5p13 Duplications (NIPBL-Containing Microduplication and 5p13.3p13.2 Duplication) and Trisomy 5p

The class of duplications of the short arm of chromosome 5: NIPBL-containing 5p13 microduplication syndrome (main entity), 5p13.3p13.2 duplication without NIPBL, complete and partial trisomy 5p, supernumerary marker chromosomes derived from chromosome 5, and isolated SLC1A3 duplication.

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Historical overview

The study of duplications of the short arm of chromosome 5 began in the era of classical cytogenetics. The first description of a partial trisomy 5p is attributed to Lejeune and colleagues, in 1964, according to the reviews by Cervera and by Erdem, which cite that work [32, 33]. In 1975, Opitz and Patau published the delineation of a "partial trisomy 5p syndrome", which established the term in the dysmorphology literature [34]. In 1982, Khodr and colleagues described the first prenatal diagnosis of a 5p13→pter duplication, by amniocentesis, in a family with a maternal t(5;13) translocation whose first child had Cri-du-Chat syndrome; in the case review accompanying that report, the severity of the phenotype was proportional to the length of the duplicated segment, with p11→pter duplications at the severe end and almost no signs when only 5p14→pter was involved [13].

Over the following two decades, attention shifted to the proximal portion of the short arm. In 1997, Lorda-Sánchez and colleagues described a 5p11→p13.3 duplication resulting from a maternal ins(19;5) insertion and confirmed the increased dosage by FISH and by assaying complement components whose genes lie in 5p13; the authors proposed that band 5p13 played a particular role in severity [35]. D'Amato Sizonenko and colleagues, in 2002, gathered seven supernumerary marker chromosomes derived from chromosome 5 (SMC5) and confirmed a critical region in 5p13, adding that the degree of mosaicism contributes to severity [14]. Loscalzo and colleagues, in 2008, described a de novo interstitial dup(5)(p11p13.3) duplication with developmental delay, seizures and congenital heart disease, which reinforced the same critical region [15].

The era of chromosomal microarray (CMA) made it possible to recognise submicroscopic duplications. In 2009, Yan and colleagues, at the Baylor College of Medicine diagnostic laboratory, identified five unrelated patients with 5p13 duplications containing the NIPBL gene and a sixth with a 7.14 Mb duplication in Xp containing SMC1A; the work followed a "reverse genomics" approach, in which the dosage change of a gene precedes clinical delineation, and concluded that increased dosage of cohesin genes produces a picture distinct from Cornelia de Lange syndrome (CdLS), without its facial gestalt [10]. OMIM entry #613174, created in December 2009, is based on that work [2]. Oexle and colleagues (2011) added a 3.7 Mb tandem duplication in 5p13.1–p13.2 in a man with macrocephaly, obesity, lymphoedema and arterial hypertension [3]. Novara and colleagues (2013) described a patient whose duplication contained only NIPBL and whose phenotype overlapped that of the smaller duplications, which reinforced NIPBL as the main dosage-sensitive gene [11].

From 2015 onwards, the literature added modes of transmission and subgroups. Walters-Sen and colleagues reported the first family with an inherited 5p13.2 duplication and several affected members, in which the duplicated segment was inserted into Xp [19]. Iourov and colleagues described, in the same year, a de novo duplication of about 994 kb in 5p13.3p13.2 that did not include NIPBL [4]. Van Amen-Hellebrekers and colleagues (2016) described four patients with gains restricted to SLC1A3 [8]. Kariminejad and colleagues (2023) reported a malformed fetus with a 667 kb duplication containing NIPBL, inherited from a healthy father, thereby documenting incomplete penetrance [18]. In 2025, Kim and colleagues reviewed complete trisomy 5p and counted 15 published cases [24]. In 2026, Wang and colleagues described a 5p13.3p13.2 duplication without NIPBL, inherited from a healthy father and diagnosed prenatally, with a normal newborn at six months [5].

1.2. Nomenclature and reclassifications

Databases use different designations for the same entities. Orphanet designates the main entity "5p13 microduplication syndrome" (ORPHA:329802), with the synonyms "Dup(5)(p13)" and "Trisomy 5p13", classifies it as a malformation syndrome and defines it as a rare partial autosomal trisomy or tetrasomy, which also includes triplications [1]. OMIM uses "chromosome 5p13 duplication syndrome" (#613174) and treats it as a contiguous gene syndrome involving duplication of several 5p13 genes, NIPBL among them [2]. Orphanet maintains, separately, "trisomy 5p syndrome" (ORPHA:1742), defined as duplication of a segment of variable size of the short arm, without a corresponding OMIM entry [6]. The literature also uses "dup(5p13) syndrome", "proximal trisomy 5p" for pericentromeric markers and "5p duplication syndrome" for large duplications [3, 7, 15]. In international cytogenetic notation (ISCN), "dup" designates a duplication, with the proximal and distal bands in parentheses; in microarray formulas, copy state is indicated as ×3 or ×4 [5, 36].

The designation "5p13.3p13.2 duplication" literally describes the TARS1–SLC45A2 interval without NIPBL, whereas the identifiers OMIM 613174 and ORPHA:329802 associated with it correspond to the NIPBL-containing syndrome in 5p13.2; this article therefore treats the NIPBL-containing syndrome as the main entity and the 5p13.3p13.2 duplication without NIPBL as a subgroup in its own right [1, 2, 4, 5].

Two database errors should be noted. GeneGuidance links CdLS type 1 (OMIM 122470) to ORPHA:329802, whereas CdLS corresponds to ORPHA:199 and ORPHA:329802 has an exact mapping to OMIM 613174 [1, 37]. The Orphanet epidemiological record for ORPHA:329802 cites PMID 20052029, which does not correspond to any article; the founding article by Yan and colleagues has PMID 19052029 [10]. There is also a cytoband discrepancy: the Oxford Desk Reference places NIPBL at 5p13.1, whereas NCBI Gene, OMIM and Orphanet place it at 5p13.2, which is the location adopted [38–40].

1.3. Definition of the entities and classification of the class

There is no formal published classification of 5p duplications. The following organisation, by gene content and size, combines the Orphanet and OMIM definitions with the published series and serves as the framework for the rest of the article [1, 2, 6, 13, 16].

NIPBL-containing 5p13 microduplication syndrome is defined by a submicroscopic interstitial duplication in 5p13.2 that includes the complete NIPBL gene, with or without neighbouring genes, in a patient with developmental delay or ID, behavioural problems and variable facial dysmorphism [10, 11, 18]. The 5p13.3p13.2 duplication without NIPBL is a more distal gain, in the TARS1–SLC45A2 interval, of uncertain clinical significance [4, 5]. Trisomy 5p is the duplication of most or all of the short arm (5p10/p11→pter), visible on karyotype, either isolated ("pure") or accompanied by a partial monosomy of another chromosome when it results from an unbalanced translocation [6, 20, 24]. SMC5 are small extra chromosomes with pericentromeric material from chromosome 5, frequently mosaic, whose effect depends on whether or not they contain band 5p13 [7, 16]. Isolated SLC1A3 duplication is a gain restricted to this gene, associated with ADHD-like or autistic behaviour [8]. Intragenic NIPBL duplications, which disrupt the gene and cause CdLS through loss of function rather than a dosage-gain phenotype, are also distinguished [41].

2. Molecular Genetics and Pathophysiology

2.1. The NIPBL gene and the cohesin complex

The NIPBL gene (NIPBL cohesin loading factor; OMIM 608667; HGNC:28862) lies at 5p13.2, at GRCh38 coordinates chr5:36,876,769–37,066,413, and encodes delangin [39, 40, 48, 49]. The MANE Select transcript is NM_133433.4 (ENST00000282516.13, transcript variant A); NM_015384, cited by GeneGuidance, corresponds to transcript variant B [12, 48]. The protein is the human homologue of Drosophila Nipped-B and yeast Scc2; together with MAU2 it forms the complex that loads the cohesin ring onto chromatin, including at sites of double-strand breaks and ultraviolet radiation damage [40, 48]. Cohesin, whose core is formed by SMC1A, SMC3 and RAD21, regulates chromosome segregation, genome stability, three-dimensional chromatin organisation and transcription; NIPBL and MAU2 also take part in chromatin loop extrusion [22]. NIPBL binds preferentially to promoters with paused RNA polymerase II and, through this transcriptional role more than through sister chromatid cohesion, controls the expression of developmental genes and cortical neuronal migration [48].

Heterozygous loss of function of NIPBL causes CdLS type 1 (OMIM #122470), with autosomal dominant inheritance; the gene was identified in 2004 from a de novo balanced translocation with a breakpoint in 5p13 and from a critical region defined by genetic linkage and by a 5p14.2-p13.1 deletion [50]. NIPBL accounts for about 80% of CdLS cases according to the 2026 GeneReviews, whereas Smith and the Brazilian book Síndromes Genéticas: Reconhecer para Tratar give about 65%; the difference reflects the period and the denominator of the series [22, 49, 51]. In CdLS, missense variants and in-frame deletions are associated with less growth deficiency and milder ID than loss-of-function variants, a gradient indicating that severity follows the reduction in gene activity [10, 22].

The dosage sensitivity curation of the Clinical Genome Resource (ClinGen), evaluated on 26 August 2020, assigns NIPBL a haploinsufficiency score of 3 (sufficient evidence) and a triplosensitivity score of 1 (little evidence for dosage pathogenicity), the latter supported by the work of Yan (2009) and Novara (2013) [29]. In the ClinGen region file consulted in October 2026 there is no curated region for the 5p13 duplication; on the short arm of chromosome 5 only the terminal 5p15.33-p15.2 Cri-du-Chat syndrome region is curated [29]. The practical consequence is that a duplication containing the whole of NIPBL does not receive, under the ACMG and ClinGen rules, the score for overlap with an established triplosensitive gene, and its classification depends on case evidence and inheritance (section 5.4) [27].

2.2. Architecture of NIPBL-containing microduplications

The duplications in the founding series are not recurrent: they are not flanked by low-copy repeats (LCR), have different breakpoints in each patient and arise by distinct mechanisms [10]. The gains were confirmed by interphase FISH, with the extra copy adjacent to the original, indicating an interstitial duplication, and were not found in the parents tested (both parents in two patients; the mother in three) or in the Database of Genomic Variants [10]. The original coordinates, in NCBI36, were converted to GRCh37 and GRCh38 with the Ensembl assembly mapping service [10, 52].

The mechanisms identified were non-homologous end joining (NHEJ), non-allelic homologous recombination (NAHR) and replication fork stalling and template switching (FoSTeS) [2, 10]. Patient 5 had NIPBL only partially duplicated, which probably does not increase gene expression, and had the phenotype least similar to the others, with interpretation complicated by maternal alcohol exposure in the first trimester [10]. Patient 4, with NIPBL as the only duplicated gene, had a severe cranial deformity due to multiple craniosynostosis, whose relationship to the duplication the authors could not establish [10].

Later observations extended the interval. Novara and colleagues described a duplication of at least 264 kb with NIPBL as the only gene, with a phenotype overlapping that of the smaller duplications [11, 16]. Oexle and colleagues described a de novo 3.7 Mb tandem duplication in 5p13.1–p13.2, between markers rs4703415 and rs261752 (chr5:35.62–39.36 Mb, genome build not stated in the abstract) [3]. Kariminejad and colleagues described a 667 kb gain in 5p13.2 with SLC1A3, NIPBL and exons 22–52 of CPLANE1, inherited from a healthy father with no evidence of mosaicism [18]. In the Walters-Sen family, the duplicated segment contained the 3′ portion of SLC1A3 and the 5′ portion of NIPBL and was inserted into Xp, der(X)ins(X;5)(p2?2.1;p13.2p13.2) [19]. In a French series of developmental language disorder without ID, autism or apraxia, one family had a 616 kb paternal tandem duplication, NC_000005.9:g.37009768_37625742dup (GRCh37; GRCh38 chr5:37,009,666–37,625,640 by Ensembl conversion), with partial NIPBL, CPLANE1 and NUP155, classified as a variant of uncertain significance (VUS) [42, 52]. Duplications described as 5p13 syndrome up to 2013 ranged from 0.25 to 13.6 Mb [11].

2.3. Clinically relevant genes in the 5p13 region

Interpreting a 5p13 duplication requires knowledge of the genes in the interval and the disorders associated with them, bearing in mind that, for almost all of them, the effect of gaining one copy has not been established.

The book Bone Dysplasias also cites a brachydactyly type A1 locus at 5p13.3-p13.2 (Armour and colleagues, 2002), as an indirect assignment and with no relationship to the duplications described [59].

2.4. 5p13.3p13.2 duplication without NIPBL

The most distal interval of 5p13 has been described in two cases. Iourov and colleagues found a de novo duplication of about 994 kb, GRCh37 chr5:33,130,008–34,124,081 (GRCh38 chr5:33,129,902–34,123,976, in two contiguous blocks), with 11 genes, six of them in OMIM (TARS1, ADAMTS12, RXFP3, SLC45A2, AMACR, C1QTNF3), without NIPBL or the critical region of 5p13 syndrome [4, 52]. In addition to the severe phenotype, the patient had low-level somatic aneuploidy (3 to 7 times above the reference mean, by interphase FISH for chromosomes 1, 7, 16, 17, 18, X and Y), which the authors linked to chromosomal instability through bioinformatic analysis of the interaction networks of ADAMTS12 and AMACR via NOTCH1 and TP53; this hypothesis has not been replicated [4, 5]. Wang and colleagues described a 762 kb duplication, arr[GRCh37] 5p13.3p13.2(33,405,597_34,167,786)×3 (GRCh38 chr5:33,405,491–34,167,681), with seven coding genes (ADAMTS12, AMACR, C1QTNF3, RXFP3, TARS1, SLC45A2 and the C1QTNF3-AMACR fusion transcript), inherited from the healthy father; none of the genes has a ClinGen triplosensitivity assignment, according to the authors, and the duplication was classified as a VUS [5, 52]. The authors propose that this duplication should not be considered part of 5p13 duplication syndrome and should be assessed on its own; they also state that the duplications of the syndrome are "typically larger than 5 Mb", which contradicts the sizes of 0.25 to 1.08 Mb in the Yan and Kariminejad series [5, 10, 18].

2.5. Trisomy 5p and marker chromosomes derived from chromosome 5

Large trisomy 5p arises through several mechanisms. Unbalanced segregation of a parental reciprocal translocation produces, in the same family, offspring with partial trisomy 5p and with 5p monosomy, as in the Brazilian family with t(5;15)(p13.3;p12) followed over four generations, with eight balanced carriers, five living patients with trisomy 5pter→p13.3 (about 32 Mb) and six with Cri-du-Chat [20]. De novo inverted duplication, such as the inv dup(5)(p15.3p13.3) of Cervera, and inverted duplication with terminal deletion, such as the 40 Mb duplication in 5p13.1→p15.33 with an 800 kb terminal loss described by Izzo, are other forms [32, 46]. Insertion of 5p into a non-homologous chromosome, such as the ins(19;5) of Lorda-Sánchez, gives proximal trisomy with a balanced parental karyotype [35]. Terminal rearrangements may be isolated or result from a reciprocal translocation, and a parent carrying a balanced translocation may have a normal microarray [31].

SMC5 are small markers, frequently mosaic, with a linear or ring structure. In the Armstrong case, the marker contained a 22 Mb duplication, hg19 chr5:31,513,816–53,752,188 (5p13.3–q11.2), with 195 genes, 68 of them in OMIM, 25 associated with disease and 10 with autosomal dominant disease, including NIPBL [16]. SMC5 account for 1.4% of characterised markers; SMC in general occur in about 0.044% of newborns, 70% de novo and 30% inherited [16]. In the marker database consulted by Armstrong, ten carriers of SMC limited to 5p11–q11.1 had no clinical findings, but three of four adult men had fertility problems [16]. In a ring marker r(5)(::p13.2~p13.3→q11.2::) present in 60% of cells, Sarri and colleagues described congenital heart disease and unusual facies [44]. Camerota and colleagues proposed that the presence of NIPBL in the marker predicts the neurobehavioural outcome [7].

2.6. Isolated SLC1A3 duplication and 5p13.1 duplication

SLC1A3 encodes EAAT1 (GLAST), a sodium-dependent glial glutamate and aspartate transporter that removes glutamate from the synaptic cleft and protects against neuronal hyperexcitability; pathogenic variants cause episodic ataxia type 6 [17]. In GRCh38 the gene occupies chr5:36,596,588–36,688,334 at 5p13.2, upstream of NIPBL, has 10 exons and encodes a 542-amino-acid protein; EAAT1 also functions as a glutamate-activated anion channel, and its expression is highest in cerebellar Bergmann glia, the substantia nigra, the red nucleus, the hippocampus and the cerebral cortex [9]. Episodic ataxia type 6 (OMIM #612656) is autosomal dominant and is known from few families: a boy with episodes of ataxia and dysarthria from birth, seizures, migraine and alternating hemiplegia, with cerebellar atrophy at 6 years, carrying the de novo variant NM_004172.5:c.869C>G p.(Pro290Arg) (c.1047C>G in historical numbering), which reduces glutamate uptake with a dominant-negative effect and increases anion currents; a Dutch family with three affected members and one unaffected carrier (reduced penetrance) with c.556T>A p.(Cys186Ser), which reduces uptake by 18% and is associated with a milder phenotype; and two cousins of European ancestry with progressive gait ataxia and dysarthria, without an episodic course, beginning in the fourth decade, with a variant that OMIM designates c.1361G>A p.(Arg454Gln) and that ClinVar describes as NM_004172.5:c.1496G>A p.(Arg499Gln), with conflicting pathogenicity classifications [9, 60]. The Glast-null mouse has motor incoordination in demanding tasks, persistent multiple innervation of Purkinje cells by climbing fibres and greater cerebellar oedema after injury; in the retina, GLAST in Müller cells is required for transmission between photoreceptors and bipolar cells [9]. These phenotypes result from loss or alteration of function, not from increased dosage, and therefore do not predict the effect of a duplication of the gene. Van Amen-Hellebrekers and colleagues described, in Nijmegen, four patients with similar gains in 5p13.2 limited to SLC1A3, with ADHD-like behavioural problems and autistic traits, and proposed that the gene contributes to the behaviour seen in the larger duplications overlapping the 5p13 syndrome region [8]. Kluger and colleagues described two children with generalised epilepsy from 2.5 years and 5p duplications of different sizes, with an overlapping region in 5p13.1 containing RICTOR, FYB, C9 and DAB2; the larger duplication was de novo and the smaller inherited from the father, and the authors proposed an epilepsy susceptibility locus in that band [43].

2.7. Intragenic NIPBL duplications

A duplication with both breakpoints within NIPBL can disrupt the reading frame and behave as a loss of function. In the cohort of Cheng and colleagues, of 510 patients with suspected CdLS and negative NIPBL sequencing, 13 copy number variants (CNV) of the gene were detected (2.5%): 12 deletions and one de novo intragenic duplication of exons 23–27, of about 5 kb, chr5:g.(37015062_37015875)_(37021035_37021455)dup in the article's coordinates (probably hg19), in tandem, with a 7 bp insertion (ATATAAT) and 1 bp of microhomology at the junction [41]. Patients with intragenic CNV had classic CdLS [41]. Under the ACMG and ClinGen rules, a duplication with both breakpoints in the same haploinsufficient gene scores as a possible loss of function (criterion 2I), which separates it from duplication of the whole gene [27].

2.8. Pathophysiology of dosage gain

The general principle is that trisomy of a segment is better tolerated than monosomy, which is why fewer duplication syndromes than deletion syndromes have been delineated [10, 31]. Yan and colleagues observed that the systems affected in NIPBL duplication are the same as in CdLS (neurodevelopment, skull and face, limbs), but with different manifestations: increased weight and long fingers in the duplication, as opposed to short stature, microcephaly and limb reduction defects in CdLS [10]. The review by Bastos and colleagues, from São Paulo, includes the 5p13 duplication among the seven CNV loci associated exclusively with macrocephaly, whereas loss of NIPBL is accompanied by microcephaly [50, 61]; the table in that review presents the NCBI36 coordinates of Yan's patient 1 as "hg38", which is a genome build error [10, 61]. The comparison suggests a mirror pattern between loss and gain, but macrocephaly is not constant: in the Unique compilation, only two adults and one child with a 5p13.2 duplication had macrocephaly, compared with eleven without known macrocephaly, and in the Yan series three of six patients had microbrachycephaly [10, 23].

In 2026, a preclinical study in mouse embryonic stem cells showed that the speed of loop extrusion by cohesin is regulated by the dosage of NIPBL and PDS5, and that NIPBL overexpression induces chromosome compaction into "vermicelli"-like structures, consistent with increased cohesin loading and faster extrusion [62]. This is a plausible mechanistic basis for an effect of dosage gain, but it has not been tested in models of the human duplication [62].

2.9. Genotype–phenotype correlations, penetrance and expressivity

The severity of 5p duplications follows their size and, above all, the inclusion of band 5p13. Among trisomies 5p, p11→pter duplications are the most severe and those involving only 5p14→pter have almost no signs [13]. Markers and proximal duplications that include 5p13 are associated with seizures, heart disease, hypotonia and poor weight gain, whereas cases without 5p13 have a milder phenotype [14, 15, 33, 44]. Izzo and colleagues suggested that the critical region for the severe phenotype is smaller than the whole band, when describing a fetus with a 40 Mb duplication that included half of 5p13 and had a mild phenotype [46]. In families with a translocation, the phenotype may be dominated by the reciprocal loss: in the t(5;15)(p13.3;q26.3), the three carriers of the 30 Mb gain of 5p had a phenotype explained mainly by the 2.5 Mb loss in 15q26.3 (IGF1R, CHSY1) [47].

In microduplications, complete NIPBL appears to be the main dosage-sensitive gene: duplication of NIPBL alone reproduces the phenotype, and partial duplication of the 3′ portion gives a less typical phenotype [10, 11]. SLC1A3 probably contributes to behaviour [8]. In the Unique compilation, corpus callosum abnormalities always occurred in duplications of the same 5p13.2 region, and the three babies who were small at birth had similar 5p13.2 duplications [23].

Penetrance is incomplete and expressivity variable. The duplication containing complete NIPBL was inherited from a healthy father in the Kariminejad fetus, with no evidence of paternal mosaicism [18]. A father with the same 5p13.2 duplication as his daughter had a first-class university degree [23]. A 5p13.2 duplication partially including NIPBL, inherited from the father, was found in a child with language disorder without ID [42]. In the 5p13.3p13.2 duplication without NIPBL, the same interval was associated with a severe de novo phenotype and with absence of signs in the father and the newborn, which is consistent with incomplete penetrance or with lack of causality [4, 5]. There is no penetrance estimate for the 5p13 region: the table of penetrance for recurrent CNV by Rosenfeld (2013), reproduced in the Oxford Desk Reference, does not include this region [31].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and limitations

Clinical knowledge of this class rests on case reports and small series. For the NIPBL-containing 5p13 microduplication, data with an explicit denominator come from the Yan series (five patients with NIPBL duplication and one with SMC1A duplication, aged six months to 30 years) and from the 2014 Unique compilation (23 people, from infancy to adulthood, nine from the literature, five association members and ten from DECIPHER, with 5p13 or 5p14 microduplications) [2, 10, 23]. The review tables of Novara (2013) and Kariminejad (2023) were not read, only the abstracts. For SMC5, the reference is the comparative table of 14 cases by Armstrong (2018); for complete trisomy 5p, the review of 15 cases by Kim (2025), read only as an abstract [16, 24]. The Orphanet phenotype annotation for trisomy 5p classifies 17 terms as "very frequent (80–99%)", without a denominator or primary source and with validation dating from 2016, so it cannot be used as a real frequency; there is no annotation for ORPHA:329802 [1, 6]. All data describe natural history under usual care, without specific treatment.

3.2. NIPBL-containing 5p13 microduplication: clinical picture

The Orphanet definition summarises the picture as global developmental delay, ID, autistic behaviour, hypotonia, macrocephaly and facial dysmorphism (frontal bossing, short palpebral fissures, low-set and dysplastic ears, short or poorly marked philtrum, high or narrow palate, micrognathia), together with sleep disturbance, seizures, aplasia or hypoplasia of the corpus callosum and skeletal anomalies (large hands and feet, long fingers, clubfoot) [1]. Kariminejad emphasises the marked variability of the facies and adds mild limb anomalies and, in some cases, brain malformations [18].

Table sources: [10, 23].

Neurodevelopment and cognition. All of Yan's patients had developmental delay and ID [2, 10]. In the Unique compilation, the need for learning support was usually mild to moderate, but a 23-year-old adult with the 3.7 Mb duplication in 5p13.1–p13.2 depended on his family for all personal care; at the opposite extreme, a father carrying the same 5p13.2 duplication as his daughter had a first-class university degree [23]. Speech delay is among the most frequent manifestations in the Unique list [23].

Behaviour. Yan's patients had self-injury, aggression, autistic traits, stereotypies, insensitivity to pain, hyperactivity, obsessive-compulsive behaviour, anxiety and attention deficit [10]. Oexle's patient had autistic behaviour [3]. Isolated SLC1A3 duplication is associated with ADHD and autistic traits, which suggests that this gene contributes to behaviour in the duplications that include it [8].

Central nervous system and epilepsy. The most frequently described abnormalities involve the corpus callosum (small, malformed or absent), followed by cortical asymmetry, periventricular hyperintensities with incomplete myelination and, in one case, an arachnoid cyst [23]. Yan described periventricular leukomalacia in the two scans available and agenesis of the corpus callosum in one patient [2, 10]. Epilepsy was described in three children in the Unique compilation; in one of them, with onset at 2.5 years, antiseizure medicines reduced the seizures, but the epilepsy remained partially drug-resistant [23]. Kluger described generalised epilepsy from 2.5 years in two children with overlapping duplications in 5p13.1, with normal MRI and, in one of them, photosensitivity on the electroencephalogram [43].

Skull and face. The dysmorphism is variable and does not form a recognisable gestalt. Common features are a broad or prominent forehead, bitemporal narrowing, short or slanting palpebral fissures, short philtrum, high palate and low-set ears; in isolated patients, strabismus, hypo- or hypertelorism, bulbous nose, micrognathia and low posterior hairline [2, 10]. The CdLS gestalt is absent: there is no synophrys, long eyelashes, long philtrum, thin upper lip or downturned corners of the mouth [10]. The skull may be elongated (dolichocephaly), tower-shaped (turricephaly) or short (brachycephaly), sometimes due to craniosynostosis [2, 23].

Growth and weight. Most of Yan's patients had low birth weight and overweight in adulthood: weight above the 95th centile at 18 years in patient 1, at the 90th centile at 6 years in patient 2 and above the 98th centile in patient 6 [10]. In the Unique compilation, most babies had a birth weight above 3 kg, three were small at birth (all with similar 5p13.2 duplications), stature followed the family pattern in most, and two of four adults were obese, one with a body mass index (BMI) of 40 and another with weight above the 95th centile; the man gained weight in adolescence [23]. Oexle's patient had obesity, lymphoedema and arterial hypertension [3].

Limbs and musculoskeletal system. Large hands and feet, long fingers, scoliosis and clubfoot are part of the definition [1, 2]. The Unique compilation adds joint hypermobility in two children, genu valgum in one and a severe lower limb deformity in a baby with a small duplication in 5p13.1, of uncertain causal relationship [23]. The Kariminejad fetus had clenched hands, flexion contractures of the elbows, knees and left wrist, bilateral clubfeet, and bowing and shortening of the long bones [18].

Other systems. In isolated cases, all with duplications in 5p13.2, unilateral renal agenesis, hypoplasia of the abdominal musculature, cryptorchidism, hypothyroidism, diabetes, hypertension, lower limb lymphoedema, strabismus, hearing impairment, dental agenesis and dry skin with easy bruising were described; they cannot be attributed to the duplication without more cases [23]. Yan described vesicoureteric reflux in two patients, and heart disease, gastro-oesophageal reflux, eczema, hirsutism and hearing impairment in isolated patients; recurrent sinus infections and otitis occurred in the patient with the Xp duplication that included WAS [10]. Feeding difficulties include refusal of the breast with good tolerance of the bottle and, in a baby with a 5p14.2p14.3 duplication, gastrostomy feeding at 2 years with gastro-oesophageal reflux [23].

3.3. Natural history by age

Prenatal period. The 25-week Kariminejad fetus, with the inherited 667 kb duplication, had hypertelorism, a broad and depressed nasal bridge, depressed nasal tip, low-set ears, joint contractures, bilateral clubfeet, short and bowed long bones and a malformation of the dorsal portion of the corpus callosum [18]. SMC5 are associated with polyhydramnios [14, 16, 25].

Neonatal period and infancy. Hypotonia is often the first sign, with sucking difficulties, drooling and delay in head control, sitting and walking; physiotherapy helps, but hypotonia persisted in at least one adult [23].

Childhood. Language delay, behavioural problems, ASD and, in some cases, epilepsy predominate, with onset described at 2.5 years [23, 43].

Adolescence and adulthood. Overweight and obesity appear in adolescence and adulthood [10, 23]. Data in adults are scarce: the oldest patient in the Yan series was 30 years old, and there are no descriptions of ageing, fertility or life expectancy [2].

3.4. 5p13.3p13.2 duplication without NIPBL

The two published cases lie at opposite extremes. Iourov's boy, with the de novo 994 kb duplication, had intrauterine growth restriction, prematurity, prolonged ventilation, sensorineural deafness, focal epileptiform activity, microcephaly, mild spastic hemiparesis, hypotonia, severe developmental delay, optic atrophy, zonular cataract, hypoplasia of the corpus callosum and low-level somatic aneuploidy (section 10.2) [4]. Wang's fetus, with the 762 kb duplication inherited from the healthy father, had no anomalies on ultrasound or MRI, and the newborn had a normal examination and normal milestones at six months [5]. With two cases, it is not possible to establish a clinical association.

3.5. Complete trisomy 5p

The review by Kim (2025) counts 15 published cases and describes neonatal hypotonia, clubfoot, seizures, macrocephaly, abnormal ears, developmental delay, facial dysmorphism, poor weight gain and recurrent respiratory infections [24]. A systematic review of overgrowth syndromes (2026), based on a compilation by Cohen (2002), brings together complete trisomy 5p and six other cases, with macrocephaly in 7/7, increased birth length in 4/7 and increased birth weight in 2/7, and adds hydrocephalus, congenital heart disease, airway problems and difficulty gaining weight [63]. Grosso and colleagues described a de novo "pure" complete trisomy 5p with progressive triventricular hydrocephalus in the first year and later stabilisation, neuronal migration disorders, drug-resistant epilepsy and low secretory IgA on several occasions, probably related to the respiratory infections [45]. The face in trisomy 5p includes macrocephaly with a wide anterior fontanelle, dolichocephaly, upslanting palpebral fissures, epicanthus, hypertelorism, midface hypoplasia, short nose with a broad nasal bridge, micrognathia and abnormal ears, and the body may show arachnodactyly, clubfoot, hypotonia and hypoplasia of the abdominal musculature [33]. In the Brazilian cohort of Rodrigues (2025), one patient had a de novo der(14)t(5;14)(p11;p11.1) with a 46 Mb gain of 5p (practically complete trisomy), without an individual clinical description [21].

3.6. Partial trisomy 5p due to rearrangement

Proximal trisomies 5p (5p11→p13.3) are associated with developmental delay, seizures and congenital heart disease [15, 35]. Distal inverted duplications give severe ID, seizures and macrodolichocephaly, as in Cervera's Mexican girl, with generalised tonic-clonic seizures from the first year [32]. Izzo's fetus, with a 40 Mb duplication and an 800 kb terminal deletion, had only a short femur, clubfeet, pyelectasis and dysmorphic features, with no heart disease or brain anomaly at 22 weeks [46]. In the Brazilian families with t(5;15), carriers of trisomy 5pter→p13.3 had phenotypes whose severity also depended on the segment lost from the reciprocal chromosome [20, 47].

3.7. Marker chromosomes derived from chromosome 5

Table source: [16].

Armstrong's index case, a boy with a 22 Mb SMC5 (40–45% mosaicism on the first karyotype and present in all cells on the second), was born at 30 weeks after polyhydramnios, weighing 1,786 g, had right clubfoot, polymicrogyria and five weeks of hospital admission for respiratory problems; he sat at 10 months and walked at 18 [16]. At 18 years he measured 185 cm and had a head circumference of 61.5 cm (above the 97th centile), dolichocephaly, long face, hypotelorism, malar hypoplasia, esotropia, myopia, operated kyphoscoliosis, chronic diarrhoea, ASD and ADHD, and mild aortic root dilatation (sinus of Valsalva 3.60 cm, Z +2.3; ascending aorta 3.38 cm, Z +2.8) treated with a beta-blocker; the 16-gene thoracic aortic aneurysm panel was negative [16]. Camerota's 17-year-old girl, with a mosaic ring marker that included NIPBL, had a large, round and elongated face, hypertelorism, obesity (BMI 37) and high-functioning autism; the authors defined the core phenotype of proximal trisomy 5p as craniofacial dysmorphism, obesity and ID or ASD [7]. Erdem's marker with partial trisomy 5p12–q11.2, without 5p13, gave ADHD, mild ID and dysmorphic features [33]. Nakamura's Japanese newborn, with an SMC5 identified by chromosome painting, had polyhydramnios, macroglossia, clubfoot and laevocardia on prenatal diagnosis and, at birth, bilateral congenital diaphragmatic hernia, hypoplasia of the corpus callosum, atrial septal defect and hypothyroidism [25].

3.8. Isolated SLC1A3 duplication and distal 5p14–p15 duplications

The four Nijmegen patients with SLC1A3 duplication had ADHD-like behavioural problems or autistic traits [8]. Duplications involving only 5p14→pter have a mild phenotype [13]; in the Unique compilation, a baby with a 5p14.2p14.3 duplication had severe feeding difficulties and mild hypothyroidism [23].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

5p13 microduplication has no recognisable gestalt, and the diagnosis almost always arises from a CMA requested for developmental delay, ID, ASD or multiple congenital anomalies, the indications for which CMA is the first-line test [10, 26, 64]. The Oxford Desk Reference describes the "chromosomal phenotype" pattern (facial dysmorphism, abnormal growth, developmental delay and characteristic behaviour) as a signal for genomic investigation [31].

In the prenatal period, suspicion arises from a CMA finding in a fetal sample or from ultrasound anomalies: contractures, clubfeet, short long bones and corpus callosum abnormalities in the NIPBL-containing duplication [18]; polyhydramnios, macroglossia, clubfoot and changes in cardiac position in SMC5 [16, 25]; short femur, clubfeet and pyelectasis in a large 5p duplication [46]. In the newborn and infant, hypotonia, feeding difficulties and an unusual skull shape (craniosynostosis, macrocephaly in trisomy 5p) are the presentations described [23, 24]. In the child, the combination of language delay, ASD or ADHD, sleep disturbance, long fingers and prominent forehead, without the CdLS facies, is the most suggestive [10, 23]. In the adolescent and adult with ID, obesity, lymphoedema and arterial hypertension have been described [3, 23].

The family context also provides guidance. A history of recurrent miscarriage, of a child with Cri-du-Chat or of a carrier of a translocation involving 5p requires partial trisomy 5p to be considered in the other children and in subsequent pregnancies [13, 20]. Several affected children of a mother without signs suggest an insertion or a balanced rearrangement [19].

4.2. Warning and emergency signs

The signs requiring targeted assessment are: epileptic seizures, especially drug-resistant ones [23, 45]; increasing head circumference with signs of intracranial hypertension in the first year of complete trisomy 5p, because of the risk of progressive hydrocephalus [45]; recurrent respiratory infections and respiratory distress in the newborn with trisomy 5p or SMC5 [16, 24, 45]; progressive abnormal skull shape, suggestive of craniosynostosis [23]; murmur or signs of congenital heart disease in large duplications and SMC5 [15, 16]; and, in the adolescent or adult with SMC5, findings of connective tissue disease (arachnodactyly, pectus, striae), which justify measurement of the aortic root [16]. Rapid weight gain deserves attention, because of the overweight described and the effect of antipsychotics used for behaviour (section 7.6) [10, 65].

4.3. Newborn screening

There is no newborn screening for these duplications. Prenatal screening by cell-free fetal DNA is not validated for microdeletions and microduplications or for genome-wide CNV, and ACOG does not recommend it for that purpose [66].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal clinical criteria for any entity in the class. The diagnosis is genomic: NIPBL-containing 5p13 microduplication is defined by demonstrating a copy gain in 5p13.2 that includes the complete NIPBL gene, in a patient with a compatible picture, and trisomy 5p by duplication of a segment of the short arm visible on karyotype or defined by CMA [1, 2, 6]. Because the triplosensitivity of NIPBL has little evidence and there are healthy carriers, interpretation of a small duplication requires formal CNV classification (section 5.4) and study of the parents [18, 27, 29].

5.2. Tests in order

Chromosomal microarray. The International Standard Cytogenomic Array (ISCA) consensus, based on 33 studies with 21,698 patients, established CMA as the first-line test in developmental delay or ID, ASD and multiple congenital anomalies, with a diagnostic yield of 15–20%, compared with about 3% for G-banded karyotyping (excluding recognisable syndromes) [26]. The American Academy of Pediatrics (AAP), in 2014, placed CMA as the first-line test in ID or global developmental delay of unknown cause, replacing karyotyping and subtelomeric FISH, while keeping fragile X testing as first line [64]. The European guideline on molecular karyotyping (2007) requires each laboratory to validate specificity and sensitivity and to have internal and external quality control [67]. Arrays with single nucleotide polymorphism (SNP) probes also detect uniparental disomy and regions of homozygosity, and are more sensitive to mosaicism than array CGH [5, 31].

Exome or genome sequencing. The 2021 American College of Medical Genetics and Genomics (ACMG) guideline strongly recommends exome or genome sequencing as a first- or second-tier test in congenital anomalies with onset before 1 year or in developmental delay or ID with onset before 18 years [68]. Quad exome sequencing was used in the Wang case to exclude a concomitant pathogenic variant [5]. The ACMG guideline for ASD (2013) recommends an individualised genetic assessment after confirmation of the diagnosis of autism [69].

FISH, karyotype and targeted methods. FISH and karyotyping define the structure of the rearrangement (tandem duplication, insertion into another chromosome, translocation, marker) and are indispensable in the study of the parents, because a balanced rearrangement does not change copy number and escapes CMA [19, 31]. Interphase FISH confirmed the adjacent location of the Yan duplications, and sequencing of the junctions by long-range PCR with divergent primers made it possible to infer the mechanism [10]. In SMC5, multicolour FISH identified the origin of the marker and CMA defined its size [16]. Small intragenic NIPBL duplications require exon-targeted array CGH or multiplex ligation-dependent probe amplification (MLPA; in the Cheng study, thresholds of 0.7–1.3, with the duplication giving a ratio of about 1.4) [22, 41].

5.3. Limitations of the tests

CMA resolution depends on the platform: on the CytoScan 750K, about 100 kb for duplications and 50 kb for deletions, below which CNV are not usually reported; on the CytoScan HD, about 2.7 million copy number markers and 750,000 SNP; on a 118,000-probe platform with 66,000 SNP, about 200 kb in the array backbone [4, 5, 16]. CMA does not detect balanced rearrangements or low-level mosaicism, which account for less than 1% of causes in the ISCA meta-analysis [26], and does not show where the extra copy is located: the duplication in the Walters-Sen family looked like a 5p13.2 duplication on the array, and only FISH showed the insertion into Xp [19]. G-banded karyotyping, with a resolution of about 5–10 Mb, does not detect the microduplications; Iourov's patient had a normal karyotype at about 500 bands [4, 31]. Sequencing does not detect duplications of exons or of the whole gene, and targeted deletion/duplication analysis does not define the breakpoints of large rearrangements [22]. In mosaic markers, the proportion of cells with the marker in blood may vary between analyses and laboratories (40–45% on one karyotype and 100% on another, in the Armstrong case) and does not necessarily reflect that in other tissues [14, 16]. A negative CMA does not exclude a balanced parental rearrangement or a duplication below the resolution.

5.4. ACMG/ClinGen classification of duplications

The 2020 joint ACMG and ClinGen standards classify constitutional CNV using a points system with five classes: pathogenic (≥0.99), likely pathogenic (0.90 to 0.98), VUS (−0.89 to 0.89), likely benign (−0.90 to −0.98) and benign (≤−0.99) [27]. The classification is "decoupled" from the patient's phenotype: it assesses the evidence about the CNV, not the match with the individual picture [27]. Cytogenetically visible changes, larger than 5 Mb, are generally classified as pathogenic, except for heteromorphisms [27].

Table source: [16, 27, 29].

The consequence is that a de novo microduplication containing complete NIPBL, in a patient with a compatible picture, accumulates points mainly from the evidence of published cases, and the same duplication inherited from a healthy parent tends towards VUS. This was the reasoning of Wang and of Ormieres, who classified the inherited duplications as VUS [5, 42]. A CNV with few genes of unknown dosage sensitivity is usually a VUS [27].

5.5. Content of the report

The CMA report should state the cytoband, size, coordinates with the genome build, copy state and mechanism when known (a tandem duplication may require additional methods), the genes in the interval (all curated genes, in the case of a VUS), the class and the follow-up recommendations, such as cytogenetic characterisation, genetic counselling and family studies [27]. Nomenclature follows ISCN; an example is arr[GRCh37] 5p13.3p13.2(33,405,597_34,167,786)×3 [5]. For a duplication defined at base-pair level, HGVS notation uses the versioned genomic reference sequence, such as NC_000005.9:g.37009768_37625742dup (GRCh37) [42]. Re-evaluation of the literature on a VUS is primarily the responsibility of the treating clinician, and laboratories may issue amended reports [27]. For markers, the report should state the proportion of cells and the tissue analysed [16].

5.6. Diagnostic algorithm

The Oxford Desk Reference adapts the algorithm of Miller (2010) [31]. In a patient with developmental delay, ID, ASD or multiple congenital anomalies without a recognisable syndrome, CMA is requested (or exome or genome sequencing with CNV analysis, according to the 2021 ACMG guideline) [26, 68]. If CMA shows a duplication in 5p, the first step is to review the gene content and similar cases in DECIPHER, the ClinGen curations and the literature [29, 31]. The second is to confirm and characterise the structure in the proband (FISH, karyotype, quantitative PCR or MLPA) and to study the parents: by CMA to establish whether the duplication is inherited or de novo, and by karyotype or FISH to look for balanced insertions, translocations or inversions [19, 31]. The CNV is classified under the ACMG/ClinGen standards [27]. If the duplication is inherited from a healthy parent, incomplete penetrance, polymorphism and a second cause are considered, and exome or genome sequencing may be indicated [5, 31]. The Oxford Desk Reference also mentions unmasking of a recessive allele, imprinting, complex inheritance and amplification of a parental duplication into a triplication in the offspring [31]. In large trisomies 5p and markers, karyotyping with FISH is the first step and CMA defines the size and the genes [16, 21].

5.7. Prenatal and preimplantation diagnosis

Practice Bulletin 226 of the American College of Obstetricians and Gynecologists (ACOG) estimates that CNV, which are independent of maternal age, occur in about 0.4% of pregnancies, and that, below 36 years, the risk of an abnormal microarray result is higher than that of trisomy 21 [66]. To assess submicroscopic changes, it recommends prenatal diagnosis with CMA on chorionic villi or amniotic fluid; no screening test covers all CNV; in the presence of an ultrasound anomaly or increased nuchal translucency, it recommends genetic counselling and diagnostic testing (level A); counselling is non-directive and should include the possibility of incidental findings [66]. In the prenatal setting, laboratories may choose to report only pathogenic and likely pathogenic CNV, with a documented policy; some laboratories do not routinely report CNV with substantial incomplete penetrance [27, 31]. In the Wang case, CMA on uncultured amniocytes identified the duplication, the karyotype of cultured cells was 46,XY, and the parental study, ultrasound and fetal MRI at 26 weeks supported the decision [5]. The first prenatally diagnosed 5p duplication was identified by amniocentesis in a family with a known translocation, in 1982 [13]. The sources consulted do not describe preimplantation genetic testing applied to these duplications; its use presupposes a known parental change (section 8).

6. Differential Diagnosis

The differential diagnosis of the class has two levels. At the clinical level, the picture of developmental delay, ID, ASD, hypotonia and mild dysmorphism is non-specific and overlaps with many other CNV and monogenic disorders, so the diagnosis depends on genomic testing. At the genomic level, the differential is interpretative: distinguishing duplication of complete NIPBL from duplications that disrupt it, from neighbouring duplications without NIPBL and from large rearrangements in which another imbalance dominates.

6.1. Cornelia de Lange syndrome and the NIPBL dosage contrast

The central differential diagnosis is CdLS, because the same gene is involved with the opposite effect. CdLS results from loss of function of NIPBL (about 80% of cases) or of other cohesin genes and is characterised by growth restriction, microcephaly, a facial gestalt with synophrys, long eyelashes, long philtrum, thin upper lip and downturned corners of the mouth, limb reduction defects and hirsutism [22, 50]. Duplication of complete NIPBL shares with CdLS low-set ears, high palate, ocular anomalies, ID and behavioural problems, but has increased weight and long fingers and lacks the facial gestalt [10]. The point of confusion is laboratory-based: a duplication that disrupts NIPBL behaves as a loss of function and gives classic CdLS, so a report describing an "NIPBL duplication" must specify whether the gene is complete or disrupted [27, 41]. Smith and Síndromes Genéticas: Reconhecer para Tratar describe CdLS as sporadic in most cases, with NIPBL deletions in about 5% [49, 51]. CdLS is part of the differential diagnosis.

6.2. Neighbouring duplications and subgroups of the region

5p13.3p13.2 duplications without NIPBL, isolated SLC1A3 duplications and 5p13.1 duplications with epilepsy are distinguished by their coordinates on CMA, not by the clinical picture. The duplication without NIPBL is, in Wang's proposal, an entity to be assessed separately from 5p13 syndrome [5]. SLC1A3 duplication gives a behavioural phenotype without the rest of the picture [8]. Kluger's 5p13.1 duplication is associated with generalised epilepsy with normal MRI [43].

6.3. Large trisomies 5p and families with a translocation

Complete trisomy 5p and large partial trisomies add constant macrocephaly, clubfoot, seizures, heart disease and respiratory problems to the developmental picture [24, 63]. In a family with a translocation involving 5p, siblings may have the reciprocal imbalance (trisomy 5p in one, Cri-du-Chat in another) [13, 20], and the phenotype of a carrier of partial trisomy 5p may be dominated by the loss on the partner chromosome, as in the 15q26.3 loss with IGF1R [47].

6.4. Connective tissue phenotype

In Armstrong's adult with SMC5, aortic root dilatation, dolichocephaly, long face, malar hypoplasia, pectus excavatum and striae, with a Ghent systemic score of 4 and a Beighton score of 0/9, raised the hypothesis of a connective tissue disorder, but the 16-gene panel was negative [16]. The authors do not exclude late-onset, low-penetrance aortic disease, because few adults with SMC5 have been phenotyped [16].

6.5. Developmental language disorder

In the French series of children with developmental language disorder without ID, autism or apraxia, a paternal 5p13.2 duplication with partial NIPBL was classified as a VUS [42]. This finding marks the lower limit of the spectrum: a partial duplication of the region may occur in a child with language disorder alone.

7. Treatments and Risk Management Strategies

7.1. Principles

No entity in the class has a specific treatment, guideline of its own or registered clinical trial: a ClinicalTrials.gov search on 28 October 2026 returned no studies for "5p13 duplication", and the results for "trisomy 5p", "chromosome 5p duplication" and "NIPBL" referred to a lithium study in CdLS, a prenatal microdeletion screening study and a registry of people with genetic changes and autistic traits [28]. The absence of a guideline in the sources consulted does not prove that none exists. Management is symptomatic, multidisciplinary and guided by each patient's manifestations, based on the general recommendations for ID, ASD and congenital anomalies and on the limited data from the series [16, 23, 64, 69]. The CdLS GeneReviews chapter has a system-based assessment scheme that cannot be transposed to the duplication without a source of its own, because the manifestations differ [10, 22].

7.2. Initial assessment after diagnosis

The sources do not define the age or exact order of these assessments; the table groups the manifestations described with the examination that identifies them.

7.3. Early intervention, rehabilitation and education

Physiotherapy and exercise improve hypotonia, and occupational, speech and developmental therapies are the interventions described by families and authors [16, 23]. Armstrong's patient received occupational, speech and developmental therapies from infancy [16]. Unique notes that oral hypotonia, combined with a high palate, can hinder the progression to solid foods during the feeding transition, and that offering fluids during the meal helps; a high, narrow palate can cause dental crowding, sleep disturbance due to nasal obstruction and speech articulation problems [23]. Education is adjusted to cognitive level, which ranges from mild difficulties to complete dependence [23].

7.4. Feeding, growth and weight

Severe feeding difficulties may require gastrostomy, as in a baby with a 5p14.2p14.3 duplication, who also had gastro-oesophageal reflux [23]. In complete trisomy 5p and in SMC5, poor weight gain is frequent (6/13 in SMC5) [16, 24]. In the NIPBL-containing microduplication, the tendency is the reverse: overweight in adolescence and adulthood, with obesity in two of four adults in the Unique compilation and in Camerota's girl (BMI 37) [7, 10, 23]. Weight control must therefore begin before adolescence and must take into account the weight gain caused by atypical antipsychotics, when used [65, 71].

7.5. Neurology and epilepsy

Seizures are treated according to seizure type and epilepsy syndrome, because the sources do not identify a preferable antiseizure medicine in these duplications [23, 43]. In the child in the Unique compilation, antiseizure medicines reduced seizure frequency, but the epilepsy remained partially drug-resistant; in Grosso's complete trisomy 5p, with a neuronal migration disorder, the epilepsy was drug-resistant [23, 45]. The medicines and doses used in these patients were not described in the sources. The progressive hydrocephalus of complete trisomy 5p requires neurosurgical assessment; in Grosso's case it stabilised after the first year [45].

7.6. Behaviour and sleep: symptomatic pharmacotherapy

There are no efficacy data for any medicine in 5p duplications. The use of medicines for irritability associated with ASD, for insomnia and for ADHD is an extrapolation from the approved indications in those disorders, with the doses from the official labels, because there is no guideline with a dose for this condition. The underlying indication (ASD, ADHD, insomnia) must have been diagnosed, and behavioural intervention and sleep hygiene precede pharmacotherapy, as the labels themselves require [72–74].

Risperidone (Risperdal®; Janssen). Dopamine D2 and serotonin 5-HT2A receptor antagonist. In the USA, it is indicated for irritability associated with autistic disorder (aggression, deliberate self-injury, temper tantrums, quickly changing moods) from 5 to 17 years [65]. The Food and Drug Administration (FDA) label dose is weight-based: below 20 kg, start at 0.25 mg/day; from 20 kg, at 0.5 mg/day; after at least four days, move to the recommended dose of 0.5 mg/day (<20 kg) or 1.0 mg/day (≥20 kg), maintained for at least 14 days; if the response is insufficient, increase at intervals of two weeks or more, in increments of 0.25 mg/day (<20 kg) or 0.5 mg/day (≥20 kg); effective dose range 0.5 to 3 mg/day, with no maximum dose defined in the label for this indication; no data below 15 kg; once daily or divided into two doses; if somnolence persists, take at bedtime, divide the dose or reduce it [65]. In Portugal, Risperdal® has no indication in ASD: it is indicated for short-term symptomatic treatment (up to six weeks) of persistent aggression in conduct disorder, from 5 years, in children and adolescents with below-average intellectual functioning or ID, as part of a programme including psychosocial and educational interventions and prescribed by a specialist; the dose is 0.25 mg/day as oral solution below 50 kg (optimal 0.5 mg/day, between 0.25 and 0.75 mg/day) and 0.5 mg/day from 50 kg (optimal 1 mg/day, between 0.5 and 1.5 mg/day), with increases no more often than on alternate days and no maximum dose defined in the SmPC for this indication; it is not recommended below 5 years; in renal and hepatic impairment, starting and maintenance doses are halved and titration is slower [74]. The Portuguese doses are lower than those of the US label and are intended for another indication; use in ASD in Portugal is off-label. Adverse effects with a frequency ≥5% and higher than placebo in the paediatric autism trials (risperidone n=107; placebo n=115) were sedation (63% vs 15%), increased appetite (44% vs 15%), fatigue (31% vs 9%), vomiting (20% vs 17%), constipation (17% vs 6%), enuresis (16% vs 10%), drooling (12% vs 4%), tremor (8% vs 1%), parkinsonism (8% vs 1%) and weight gain (8% vs 2%) [65]. Mean weight gain was 2 kg vs 0.6 kg over 3–8 weeks, with about 33% gaining ≥7% of body weight (vs 7%), and 5.5 kg at 24 weeks and 8 kg at 48 weeks in the open-label studies; risperidone raises prolactin more than other antipsychotics and can cause hyperglycaemia and dyslipidaemia [65]. The contraindication is hypersensitivity to risperidone or paliperidone [65].

Aripiprazole (Abilify®; Otsuka). Partial D2 receptor agonist. In the USA, it is indicated for irritability associated with autistic disorder from 6 to 17 years, starting at 2 mg/day, increasing to 5 mg/day and, if necessary, to 10 or 15 mg/day, in adjustments of up to 5 mg/day at intervals of at least one week; recommended range 5 to 15 mg/day and maximum 15 mg/day; in CYP2D6 poor metabolisers, half the usual dose [71]. In the European Union, the summary of product characteristics (SmPC) of Abilify® states that safety and efficacy in irritability associated with autistic disorder below 18 years have not been established and that no posology recommendation can be made; it describes the US trials, states that the clinical relevance of the improvement on the irritability scale has not been established and mentions weight gain (1.6 kg vs 0.4 kg with placebo) and prolactin changes [75]. Use in ASD in Europe is therefore off-label. Adverse effects in the US trials (aripiprazole n=212; placebo n=101) included sedation (21% vs 4%), fatigue (17% vs 2%), vomiting (14% vs 7%), somnolence (10% vs 4%), tremor (10% vs 0%), pyrexia (9% vs 1%), drooling (9% vs 0%) and decreased appetite (7% vs 2%); discontinuation due to adverse effects was 10% vs 8% [71].

Prolonged-release melatonin (Slenyto®, 1 mg and 5 mg tablets; EU centralised authorisation). Melatonin receptor agonist. It is indicated for insomnia in children and adolescents aged 2 to 18 years with ASD and/or neurogenetic disorders with abnormal daytime melatonin secretion and/or night-time awakenings, when sleep hygiene has been insufficient, and from 6 to 17 years with ADHD [72]. In ASD and neurogenetic disorders, the starting dose is 2 mg, increased to 5 mg if the response is insufficient, with a maximum of 10 mg (in ADHD, start with 1–2 mg, adjust up to 5 mg and maximum 10 mg), once daily, 0.5 to 1 hour before bedtime, with or after food; the tablets are swallowed whole and may be mixed into yoghurt, orange juice or ice cream and taken immediately; response is reassessed after at least 3 months and then at least every 6 months; there are safety data up to 2 years; it is not recommended in hepatic impairment [72]. The sources consulted do not include a US melatonin label. Use in a child with a 5p duplication and ASD falls within the European indication when the SmPC criteria are met.

Immediate-release methylphenidate (Rubifen® 5, 10 and 20 mg; Portugal). Dopamine and noradrenaline reuptake inhibitor. It is indicated for ADHD from 6 years, as part of a comprehensive treatment programme, when other measures are insufficient [73]. The starting dose is 5 mg once or twice daily (at breakfast and lunch), with weekly increments of 5 to 10 mg if necessary, up to a maximum of 60 mg/day; before starting, blood pressure, heart rate and family history of sudden death are assessed; blood pressure and pulse are recorded at each adjustment and at least every 6 months, and height, weight and appetite at least every 6 months; treatment is stopped at least once a year for reassessment and discontinued if there is no improvement after one month of adjustment; it is not used below 6 years, and this SmPC does not authorise it in adults [73]. ADHD has been described in SLC1A3 duplication, in SMC5 and in the Yan series [8, 10, 16, 33]. The sources consulted do not include the US methylphenidate label.

Table abbreviations: PR, prolonged release; IR, immediate release; BP, blood pressure.

7.7. Heart and aorta

Congenital heart disease in large trisomies 5p and SMC5 is treated according to the defect [15, 16, 44]. Armstrong and colleagues recommend, as the authors' opinion and not as a guideline, that people with similar SMC5 undergo cardiac assessment for aortic dilatation and receive a beta-blocker if the dilatation is significant or progressive; their patient received a beta-blocker, without the medicine and dose being stated [16]. None of the earlier SMC5 cases had serial cardiac imaging, so the frequency of aortic dilatation is unknown [16]. In the NIPBL-containing microduplication, arterial hypertension in an obese adult with lymphoedema justifies measuring blood pressure in adults [3].

7.8. Surgery, orthopaedics and other measures

Craniosynostosis may require surgery to release the sutures and allow brain growth [23]. Scoliosis and kyphoscoliosis may require spinal fusion, as in Armstrong's patient, operated on at 18 years (Risser 4) [16]. Clubfoot is treated according to usual orthopaedic practice. Hypothyroidism was treated with levothyroxine in a baby in the Unique compilation [23]. The bilateral congenital diaphragmatic hernia of Nakamura's newborn illustrates that, in SMC5, malformations requiring neonatal surgery may occur [25].

7.9. Regulatory status of symptomatic medicines

The US approval dates for the paediatric indications of risperidone and aripiprazole were not verified in a primary source and are not given. The sources consulted do not include the Brazilian package inserts for these medicines.

7.10. Trials supporting the extrapolated doses

These trials were conducted in autistic disorder, insomnia or ADHD of mixed aetiology, and none included patients identified as having 5p duplications; the extrapolation assumes that the response of irritability, sleep or attention does not depend on the genetic cause, which has not been demonstrated. The labels do not give confidence intervals for the irritability outcomes, and the European SmPC for aripiprazole considers that the clinical relevance of the improvement in ABC-I has not been established [75]. Medicines should not be compared across different trials. The metabolic adverse effects of antipsychotics are relevant in a condition with a tendency towards overweight [10, 65].

7.11. Developments in the last 12 months

Between November 2025 and October 2026, the sources consulted record three relevant publications, none therapeutic. In May 2026, Wang and colleagues published the first inherited case of 5p13.3p13.2 duplication without NIPBL, with a normal newborn at six months (human study, case report) [5]. In the same month, a preclinical study in mouse stem cells showed that NIPBL dosage regulates the speed of cohesin loop extrusion and that its overexpression compacts chromatin [62]. In 2026, a systematic review of dysmorphic syndromes with overgrowth included trisomy 5p, with macrocephaly in 7/7 cases [63]. Shortly before this window, the review of 15 cases of complete trisomy 5p (August 2025) and the French language disorder series with a partial 5p13.2 duplication (February 2025) were published [24, 42]. There are no clinical trials, press releases, opinions or authorisations for these duplications [28]. The Simons Searchlight registry (NCT01238250), currently recruiting, studies people with genetic changes and autistic traits from a list of eligible conditions; the sources consulted do not confirm whether 5p13 duplication is on that list [28].

7.12. Agents to avoid, pregnancy, anaesthesia and transition

The sources do not identify medicines specifically contraindicated in these duplications. Precautions derive from the manifestations: with the tendency towards overweight, atypical antipsychotics increase weight and alter blood glucose and lipids [65, 71]; with methylphenidate, prior cardiovascular assessment is mandatory, which weighs more heavily in large duplications and in SMC5 with heart disease [16, 73]. The sources consulted do not describe pregnancies in women with these duplications, or anaesthetic complications. Transition to adult care should include control of weight and blood pressure, behavioural surveillance and, in SMC5, aortic surveillance, because descriptions of adults are scarce and include obesity, hypertension, lymphoedema and aortic dilatation [3, 10, 16, 23].

7.13. Recommendations of the applicable guidelines

There is no specific guideline. The applicable general guidelines converge on diagnosis: the ISCA consensus (2010), the AAP (2014) and the ACMG (2021) recommend CMA or exome or genome sequencing as first-line tests, and the ACMG and ClinGen (2020) standardise CNV classification [26, 27, 64, 68]. The main divergence is temporal: the 2014 AAP places CMA as first line and the exome afterwards, whereas the 2021 ACMG accepts exome or genome sequencing as first line [64, 68]. In symptomatic pharmacotherapy, the divergence is regulatory: antipsychotic doses for irritability in ASD exist in the US label but are not approved in Europe for that indication [65, 71, 74, 75].

8. Reproductive Options and Family Counselling

8.1. Recurrence risk by scenario

The recurrence risk depends on the mechanism, which is why study of the parents, by CMA and by karyotype or FISH, is the central step of counselling [19, 23, 31].

The duplications with complete NIPBL described up to 2023 were all de novo, until the Kariminejad case, in which a healthy father with no detected mosaicism transmitted the duplication to a malformed fetus [18]. In Wang's 5p13.3p13.2 duplication without NIPBL, the healthy father transmitted it to a normal newborn [5]. These two cases show that a healthy parent with the same duplication neither guarantees a normal outcome nor proves that the CNV is benign.

8.2. Cascade testing and carriers

When a parent has a balanced rearrangement (translocation, insertion or inversion), testing extends to the wider family, because other relatives may be carriers; in the Brazilian family with t(5;15)(p13.3;p12), the rearrangement was followed over four generations, with eight balanced carriers [20, 31]. In the Brazilian cohort of 31 patients with additional autosomal material, 45.4% of the imbalances with informative trios were inherited from a parental rearrangement (31.9% of maternal and 13.6% of paternal origin) and 54.5% were de novo; in 51.6% there was an associated deletion [21]. CMA may be normal in a parent with a balanced rearrangement, so karyotyping, FISH or genome sequencing are needed [31]. When the duplication is inherited from a parent without signs, clinical assessment of that parent helps to decide on pathogenicity, and assessment of symptomatic siblings may identify other carriers [18, 31].

8.3. Prenatal and preimplantation diagnosis

For a couple with a child with a de novo duplication, prenatal diagnosis by chorionic villus sampling or amniocentesis may be offered for reassurance [31]. When a parent has the CNV, prenatal diagnosis is offered to families in whom the CNV causes the disorder, with adequate time and consent if the parent has learning difficulties and with caution in view of variable penetrance; if the carrier parent has no signs and the CNV may be a polymorphism, prenatal diagnosis may not be indicated [31]. There is no consensus on prenatal and cascade screening for susceptibility loci [31]. In families with a translocation, prenatal diagnosis of trisomy 5p has been possible since 1982 [13]. Preimplantation genetic testing presupposes an identified parental change; the sources consulted do not describe its application to these duplications.

Interpreting a 5p13 duplication found in a fetus requires integration of the gene content, the parental study, ultrasound and, if necessary, fetal MRI and exome sequencing: in the Wang case, the inherited duplication, the absence of anomalies at 26 weeks and a quad exome without a pathogenic variant supported the couple's decision to continue the pregnancy [5]. The prenatal findings described are variable: contractures, clubfeet and short long bones (NIPBL-containing duplication), polyhydramnios, macroglossia, clubfoot and changes in cardiac position (SMC5), and short femur, clubfeet and pyelectasis (large 5p duplication) [18, 25, 46].

8.4. Counselling of minors and communication with the family

Families should know that nothing they did before or during pregnancy caused the duplication [23]. Testing asymptomatic minor siblings to establish carrier status for an inherited duplication, or for a balanced rearrangement, raises the question of reproductive carrier status; the sources consulted make no specific recommendation. For a carrier parent with ID, reproductive information requires time and adapted consent [31].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what the figures measure

There are no population-based prevalence studies. Orphanet assigns both entities a point prevalence below 1/1,000,000, which is a class and not a measurement, and counts 7 cases or families for 5p13 microduplication and 40 for trisomy 5p [1, 6]. The published counts are of reported cases: six patients at the Baylor College of Medicine diagnostic laboratory, with no published denominator [10]; 23 people compiled in 2014 by Unique, including 10 from DECIPHER [23]; 15 cases of complete trisomy 5p up to 2025 [24]; seven SMC5 in 2002 and eight similar cases in 2006 [14, 44]. SMC5 account for 1.4% of characterised markers, and SMC in general occur in about 0.044% of newborns [16]. CNV in general occur in about 0.4% of pregnancies [66]. In the cohort of 510 patients with suspected CdLS and negative sequencing, intragenic NIPBL duplication occurred in 1 (0.2%) [41]. DECIPHER was not consulted for this article, and the current count of patients in that database is not available. These counts underestimate the real frequency, because small duplications are only detectable by CMA and because carriers without signs are not studied.

9.2. Geographical distribution of published cases

The cases come from several regions: the USA (Yan, Armstrong, Walters-Sen, Loscalzo, Kim), Europe (Italy: Novara, Camerota, Izzo, Grosso; Germany: Oexle, Kluger; the Netherlands: van Amen-Hellebrekers; France: Ormieres; Greece: Sarri; Spain: Lorda-Sánchez), Brazil, Mexico, Iran, China, Japan, Russia, Polynesia and Turkey [3–5, 7, 8, 10, 11, 14–16, 18, 19, 24, 25, 32, 33, 35, 42–46]. The duplications are non-recurrent, with variable breakpoints and without flanking LCR, and there is no known founder effect [10].

9.3. Brazil and Portugal

Brazil contributes data from families with a translocation and from cytogenomic cohorts. The family with t(5;15)(p13.3;p12) had 11 affected members over four generations, five with partial trisomy 5p and six with 5p monosomy [20]. A second family, with t(5;15)(p13.3;q26.3), showed that the 30 Mb gain of 5p may have a smaller effect than the loss of 15q26.3 [47]. The cohort from the Federal University of São Paulo and the Instituto da Criança of the Hospital das Clínicas of the University of São Paulo included one patient with practically complete trisomy 5p due to der(14)t(5;14) and another with a 5p15.33p15.1 duplication with a 5q35.3 deletion, and quantified the origin of imbalances involving additional material [21]. The review of CNV with macrocephaly, also from São Paulo, includes the 5p13 duplication [61]. The sources consulted do not include data from Portugal.

9.4. Special populations

Adults are under-represented: the oldest patient with the NIPBL-containing microduplication was 30 years old, and Armstrong's adult with SMC5 showed findings (aortic dilatation, kyphoscoliosis, striae) that were not part of the paediatric descriptions [2, 16]. Fetuses are another particular population, because prenatal diagnosis by CMA is adding inherited duplications and duplications of uncertain significance [5, 18]. In mosaic markers, the proportion of affected cells varies between tissues and analyses [14, 16].

9.5. European networks and patient associations

The relevant European reference network is ERN ITHACA, dedicated to rare congenital malformations and rare ID [30]. Unique (Rare Chromosome Disorder Support Group), in the United Kingdom, publishes the family guide "Trisomy 5p: Microduplications of 5p13 & 5p14" (2014), reviewed by Jennifer Hague, of Addenbrooke's Hospital, and other guides on duplications of the short arm of chromosome 5 [23, 31].

10. Illustrative Clinical Case

10.1. Inherited 5p13.3p13.2 duplication without NIPBL, diagnosed prenatally (Wang et al., 2026)

A 35-year-old woman in her second pregnancy, with a healthy 3-year-old daughter and a 36-year-old husband, with no relevant history, underwent amniocentesis at 18 weeks for advanced maternal age, in 2024, at Wuhan Children's Hospital, China [5]. The karyotype of cultured amniocytes was 46,XY. CMA (CytoScan 750K) on uncultured amniocytes identified a 762 kb microduplication, arr[GRCh37] 5p13.3p13.2(33,405,597_34,167,786)×3, classified as a VUS; the interval contains ADAMTS12, AMACR, C1QTNF3, RXFP3, TARS1, SLC45A2 and C1QTNF3-AMACR, and does not include NIPBL (Figure 1 of Wang 2026) [5]. Karyotyping and CMA of the father, mother and sister, and a quad exome, showed normal karyotypes, no pathogenic variant and the same microduplication in the father (Figure 2 of Wang 2026) [5]. Physical examination of the three relatives was normal. Fetal ultrasound and MRI at 26 weeks showed no structural anomalies or growth restriction. After genetic counselling, the parents decided to continue the pregnancy [5]. Delivery was vaginal at 40 weeks, with normal weight, length and head circumference and Apgar scores of 9, 10 and 10; examination was normal at birth and at 6 months, with appropriate motor and social milestones, and developmental follow-up was planned [5].

10.2. Contrast: de novo 5p13.3p13.2 duplication with a severe phenotype (Iourov et al., 2015)

A Russian boy, the child of a primigravida, was born by caesarean section at 34 weeks, after threatened miscarriage, low-grade fever, oligohydramnios and intrauterine growth restriction, weighing 1,297 g, measuring 38 cm (below the 3rd centile) and with Apgar scores of 1 and 4; he was intubated and ventilated for 20 days and had a diffuse haemorrhagic rash and persistent regurgitation [4]. In the first year, growth remained below the 3rd centile, and at 1 year sensorineural deafness was diagnosed; the electroencephalogram showed left parieto-occipital focal epileptiform activity [4]. At 15 months he had a head circumference below the 3rd centile, dolichomicrocephaly, high forehead, hypotelorism, epicanthus, long philtrum, low-set ears, enamel hypoplasia, mild left spastic hemiparesis, hypotonia, development at the level of 5–6 months (developmental quotient below 50%), stereotypies (head banging), mild splenomegaly, descending optic atrophy, strabismus, nystagmus, left zonular cataract and hypoplasia of the corpus callosum [4]. The parental karyotypes were normal; CMA (CytoScan HD) identified a de novo duplication of about 994 kb in 5p13.3p13.2, without NIPBL (Figure 2 of Iourov 2015), and interphase FISH showed somatic aneuploidy 3 to 7 times above the reference mean [4].

10.3. Interpretation

The two cases share the same genomic interval and have opposite outcomes. The Wang case shows that the duplication can be transmitted by a healthy adult and be associated with a normal newborn; the Iourov case shows that, when it arises de novo, it may accompany a severe phenotype, but with perinatal factors (prematurity, growth restriction, low Apgar score, prolonged ventilation) that may explain part of the picture and without proof of causality [4, 5]. The combination is consistent with incomplete penetrance, with a CNV without clinical effect or with another cause in the severe case, which is why the most recent authors recommend assessing this duplication separately from the NIPBL-containing 5p13 syndrome and classifying it as a VUS [5, 27]. Wang's management (parental study, quad exome, fetal imaging and non-directive counselling) follows ACOG's general recommendations on prenatal diagnosis and the CNV classification standards [27, 66]. For the NIPBL-containing syndrome, Yan's founding series includes frontal and profile photographs of five patients, with "mild craniofacial defects" according to the legend, and a skull CT with severe deformity (Figure 4 of Yan 2009); the legend attributes the CT to patient 3, whereas the text attributes the cranial deformity to patient 4 [10].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

There are no survival or longitudinal follow-up studies for any entity in the class. In the NIPBL-containing microduplication, the patients described range from six months to 30 years of age, and the functional prognosis ranges from complete dependence in an adult with a 3.7 Mb duplication to a first-class university degree in a carrier father [2, 23]. ID is usually mild to moderate [23]. Adult morbidity includes overweight or obesity, arterial hypertension and lymphoedema [3, 10, 23]. Epilepsy may be partially drug-resistant [23]. In complete trisomy 5p and large partial trisomies, severity is greater and depends on the inclusion of 5p13, with seizures, heart disease, respiratory problems, recurrent infections and, in some cases, hydrocephalus and drug-resistant epilepsy [13, 24, 45]. In SMC5, the prognosis depends on the content of the marker and the degree of mosaicism; markers without 5p13 may have no clinical consequence [14, 16]. In 5p13.3p13.2 duplications without NIPBL, the two cases do not allow a prognosis [4, 5].

11.2. Surveillance

There is no published surveillance protocol for these duplications. The table brings together the examinations suggested by the sources, with the intervals they define; where the sources do not define an interval, this is stated.

12. Summary and Final Considerations

Duplications of the short arm of chromosome 5 form a heterogeneous class, organised by gene content. The main entity, 5p13 microduplication syndrome (OMIM #613174; ORPHA:329802), results from non-recurrent interstitial duplications, from 0.25 to about 1 Mb in the founding series, that include the complete NIPBL gene, the same gene whose loss of function causes Cornelia de Lange syndrome. The picture is the partial inverse of CdLS: developmental delay and usually mild to moderate ID, ASD and other behavioural problems, sleep disturbance, hypotonia, variable dysmorphism without the CdLS gestalt, long fingers, corpus callosum abnormalities and a tendency towards overweight in adolescence and adulthood. The triplosensitivity of NIPBL has little evidence in ClinGen, and incomplete penetrance, demonstrated by a healthy father who transmitted the duplication to a malformed fetus, means that each duplication must be interpreted with the parental study and the ACMG/ClinGen standards.

Around this entity lie the partial and intragenic NIPBL duplications (the latter cause CdLS through loss of function), isolated SLC1A3 duplication, associated with ADHD and autism, 5p13.1 duplication with generalised epilepsy, and 5p13.3p13.2 duplication without NIPBL, of uncertain significance, whose two published cases range from a severe de novo phenotype to a normal newborn with a carrier father. At the other extreme, complete trisomy 5p and large partial trisomies, due to translocation, insertion, inverted duplication or marker chromosome, give a more severe picture when they include 5p13, with macrocephaly, clubfoot, seizures, heart disease and respiratory problems, and in families with a translocation they may coexist with Cri-du-Chat syndrome.

Diagnosis rests on CMA, complemented by FISH and karyotyping of the proband and the parents to define the structure and the recurrence risk, which ranges from about 1% in de novo duplications to 50% in inherited ones and to high values in parental insertions and translocations. There is no specific treatment and there are no trials; management is symptomatic, with early intervention, weight control, neurological surveillance, cardiac surveillance in SMC5 and large trisomies, and pharmacotherapy for behaviour and sleep extrapolated from labels for other indications, with differences between the USA and Europe. The data rest on a few dozen cases, without population studies, without data from Portugal and with scarce information on adults.

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