Sotos Syndrome

Literature and regulatory information updated: 17 October 2026.

Sotos syndrome (Sotos 1), including NSD1 haploinsufficiency due to an intragenic variant, a partial gene deletion or a 5q35 microdeletion (with the recurrent 1.9 Mb common deletion); former designation "cerebral gigantism", now obsolete

0. Initial Reference Table

1. Introduction

1.1. Original description and clinical delineation

In 1964, Juan F. Sotos, Philip R. Dodge, D. Muirhead, John D. Crawford and Nathan B. Talbot published in the New England Journal of Medicine a description of five children with excessively rapid growth, acromegaloid features and a non-progressive neurological disorder with intellectual disability, which they called "cerebral gigantism in childhood" [16, 28]. Birth length lay between the 90th and 97th centiles in all the children, bone age was advanced in most and several patients had a high palate and a prominent mandible [12]. In 1967, Hook and Reynolds added that the hands and feet are large from birth, that growth is rapid in the first years but final height may not be excessive, and described concordant monozygotic twins [12]. The designation "cerebral gigantism" is now considered outdated and should not be used, because adult height is often normal and the term does not describe the phenotype [1].

Before the molecular era, diagnosis was clinical and heterogeneous. In 1988, Fryns suggested the designation "Sotos sequence" after recognising patients with fragile X syndrome who had been diagnosed with Sotos [12]. In 1994, Cole and Hughes assessed 79 patients with a provisional diagnosis and asked four geneticists to review photographs taken between 1 and 6 years of age; the facial gestalt was considered characteristic in 41 probands and in no first-degree relative [29]. In these 41 patients, early developmental delay was present in 100% and advanced bone age in 84%; length was the most increased prenatal parameter, head circumference remained above the 97th centile in all but one throughout childhood and adulthood, and height and weight tended to normalise, especially in girls [29]. The authors proposed four major criteria (facial gestalt, growth pattern, advanced bone age and developmental delay) and noted that behavioural difficulties were the parents' main concern, with few long-term medical complications [29]. In 1996, Allanson and Cole showed that the facial gestalt is established early and evolves with age: the forehead loses predominance and the chin gains prominence [30].

1.2. Molecular discovery

The gene was identified from chromosomal rearrangements. In 2002, Imaizumi and colleagues described a 15-month-old girl with a typical phenotype and a de novo balanced reciprocal translocation t(5;8)(q35;q24.1) [12]. In the same year, Kurotaki and colleagues isolated NSD1 from the 5q35 breakpoint and, in 42 sporadic Japanese cases, found one nonsense variant, three frameshift variants and 20 submicroscopic microdeletions, concluding that NSD1 haploinsufficiency is the main cause of the syndrome [31]. The human gene had been characterised in 2001 as the homologue of murine Nsd1 [32]. In 2003, Douglas and colleagues, in the United Kingdom, studied 75 patients with overgrowth: 28 of the 37 patients with typical Sotos (76%) had an NSD1 alteration, whereas none of the 18 with another type of overgrowth did, and intragenic variants, not deletions, were the main cause outside Japan [33]. Türkmen and colleagues found variants in 18 of 20 patients with Sotos and in the familial case studied (90%), and none in patients with Weaver or other overgrowth phenotypes [12].

The series by Tatton-Brown and colleagues, published in 2005, analysed 530 individuals and identified 266 with an NSD1 alteration. Of the 166 carriers with photographs, 164 (99%) had a clinical diagnosis of Sotos assigned without knowledge of the molecular result, and 93% of British patients with a clinical diagnosis had an identifiable alteration of the gene (83% intragenic variants and 10% 5q35 microdeletions) [8, 12]. These data established the near-equivalence between Sotos syndrome and NSD1 haploinsufficiency and made it possible to define the frequencies of the manifestations that still underpin the classification into cardinal, major and associated features [1].

1.3. Reclassifications and nomenclature

The identification of genes for overlapping phenotypes changed the nosology. In 2010, Malan and colleagues showed that NFIX variants subject to nonsense-mediated mRNA decay (NMD) cause a Sotos-like syndrome, later called Malan syndrome and listed in OMIM as "Sotos syndrome 2", whereas variants escaping NMD cause Marshall-Smith syndrome [34–36]. In 2011 and 2012, two groups identified EZH2 as the Weaver syndrome gene [37, 38], and in 2014 de novo DNMT3A variants were found in 13 of 152 patients with overgrowth and in none of 1000 British controls (Tatton-Brown-Rahman syndrome) [39]. In 2015, Almuriekhi and colleagues described two siblings from Qatar with Sotos features, no NSD1 variant and a homozygous frameshift variant in APC2, an entity initially called "Sotos 3" and now listed in OMIM as autosomal recessive intellectual developmental disorder 74 [11, 40]. In 2017, analysis of 710 individuals with overgrowth and intellectual disability identified the cause in 50% in 14 genes, six of them involved in epigenetic regulation, and consolidated the OGID concept [27].

The clinical scope of this article is Sotos syndrome caused by a heterozygous pathogenic NSD1 variant or by a deletion including NSD1, including the 1.9 Mb common deletion at 5q35. Larger deletions that include NKX2-5, and subtelomeric 5q35.3 deletions, belong to the broader spectrum of 5q35 deletion syndrome (ORPHA:1627) and are described where they differ [14]. The reciprocal 5q35.2–q35.3 duplication including NSD1, sometimes called "reverse Sotos", has an opposite phenotype and is covered in the differential diagnosis [1, 15]. Malan, Marshall-Smith, Weaver, Cohen-Gibson, Tatton-Brown-Rahman, CHD8- and APC2-related overgrowth and the Beckwith-Wiedemann spectrum are distinct entities with their own genes [1, 2]. Three entities with "Sotos" or "cerebral gigantism" in their name are unrelated to NSD1: Vasquez-Hurst-Sotos syndrome (ORPHA:3423), cerebral gigantism with jaw cysts (ORPHA:2081) and Nevo syndrome (ORPHA:2691, "cerebral gigantism, Nevo type"), although an infant with features of both Sotos and Nevo had the 2.2 Mb common deletion [2, 13].

2. Molecular Genetics and Pathophysiology

2.1. The NSD1 gene and protein

NSD1 is located at 5q35.3, has 23 exons and encodes an H3K36-specific histone-lysine N-methyltransferase of 2696 amino acids in the full-length isoform [1, 8, 13]. The MANE Select (Matched Annotation from NCBI and EMBL-EBI) reference transcript is NM_022455.5 (protein NP_071900.2, GRCh38); RefSeq NM_172349, which some databases present as the gene's reference, corresponds to an alternative transcript and should not be used for variant nomenclature [4, 6]. Historical synonyms include ARA267, KMT3B and STO, and the gene is expressed in fetal and adult brain, kidney, skeletal muscle, spleen, thymus and, to a lesser extent, lung [1, 4, 13].

The protein has at least 12 functional domains: two nuclear receptor interaction domains (NID-L and NID+L), two PWWP domains, five PHD fingers, a catalytic SET domain and an associated cysteine-rich domain (SAC) [1]. The functional domains occupy 622 of the 2696 amino acids, that is, 23% of the protein [8]. The SET domain dimethylates lysine 36 of histone H3 (H3K36me2) and, to a lesser extent, lysine 20 of histone H4; the NID domains are typical of corepressors and coactivators, and NSD1 behaves as an intermediary transcription factor that can repress or activate genes depending on context and that enhances androgen receptor transactivation [1, 4, 13]. NSD1 and SETD2 encode enzymes that deposit the H3K36me mark ("writers"), whereas DNMT3A encodes a protein that reads that mark ("reader"), which explains the clinical overlap between Sotos, Luscan-Lumish and Tatton-Brown-Rahman syndromes [16].

2.2. Molecular, tissue and physiological mechanism

The disease mechanism is loss of function with haploinsufficiency: truncating variants are distributed throughout the gene, pathogenic missense variants cluster in the functional domains, and microdeletions removing the whole gene reproduce the phenotype [1, 8, 41]. The H3K36me2 mark deposited by NSD1 is required to recruit the DNA methyltransferase DNMT3A and maintain DNA methylation in intergenic regions; blood from patients with Sotos and tumours with NSD1 loss show intergenic DNA hypomethylation, and the DNMT3A missense variants of Tatton-Brown-Rahman syndrome abolish binding of the DNMT3A PWWP domain to H3K36me2 [13]. H3K36 methylation antagonises the deposition of H3K27me3 by Polycomb repressive complex 2 (PRC2), whose components EZH2, EED and SUZ12 cause Weaver, Cohen-Gibson and Imagawa-Matsumoto syndromes [42, 43].

Study of the transcriptome and methylome of patients showed that most dysregulated genes have reduced expression, especially bivalent genes regulating development and the synapse, with hypomethylation of their promoters and a pattern of accelerated molecular ageing [42]. This effect produces an NSD1-specific DNA methylation episignature in leucocytes, which distinguishes pathogenic variants from controls, from benign variants and from Weaver syndrome and which affects genes of cell morphogenesis and neuronal differentiation [16, 44]. In patient fibroblasts, MAPK/ERK pathway activity is decreased and RASIP1 protein overexpressed; as NSD1 is expressed in hypertrophic chondrocytes of the growth plate, the authors proposed that altered hypertrophic differentiation explains the overgrowth and accelerated skeletal maturation, by inverse analogy with hypochondroplasia and Noonan syndrome [45]. Concentrations of insulin-like growth factors (IGF-I and IGF-II) and of the binding proteins IGFBP-3 and IGFBP-4 are reduced and those of IGFBP-2 and IGFBP-6 slightly increased, and the relationship with the growth hormone axis remains uncertain [46].

Experimental models are preclinical. In mouse embryonic stem cells, Nsd1 is indispensable for differentiation into the three germ layers, especially into the mesendoderm that gives rise to the heart and skeleton, through deposition of H3K36me2 at distal enhancers of lineage factors such as T and Gata4, antagonising H3K27me3 [47]. In human induced pluripotent stem cells lacking NSD1, proliferation decreases, H3K36me2 is reduced, extensive hypomethylation appears and endodermal and mesodermal differentiation is diverted [48]. In mouse cortex, reduction of Nsd1 decreases Apc2 expression and disturbs neuronal migration, which is rescued by re-expression of Apc2; APC2 acts as a downstream effector of NSD1 in neurons [40].

NSD1 also has a somatic role in cancer. The NUP98-NSD1 fusion, resulting from the cryptic translocation t(5;11)(q35.3;p15.5), occurs in about 5% of paediatric acute myeloid leukaemias and should not be confused with the germline variant of the syndrome [13, 41]. Truncating somatic NSD1 variants occur in about 10% of head and neck squamous cell carcinomas [27]. In 2026, Borja and colleagues demonstrated biallelic NSD1 inactivation in a pineoblastoma in a child with Sotos and loss of heterozygosity in a neuroblastoma in another patient, data consistent with a two-hit model and a tumour suppressor function [49].

2.3. Variant spectrum

In the series of 266 individuals with an NSD1 alteration (122 girls and 144 boys), the distribution of alteration types was as follows [8]:

The 34 de novo missense variants were all in functional domains, whereas 24 polymorphisms were located outside them (P=2×10⁻¹²); no pathogenic missense variant was found in the two NID domains at the 5′ end or in the central region without domains, which includes exon 5 (2.56 kb), absent from the paralogues NSD2 and NSD3 [8]. Twenty-eight variants were recurrent in unrelated individuals, 21 of them substitutions, 18 at CpG dinucleotides [8]. Three variants remained classified as of uncertain significance, which shows that interpretation of missense variants outside known domains was already difficult before the classification criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [8]. In a series of 104 patients from 102 families, point variants accounted for 80%, whole-gene deletions (1 to 4.5 Mb) for 14% and intragenic rearrangements for 6% [13].

Partial gene deletions account for about 5% of cases; in a study of 18 classical patients without a variant or microdeletion, eight had unique partial deletions (exons 1–2 in four, and exons 3–5, 9–13, 19–21 and 22), three generated by recombination between Alu elements and two by non-homologous end joining [10]. MLPA detects, in a single assay, 5q35 microdeletions and partial deletions, which together account for about 15% of cases [10]. Deep intronic variants are an emerging cause: in 2025, a de novo intronic variant detected by whole-genome sequencing created a new exon, demonstrated by RNA sequencing, and the episignature confirmed the diagnosis [50]. GeneReviews mentions other atypical splicing variants and predicts that RNA sequencing will identify more cases [1].

The following variants were normalised in VariantValidator against NM_022455.5 (GRCh38) and are cited throughout this article:

The variants in the 2005 series and in OMIM use historical nomenclature, with the protein in one-letter code (R1984Q, R1811X, R2005X, H2143Q, C2183S, C2202Y) or nucleotide positions without prefix (896delC, 3536delA, 5998insT), and have not been converted to Human Genome Variation Society (HGVS) nomenclature [8, 13]. An exon 3 deletion was published against the previous version of the transcript (MANE Select is NM_022455.5), NM_022455.4:c.(921+1_928-1)_(1063+1_1064-1)del, with predicted p.(Cys310PhefsTer64); this is the published designation, with uncertain intronic breakpoints, and has no automatic mapping [57]. The variants described in 2026 in the pineoblastoma, NM_022455.5:c.3584dup p.(Val1196CysfsTer7) germline and c.4591dup p.(Met1531AsnfsTer4) somatic, are reproduced as the authors published them [49].

2.4. The 5q35 microdeletion and the 1.9 Mb common deletion

The common deletion, initially estimated at 2.2 Mb and refined to 1.9 Mb, encompasses NSD1 and neighbouring genes and is flanked by two low-copy repeats (LCRs), a proximal one of 394.0 kb and a distal one of 429.8 kb, with about 98.5% homology [7]. The deletion results from non-allelic homologous recombination (NAHR) between these repeats; the breakpoints of 37 of 47 Japanese patients (78.7%) mapped to a 3.0 kb recombination hotspot, in the only LCR subregions in direct orientation [7]. Kurotaki and colleagues characterised the repeats as complex mosaics of six subunits (Sos-PREP of ~390 kb and Sos-DREP of ~429 kb), demonstrated a ~550 kb junction fragment generated by NAHR between subunits C and C′, absent in 51 controls, and identified a 2.5 kb hotspot in six of nine patients [13]. All parents of children with a deletion on the paternal chromosome were heterozygous carriers of an inversion of the interval between the LCRs, which predisposes to the rearrangement without causing a phenotype; the ancestral duplication of the LCRs is estimated to have occurred 23.3–47.6 million years ago [7]. In 46 of 49 Japanese deletions the breakpoints lay in the LCRs, and the three atypical deletions (1.07 Mb, 1.23 Mb and a complex rearrangement) had Alu elements at the junctions [58].

The frequency of the microdeletion differs between populations. Kurotaki and colleagues found deletions in 49 of 95 Japanese patients (52%) and in 1 of 17 non-Japanese patients (6%), a difference they attributed to selection bias [9]. Tatton-Brown and colleagues screened 471 cases outside Japan and found 23 microdeletions, which together with ten published ones showed at least eight sizes (0.4 to 5 Mb), up to 18 cases with the same size, three repeats involved (REPcen, REPmid and REPtel) and at least 15 deletions not explicable by NAHR between REPcen and REPtel; most were of paternal origin through interchromosomal rearrangement [59]. The authors concluded that genomic architecture partly explains the difference between populations (~50% in Japan and ~10% elsewhere) [59]. In Kaminsky's case-control study of copy number variants, with 15,749 patients with developmental disorders studied by microarray, the 5q35 deletion was found in eight patients and in no control (1 in 1969 patients) [12].

The common deletion is a contiguous gene syndrome. In ten patients with the common deletion, seven had low coagulation factor XII activity and the remaining 46T allele of the F12 46C/T polymorphism, and three had normal activity with the 46C allele [60]. Deletion of SLC34A1, which encodes the sodium-phosphate cotransporter NaPi-IIa, explains hypercalciuria and nephrocalcinosis in a boy with a 2.2 Mb deletion [61]. Larger deletions extending into 5q35.1 include NKX2-5 and are associated with microcephaly, severe delay and significant heart disease (atrial septal defect with or without atrioventricular conduction defects, Ebstein anomaly, tetralogy of Fallot); terminal subtelomeric 3.5 Mb deletions at 5q35.3 cause prenatal lymphoedema with increased nuchal translucency, marked hypotonia, borderline intelligence and postnatal short stature due to growth hormone deficiency [14]. A Swedish newborn with a deletion of 24 OMIM genes, including NSD1, had congenital hyperinsulinism for almost two years [62].

2.5. Genotype-phenotype correlations

In the 239 carriers with a clinical questionnaire, patients with a microdeletion had less marked overgrowth (P=0.0003) and more severe intellectual disability (P=3×10⁻⁹) than carriers of intragenic variants, with no correlation with deletion size; all features observed in microdeletions also occurred with intragenic variants [8]. Nagai's proposal, based on 5 patients with variants and 21 with deletions, that major central nervous system, cardiac and urinary anomalies would be exclusive to deletions was not confirmed in 208 patients with variants and 31 with deletions; only a trend towards more heart disease in deletions was observed (P=0.01), and nephrocalcinosis occurred only in two patients with a microdeletion [8, 63]. There was no difference between truncating and missense variants or between 5′ and 3′ positions, and heart disease, renal anomalies, seizures and scoliosis were mutually independent [1, 8]. The 2007 series, in contrast, described a more severe phenotype with truncating variants, a discrepancy that later series have not resolved [13]. A Korean cohort of 57 children replicated the effect of deletion on growth: the 48 with an intragenic variant had higher standard deviation scores for height and weight (boys) and head circumference (girls) than the nine with a microdeletion [64]. Premolar hypodontia affected 9 of 13 Finnish children, and the most extensive form occurred in a patient with a microdeletion [12].

The same variant produces different phenotypes. The R1984Q variant, in four patients, was associated with mild intellectual disability with seizures, heart disease and Chiari malformation in one, moderate disability with atrial septal defect in another, moderate disability with seizures and scoliosis in a third, and cryptorchidism with phimosis in a fourth [8]. Among the 13 familial cases, seven of the 12 families had missense variants, compared with 48 of 240 non-familial cases (P=0.005), and all familial missense variants lay outside the SET domain, suggesting that some missense variants produce a milder phenotype compatible with reproduction [8]. Cases of extreme overgrowth with borderline or absent intellectual disability (11 patients with height ≥+4.0 SD), the family with the C2202Y variant and normal intelligence over three generations and the families in which adult carriers have only tall stature illustrate the mild end of the spectrum [13, 46, 56]. In a British family with an exon 3 deletion, DNA hypomethylation was present in all three affected members and was most marked in the most severely affected proband, suggesting that the intensity of the episignature may track severity [57].

2.6. Penetrance, expressivity, allelic disorders and modifiers

No clinically unaffected parent or sibling with an NSD1 variant or deletion is known, and 303 unaffected parents tested were not carriers, so penetrance is considered complete; expressivity is highly variable, even within the same family [1, 8]. Families in which a parent has only tall stature show that apparent "non-penetrance" may be unrecognised minimal expressivity [46, 57]. There is no other germline phenotype associated with intragenic NSD1 variants; more than 500 individuals with other diagnoses (Marshall-Smith, non-specific overgrowth, macrocephaly with autism) had no variants [1]. Dosage acts in both directions: duplication of 5q35.2–q35.3 including NSD1 produces short stature, microcephaly and delayed bone age [1, 15, 65]. The factors explaining variability between patients with the same variant remain unknown [13]. Uniparental disomy is not a cause of the syndrome: 29 patients studied with 112 markers had biparental inheritance [12]. Two intronic NSD1 polymorphisms are associated with height in genome-wide association studies, linking the gene to normal variation in stature [27].

3. Clinical Spectrum and Manifestations by System

3.1. Datasets and classification of manifestations

More than 900 individuals with an NSD1 variant or deletion have been identified, but the largest series with systematic clinical description remains the 266 people published in 2005, with a clinical questionnaire for 239 [1, 8]. This series, recruited mainly through the British Childhood Overgrowth Study and centres in France, Germany, Italy and the United States, is the basis of the classification used by GeneReviews: cardinal (≥90%), major (15–89%) and associated (≥2% and <15%) features [1, 8]. Since then, reports have mostly added isolated cases, without robust new associations, and later regional series (Barcelona, Rome, Turkey, China, Korea) use different inclusion criteria and ascertainment methods, which explains part of the discrepancies in frequency [1, 51, 52, 64, 66, 67]. The 2005 series has a referral bias towards patients with a clinical diagnosis, and the frequencies of manifestations requiring active ascertainment (echocardiography, renal ultrasound) depend on how many patients were actually investigated [8].

Table sources: [1, 8, 16, 52]. HC: head circumference; VUR: vesicoureteric reflux; ENT: ear, nose and throat.

3.2. Facial gestalt

The facial gestalt is the most specific criterion and also the one most prone to error by an inexperienced observer [1]. It includes a broad and prominent forehead with dolichocephaly, sparse frontotemporal hair and a high anterior hairline, downslanting palpebral fissures, malar flushing (often extending to the nose and perioral region), a long and narrow face with bitemporal narrowing and a high, pointed chin [1, 16]. Apparent hypertelorism is not always confirmed by measurement; the palate is high and narrow, with prominent lateral palatine ridges, and early dental eruption, crowding, hypodontia and deep overbite are frequent [16]. Premolar hypodontia was found in 9 of 13 Finnish children with an NSD1 variant, and all eight Japanese patients in a dental series had a high palate, excessive tooth wear and crowding [12].

The facial gestalt is evident at birth, is most recognisable between 1 and 6 years and becomes more subtle in older children and adults [1]. In 45 individuals aged 1 to 25 years, the large dolichocephalic head, the rounded forehead accentuated by frontoparietal balding and full cheeks predominated in childhood; with age, the forehead lost dominance and the chin gained prominence, the mandible became long and square or pointed, and prognathism was rare [30]. Some infants have a rounder face, and the diagnosis only becomes clear with follow-up [30]. In adults, the chin is high, square and prominent [69]. Because of this evolution, when the diagnosis is suspected in adulthood it is useful to ask for photographs from younger ages [70].

3.3. Growth

Overgrowth begins before birth and delivery is usually at term [1]. Mean birth length lies near the 98th centile, head circumference between the 91st and 98th centiles, and mean weight is normal (50th–91st centiles) [1]. Smith's gives mean values at term of 55.2 cm in length and 3.9 kg in weight, with a rapid increase in length, which remains at or above the 97th centile during childhood and early adolescence [16]. Before 10 years of age, about 90% of children have height and/or head circumference ≥2 SD, and in 60% both are above the 99.6th centile; height is influenced by parental heights, and about 10% have height and head circumference within the normal range, so normal growth does not exclude the diagnosis [4, 8].

Distribution by centile in the 2005 series [8]. The difference in height between intragenic variants and microdeletions was significant (P=0.0003); that in head circumference was not [8].

In adulthood, height tends to normalise and macrocephaly persists. In the 2005 series, only 8 of 32 adults had height at or above the 99.6th centile and 10 had height at or below the 50th centile [8]. In 44 adults, median height was +1.9 SD in women and +0.5 SD in men [69]. Smith's gives adult means of 182 cm in men and 174 cm in women, with macrocephaly of prenatal onset in 50%, present in 100% at one year of age and persisting into adulthood in 86% [16]. The increase in height is mainly due to limb length: the arm span/height ratio is increased, the sitting height/standing height ratio decreased and the hands and feet are large [1, 16]. Korean growth charts, built from 339 measurements in 57 children followed for a mean of 4.3 years, showed boys taller than the reference until 12.0 years, with greater weight until 10.0 and greater head circumference until 15.5, and girls taller until 17.0 years, with greater weight until 10.5 and greater head circumference until 12.0; predicted adult height did not differ from familial target height [64]. In 1994, normalisation of height and weight was more marked in girls, attributed to early puberty [29].

Patients with extreme overgrowth (height ≥+4.0 SD) and borderline or absent intellectual disability form a subgroup in which growth is the dominant manifestation [56]. In a boy aged 2 years and 8 months, height was 105.2 cm (+4.4 SD) and that of his carrier mother 180.8 cm (+4.1 SD); in a girl aged 12 years and 10 months, height was 189.4 cm (+6.3 SD) [56].

3.4. Development, cognition and behaviour

Early developmental delay is very common, and motor skills appear particularly delayed because of body size, hypotonia and poor coordination [1]. Most have some degree of intellectual disability (ID), on a spectrum from mild, compatible with independent living and having a family, to severe, in which independent living is unlikely; the level tends to remain stable throughout life [1, 69]. In the 2005 series, 97% had learning disability (severe 21%, moderate 46%, mild 30%) and only seven had normal development, a figure influenced by referral bias [8]. Early assessments, heavily dependent on motor and verbal skills, may poorly predict final intellectual performance, and even children with normal intelligence have expressive language and motor delay in childhood [16]. In São Paulo, a study of seven patients with a review of 198 published cases attributed part of the poor performance on intelligence quotient (IQ) tests to early motor difficulties [71].

The systematic review covering 1964–2015 brought together 34 articles and 247 individuals with cognitive or behavioural data; IQ was assessed in 172 participants from 25 studies [72]. Mean full-scale IQs were 76 (n=21) and 73.8 (n=15), and the median 62 (n=11), with ranges of 47–105, 21–103, 54–96 and 40–85 in the different studies; most had intellectual disability (IQ <70) or borderline functioning (70–84), and verbal IQ exceeded performance IQ in all studies except one case [72]. In a longitudinal study of ten children, abilities improved with age (IQ from 56 to 113) [72]. In 52 individuals assessed with the British Ability Scales 3 (BAS3), the Sotos cognitive profile, defined by four criteria (strength in verbal ability and visuospatial memory, weakness in non-verbal and quantitative reasoning), was met in full by 28 of 35 patients, with a sensitivity of 0.8 for the set and above 0.9 for each criterion [73]. Language is consistent with full-scale IQ in some studies, and in others the expressive deficit exceeds the receptive one [72].

Behaviour is the dimension of greatest concern to families [29]. Autism spectrum disorder (ASD), phobias, anxiety, sleep disturbance with an early sleep schedule, hyperactivity, aggression and tantrums have been described [1, 74]. In the 2016 review, tantrums and aggression were reported by parents in 13 of 16 patients, autistic traits in 5 of 12, phobias in 10 of 16, and attention deficit hyperactivity disorder (ADHD) in 10 of 27 and 3 of 11, depending on the study; a Dutch study found no difference on the ADHD scale, and separation anxiety was greater than in controls matched for age and cognitive level [72]. GeneReviews considers ADHD uncommon, whereas Smith's reports overlap with ASD and ADHD, and in the Barcelona cohort 25.8% had ADHD and 12.9% severe ASD, the latter more frequent in boys [1, 16, 52]. Difficulty with peers is precipitated by size, naivety and poor perception of social cues, and immaturity may persist into adulthood, with depression, anxiety and social isolation in some adults [1, 16]. In an Italian study from 2026, 33 adolescents with Beckwith-Wiedemann spectrum, Sotos or Malan syndrome had larger peripersonal space and interpersonal distance than 33 controls, independently of autistic traits [75].

3.5. Central nervous system and seizures

Brain magnetic resonance imaging (MRI) or computed tomography (CT) is abnormal in most patients [1]. In a neuroimaging series, prominence of the ventricular trigone was present in 90%, of the occipital horns in 75% and ventriculomegaly in 63%; supratentorial extracerebral spaces and posterior fossa spaces were enlarged in 70%, and corpus callosum anomalies were almost universal [12]. Hypoplasia or agenesis of the corpus callosum, mega cisterna magna, cavum septum pellucidum, cerebral atrophy, small cerebellar vermis, white matter demyelination and arachnoid cyst have also been described [1, 16]. Ventricular dilatation ("arrested hydrocephalus") is not typically obstructive or associated with raised intracranial pressure [1].

About 25% have afebrile seizures at some point in life, with absence, tonic-clonic, myoclonic and complex partial seizures; some require continuous treatment [1]. Smith's states that half of the seizures are febrile and describes frequent electroencephalographic abnormalities [16]. In the Barcelona cohort, 45.2% had epileptic seizures and nine were treated with antiseizure medication, with no genotype correlation [52]. In a family with an exon 3 deletion, the proband had infantile spasms with hypsarrhythmia at 8 months [57]. Hypotonia, hyperreflexia and poor coordination are frequent; in a 17-month-old child with a truncating variant, the developmental quotient fell from 45.8 to 39.9 at 28 months despite continuous rehabilitation, with corpus callosum anomalies and reduced white matter volume [16, 53].

3.6. Neonatal period and glucose metabolism

Maternal pre-eclampsia complicates about 15% of pregnancies with affected fetuses (17% in the 2005 series) [1, 8]. Neonatal complications (jaundice in ~65%, hypotonia in ~75% and poor feeding in ~70%) usually resolve without treatment, and only a small minority require intervention [1]. Prolonged neonatal jaundice is one of the presentations in which the syndrome should be considered [76]. In the Barcelona cohort, hypotonia and jaundice affected about one third, more often in preterm infants (P=0.049 and P=0.003), and 40.9% had length >52 cm and weight >4 kg at birth [52].

Hyperinsulinaemic hypoglycaemia (hyperinsulinism, HI) is a recognised manifestation. By 2019, eight cases with a 5q35 deletion and one with an intragenic variant with transient HI had been described; Grand and colleagues described seven patients with de novo NSD1 variants and HI, persisting beyond the first year in at least three, six of whom were diagnosed by exome because they lacked a classical phenotype at presentation [12, 77]. These cases show that NSD1 haploinsufficiency is sufficient to cause HI and that the syndrome should be considered in neonatal HI [77]. Syndromic HI accounts for up to 10% of patients with congenital HI, generally responds to diazoxide and, in Sotos syndrome, may be severe in the neonatal period and resolve within it [78]. A Swedish newborn with an extensive deletion had HI for almost two years, and a Spanish newborn girl with the c.5990A>G p.(Tyr1997Cys) variant presented with early hypoglycaemia, hypotonia, hyperlaxity with dislocation of both wrists, a haemodynamically significant ventricular septal defect, feeding difficulties and multifactorial cholestasis [55, 62]. Transient neonatal hypoglycaemia is on the list of associations with a frequency between 2% and 15%, and an abnormal glucose tolerance test occurs in 14% in Smith's [1, 16].

3.7. Heart and great vessels

Cardiac anomalies affect 15% to 40% of patients, ranging from isolated, often self-limiting defects, such as patent ductus arteriosus (PDA), atrial septal defect (ASD) and ventricular septal defect (VSD), to complex heart disease [1]. The frequency depends on ascertainment: 21% in the 2005 series, 20% in Smith's, 41.9% in Barcelona and 60.0% in a Rome series with systematic echocardiography [8, 16, 52, 66]. In Rome, 27 of 45 patients (39 with a variant and 6 with a deletion; age 14 ± 7 years) had heart disease: septal defects in 12, aortic anomalies in 9, PDA in 3, left ventricular non-compaction or hypertrabeculation in 4, pulmonary valve anomalies in 3, and coarctation, aortopulmonary window and mitral or tricuspid dysplasia in one each; the frequency was 66.7% with deletions and 58.9% with variants [66]. Left ventricular non-compaction has been described in six unrelated individuals and aortic dilatation in 16 [1, 79]. Sotos syndrome also appears in the list of syndromes associated with left ventricular non-compaction or hypertrabeculation to be considered in non-isolated non-compaction with dysmorphic features or growth abnormalities [80]. In Barcelona, two patients had recurrent pericarditis with effusion, triggered by viral infection and treated with prolonged corticosteroid therapy, one of them with the c.3811A>T p.(Lys1271Ter) variant, and one patient had ventricular pre-excitation; heart disease was more frequent in those with hypotonia at birth (P=0.042) [52].

3.8. Kidney and urinary tract

About 15% have renal anomalies, vesicoureteric reflux (VUR) being the most common; silent VUR may present in adulthood with renal failure [1]. In Barcelona, 25.8% had genitourinary anomalies (dilatation or duplication of the collecting system, renal dysplasia or hypoplasia and renal agenesis), and there was unilateral cryptorchidism in two and hydrocele in one [52]. Nephrocalcinosis is rare and associated with microdeletions, in which loss of SLC34A1 may play a part [8, 61]. The 63-year-old woman with an NSD1 variant, the oldest published, had chronic kidney disease due to fibromuscular dysplasia and received a kidney transplant [68].

3.9. Musculoskeletal system

Scoliosis affects about 30% and rarely requires bracing or surgery [1]. In Barcelona, 35.5% had scoliosis (two operated on), 22.6% valgus foot and 16.1% recurrent ingrown toenail requiring surgery [52]. Joint hyperlaxity, with or without flat feet, occurs in at least 20%; kyphosis, kyphoscoliosis, genu valgum, pectus excavatum, clubfoot, vertebral anomalies, contractures and syndactyly of the second and third toes have been described [1, 16]. Smith's reports a propensity to fractures with minimal trauma [16].

3.10. Eyes, ears, head and neck

Ocular changes include astigmatism, cataracts, myopia, strabismus, nystagmus and hypermetropia, and more rarely optic disc pallor, retinal atrophy, iris hypoplasia and glaucoma [1, 16]. In Barcelona, 71% had ophthalmological changes: strabismus in eight, hypermetropia in six, congenital nystagmus in four, astigmatism, bilateral cataract operated on in the first months and retinal atrophy in three each, and one retinal melanocytoma [52]. Chronic otitis media with conductive hearing loss is frequent and probably affects at least 15% [8, 16]. In a review of 160 patients published between 1964 and 2020, otological changes affected 14%, head and neck malformations 24% (high palate, cleft lip and palate) and feeding difficulties 29% [3]. In Barcelona, six children had adenotonsillar hypertrophy, four obstructive sleep apnoea-hypopnoea syndrome and two operated cholesteatoma [52].

3.11. Other systems

Constipation is common, and gastro-oesophageal reflux and Hirschsprung disease appear among the associations [1]. Findings with a frequency of 2% to 15% include cryptorchidism, hypospadias, hydrocele and phimosis, haemangiomas and pigmentary changes, craniosynostosis, hypothyroidism, nephrocalcinosis, subpleural blebs, hemihypertrophy, umbilical and inguinal hernias and hypoplastic nails [1]. Two British patients, one with a 1.9 Mb deletion and the other with a truncating variant, had pneumothorax due to multiple subpleural blebs at 18 months and at 9 years, with recurrence after drainage, and were treated with pleurodesis and resection [81]. Low factor XII activity occurs with the common deletion when the remaining F12 allele is a low-expression allele [60].

3.12. Tumours

About 3% of patients develop tumours [1]. In the 2005 series, eight of 239 had tumours: one neuroblastoma, three sacrococcygeal teratomas, one presacral ganglioneuroma, two acute lymphoblastic leukaemias (ALL) and one small cell lung carcinoma [8]. The literature adds hepatoblastoma, ganglioglioma, astrocytoma, acute myeloid leukaemia (AML), Wilms tumour, lymphoma, ovarian and cardiac fibromas, diffuse gastric carcinoma, testicular yolk sac tumour and pineoblastoma [1, 16, 82, 83]. Smith's estimates a malignancy risk of 2.2%, OMIM records an old estimate of 3.9% for benign and malignant tumours, and the 2024 update from the American Association for Cancer Research (AACR) estimates that the overall risk does not exceed 3–5%, with the risk of each type, including Wilms tumour, probably at or below 1% [12, 16, 19]. The absolute risk of sacrococcygeal teratoma and of neuroblastoma is about 1% [1]. Recent cases include ALL at 14 years, a splenic hamartoma and a retinal melanocytoma with spontaneous involution in Barcelona, acute megakaryoblastic leukaemia, a pineoblastoma with biallelic NSD1 inactivation and a malignant peripheral nerve sheath tumour (MPNST) in a 49-year-old man with previous lymphoma [49, 52, 84, 85]. In the adult series, four neoplasms in 21 patients, including basal cell and squamous cell skin carcinomas, do not allow incidence to be calculated [68]. Most of these tumours are isolated cases, and it is not known whether they represent a specific association or coincidence [1].

3.13. Adulthood

In 44 adults, intellectual ability ranged from full independence to full dependence, reproduction rates were low and adults were generally healthy, with few new problems; lymphoedema, poor dentition, hearing loss, contractures and tremor appeared in small numbers [69]. In a series of 27 adults (15 from the Spanish Registry of Overgrowth Syndromes and 11 from the literature, plus the index case), with a mean age of 26 years and 21 with molecular confirmation, learning difficulties affected 90%, scoliosis 52%, ocular problems 43%, psychiatric problems 30% and brain imaging anomalies 28%, and intellectual disability was more severe with microdeletions [68]. Smith's describes occasional psychosis and psychiatric problems in some adults [16].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In the prenatal period, ultrasound does not allow a precise diagnosis, because macrocephaly and increased length are non-specific [1]. In a Chinese series of 13 fetuses diagnosed prenatally between January 2016 and March 2025, the findings were increased nuchal translucency (NT) in 5, central nervous system (CNS) anomalies in 6, detected in the second and third trimesters, growth abnormalities in 2, and also polyhydramnios and cardiac and renal anomalies [86]. Mild prenatal ventriculomegaly was the only prior finding in the child with pineoblastoma described in 2026 [49]. Pre-eclampsia in a pregnancy with a large, macrocephalic fetus has no diagnostic value on its own, but forms part of the pattern [1].

In the newborn, the combination of increased length and head circumference with relatively lower weight, hypotonia, poor feeding, prolonged jaundice and hypoglycaemia should prompt consideration of the syndrome [1, 76, 87]. Neonatal hyperinsulinism, transient or persistent, is a point of entry, and in the Philadelphia series six of seven patients with HI were diagnosed only by exome, because they had no classical phenotype at presentation [12, 77]. Neonatal hypoglycaemia with overgrowth and macrocephaly, hypotonia and delay, often with jaundice, appears in the Oxford differential alongside the Beckwith-Wiedemann spectrum [87].

In early childhood (1 to 6 years), the facial gestalt is most recognisable and the full pattern includes macrocephaly, tall stature, large hands and feet, advanced bone age, motor and language delay and hypotonia [1, 16]. Suspicion should arise with global overgrowth (increased height and head circumference) accompanied by intellectual disability or a congenital anomaly [70]. In the older child and adolescent, the facial gestalt is more subtle and height may be within the normal range; macrocephaly, a cognitive profile with verbal above non-verbal abilities and behavioural difficulties persist [1, 73]. In the adult, the high, square chin, macrocephaly and stable intellectual disability guide the diagnosis, which benefits from review of childhood photographs [69, 70]. Diagnosis may be late: the oldest published patient was diagnosed at 63 years of age [68].

4.2. Warning and emergency signs

4.3. Newborn screening

Sotos syndrome has no measurable metabolite and is therefore not part of biochemical newborn screening programmes [4]. Early diagnosis depends on clinical recognition and, increasingly, on genomic testing of newborns with hypotonia, hyperinsulinaemic hypoglycaemia or congenital anomalies, as proposed by the authors who described prolonged HI [62].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

No published consensus clinical criteria exist [1]. Suspicion rests on the three cardinal features, present in ≥90% of the more than 266 NSD1 carriers in the reference series: characteristic facial gestalt, most recognisable between 1 and 6 years; learning disability, with early delay and mild to severe intellectual disability; and overgrowth, with height ≥2 SD (approximately the 98th centile), which may normalise in the adult, and macrocephaly (head circumference ≥2 SD), usually present at all ages, congenital in most, with increased head growth velocity in the first year [1]. The Oxford defines overgrowth as a value >2 SD above the mean and macrocephaly as head circumference >3 SD, a more restrictive definition than that of GeneReviews [70, 88]. The major criteria of Cole and Hughes (1994) had been facial gestalt, growth pattern, advanced bone age and developmental delay [29]. The specificity of the phenotype is high: 99% of carriers with a photograph had a clinical diagnosis of Sotos assigned without knowledge of the molecular result [8].

The clinical history should include a three-generation pedigree with birth weights and parental heights, pregnancy (gestational diabetes, assisted reproduction, ultrasound scans), neonatal data (weight, length, head circumference, gestational age, polyhydramnios, hypoglycaemia, abdominal wall defect), periods of growth acceleration, developmental milestones and skeletal, cardiac, renal and neurological history [70]. The examination records height, weight and head circumference in SD for age and looks for signs pointing to other diagnoses: macroglossia, ear lobe creases and helical pits (Beckwith-Wiedemann), midline groove of the tongue, supernumerary nipples and polydactyly (Simpson-Golabi-Behmel), penile freckling, lipomas and haemangiomas (PTEN), hemihypertrophy, umbilical hernia, scoliosis and cardiac murmurs [70].

5.2. Non-molecular investigations

Bone age is advanced in 75–80% of prepubertal children, but interpretation depends on the threshold, method, subjective error and age, and about 15% to 25% have normal bone age [1, 8, 70]. In Sotos, carpal ossification is delayed relative to that of the phalanges and metacarpals, the inverse of the pattern in Weaver syndrome [89]. Growth charts, bone age and the gestalt support the diagnosis but never confirm it [4]. Brain MRI, echocardiography, renal ultrasound and EEG assess complications, and have no value as diagnostic tests [4]. Metacarpophalangeal pattern profile analysis, proposed in 1985 as a diagnostic tool, is now of historical interest [12].

5.3. Molecular tests

The diagnosis is established by identifying a heterozygous pathogenic or likely pathogenic variant in NSD1 or a deletion that includes NSD1 [1]. GeneReviews proposes two approaches [1]. When the phenotype is suggestive, NSD1 sequencing is performed (detecting missense, nonsense and splicing variants and small insertions and deletions) and, if negative, targeted deletion and duplication analysis; alternatively, a multigene panel including NSD1 and the genes of the differential is used. When the phenotype is atypical, exome or genome is preferred. Chromosomal microarray analysis (CMA) detects large deletions, and current designs cover the NSD1 region at 5q35; targeted analysis (quantitative or long-range polymerase chain reaction, PCR, MLPA or targeted microarray) has higher resolution, but is unlikely to find alterations when sequencing and CMA have been negative [1].

Source: GeneReviews, Table 1 [1]. The values are proportions of pathogenic variants identified by each method in the mutation database and do not correspond to the clinical sensitivity of the test; the distribution of the microdeletion varies by population (most Japanese cases and ~10% outside Japan) [1, 59].

Overall clinical sensitivity is high but not complete. In the British series, 93% of patients with a clinical diagnosis had an NSD1 alteration; in other series, the proportion fell to 71% (17 of 24 patients with classical Sotos) and, according to Smith's, ranges from 60% to 90% of patients identified as Sotos or "Sotos-like", because several overlapping phenotypes receive that diagnosis [8, 13, 16]. In the British study of 710 patients with OGID, NSD1 was the cause in 240 (34%), followed by EZH2 (4.8%), DNMT3A (2.5%), PTEN (2.3%), NFIX (2.0%) and CHD8 (1.7%); 5q35 microdeletions accounted for 29 cases and exonic copy number variants for about 5% of NSD1 alterations [27]. Therefore, an overgrowth panel with NSD1 copy number analysis resolves most cases, and a negative result requires clinical reassessment and study of the genes of the differential [1, 27].

5.4. DNA methylation episignature

NSD1 haploinsufficiency produces a genomic DNA methylation signature in leucocytes [1, 44]. In 2015, this signature correctly classified 100% of validation samples, distinguishing pathogenic variants, benign NSD1 variants and Weaver syndrome [44]. In an analysis of 42 syndromes, 34 had robust episignatures, and the authors stressed the need for multiclass classification models to avoid confusion between similar signatures [90]. An independent evaluation in France, with 101 carriers of pathogenic or likely pathogenic variants in ten genes, 57 variants of uncertain significance and 25 controls, showed 100% specificity and 100% sensitivity for the NSD1 signature [17]. The episignature is indicated when the clinical picture is suggestive and sequencing and CMA have not found a pathogenic variant, and when there is a variant of uncertain significance in NSD1; it is performed on blood or stored DNA [1]. It is the closest thing to a non-sequence-based confirmatory test [4].

Methods continue to evolve. Nanopore sequencing of 9 patients with Sotos, 7 with alpha-thalassaemia X-linked intellectual disability (ATR-X) syndrome and 22 controls identified hypomethylation of part of the NSD1 CpG island in a further 22 patients (with point variants or 5q35 deletions) and its absence in 9 patients with OGID without an NSD1 alteration, which led the authors to propose a single-locus methylation test [91]. The combination of genome, RNA sequencing and episignature solved an exome-negative case [50].

5.5. Limitations of the tests

A negative result does not exclude the syndrome. Exome sequencing does not cover deep intronic variants, copy number variant detection by exome is less sensitive, CMA does not see single-exon deletions and analysis of leucocytes does not detect mosaicism restricted to other tissues [1, 50]. The exon 3 deletion in the British family, detected by microarray and MLPA, and the previously described mosaic deletion of intron 2 and exon 3 show that small copy number changes and mosaicism can give atypical phenotypes [57]. The proportion of variants detected by a method should not be confused with the clinical sensitivity of the diagnosis, which depends on patient preselection [1].

5.6. Report content and variants of uncertain significance

The report should state the gene, the transcript with version (NM_022455.5), the variant in HGVS nomenclature at c. and p. level, the zygosity (heterozygous), the ACMG/AMP class and, for deletions, the genomic coordinates with the reference genome build and the genes included (for example, NKX2-5, F12 or SLC34A1), because the extent of the deletion modifies the phenotype and counselling [6, 14, 60, 61]. A variant of uncertain significance in NSD1 neither establishes nor excludes the diagnosis [1]. Segregation is useful when a parent has a suggestive phenotype, even a mild one; de novo occurrence with confirmed maternity and paternity supports pathogenicity [1, 46]. In the 2026 Turkish cohort, 3 of the 38 NSD1 variants were classified as of uncertain significance [67]. The episignature is the most widely used functional reclassification tool [1, 17].

5.7. Practical algorithm

Sources: [1, 8, 17, 50].

5.8. Prenatal and preimplantation diagnosis

When the familial alteration is known, prenatal diagnosis and preimplantation genetic testing (PGT) are technically possible, but the result does not predict severity [1]. When there are fetal ultrasound findings, CMA identifies deletions and exome identifies intragenic variants: in the Chinese series, nine deletions were detected by CMA and four variants by exome, all de novo [86]. Orphanet accepts prenatal diagnosis in the case of strong ultrasound suspicion, such as macrocephaly [2].

6. Differential Diagnosis

6.1. Framework

Overgrowth is defined as regional or global growth more than 2 SD above peers of the same age, and overgrowth syndromes fall into two main families: those of epigenetic regulators (NSD1, EZH2, EED, SUZ12, DNMT3A, CHD8, HIST1H1E, NFIX) and those of the PI3K/AKT/mTOR pathway (activation of AKT1, AKT3, PIK3CA, PIK3R2 or MTOR, or inactivation of inhibitors such as PTEN and PPP2R5D) [27, 70]. Suspicion of a syndrome is justified when global overgrowth is accompanied by intellectual disability or congenital anomalies [70]. NSD1 alterations are essentially specific to Sotos syndrome, and the phenotype of a child with an NSD1 variant may evolve with age, so some patients initially considered to have Weaver were reclassified after review of photographs at several ages [1, 8].

6.2. Comparative table

Table sources: [1, 5, 11, 14, 27, 35, 43, 65, 70, 88, 92–99]. AD: autosomal dominant; AR: autosomal recessive; ID: intellectual disability.

6.3. Weaver syndrome and other PRC2 complex disorders

Weaver syndrome was described in 1974 in two boys and shares with Sotos overgrowth of prenatal onset, advanced bone age, macrocephaly and variable intellectual disability [43]. The gene is EZH2, at 7q36.1 (the Oxford gives 7q35, a cytoband corrected by NCBI Gene), which encodes the H3K27 methyltransferase of PRC2 [5, 41, 70]. In 48 individuals, the variants were mainly missense, 12 in the SET domain, and truncating variants (4 of 48) were only in the last exon, indicating that the mechanism is not simple haploinsufficiency; tall stature occurred in more than 90% and intellectual disability in about 80%, often mild [100]. In GeneReviews, with more than 70 individuals, overgrowth affected 91%, advanced bone age 100% of the 33 studied, camptodactyly 44%, umbilical hernia 49%, soft skin 52% and hoarse cry 46%; mean height was +3.5 SD, and mean final height is 194.2 cm in men and 176.3 cm in women [43, 93]. Facial distinction is easiest between 1 and 3 years: round face, hypertelorism, absence of prognathism and small chin with a horizontal crease between the chin and lower lip [1, 70]. In Weaver syndrome, weight increases more than height in childhood (the inverse of Sotos), and carpal ossification is more advanced than that of the phalanges, unlike in Sotos [43, 89].

The difference with the greatest clinical consequence is neuroblastoma. GeneReviews estimates 5–7%, the 2024 AACR update reports about 9% (5 of 56) in the largest review and the AACR review on neuroblastoma describes 8 cancers in 56 patients, 6 of them neuroblastomas; in the study of 710 patients with OGID, 3 of 34 EZH2 carriers (9%) had childhood cancer [19, 27, 93, 101]. For the neuroblastoma predisposition syndromes in which it includes Weaver, the AACR recommends abdominal ultrasound with urinary vanillylmandelic and homovanillic acids every 3 months and chest radiograph every 6 months until 6 years of age, and then ultrasound and urinary biochemistry every 6 months and chest radiograph every 6 to 12 months until 10 years [101]. The EZH2 GeneReviews notes that there is no ratified international guideline and refers to these North American recommendations [93]. This divergence in surveillance between Weaver and Sotos is one of the reasons for confirming the gene, because no screening is recommended in Sotos [19].

Cohen-Gibson syndrome, due to EED variants, has been compared with 56 patients with Weaver: it has more heart disease, cervical spine anomalies and cryptorchidism, and a distinguishable facial gestalt [102]. Nineteen individuals had been described, with birth weights of 3550 to 5160 g, mild to severe intellectual disability in all, osteopenia and a possible MPNST risk [94]. SUZ12 variants (Imagawa-Matsumoto syndrome) give a phenotype similar to Weaver [1, 43]. The EZH2 episignature, developed in 187 patients with OGID and 969 controls, distinguishes loss of function from gain of function, detects mosaicism and classifies EED and SUZ12 variants [103]. When Weaver features are present, the recommended testing order is NSD1, EZH2, EED and SUZ12; the British authors test NSD1 in all suspected Weaver cases and, if positive, the diagnosis is Sotos [1, 8]. The H2143Q, C2183S and 6450insC variants, found in patients initially classified as atypical Weaver, correspond to cases later reclassified as Sotos [13].

6.4. Malan and Marshall-Smith syndromes

In 2010, deletions and nonsense NFIX variants subject to NMD were described in sporadic cases of a "Sotos-like" syndrome with advanced bone age, macrocephaly, delay, scoliosis and unusual facies, and variants escaping NMD in nine patients with Marshall-Smith [34, 35]. Malan syndrome was delineated in 45 new and 35 published cases: height >+2 SD in childhood but in only half of adults, long and triangular face, macrocephaly, prominent forehead, everted lower lip and prominent chin, universal intellectual disability, characteristic anxiety and 19p13.2 microdeletions with more epilepsy; the distinction from Sotos and Weaver is purely clinical [104]. GeneReviews reports macrocephaly in 100% (77% of adults keep head circumference >2 SD), advanced bone age in 76%, refractive errors in 75%, aortic root dilatation in four patients (one with dissection at 38 years) and malignancy in about 2% [95]. The CACNA1A gene, located 109 kb from NFIX, appears to explain the seizures and episodic ataxia of the microdeletions [35]. In a survey of 28 adults with Malan, anxiety affected 79%, hypotonia 75%, scoliosis 64%, strabismus 57% and optic atrophy 32%; compared with adults with Sotos, intellectual disability is more frequent and severe, and behavioural and visual problems more common [36]. Orphanet lists 20 cases or families and a prevalence <1/1,000,000, and GeneReviews estimates about 1:1,000,000, probably an underestimate [95, 105]. In Marshall-Smith syndrome, accelerated skeletal maturation coexists with relative failure to thrive, respiratory insufficiency and osteopenia [34, 92]. In the 2026 Turkish cohort, six of the 48 patients had Malan [67].

6.5. Tatton-Brown-Rahman syndrome and CHD8-related overgrowth

In 55 individuals with de novo DNMT3A variants, intellectual disability and overgrowth affected more than 80%, hypermobility 74%, obesity (weight ≥+2 SD) 67%, hypotonia 54%, behavioural or psychiatric problems 51%, kyphoscoliosis 33% and afebrile seizures 22% [106]. The gestalt, with low, thick, horizontal eyebrows and prominent upper central incisors, is most recognisable in adolescence [96]. GeneReviews describes haematological neoplasms in eight patients (~4%), half AML, and recommends a low threshold for a full blood count, without a screening consensus [96]. CHD8 variants were found in 12 of 710 patients with OGID (1.7%); in 27 patients, the male:female ratio was 3.5:1, intellectual disability was present in all (85% mild or moderate), 85% had height and/or head circumference ≥+2 SD and 56% ASD or autistic traits [27, 107]. The CHD8 GeneReviews describes macrocephaly mainly in infancy, tall stature mainly at puberty, sleep disturbance and constipation [97].

6.6. APC2 and reciprocal 5q35 duplication

Orphanet associates APC2 with Sotos syndrome because of some cases with biallelic variants [2]. In OMIM, the corresponding entity is autosomal recessive intellectual developmental disorder 74 (#617169, formerly "Sotos syndrome 3"), with intellectual disability, macrocephaly and dysmorphism, and phenotype #618677 (complex cortical dysplasia with other brain malformations 10) is another entity associated with the same gene, unrelated to Sotos [11]. The founder case was that of two siblings from Qatar with Sotos features and a homozygous frameshift variant [40]. The 2024 AACR update and a Spanish cohort group NFIX and APC2 with NSD1 as causes of overlapping phenotypes [19, 52].

The reciprocal 5q35.2–q35.3 duplication including NSD1 produces short stature from birth, microcephaly, brachydactyly, delayed bone age, mild to moderate intellectual disability and mild dysmorphism [15, 65]. By 2025, 43 cases had been published; the smallest duplication described, of about 332 kb (arr[hg19] 5q35.2q35.3(176493106-176824785)x3), occurred in a Dutch mother and son and shows intrafamilial variability [108, 109]. A 43-month-old Korean girl with intrauterine growth restriction and a de novo 1.8 Mb duplication had confirmed growth hormone deficiency (peaks of 9.87 and 6.42 ng/mL) and improved to the 5th–10th centiles after six months of recombinant growth hormone at 0.033 mg/kg/day (dose corrected in an erratum of March 2026) [110]. Other patients had seizures and faltering weight gain, or ADHD with normal IGF-1 [108, 111].

6.7. Beckwith-Wiedemann spectrum

The Beckwith-Wiedemann spectrum shares with Sotos weight or length ≥2 SD at birth, neonatal hypoglycaemia, umbilical hernia and VUR [1, 8]. Macroglossia has never been seen in carriers of an NSD1 alteration, and the facial dysmorphism and intellectual disability, almost universal in Sotos, are rare in Beckwith-Wiedemann [8]. A carrier of an NSD1 alteration published as Beckwith-Wiedemann had neonatal hypoglycaemia, umbilical hernia and persistent VUR, findings that also occur in Sotos [8]. In a series of patients with overlapping phenotypes, two NSD1 variants were found in patients with a clinical diagnosis of Beckwith-Wiedemann (one of them with a large umbilical hernia and left hemihypertrophy), and two 11p15 alterations in 20 patients with a clinical diagnosis of Sotos without an NSD1 alteration [12, 13]. With overlapping phenotypes, 11p15 and NSD1 are both studied [8]. The recurrence risk in Beckwith-Wiedemann is below 1% in most families, but may reach 50% with certain mechanisms [1].

6.8. Other differentials

Fragile X was the cause of mistaken diagnoses of Sotos that led Fryns to propose the designation "Sotos sequence"; macrocephaly, intellectual disability and a subtly overlapping face (dolichocephaly, prominent mandible and forehead) explain the confusion, and large ears and postpubertal macro-orchidism guide the diagnosis [1, 12]. PTEN hamartoma tumour syndrome gives macrocephaly (head circumference above the 99.6th centile) with weight usually >+2 SD but without macrosomia, ASD, haemangiomas, lipomas and penile freckling, and a risk of thyroid, breast and endometrial cancer in the adult [70]. Simpson-Golabi-Behmel syndrome and Perlman syndrome carry a Wilms tumour risk sufficient to warrant renal surveillance [20, 70]. Mosaic trisomy 20p, 4p duplication and 22q13.3 deletion (Phelan-McDermid) can give a "Sotos-like" phenotype [1, 12]. Macrocephaly with a prominent forehead, long face and large mandible also suggests Van Buchem disease and craniodiaphyseal and craniometaphyseal dysplasias, recognisable on skeletal radiographs [88]. The Brazilian reference textbook includes Sotos in the differential of Smith-Magenis syndrome, because of the facial and neurological features [112]. Non-specific overgrowth is a heterogeneous group, without NSD1 alterations [1].

7. Treatments and Risk Management Strategies

7.1. Principles and evidence base

There is no disease-modifying treatment, and management is supportive, multidisciplinary and lifelong [1, 2, 4]. GeneReviews states that no clinical practice guidelines have been published for Sotos syndrome and bases its recommendations on the authors' experience, summarised by Tatton-Brown and Rahman in 2007 [1, 113]. The available evidence is expert consensus and cohorts, without randomised trials, and the Clinical Genome Resource (ClinGen) has no actionability assessment for NSD1, because the diagnosis changes education, therapies and counselling, but does not trigger interventions that modify survival [4]. Recommendations on oncological surveillance are the only ones formalised by societies, and all conclude that routine screening is not indicated [19, 20, 82].

7.2. Assessments after diagnosis

7.3. Treatment of manifestations

GeneReviews describes educational and social services in the North American context (early intervention from 0 to 3 years, individualised education programmes from 3 years, services up to 21 years), which vary between countries [1]. Adapted sport, respite care, care coordination and, when necessary, palliative care and home nursing form part of the plan [1].

7.4. Pharmacotherapy

No medicinal product is indicated for Sotos syndrome. The drugs used treat complications and follow the guidelines for that complication, and the sources consulted do not describe syndrome-specific doses [1, 4].

Syndromic HI, including that of Sotos syndrome, generally responds to diazoxide [78]. It acts by inhibiting insulin release from the pancreas, an effect the label documents even in the newborn exposed transplacentally. The United States Food and Drug Administration (FDA) label for the oral suspension (Proglycem® was the historical brand name in the United States; the label consulted is that of a generic) indicates it for the treatment of hypoglycaemia due to hyperinsulinism [114].

Source: [114]. Pericardial effusion and fluid retention deserve particular attention in a patient with congenital heart disease, which is frequent in the syndrome [1, 114]. The seven Philadelphia patients and the Swedish newborn received medical treatment for HI, but the abstracts consulted do not state the drug, dose or duration [62, 77]. The biochemical diagnosis of HI requires fasting or postprandial hypoglycaemia (<2.5–3 mmol/L) with inappropriate insulin (≥1 µIU/mL) and C-peptide ≥0.2 ng/mL at the time of hypoglycaemia [78].

The antiseizure medications used in the Barcelona cohort were valproate, levetiracetam, topiramate and vigabatrin, alone or in combination, with no published doses [52]. The infantile spasms of the proband with an exon 3 deletion were treated with adrenocorticotrophic hormone (ACTH) and vigabatrin [57]. Baclofen, tizanidine, botulinum toxin (Botox®) and antiparkinsonian drugs are mentioned generically for hypertonia and dystonia, and laxatives and prokinetics for digestive complaints, without syndrome-specific doses [1]. Recombinant growth hormone has no role in Sotos syndrome, which is an overgrowth disorder; the only use described in the sources was in the reciprocal 5q35 duplication with documented growth hormone deficiency [110].

7.5. Regulatory status

Source: [1, 114].

7.6. Clinical trials and ongoing studies

Source: ClinicalTrials.gov search of 17 October 2026 with the terms "Sotos syndrome", "NSD1", "Weaver syndrome", "Malan syndrome" and "overgrowth intellectual disability" [18, 75]. No interventional trial was found; trials with NUP98-NSD1 concern somatic acute myeloid leukaemia and are outside the scope. A negative search does not prove the absence of preclinical programmes, and there are no trial results allowing treatments to be compared, risk reductions to be calculated or absolute effects to be estimated; the available therapeutic data are observational and from case series, with the publication bias inherent to isolated reports.

7.7. Developments in the last 12 months

The literature search from October 2025 to October 2026 identified no new therapy, interventional trial or regulatory process for Sotos syndrome. Recent publications deal with mechanism, diagnosis and natural history:

7.8. Agents to avoid, pregnancy, perioperative care and transition

The sources consulted identify no drugs specifically contraindicated in Sotos syndrome. Growth hormone is not indicated, as this is an overgrowth disorder, and diazoxide requires caution with fluid overload in patients with heart disease [110, 114].

Pregnancy with an affected fetus is complicated by pre-eclampsia in about 15% (17% in the 2005 series) [1, 8]. In an Italian family, the proband's gestation had pre-eclampsia and gestational diabetes [46]. Reproduction rates in adults with Sotos are low, and the sources consulted describe no specific obstetric recommendations for affected women nor lactation data [69].

Regarding anaesthesia, a non-verbal adult with hypotonia and craniofacial anomalies underwent general anaesthesia for multiple dental extractions without complications apart from delayed emergence reversed with naloxone; with seven previous cases, the authors considered anaesthesia with neuromuscular blocking agents and intubation to be safe [115]. The high, narrow palate, dental anomalies and hypotonia are factors to consider in airway assessment [12, 16]. Patients with the common deletion may have low coagulation factor XII activity, and the sources consulted describe neither its clinical consequences nor specific perioperative recommendations [60].

Transition to adult care should be planned from 10 years of age, with realistic goals for education, work and autonomy [1]. In adults, surveillance adjustments are modest and age-appropriate cancer screening for the general population is maintained [68]. The authors of the survey of adults with Malan note that existing guidance is limited to the paediatric age group, and the Sotos GeneReviews likewise has no specific recommendations for adults beyond the baseline assessments [1, 36].

7.9. Guidelines and divergences between sources

Sources: [1, 2, 19, 20, 82, 116, 117].

The societies agree in not recommending tumour screening in Sotos syndrome, although they use different thresholds for Wilms tumour surveillance (1% in North America and 5% in Europe); for Sotos syndrome, both thresholds lead to the same conclusion [19, 20]. The divergence over the duration of renal surveillance in the syndromes in which it is indicated (5 years in 2006, 7 years in 2021) does not apply to Sotos syndrome [20, 117]. The 2017 AACR stressed the importance of promptly assessing symptoms, and neuroblastoma screening by urinary metabolites, studied in infants, did not reduce mortality and generated false positives, an additional reason not to propose it in Sotos [1, 82, 118]. The proposal for urinary calcium and phosphate screening in all children with Sotos, formulated from a single case with an SLC34A1 deletion, has not been adopted by any society [61].

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

Sotos syndrome has autosomal dominant inheritance; about 95% of cases result from a de novo variant or deletion and about 5% have an affected parent [1]. In the 2005 series, the 141 non-familial cases with both parents tested were all de novo, none of the 303 unaffected parents tested was a carrier, and there were no cases of non-penetrance nor affected siblings of unaffected parents; the authors considered the recurrence risk for unaffected parents "extremely low" [8]. The mean parental age of 46 British patients born between 1997 and 2003 (30.2 years for mothers and 33.2 for fathers) was slightly above the national means (29.1 and 32.3 years) [8]. Microdeletions occur mainly on the chromosome of paternal origin, and in Japan all fathers of children with a paternal deletion had a heterozygous inversion of the interval between the LCRs, with no phenotype of its own [7, 59].

In the Chinese family, the proband had the NSD1 c.4138del variant (normalised as p.(Glu1380LysfsTer14) on NM_022455.5, with the transcript not stated in the abstract), the parents had a normal genotype in blood, and a subsequent fetus with the same variant inherited the same maternal chromosome 5, indicating probable maternal germline mosaicism [120]. Leucocyte DNA may not detect somatic mosaicism and does not detect exclusively gonadal mosaicism [1].

8.2. Cascade testing and relatives

Testing of the parents confirms whether the alteration is de novo, and a parent without clinical features has a very low probability of being heterozygous [1]. By 2017, 23 families with familial Sotos syndrome had been published, some with adult carriers who had only tall stature, which calls for examining the parents with attention to height, head circumference and childhood photographs [46]. The risks to other relatives depend on the parents' status [1]. Familial cases are more often associated with missense variants outside the SET domain, and transmission was maternal in nine and paternal in three of the 12 families with demonstrated segregation [8].

8.3. Prenatal and preimplantation diagnosis

When the familial alteration has been identified, prenatal diagnosis and PGT are possible; the result does not allow the phenotype to be predicted, and views on its use differ between professionals and families [1]. The optimal time to discuss the risk and options is before pregnancy [1]. Without a known alteration, ultrasound does not make the diagnosis, but increased NT, CNS anomalies and polyhydramnios may lead to fetal CMA and exome; in the Chinese series, the 13 pregnancies with a prenatal diagnosis were terminated [1, 86].

8.4. Counselling of affected young people and adults

Counselling should be offered to affected young adults and repeated at reproductive age, because the risk to offspring is 50% and severity is not predictable [1]. Decision-making capacity varies with the degree of intellectual disability, from full independence to full dependence, and reproduction rates are low [69]. In minors, testing is performed for a diagnostic indication; the sources consulted describe no specific recommendations on when to discuss reproductive risk, beyond the offer of counselling to young adults and the renewed counselling on family planning included in surveillance [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The difference of about 140-fold between the clinical value (1:14,000) and the EUROCAT value results from their measuring different things: congenital anomaly registries capture what is recognised in the neonatal period, whereas the clinical estimate includes diagnoses made in childhood [4]. There is no population-based study measuring the true prevalence, and Orphanet also lists a point prevalence of 1–9/1,000,000 in Europe (EUROCAT 2005–2010) [2].

9.2. Population diversity

Japan is the population with a distinct molecular profile: the common microdeletion accounted for 52% of Japanese cases in the Kurotaki series and about 50% in later series, compared with about 10% outside Japan, a difference attributed to genomic architecture and to inversion of the interval between the LCRs in the parents [7, 9, 59]. Copy number analysis therefore has greater relative weight in Japan, and outside Japan sequencing accounts for most diagnoses [8, 9]. The population frequency of the microdeletion is not available for lack of distribution studies [1].

American and European data come from clinical series. The reference series brought together patients from the United Kingdom, France, Germany, Italy and the United States [8]; the Philadelphia children's hospital described HI [77]; Italy has cardiology series (Rome), a three-generation family and body perception studies [46, 66, 75]; Spain has the Barcelona cohort, the Spanish Registry of Overgrowth Syndromes and neonatal and genomic diagnosis cases [50, 52, 55, 68]; the Netherlands, Poland and Sweden contributed deletion and duplication cases [61, 62, 109]. Outside Europe and North America, there are cohorts from Turkey, China and Korea and a Chinese prenatal diagnosis series [51, 64, 67, 86]. The existing specific growth charts were built in Korean children, and their application to other populations has not been validated [64].

From Brazil, the sources consulted include a São Paulo series from 1991, with seven patients and a review of 198 published cases [71], and the mention of the syndrome in the differential of Smith-Magenis in a Brazilian reference textbook [112]. The sources consulted contain no data from Portugal; this absence does not demonstrate the absence of cases or publications.

9.3. Special populations

Preterm newborns have more hypotonia and jaundice [52]. Adults are generally healthy, but diagnosis may be late, as in the 63-year-old woman, and renal damage due to silent VUR, scoliosis, ocular and psychiatric problems and general population cancer screening deserve attention [1, 68, 69]. In non-verbal patients with severe intellectual disability, simple procedures such as dental extractions may require general anaesthesia [115].

9.4. Reference networks and patient organisations

The relevant European reference network is ERN ITHACA, dedicated to rare congenital malformations and rare intellectual disability (https://ern-ithaca.eu/), and the Orphanet summary on the syndrome was reviewed in 2020 by an expert from the network [2, 21]. Patient organisations include the Sotos Syndrome Support Association in the United States (https://www.sotossyndrome.org/), the Child Growth Foundation in the United Kingdom (https://childgrowthfoundation.org/), the Asociación Española de Síndrome de Sotos (https://www.asociacionsotos.org/) and A.S.S.I. Gulliver in Italy (https://www.assigulliver.it/) [1, 22–25]. The Overgrowth Syndromes Alliance, formed in 2023 by the Malan Syndrome Foundation and the TBRS Community, brings together these organisations and those of other overgrowth syndromes and has opened a research priorities survey in which epileptic seizures are among the main ones [26, 121, 122].

10. Illustrative Clinical Case

10.1. 5q35 microdeletion including NSD1 and SLC34A1 with nephrocalcinosis

In 2025, Bargenda-Lange and colleagues described a Polish boy born to non-consanguineous parents with no relevant family history, delivered by caesarean section at 39 weeks because of suspected fetal macrosomia, weighing 3980 g (90th centile on the Fenton charts) [61]. In the neonatal period he had hypotonia and transient hypoglycaemia, with large hands and feet, coarse facies and macrocephaly; the published facial photograph (Figure 1, "typical facial features of Sotos syndrome in the presented patient", https://pmc.ncbi.nlm.nih.gov/articles/PMC12653577/figure/jcm-14-08200-f001/) was consulted through its legend [61]. Ultrasound showed nephrocalcinosis and mild bilateral pelvicalyceal dilatation, and vitamin D was started at 400 IU/day, in line with general population recommendations [61]. The clinical suspicion of Sotos was confirmed by MLPA (kit P245), with deletion of two NSD1 probes [61].

The multidisciplinary assessment identified patent ductus arteriosus, hypoplasia of the corpus callosum, sacrococcygeal teratoma and sensorineural hearing loss, and the child had psychomotor delay [61]. At 2.5 years, he was referred to nephrology: phosphate, calcium, parathyroid hormone, 25(OH)-vitamin D, 1,25(OH)₂-vitamin D and renal function were normal, but there was hypercalciuria (urinary calcium/creatinine ratio of 0.74 mg/mg, with a reference below 0.5), with tubular phosphate reabsorption of 89% and a ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) of 1.67 mmol/L (reference 1.04–2.79) [61]. A CYP24A1 and SLC34A1 panel suggested a multiexon SLC34A1 deletion, and CMA (resolution of about 300 kb) showed a heterozygous deletion of about 2.2 Mb at 5q35.3 including NSD1 and SLC34A1 [61].

Vitamin D was stopped and a normocalcaemic, phosphorus-rich diet was instituted; when 25(OH)-vitamin D fell and episodes of hypercalciuria linked to excess dietary calcium appeared, colecalciferol was cautiously reintroduced with biochemical monitoring, without signs of rickets [61]. The calcium/creatinine ratio fell to 0.08 at 4 years, 0.15 at 7.5 years and 0.19 at 10 years, nephrocalcinosis was no longer visible on ultrasound from 8 years, and creatinine and glomerular filtration rate remained normal [61]. At 10 years, the boy was non-verbal but had preserved comprehension and followed simple commands, with global hypotonia, independent walking and marked valgus of the feet and knees; the parents were not tested [61].

The case illustrates the contiguous gene syndrome of the 5q35 microdeletion and the need to define the extent of the deletion, because loss of SLC34A1 modifies vitamin D management [1, 61]. The management described is specific to this deletion and does not represent practice for all patients with Sotos. The authors proposed screening calciuria and phosphaturia every 3 months in the first two years and performing renal ultrasound every 6 months in all children with Sotos, a proposal based on a single case that diverges from GeneReviews, for which renal ultrasound is a baseline investigation directed at structural anomalies and VUR [1, 61]. This patient's sacrococcygeal teratoma corresponds to one of the tumours with an absolute risk of about 1% in the syndrome [1].

10.2. Pineoblastoma with biallelic NSD1 inactivation

In 2026, Borja and colleagues described a first-born girl of non-consanguineous parents of Haitian and Puerto Rican ancestry, with stable mild prenatal ventriculomegaly and normal early development [49]. At 2.5 years she presented with persistent vomiting; MRI showed obstructive hydrocephalus and a 1.7 × 1.4 cm pineal region mass, and biopsy revealed a pineoblastoma (World Health Organization grade 4), classified by methylation profiling as MYC/FOXR2-activated [49]. Examination showed marked macrocephaly (head circumference 55 cm, z=+5.0), height of 107 cm (z=+4.1) and weight of 18.4 kg (z=+2.4), with a prominent forehead, long face, hypertelorism, downslanting palpebral fissures and a broad nasal root [49]. Trio exome sequencing identified the de novo variant NM_022455.5:c.3584dup p.(Val1196CysfsTer7), classified as pathogenic, and tumour exome sequencing a second truncating variant, c.4591dup p.(Met1531AsnfsTer4), with an allele frequency of 39% [49]. The child was treated according to the Children's Oncology Group ACNS0034 protocol, with induction chemotherapy, complete resection, high-dose chemotherapy with autologous stem cell rescue and 54 Gy proton therapy, and had no evidence of disease seven months after treatment [49]. Figure 1 of the article (MRI, Sanger chromatograms of the trio and visualisation of the two variants in the tumour) was consulted through the legends in the full text [49]. The authors maintain that routine oncological screening is not recommended, and the case reinforces the prompt assessment of new neurological symptoms, such as persistent vomiting [19, 49].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Life expectancy is not quantified in the sources consulted, but adults are generally healthy with few new medical problems; the oldest published patient was 63 years old [2, 68, 69]. The level of intellectual disability tends to remain stable, height often normalises in the adult and macrocephaly persists [1, 69]. Many childhood complications (neonatal complications, septal heart defects, conductive hearing loss) are self-limiting, and scoliosis rarely requires surgery [1]. Functional prognosis depends mainly on the degree of intellectual disability and on behaviour, and the capacity for independent living ranges from full autonomy to full dependence [1, 69]. Microdeletions are associated with more severe intellectual disability [8, 68]. The overall risk of childhood cancer is low (≤3–5%) and does not justify screening [19].

11.2. Surveillance

GeneReviews assigns an explicit interval ("at each visit") to only some of the assessments and leaves the rest to clinical indication or to the specialist; it recommends regular review by the paediatrician for young children, patients with many complications and families with greater needs, and less frequent review for older children and adolescents without complications, without a numerical interval [1]. In the practice of a Barcelona centre, follow-up included an annual multidisciplinary genetics and paediatric neurology clinic with anthropometry, dysmorphology and spinal examination, six-monthly endocrinology, oncological assessment after confirmation, echocardiogram and renal ultrasound at diagnosis, systematic referral to audiology and a case manager [52]. This protocol is the practice of one centre and not a society recommendation [52].

Tumour screening is not recommended: the absolute risk of sacrococcygeal teratoma and of neuroblastoma is about 1%, neuroblastoma screening did not reduce mortality and generates false positives, and the risk of Wilms tumour is not significantly increased, so routine renal ultrasound is not indicated [1, 20, 117, 118]. There is also no screening for subpleural blebs; with sudden dyspnoea, pneumothorax should be considered [81]. The proposal to screen calciuria and phosphaturia in all children, based on one case, is not part of the recommendations [61].

12. Summary and Final Considerations

Sotos syndrome is the most frequent genetic cause of overgrowth with intellectual disability and results from haploinsufficiency of NSD1, an H3K36 methyltransferase that regulates DNA methylation and antagonises the PRC2 complex. Diagnosis rests on the triad of characteristic facial gestalt, learning disability and overgrowth, present in at least 90% of carriers, but about 10% have normal height and head circumference and the facial gestalt becomes more subtle with age, so normal growth or adulthood does not exclude the hypothesis. Confirmation is by NSD1 sequencing and copy number analysis, or by panel, exome or genome, and the methylation episignature resolves negative cases and variants of uncertain significance. Outside Japan intragenic variants predominate and about 10% of cases have a 5q35 microdeletion; in Japan, the 1.9 Mb common deletion mediated by low-copy repeats accounts for about half. Microdeletions are associated with less marked overgrowth, more severe intellectual disability and, depending on the genes included, additional manifestations, such as factor XII deficiency or nephrocalcinosis due to loss of SLC34A1.

The natural history is dominated by transient neonatal complications, developmental delay, behaviour and frequent but generally treatable systemic manifestations: heart disease, renal anomalies with VUR, scoliosis, seizures, ocular and auditory problems and, in a minority, hyperinsulinism, which may be persistent and generally responds to diazoxide. There is no specific therapy or interventional trial, and management is multidisciplinary, with baseline cardiac, renal, ophthalmological and audiological assessments, early intervention and clinical surveillance at each visit. The risk of childhood cancer is low (about 3%), with a Wilms risk below 1%, and North American and European recommendations agree on not performing tumour screening, unlike Weaver syndrome, in which neuroblastoma surveillance is recommended. Almost all cases are de novo, with a low but non-zero recurrence risk due to germline mosaicism, and affected individuals transmit the alteration to 50% of their offspring with unpredictable expressivity. Adults are generally healthy, with stable intellectual disability and often normalised height, and the lack of specific guidance for adulthood and of population-based prevalence studies are the main gaps.

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