated (recommendations 8.1–8.7, A+++) [1]. Dental abnormalities and micrognathia may complicate intubation at any age [1]. The French PNDS agrees and adds four points. Surgery and anaesthesia should take place in a specialist paediatric centre. Non-urgent surgery should be deferred whenever possible in younger children. Undernutrition also exposes the child to poor wound healing, which requires optimised nutritional intake and regular glycaemic monitoring before and after the procedure. Difficult intubation should be prepared for with appropriate equipment and, if necessary, with an ear, nose and throat surgeon present [11]. A Japanese report described a 33-year-old woman with clinically diagnosed SRS, weighing 16.8 kg and measuring 131 cm, with chronic hypercapnic respiratory failure and superior mesenteric artery syndrome, who lost consciousness from CO₂ narcosis during endoscopy for gastrostomy under epidural anaesthesia and required emergency intubation; the authors emphasise preparation for a difficult airway and respiratory risk in adults, and blood glucose remained at 100 mg/dl [45].

7.5 Growth hormone

Rationale and evidence. SRS was the only syndrome included in GH trials in SGA children leading to the SGA indications from the Food and Drug Administration (FDA) in 2001 and the European Medicines Agency (EMA) in 2003, and GH is prescribed under that indication rather than an SRS-specific indication [1, 3]. In a Dutch longitudinal study of 62 children with SRS (31 with 11p15 alterations, 11 with upd(7)mat and 20 idiopathic) and 227 SGA children without SRS treated with 1 mg/m²/day, starting height was lower in SRS (−3.67 versus −2.92 SD), as was adult height (−2.17 versus −1.65 SD), but total height gain was similar, with a trend towards greater gain in upd(7)mat [46]. In a Polish study cited by the 2026 consensus, gain over the first 3 years was greater in molecularly confirmed SRS than in an SGA control group (1.5 versus 1.3 SD), with reduced percentage body fat [1]. In a French single-centre retrospective study of 77 prepubertal children with confirmed SRS published in 2026, GH started at a mean of 3.7 years increased height by 0.8 SD in the first year and 1.3 SD over 2 years and weight/height ratio from 81% to 86%; the proportion below 75% fell from 22.1% to 7.8%, and starting before 4 years was associated with greater gain (1.5 versus 1.1 SD) [47]. The strongest response predictors are age and height SD score at initiation, both inversely related [1]. GeneReviews notes that GH improves height without altering body or limb asymmetry [4]. The French PNDS summarises the evidence in the same way. The response in SRS is similar to that of SGA children without SRS, with a mean gain of approximately +1.3 SD in final height, and tolerability is also equivalent, without specific precautions. The non-statural benefits are fewer hypoglycaemic episodes, increased appetite, gains in lean mass and muscle strength and improved gross motor skills [11].

Consensus recommendations. Defer GH until calorie deficit is corrected (9.1, A++); avoid stimulation tests (9.2, A+++); aims are to improve body composition, psychomotor development and appetite, reduce hypoglycaemia and optimise linear growth (9.3, A+++); treat as early as possible, with initiation between 2 and 4 years appropriate, with exceptions used in some centres below 2 years, even with height above −2 SD, for severe fasting hypoglycaemia, severe malnutrition that would lead to gastrostomy or severe muscular hypotonia (9.4, A+++); consider GH for its effect on body composition and metabolic risk even with normal height, a prognosis compromised by advancing bone age or height well below the parental target (9.5, A+++); start at approximately 33 µg/kg/day and use the lowest dose producing a minimum increase of +0.5 SD in the first year, (9.6, A+++), with the supporting text allowing dose escalation to 67 µg/kg/day on the basis of the SGA consensus; reassess diagnosis, dose, IGF1, adherence and systemic problems if response is poor (9.7); stop after epiphyseal closure, with bone age above 14 years in girls and 16 in boys (9.8, A+++); measure IGF1 before treatment, at 6 months and at least annually (9.9, A+++); and, if optimal growth can only be achieved with IGF1 above +2 SD owing to IGF1 insensitivity, consider maintaining the dose through shared decision-making (9.10, A+++) [1]. The first consensus recommended a starting dose of approximately 35 µg/kg/day (no maximum dose defined in the source), a minimum response of ≥3 cm/year increase in velocity and stopping at velocity <2 cm/year over 6 months and bone age above 14 years (girls) or 17 years (boys); the second consensus supersedes these values [1, 3]. No upper IGF1 limit has been associated with GH safety problems, but long-term data are scarce and the issue should be discussed with caregivers [1].

French PNDS and divergences. The 2021 PNDS recommends starting GH early, usually at around 2 years, once the caloric component of the height deficit has been corrected. In France, SRS benefits from the GH marketing authorisation under the European indication of intrauterine growth restriction without catch-up, but starting before 4 years falls outside the marketing authorisation and requires the reference centre's opinion [11]. The PNDS gives no dose; the marketing authorisation dose for the SGA indication is 0.035 mg/kg/day in the European SmPC consulted [11, 48]. As for IGF1, it acknowledges that the baseline value is often above +2 SD, particularly in 11p15 LoM, despite undernutrition, and the same applies to IGFBP3. On GH, IGF1 often rises well above the reference range. The PNDS allows it to be measured, but advises against adjusting the dose to keep it within the range and calls for adjustment according to growth velocity [11]. This is the same approach that the 2026 consensus formalises in recommendation 9.10. As for the divergences: the 2026 consensus proposes a starting dose of approximately 33 µg/kg/day (increase allowed up to 67 µg/kg/day), with initiation allowed between 2 and 4 years; the PNDS and the European SmPC require off-label justification before 4 years; and the PNDS does not define its own response or stopping criteria [1, 11, 48]. Before starting GH, the PNDS recommends at least one ear, nose and throat consultation, to look for tonsillar and/or adenoid hypertrophy, and, if possible, polysomnography. These assessments make it possible to decide on adenoidectomy and/or tonsillectomy before treatment and should be repeated during childhood and on GH (see section 7.8) [11].

Safety. SRS-specific safety data are limited, but SGA data are reassuring: treated SGA children had metabolic and cardiovascular health similar to controls 12 years after stopping GH, and cerebrovascular abnormality prevalence did not differ between adults with GH-induced and spontaneous catch-up [1]. Patients with scoliosis should be referred to orthopaedics before GH and monitored during treatment (13.4, A+++); limb discrepancy does not appear to worsen with GH, and scoliosis data from other cohorts are reassuring [1]. The European summary of product characteristics for Omnitrope® recommends fasting glucose and insulin before treatment and annually in SGA children, an oral glucose tolerance test if diabetes risk exists, IGF1 before treatment and twice yearly, and avoiding initiation near pubertal onset, and notes limited experience in Silver-Russell syndrome; somatropin is contraindicated with an active tumour, closed epiphyses for growth promotion and acute critical illness, and warnings include slipped capital femoral epiphysis, benign intracranial hypertension, pancreatitis, scoliosis progression and hypothyroidism; peripheral oedema and arthralgia are very common [48].

The European dose of 0.035 mg/kg/day corresponds to the consensus starting dose (35 µg/kg/day in 2017; approximately 33 µg/kg/day in 2026), whereas US labels allow up to 0.47–0.48 mg/kg/week, and the Sogroya® label gives 0.067 mg/kg/day as the maximum approved daily somatropin dose for SGA in the United States, equal to the 67 µg/kg/day maximum allowed by the consensus [1, 50, 55]. The consulted sources contain no information on national authorisation or reimbursement in Portugal (INFARMED) or Brazil (ANVISA/CONITEC).

7.6 Puberty, adrenarche and bone age

The 2026 consensus recommends monitoring premature adrenarche and early and accelerated central puberty (10.1, A+++); anticipating bone age acceleration with close monitoring from 5 years (10.2, A+++); confirming pubertal onset with LH, FSH and oestradiol (girls) or testosterone (boys) (10.3, A+++); considering personalised treatment with a GnRH agonist (GnRHa), after discussion with the patient and family, for at least 2 years in children with central pubertal onset, to preserve adult height potential and aim for normal adult height (10.4, A+++), without starting after 12 years in girls or 13 in boys (10.5, A+++); considering aromatase inhibitors when height prognosis is severely compromised, in boys, prepubertal girls or girls with central puberty suppressed by GnRHa (10.6, A++); and preventing excessive or rapid weight gain to reduce insulin resistance (10.7, A+++) [1]. Combined GH and GnRHa has been used in children with SGA and/or SRS and predicted adult height below −2.5 SD at pubertal onset; in a French cohort of 39 children with confirmed SRS (17 girls, 22 boys) who started GH at 3.9 years (median) and GnRHa at 10.0 years, 30 reached adult height, with a median of −1.8 SD (−2.1 in girls and −1.4 in boys), pubertal gain of 26 cm in girls and 30 cm in boys and good tolerability [58]. An earlier retrospective study, in which GnRHa was used non-standardly in 16 of 37 patients, detected no effect on adult height [3]. The 2021 French PNDS relies on data from SGA children, including SRS: adding GnRHa to GH at pubertal onset improved final height when height was below 140 cm and GnRHa was maintained for at least 2 years. It considers, however, that SRS-specific studies are lacking and requires a collegial decision by the paediatric endocrinology department of the reference university hospital [11]. It also notes that, in children with SRS and adrenarche, central puberty appears earlier and progresses faster, and that a rapid rise in BMI reinforces this tendency [11]. The 140 cm threshold does not appear in the 2026 recommendations 10.4–10.5, which set the minimum duration of 2 years and age limits for initiation (12 years in girls and 13 in boys) [1].

GnRHa are authorised in the United States for central precocious puberty, which does not always correspond to SRS, in which puberty frequently starts within the normal age range; in that circumstance, use to preserve height is off-label [1, 59]. As dosing references from central precocious puberty labels: Lupron Depot-PED® (leuprorelin) intramuscularly monthly at 7.5, 11.25 or 15 mg according to weight, every three months at 11.25 or 30 mg, or every six months at 45 mg [59]; Fensolvi® (leuprorelin) 45 mg subcutaneously every six months from 2 years [60]; Triptodur® (triptorelin) 22.5 mg intramuscularly every 24 weeks from 2 years [61]. These labels recommend confirming suppression with LH (stimulated or basal) or sex steroids 1–2 months after initiation, measuring height every 3 to 6 months and monitoring bone age [60, 61]. In the EU, paediatric GnRHa do not appear in the centralised authorisation medicines list consulted, so the indication depends on national SmPCs [53].

Aromatase inhibitors. Aromatase converts androstenedione to oestrone and testosterone to oestradiol; third-generation inhibitors, such as anastrozole, have been used off-label to delay bone maturation [1]. The French randomised, quadruple-masked NCT01520467 trial compared anastrozole 1 mg/day with placebo for 18 months in children with genetically confirmed SRS or Prader-Willi, receiving GH, with adrenarche and bone age advanced by ≥6 months without central puberty (aged 5 to 10 years in girls and up to 12 years in boys), with success defined as a difference of at least 9 months in bone age progression [62]. According to the 2026 consensus, citing a 2022 conference abstract, treatment in 25 children was well tolerated and delayed bone maturation; the effect on bone mineral density is smaller if treatment lasts less than 3 years; the ClinicalTrials.gov record remains “unknown” without published results [1, 62]. On this question, the 2021 French PNDS diverges from the 2026 consensus. It acknowledges that third-generation aromatase inhibitors, such as anastrozole, could be useful in adrenarche with advanced bone maturation without central puberty. However, because they are not authorised for growth disorders, it did not recommend them, except in exceptional situations discussed with the reference centre [11]. The 2026 consensus now recommends that they be considered (10.6, A++), citing the conference abstract of the French trial, not yet published in full [1]. The US Arimidex® label (1 mg/day) is oncological and states that efficacy in pubertal gynaecomastia and precocious puberty in McCune-Albright syndrome has not been demonstrated [63].

7.7 Metabolism

Recommendations are to raise awareness among gastroenterologists, dietitians, neonatologists, paediatricians and primary care professionals to avoid overfeeding these children; inform parents, grandparents and carers about the insulin resistance risk associated with excessive weight gain, overfeeding and refined carbohydrates; screen annually during childhood for clinical and biochemical indicators of insulin resistance, including during GH; with clinical signs or a high waist circumference/height ratio, assess insulin sensitivity using fasting glucose, HbA1c and/or a 2-hour oral glucose tolerance test with insulin; consider body composition assessment every 3 years and at transition; consider lifestyle support and metformin or other pharmacological interventions if BMI or insulin resistance is elevated; and, at transition to adult care, annual monitoring of blood pressure, lipids, insulin resistance and diabetes (recommendations 11.1–11.8, A+++) [1]. The consensus gives no metformin doses for this population.

7.8 Orthopaedics, maxillofacial care, sleep, urology and neurodevelopment

Lower limb discrepancy greater than 2 cm requires intervention; initial treatment may be a shoe lift, and in older children lengthening by distraction osteogenesis is the most commonly used procedure, with internal femoral distractors near the end of growth when one segment suffices and external tibial fixators in young children with discrepancy greater than 4 cm; scoliosis and kyphosis should be monitored, with early bracing, and many patients require surgery [4]. All patients should be examined for scoliosis at every visit, seated if limb discrepancy is present, and height should be measured on the longer side [1]. Referral to an experienced maxillofacial team or orthodontist after deciduous tooth eruption, early orthodontic intervention (techniques such as rapid palatal expansion), screening for sleep-disordered breathing and referral for obstructive apnoea assessment are recommended (recommendations 14.1–14.5) [1, 3]. Children with hypospadias or cryptorchidism should be referred to urology, and micropenis or female internal genital anomalies to multidisciplinary centres for sex development; girls with primary amenorrhoea should be investigated for Mayer-Rokitansky-Küster-Hauser syndrome (15.3, A+++) [1, 4]. Developmental assessment should be early, with monitoring for verbal or oromotor dyspraxia and autism spectrum disorder, school follow-up and examination for myoclonus-dystonia at every visit in upd(7)mat (recommendations 12.1–12.4, A+++) [1]. GeneReviews describes early intervention, physiotherapy, occupational and speech and language therapy and augmentative and alternative communication when needed [4].

The French PNDS specifies several of these measures [11]. Orthopaedics: lower limb length discrepancy is generally moderate, less than 3 cm. Above 2 cm, it may justify lengthening of the shorter limb by an experienced paediatric team, now mainly with a telescopic intramedullary nail, or, more rarely, epiphysiodesis of the longer limb. Until then, it is compensated with insoles covering the whole foot, preferably on the outside of the shoe, made by a podiatrist. Scoliosis should be screened clinically once a year by looking for a rib hump on forward trunk flexion, with the pelvis first levelled by a compensating board under the shorter limb. Hip dysplasia, shortening of the fifth ray and stiffness of the interphalangeal joints require early orthopaedic treatment, which does not differ from usual practice. Maxillofacial: deep overbite, increased overjet and narrow dental arches, particularly the mandibular arch, are frequent, with crowding that is sometimes severe in the permanent dentition. Velopharyngeal insufficiency, with or without a submucous cleft, is relatively frequent in 11p15 LoM. Orthodontic and maxillofacial assessment should ideally take place on entry to primary school. Otorhinolaryngology: acute otitis media is frequent in young children and can be prevented with tympanostomy tubes. Overnight recordings found mild to moderate sleep-disordered breathing in approximately 74% of patients, and the ENT and polysomnographic assessment before GH was described in section 7.5. Urology and gynaecology: urogenital anomalies should be referred to a reference centre before 9 months in boys and soon after diagnosis in girls. Neurodevelopment: depending on the situation, assessment of intellectual and neuropsychological functioning (attention, fine motor skills, executive functions) is recommended at 3–4, 6–7, 11–12 and 15–16 years and in adulthood. Speech therapy should be early, provided by a professional trained in oral feeding and speech disorders, and extends to language disorders. Physiotherapy and/or psychomotor therapy are indicated in severe hypotonia. Occupational therapy or psychomotor therapy help with dyspraxia and with the myoclonus-dystonia of upd(7)mat [11].

7.9 Agents and circumstances to avoid

Prolonged fasting in infants and young children, fasting GH stimulation tests, unnecessary elective surgery, glucagon to correct hypoglycaemia and overfeeding, particularly unintentional, should be avoided [1, 4].

7.10 Developments in the past 12 months and trials

The limitations of these data should be explicit. There is no SRS-specific randomised GH trial; evidence derives from SGA trials including SRS and retrospective reference-centre cohorts, with selection bias and no concurrent control [1, 3]. REAL8 explicitly excluded Russell-Silver syndrome, so its results cannot be extrapolated to these patients, and superiority over daily GH at 0.035 mg/kg/day was not maintained against 0.067 mg/kg/day [57, 64]. The anastrozole result comes from a conference abstract cited in the consensus rather than a full publication, and the endpoint was bone age, not adult height [1]. GnRHa and cyproheptadine cohorts are retrospective without comparison groups, and median gains do not equal the expected benefit for an individual patient [43, 58]. Consensus recommendations result from Delphi voting; “A+++” expresses agreement (≥70% of votes for “strongly agree”) rather than evidence quality [1]. GeneReviews identified no investigational therapies specific to SRS, and a ClinicalTrials.gov search on 6 October 2026 found only active observational records (French RaDiCo-IDMet cohort and parental fertility and assisted reproduction study NCT06878716), the 2012–2016 anastrozole trial and a Chinese study of genetic diagnosis and GH in SGA children (2021–2022) with unknown status [4, 65].

8. Reproductive Options and Family Counselling

8.1 Principles

Genetic counselling should be provided by a professional experienced in imprinting disorders, and risk depends on the molecular mechanism, so defining the subtype (epimutation, UPD or copy number variant) is essential (recommendations 4.4 and 17.1, A+++) [1]. In most families, the proband is an isolated case due to an apparently de novo epigenetic or genetic alteration, with a very low recurrence risk, but some mechanisms carry a risk of up to 50% depending on the nature of the alteration and the sex of the transmitting parent [4]. An apparently negative family history does not exclude a carrier parent when penetrance depends on sex, as with IGF2 and CDKN1C variants [4]. DNA banking of the proband without a molecular diagnosis should be considered [4]. The French PNDS defines the content of the diagnostic disclosure: the main features of the disease, emphasising the wide variability of expression between individuals; the genetic mechanisms; the treatment options; the existence of patient associations; and the offer of psychological support to the parents [11]. It classifies counselling as reassuring in most cases (11p15 LoM without deletion, upd(7)mat and clinical SRS without an identified cause). It acknowledges a recurrence risk of up to 50% in the rare families with an 11p15 copy number variant or a variant in IGF2, CDKN1C, HMGA2 or PLAG1, depending on the type of variant and the sex of the transmitting parent, and requires in-depth genetic investigation by a physician experienced in imprinting disorders [11].

The 2026 consensus emphasises that testing for IGF2, CDKN1C, PLAG1 and HMGA2 variants is particularly important with a family history of growth restriction, because parental testing allows estimation of risks that may reach 50% [1]. In a British series of 33 adults with confirmed SRS, 9 of 25 were parents and none of the 17 children had SRS [30].

8.2 Prenatal and preimplantation diagnosis

Reliable prenatal testing for paternal ICR1 loss of methylation is not possible because differentially methylated regions are not yet firmly established at the gestational age of chorionic villus sampling (10–12 weeks), no validated studies exist in amniocytes and most epimutations are mosaic [4]. The 2026 consensus adds that prenatal 11p15 methylation should be interpreted cautiously because of sample type, culture, fetal age and mosaicism, that a prenatal diagnosis does not predict clinical course and that, in practice, when SRS is suspected on ultrasound, prenatal testing is rarely performed [1]. upd(7)mat can be diagnosed prenatally: isodisomy by fetal SNP microarray and heterodisomy by comparison with parental microarrays [4]. When a causal chromosomal alteration (unbalanced 11p15.5 translocation, paternal deletion or maternal duplication including CDKN1C, maternal duplication or paternal 7q32.2 deletion including MEST) or an intragenic variant in CDKN1C, IGF2, HMGA2 or PLAG1 has been identified in the family, prenatal diagnosis through chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible [4]. Discovery of mosaic trisomy 7 at amniocentesis raises the possibility of meiotic origin with trisomy rescue and UPD with an SRS phenotype, whereas trisomy 7 detected in chorionic villi is generally confined to the placenta [66]. Fetal growth restriction is rarely detectable before 28 weeks [22]. In Temple syndrome, methylation testing in fetal DNA is not recommended; with a familial Robertsonian translocation or 14q32 deletion, prenatal and preimplantation genomic testing is possible [9]. The French PNDS agrees that methylation analysis of chromosomes 7, 11 and 14 in amniotic fluid is not validated. It notes that early and severe intrauterine growth restriction sometimes leads to prenatal diagnosis to look for serious disorders, which may identify point variants, maternal uniparental disomies or chromosomal microrearrangements [11]. Decisions about prenatal and preimplantation testing are personal, and variability in GH response and development prevents prediction of outcome from a positive result [4].

8.3 Assisted reproduction

SRS has been associated with assisted reproductive techniques, without a clear mechanism [13]. The Oxford Desk Reference reports a 4.2-fold increase in BWS risk following in vitro fertilisation and intracytoplasmic sperm injection [20]. In 2025, a retrospective cohort study of parental fertility and assisted reproduction in parents of children with SRS was registered in Paris (NCT06878716), not yet recruiting at the last registration; the record describes SRS as affecting approximately 1 in 16,000 [67]. The French PNDS notes that imprinting disorders are more frequent in monozygotic multiple pregnancies and after medically assisted reproduction. It is not known whether the responsible factor is the cause of infertility, the techniques themselves (which may interfere with the establishment of epigenetic marks) or both [11]. The consulted sources provide no absolute risk of SRS following assisted reproduction.

8.4 Adults with SRS and reproduction

The second consensus recommends that the adult endocrinologist coordinate monitoring of gonadal and reproductive function and fertility counselling, and includes gonadal function, fertility, menopause and pregnancy course and outcome among research priorities [1]. In Temple syndrome, gestational diabetes surveillance is recommended in affected pregnant women [9]. The French PNDS points out that pregnancy in SRS is poorly documented. Beyond genetic counselling, short maternal stature exposes to prematurity and obstetric complications, because the fetus is usually of normal size and weight; follow-up should therefore take place in a maternity unit with neonatal intensive care, at least level IIb [11]. Regarding fertility, women with uterine agenesis should be identified as early as possible and followed in a multidisciplinary reference centre. In men, the external genitalia may remain abnormal, with small testes and/or micropenis, and gonadal insufficiency has been described; early exploration of the gonadotrophic axis is recommended, looking for exocrine testicular insufficiency [11].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

SRS frequency remains unknown. Historical global incidence estimates range from 1:30,000 to 1:100,000, the same range cited by the Brazilian book [3, 7]. The first consensus cited a 2015 Estonian study with an incidence of 1:70,000 restricted to molecularly confirmed cases, and the Estonian retrospective and prospective study published in 2019 identified 87 patients with imprinting disorders between 1998 and 2016, of whom 15 (17%) had SRS, estimating a minimum SRS birth prevalence of 1:15,886 [3, 4, 8]. Orphanet records a validated point prevalence of 1/100,000 in the United Kingdom, a birth prevalence of 0.7 per 100,000 (7 per million, class 1–9/1,000,000) in European EUROCAT surveillance from 2005–2012 and an expert estimate of annual European incidence of 15.5 per 100,000; disparity between these sources reflects different ascertainment methods, and congenital anomaly registries are not designed to capture imprinting disorders without major malformations [68]. The 2017 consensus concludes that SRS is probably more common than some estimates suggest [3]. The 2021 French PNDS repeats the international range of 1:30,000 to 1:100,000 children and declares the prevalence in France unknown, where the diagnosis is made mainly in childhood [11].

9.2 Cohorts and distribution of mechanisms by population

Hospital series measure the distribution of mechanisms among referred patients rather than population prevalences [1]. The consulted sources include Japanese series (138 patients, and a 2022 NH-CSS-based study), Taiwanese and Hong Kong series cited in consensus supplements, which were not read in full [1]. No founder effect was identified for SRS, consistent with the predominantly postzygotic origin of LoM and with UPD through trisomy rescue; relevant founder effects occur in differential diagnoses, such as Bloom syndrome in Ashkenazi Jews, Nijmegen syndrome in Slavic populations and Mulibrey nanism in Finland [3]. The consulted sources contain no Portuguese epidemiological data; for Brazil, there are the above São Paulo series, a series of three boys from Bauru with neurodevelopmental and communication characterisation and the chapter in the Brazilian book Síndromes Genéticas: Reconhecer para Tratar [7, 31, 69]. Absence of data in these sources does not demonstrate absence of published studies.

9.3 Special populations

In low-resource settings, the 2026 consensus notes lack of testing, clinicians and supportive care, GH unavailability or lack of reimbursement, greater prevalence of malnutrition and infections and other socioeconomic factors, and proposes the strategies already described in section 7.1, including exclusive breastfeeding recommended by the World Health Organization for SGA children [1]. Premature children require correction for gestational age in measurements, and premature infants and newborns must not receive cyproheptadine according to the US label [32, 44]. At transition to adulthood, the consensus recommends systematic psychosocial support, integration of psychology into teams and a case manager in adult services (recommendations 16.4–16.6) [1].

9.4 Reference networks and patient associations

In the European Union, SRS falls within main thematic group 5 (growth and genetic obesity syndromes) of the Endo-ERN European Reference Network, which lists the SRS consensuses and EMQN laboratory recommendations [12]. The second consensus includes representatives of patient associations such as the MAGIC Foundation (United States) and Child Growth Foundation (United Kingdom) [1]. GeneReviews lists the Associazione Italiana Sindrome di Russell-Silver, the Belgian association ALICE, the Association Française des Familles touchées par le syndrome de Silver Russell, the MAGIC Foundation, the Silver Russell Syndrome Global Alliance, the Bundesverband Kleinwüchsige Menschen (Germany), the Child Growth Foundation, the Human Growth Foundation, Little People of America, NORD and GARD [4]. The Brazilian book does not mention specific Brazilian associations [7]. In France, the PNDS identifies the care network (annex 2) [11]. The molecular diagnosis centre is the department of molecular endocrinology and imprinting disorders of the Armand Trousseau Hospital (AP-HP, Paris). The national reference centre is the CRMERCD (Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, http://crmerc.aphp.fr/), and the competence centres belong to the FIRENDO rare endocrine disease network (filière) (http://www.firendo.fr). The patient associations are AFIF-SSR-PAG, which brings together families with SRS and people born small for gestational age (http://silver-russell.fr/), and Grandir, for parents of children with growth problems (http://www.grandir.asso.fr/) [11].

10. Illustrative Clinical Case

10.1 Brazilian boy with ICR1 loss of methylation (Bauru, São Paulo)

Ribeiro and colleagues, from the Bauru School of Dentistry at the University of São Paulo, described three boys with clinical and genetic diagnoses of SRS assessed in speech and language therapy [69]. The first (P1) was the second child of a non-consanguineous couple, assessed at 16 months. Prenatal ultrasound had shown fetal growth difficulty, and he was delivered by caesarean section at 37 weeks, measuring 45 cm, weighing 2,270 g, with head circumference 32 cm and Apgar score 10/10. Growth and weight gain were abnormal and measurements remained below the standard deviation for age. He received speech and language therapy in the first 6 months for sucking difficulty and was followed by a nutritionist; at assessment he had poor appetite, agitation at meals and slow feeding. He achieved head control at around 3 months, sat unsupported at 8, crawled at 10, stood at 12 and took his first steps at 16 months; he said his first word (“mama”) at 12 months, but at 16 months still had this single word and communicated by gestures. During speech and language assessment he was referred to genetics; the clinical history fulfilled the principal features for clinical diagnosis, and genetic testing showed SRS due to loss of methylation of the 11p15 imprinting control region ICR1 [69]. The second boy (P2), aged 18 months, had been born at 38 weeks weighing 1,860 g, measuring 45 cm and with head circumference 35 cm, had gastro-oesophageal reflux and also 11p15 LoM; the third (P3), aged 44 months, had lumbar scoliosis and a clinical diagnosis without molecular testing performed [69]. The article contains no clinical figures.

This case illustrates the most frequent sequence: fetal growth restriction, head circumference relatively preserved in relation to weight, feeding difficulties beginning with sucking, motor and expressive language delay, and diagnosis triggered by a professional outside genetics. Under the 2026 consensus, ICR1 LoM confirms SRS, and subtype definition (epimutation, copy number variant or UPD) is necessary for counselling; the third brother in the report, untested, would now be classified at most as “suspected SRS” until methylation testing of 11p15, 7 and 14q32 [1].

10.2 Paternal IGF2 variant and prolonged response to GH (Rome, Italy)

Ventresca and colleagues described an Italian boy referred at 2 years for suspected SRS, born to non-consanguineous parents measuring 179 and 167 cm [70]. He was delivered by caesarean section at 37 weeks for severe growth restriction, with weight −2.9 SD and length −4 SD, and had prenatal and postnatal growth failure, a very prominent forehead, feeding difficulties and low BMI (NH-CSS of 4). SNP microarray and MS-MLPA excluded chromosome 7 and 11 alterations, and panel sequencing identified the heterozygous IGF2 splice variant c.[-6-2A>G] (described against “NM_000612”, without a version), classified by the authors as “possibly pathogenic” according to ACMG; the variant was inherited from the asymptomatic father, who had inherited it from his mother, consistent with maternal IGF2 imprinting [70]. The description is valid on the MANE transcript NM_000612.6:c.-6-2A>G (NC_000011.10:g.2135531T>C) according to VariantValidator [26]. GH was started at 3 years (height −3 SD) at 0.33 mg/kg/week; growth velocity rose from 5 to 8 cm/year in the first year, height changed from −3.50 SD to −1.29 SD at 8 years, without adverse effects, and psychomotor development was normal [70]. IGF1 remained normal for 1.5 years and subsequently above +2 SD (last value +3.17 SD), with doses progressively reduced to 0.23 mg/kg/week; bone age was 7.8 years at chronological age 7.7 years and 9.6 years at 8.8 years [70]. The growth curve on Italian charts, with target height and GH initiation, is in figure 2 of the original article (https://pmc.ncbi.nlm.nih.gov/articles/PMC11002242/figure/f2/), and the three-generation segregation study in figure 1 (https://pmc.ncbi.nlm.nih.gov/articles/PMC11002242/figure/f1/) [70].

The case illustrates three points from the 2026 consensus: IGF2 variants are sought second line after normal methylation and are particularly relevant with a family history; paternal transmission entails a 50% risk for children of a male carrier and no disease risk for children of a female carrier; and maintaining IGF1 above +2 SD to achieve optimal growth is allowed through shared decision-making [1]. The authors’ “possibly pathogenic” classification, with segregation in a single family, is not equivalent to a pathogenic classification; the 2026 consensus excludes IGF2 from the molecular SRS definition but directs the same management pathway [1, 70]. The GH dose used by the authors (0.33 mg/kg/week) is their clinical choice rather than a routine recommendation.

11. Prognosis and Long-Term Follow-Up

11.1 Natural history and treated course

Untreated adult height averages approximately 3 SD below the mean [1, 4]. With historical GH regimens, mean adult height was −2.17 SD in the Dutch cohort, and in a British series of 33 molecularly confirmed patients with median age 29.6 years, 60.6% had height ≤−2 SD despite 70% having received GH [30, 46]. With early GH initiation and GnRHa at pubertal onset, median adult height reached −1.8 SD in a French cohort [58]. These figures come from different eras and protocols and are not directly comparable. Growth, weight and appearance improve throughout childhood and adolescence, and most school-aged children eat normally [13]. In adulthood, relative macrocephaly, feeding difficulties and the typical face cease to discriminate, and diagnosis requires molecular confirmation [30]. Quality of life did not correlate with height in that series, and many adults completed university education and had children [30]. The Brazilian book reports a good prognosis with early diagnosis and appropriate treatment and increased risks of coronary disease, hypertension, dyslipidaemia, diabetes and obesity [7].

11.2 Metabolic risk and adult body composition

Low birth weight is associated with coronary disease and metabolic syndrome, with particular risk when rapid weight catch-up occurs in the first months, and metabolic alterations in SRS are evident even in prepubertal children, increasing at puberty and in adulthood [1]. In the British adult series, among those older than 18 years, 25% had glucose intolerance, 33% hypertension and 52% hypercholesterolaemia [30]. In a study of 25 adults with confirmed SRS (median age 32.9 years), compared with a Southampton population cohort, body fat percentage was 44.1% versus 30.3%, lean mass index and bone mineral density were lower, total cholesterol was ≥5 mmol/l in 52.0%, triglycerides ≥1.7 mmol/l in 20.8%, fasting glucose ≥6.1 mmol/l in 25.0%, and hypertension was present in 33.3% [29]. During GH, children with SRS maintained normal blood pressure, lipids and insulin sensitivity, and two years after stopping, cardiometabolic parameters remained normal although fat mass increased [1]. Adults also report respiratory and gastrointestinal problems and unexplained episodes of falls or dizziness, and adolescents describe pain, disability, fatigue, feeling different, obsessive thinking and concerns about stigma [1]. Hypertension, dilated cardiomyopathy, type 2 diabetes, hypercholesterolaemia and hepatic steatosis have been reported in adults with 11p15 LoM [3]. The French PNDS stresses that these reports are few and perhaps not representative. Pending higher-level evidence, it proposes clinical surveillance (weight, BMI, blood pressure and auscultation) and laboratory surveillance (blood glucose, insulinaemia, lipid profile, liver function tests and vascular risk stratification) [11]. It also describes complaints in adults without an established pathophysiological link: vasomotor disturbances (flushing, orthostatic hypotension, malaise) and chronic diffuse pain that is sometimes disabling. Studies of cognitive function and quality of life in adults have shown normal performance, but low self-esteem, anxiety or depression in some respondents, which may justify psychological support [11]. Transition is a sensitive period, because it often coincides with stopping GH and with the easing of nutritional difficulties [11].

11.3 Follow-up plan

Sources: table 2 of the 2026 consensus and annex 6 and text of the 2021 French PNDS (which has no adult column); R, recommended assessment; C, consider according to clinical findings [1, 11]. Beyond this list, the consensus recommends measuring IGF1 before GH, at 6 months and at least annually; monitoring bone age from 5 years; screening annually for insulin resistance; considering body composition every 3 years and at transition; and, in adults, monitoring blood pressure, lipids, insulin resistance and diabetes annually and bone mineral density and body composition periodically, with the adult endocrinologist coordinating cardiometabolic, gastrointestinal, gonadal and reproductive monitoring [1]. GeneReviews adds measurement of growth parameters at every visit, measurement of both legs with the longer limb recorded on the growth curve, use of a lift beneath the shorter limb’s foot to measure height, examination for cryptorchidism at every visit in early childhood and assessment of social support needs [4]. The consensus also calls for maintaining contact with adults so that they can participate in future research [1].

12. Summary and Final Considerations

Silver-Russell syndrome is an imprinting growth disorder described by Silver in 1953 and Russell in 1954, whose molecular basis was established with upd(7)mat in 1995 and H19/IGF2:IG-DMR loss of methylation in 2005 [13, 16, 17]. Paternal loss of methylation of this region, frequently mosaic, silences IGF2 and restricts fetal and postnatal growth with relative preservation of head growth; upd(7)mat acts through genes not yet defined, with GRB10 and MEST the main candidates [1]. Transition from the first consensus (2017) to the second (September 2026) changed the definition: SRS diagnosis is now molecular, restricted to 11p15 LoM and upd(7)mat, and the typical clinical presentation with negative testing becomes “suspected SRS”, with regular review, whereas IGF2, CDKN1C, HMGA2, PLAG1 alterations, upd(20)mat and Temple syndrome are distinct conditions managed through the same pathway [1]. First-line laboratory testing includes methylation of 11p15, chromosome 7 and 14q32, and reports should define the subtype, mention the limitation imposed by mosaicism and standardise sequence variants on the MANE transcript, because the most cited CDKN1C and IGF2 variants use different historical numbering [1, 26].

Management in the early years centres on nutrition without overfeeding, prevention of ketotic hypoglycaemia through ketonuria monitoring, emergency plans and avoidance of glucagon, and careful preparation for any surgery [1]. Daily GH, prescribed under the SGA indication, should start between 2 and 4 years at approximately 33 µg/kg/day (increase allowed up to 67 µg/kg/day) and targets body composition, appetite, psychomotor development, hypoglycaemia prevention and height; weekly GH recently approved in the United States for SGA has not been studied in SRS [1, 55, 57]. Early and rapid puberty and adrenarche require monitoring from 5 years, GnRHa for at least 2 years if central puberty begins (up to 12 years in girls and 13 in boys) and, in selected cases, off-label aromatase inhibitors [1]. Evidence supporting these recommendations derives mainly from retrospective cohorts and SGA trials, without SRS-specific randomised trials [1]. Adulthood brings unfavourable body composition and cardiometabolic risk, warranting annual monitoring and structured transition to adult endocrinology within networks such as Endo-ERN [1, 12, 29]. Genetic counselling depends on mechanism: low risk in epimutations and upd(7)mat without rearrangement, up to 50% in 11p15 copy number variants and gene variants with transmission dependent on the parent’s sex [1, 4]. The 2021 French PNDS, which predates the second consensus, retains “clinical SRS”, a first line limited to 11p15 and chromosome 7 and reservations about aromatase inhibitors. It adds its own emergency protocol and emergency card, a schedule of neuropsychological assessment, ENT and polysomnographic assessment before GH and the French organisation of care around the CRMERCD and FIRENDO [11].

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