Overgrowth Syndromes – Diagnostic Approach

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition of overgrowth and scope of the article

Overgrowth is defined as excessive growth, global or regional, compared with an equivalent body part or with a peer group of the same age; by convention a parameter more than 2 standard deviations (SD) above the mean is considered excessive, which corresponds approximately to the 98th centile [1]. A child with increased height and head circumference (HC) is suspected of having an overgrowth syndrome when there is also intellectual disability (ID) or a congenital anomaly; regional overgrowth frequently affects one or more limbs and may be static or progressive [1]. Tall stature has no definition of its own beyond this statistical criterion, and children above the 95th centile are referred less often than children with short stature, which delays recognition of pathological forms [5].

The review by Manor and Lalani describes three phenotypes under the term overgrowth [5]. Prenatal overgrowth corresponds to the newborn who is large for gestational age, macrosomic (more than 4000 g) or with length and weight at or above the 97th centile; maternal diabetes and Beckwith-Wiedemann-type syndromes are the initial considerations, and the child may maintain accelerated growth or return to the normal range [5]. Postnatal overgrowth arises in childhood or adolescence and corresponds, in most cases, to hormone-dependent growth (thyroid, growth hormone, sex steroids, glucocorticoids), familial tall stature, precocious puberty, obesity or syndromes such as Marfan, homocystinuria, Klinefelter and 47,XYY [5]. Segmental overgrowth is limited to one or a few regions (a digit, a limb, a hemiface or the head) and often results from mosaic activation of the phosphoinositide 3-kinase (PI3K), protein kinase B (AKT) and mammalian target of rapamycin (mTOR) pathway [5].

This article covers the class of overgrowth syndromes as a clinical approach problem: how to measure and classify the growth pattern, which syndromes to consider for each pattern, which tests to request and in which tissue, and which tumour surveillance corresponds to each diagnosis. The following entities are described here mainly in terms of what distinguishes them from one another: Beckwith-Wiedemann spectrum, Sotos syndrome, PIK3CA-related overgrowth spectrum (which includes Klippel-Trenaunay syndrome), Weaver syndrome and Polycomb repressive complex 2-related overgrowth, Simpson-Golabi-Behmel syndrome, Proteus syndrome, Tatton-Brown-Rahman syndrome, PTEN hamartoma tumour syndrome, Pallister-Killian syndrome, Wilms tumour predisposition, fragile X syndrome, Klinefelter syndrome, Marfan syndrome, homocystinuria, McCune-Albright syndrome, RASopathies and congenital hyperinsulinism. The rarer entities (Malan and Marshall-Smith syndromes, Perlman syndrome, CHD8-related neurodevelopmental disorder with overgrowth, SETD2-related disorders, Smith-Kingsmore syndrome, skeletal overgrowth due to excess C-type natriuretic peptide, Kosaki syndrome, isolated lateralised overgrowth and genome-wide paternal uniparental disomy in mosaic form) are described in greater detail.

1.2. Classifications in use

Classification by growth pattern distinguishes global overgrowth (prenatal, postnatal or both), segmental or lateralised overgrowth and macrocephaly disproportionate to height [1, 4, 5]. Macrocephaly is defined, in the Oxford Desk Reference, as HC more than 3 SD above the mean for age, and is assessed relative to length or height to separate proportionate macrocephaly in global overgrowth syndromes from isolated macrocephaly [4]. Manor and Lalani consider that an HC at or above the 98th centile may be associated with autism spectrum disorder (ASD) or ID even without other findings, and that an HC greater than 3 SD (99.7th centile or above) is highly suggestive of PTEN hamartoma tumour syndrome (PHTS) [5].

For asymmetry, an international consensus proposed in 2017 replacing hemihyperplasia and hemihypertrophy with the term lateralised overgrowth, defined as a significant increase in the length and/or circumference of most or all of one side of the body compared with the contralateral side [2]. The rationale was threefold: the terms hyperplasia and hypertrophy are histological and there is rarely histological proof; the prefix hemi suggests that overgrowth affects the same half of the body, when it may be crossed; and in many patients it is not known whether one side has grown too much or the other too little [2]. The definition excludes oedema, does not require organ enlargement and does not set a significance threshold, because inspection, palpation and measurement are not sufficiently reliable; the authors estimate that differences of 10% in length or circumference are usually detectable and that three-dimensional imaging or densitometry techniques need normative values [2]. Isolated lateralised overgrowth (formerly isolated hemihyperplasia) is lateralised overgrowth without a recognisable pattern of major or minor malformations; it is probably heterogeneous, and careful phenotyping has already separated from it Proteus syndrome, CLOVES syndrome and hemihyperplasia with multiple lipomatosis [2].

The aetiological classification groups the monogenic syndromes into two main families, genes of epigenetic regulators and genes of components of the PI3K/AKT/mTOR pathway, to which are added imprinting disorders of the 11p15 region, chromosomal abnormalities and skeletal overgrowth syndromes [1, 7]. In the PI3K/AKT/mTOR pathway, both activating variants in components of the cascade (AKT1, AKT3, PIK3CA, PIK3R2) and inactivating variants in pathway inhibitors (PTEN) cause overgrowth [1]. The designation overgrowth with intellectual disability (OGID), used in the British Childhood Overgrowth study, applies to individuals with height and/or HC at or above +2 SD at some point in childhood and with ID; in that study's cohort of 710 patients, epigenetic regulation genes accounted for 44% of cases [3]. The Beckwith-Wiedemann spectrum (BWSp) is a clinico-molecular classification that includes the classical syndrome, the atypical form and isolated lateralised overgrowth with an 11p15 (epi)genetic alteration [58]. Orphanet groups these disorders in the categories Overgrowth syndrome (ORPHA:93460) and Genetic overgrowth/obesity syndrome (ORPHA:183573) [14, 15].

1.3. Historical milestones

Sotos syndrome was described by Sotos and colleagues in 1964, in five patients with cerebral gigantism [59]. Beckwith-Wiedemann syndrome was published by Wiedemann in 1964 and by Beckwith in 1969 [60]. Marshall and Smith described in 1971 the syndrome of accelerated skeletal maturation with failure to thrive that bears their name, and Weaver and colleagues described in 1974 two boys with overgrowth, accelerated skeletal maturation, unusual facies and camptodactyly [61, 62]. Simpson-Golabi-Behmel syndrome brings together the descriptions of Simpson (1975), Behmel and Golabi and Rosen (both 1984), recognised as the same entity by Neri and by Opitz in 1988 [63].

The molecular era brought genes for almost all these entities [1]. The Oxford Desk Reference cites the identification of EZH2 variants in Weaver syndrome by Tatton-Brown and colleagues in 2011, of the mosaic AKT1 variant in Proteus syndrome by Lindhurst and colleagues in 2011, of DIS3L2 variants in Perlman syndrome by Astuti and colleagues in 2012 and of germline and postzygotic AKT3, PIK3R2 and PIK3CA variants in the megalencephaly syndromes by Rivière and colleagues in 2012 [1]. In 2010, Malan and colleagues showed that NFIX variants subject to nonsense-mediated messenger RNA decay cause a Sotos-like picture, whereas those that escape this decay cause Marshall-Smith syndrome [25, 64]. In 2017, the study of 710 individuals with OGID added HIST1H1E (now H1-4) to the list of genes and estimated the relative contribution of 14 genes [3].

1.4. Nomenclature

The designation Sotos syndrome type 2 for the NFIX-related disorder is outdated and has been replaced by Malan syndrome [25]. The SETD2-related disorder with macrocephaly and overgrowth is also known as Luscan-Lumish syndrome or Sotos-like syndrome [27]. The EED-related disorder is sometimes called Cohen-Gibson syndrome and the SUZ12-related disorder Imagawa-Matsumoto syndrome [25, 62]. The term “cerebral gigantism”, applied to Sotos syndrome, has fallen out of use [59].

In OMIM, entry 117550 is now called Sotos syndrome (formerly Sotos syndrome 1); the CHD8-related disorder is designated intellectual developmental disorder with autism and macrocephaly (615032); the PPP2R5D-related disorder corresponds to Houge-Janssens syndrome 1 (616355); overgrowth due to NPR2 gain of function corresponds to epiphyseal chondrodysplasia, Miura type (615923); the megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndromes types 1 and 2 correspond to PIK3R2 (603387) and AKT3 (615937); entry 614846 describes tetrasomy 15q26-qter; and isolated hemihyperplasia retains its own entry (235000) [11, 13, 55, 65–69].

2. Molecular Genetics and Pathophysiology

2.1. Two main pathways: epigenetic regulation and PI3K/AKT/mTOR signalling

In the British cohort of 710 individuals with OGID, functional enrichment analysis of the 14 causal genes identified two significant sets: chromatin binding (false discovery rate, q = 1.58 × 10⁻⁶) and the PI3K/AKT signalling pathway (q = 6.80 × 10⁻⁵) [3]. The first set includes NSD1, EZH2, DNMT3A, EED, CHD8 and HIST1H1E, which together accounted for 311 of the 710 cases (44%) [3]. NSD1 is a histone methyltransferase that methylates lysine 36 of histone H3 (H3K36), associated mainly with transcriptional activation; EZH2 and EED are core components of Polycomb repressive complex 2 (PRC2), which methylates lysine 27 of histone H3 (H3K27) and represses target genes; DNMT3A is a DNA methyltransferase responsible for de novo methylation marks; CHD8 is an ATP-dependent chromatin remodeller that binds methylated H3K4; and histone H1.4, encoded by HIST1H1E, stabilises higher-order chromatin structures [3]. Smith's Recognizable Patterns of Human Malformation adds that NSD1 and SETD2 “write” the H3K36me mark and that DNMT3A “reads” it, which mechanistically links Sotos, Luscan-Lumish and Tatton-Brown-Rahman syndromes [59].

In the second set, the AKT3, MTOR and PIK3CA variants found in OGID are activating, whereas those in PTEN and PPP2R5D (which encodes the B56δ subunit of the PP2A phosphatase) inactivate suppressors of the pathway [3]. All 17 patients in the cohort with a variant in a PI3K/AKT pathway gene had macrocephaly, compared with 140 of 200 with a variant in an epigenetic gene [3]. Manor and Lalani stress that the PI3K/AKT/mTOR pathway responds to growth factors (epidermal, vascular endothelial, platelet-derived and insulin-like type 1), is linked to the RAS/MAPK pathway and is activated in many neoplasms; inactivation of PTEN, TSC1 or TSC2 can also cause segmental overgrowth [5].

Six of the 14 OGID genes are located in regions associated with height in genome-wide association studies, with overlap mainly for the epigenetic genes, and eight are somatically mutated in cancers (NSD1, EZH2, DNMT3A, PTEN, CHD8, HIST1H1E, MTOR, PIK3CA) [3]. In the PI3K/AKT pathway genes, the variant spectrum in OGID is similar to that in cancer; in the epigenetic genes, the germline and somatic spectra differ, which limits extrapolation from the somatic oncogenic role to constitutional tumour risk [3].

2.2. Imprinting of the 11p15 region

The 11p15.5 region contains two imprinted domains [5, 60]. In domain 1, imprinting centre 1 (IC1, H19/IGF2:IG-DMR) is methylated on the paternal allele, which silences H19 (a non-coding RNA that represses growth) and allows expression of IGF2 (a growth factor); on the maternal allele, the absence of methylation allows the CTCF protein to bind IC1 and insulate IGF2 from its enhancers [5]. In domain 2, imprinting centre 2 (IC2, KCNQ1OT1:TSS-DMR) is methylated on the maternal allele, which allows expression of the cell cycle inhibitor CDKN1C; on the paternal allele, the absence of methylation allows transcription of KCNQ1OT1, which silences CDKN1C [5]. Maternal gain of methylation at IC1, maternal loss of methylation at IC2, segmental paternal uniparental disomy of 11p15, loss-of-function variants in maternal CDKN1C and rearrangements with a parent-of-origin effect unbalance these domains and cause BWSp [5, 58]. IGF2 overexpression is observed in about 70% of Wilms tumours, which helps to explain the tumour predisposition [5].

2.3. Other mechanisms

In Simpson-Golabi-Behmel syndrome, loss of function of glypican 3 (GPC3, Xq26) alters Hedgehog signalling and growth control in the embryonic mesoderm [63]. In Perlman syndrome, biallelic loss of the exoribonuclease DIS3L2 impairs degradation of uridylated RNAs, including precursors of the suppressor microRNA let-7 [6]. In skeletal overgrowth syndromes due to excess C-type natriuretic peptide (CNP), hyperactivity of CNP/NPR2 signalling increases cyclic GMP, inhibits the MAPK pathway downstream of the FGFR3 receptor and accelerates endochondral ossification; the mechanism is the reverse of that of achondroplasia [7]. In Kosaki syndrome, a heterozygous variant in the juxtamembrane domain of platelet-derived growth factor receptor beta (PDGFRB) causes progressive overgrowth with lipodystrophy and neurological deterioration [8].

Chromosomal abnormalities associated with global overgrowth include 4p16.3 duplication (which contains FGFR3), 11p15 duplication (BWS), mosaic tetrasomy 12p (Pallister-Killian), duplication or triplication of 15q26 (which contains IGF1R), 5q35 deletion (Sotos), 19p13.2 deletion (Malan) and terminal 22q13 deletion [1].

2.4. Postzygotic mosaicism

A variant acquired after formation of the zygote is present only in tissues derived from the cell in which it arose; the phenotype depends on the timing, the tissue and the fraction of affected cells [1, 5]. PIK3CA variants of the PROS spectrum are typically acquired between days 20 and 56 after gastrulation, are located in mesodermal and neuroectodermal derivatives and are rarely germline [36]. Proteus syndrome results from a mosaic AKT1 variant, present in peripheral blood in only two known individuals and with an allele fraction below 1% in some tissues [33]. In Smith-Kingsmore syndrome, 20% to 25% of activating MTOR variants are postzygotic [28]. Mosaicism also occurs in classical constitutional disorders: in BWSp, the blood epigenotype does not always match that of the tumour or of the organ from which the tumour arises, and the level of mosaicism varies between tissues of the same individual [36].

2.5. Variant spectrum and nomenclature

The recurrent Proteus syndrome variant is written NM_001382430.1:c.49G>A, p.(Glu17Lys), in the MANE Select transcript of AKT1, as confirmed in VariantValidator; two individuals have the variant c.49_50delinsAG, p.(Glu17Arg) [33, 70]. In PIK3CA (NM_006218.4), the most cited recurrent variants are c.3140A>G p.(His1047Arg), c.1633G>A p.(Glu545Lys) and c.1624G>A p.(Glu542Lys), but many PROS spectrum variants lie outside codons 542, 545 and 1047, which limits hotspot-targeted tests [32, 70]. The SETD2 variant associated with the phenotype with multiple congenital anomalies is NM_014159.7:c.5218C>T, p.(Arg1740Trp) [27, 70]. In NFIX, Malan syndrome variants (loss of function, mainly in exon 2, which encodes the DNA-binding domain) undergo nonsense-mediated decay, and Marshall-Smith syndrome variants (truncating in exons 6 to 10, including a recurrent deletion of exons 6 and 7 mediated by AluY elements) escape it and produce a protein with a conserved binding domain and an altered C-terminus [25, 61, 71]. In EZH2, missense variants predominate, with some truncating variants in the last exon that spare the SET domain [1].

2.6. Table of entities and genes in the class

Table sources: genes, inheritance and mechanisms [1, 3, 7, 8, 10, 23, 25–29, 32–34, 61, 72]; cytobands [6]; OMIM numbers [11, 12, 40, 45, 46, 55, 65–69, 73–87].

2.7. NFIX: haploinsufficiency in Malan syndrome and dominant-negative effect in Marshall-Smith syndrome

NFIX encodes nuclear factor I/X, a member of the NFI (nuclear factor one) family of transcription factors; the gene has 11 exons, and the protein has an N-terminal DNA-binding and dimerisation domain followed by a C-terminal portion [44, 49]. Malan and colleagues showed in 2010 that NFIX is expressed in the brain and skeleton during human prenatal development and identified the two allelic syndromes by different routes [88]. Array comparative genomic hybridisation in 18 patients with undiagnosed syndromic overgrowth revealed two de novo 19p13 monosomies whose only common gene was NFIX, and sequencing of the gene in 76 patients found a de novo nonsense variant in exon 3 in a patient with a previous diagnosis of “Sotos-like” syndrome [44, 88]. The phenotype of Nfix-null mice (failure to gain weight, death in the first three weeks, spinal deformity and reduced bone mineralisation) led the same authors to sequence the gene in nine patients with Marshall-Smith syndrome: all had de novo variants, seven frameshift and two at the splice donor site of exon 6 [44, 88].

The effect on nonsense-mediated messenger RNA decay separates the two disorders. In patients' fibroblasts, the mutant messenger RNA of Malan syndrome is degraded, resulting in haploinsufficiency; the mutant messenger RNAs of Marshall-Smith syndrome escape this decay and encode abnormal proteins with a probable dominant-negative effect on the normal allele, which explains a more severe phenotype closer to that of the Nfix-null mouse [44, 88]. In the series by Schanze and colleagues, all 17 patients with a clinical diagnosis of Marshall-Smith syndrome had an NFIX alteration: ten had frameshift or splice variants, five had an almost identical deletion of exons 6 and 7, produced by recombination between AluY elements in introns 5 and 7, and two had smaller deletions involving exon 6 [44, 49]. The predicted proteins retained the DNA-binding and dimerisation domain and differed in the C-terminal portion, with no evident correlation between the site of the alteration and the phenotype, which made Marshall-Smith syndrome a genetically homogeneous disorder [49]. Martinez and colleagues, in Valencia, summarised the distribution of variants: those of Marshall-Smith syndrome are scattered across exons 6 to 10, and most point variants of Malan syndrome are concentrated in exon 2, including missense variants in the DNA-binding and dimerisation domain in patients with a marfanoid habitus and very low BMI [89]. In the international survey of carers of adults with Malan syndrome, 6 of 28 (21%) had a 19p13.2 microdeletion and the remainder intragenic variants, mainly in exons 2 to 4 [90].

2.8. DIS3L2 and Perlman syndrome

DIS3L2 (2q37.1) encodes a cytoplasmic 3'→5' exoribonuclease of 885 amino acids, with cold-shock domains, an RNB catalytic domain and an S1 RNA-binding domain; it differs from the homologous proteins DIS3 and DIS3L1 by its cytoplasmic localisation, the lack of a conserved PIN domain and its exosome-independent action [6, 41, 91]. It recognises RNAs with a 3' oligouridine tail and degrades deadenylated and uridylated messenger RNAs and the precursor of the microRNA let-7 uridylated by the uridyltransferases recruited by the LIN28 protein [6, 41]. Astuti and colleagues mapped the locus in 2012 by autozygosity mapping in a consanguineous Pakistani family and two Dutch families and identified a homozygous 82.8 kb deletion removing exon 6 and a homozygous deletion of about 22 kb removing exon 9 and part of the RNB domain, in addition to compound heterozygous variants in other patients [41, 91]. Inactivation of the gene in cells was associated with mitotic abnormalities and altered expression of mitotic checkpoint proteins; overexpression suppressed the growth of tumour cell lines and silencing increased it [91].

The mechanism of overgrowth and Wilms tumour has not been elucidated. In Dis3l2-null mice, which partly reproduce the syndrome (fetal overgrowth and urinary tract anomalies), loss of the gene did not alter mature let-7 levels and was associated with Igf2 overexpression in nephron progenitor cells, candidate cells of origin of Wilms tumour [35, 43, 92]. The exon 9 deletion is recurrent: in a Japanese patient, the paternal and maternal alleles had different junction points, both produced by non-allelic homologous recombination between LINE-1 elements, which points to a rearrangement hotspot rather than a founder effect [93].

The genotype–phenotype correlation is based on few patients. In the review by Meyer and colleagues (2025), 6 of 7 patients with molecular confirmation who died before 12 months had two loss-of-function variants, mainly homozygous deletions of exon 9 or exon 6, whereas 5 of 7 patients who lived more than 12 months had at least one variant compatible with residual protein (missense or splice) [43]. Examples normalised to the MANE Select transcript NM_152383.5 and confirmed in VariantValidator are c.1328T>A, p.(Met443Lys), in compound heterozygosity with c.367-2A>G in a Japanese girl alive at 6 years [70, 94]; c.127C>T, p.(Arg43Ter), with c.2381G>A, p.(Arg794His), in the S1 domain, in three North American siblings with an attenuated phenotype [43, 70]; and c.1466G>A, p.(Cys489Tyr), in compound heterozygosity with the exon 9 deletion in a fetus from the original study [41, 70, 91]. The p.(Arg794His) variant was classified by the laboratory as of uncertain significance and supported by the trans phase, segregation in three affected siblings and the absence of splicing alteration on RNA sequencing [43]. The correlation is not absolute, because a boy with a homozygous exon 9 deletion survived to 32 months [95].

Heterozygous germline DIS3L2 variants also predispose to Wilms tumour without the syndrome. In an international cohort of 34 children with Wilms tumour and a heterozygous pathogenic or likely pathogenic variant, recruited mainly in the SIOP-WT 2001, UMBRELLA and IMPORT studies, the exon 9 deletion was the germline event in 28; the median age at diagnosis was 40.5 months (8 to 101), five children had bilateral tumours, about one-third had metastases at diagnosis and the second somatic DIS3L2 event was found in almost all tumours with genetic data (19 of 20) [96]. A total of 17 carrier parents were confirmed, one of whom had had Wilms tumour, indicating low penetrance; the children had no recognisable phenotype, and haplotype comparison between unrelated Dutch carriers showed no common founder [96].

2.9. FIBP and Thauvin-Robinet-Faivre syndrome

FIBP (11q13.1; 10 exons in just over 5 kb; OMIM gene 608296) encodes the intracellular acidic fibroblast growth factor (FGF1)-binding protein, present in microsomal and mitochondrial membranes, the cytoplasm and the nucleus, which binds selectively to FGF1 and is thought to mediate its mitogenic action [6, 54, 97]. FGF receptors are tyrosine kinases that activate, downstream, the MAPK and PI3K/AKT pathways, involved in proliferation, differentiation, angiogenesis and the formation of bone, cartilage and vessels [54]. Thauvin-Robinet-Faivre syndrome (TROFAS) results from biallelic loss of function of the gene, with autosomal recessive inheritance [9, 98].

The mechanism of overgrowth has a paradoxical aspect: loss of a protein that mediates the mitogenic action of FGF1 is accompanied by more proliferation, not less. In the two families that defined the syndrome, patients' skin fibroblasts proliferated more than those of controls; in the patient homozygous for a nonsense variant, the FIBP transcript was reduced, which is compatible with nonsense-mediated decay [97–99]. Akawi and colleagues detected Fibp expression mainly in the brain of mouse embryos and related it to the cognitive phenotype [98]. The link between loss of FIBP and excessive growth remains unclear: the authors of the first report attributed it to an alteration of the FGF receptor pathway, and Şiraz and colleagues invoked data from tumour cell lines in which the protein regulates the mTOR/STAT3 pathway, noting that FIBP is overexpressed in colon and head and neck carcinomas; these are hypotheses, without demonstration in patient tissues [54, 99].

The variants described, normalised in VariantValidator to the MANE Select transcript NM_004214.5, are four, all biallelic [70]. The original patient was homozygous for c.652C>T p.(Gln218Ter) [97]. The three siblings reported by Akawi and colleagues were homozygous for the in-frame insertion c.175_176insTAA p.(His59delinsLeuAsn), published on transcript NM_198897.1 with the same numbering [70, 98]. In the five published Turkish families the same homozygous variant was found, described as NM_198897.2:c.415_416insCAGTTTG p.(Asp139AlafsTer3) by Duzenli and colleagues and as NM_004214.5:c.412-3_415dup p.(Asp139AlafsTer3) in subsequent reports; on the MANE transcript, VariantValidator describes it as a 7 bp duplication spanning the junction between an intron and the following exon, with a protein effect not predictable from DNA (p.?), and the consequence for RNA processing has not been studied [52, 54, 70, 100, 101]. Recurrence in unrelated Turkish families suggests a founder effect [9, 51]. The patient reported by Cosentino and colleagues, the daughter of non-consanguineous parents, was compound heterozygous for c.1003C>T p.(Arg335Ter) and c.497_498del p.(Ser166Ter) [53, 70].

There is no established genotype–phenotype correlation with 12 patients: the same recurrent variant was associated both with generalised overgrowth with macrocephaly and, in the patient reported by Şiraz and colleagues, with height and HC within the normal centiles together with soft tissue overgrowth and vascular malformations [54, 101]. The heterozygous father of the two siblings reported by Kılıç and Koşukcu had undergone nephrectomy for renal cell carcinoma and the paternal grandfather, a probable carrier, had had a renal tumour; the authors raised the hypothesis of renal tumour predisposition in heterozygotes, which has not been demonstrated [9, 101].

2.10. The CNP–NPR-B pathway: NPPC overexpression and NPR2 gain of function

C-type natriuretic peptide (CNP), encoded by NPPC (2q37.1; OMIM gene 600296), binds to natriuretic peptide receptor B (NPR-B), a transmembrane guanylyl cyclase encoded by NPR2 (9p13.3; OMIM gene 108961) [7, 55]. Receptor activation increases cyclic guanosine monophosphate (cGMP), inhibits the MAPK pathway of FGF signalling through FGFR3 and stimulates endochondral ossification at the growth plate [7]. Height varies with pathway activity: biallelic loss of function of NPR2 causes acromesomelic dysplasia, Maroteaux type, heterozygous loss causes short stature with normal body proportions [102], and excess activity, through overproduction of the ligand or a constitutively active receptor, causes skeletal overgrowth [7, 103]. Miura and colleagues grouped these two forms under the designation CNP/NPR2 overgrowth signalopathy, and the bone dysplasia atlas treats them as a single entity (overgrowth syndrome due to CNP overexpression), which includes epiphyseal chondrodysplasia, Miura type [7, 103].

NPPC overexpression was described in 2007 by Bocciardi and colleagues in a young woman with a marfanoid habitus and skeletal anomalies and a de novo balanced translocation t(2;7)(q37.1;q21.3) [104]. The breakpoint at 2q37.1 disrupted DIS3L2 (the Perlman syndrome gene, section 2.8) next to NPPC; plasma CNP was twice that of five controls, NPPC was overexpressed in fibroblasts and a transgenic mouse with bone-specific NPPC overexpression reproduced the phenotype [104]. Moncla and colleagues described in the same year two patients with a similar phenotype and balanced translocations between 2q37.1 and chromosomes 8 and 13, with NPPC overexpression and signs of generalised cartilage dysplasia; the clustering of breakpoints downstream of the gene, with three different partner chromosomes, led them to propose separation of NPPC from a negative regulatory element located on chromosome 2 as the mutational mechanism [105]. Ko and colleagues confirmed this model in a girl with t(1;2)(q41;q37.1), in whom the breakpoint lay 200,365 bp downstream of NPPC and serum NT-proCNP was raised; the other breakpoint disrupted TGFB2, whose haploinsufficiency causes Loeys-Dietz syndrome type 4, and the authors attributed the patient's aortic root dilatation to it [57]. A 4.5 Mb 2q37.1q37.3 deletion disrupting DIS3L2 at exon 6 was also accompanied by plasma CNP-22 more than four times that of controls and a marfanoid habitus, whereas an interstitial deletion that included NPPC itself resulted in short stature [106].

NPR2 gain of function was demonstrated in 2012 by Miura and colleagues in a three-generation Japanese family with the variant NM_003995.4:c.2647G>A p.(Val883Met), in the guanylyl cyclase domain: the mutant receptor produced cGMP without ligand and more cGMP than the wild type in the presence of CNP, patients' blood cGMP was raised and transgenic mice expressing the mutant in chondrocytes reproduced the elongation of the long bones, vertebrae and metatarsals [55, 70, 107]. There followed p.(Arg655Cys) (c.1963C>T), in the kinase homology domain, in a Dutch man at +5.2 SD, with increased cGMP production in fibroblasts and in transfected cells [108]; p.(Ala488Pro) (c.1462G>C), in a four-generation Korean family, active in the absence and presence of ligand [103]; a 6 bp deletion that stabilises the active conformation of the receptor, in a mother and two daughters [55]; and p.(Val883Met) again, in a Russian family [56]. The three missense variants were confirmed in VariantValidator on the MANE Select transcript NM_003995.4, without warnings [70]. Inheritance is autosomal dominant, with variable expressivity within the same family [55, 56]. As loss-of-function variants in the same gene cause short stature, a novel missense variant in NPR2 cannot be interpreted without a functional study of cGMP production [103, 108].

3. Clinical Spectrum and Manifestations by System

3.1. Normal growth as a reference

After birth, linear growth velocity falls to 15 to 17 cm per year in the first two years and to about 5 cm per year until puberty; the pubertal peak lies between 6 and 10 cm per year in girls and between 5 and 11 cm per year in boys [5]. According to the United States Centers for Disease Control and Prevention charts, final height between the 5th and 95th centiles ranges from 153 to 174 cm in women and from 165 to 189 cm in men; final height varies by 12% to 14% in the population, compared with 56% to 66% for final weight [5]. The growth plate is regulated by the Indian hedgehog/PTHrP pathway, bone morphogenetic proteins, the FGF/FGFR3 pathway (which inhibits proliferation), thyroid hormones, the growth hormone/IGF-1 axis and oestrogens, which close the growth plates at puberty; this physiology explains why precocious puberty accelerates growth but reduces final height [5].

3.2. Global overgrowth with prenatal onset

Prenatal overgrowth is characteristic of BWSp, Simpson-Golabi-Behmel syndrome, Perlman syndrome, Weaver syndrome and Sotos syndrome, and also of the infant of a diabetic mother [1, 5]. In BWS, the mean birth weight is 4 kg and length 52.6 cm; polyhydramnios, prematurity and placentomegaly are frequent [60]. In Sotos syndrome, the mean length at term birth is 55.2 cm and weight 3.9 kg, meaning that length is more increased than weight [59]. In Weaver syndrome, weight is more increased than length in early childhood, birth length is around 56 cm in boys and 53 cm in girls, and mean adult height is 194.2 cm in men and 176.3 cm in women, above +3.5 SD [62, 109]. In Simpson-Golabi-Behmel syndrome, birth weight reached 5.9 kg and seven of eight adults had height above the 97th centile (188 to 210 cm) [63]. In the infant of a diabetic mother, macrosomia is accompanied by a risk of neonatal hypoglycaemia and congenital malformations, mainly heart defects, neural tube defects and skeletal defects [1].

Prenatal overgrowth is not constant in all syndromes of the class: in BWSp it occurs in only 43% to 65% of patients [58]; in Malan syndrome about 15% of newborns are large for gestational age, although weight is above the mean in about 90% [25]; and in Marshall-Smith syndrome only a minority are large at birth, despite advanced bone maturation [71].

3.3. Global overgrowth with postnatal onset and evolution of height

In several syndromes, overgrowth attenuates with age, and adult height falls within the normal range. In Sotos syndrome, length remains at or above the 97th centile during childhood and early adolescence, but mean adult height is 182 cm in men and 174 cm in women, often within the normal range; macrocephaly is present in 50% at birth, in 100% at 12 months and in 86% in adulthood [59]. In BWS, length follows the 95th centile or above until adolescence and adult height is normal [60]; Manor and Lalani place final height between the 50th and 90th centiles in most [5]. In Malan syndrome, height exceeds +2 SD in 56% and adult height lies within 2 SD of the mean in about two-thirds [25]. In the CHD8-related disorder, macrocephaly arises mainly in early childhood and tall stature mainly at puberty [26]. In Tatton-Brown-Rahman syndrome, tall stature is accompanied by increased weight, often with rapid gain in late childhood [1]. In Marshall-Smith syndrome, adults have short stature [61].

Postnatal tall stature without a syndrome is, in most referred children, idiopathic tall stature, familial or non-familial [37]. The main secondary causes are precocious or pseudoprecocious puberty, hyperthyroidism, growth hormone excess and obesity; obesity accelerates growth and bone age, but adult height is normal [37]. Klinefelter syndrome, with an incidence of 1.0 to 1.5 per 1000 births, is the most frequent primary cause, but only 10% of patients are diagnosed before puberty because height is often within the population range and the signs are subtle [37].

3.4. Macrocephaly

Macrocephaly is the manifestation that most closely links the PI3K/AKT/mTOR pathway syndromes: in the OGID cohort, all patients with a variant in this pathway had macrocephaly [3]. In PHTS, birth weight is usually above +2 SD but the phenotype is dominated by macrocephaly above the 99.6th centile, and the Oxford Desk Reference reports HC frequently above 4.5 SD, mild proximal myopathy in 60%, delay in 70% and seizures in 25% in a synthesis predating the current molecular era [1, 4]. In fragile X syndrome, HC is usually near the 75th centile, linear growth is slightly accelerated in the first years and motor delay may suggest Sotos [4, 110]. In an Israeli community study of more than 4000 children with a neurodevelopmental disorder, 1.4% had macrocephaly (HC above the 98th centile), with a 7.7-fold increased risk of seizures; idiopathic infantile macrocephaly was associated, in another study, with ASD with an odds ratio of 5.44 [4].

3.5. Lateralised and segmental overgrowth

Minor asymmetry is frequent in the population; a limb length difference greater than 1 cm with a measurable difference in circumference should be considered abnormal [111]. Asymmetry due to overgrowth is more common in a large child or one with normal development, and asymmetry due to undergrowth is more likely in chromosomal mosaicism, with delay, growth restriction and dysmorphism [111]. Lateralised overgrowth occurs in about 25% of patients with BWSp, may not be evident at birth and tends to attenuate [5]; its overall incidence is estimated at between 1 in 13,000 and 1 in 86,000 live births [35].

The rate of progression distinguishes the main mosaic entities. In Proteus syndrome, asymmetry is slight at birth, overgrowth is distorting and highly progressive in early childhood and changes little after adolescence; IQ is usually normal [33, 111]. In the megalencephaly-capillary malformation family of syndromes and related conditions, overgrowth may be present before birth and progresses less aggressively [111]. In Klippel-Trenaunay syndrome, the lower limb is involved in 95% of cases and the upper limb in 5%, and 15% have combined involvement of the upper and lower limbs; the source presents the three percentages without a common denominator and they are not mutually exclusive (they add up to more than 100%), so they indicate only the clear predominance of the lower limb [111]. The malformation is capillary, lymphatic and venous, with frequent lymphoedema [111]. In Parkes Weber syndrome, capillary malformation is associated with arteriovenous fistulae and limb hypertrophy, due to RASA1 variants in some patients [111]. A 2026 Italian cohort of 41 children with vascular malformation and regional overgrowth without a PIK3CA variant found variants in TEK (24.4%), GNAQ (21.9%), GNA11 (21.9%), PTEN (14.6%), RASA1 (12.2%), AKT3 and EPHB4 (2.4% each), 65.9% somatic, with skeletal anomalies in 46.3%, soft tissue overgrowth in 60.9%, macrocrania in 19.5% and functional limitation in 43.9%; phenotypic overlap between genes made classification by phenotype unreliable [112].

3.6. Malan syndrome

Malan syndrome is characterised by prenatal and postnatal overgrowth, macrocephaly, advanced bone age or skeletal anomalies, slender habitus, typically moderate to severe ID, an anxious behavioural profile, attention deficit hyperactivity disorder (ADHD) and ocular abnormalities [25]. The face is long and triangular, with a high anterior hairline, prominent forehead, depressed nasal bridge, deep-set eyes, down-slanting palpebral fissures, short nose with anteverted nares, long philtrum, small mouth held open, thin upper lip, everted lower lip and prominent chin [25]. In a detailed phenotyping series of 16 patients and in published series, the distinctive face, macrocephaly and ID were present in all; slender habitus in 16 of 16; advanced bone age in 76%; abnormal spinal curvature in 12 of 16; flat feet in 11 of 16; long bone fractures in 5 of 16; refractive errors in 75%; strabismus in 10 of 16; blue sclerae in 11 of 16; optic nerve hypoplasia in 25%; epilepsy or electroencephalographic abnormalities in 10 of 16; autonomic signs (episodic ataxia with dizziness and nausea, postural syncope) in 4 of 16; neurobehavioural manifestations in 12 of 14, with hypersensitivity to noise in 10 of 15; constipation in 8 of 16; and a body mass index (BMI) below −2 SD in 6 of 16, despite normal food intake [25]. Four patients had aortic root dilatation, and one adult had progressive dilatation with dissection at 38 years [25]. Patients with a 19p13.2 deletion including contiguous genes have more seizures than patients with an intragenic variant, possibly owing to deletion of CACNA1A, located about 109 kb from NFIX [25]. A rib osteosarcoma and a Wilms tumour have been described, corresponding to a prevalence of malignant neoplasia of about 2% in the published series [25].

The natural history in adulthood was described in a survey of carers of 28 adults with a molecular diagnosis (16 men and 12 women, 18 to 60 years, median 23.5 years), recruited in eight countries in Europe, the Americas and Oceania with the patient foundation and the Naples and Amsterdam centres [90]. Only 9 (32%) maintained height above +2 SD, but HC was above +2 SD in the 16 adults with a measurement, and mean height was 185.7 cm in men (+1.29 SD) and 177.3 cm in women (+2.18 SD) [90]. Psychobehavioural (96%; anxiety in 79%, restricted interests, stereotypies and echolalia in 50%, autistic traits in 46%), musculoskeletal (96%; hypotonia in 75%, scoliosis in 64%, with spinal surgery in 8 of the 18 with scoliosis), visual (96%; strabismus in 57%, declining vision in 36%, optic atrophy in 32%) and neurological (86%) manifestations dominated the picture [90]. Seizures or electroencephalographic abnormalities occurred in 46%, with onset in adulthood in three patients with an intragenic variant, and aortic dilatation or valvular disease in 29%; a high pain threshold (46%), incontinence (25%), tremor (21%), cataracts at 4, 13 and 22 years, obesity (11%) and underweight (21%) were also described [90]. Verbal communication was present in 82% and had improved with age in 16 of 21; no adult was independent in activities of daily living, 86% lived with their family and 29% had supervised employment [90]. The data depend on carer report, and signs such as ataxia were not confirmed by examination [90]. A North American series of eight patients with a literature review, published in 2026, added ophthalmological findings and episodes of respiratory difficulty to the phenotype and updated the management recommendations [113].

3.7. Marshall-Smith syndrome

Marshall-Smith syndrome combines accelerated linear growth and skeletal maturation of prenatal onset with low weight for length and failure to thrive, with short stature in adulthood [61]. Estimated bone age in the neonatal period ranges from three to four years; the proximal and middle phalanges are broad and the distal ones narrow (“bullet-shaped phalanges”), the long bones are overtubulated and osteopenia and bone fragility increase with age [71]. The facies includes a prominent forehead, shallow orbits with proptosis, blue sclerae, a short upturned nose and micrognathia [61]. Upper airway obstruction, at several levels, and recurrent pneumonia caused early death in the first patients described; with aggressive airway management, many survive into adulthood, often with a tracheostomy [61]. ID is moderate to severe, with very limited speech; cervical stenosis may compress the spinal cord, and kyphoscoliosis is progressive [61].

The most extensive clinical delineation brought together 15 new patients and an update of 4 already published, the oldest aged 30 years, in an international collaboration with data collection on a wiki platform [114]. The main manifestations were moderate to severe developmental delay with absent or limited speech, unusual behaviour, disharmonic bone maturation, respiratory compromise due to upper airway obstruction, short stature and kyphoscoliosis; the face had a high forehead, midface hypoplasia, proptosis, anteverted nares and everted lips, and minor changes in brain morphology, such as hypoplasia of the corpus callosum, were frequent [114]. Microarray in 12 patients showed no clinically relevant copy number variants, before the gene was identified [114]. In the literature compilation up to 2020, abnormal bone maturation was present in 57 of 57 patients, prominent forehead in 55 of 57, proptosis in 55 of 56, airway obstruction in 45 of 55, height below the 3rd centile in 38 of 39 and moderate to severe ID in 57 of 57 [50]. Adam and colleagues, in a series of five children and a review of three others, described non-traumatic fractures and other bone and connective tissue changes that led to the syndrome being classified as an osteochondrodysplasia, and showed that survival beyond infancy is possible with anticipatory and aggressive treatment of respiratory problems [115].

The developmental profile differs from that of Malan syndrome. In an exploratory study of six children, delays in mental age, motor skills and adaptive functioning were moderate to severe, with a friendly mood, enjoyment of interaction with familiar people and few maladaptive behaviours, but with deficits in reciprocal communication, limited imaginative play and stereotyped behaviours [116]. In a direct comparison between eight patients with Marshall-Smith syndrome and seven with Malan syndrome, the mean developmental age was 15.9 months (9 to 26) in the former and 39.5 months (24 to 66) in the latter; patients with Marshall-Smith syndrome, who were younger, had more severe ID, adaptive functioning below the 0.1st centile in all domains in the three assessed, expressive speech limited to a few words and less reciprocal interaction, and sensory processing difficulties were common to both syndromes [50].

3.8. Perlman syndrome

Perlman syndrome, autosomal recessive and very rare, combines prenatal and postnatal overgrowth, polyhydramnios, nephromegaly and a facies with a broad flat nasal bridge, an everted inverted-V upper lip, deep-set eyes and low-set ears [1]. Nephroblastomatosis occurs in about 75% of patients and neonatal mortality is high, due to renal failure, hypoxaemia and pulmonary hypoplasia [1]. According to the European host genome group of the International Society of Paediatric Oncology, more than half of children die in the first year of life, from respiratory failure, sepsis or renal failure [35].

The syndrome was described by Liban and Kozenitzky in 1970 and by Perlman and colleagues in 1973, in five children of second-cousin parents of Yemenite Jewish origin, with macrosomia, bilateral renal hamartomas with or without nephroblastomatosis, hypertrophy of the islets of Langerhans and unusual facies; maximum survival was 27 days, and a sixth child, described in 1975, developed Wilms tumour [40]. The review by Alessandri and colleagues (2008), based on a newborn from Réunion Island and 28 published patients, confirmed the high neonatal mortality, mainly due to respiratory distress with refractory hypoxaemia and renal failure in the first hours or days of life; among those who survived the neonatal period, 64% developed Wilms tumour and all had developmental delay [42]. The tumour arises earlier than sporadic Wilms tumour (before 2 years, compared with 3 to 4 years) and is bilateral in 55% of cases [40]. A North American review, which counts all patients and not only survivors, reports nephromegaly in 80% to 100%, death in the first hours or days in about 87% and Wilms tumour in about one-third [5]. The Oxford Desk Reference gives a Wilms tumour incidence of 25% to 50%, lower than the 64% to 70% of the surveillance guidelines, which refer to survivors of the neonatal period [35, 36, 117].

Findings described in isolated cases or small series include fetal ascites without hydrops, hypoplasia of the abdominal musculature, diaphragmatic hernia, interrupted aortic arch, volvulus and ileal atresia, agenesis of the corpus callosum, choroid plexus haemangiomas, portal hepatic fibrosis, cleft palate, thymic hyperplasia and cryptorchidism; hyperinsulinism has been suggested as a potentially preventable cause of death [40]. In a newborn of Albanian parents, the enlarged kidneys with multiple microcysts were indistinguishable, on ultrasound and MRI, from those of polycystic kidney disease [40].

Survivors beyond the first year are a minority: by 2025 nine patients aged over one year had been described, three with molecular confirmation [43]. Meyer and colleagues (Ohio, 2025) described three siblings with compound heterozygous DIS3L2 variants and an attenuated phenotype, children of non-consanguineous parents with two other healthy children [43]. All three were born with macrosomia (3.8 to 4.6 kg, +2.0 to +2.1 SD), facial hypotonia and a facies with prominent forehead, everted upper lip, depressed nasal bridge and deep-set eyes; all had developmental delay, obstructive sleep apnoea syndrome and one slightly enlarged kidney for age [43]. The sister developed a stage 2 Wilms tumour at 3 years, with metastatic relapse at 6, and the brothers had normal ultrasound scans at 10 and 2 years; the eldest also had cricopharyngeal achalasia, autism spectrum disorder, attention deficit hyperactivity disorder and mild spastic diplegia [43]. In the seven patients with molecular confirmation who lived more than 12 months, macrosomia, developmental delay and facial dysmorphism (with an everted upper lip in all) were present in all, hypotonia in 6, nephromegaly in 5, brain MRI abnormalities in 4, Wilms tumour in 3 (mean age 4.3 years) and obstructive apnoea in 3 [43]. In all published survivors, with or without molecular confirmation, the mean age at diagnosis of Wilms tumour was 2.4 years, with one diagnosis at 6 years [43]. Height normalises in childhood: at 9 and 10 years, the two older siblings had heights between −0.34 and +0.33 SD [43].

3.9. Other rare monogenic syndromes

CHD8-related neurodevelopmental disorder with overgrowth combines generalised overgrowth, developmental delay, usually mild to moderate ID, ASD, sleep disturbance with difficulty initiating and maintaining sleep, and constipation; hypotonia occurs in about 30%, seizures in 10% to 15% and Chiari I malformation is rare [26]. SETD2-related neurodevelopmental disorders include a form with macrocephaly, ventriculomegaly, Chiari I malformation or syringomyelia, obesity with generalised overgrowth and advanced bone age, and a form with multiple congenital anomalies associated with the p.(Arg1740Trp) variant, with microcephaly and growth restriction [27]. Smith-Kingsmore syndrome, due to activating MTOR variants, combines variable overgrowth, macrocephaly, moderate to severe ID, verbal speech in about half of patients, epilepsy, hyperphagia, sleep disturbance, stable aortic root dilatation and genitourinary anomalies in boys [28]. The EED-related disorder presents with fetal or early childhood overgrowth (tall stature, macrocephaly, large hands and feet, advanced bone age) and mild to severe ID, with a risk of cervical spine instability [23].

3.10. Skeletal overgrowth syndromes

Overgrowth due to excess CNP (epiphyseal chondrodysplasia, Miura type) causes birth length and height between +3 and +6 SD, a tall proportionate or marfanoid habitus, long and broad halluces, arachnodactyly, kyphoscoliosis and, sometimes, arterial hypertension in adulthood; it results from chromosomal rearrangements involving NPPC (2q37.1) or from gain-of-function variants in NPR2 [7]. Moreno-Nishimura-Schmidt syndrome, known in four patients, causes birth length between +2.6 and +6.6 SD and height between +6.8 and +8.5 SD, with skull base hyperostosis, megaspondyly and megaepiphyses; the genetic basis is unknown and one patient died suddenly in adolescence [72]. Kosaki syndrome, known in five patients at the time of Smith's, has normal prenatal growth, acceleration in infancy and childhood, progressive neurological deterioration, lipodystrophy with a progeroid appearance at around eight years and myofibromas [8].

3.11. Tumours

Tumour predisposition distinguishes the overgrowth syndromes from one another more than any other manifestation, and the figures are gathered in section 11. Embryonal tumours (Wilms, hepatoblastoma, neuroblastoma, rhabdomyosarcoma, adrenocortical carcinoma) predominate in BWSp, Simpson-Golabi-Behmel syndrome and Perlman syndrome [36]; neuroblastoma predominates in Weaver syndrome and in BWSp due to a CDKN1C variant [39]; haematological neoplasms occur in Tatton-Brown-Rahman syndrome [24]; benign and malignant tumours of the thyroid, breast and endometrium dominate PHTS from adolescence onwards [1]; and Proteus syndrome is associated with meningiomas, ovarian cystadenomas and a modest increase in several tumours [33]. In Sotos, Malan, CHD8 and EED syndromes, tumour risk is low or not demonstrated [21, 23, 25, 26].

3.12. Thauvin-Robinet-Faivre syndrome

Thauvin-Robinet and colleagues described in 2016 a 23-year-old man, the son of consanguineous North African parents, born at term with macrosomia and macrocephaly, with persistent overgrowth during childhood, developmental delay with language disorder and severe learning difficulties [9, 99]. He also had retinal coloboma, ventricular septal defect, mitral valve prolapse, renal malrotation with a left bifid ureter, transient neutropenia and severe varicose veins, operated on at 21 years together with an inguinal hernia; the palpebral fissures were long and down-slanting, the ears large and prominent, the lips thick, there was macroglossia, and the hands and feet were large, with large thumbs and halluces; brain imaging and cardiac function were normal [9]. In the same year, Akawi and colleagues described three siblings, aged 14, 10 and 3 years, children of consanguineous Arab parents, with tall stature, mild delay of developmental milestones, ID and a round face with widely spaced deep-set eyes, epicanthus, flat midface and full lips [9, 98]. The eldest sister had a ventricular septal defect, double-chambered right ventricle, sensorineural deafness and astigmatism, and developed Wilms tumour at 4 years; the middle brother had clubfoot, internal rotation of the femora and tibiae, bowing of the legs and spina bifida occulta; the youngest had nephromegaly with cystic dysplastic kidneys and a non-functioning right kidney [9]. Orphanet records the entity as tall stature-intellectual disability-renal anomalies syndrome (ORPHA:500095) [18].

Subsequent reports came mainly from Turkey. Duzenli and colleagues described a 4-year-old boy, the son of first cousins, with generalised overgrowth, developmental delay, sialorrhoea, recurrent pulmonary infections with chronic lung disease, hyperextensible elbows, hypoplastic nipples, unilateral cryptorchidism and frequent spontaneous erections [100]. In a Turkish cohort of 35 children with overgrowth and ID, with a diagnostic yield of 88% (31 of 35), one boy had TROFAS and presented at 6.5 months with macrocephaly, developmental delay, pectus excavatum, inverted nipples, umbilical hernia and coxa valga, and only later had tall stature [9, 118]. The two siblings reported by Kılıç and Koşukcu had macrocephaly, tall stature, developmental delay, mild ID and facial dysmorphism; one of them had scoliosis, skin striae attributed to rapid growth and a dysplastic and atrophic right kidney [9, 101]. Ruscitti and colleagues described in 2026 two Turkish siblings from another family, with the same variant; the boy had a more severe neurodevelopmental disorder, postaxial polydactyly and a vascular malformation of the upper lip, findings not previously described that need confirmation in other patients [52].

Two 2026 reports extended the spectrum to manifestations with direct clinical consequences. The patient reported by Cosentino and colleagues, a Caucasian girl, the daughter of non-consanguineous parents, measured 161 cm (about +1.2 SD) and weighed 60 kg at 14 years; she walked independently at around 2 years, had speech delay and needed educational support, non-ossifying fibromas of the knees, bowing of the tibia, radius and ulna, subglottic tracheal stenosis, intermittent conductive hearing loss, double-chambered right ventricle, patent foramen ovale and ventricular septal defect surgically repaired, atresia of the left pulmonary vein with a progressive mediastinal vascular conglomerate, complete atrioventricular block requiring a pacemaker at 14 years and intermediate uveitis treated with adalimumab [53]. The patient reported by Şiraz and colleagues, described in section 10, developed a follicular thyroid carcinoma and a mucoepidermoid carcinoma of the parotid at 16 years [54]. Early-onset psychosis in an adult patient has also been published [53, 119].

The synthesis by Duzenli and colleagues of 8 patients from 5 families gives the frequency of findings: tall stature and developmental delay or ID in 8 of 8, speech delay or disorder in 6 of 6, macrosomia at birth in 3 of 6, macrocephaly in 6 of 8, cardiovascular, genitourinary and skeletal anomalies in 5 of 8 each, and ocular anomalies in 3 of 8; all had facial dysmorphism, with hypertelorism in 6 of 8, thick eyebrows and midface hypoplasia in 5 of 8, down-slanting palpebral fissures in 4 of 8, epicanthus and thick lips in 3 of 8, and a triangular or round face in 2 of 8 each [9, 51]. With 12 patients from 8 families published up to 2026, the frequencies are unstable and biased towards the most severe cases, and the absence of tall stature or macrocephaly does not exclude the diagnosis [52, 54]. ID ranges from mild learning difficulties to severe delay [53]. Adult natural history data are limited to the original patient, and the tumours (one Wilms tumour at 4 years and the adolescent's two carcinomas) are isolated observations that do not allow risk to be estimated [6, 54, 98].

3.13. Overgrowth due to excess CNP–NPR-B signalling

The translocation forms and the NPR2 gain-of-function forms share the phenotype described in section 3.10, with differences that help to guide testing. In patients with a translocation, the habitus is tall and slender or marfanoid, with macrodactyly of the halluces, scoliosis, ankle valgus, coxa valga and slipped capital femoral epiphysis; the girl reported by Ko and colleagues also had aortic root dilatation, attributed to concomitant disruption of TGFB2 [57, 104, 105]. In the two patients in the bone dysplasia atlas, an 11-year-old boy and a girl followed from 6 to 13 years, the legends of figures 22.4.1 to 22.4.5 describe arachnodactyly of the feet and hands, elongated halluces, especially on the left, overlapping toes, camptodactyly, metatarsals of irregular length with lateral deviation of the halluces, pseudoepiphyses at the distal end of the proximal phalanges, severe double-curve scoliosis with a possible surgical indication and elongated long bones with symmetric or asymmetric bowing [7].

In families with NPR2 gain of function, expressivity varies between generations: in the Russian family, the mother had borderline tall stature and elongated halluces operated on in childhood, and the children had tall stature, scoliosis and progressive valgus deformities of the hip, knee and ankle [56]; in the family described by Lauffer and colleagues in 2020, the mother and two daughters underwent percutaneous epiphysiodesis of the halluces at 8 and 5 years, and the daughters had progressive macrodactyly of the halluces, ankle valgus, long thumbs and a positive thumb sign [55]. The Dutch patient with p.(Arg655Cys) had no elongation of the halluces, which shows that the absence of this sign does not exclude the pathway [7, 108]. Markers of bone formation and resorption were increased in the Japanese and Korean families, and the Japanese proband had a spinal bone mineral density of −3.9 SD corrected for height [55]. Arterial hypertension may arise in adulthood [7]. The table brings together the patients published in the sources consulted, including families with NPR2 variants associated with short stature.

4. Clinical Recognition and Warning Signs

4.1. Prenatal and neonatal

On prenatal ultrasound, polyhydramnios, macrosomia, visceromegaly, nephromegaly, placentomegaly, a long umbilical cord, adrenal cysts and an abdominal wall defect suggest BWSp; omphalocele is the most frequent prenatal finding in this syndrome [5, 60]. The combination of polyhydramnios, macrosomia, visceromegaly, nephromegaly with hydronephrosis, ascites or hydrops suggests Perlman syndrome [6]. Prenatal suspicion of BWSp justifies delivery at a centre prepared for hypoglycaemia, macrosomia, omphalocele and macroglossia [5].

In the newborn, hypoglycaemia is the main emergency sign: it occurs through hyperinsulinism in one-third to one-half of children with BWS and also in Simpson-Golabi-Behmel syndrome and, sometimes, in Sotos syndrome [59, 60, 63]. Manor and Lalani recommend monitoring blood glucose in a newborn with an early diagnosis of BWSp as if it were the infant of a diabetic mother, and also monitoring newborn siblings, even without classic signs [5]. Airway obstruction due to macroglossia and hypotonia (BWS, Simpson-Golabi-Behmel) or due to narrowing at several levels (Marshall-Smith) is the other neonatal emergency [60, 61, 63]. Jaundice, hypotonia and feeding difficulties are frequent in the newborn with Sotos syndrome, and camptodactyly, a hoarse low-pitched cry and umbilical hernia suggest Weaver syndrome [1].

4.2. Childhood and adolescence

The Dutch Working Group on Tall Stature summarised the clues to a primary growth disorder: motor, speech or cognitive developmental delay, behavioural problems, excessive fetal growth, cardiac or ocular anomalies, dominant inheritance of tall stature, disproportion or dysmorphism, arachnodactyly, thumb and wrist signs, chest deformity, macrocephaly, gynaecomastia, cryptorchidism or micropenis, and accelerated growth between five and eight years [37]. The clues to a secondary disorder are increased appetite with weight loss, irritability, sweating, headaches, visual disturbances, nausea and vomiting, cranial irradiation, familial thyroid disease, pubertal onset before eight years in girls or nine in boys, thyrotoxic or neurological signs and height acceleration greater than 1 SD [37]. Height greater than +3 SD, or more than 2.5 SD above target height, justifies referral to paediatric endocrinology, clinical genetics or a reference centre, even without other clues [37].

4.3. Specific warning signs

An HC greater than 3 SD should raise the possibility of PHTS, especially with lipomas, haemangiomas, freckling of the penis or vulva, trichilemmomas or a family history of breast, thyroid or endometrial cancer or gastrointestinal polyps [4, 5]. Asymmetry with capillary malformation, 2–3 toe syndactyly, polydactyly or haemangioma of the philtrum suggests megalencephaly-capillary malformation; the onset of hydrocephalus, intracranial hypertension or signs of Chiari malformation in these children is a neurosurgical emergency [4, 32]. Asymmetry barely visible at birth that progresses rapidly with cerebriform connective tissue naevi on the soles of the feet suggests Proteus syndrome, in which deep vein thrombosis and pulmonary embolism are potentially fatal complications [33, 111]. Any abdominal mass, haematuria or abdominal pain in a child with an embryonal tumour predisposition syndrome requires immediate imaging, regardless of the surveillance schedule [36]. The signs of neuroblastoma to teach families include an abdominal mass or pain, opsoclonus-myoclonus or ataxia, subcutaneous nodules, watery diarrhoea, abdominal distension and periorbital ecchymoses [39].

Thauvin-Robinet-Faivre syndrome enters the differential diagnosis of any child with overgrowth, macrocephaly and developmental delay who also has congenital heart disease, renal dysplasia, coloboma or another ocular anomaly, especially if the parents are consanguineous or of Turkish origin [9, 51]. In this syndrome, syncope, bradycardia or exercise intolerance require an electrocardiogram, because of the complete atrioventricular block described, and stridor or recurrent respiratory infections require assessment of the airway [6, 53]. Overgrowth due to excess CNP is suspected in the very tall child or adolescent with long and broad halluces, arachnodactyly, camptodactyly, scoliosis or coxa valga, especially when suspicion of Marfan syndrome is not confirmed because of the absence of ectopia lentis and aortic dilatation [7, 56, 103]. Hip or knee pain, or a limp, require exclusion of slipped capital femoral epiphysis, described in patients with a translocation and with NPR2 gain of function [57, 103].

4.4. Newborn screening

There is no population newborn screening for overgrowth syndromes. Detection depends on clinical observation and on systematic measurement of weight, length and HC at birth, with calculation of the deviation for gestational age [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Targeted history and examination

The history includes a three-generation pedigree, with birth weights, parental growth and family history of ID and cancer; the pregnancy history (gestational diabetes, assisted reproduction, fetal growth, ultrasound findings, polyhydramnios); birth parameters with gestational age; abdominal wall defects and neonatal hypoglycaemia; the chronology of postnatal growth (periods of acceleration, static or progressive asymmetry); development; and review of the skeletal, cardiac, renal, neurological and cutaneous systems [1, 111]. The examination records height, weight and HC with age and deviation from the mean; it looks for ear lobe creases and posterior helical pits, macroglossia or a median tongue groove, supernumerary nipples, polydactyly, brachydactyly or syndactyly, skin changes (pigmentation, lipomas, haemangiomas, connective tissue naevi on the soles), scoliosis and abdominal wall defects [1]. Parental HC should be recorded and compared with their height [4].

Asymmetry is measured in a standardised way: the upper limb is measured from the acromion to the tip of the middle finger with the arms hanging; the lower limb is measured from the greater trochanter to the floor, with the child standing, or to the lateral malleolus, in infants; circumferences are measured at the greatest diameter or from a fixed bony landmark (for example, 10 cm below the lower border of the patella), at mid-biceps on the arm, below the gluteal fold on the thigh and at the upper third of the calf muscle on the leg [111]. Serial photographs help to document progression [111].

For tall stature, the Dutch Working Group proposes three criteria: height greater than +2 SD for the population; height above the expected range for the conditional target height, calculated as 0.72 times the mean of the parental standard deviations, with a range of ±1.6 SD; and growth acceleration, defined as a rise in height standard deviation greater than 1 before puberty [37]. An arm span/height ratio above 1.05 suggests Marfan syndrome, although its value in children is doubtful, and a sitting height/height ratio below −2 SD is seen in Marfan syndrome, Klinefelter syndrome and SHOX triplication [37].

5.2. Initial non-molecular tests

Bone age (radiograph of the left hand and wrist) is the common screening test; it is assessed using the Greulich and Pyle atlas (1959), the Tanner-Whitehouse method (1975) or the automated BoneXpert system, approved in Europe; a difference of 2 SD from chronological age is considered abnormal, with inter-observer variability of 0.4 to 0.8 years and the need for a hemiskeleton radiograph before one year of age [5]. Prediction of adult height by the Bayley-Pinneau method overestimates by a mean of 2.5 cm in boys (SD 4.3 cm), and is on average correct in girls (SD 4.6 cm) [37]. Bone age also has discriminating value: in Weaver syndrome, carpal ossification is much more advanced than that of the metacarpals and phalanges, whereas in Sotos syndrome carpal ossification is delayed relative to that of the phalanges and metacarpals [109].

Manor and Lalani include in the ancillary tests a full blood count, biochemistry, IGF-1, IGFBP-3, free T4, thyroid-stimulating hormone and karyotype [5]. When there are clues to a secondary disorder, the Dutch Working Group proposes luteinising hormone, follicle-stimulating hormone, testosterone, oestradiol and a GnRH test when central precocious puberty is suspected; 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone and its sulphate and a urinary steroid profile in precocious pseudopuberty; growth hormone, IGF-1 and an oral glucose tolerance test with growth hormone measurement in growth hormone excess; and free T4 and thyroid-stimulating hormone in hyperthyroidism [37]. In macrocephaly with delay, brain magnetic resonance imaging (MRI), developmental assessment, urinary organic acids and mucopolysaccharide screening complete the assessment [4]. Renal ultrasound is indicated when syndromes with Wilms tumour risk are suspected and, as a baseline assessment of renal anomalies, in Sotos syndrome and in 15q overgrowth; baseline echocardiography in Sotos syndrome and Simpson-Golabi-Behmel syndrome; and electrocardiography in Simpson-Golabi-Behmel syndrome [1].

5.3. Scores and clinical criteria

The Proteus score assigns 5 points to the cerebriform connective tissue naevus, 5 to asymmetric and disproportionate overgrowth (limbs, hyperostosis of the skull or external auditory canal, megaspondylodysplasia, scoliosis or rib hyperostosis) and 5 to overgrowth of at least two organs; 2 points to pulmonary bullae or cysts, adipose tissue dysregulation, the facial phenotype with at least three features and deep vein thrombosis or pulmonary embolism; additional points to linear verrucous epidermal naevus, vascular and lymphatic malformations and specific tumours; and subtracts 5 points for substantial prenatal extracranial overgrowth and for “ballooning” overgrowth [33]. The 1999 criteria reproduced in the Oxford Desk Reference (one A criterion, two B or three C) have been replaced by this score [33, 111].

5.4. Genetic tests: choice and order

There is no single consensus algorithm for overgrowth; the choice starts from the clinical pattern [5]. When the phenotype points to an entity (for example, macroglossia and omphalocele, asymmetry with capillary malformation, typical Sotos face), targeted testing or an overgrowth panel identifies the cause with a lower risk of variants of uncertain significance in irrelevant genes; when the phenotype is non-specific, chromosomal microarray followed by exome sequencing, or genome sequencing, are the options [25]. Testing for FMR1 expansion is part of the assessment of a child with delay and macrocephaly or accelerated growth [1, 37]. When Klinefelter syndrome, 47,XYY or 47,XXX is suspected, the Dutch Working Group prefers single nucleotide polymorphism microarray to karyotype, with fluorescence in situ hybridisation on lymphocytes or buccal mucosa when suspicion persists with a normal array; when Marfan syndrome is suspected, it applies the revised Ghent criteria and requests FBN1 or a connective tissue disorder panel, and adds plasma homocysteine in marfanoid syndromes [37]. Without specific clues, it proposes microarray and exome or genome sequencing with a tall stature panel first; with global delay, metabolic screening, FMR1, microarray and trio exome [37].

In BWSp, the first step is IC1 and IC2 methylation testing (usually by methylation-specific multiplex ligation-dependent probe amplification, MS-MLPA), abnormal in about 75% of patients; if abnormal, single nucleotide polymorphism microarray distinguishes copy number variants and paternal uniparental disomy (about 20%); if normal, CDKN1C is sequenced (about 5% of sporadic cases, 40% of familial cases) [5, 58]. About 20% of patients with clinical BWSp have negative tests in blood; analysis of another tissue (saliva, skin or hypertrophied tissue) detects low-level alterations in up to 10% [5]. In Sotos syndrome, multiplex ligation-dependent probe amplification of NSD1 detects the 5q35 microdeletion and exonic copy number variants, which account for about 5% of NSD1 variants [3]; the DNA methylation signature in peripheral blood is sensitive and specific for the diagnosis [6, 59].

In the OGID cohort, the diagnostic yield was 50% (357 of 710; the article's abstract states 353), with NSD1 in 34%, EZH2 in 4.8%, DNMT3A in 2.5%, PTEN in 2.3%, NFIX in 2.0%, CHD8 in 1.7%, BRWD3 in 1.0%, HIST1H1E in 0.7%, PPP2R5D in 0.4% and isolated cases of EED, GPC3, MTOR, AKT3 and PIK3CA [3]. The yield was 59% (120 of 205) when height and HC were both increased, 43% (47 of 109) with macrocephaly alone and 45% (62 of 138) with tall stature alone [3]. This proportion of diagnoses in a clinical genetics cohort recruited since 2005 is not equivalent to the sensitivity of a test in an individual patient, and recruitment began before the discovery of most of the genes, which reduces bias from prior negative tests [3].

5.5. Mosaicism: tissue, depth and method

In mosaic disorders, the choice of tissue determines the result. In PROS, DNA from affected tissue should be preferred: a fresh skin biopsy over the affected area, a surgical specimen of overgrown tissue or uncultured tissues; testing in blood is not recommended, because PIK3CA variants were found in blood in only 2 of 24 patients with megalencephaly-capillary malformation, carriers of an apparently de novo germline variant [32]. In Proteus syndrome, punch biopsy of affected skin is the usual test, more than one sample may be needed and a negative result in blood does not exclude the diagnosis [33]. In Smith-Kingsmore syndrome, about 20% to 25% of variants are postzygotic, and a dermal biopsy may be necessary [28]. The Oxford Desk Reference recommends DNA from skin (or another tissue other than blood) in hemihypertrophy, Proteus syndrome, CLOVES syndrome and megalencephaly-capillary malformation, and very high-depth sequencing (more than 1000 reads) when a PIK3CA/AKT pathway disorder is suspected [1, 4]. In hemihypotrophy with delay, especially with syndactyly or hypomelanosis of Ito, a skin biopsy for karyotype looks for chromosomal mosaicism when the blood karyotype is normal [111]. The Italian cohort of vascular malformations with overgrowth used a 17-gene panel with a depth greater than 2000 reads in blood, buccal mucosa or biopsy and recommended tissue analysis and systematic parental testing [112].

5.6. Limitations of tests

No single test detects all relevant alterations: sequencing (panel or exome) with microarray detects single nucleotide variants, small insertions and deletions and copy number variants only in the tissue analysed, and does not detect methylation alterations; 11p15 methylation requires its own test [5]. Sensitivity for mosaicism depends on read depth and tissue; in some patients with Proteus syndrome the allele fraction is below 1%, below the detection threshold of several methods [33]. Tests targeting recurrent PIK3CA codons (hotspots) miss variants located outside codons 542, 545 and 1047 [32]. MS-MLPA may misclassify BWSp subgroups, and results in blood should be used with caution to estimate tumour risk [10]. A negative result in blood does not exclude a mosaic disorder, and a clinical diagnosis of BWSp stands despite negative tests [5, 36].

5.7. Report and variants of uncertain significance

The report should state the gene, the reference transcript with version, the HGVS nomenclature, the zygosity or allele fraction (in mosaics, the tissue analysed), and the class according to the rules of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [5, 25]. A variant of uncertain significance in an overgrowth gene neither confirms nor excludes the diagnosis; family segregation and, in the case of NSD1 and other genes with an episignature, methylation analysis can help to reclassify it [6, 25]. A variant of uncertain significance inherited from an unaffected parent tends to be benign, with the caveat of incomplete penetrance and parental mosaicism [5].

5.8. Practical algorithm

The algorithm summarises the recommendations of the Oxford Desk Reference, Manor and Lalani, the Dutch Working Group and the European host genome group [1, 4, 5, 35, 37, 111].

5.9. Prenatal and preimplantation diagnosis

Prenatal diagnosis is usually possible only when a variant or chromosomal alteration has been identified [1]. In BWSp, methylation testing on amniotic fluid cells or chorionic villi can confirm the diagnosis early [5]. In non-inherited mosaic disorders (PROS, Proteus), targeted prenatal testing has no application in the family of a patient [10]. Preimplantation diagnosis is available when the familial variant is known, for example in Malan and Smith-Kingsmore syndromes [25, 28].

5.10. Diagnosis of the NFIX syndromes and Perlman syndrome

When Malan syndrome is suspected, the authors of the adult natural history study recommend molecular confirmation by exome or by an overgrowth panel that includes NFIX, NSD1 and the other genes of the differential diagnosis, and microarray identifies 19p13.2 deletions with contiguous genes [25, 90]. In Marshall-Smith syndrome, sequencing alone is insufficient: in the series by Schanze and colleagues, 7 of 17 patients (41%) had exonic deletions (five recurrent deletions of exons 6 and 7 and two of exon 6) detected by multiplex ligation-dependent probe amplification (MLPA), and the combination of the two methods identified the alteration in all patients with a clinical diagnosis [49]. Interpretation of an NFIX variant depends on its position and its predicted effect on nonsense-mediated decay: a proximal truncating variant, a missense variant in the DNA-binding domain or a deletion of the gene are compatible with Malan syndrome, and a truncating variant in exons 6 to 10 that escapes this decay is compatible with Marshall-Smith syndrome; the phenotype, especially growth and bone maturation, should agree with the molecular prediction [25, 88, 89]. A hand radiograph, with markedly advanced bone age and bullet-shaped phalanges, supports the clinical diagnosis of Marshall-Smith syndrome in infancy [71].

Perlman syndrome is suspected in the presence of polyhydramnios, fetal macrosomia, nephromegaly, fetal ascites and visceromegaly, and is confirmed by identifying biallelic DIS3L2 variants [5, 6, 40]. The difficulty of separating it clinically from other overgrowth syndromes makes genetic testing an essential part of the assessment [5]. The most frequent alterations are intragenic deletions (exon 9 and exon 6), which exome analysis limited to single nucleotide variants may fail to detect: in a boy with enlarged kidneys and a deceased sister with suspected autosomal recessive polycystic kidney disease, the exome was normal and single nucleotide polymorphism microarray revealed an 18 kb homozygous deletion at 2q37.1, within DIS3L2 [95]. Testing should therefore include copy number variant analysis with exonic resolution, by high-density microarray or by long-range PCR with primers in exons 8 and 10, the method used in the van Peer cohort [95, 96]. DIS3L2 is not part of most developmental delay panels, and testing should be considered in a child with Wilms tumour and developmental delay, macrosomia or facial dysmorphism in the child or in siblings, and also in a child with fetal macrosomia, delay and the characteristic facies without a tumour [43]. In children with Wilms tumour, 28 of 34 heterozygous germline DIS3L2 variants were found in predisposition tests offered solely because of the tumour diagnosis [96]. Before the gene was identified, diagnosis required exclusion of 11p15 and GPC3 alterations, which had not been studied in most published patients [42]. Renal histology shows dysplasia, nephroblastomatosis and nephrogenic rests, and there is no biochemical biomarker [6, 40].

5.11. Diagnosis of Thauvin-Robinet-Faivre syndrome and of overgrowth due to excess CNP

There are no clinical criteria or biochemical marker for Thauvin-Robinet-Faivre syndrome, and all published patients were diagnosed by exome or genome sequencing, the family reported by Akawi and colleagues after homozygosity mapping [6, 98]. The overgrowth panel chosen should include FIBP; in children of consanguineous parents, regions of homozygosity on SNP microarray or exome help to prioritise recessive genes [98, 118]. The recurrent variant in the Turkish families is a duplication spanning an intron-exon junction and is described differently depending on the transcript; the report should use the MANE Select transcript NM_004214.5 and state the alternative published description, to avoid the same variant being recorded as two [54, 70, 100]. Şiraz and colleagues classified it as likely pathogenic by the ACMG PVS1 and PM2 criteria [54]. When the phenotype is segmental overgrowth with vascular malformations, a FIBP result does not remove the need to look for PIK3CA mosaicism in affected tissue, which could not be excluded in the patient reported by Şiraz and colleagues [54]. Confirmation of carrier status in both parents supports the interpretation [100].

In overgrowth due to excess CNP, the test is chosen according to the mechanism. Balanced translocations do not alter dosage and escape microarray and exome sequencing, so karyotyping is indispensable; breakpoints are mapped by fluorescence in situ hybridisation (FISH), targeted resequencing or genome sequencing, and the breakpoint on the partner chromosome may disrupt another gene with its own consequences, such as TGFB2 [57, 104, 105]. Microarray detects 2q37 deletions affecting NPPC [106]. NPR2 variants are identified by an overgrowth panel, a skeletal dysplasia panel or exome, and their functional direction is confirmed by cGMP production in transfected cells or fibroblasts [55, 107, 108]. Serum CNP or NT-proCNP is raised in NPPC overexpression and normal or reduced in NPR2 gain of function, and blood cGMP was raised in the Japanese family; these measurements are research assays, without validated paediatric reference intervals in the sources consulted [57, 103, 104, 106–108]. Radiographs of the feet and hands show the most specific signs: elongated and broad metatarsal and phalanges of the hallux, irregular epiphyseal ossification of the first metatarsal, phalangeal pseudoepiphyses and arachnodactyly [7].

6. Differential Diagnosis

6.1. Framework

The differential diagnosis is organised by growth pattern: global overgrowth with ID (epigenetic syndromes and PI3K/AKT/mTOR pathway syndromes), global overgrowth without ID (familial tall stature, endocrine causes, connective tissue syndromes and sex chromosome aneuploidies), prenatal overgrowth with embryonal tumours (BWSp, Simpson-Golabi-Behmel, Perlman), disproportionate macrocephaly and lateralised or segmental overgrowth [1, 5, 37]. In asymmetry, the first decision is to separate overgrowth of one side from undergrowth of the other, and to exclude plagiocephaly, developmental dysplasia of the hip and chest deformities [10, 111].

6.2. Comparative table

Table sources: [1, 4, 5, 7, 10, 25, 32, 33, 37, 61, 71, 109–112].

6.3. Sotos, Malan, Weaver and the PRC2 disorders

Sotos syndrome is the main differential diagnosis of Malan syndrome [25]. ID is usually more severe in Malan syndrome: at least one-third of patients with Sotos syndrome have normal intelligence or mild ID, whereas in Malan syndrome normal intelligence has never been described and mild ID is rare [25]. Generalised anxiety, separation anxiety with specific phobias and social difficulties are more frequent in Malan syndrome, as are severe ophthalmological abnormalities (optic nerve hypoplasia or atrophy) [25]. Musculoskeletal anomalies, except scoliosis (present in about 30% of patients with Sotos syndrome), are less frequent and less severe in Sotos syndrome, and low BMI is rare in Sotos syndrome but affects at least one-third of patients with Malan syndrome [25]. The facial overlap between the two is considerable [1].

Weaver syndrome is distinguished by a round face with frontal bossing, hypertelorism and a “stuck-on” chin with a horizontal crease, most recognisable between one and three years, by neonatal camptodactyly, soft doughy skin, a hoarse low-pitched cry and umbilical hernia; EZH2 should be tested in a patient with a Sotos phenotype without an NSD1 variant [1]. The hand radiograph helps: carpal bone age is markedly advanced in Weaver syndrome and delayed relative to the phalanges and metacarpals in Sotos syndrome [109]. Patients with EED (Cohen-Gibson syndrome) and SUZ12 variants have a Weaver-like phenotype; patients with EED variants have more heart defects and cervical spine anomalies, and the face may be distinguished by telecanthus, narrow palpebral fissures with lateral ptosis and lateral eversion of the lower eyelid [62].

6.4. Malan and Marshall-Smith

The two allelic NFIX syndromes are distinguished mainly by growth: overgrowth in Malan syndrome, failure to thrive and short final stature in Marshall-Smith syndrome [25]. Macrocephaly is absent in Marshall-Smith syndrome, and proptosis, midface hypoplasia and a small chin are characteristic of it; hypertrichosis and gingival hypertrophy are almost exclusive to Marshall-Smith syndrome, and scoliosis, common to both, is typically more progressive in Marshall-Smith syndrome [25]. Marshall-Smith syndrome also enters the differential diagnosis of Weaver syndrome, because of the accelerated skeletal maturation; Weaver syndrome has evident prenatal somatic overgrowth, undermodelling of the long bones and absence of bullet-shaped phalanges [71].

6.5. Marfanoid syndromes and tall stature

In tall stature with a slender habitus, the differential diagnosis includes Malan, Marfan, Lujan (MED12) and Snyder-Robinson (SMS) syndromes and classical homocystinuria; all except Marfan syndrome are accompanied by delay or ID [25]. Homocystinuria and Marfan syndrome share ectopia lentis, homocystinuria adds thromboembolism and Marfan syndrome aortic root disease [25]. Klinefelter syndrome and sex chromosome polysomies are the most frequent chromosomal causes of tall stature and are often diagnosed late [37]. Overgrowth due to excess CNP is distinguished from Marfan syndrome by the disproportionate elongation of the hallux and the absence of typical extraskeletal manifestations, and from CATSHL syndrome (camptodactyly, tall stature, scoliosis and hearing loss, due to an inactivating FGFR3 variant) by the absence of hallux elongation in the latter [7].

6.6. BWSp and other syndromes with neonatal macrosomia

BWSp is distinguished from the other neonatal macrosomia syndromes by macroglossia, omphalocele, hypoglycaemia due to hyperinsulinism, ear lobe creases and helical pits and lateralised overgrowth [1, 58]. Simpson-Golabi-Behmel syndrome shares macroglossia, visceromegaly, renal anomalies and the risk of embryonal tumours, but has a coarse face with hypertelorism and macrostomia, a median groove of the lower lip, cleft lip, structural and conduction heart disease and polydactyly [10]. Perlman syndrome adds high neonatal mortality and frequent ID; Costello syndrome may mimic BWS in the neonatal period, but evolves with failure to thrive, hypertrophic cardiomyopathy and a coarse face [10]. Mosaic genome-wide paternal UPD resembles severe BWS, with features of several imprinting disorders, more delay and a high tumour risk; multilocus imprinting disorders may be associated with maternal variants in maternal-effect genes (NLRP2, NLRP5, NLRP7, PADI6) [10].

6.7. Lateralised and segmental overgrowth

In lateralised overgrowth, the main differential is between BWSp, PROS, Proteus syndrome, PHTS, NF1, Klippel-Trenaunay and Parkes Weber syndromes, McCune-Albright syndrome and isolated lateralised overgrowth; Silver-Russell syndrome enters from the opposite side, as asymmetry due to undergrowth without a risk of embryonal tumours [10, 111]. Isolated lateralised overgrowth has an 11p15 alteration in about 20% of patients, which places it within BWSp; in the remainder, it may be due to mosaicism of genes outside 11p15 [10, 111]. The 2026 Italian cohort showed that vascular malformations with overgrowth without a PIK3CA variant (due to TEK, GNAQ, GNA11, PTEN, RASA1, AKT3, EPHB4) overlap clinically with one another and with PROS, which makes molecular classification necessary [112].

6.8. Disproportionate macrocephaly

In disproportionate macrocephaly, in addition to PHTS and the PI3K/AKT pathway disorders (megalencephaly-capillary malformation-polymicrogyria and megalencephaly-polymicrogyria-polydactyly-hydrocephalus), the differential diagnosis includes benign familial macrocephaly (with compatible parental HC and normal development), NF1, fragile X syndrome, Gorlin syndrome, RASopathies, skeletal dysplasias (achondroplasia), dysplasias with cranial thickening (Van Buchem, craniodiaphyseal and craniometaphyseal dysplasias), the mucopolysaccharidoses (especially type III) and glutaric aciduria type 1 [4]. The Oxford Desk Reference warns that PTEN and PTCH1 may present with few syndromic signs in apparently familial macrocephaly [4].

6.9. Perlman syndrome and other causes of macrosomia with nephromegaly

Perlman syndrome shares with BWSp macrosomia, visceromegaly and predisposition to Wilms tumour, and neonatal hypoglycaemia, with hyperinsulinism, has also been described in some patients; the textbook of inherited metabolic diseases includes Perlman syndrome, Sotos syndrome (including the NFIX forms) and Simpson-Golabi-Behmel syndrome among the syndromic causes of hyperinsulinism [40, 43, 120]. It is distinguished by the absence of abdominal wall defects, macroglossia and lateralised overgrowth, by the face with an everted inverted-V upper lip, broad flat nasal bridge and deep-set eyes, and by high neonatal mortality [40, 95]. In Sotos syndrome, overgrowth is mainly postnatal, and Simpson-Golabi-Behmel syndrome is distinguished by X-linked inheritance, the coarse face and associated malformations [10, 95]. Large, hyperechogenic kidneys with microcysts may mimic polycystic kidney disease, and fetal ascites with hypoplasia of the abdominal musculature historically entered the differential diagnosis of the prune belly sequence [40, 95]. The 2q37 deletion encompassing 2q37.1 includes DIS3L2; Wilms tumour has been described in three patients with such deletions, and the SIOP-E group suggests considering surveillance when the deletion includes 2q37.1 [35]. Heterozygous carriers of DIS3L2 variants with Wilms tumour do not have the syndromic phenotype [96].

6.10. Thauvin-Robinet-Faivre syndrome and overgrowth due to excess CNP

Thauvin-Robinet-Faivre syndrome shares with Sotos syndrome tall stature, macrocephaly and developmental delay, and with Perlman and Simpson-Golabi-Behmel syndromes renal dysplasia and the Wilms tumour described; it is distinguished by autosomal recessive inheritance, frequent consanguinity and the association of structural or conduction heart disease, coloboma and varicose veins, and only molecular testing separates it reliably [51, 98, 99]. The patient reported by Şiraz and colleagues, with soft tissue overgrowth, port-wine stains, multiple haemangiomas and varicose veins, was first investigated as a possible PIK3CA-related overgrowth spectrum [54].

Overgrowth due to excess CNP is distinguished from Marfan syndrome and related syndromes by the disproportionate elongation of the hallux and by the absence of the extraskeletal manifestations characteristic of those syndromes, such as ectopia lentis [7, 103]. CATSHL syndrome (camptodactyly, tall stature, scoliosis and hearing loss), due to inactivating FGFR3 variants, shares arachnodactyly, camptodactyly and kyphoscoliosis, but has no long halluces [7]. Aortic root dilatation is not part of the CNP–NPR-B pathway phenotype, and its presence in a patient with a translocation led to the identification of a second lesion, disruption of TGFB2 [57]. In classical homocystinuria, the marfanoid habitus is accompanied by ectopia lentis, thromboembolism and ID, which are absent in these entities [7, 25].

7. Treatments and Risk Management Strategies

7.1. Principles

For most overgrowth syndromes there is no treatment directed at the cause; management is anticipatory and complication-oriented, and the aetiological diagnosis mainly determines tumour surveillance, counselling and referrals [1, 5]. The exceptions are the PI3K/AKT/mTOR pathway disorders, for which targeted inhibitors exist, with evidence and regulatory status differing from entity to entity [1, 32]. The section summarises the therapeutic decisions common to the class; specific treatment depends on each syndrome.

7.2. Acute complications of childhood

Neonatal hypoglycaemia in BWS, Simpson-Golabi-Behmel syndrome and Sotos syndrome is treated as congenital hyperinsulinism; in BWSp, pre-feed blood glucose is monitored according to endocrinology advice in infants with hypoglycaemia or hyperinsulinism [5, 10]. Airway obstruction due to macroglossia and micrognathia (BWS, Simpson-Golabi-Behmel) requires immediate treatment; in Marshall-Smith syndrome, aggressive airway management, often with tracheostomy, has allowed survival into adulthood [34, 61]. In megalencephaly-capillary malformation and other forms with brain overgrowth, obstructive hydrocephalus, intracranial hypertension, cerebellar tonsillar ectopia and epilepsy may require neurosurgical intervention [32]. In Proteus syndrome, deep vein thrombosis and pulmonary embolism require immediate assessment and treatment [33].

7.3. Orthopaedics, surgery and rehabilitation

Limb length discrepancy and scoliosis are treated by orthopaedics, with physiotherapy and, when indicated, surgery; in segmental lipomatous overgrowth surgical debulking may be necessary, and in Proteus syndrome procedures are used to slow or stop bone growth and correct deformities [6, 32]. The macroglossia of BWS may be treated by partial glossectomy [60]. In idiopathic or syndromic tall stature, the Dutch Working Group discusses the options (percutaneous epiphysiodesis or no treatment) when predicted adult height exceeds +2.3 SD; in the Netherlands, epiphysiodesis around the knee is performed only if predicted height is greater than 205 cm in men or 185 cm in women, and it reduces the expected residual growth by about one-third, with a prediction imprecision of the order of ±5 cm [37].

7.4. Neurodevelopment, behaviour and other manifestations

Developmental delay and ID require early intervention and educational support; epilepsy, scoliosis, ophthalmological abnormalities, hearing loss and heart defects are treated according to usual practice [23, 25, 26]. In Malan syndrome, cognitive behavioural therapy is used for anxiety and ADHD, and aids such as tinted glasses or a quiet tone of voice may reduce anxiety crises [25]. In the CHD8-related disorder, sleep disturbance is treated with behavioural and, if necessary, pharmacological interventions [26]. In the SETD2-related disorder with obesity, nutritional management and exercise are recommended [27].

7.5. Therapy targeted at the PI3K/AKT/mTOR pathway

Alpelisib (Vijoice®), an inhibitor of the alpha subunit of PI3K, is the only drug authorised for an overgrowth syndrome, the PROS spectrum; GeneReviews indicates 50 mg orally, with food, once daily, from 2 to 17 years, with a possible increase to 125 mg once daily after 24 weeks from 6 years of age, and 250 mg once daily in adults, approved to reduce overgrowth, vascular lesions and other functional complications, with no known efficacy on the neurological manifestations of megalencephaly-capillary malformation [32]. Doses and formulations follow the alpelisib label for PROS, with monitoring for hyperglycaemia, diarrhoea and stomatitis. Sirolimus is used off-label in complex vascular and lymphatic malformations and in progressive overgrowth in PROS [32]; in Smith-Kingsmore syndrome, it was used off-label in seven patients, at low to moderate doses, with behavioural improvements reported by parents (speech, attention, self-injury, hyperphagia), and the GeneReviews authors advise assessing the functional impact of the variant before using mTOR inhibitors [28]. In the Italian cohort of vascular malformations with overgrowth without a PIK3CA variant, off-label alpelisib was associated with clinical improvement in selected patients with a TEK variant, whereas sirolimus showed limited efficacy; this is a retrospective series without a control group [112].

7.6. Clinical trials

The EPIK-P2 results were posted on the ClinicalTrials.gov registry on 10 February 2025, and the study remained active, not recruiting, at the update of 7 October 2026 [122]. The response proportions measure a volumetric reduction of at least 20% in a target lesion and not a functional benefit; the placebo-controlled phase lasted only 16 weeks, and comparison with other alpelisib studies is not valid because of differences in design and population.

7.7. Developments in the last 12 months

Vijoice® (alpelisib) received, on 15 July 2026, a conditional marketing authorisation valid throughout the European Union, according to the EMA European public assessment report page, whose summary was published on 26 August 2026 (level of evidence: authorisation) [38]. In 2026 the Italian cohort of 41 children with vascular malformations and overgrowth without a PIK3CA variant was published, which advocates broad panels in tissue and molecular classification and describes response to alpelisib in cases with a TEK variant (level: retrospective observational study) [112]. Searches of bibliographic and regulatory databases between October 2025 and October 2026 identified no new general guideline on the approach to overgrowth; this absence in the sources searched does not prove that none exists.

For the rarer entities, publications in the last 12 months include a North American series of eight patients with Malan syndrome, with a literature review and updated management recommendations (April 2026; observational study) [113], and the first report of survival to 32 months with a homozygous deletion of DIS3L2 exon 9 (April 2026; case report) [95]. In 2025 the international cohort of 34 children with Wilms tumour and a heterozygous germline DIS3L2 variant (retrospective observational study) [96] and the description of three siblings with attenuated Perlman syndrome (case report with review) [43] were published.

7.8. Agents to avoid and special populations

In the EED-related disorder, activities involving rapid neck movements or a risk of cervical trauma (contact sports, amusement park rides) should be avoided because of the risk of cervical spine instability [23]. In Costello syndrome, urinary catecholamine metabolites are frequently raised and should not be used as a neuroblastoma surveillance test [39]. In assisted reproduction, the risk of BWSp is increased (3 to 10 times in European cohorts, pooled odds ratio of 5.8 in a 2018 meta-analysis), but the absolute risk remains below 1 in 1000, and couples should be informed [5]. In Marshall-Smith syndrome, cervical stenosis and craniocervical junction instability require anaesthetic and surgical attention [61].

7.9. Guidelines and divergences between sources

The two major Wilms tumour surveillance guidelines diverge on the risk threshold: the American Association for Cancer Research (AACR) paediatric cancer working group recommends surveillance from a risk of 1%, whereas the European host genome group of the International Society of Paediatric Oncology (SIOP-E) and the SIOP renal tumour study group recommend it from 5% [35, 36]. This results in practical differences: the AACR recommends Wilms and hepatoblastoma surveillance in all BWSp except CDKN1C, including IC2 loss of methylation, because it considers the blood epigenotype unreliable; SIOP-E does not recommend Wilms surveillance in IC2 loss of methylation (risk below 1%) and recommends it for CDKN1C (about 1%) [35, 36]. In PROS, the AACR proposes shared decision-making in CLOVES syndrome, and SIOP-E does not recommend surveillance [35, 36]. In isolated lateralised overgrowth without other features of BWSp and without a molecular alteration, SIOP-E does not recommend surveillance, but advises testing the overgrown tissue in significant cases and starting surveillance while awaiting the result [35]. The 2006 United Kingdom protocols (renal ultrasound every 3 to 4 months until 5 years, or until 7 in BWS and Simpson-Golabi-Behmel syndrome), reproduced in reference books, have been superseded by the 2021 SIOP-E guideline [35, 117].

For neuroblastoma in Weaver syndrome, the sources give different estimates: 5% to 7% in GeneReviews, 9% (3 of 34 carriers of an EZH2 variant) in the OGID cohort, about 9% (5 of 56) in the review cited by the AACR for Wilms and a penetrance of 11% in the AACR table for neuroblastoma, which counts 6 neuroblastomas in 56 patients [3, 22, 36, 39]. All derive from small series with probable publication bias, but converge on the recommendation of neuroblastoma surveillance in the United States [22, 39].

7.10. Management in Perlman syndrome and the NFIX syndromes

There is no targeted treatment for Perlman syndrome, and management relies on neonatal intensive care, supportive care and Wilms tumour surveillance [6, 36]. In the neonatal period, care focuses on respiratory failure due to pulmonary hypoplasia, renal function and hydronephrosis, feeding and blood glucose, given the hyperinsulinism described [6, 40, 95]. In survivors, obstructive sleep apnoea was frequent and required adenotonsillectomy, lingual tonsillectomy, nocturnal continuous positive airway pressure and oxygen, or mandibular distraction in a child with progressive micrognathia; cricopharyngeal achalasia required annual dilatation, focal epilepsy required three antiseizure medications, and physiotherapy and occupational therapy were part of early intervention [43, 95]. Wilms tumour is treated according to the usual protocols, and nephron-sparing surgery, recommended by the UMBRELLA protocol in children with a genetic predisposition when size and location allow, is of particular interest because of the frequent bilaterality and diffuse nephroblastomatosis [35, 40]. Tolerance of chemotherapy was worse than expected in two reports: the patient reported by Meyer and colleagues had high-grade peripheral neuropathy and liver disease, attributed to sinusoidal obstruction syndrome, with vincristine and dactinomycin, and recurrent grade 4 myelosuppression during treatment of the relapse; the patient reported by Levy and colleagues, with bilateral nephroblastomatosis detected by surveillance at 6 months, had metachronous tumours with diffuse anaplasia, sequential partial nephrectomies and radical nephrectomy, and died at 32 months, in palliative care, after respiratory failure with sepsis and a pulmonary metastasis [43, 95]. These are isolated cases, which do not allow toxicity or tumour prognosis to be estimated across patients; Meyer and colleagues hypothesise that loss of exoribonucleases such as DIS3L2 may influence chemotherapy toxicity [43].

In Marshall-Smith syndrome, the priority is the airway: multilevel upper airway obstruction and recurrent pneumonia were the main cause of death, and an anticipatory and aggressive approach, often with tracheostomy, allowed survival into adulthood [61, 114, 115]. Non-traumatic fractures, osteopenia, progressive kyphoscoliosis and cervical stenosis with a risk of spinal cord compression require orthopaedic and neurosurgical follow-up [61, 71, 115]. Among adults with Malan syndrome, 86% were taking medication, mainly psychotropic drugs (58% of those taking drugs) and antiseizure medications (77% of those with electroencephalographic abnormalities), and 38% had difficulties taking them, requiring tablets to be crushed or liquids thickened [90]. The authors recommend prescribing psychotropic drugs only after interdisciplinary assessment, with monitoring of efficacy, adverse effects and weight, and considering densitometry and vitamin D supplementation because of the risk of fractures; only 29% were followed at a multidisciplinary centre with experience in the syndrome, and 54% had no regular mental health follow-up [90].

7.11. Management in Thauvin-Robinet-Faivre syndrome and in overgrowth due to excess CNP

There is no specific treatment or guideline for Thauvin-Robinet-Faivre syndrome; the most recent review recommends multidisciplinary management and prolonged follow-up, guided by each patient's manifestations rather than by a protocol [6, 53]. In practice, this means cardiological assessment with echocardiography and electrocardiography at diagnosis and serial electrocardiograms, because of the complete atrioventricular block that arose in adolescence in a patient already operated on for congenital heart disease; renal ultrasound; ophthalmological examination, because of the coloboma, cataracts, refractive errors and uveitis described; hearing assessment; airway assessment in the presence of stridor or respiratory infections; developmental assessment with educational support; and orthopaedic follow-up of deformities and bone lesions [9, 53, 98]. Complications are treated according to the standards for each, such as a pacemaker for atrioventricular block, surgery for subglottic stenosis, immunomodulation for intermediate uveitis and surgery for varicose veins in adults [53, 99]. The European Wilms tumour surveillance consensus (SIOP-E, 2021) considers that, in this syndrome, Wilms tumours have been described only sporadically and does not recommend ultrasound surveillance [35]. The predisposition to carcinomas rests on a single patient, and the sources consulted do not propose screening; prompt assessment of cervical, thyroid or parotid masses and of renal symptoms is the approach that follows from the cases described [6, 54].

In overgrowth due to excess CNP there is also no pharmacological treatment. Management is orthopaedic: percutaneous epiphysiodesis of the halluces in childhood, as in the mother and the elder daughter of the family described by Lauffer and colleagues in 2020, at 8 and 5 years; arthrodesis of elongated halluces; osteotomies and guided growth for valgus deformities of the hip, knee and ankle; surveillance and treatment of scoliosis, which may require surgery; and early diagnosis of slipped capital femoral epiphysis [7, 55, 56, 103]. For very high predicted height, knee epiphysiodesis was used in the Dutch patient, and the Dutch approach to tall stature proposes discussing this intervention when predicted adult height exceeds +2.3 SD [37, 108]. Blood pressure should be measured in adults, because of the hypertension described, and the low bone mineral density of the Japanese proband justifies considering densitometry [7, 55]. Vosoritide (Voxzogo®), a CNP analogue approved for achondroplasia, increases signalling through the same pathway and has no place in these entities, whose mechanism is excess of that signalling; there is no pathway antagonist in clinical use [7, 107].

8. Reproductive Options and Family Counselling

8.1. General principle

Recurrence risk, carrier detection and prenatal diagnosis depend on the specific diagnosis; the aetiological diagnosis is therefore the basis of counselling [1]. Several overgrowth syndromes are autosomal dominant and may be present in mildly affected relatives; when a family member has a known pathogenic variant, testing should be offered to other affected relatives, and the 50% transmission risk to offspring should be discussed, even if it seems early to do so with a paediatric patient [5].

8.2. Recurrence risks by mechanism

In Malan syndrome, most variants are de novo, but cases inherited from a mosaic parent and sibling recurrence due to gonadal or somatic and gonadal mosaicism have been described [25]. In Smith-Kingsmore syndrome, about 86% of patients have a de novo constitutional or early postzygotic variant, about 11% inherited it from an unaffected parent with gonadal mosaicism and about 3% from an affected parent [28]. In BWSp, maternal autosomal dominant transmission occurs in 10% to 15% of cases, and CDKN1C is altered in 10% of sporadic cases and in 40% of familial cases according to Smith's, whereas the 2018 international consensus gives about 5% of sporadic cases and the same figure of 40% in familial cases (section 5.4) [58, 60]; when a CDKN1C variant is identified, the mother and other relatives should be assessed, because expression may be subtle [5, 60]. In multilocus imprinting disorders, a maternal history of recurrent miscarriage or molar pregnancy should prompt consideration of maternal variants in maternal-effect genes, which imply a high risk of reproductive complications and of children with imprinting disorders [10].

8.3. Twins and assisted reproduction

Monozygotic twinning is more frequent in BWS, and discordant monozygotic twins (mainly female, with IC2 loss of methylation) are well known; the apparently unaffected twin should be examined and tested in several tissues and inclusion in tumour surveillance should be considered, because of the shared fetal circulation [10, 60]. BWSp due to IC2 loss of methylation is about ten times more frequent after assisted reproduction, with a low absolute risk [5, 60].

8.4. Testing of relatives and minors

In syndromes with tumour surveillance (hereditary BWSp, Simpson-Golabi-Behmel, Perlman, WT1 syndromes), testing of asymptomatic siblings has a direct benefit because it identifies those who need surveillance [34, 36]. The AACR recommends that siblings of a child with BWSp undergo genetic testing only if a hereditary cause has been identified, and that they be assessed clinically if they have features of the spectrum; positive siblings without cancer follow the same surveillance protocol [36]. The AACR also supports germline testing in all children with Wilms tumour or hepatoblastoma [36].

8.5. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic diagnosis are possible when the familial variant or chromosomal alteration is known [1, 25, 28]. In BWSp, methylation testing on amniocytes or chorionic villi can confirm the ultrasound suspicion, and maternal serum alpha-fetoprotein may be raised at 16 weeks in the presence of omphalocele [5, 10].

8.6. Perlman syndrome and the NFIX syndromes

In Perlman syndrome, the parents of a patient are carriers and each pregnancy has a 25% risk [1, 40]. Recurrence in sibships is documented from the Yemenite and Dutch families to the three affected siblings of non-consanguineous parents described in 2025, and consanguinity is rare in the published series (two of seven sibships in the 2008 review) [40, 42, 43]. In a non-consanguineous North American family of Polish and German origin, both parents were carriers of the exon 9 deletion; with a carrier frequency of about 1 in 1233 in non-Finnish Europeans, the authors calculated a birth prevalence of about 1 in 6 million in that population [95]. Carrier testing of the partner of a carrier requires analysis of exonic deletions, because the exon 9 deletion is recurrent and arises by independent mechanisms [93, 96]. Heterozygous carriers do not have the syndromic phenotype, but heterozygous germline DIS3L2 variants predispose to Wilms tumour with low penetrance [96]. The sources consulted do not establish a surveillance recommendation for heterozygous siblings of a patient with Perlman syndrome, and the decision should be discussed with paediatric oncology. Siblings with a biallelic genotype should be identified early, because the attenuated phenotype may go unnoticed and quarterly renal surveillance until 7 years is recommended [36, 43]. Prenatal diagnosis and preimplantation genetic diagnosis are possible when the familial variants have been identified, and ultrasound in subsequent pregnancies may show polyhydramnios, macrosomia, nephromegaly and ascites [40, 42].

In Malan and Marshall-Smith syndromes, almost all variants arise de novo [25, 49, 88]. In Malan syndrome, the risk to siblings is slightly higher than that of the population because of the possibility of parental gonadal mosaicism, already described in several families, and the parents should be tested for the proband's alteration; each child of an affected person would have a 50% risk, but there are no descriptions of people with Malan syndrome who have had children [25].

8.7. Thauvin-Robinet-Faivre syndrome and overgrowth due to excess CNP

In Thauvin-Robinet-Faivre syndrome, the parents of a patient are carriers, each pregnancy has a 25% risk and unaffected siblings have a two-thirds probability of being carriers; both parents and a sister of the patient reported by Duzenli and colleagues were heterozygous, and in the patient reported by Şiraz and colleagues only the father could be tested [9, 54, 100]. In consanguineous families and in those of Turkish origin, because of the recurrent variant, cascade testing of relatives and consanguineous partners has a high yield [51, 52]. The tumour risk of heterozygous carriers is a hypothesis raised from a single family, without data to justify surveillance [101]. Once both variants have been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic diagnosis are possible.

In NPR2 gain of function, inheritance is autosomal dominant and each child of an affected person has a 50% risk, with variable expressivity, so a parent with mild signs (borderline tall stature, halluces operated on in childhood) should be examined and tested [55, 56]. In NPPC overexpression due to translocation, the translocation in the patient reported by Bocciardi and colleagues was de novo [104]; parental karyotyping is always indicated, because a carrier of a balanced rearrangement may transmit it in balanced form or give rise to offspring with chromosomal imbalances, and the specific risk depends on the chromosomes and segments involved. With a de novo translocation, the recurrence risk for siblings is low.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency of the main entities

Frequency estimates for the rare syndromes are based on counts of published cases and not on population studies; for EED there were 19 published patients, for SETD2 fewer than 40, for PPP2R5D more than 100, for Tatton-Brown-Rahman syndrome more than 90 and for megalencephaly-capillary malformation more than 200 [23, 24, 27, 29, 32]. In the OGID cohort, recruited mainly from clinical genetics services in the United Kingdom, CHD8 variants accounted for 12 of 710 cases (1.7%), and in other studies de novo loss-of-function CHD8 variants were found in 9 of 2446 individuals with ASD and in 8 of 3730 with neurodevelopmental disorders [3, 26]. These figures describe selected cohorts and cannot be read as population prevalence.

9.2. Differences between populations

In Sotos syndrome, the recurrent 1.9 Mb microdeletion including NSD1 is the most frequent molecular finding in the Japanese population (49 of 95 patients, 52%), whereas outside Japan intragenic variants predominate (1 of 17 non-Japanese patients with a microdeletion; 83% intragenic variants and 10% microdeletions in a mainly European cohort of 266 patients) [6, 59]. In BWS, Caucasian patients had more omphalocele and non-Caucasian patients more nephromegaly and hyperinsulinism, sometimes requiring partial pancreatectomy; umbilical hernia is more frequent in African Americans in the general paediatric population [60]. Mulibrey nanism, which enters the differential diagnosis of Wilms tumour with growth restriction, has a Finnish founder variant, TRIM37 NM_015294.6:c.493-2A>G p.?, at a splice acceptor site [36].

Data from Portugal are not included in the sources consulted. From Brazil, the sources include the first published Brazilian case of Malan syndrome, described at the Federal University of São Paulo and summarised in section 10 [123]. The absence of national estimates in the sources consulted does not mean that no published data exist.

In rare syndromes without a population estimate, the geographical distribution mainly reflects the published series. In Perlman syndrome, the families described include the original Yemenite Jewish family, Pakistani and Dutch families in the identification of the gene, and patients of Albanian, French (Réunion Island), Japanese and North American origin; the exon 9 deletion was found in homozygous form in Dutch and Japanese patients and in heterozygous form in 28 of 34 children from nine countries with Wilms tumour and a DIS3L2 variant, without evidence of a common founder among the Dutch carriers [40, 42, 91, 93, 96]. In the NFIX syndromes, the main series come from France, the Netherlands, the United Kingdom, Germany, Italy, Spain and the United States [49, 50, 88–90, 114].

In Thauvin-Robinet-Faivre syndrome, the first family was North African and was studied in France, the second was Arab, and five of the eight published families are Turkish and share the same variant, suggesting a founder effect in that population; the compound heterozygous patient was Caucasian and the daughter of non-consanguineous parents [51–53, 98, 99]. Patients with NPPC overexpression due to rearrangement come from Italy, France and Korea, and families with NPR2 gain of function from Japan, the Netherlands, Korea and Russia [56, 57, 103–108]. The sources consulted include no patients from Portugal or Brazil with these two entities.

9.3. Special populations

The North American and European guidelines differ in the risk threshold that justifies surveillance (1% versus 5%), which reflects differences in healthcare culture and not in evidence; the AACR acknowledges that its recommendations are based on the North American culture of care [35, 36]. In trisomy 18, Wilms and hepatoblastoma surveillance should be decided jointly, considering the family's goals of care, and, if carried out, renal ultrasound is extended until 12 years [36]. Parents of children with BWSp who were surveyed reported that surveillance gave them comfort, as did knowing their child's actual risk [36].

9.4. European reference networks and patient associations

The relevant European reference networks are ERN ITHACA, for rare congenital anomalies and intellectual disability (https://ern-ithaca.eu), ERN GENTURIS, for genetic tumour risk syndromes (https://www.genturis.eu), VASCERN, for rare vascular diseases, including vascular anomalies (https://vascern.eu), and ERN PaedCan, for paediatric cancer (https://paedcan.ern-net.eu). Patient associations include the Child Growth Foundation (https://www.childgrowthfoundation.org), the Sotos Syndrome Support Association (https://sotossyndrome.org), the Beckwith-Wiedemann Children's Foundation International (https://beckwith-wiedemannsyndrome.org), the Proteus Syndrome Foundation (https://www.proteus-syndrome.org), the CLOVES Syndrome Community (https://www.clovessyndrome.org) and the M-CM Network (https://www.m-cm.net) [1, 117].

10. Illustrative Clinical Case

Bellucco and colleagues, from the Federal University of São Paulo, published in 2019 the first Brazilian case of Malan syndrome [123]. The patient was the first child of healthy, non-consanguineous parents, born at 34 weeks and 1 day after an uneventful pregnancy, with a weight of 2645 g (+0.37 SD), length of 47 cm (+1.9 SD) and HC of 35 cm (+3.9 SD), corrected for gestational age [123]. At 20 months he measured 87 cm (+1 SD), weighed 12 kg and had an HC of 50 cm (+1.72 SD); he had relative macrocephaly, a long face, frontal bossing, a flat frontal haemangioma, down-slanting palpebral fissures, deep-set eyes, long eyelashes, an open mouth, a pointed chin, long hands, a slender habitus and severe hypotonia [123]. The first seizure occurred at 10 months and evolved into tonic seizures, controlled first with phenobarbital and then with clonazepam and valproate; the electroencephalogram showed bilateral frontotemporal sharp waves, and brain MRI showed reduced periventricular white matter with compensatory dilatation of the lateral and third ventricles [123].

At 9 years and 8 months he measured 135 cm (−0.24 SD) and had an HC of 56.5 cm (more than 3 SD), moderate thoracolumbar scoliosis, pectus carinatum, exotropia and a pale retina; at 19 years and 7 months he measured 155 cm (−3.01 SD), weighed 45 kg and had an HC of 57.5 cm (+2 SD), that is, relative macrocephaly, with the scoliosis reducing his height [123]. Assessment at 19 years showed standard scores below 40 in all domains of the Vineland Adaptive Behavior Scale (second edition), communication limited to vocalisations and some gestures, IQ impossible to determine and no clinically significant behavioural problems on the Child Behavior Checklist, although the mother and the geneticist noted anxiety in new situations [123]. The karyotype was normal, and CytoScan 750K microarray showed a 990 kb deletion, arr[GRCh37] 19p13.2p13.12(13068720_14053305)×1, which includes NFIX, CACNA1A and 15 other coding genes, among them CC2D1A and NACC1 [123]. Figure 1 of the article shows the patient at 19 years and 7 months with macrocephaly, a long face, frontal bossing, down-slanting palpebral fissures, deep-set eyes, anteverted nares, an open mouth and a pointed chin; the legend was read in the PubMed Central full text, and the article is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC6900369/ [123].

In the review accompanying the case, 15 of 31 patients (48.5%) with a 19p13 deletion including NFIX had postnatal overgrowth in height, only 2 of 22 (9%) had a birth length greater than 2 SD, 9 of 25 (36%) had an HC greater than 2 SD at birth and 18 of 31 (58%) after birth [123]. Seizures occurred in 12 of 27 patients with a deletion including CACNA1A and in 4 of 8 with a deletion not including it, so the authors could not confirm that CACNA1A haploinsufficiency is the only factor responsible for the seizures [123]. The case illustrates three aspects of the approach: overgrowth may be limited to HC and to early childhood, adult height may fall below the mean, and microarray identifies contiguous gene deletion syndromes that a sequencing panel may not detect. The antiseizure treatment described is that of the report and does not constitute a specific recommendation.

The second case illustrates Thauvin-Robinet-Faivre syndrome and was published by Şiraz and colleagues in 2026 [54]. A 16-year-old girl, the daughter of consanguineous Turkish parents, was seen for a right cervical and chin swelling of six months' duration, after right hemithyroidectomy and excision of a right parotid mass at another hospital, whose histology showed a non-invasive follicular thyroid carcinoma (3 × 2.5 cm nodule) and a low-grade mucoepidermoid carcinoma of the parotid (3.5 × 3 cm). She had been born at term weighing 2800 g, walked at 3 years and began to speak between 6 and 7 years; she had two healthy siblings, a sister with congenital heart disease and two siblings who had died in the neonatal period of unknown cause. She measured 159.3 cm (29th centile), weighed 59.6 kg (66th centile) and had an HC of 56.8 cm (77th centile) and an arm span of 163 cm, with complete puberty and menarche at 12.5 years. She had a flat midface, mild right ptosis, deep-set eyes, thick lips, thick eyebrows with mild synophrys, a pointed chin and posteriorly rotated ears; mild pectus excavatum, flat feet, large hands and feet, extensive port-wine stains on the limbs, varicose veins in both lower limbs, syndactyly of the 2nd and 3rd toes of the left foot, flexion contracture of a finger after haemangioma surgery, multiple naevi and ID, with an intelligence quotient of 65. Radiography showed mild thoracic scoliosis, renal ultrasound was normal, venous Doppler ultrasound showed dilated perforating veins with reflux and echocardiography mild mitral valve prolapse and a small atrial septal defect. Exome sequencing of the patient and her father identified the homozygous variant NM_004214.5:c.412-3_415dup, classified as likely pathogenic (PVS1, PM2), with the father heterozygous; no maternal DNA was available. No metastatic or residual disease was found. The case shows that the syndrome can present without macrosomia, tall stature or macrocephaly, with soft tissue overgrowth and vascular malformations that lead first to consideration of the PIK3CA-related spectrum, and that the tumours described in this syndrome are not limited to Wilms tumour; this is an isolated observation, which does not support a screening protocol [35, 54].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Prognosis depends on the entity. Marshall-Smith syndrome has early mortality due to airway obstruction, reduced with aggressive airway management [61, 71]. In Perlman syndrome, more than half of children die in the first year of life, and about 70% of survivors of the neonatal period develop Wilms tumour; survival after multimodal therapy of tumours detected by surveillance has been described [35, 36]. In BWS, infant mortality was estimated at 21% in older series, children who survive infancy are generally healthy and adult height is normal; neurodevelopment is similar to that of the population, except when there is prematurity (34% to 41%) or hypoglycaemia (30% to 50%) with sequelae [5, 60]. In Sotos syndrome, the estimated overall tumour risk does not exceed 3% to 5% [36]. Proteus syndrome stabilises after adolescence, but thromboembolic and tumour complications persist [33, 111]. In PHTS, adult tumour risk (thyroid, breast, endometrium) defines follow-up from adolescence onwards [1, 6].

Wilms tumour has a survival of about 90% in localised disease and 70% in metastatic disease; the main aim of surveillance is to diagnose smaller and less advanced tumours, with less treatment and less morbidity [117]. Detection of smaller tumours allows nephron-sparing surgery, recommended by the 2016 SIOP-RTSG UMBRELLA protocol in children with a genetic predisposition when size and location allow [35]. In BWSp, children under surveillance had earlier diagnosis of Wilms tumour than those not under surveillance, and alpha-fetoprotein screening was associated with earlier-stage hepatoblastoma and a better prognosis [10, 36]. Surveillance has costs: in one series, 25 of 63 children (40%) with BWSp under surveillance had renal or hepatic findings that prompted investigation, and nephrectomies for infected renal cysts interpreted as tumour have been described [35].

In the rarer entities, prognosis has changed with survival beyond childhood. In Perlman syndrome, most die in the first year, but there are patients with molecular confirmation alive at 6, 9, 10 and 12 years at the time of publication, most with at least one variant compatible with residual protein and all with developmental delay [43, 94]. In Marshall-Smith syndrome, the oldest patient in the international series was 30 years old [114]. In Malan syndrome, the oldest adult in the survey was 60 years old and in relatively stable health, with age-related manifestations (presbyopia, arterial hypertension, left ventricular dilatation), and speech improved with age in most adults [90].

In Thauvin-Robinet-Faivre syndrome, the vital prognosis depends mainly on cardiac malformations, conduction disorders and the airway, and the oldest patient described was over 23 years old; in overgrowth due to excess CNP, the vital prognosis does not appear to be altered in the sources, and the oldest patient with NPR2 gain of function was assessed at 61 years, morbidity being mainly orthopaedic [53, 56, 99, 108].

11.2. Comparative tumour surveillance

In practice, the AACR recommends, for all syndromes with a Wilms risk above 1%, renal ultrasound every three months from birth or diagnosis until the seventh birthday, which covers the age at which 95% of tumours arise; when there is also a risk of hepatoblastoma (BWSp, trisomy 18, Simpson-Golabi-Behmel, Bohring-Opitz, one of the ASXL syndromes), the ultrasound is complete abdominal until the third birthday and serum alpha-fetoprotein is measured every three months until 36 months, a period reduced from the 48 months of the 2017 recommendations [36]. Interpretation of alpha-fetoprotein uses BWSp-specific normative values and the trend over time: small rises do not require investigation; a rise above 50 to 100 ng/mL leads to review of the last ultrasound and repeat measurement six weeks later; two successive rises lead to MRI or contrast-enhanced ultrasound; and values above 1000 ng/mL require confirmation and urgent imaging [36]. Six-monthly physical examination by a geneticist or paediatric oncologist is also recommended, with education of the family about tumour signs [36]. SIOP-E recommends the same three-month interval (and not four, because practical delays would increase the stage at diagnosis) until the seventh birthday, the age by which 90% of sporadic Wilms tumours, 94% of BWS tumours and more than 95% of tumours in WT1 syndromes have been diagnosed; the ultrasound is renal, except in BWSp, lateralised overgrowth and Simpson-Golabi-Behmel syndrome, in which it is complete abdominal [35]. Ultrasound should be performed by an operator experienced in paediatric ultrasound, without the need for fasting or bladder preparation, with high-frequency probes, and lesions detected should be managed at a specialist centre; contrast-enhanced ultrasound helps to distinguish haemangioma from hepatoblastoma without sedation [35, 36].

11.3. Non-tumour surveillance

11.4. Transition to adulthood

The transition to adult care should convey the aetiological diagnosis and its significance: in PHTS adult cancer surveillance begins, in Malan syndrome and Smith-Kingsmore syndrome aortic root surveillance continues, and in syndromes in which tumour surveillance ended in childhood adults should know that the residual risk is low but not zero [6, 25, 28, 36]. In BWS, data on tumour risk in adulthood are insufficient, and Smith's reports a risk of hearing loss, aneurysmal arterial dilatations and male infertility in adults [60].

12. Summary and Final Considerations

Overgrowth is a finding, not a diagnosis. The approach begins with rigorous measurement and classification of the pattern: global overgrowth of prenatal or postnatal onset, disproportionate macrocephaly, or lateralised or segmental overgrowth. In global overgrowth with ID, the most frequent monogenic causes are the epigenetic regulation genes, led by NSD1, followed by the PI3K/AKT/mTOR pathway genes, and a panel or exome with copy number variant analysis identifies the cause in about half of clinical genetics patients. In tall stature without ID, secondary causes (precocious puberty, hyperthyroidism, growth hormone excess, obesity) and the most frequent primary causes (Klinefelter, Marfan) should be sought before concluding that tall stature is idiopathic. In prenatal overgrowth with macroglossia, omphalocele or hypoglycaemia, 11p15 methylation testing is the first test. In lateralised or segmental overgrowth, mosaicism is the rule, testing should be performed on affected tissue and at high depth, and a negative result in blood does not exclude the diagnosis.

The aetiological diagnosis determines tumour surveillance, which is the decision with the greatest consequences for the child. Syndromes with embryonal tumours (BWSp, Simpson-Golabi-Behmel, Perlman) justify quarterly ultrasound until seven years, with abdominal ultrasound and alpha-fetoprotein until three years when there is a hepatoblastoma risk; Weaver syndrome and BWSp due to CDKN1C justify neuroblastoma surveillance until ten years in the North American guideline; and Sotos, Malan and CHD8 syndromes do not justify routine surveillance. The North American and European guidelines diverge on the risk threshold (1% versus 5%), especially in IC2 loss of methylation, CLOVES syndrome and isolated lateralised overgrowth, and the decision should be shared with the family. Alpelisib is the only authorised targeted therapy, only for severe PROS, with accelerated approval in the United States and conditional authorisation in the European Union since July 2026.

Thauvin-Robinet-Faivre syndrome, recessive due to loss of FIBP, combines overgrowth, macrocephaly and ID with cardiac, renal and ocular malformations and, in one patient, complete atrioventricular block, and requires cardiac surveillance without protocol-based tumour surveillance; overgrowth due to excess CNP–NPR-B signalling, caused by a translocation next to NPPC or by NPR2 gain of function, is recognised by long and broad halluces, requires karyotyping in addition to sequencing and is managed orthopaedically.

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