Smith-Magenis Syndrome and Potocki-Lupski Syndrome (17p11.2)

Reciprocal RAI1 dosage disorders: 17p11.2 deletion or an intragenic loss-of-function variant (Smith-Magenis) and 17p11.2 duplication (Potocki-Lupski).

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

The 17p11.2 region helped establish the concept of genomic disease: local chromosome architecture, rich in low-copy repeats, predisposes to recurrent rearrangements, and loss or gain of the same segment produces distinct clinical conditions. Smith-Magenis syndrome results from halving the functional dosage of RAI1 through a deletion or intragenic variant; Potocki-Lupski syndrome results from excess dosage of the same gene, usually through the reciprocal duplication of the common deletion. Considering both conditions together clarifies gene dosage sensitivity, the clinical significance of a reciprocal recombination product and the practical differences between a highly characteristic behavioural phenotype and one that is difficult to recognise clinically [2, 3, 20].

The initial description of SMS was made by Ann C. M. Smith and colleagues, who presented two patients with facial clefts, congenital heart disease and a deletion of chromosome 17’s short arm in a 1982 American Society of Human Genetics meeting abstract [1]. In 1986, the group, including cytogeneticist R. Ellen Magenis, published nine unrelated patients aged 3 months–65 years with an interstitial deletion involving part of band 17p11.2. Eight shared brachycephaly, midface hypoplasia, prognathism, hoarse voice, speech delay with or without hearing loss, psychomotor and growth delay, and behavioural abnormalities. The only patient with deletion of the entire band had cardiac, skeletal and genitourinary malformations and died at 6 months [28]. Patil and Bartley had described a child with an interstitial short-arm chromosome 17 deletion in 1984. In 1990, Colley and colleagues emphasised in five Australian children that behavioural abnormalities could precede and overshadow cognitive impairment, already using the term Smith-Magenis syndrome [29, 30].

Molecular investigation began with Greenberg and colleagues in 1991. They assessed 32 patients clinically and 31 molecularly, confirmed 17p11.2 deletion as a contiguous gene syndrome, found clinical signs of peripheral neuropathy in 55% (with normal conduction velocities), and estimated incidence at 1:25,000 births [31]. In 1997, Chen and colleagues identified three copies of a low-copy repeat, the SMS-REPs, flanking the common region and demonstrated that homologous recombination between them produces the deletion. The same study identified a differently sized junction fragment in a patient with 17p11.2 duplication [32]. In 2003, Slager and colleagues identified truncating RAI1 variants in three people with an SMS phenotype but no deletion detectable by fluorescence in situ hybridisation (FISH), establishing RAI1 as the gene responsible for most of the phenotype [33].

The reciprocal duplication was predicted by the recombination model and confirmed in 2000 by Lorraine Potocki, James R. Lupski and colleagues. They described seven unrelated patients with a de novo duplication of the same region deleted in SMS, an identically sized junction fragment, preferential paternal origin and a milder phenotype than the deletion [34]. In 2007, the same group characterised 35 patients, defined a 1.3 Mb critical region containing RAI1, and described infantile hypotonia, growth delay, intellectual disability, autistic features, sleep apnoea and structural cardiovascular abnormalities. The condition became known as Potocki-Lupski syndrome [1, 20]. The Dp(11)17 mouse model with a null Rai1 allele demonstrated that normalising Rai1 dosage alone corrects the duplication phenotype despite trisomy of the other regional genes [35].

In 2025 and 2026 knowledge was updated along several lines: the SMS GeneReviews chapter was comprehensively revised in May 2025 and in April 2026 incorporated syndrome-specific growth charts; publications included a French series of 56 PTLS patients, mirror-image methylation episignatures for the two syndromes, studies of genotype-specific neuropsychiatric profiles and of melatonin levels in 89 patients, and paediatric recommendations for sleep disorders [2, 14, 36–40]. In October 2026 the Haute Autorité de Santé published the first French National Diagnosis and Care Protocol (PNDS) dedicated to PTLS, prepared by the western France developmental anomalies reference centre (Angers University Hospital) within the AnDDI-Rares network, which adds to the 2017 GeneReviews an age-based surveillance schedule, anaesthetic and vaccination precautions and the French organisation of care [19]. Therapeutically, the only disease-specific regulatory indication remains tasimelteon in the United States, approved in December 2020 [22].

The scope also includes TCF20-associated neurodevelopmental disorder (TAND), caused by haploinsufficiency of the RAI1 paralogue at 22q13.2. Babbs and colleagues proposed TCF20 as an ASD gene in 2014, based on two brothers with autism, mild intellectual disability and a pericentric inversion of chromosome 22 disrupting the gene; in 2016 Schäfgen and colleagues associated de novo truncating variants with intellectual disability and postnatal overgrowth; in 2019 two independent cohorts, those of Vetrini and colleagues (32 patients and four affected parents) and of Torti and colleagues (27 patients), defined the entity, designated in OMIM as developmental delay with variable intellectual impairment and behavioural abnormalities (OMIM 618430) [5, 6, 11, 41, 42]. The similarity to SMS, highlighted in the title of the Vetrini paper, justifies considering them together: some individuals with TAND have a tented upper lip, brachycephaly, midface hypoplasia, food seeking and sleep disturbance [6].

2. Molecular Genetics and Pathophysiology

2.1. Genomic architecture of 17p11.2 and rearrangement mechanisms

The proximal short arm of chromosome 17 contains low-copy repeats (LCRs, also termed segmental duplications), including proximal, middle and distal SMS-REPs. Non-allelic homologous recombination (NAHR) between directly oriented LCRs through unequal exchange reciprocally generates the approximately 3.7 Mb SMS deletion and approximately 3.7 Mb PTLS duplication [3, 32, 34]. Recombination between other LCRs produces an uncommon recurrent deletion of approximately 5 Mb and its corresponding reciprocal duplication, identified in two of 74 PTLS patients studied by Zhang and colleagues [10]. Non-recurrent rearrangements of variable size arise mainly through replication-based mechanisms such as fork stalling and template switching and microhomology-mediated break-induced replication (FoSTeS/MMBIR). These mechanisms can generate gains encompassing both RAI1 and PMP22 (17p12) [3, 43].

The neighbouring 17p12 region has diagnostic implications. A 1.5 Mb duplication including PMP22 causes Charcot-Marie-Tooth disease type 1A (CMT1A), while its reciprocal deletion causes hereditary neuropathy with liability to pressure palsies (HNPP), through NAHR between CMT1A-REPs [34]. The Oxford Desk Reference describes this duplication as “17p11.2”; the correct PMP22 location is 17p12, and reports should avoid this nomenclature confusion [34, 44, 45]. SMS deletions extending into 17p12 and including PMP22 add HNPP risk. Duplications involving RAI1 and PMP22 cause Yuan-Harel-Lupski syndrome (YUHAL; OMIM 616652; ORPHA:477817), with developmental delay and early-onset peripheral neuropathy [2, 43, 46].

2.2. Mechanism proportions

Proportions depend on the period and ascertainment method. The 2025 GeneReviews chapter attributes approximately 80–90% of SMS cases to CMA-detectable deletions and approximately 10–20% to RAI1 sequence variants. The common approximately 3.7 Mb deletion accounts for approximately 70% of patients, with larger or smaller deletions accounting for approximately 20% [2]. Smith’s Recognizable Patterns gives 90% deletions and 10% variants; the Brazilian textbook Síndromes Genéticas: Reconhecer para Tratar gives 95% and 5%. The French PNDS gives approximately 90% and 10%, adding that 20% of atypical deletions exceed 9 Mb [1, 25, 47]. Boot and colleagues suggested underreporting of RAI1 variants, consistent with the increased proportion attributed to intragenic variants following widespread exome use [2].

For PTLS, GeneReviews reports approximately two thirds recurrent 3.7 Mb duplications and one third non-recurrent duplications of 0.41–19.7 Mb, all including RAI1 [3]. Potocki and colleagues found 22 recurrent duplications in 35 patients (approximately 63%) and 13 non-recurrent duplications of 1.3–15.2 Mb [20]. In the 2026 French series, 46 of 54 characterised duplications (85%) were recurrent, five (9%) larger and three (6%) smaller [14]. The smallest overlapping region among 74 PTLS-associated duplications spans 125 kb and contains only RAI1 [10].

2.3. RAI1: structure, function and dosage consequences

RAI1 encodes a neuron-enriched nuclear protein that functions as a chromatin-associated transcriptional regulator. In mouse models, it preferentially binds neuronal gene promoters, upregulates circadian clock genes including CLOCK, and controls BDNF (brain-derived neurotrophic factor) expression in hypothalamic neurons, affecting satiety, food intake and fat distribution [2, 9]. Mice lacking Rai1 show exaggerated light-induced wakefulness and disturbed circadian rhythms; haploinsufficiency reproduces hyperphagia and obesity [2]. Smith’s Recognizable Patterns summarises that RAI1 regulates transcription of CLOCK, a principal component of the mammalian circadian oscillator [1].

In SMS, the mechanism is loss of function. ClinGen assigns a haploinsufficiency score of 3 (sufficient evidence) to RAI1 and the recurrent ISCA-37418 region (GRCh38 chr17:16906714-20309889). The same region has a triplosensitivity score of 3, associated with PTLS, assessed on 10 October 2025 [16]. Gene-level RAI1 curation, assessed in 2020, still records triplosensitivity 0 (“no evidence available”), reflecting that curation’s scope and date rather than contradicting evidence that RAI1 duplication is sufficient for the phenotype [10, 16, 35].

In deletions, loss of other genes modifies the phenotype. Approximately 25 genes lie within the critical region according to Smith’s Recognizable Patterns, whereas the recurrent duplication encompasses approximately 70 genes [1, 3]. Girirajan and colleagues attributed 21 of 30 features to RAI1 haploinsufficiency, with heart defects, speech and motor delay, hypotonia, short stature and hearing loss more frequent in large or atypical deletions [48]. Candidate genes cited by the sources include SREBF1, a regulator of the low-density lipoprotein receptor discussed in relation to hypercholesterolaemia; MYO15A, the autosomal recessive deafness gene (DFNB3), mentioned by the PNDS in relation to deafness; and FLCN, the Birt-Hogg-Dubé syndrome (BHDS) tumour suppressor gene, included in most deletions [2, 25, 49]. Parental deletion origin does not alter phenotype, excluding a substantial role for imprinting [2].

2.4. Intragenic RAI1 variants and nomenclature

The RAI1 MANE Select transcript is NM_030665.4 (ENST00000353383.6), encoding NP_109590.3 with 1906 amino acids [12]. More than 99% of known pathogenic and likely pathogenic variants lie in exon 3, predominantly truncating variants (nonsense and frameshift), with some missense variants [2]. Truong and colleagues described a hotspot in a seven-cytosine tract in exon 3, with a cytosine deletion and insertion designated c.3103delC and c.3103insC in the publication [50]. ClinVar records these changes on NM_030665.4 as NM_030665.4(RAI1):c.3103dup p.(Gln1035fs) (VCV003907775, pathogenic, multiple submitters without conflict, assessed 5 December 2025) and c.3103del p.(Gln1035fs) (VCV003252423, pathogenic, one submitter) [51]. Other examples with concordant submitter classifications are c.3265C>T p.(Arg1089Ter) (VCV001459297) and c.5296C>T p.(Gln1766Ter) (VCV003312557) [51]. When reading pre-2010 literature, historical designations must be converted to HGVS using the stated transcript version and ClinVar or a validator, without manually recalculating positions.

Missense variants of uncertain significance require caution. Vieira and colleagues identified two non-synonymous variants of uncertain significance in patients with suspected SMS, without alterations in protein molecular weight, subcellular localisation or transcriptional activity [52]. GeneReviews emphasises that an RAI1 variant of uncertain significance neither establishes nor excludes the diagnosis [2]. In SMS caused by intragenic variants, melatonin also has an inverted profile, so this finding does not distinguish deletion from sequence variant [2, 53].

2.5. Methylation episignature and other 17p11.2 rearrangements

Van der Laan and colleagues analysed genomic DNA methylation by Infinium EPIC microarray in 26 people with SMS and 27 with PTLS due to copy-number changes and defined classifiers with high sensitivity and specificity. SMS showed predominant hypomethylation and PTLS hypermethylation at the same loci, a mirror-image pattern overlapping episignatures of MEF2C-related disorders [37]. People with RAI1 sequence variants did not show this pattern, suggesting that the episignature depends on copy-number changes and cannot classify RAI1 missense variants [37]. Grochowski and colleagues described 15 individuals from 11 families with 17p11.2 gains excluding RAI1, with developmental delay, intellectual disability and behavioural problems. Four families had inherited gains; these rearrangements should not be interpreted as PTLS [54].

2.6. System-specific pathophysiology

Sleep disturbance results from central clock misalignment rather than melatonin synthesis alone. In eight children, De Leersnyder and colleagues measured melatonin secretion onset at 6 h ± 2, a peak at noon ± 1 and cessation at 20 h ± 1, compared with 21 h, 3h30 and 6 h in controls, and correlated behavioural problems with the inversion [55]. Boudreau and colleagues documented the inverted pattern in approximately 96% of two cohorts from the United States and France, and described normal secretion in one patient with an atypical interstitial deletion [53]. Body temperature rhythm is not inverted but advanced by approximately three hours, supporting central clock dysfunction [2]. Daytime hyperactivity may represent an effort to resist sleep during the phase of elevated melatonin [1].

Abdominal obesity, hyperphagia and food fixation relate to reduced hypothalamic BDNF. Lack of response to the melanocortin 4 receptor (MC4R) agonist setmelanotide suggests that the proximal MC4R pathway is not the principal mechanism [2, 56]. Peripheral neuropathy (hyporeflexia, relative pain insensitivity, cavus or flat feet) occurs with any deletion size and usually normal conduction velocities. When the deletion includes PMP22, HNPP susceptibility is added [2, 25, 31]. FLCN haploinsufficiency provides a “first hit” for BHDS-spectrum tumours; a somatic second hit in FLCN has been documented in renal tumours from SMS patients [57, 58].

In PTLS, excess RAI1 appears to alter circadian gene expression and is associated with dyssomnia, although clinical sleep disorders are predominantly respiratory [1, 3]. For duplications with a renal phenotype, FLCN has been proposed as a contributor to renal abnormalities based on comparison with the mouse model [3].

2.7. TCF20-related disorder: the RAI1 paralogue

TCF20 lies at 22q13.2, upstream of the Phelan-McDermid syndrome critical region (22q13.3, SHANK3), and encodes a nuclear transcriptional coregulator first identified by its binding to the platelet-derived growth factor responsive element of the MMP3 (stromelysin 1) promoter, hence the name SPBP (SPRE-binding protein) [6, 11]. The protein enhances the activity of several transcription factors (JUN, SP1, PAX6, ETS1) and of steroid receptors (androgen and oestrogen), and has an N-terminal transactivation domain, three nuclear localisation signals, three PEST domains, a minimal DNA-binding domain, a zinc finger and a C-terminal PHD/ADD (plant homeodomain/ATRX-DNMT3-DNMT3L) domain that binds nucleosomes in a histone-tail-dependent manner [6, 11]. It is expressed in the developing brain, peaking between 7 weeks post-conception and 2 years, and in the mouse it is concentrated in the hippocampus and cerebellum [6, 18].

The relationship with RAI1 is structural and functional. The two genes probably arose from an ancestral duplication early in vertebrate evolution, share the organisation of the transactivation domain, nuclear localisation signals and PHD/ADD domain (TCF20 positions 1690–1930), and the proteins interact in a yeast two-hybrid assay [6, 11]. Using proximity biotinylation, Zhou and colleagues identified a TCF20 complex including PHF14, RAI1 and HMG20A that binds MeCP2 on chromatin; Rett syndrome-causing MECP2 variants disrupt the interaction, the two genes co-regulate neuronal genes, reducing Tcf20 partially rescued the behavioural deficits of the MeCP2-overexpressing mouse, and a PHF14 missense variant abolishing binding was found in a person with a Rett-like presentation [24, 59]. This shared-complex model explains the clinical overlap between TAND, SMS and MECP2-related disorders, but the pathway linking loss of TCF20 to sleep disturbance remains hypothetical: Vetrini and colleagues proposed modulation of steroid receptors and BDNF in the suprachiasmatic nucleus, by analogy with the Rai1+/− mouse, without experimental demonstration [6].

The established mechanism is haploinsufficiency. The gene is highly intolerant of loss of function (pLI 1; LOEUF 0.05); ClinGen assigns it haploinsufficiency 3 (sufficient evidence, 2019) and triplosensitivity 0, and classified the gene-disease relationship as definitive in 2020 [6, 17, 24]. In the Vetrini cohort, the 25 distinct point variants comprised 18 frameshift, five nonsense, one canonical splice-site and one missense variant, in addition to four deletions of 128 kb to 2.64 Mb; in the Torti cohort there were 23 truncating variants and one de novo missense variant, none recurrent [6, 11]. In November 2025 ClinVar listed 131 pathogenic or likely pathogenic variants, 128 of them truncating or small delins [24]. Almost all cluster in the large first coding exon, of approximately 5.7 kb [6, 60]. Vetrini's RNA studies showed that alleles with a premature termination codon escaped nonsense-mediated decay, which points to loss of C-terminal domains or cytoplasmic accumulation of truncated protein, rather than absence of RNA, as the probable mechanism [6]. A pericentric inversion disrupting the gene, chromoanagenesis of chromosome 22 and an SVA retrotransposon insertion in exon 2 have also been described [18, 41, 61].

Examples of variants, all normalised in VariantValidator to the MANE transcript NM_001378418.1, whose coding numbering coincides with that of NM_005650.3 used in 2019: c.5719C>T p.(Arg1907Ter) and c.3027T>A p.(Tyr1009Ter), recurrent in unrelated families of the Vetrini cohort without occurring at CpG dinucleotides; c.5129A>G p.(Lys1710Arg), a de novo missense variant in the PHD/ADD domain, in a patient with SMS-like features who also had a de novo ZBTB18 variant; c.4737del p.(Lys1579AsnfsTer36), transmitted through paternal germline mosaicism; c.932_933del p.(Gln311ArgfsTer22) (ClinVar VCV000599637, pathogenic), described in three unrelated women; and c.5009dup p.(Thr1671AspfsTer5) [6, 13, 18, 24, 60]. There are no founder variants.

No genotype-phenotype correlation has been identified: distal truncating variants, the missense variant and multigene deletions produced similar presentations [6]. Variability is wide even within families, and carrier parents had milder phenotypes (one mother with only mild facial dysmorphism, another with intellectual disability and a tented upper lip) [6]. In about one fifth of Torti's patients there was another pathogenic variant that could contribute to the phenotype (FLG, TNFRSF13B, DNM2), and in the Vetrini cohort two patients had a second diagnosis (SLC6A1, ZBTB18), so the frequencies must be read with caution [6, 11]. 22q13.2 deletions including TCF20 and TNFRSF13C (BAFF receptor) are associated with immunodeficiency, as in the 13-month-old child with a 1.16 Mb de novo deletion described by Upadia and colleagues [62].

Gain of dosage has less clear significance than in PTLS. Lévy and colleagues described three patients with de novo 22q13.2 duplications including TCF20 and proposed a highly penetrant microduplication syndrome; Bizot and colleagues added six carriers, with the first triplication (440 kb, de novo) and the smallest duplication (82.5 kb, maternally inherited, spanning exons 2 and 3), but co-segregation showed variable expressivity and complete penetrance was called into question [15, 63]. In the ClinGen assessment there is no evidence of triplosensitivity, so a TCF20 duplication is interpreted case by case and does not carry the same diagnostic weight as a RAI1 duplication [15, 17].

3. Clinical Spectrum and Manifestations by System

3.1. Smith-Magenis syndrome: reference frequencies

GeneReviews bases its description on more than 400 people with a deletion or pathogenic RAI1 variant. The phenotype is subtle in infancy and becomes more recognisable at school age, when facial and behavioural features become apparent. Frequencies vary between studies according to ascertainment and the proportion with deletions [2].

Source: GeneReviews, Table 2, based on several cohorts from 1996–2021 [2].

3.2. Facial appearance and morphology

SMS facial features include a broad, square face, brachycephaly, prominent forehead, synophrys, slightly upslanting palpebral fissures, deep-set eyes, broad nasal bridge, midface retrusion, short nose with a full tip, infantile micrognathia evolving into relative prognathism, and a fleshy, everted, tented upper lip [2, 64]. In newborns and infants, the face may resemble Down syndrome. Frontal prominence, prognathism, brachydactyly, a deep hoarse voice and coarser appearance become evident with age, as illustrated in figures 1 and 2 of Smith’s Recognizable Patterns and figures 1–3 of GeneReviews [1, 2]. The Brazilian textbook’s table lists “hypertelorism” and, on the same line, “reduced distance between the eyes”. Allanson and colleagues’ anthropometric study of 55 patients describes apparently closely spaced, deep-set eyes, whereas the PNDS reports hypertelorism. Intercanthal distance should therefore be measured rather than inferred from gestalt [25, 47, 64].

Other findings include small hands and feet, brachydactyly, fifth-finger clinodactyly, second–third toe syndactyly, limited elbow extension, flat or varus feet, dry itchy skin, keratosis pilaris and hyperkeratosis, thick hair and eyebrows, and occasional postaxial polydactyly [1, 25, 47]. Occasional findings listed by Smith’s Recognizable Patterns include microcephaly, craniosynostosis, Brushfield spots, cleft lip and/or palate, iris coloboma, bifid rib, hemivertebrae, hand and foot lymphoedema, a short or bowed ulna, cryptorchidism, jejunal atresia, bladder exstrophy and diaphragmatic hernia [1].

3.3. Neurodevelopment and cognition

Most people with SMS function within the mild-to-moderate intellectual disability range. Measured IQs range from 20 to 78, predominantly within the moderate range [1, 2]. Deletions are associated with greater cognitive impairment than intragenic variants: at a Dutch clinic, median full-scale IQ was 56.0 with deletions and 73.5 with RAI1 variants (n=66). In a French series of 52 patients assessed at a genetic psychiatry referral centre, intellectual disability was present in 37 of 43 deletion carriers (86.0%) and none of nine sequence-variant carriers [38, 65]. These hospital-ascertained series do not estimate the population distribution of IQ.

The cognitive profile shows weaknesses in sequential processing and short-term memory, with relative strengths in long-term memory and perceptual closure [2]. In a Wechsler-based study of Southern European children and adults coordinated at the University of Minho, Osório and colleagues confirmed predominantly moderate intellectual disability, verbal comprehension as a relative strength, working memory as a relative weakness and no global cognitive decline with age [66]. Behaviour and sleep may cause formal assessments to underestimate actual ability [2].

Expressive language is more delayed than receptive language; infants cry infrequently with a hoarse cry and have reduced babbling [1, 2]. In the international PRISMS (Parents and Researchers Interested in Smith-Magenis Syndrome) registry, 60% communicated verbally, 79% said their first words at 24 months or later, 92% combined words at 36 months or later, and 41% used sign language before speech. A hoarse voice occurs in 50–80% [2, 67]. The PNDS reports language emerging around ages 4–5, sometimes becoming intelligible only at 8–9, and independent walking around 24 months [25]. The Brazilian textbook describes greater receptive than expressive difficulty, contrary to the other sources; convergence between GeneReviews, Smith’s Recognizable Patterns and the PNDS favours predominantly expressive delay [1, 2, 25, 47].

In a systematic review of 14 studies (451 patients), ASD feature prevalence ranged from 14% to 95%, averaging 43% with deletions and 80% with RAI1 variants. Attention deficit hyperactivity disorder (ADHD) was assessed using standardised clinical criteria in only one study, which reported 100%; methodological heterogeneity prevented meta-analysis [68]. A scoping review of adults showed persistence of intellectual disability, ASD and/or ADHD features (40%), self-injury and aggression (>50%), self-hugging, circadian disturbance and epileptic seizures (20%) into adulthood [2, 69].

3.4. Behavioural phenotype

Behavioural manifestations are rarely recognised before 18 months and intensify at predictable stages: 18–24 months, school age and puberty [2]. The PNDS notes crisis peaks in late morning, during sleepiness, and late afternoon, related to the advanced sleep phase, with fewer crises in one-to-one than group situations [25]. Development is asynchronous: emotional maturity falls below intellectual level, and adults with academic skills equivalent to ages 6–8 may show emotional reactions equivalent to ages 1–3, termed the “inner toddler” [2].

Self-injury is present in most individuals after age 2 and increases in prevalence and variety with age: hitting themselves (71%), self-biting (77%) and skin picking (65%) [2]. Three distinctive behaviours are onychotillomania (pulling out fingernails and toenails), skin picking and polyembolokoilamania (inserting objects into body orifices), with prevalences of 25–90% depending on age and sample [2]. Ear insertion is most frequent; insertion into the nose, vagina or rectum is generally described only in late adolescence or adulthood [2]. Head banging and wrist biting may begin in the second year, whereas onychotillomania is rare before ages 5–6 and may relate to relative pain insensitivity [1, 2]. The Atlas chapter on Lesch-Nyhan describes SMS self-injury as almost universal, predominantly hand biting [70].

Among stereotypies, “self-hugging” (a spasmodic contraction of the upper trunk) may serve as a diagnostic marker. Others include mouthing hands and objects, bruxism, stereotyped vocalisations, body rocking, spinning objects and the “lick and flip” behaviour of licking a finger and turning pages [2, 47]. Common behaviours also include tantrums, attention seeking (particularly from adults and attachment figures), impulsivity that may increase with age in girls, inattention, opposition, aggression, rapid mood changes, increasing adolescent anxiety and toileting difficulties [2, 25]. In a sample aged 4–18, 90% had significant social impairment on the Social Responsiveness Scale. Compared with six other syndromes, SMS had the highest score for restricted interests and repetitive behaviours [2]. Sexual disinhibition may emerge at puberty [25].

Sleep disturbance is among the strongest predictors of disruptive behaviour [2]. Frequent self-injury and insertion of objects into body orifices require caution when evaluating suspected abuse: people with intellectual disability face a real abuse risk, but suspicion may be mistaken when injury is self-inflicted [2]. Genotype series suggest two partly distinct trajectories: deletions carry a greater developmental burden and externalising dysregulation (self-injury 34/43; aggression towards others 28/43), while RAI1 variants are associated with better-preserved cognition and more anxiety (5/9 versus 5/43) and social withdrawal (4/9 versus 4/43) [38, 65].

3.5. Sleep and circadian rhythm

The inverted melatonin pattern, with daytime secretion, is considered pathognomonic and has been documented in more than 90% of individuals studied [2, 53]. Sleep is fragmented and shortened, with frequent, early nocturnal awakenings and excessive daytime sleepiness. Parents rarely recognise the problem before 12–18 months, although reduced total sleep time has been documented at 6 months [2]. Children fall asleep early, around 19–20 h, wake at 1–2 h with restless periods, and finally wake between 4 and 6 h. They nap or become sleepy after lunch and cannot remain awake in the early evening [1, 25]. Actigraphy shows approximately one hour less sleep than expected at all ages, with lower efficiency and more wakefulness after sleep onset; REM sleep was reduced in more than half of polysomnographies [2]. In a French cohort of 20 children aged 5–13, 95% took melatonin, 55% psychostimulants and 20% beta-blockers. Nevertheless, actigraphy showed reduced total sleep time in 71%, reduced efficiency in 88% and more than 60 minutes of wakefulness after sleep onset in 59% [71]. Weight gain promotes obstructive sleep apnoea, adding to circadian disturbance [2]. Caregiver sleep deprivation is substantial. Night-time supervision to prevent wandering, food seeking and self-injury leads to enclosed beds, bedroom adaptations and cupboard locks [2].

3.6. Neurology

Hypotonia is present in almost all infants, with hyporeflexia (84%) and lethargy. Approximately 75% have clinical signs of peripheral neuropathy regardless of deletion size: relative pain insensitivity, mild intention tremor (6–8 Hz), “inverted champagne bottle” legs, cavus or flat feet, and a broad-based gait [2]. Toe walking occurs in approximately 60% without Achilles tendon shortening [2]. Large deletions including PMP22 may cause painless focal palsies at compression sites [2]. Head circumference is usually normal at birth, with microcephaly potentially developing later [2].

Epileptic seizures occur in 11–30% and abnormal EEG without seizures in approximately 25%. The PNDS reports abnormal interictal EEG in 25–50% and various seizure types, including West syndrome [2, 25]. Stroke has been described in three patients: one with moyamoya disease and a large deletion, an adult with severe intracranial atherosclerosis after repeated cardiac surgery, and a child with a cleft and heart disease. In 2026, a child with progressive multifocal systemic arteriopathy and recurrent hypoperfusion infarcts was reported [2, 72]. Neuroimaging shows non-specific abnormalities in more than 50%, principally ventriculomegaly and cortical atrophy; periventricular heterotopia, a thin corpus callosum, enlarged posterior fossa and reduced insular and lenticular grey matter have been described [2, 25].

3.7. Growth, feeding, metabolism and endocrinology

Birth weight, length and head circumference are usually normal. Infant feeding difficulties (weak sucking and swallowing, texture aversion) lead to growth delay, and short stature (<percentile 5) is frequent (67%), particularly early in life, but may not persist into adulthood [2]. The PNDS describes childhood height between −2 and −3 standard deviations and adult height between percentiles 3 and 10 [25]. Sex-specific growth charts published in 2026 provide percentiles 5, 50 and 95 for length, weight and head circumference from 0–36 months and 2–15 years and have been incorporated into GeneReviews [2, 36].

Predominantly abdominal obesity usually begins between ages 6 and 9 and reflects hyperphagia, nocturnal food seeking, inactivity and psychotropic medication effects; food fixation is not explained by hunger alone [2]. Hypercholesterolaemia unrelated to diet or body mass index was found in more than 50%. Among 49 children with deletions, one third had borderline total or LDL cholesterol, more than one third had high values, and fewer than one third had all three parameters normal [2, 49]. In an Italian cohort with mean age 13.9, 20% had high total and LDL cholesterol and 63% low HDL; dyslipidaemia was not documented in RAI1 sequence-variant carriers [2]. The PNDS reports hypercholesterolaemia in up to 70% and obesity-associated type 2 diabetes and sleep apnoea risk [25].

Approximately 25% have mild hypothyroidism. Puberty usually occurs at the normal age, with reports of premature adrenarche, premature ovarian insufficiency and delayed puberty [2]. Only one case of isolated growth hormone deficiency has been published. Adrenal aplasia or hypoplasia was described in an infant who died after palatoplasty; adrenal function screening is therefore recommended for deletions extending into 17p12 [2, 25]. Gastro-oesophageal reflux and constipation are common (chronic constipation in more than half according to the PNDS) [2, 25].

3.8. Sensory organs, airway and mouth

Approximately 85% have ophthalmological abnormalities (strabismus, progressive myopia, iris abnormalities, microcornea). Approximately 20% of those older than 10 experience retinal detachment, to which high myopia and self-inflicted trauma contribute; keratoconus and glaucoma emerge in adulthood [2]. A 2026 report described bilateral rhegmatogenous detachments in an adolescent girl [73]. Otitis media is frequent (≥3 episodes annually), with ventilation tubes inserted in 85%. Hearing loss affects more than 79%, predominantly conductive before age 10 and sensorineural (48%) after age 11; hyperacusis affects approximately 74% [2, 74]. The Brazilian textbook reports deafness in 60% and vestibular dysfunction; the PNDS reports deafness in two thirds and positional vertigo [25, 47]. Vocal cord polyps, nodules, oedema and partial paresis, velopharyngeal insufficiency and hoarse voice contribute to expressive delay [2].

Oral findings commonly include tongue weakness and asymmetry, weak lip closure (64%), palatal abnormalities (64%; cleft in fewer than 25%), an open mouth with tongue protrusion and drooling. Dental abnormalities (premolar agenesis and taurodontism) affect approximately 90%, with increased caries and gingivitis in adolescence [2, 47].

3.9. Immunity, heart, kidneys and skin

More than half have low immunoglobulins. In a cohort of 76 patients with deletions, 74 reported recurrent infections, including otitis (88%), pneumonia (47%), sinusitis (42%) and gastroenteritis (34%). Among 25 investigated in detail, class-switched memory B cells were deficient and many lacked protective pneumococcal antibodies. There was no increase in autoimmunity, atopy or malignancy, and infections worsened behaviour [2, 75].

Congenital heart disease occurs in fewer than 50% of patients with deletions (37–47% according to the PNDS) and in only one reported RAI1 variant case: tricuspid or mitral regurgitation or stenosis, atrial or ventricular septal defects, supravalvar aortic or pulmonary stenosis, tetralogy of Fallot and total anomalous pulmonary venous return [2, 25]. The Oxford Desk Reference lists SMS among the syndromic diagnoses to consider in the presence of an atrioventricular septal defect, alongside Down syndrome (60% of these defects), Smith-Lemli-Opitz syndrome, Ellis-van Creveld syndrome and CHARGE syndrome [76]. Genitourinary abnormalities (15–35% with deletions, not described with sequence variants) include duplicated collecting systems, unilateral renal agenesis, ectopic kidney and ureterovesical junction abnormalities; most have nocturnal enuresis, and cryptorchidism, an underdeveloped scrotum and uterine hypoplasia have been described [1, 2].

Xerosis is more frequent with RAI1 variants (100%) than deletions (44%). Approximately 20% have hyperkeratosis, and hair and skin are often lighter than those of family members [2]. Fibrofolliculomas may emerge from late childhood in deletions including FLCN [2].

3.10. Birt-Hogg-Dubé manifestations in deletions including FLCN

Most SMS deletions include FLCN. Cancer risk appears not to exceed population risk for most patients, but FLCN haploinsufficiency confers risk of BHDS manifestations: fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax and renal tumours. A BHDS diagnosis should not be assigned without manifestations [2]. In four patients with deletions, pneumothoraces occurred between ages 2 and 22, earlier than usual in BHDS (before age 40). A survey of 117 families reported five pneumothoraces (four with deletions), two fibrofolliculoma cases and no renal cancers [2, 77]. Pneumothoraces were also described in two children with RAI1 variants without FLCN loss [2].

Vocke and colleagues described four adults with deletions and BHDS manifestations: three had histologically characteristic renal tumours (hybrid oncocytic tumours, a neoplasm with chromophobe carcinoma features, and oncocytoma), two with a second FLCN hit in the tumour, and one had confirmed fibrofolliculomas. Including a man with bilateral tumours at age 57, GeneReviews counts four adults with renal tumours [2, 57]. In 2026, a 35-year-old man with SMS and two renal tumours, one carrying a somatic FLCN variant, was described [58].

3.11. Potocki-Lupski syndrome

PTLS presents in two ways: in infancy, through hypotonia, oropharyngeal dysphagia with growth delay, congenital heart disease and growth-hormone-deficiency-associated hypoglycaemia; in milder cases, through cognitive and behavioural abnormalities alone, recognised later in childhood [3]. Among 24 patients followed from birth to age 5, weight-for-age and weight-for-length indices were below reference values, and swallowing studies documented oropharyngeal dysphagia [78]. Gross motor delay is almost universal, but most walk by age 2 (rarely only by age 4) [3].

Cognitive impairment is among the most frequent features and is usually moderate. Speech delay is universal, involving expressive and receptive impairment, altered intonation and prosody and, in some, verbal apraxia [3]. Treadwell-Deering and colleagues found intellectual disability in 13 of 15 patients and ASD criteria in 10 of 15 assessed (autism or pervasive developmental disorder not otherwise specified), with inattention, isolation, anxiety and atypical behaviour [3, 79]. The Oxford Desk Reference includes PTLS among ASD-associated syndromes [80].

Cardiovascular abnormalities were found in 10 of 25 patients (40%): dilated aortic root (20%), bicommissural aortic valve (2/25), atrial (3/25) and ventricular (2/25) septal defects and patent foramen ovale (4/25), alongside ECG abnormalities [81]. Hypoplastic left heart syndrome, including fatal cases, is described [1, 3]. In the original description, five of seven had short stature and one growth hormone deficiency; in 2007, one of ten had short stature. Subsequent cases include neonatal hypoglycaemia and early short stature [3].

Sleep disorders predominantly involve breathing (mild central and/or obstructive apnoea) and periodic limb movements, often recognised only on polysomnography. Sleep EEG may show a slow occipital rhythm and epileptiform activity without clinical seizures [3]. Other findings include hypermetropia, mild high-frequency sensorineural hearing loss, malocclusion and dental crowding, bilateral clubfoot, joint hypermobility, kyphoscoliosis, flat feet, long fingers (sometimes resembling a connective tissue disorder) and renal abnormalities (hypoplastic or multicystic dysplastic kidneys, hydronephrosis) [3]. Dysmorphism is mild: broad forehead, slightly downslanting palpebral fissures, broad nasal bridge, epicanthic folds, relatively long nasal tip, a triangular face with micrognathia in children and an oval face with a larger chin in adults, broad distal phalanges and increased first–second toe spacing [1, 3].

The 2026 French series (56 carriers) confirmed these signs and added intrauterine growth delay or low birth weight, musculoskeletal and ophthalmological abnormalities, and skin appendage abnormalities. Behavioural disturbances occurred in 23%; unexpectedly, self-injury and aggression towards others, typical of SMS, occurred in a small number [14]. Penetrance is described as complete with variable expressivity [3].

The 2026 French PNDS compiles the published frequencies, which come from small series, case reports and the French series, with heterogeneous denominators; they serve as orders of magnitude and not as prevalences in the PTLS population [19].

The PNDS adds several findings to the GeneReviews description. Neuroimaging is usually normal, but Chiari type 1 malformation, one case of holoprosencephaly and non-specific white matter changes have been described; the EEG frequently shows excess diffuse rhythmic activity at sleep onset and during sleep, and there is no epilepsy characteristically associated with PTLS, including in mouse models. Executive functions (initiating and carrying out activities, working memory) are impaired, and some patients have an intelligence quotient in the normal range. In a cross-syndrome comparison cited by the PNDS, compulsive behaviours were more marked in PTLS than in SMS and idiopathic ASD. In the eyes, besides hypermetropia, strabismus, anisocoria and glaucoma are described; in the mouth, the difficulty with oral hygiene associated with neurodevelopmental disorders increases the risk of plaque, chronic gingivitis and caries. Severity may relate to the size of the duplication (milder phenotype in a 0.25 Mb microduplication including RAI1), but the correlation is not consistent [19]. Two numerical differences from other sources deserve mention: the PNDS states 25% short stature in the initial description, attributing the figure to a reference that is not the original description, whereas GeneReviews reports five of seven patients; and it gives the recurrent 3.7 Mb duplication at times as 60% and at times as about two thirds of cases, within the two-thirds-to-85% range of the other series [3, 14, 19].

3.12. Comparison of the reciprocal syndromes

3.13. TCF20-related disorder

The two 2019 cohorts resulted from genotype-first rather than clinical ascertainment — patients identified by exome or microarray in clinical laboratories and in the British DDD (Deciphering Developmental Disorders) study — which reduces phenotype-driven selection bias but leaves incomplete data, because not every feature was systematically sought in all patients [6, 11]. The Vetrini cohort (United States, United Kingdom, Israel and other centres; 20 boys and 12 girls, almost all of paediatric age) and the Torti cohort (GeneDx laboratory and GeneMatcher; 15 males and 12 females aged 2 to 68 years, median 10 years, including seven adults) are the largest described [6, 11].

Source: [6, 11].

Developmental delay is constant, but cognitive severity varies. In the seven Torti patients with a measured intelligence quotient, values ranged from the low 60s to the normal range, with a mean and median of 69; the mean milestones were sitting at 10 months, walking at 20 months and first words at 23 months, and 11 patients had no speech concerns [11]. In the Vetrini cohort moderate to severe disability predominated [6]. Behavioural abnormalities are the most frequent domain after cognition: ASD, ADHD, anxiety (10 of 27 Torti patients), learning difficulties, sensory processing disorder, depression, obsessive traits, stereotypies, aggression and tantrums; food seeking and early obesity (16% in the Vetrini cohort) and self-injury, described in some patients, resemble SMS [6, 11].

Non-cognitive neurological features distinguish TAND from many other neurodevelopmental disorders. Besides hypotonia, ataxia and impaired coordination, dyspraxia (including oculomotor dyspraxia), tremor, hyperreflexia, muscle weakness and, in a few patients, lower-limb hypertonia are described [6, 11, 24]. Dystonia was recognised later: Svorenova and colleagues described two patients, one with a progressive spastic-ataxic-dystonic syndrome with generalised dystonia and myoclonus unresponsive to levodopa, the other with toe walking in childhood followed by generalised dystonia; Prasun and colleagues described an adolescent girl initially diagnosed with dystonic cerebral palsy; Magistrelli and colleagues, a 70-year-old man with upper-limb myoclonus and craniocervical dystonia since age 40, mild ataxia since childhood and intellectual disability (IQ 51), in a myoclonus-dystonia “plus” presentation; and Kilic and colleagues, a 23-year-old woman with generalised, predominantly cervical dystonia (section 10.3) [60, 82–84]. Dystonia may therefore be progressive, fluctuating or of late onset, and may go unnoticed in cohorts characterised by questionnaire [60]. Seizures are infrequent and begin in childhood, with variable course, from focal epilepsy that remitted to refractory generalised epilepsy [11].

Magnetic resonance imaging is normal in most patients. The abnormalities described are non-specific: thickening or thinning of the corpus callosum, mild cerebellar atrophy, delayed myelination, subependymal heterotopias, gliosis and Chiari type I malformation (6 mm tonsillar descent in an 11-year-old boy, without brainstem compression) [6, 11, 24]. In one case, quantitative susceptibility mapping showed numerically higher values and smaller volume of the globi pallidi, without allowing statistical inference [60].

Growth is normal in most (20 of 27 Torti patients) [11]. Postnatal overgrowth with macrocephaly, described in the two Schäfgen patients, occurred in a minority in subsequent cohorts; in the Vetrini cohort, overgrowth, obesity or tall stature affected 8 of the 11 patients older than 9.5 years and only 1 of the 15 younger ones, suggesting an age-dependent feature, not confirmed longitudinally [6, 11, 42]. Craniosynostosis (metopic and coronal in the Babbs proband) was not described again in the 2019 cohorts and may be coincidental [11, 41].

Outside the nervous system, the most frequent complaints are gastrointestinal (constipation, reflux, gastroparesis), and there is one case of biopsy-confirmed Hirschsprung disease in a 40-year-old man with an SVA insertion, which the authors interpret as a rare extension of motility involvement [11, 61]. Ocular (strabismus, myopia, keratoconus, cataract in one adult), skeletal (flat feet, scoliosis, pectus, joint hypermobility) and cutaneous abnormalities (eczema, keratosis pilaris, ichthyosis, four of six patients with an FLG variant), isolated malformations (hypertrophic pyloric stenosis in two, hypospadias in one), inverted nipples and cardiovascular problems (mitral valve prolapse, bundle branch block, pre-excitation) are occasional [6, 11]. Immune problems are rare with point variants (autoimmune hepatitis and hyper-IgE syndrome, one patient each) and more expected with deletions including TNFRSF13C [11, 62].

In adulthood, Torti's seven adults (aged 19 to 68 years) added diverticulosis, suspected Crohn disease, cataract, mitral prolapse, borderline arterial hypertension and, in a man in his sixties, evaluation for possible cognitive decline; three adult siblings lived in supported housing with sheltered employment [11]. Carrier parents identified after their child's diagnosis had mild presentations, which shows that expressivity includes independent adults [6].

4. Clinical Recognition and Warning Signs

No sign permits a clinical SMS diagnosis in newborns or infants. Pregnancy is usually normal, although some parents retrospectively report reduced fetal movements. Diagnosis is almost always incidental, through CMA requested for hypotonia, feeding difficulty or a malformation [25]. An “overly quiet” infant needing to be awakened to feed, with hypotonia, hyporeflexia, an infrequent hoarse cry, little vocalisation and growth delay should prompt consideration of SMS [2, 25].

At preschool and school age, the most suggestive combination is disturbed sleep with early sleep onset and waking between 4 and 6 h, daytime sleepiness, tantrums and intense attention seeking, hand and wrist biting, self-hugging, “lick and flip” behaviour, and a square face with a tented upper lip [1, 2]. The Oxford Desk Reference recommends considering SMS in short stature with obesity, small hands and feet, a square heavy facial appearance, infantile hypotonia, developmental delay, behavioural problems (particularly sleep) and food seeking. It proposes investigating 17p when Prader-Willi testing is negative and sleep disturbance is present [85, 86]. A child with hereditary neuropathy and cognitive impairment should undergo microarray rather than PMP22 testing alone [45].

Clinical warning signs require immediate action or specific surveillance. A sudden behavioural change should prompt investigation of unexpressed pain: otitis, urinary infection (dysuria may go unnoticed), dental pain, an epileptic seizure or fracture, because relative pain insensitivity and communication difficulties obscure the cause [25, 87]. Sudden visual deterioration, altered pupillary reflex or repeated ocular trauma suggest retinal detachment [2, 25]. Sudden dyspnoea or chest pain in a carrier of a deletion including FLCN suggests pneumothorax, including in children [77]. Focal neurological deficits, gait change, loss of continence or progressive foot deformity warrant lumbar MRI for suspected tethered cord, described in three patients [2]. Injuries from self-harm or object insertion must be interpreted in the syndrome’s context before abuse is presumed [2].

In PTLS, the most useful signs are infantile hypotonia with oropharyngeal dysphagia and growth delay, language delay with autistic features, and left ventricular outflow tract heart disease or aortic root dilatation; facial appearance rarely guides diagnosis, which almost always follows CMA [3, 20]. Adults with undiagnosed intellectual disability or psychiatric disorders may receive a PTLS diagnosis only after an affected child is born [3, 88]. The PNDS organises the circumstances of diagnosis by age: prenatally, fetal CMA requested for intrauterine growth restriction or for a cardiac or renal malformation; at birth, hypotonia, oral feeding difficulty or malformations; in early childhood, a neurodevelopmental disorder or a cardiac or renal malformation; in the older child and adult, an incidental finding or targeted testing for a neurodevelopmental disorder, short stature or peripheral neuropathy associated with other signs, which suggests a duplication that also encompasses PMP22 [19].

TAND has no clinical signs that allow diagnosis without molecular testing [6]. It should be considered in developmental delay with ASD or ADHD and hypotonia when CMA and RAI1 testing are normal, especially if there are SMS-like features (tented upper lip, food seeking, sleep disturbance), ataxia, tremor or dyspraxia of unexplained cause, or generalised dystonia in a child or adult with intellectual disability, including people previously diagnosed with dystonic cerebral palsy without a perinatal injury to explain it [6, 24, 60, 83]. There is no newborn screening.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

No published consensus clinical criteria exist for SMS. Diagnosis is established in a proband with suggestive findings and a heterozygous 17p11.2 deletion including RAI1, or a heterozygous pathogenic or likely pathogenic RAI1 variant. In clinical practice, “pathogenic” and “likely pathogenic” have the same decision-making significance according to the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) [2]. PTLS is diagnosed by detecting a heterozygous 17p11.2 duplication including RAI1 [3].

5.2. Genetic tests and their limitations

Reports should identify the alteration through genomic coordinates and genome version (for example, arr[hg19] 17p11.2(16,757,111-20,219,651)x3 for the recurrent duplication, or the ClinGen ISCA-37418 region on GRCh38), included genes of interest (RAI1, FLCN, PMP22 when encompassed), zygosity, classification under ACMG/ClinGen CNV standards and method limitations. Sequence-variant reports should specify the gene, versioned transcript (NM_030665.4), HGVS c. and p. nomenclature, zygosity, ACMG/AMP classification and coverage limitations [2, 3, 16]. Inclusion of FLCN and PMP22 affects surveillance and counselling and should be explicit.

The proportion of alterations detected by a method is not its clinical sensitivity: CMA’s 80–90% describes mechanism distribution among diagnosed patients rather than the probability of detecting SMS in a clinically suspected patient. Normal CMA does not exclude SMS with a convincing phenotype, because approximately 10–20% of cases involve intragenic variants. Negative sequencing does not exclude a variant in a poorly covered region or low-level mosaicism [2, 25]. Mosaic SMS may be asymptomatic or attenuated [25].

For PTLS, the French PNDS describes three diagnostic routes: FISH with a specific probe, reserved for clinical suspicion, because the common duplication is not visible on conventional karyotype; CMA (comparative genomic hybridisation or SNP array), for years the first-line test for neurodevelopmental disorders; and, currently in France, first-line genome sequencing for developmental anomalies and intellectual disability under the France Genomic Medicine Plan 2025, with detection of the duplication by copy number variation analysis [19]. GeneReviews, which predates the widespread use of genome sequencing, retains CMA as first line [3].

5.3. Supportive non-molecular tests

A 24-hour melatonin profile or daytime salivary melatonin documents circadian inversion and supports but does not confirm diagnosis; exceptions with normal secretion exist [2, 53]. A single measurement has limited value: in the section 10 case, serum melatonin of 57 pg/mL at 7 h was considered compatible, but one timepoint does not define the profile [87]. In a retrospective analysis of 89 patients, Braam and Smith found higher levels in those taking exogenous melatonin, falling after discontinuation in nine patients with very high levels and rising after treatment initiation in 12. They recommended measuring melatonin before and during treatment and noted that CYP1A2 genotyping does not predict enzyme activity [39]. Childhood hypercholesterolaemia in deletion carriers has been proposed as an early biochemical marker [49]. Sleep questionnaires, diaries and actigraphy are first-line tools; suspected apnoea warrants polysomnography [2, 25].

5.4. Diagnostic algorithm

5.5. Assessment of involvement following diagnosis

For SMS, GeneReviews recommends EEG for seizures or suspicion thereof; neuroimaging according to findings; developmental and neuropsychological assessment (screening for sleep disturbance, ADHD, anxiety and ASD from 12 months); sleep history, diary or actigraphy and polysomnography for suspected apnoea; syndrome-specific growth charts; fasting lipid profile; assessment of reflux, constipation and intake; palate and dental assessment; spinal radiographs; ophthalmological examination; audiogram; echocardiography; renal ultrasound; quantitative immunoglobulins (IgG, IgA, IgM) and vaccine titres, including pneumococcal antibodies; TSH and free thyroxine; skin examination; and safety risk assessment [2]. Deletions including FLCN require detailed dermatological examination with biopsy of suspicious lesions, chest radiography or CT when symptomatic, and abdominal MRI from age 21 [2]. The PNDS specifies age-based initial assessment: complete examination, echocardiography and renal ultrasound, spinal radiographs, ENT assessment with audiometry, ophthalmological examination, immunoglobulins and thyroid function in newborns and infants; in older children, add a lipid profile, developmental assessment and sleep diary, IGF-1 and bone age for short stature, and polysomnography for suspected apnoea. At any age, screen adrenal function (basal cortisol and stimulation testing) for deletions extending into 17p12 and provide HNPP information if PMP22 is included [25].

Initial PTLS assessment includes growth (swallowing assessment for growth delay; bone age, IGF-1, IGFBP-3 and endocrinology for short stature), ophthalmology (strabismus, refraction), audiometry, sleep studies for suspected apnoea, dental assessment, ECG and echocardiography measuring the aortic root, renal ultrasound, assessment of hypermobility, scoliosis, clubfoot and flat feet, hypoglycaemia history, developmental and behavioural screening with ADOS for suspected ASD, and a genetics clinic appointment [3]. The PNDS follows this list and adds: consultation at a sleep or paediatric neurology centre, with polysomnography if the targeted history warrants it; brain MRI if needed; psychological or child psychiatric assessment; nutritional and oral-motor assessment (speech and language therapy, physiotherapy, dietitian and, if needed, psychologist); search for adenotonsillar hypertrophy as a treatable cause of apnoea; and bone densitometry from age 16, repeated every 2 years [19]. The diagnosis should be disclosed in a private setting, with sufficient time, in the presence of both parents or a trusted person, with psychological support during or after the consultation, attention to siblings, a follow-up appointment at a later date and information about patient associations [19].

5.6. Diagnosis of TCF20-related disorder

There are no clinical criteria or biochemical biomarker; diagnosis is established by identification of a heterozygous pathogenic or likely pathogenic TCF20 variant or a deletion including the gene [6, 11]. Trio exome or genome sequencing is the first-line test, because TAND cannot be distinguished clinically from other neurodevelopmental disorders and because the exome also detects small copy number variants; CMA identifies the larger deletions, but not point variants, which are the majority [6, 11]. Neurodevelopmental, ataxia and dystonia panels should include the gene: in the boy described by Ziveri and colleagues, a spinocerebellar ataxia panel was negative before trio exome sequencing identified the variant [24, 60].

Test limitations constrain the interpretation of a negative result. Short-read sequencing with standard algorithms may fail to detect mobile element insertions, such as the SVA insertion identified in a patient with Hirschsprung disease [61]. Sanger sequencing of parental blood does not exclude low-level mosaicism: in the Poquérusse family, the variant was not visible by Sanger, targeted short-read sequencing or nanopore sequencing of paternal blood, and only droplet digital PCR detected it in 3.2% of the father's urothelial cells [18]. Missense variants are rare, have no validated functional assay and are usually classified as of uncertain significance, unless there is evidence of de novo occurrence with a compatible phenotype [6, 24]. Interpretation of 22q13.2 duplications including TCF20 is debatable, given ClinGen triplosensitivity 0 and the incomplete penetrance in the Bizot series [15, 17]. Because five of Torti's 27 patients and two of Vetrini's 32 had a second relevant variant, a positive TCF20 result does not obviate analysis of the rest of the exome [6, 11].

The report should state the MANE transcript NM_001378418.1 and its version, the HGVS nomenclature, zygosity, origin (de novo with or without confirmed parentage) and the class according to ACMG/AMP criteria; in practice, truncating variants absent from population databases and de novo usually meet criteria PVS1, PM2 and PS2 (or PM6 when parentage has not been confirmed) [18, 24, 60]. After diagnosis, the initial evaluation includes assessment of development, behaviour (ASD, ADHD, anxiety) and sleep, neurological examination focused on movement disorders, ophthalmological examination with refraction, gastrointestinal assessment (constipation, reflux), examination of the spine and feet, EEG if seizures are suspected and brain MRI when there are neurological signs; with deletions including TNFRSF13C, immunoglobulins and vaccine responses [6, 11, 62]. Prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known.

6. Differential Diagnosis

The SMS differential includes all causes of intellectual disability without distinctive signs, but circadian disturbance, self-injury and evolving facial features together narrow the possibilities. Down syndrome is the classic infant differential because of brachycephaly, a flat face and hypotonia [1, 2]. GeneReviews, the PNDS, the Brazilian textbook and the Oxford Desk Reference identify the following conditions [2, 25, 47, 85, 86].

Features supporting SMS when the facial appearance is coarse include a square heavy face, short stature, obesity and small hands. The Oxford Desk Reference also lists SMS among causes of small but structurally normal hands, distinguished from true brachydactyly [86, 89].

The PTLS differential is broad because each manifestation (developmental delay, ASD, hypotonia, heart disease) may occur independently in other genomic disorders; in practice, diagnosis is molecular [3]. Two molecular differentials deserve particular attention: 17p11.2 gains sparing RAI1, with less defined and frequently inherited neurodevelopmental phenotypes, and YUHAL syndrome, in which the duplication includes RAI1 and PMP22 and the child also has CMT1A-type demyelinating neuropathy [43, 54]. In YUHAL, the two loci are about 2.5 Mb apart, peripheral neuropathy begins particularly early and the presentation may be more severe than the sum of the two disorders, with simultaneous involvement of the central and peripheral nervous systems [19, 43]. Isolated 17p12 microduplication (the CMT1A region) causes neuropathy without the PTLS phenotype [34].

TAND is the closest molecular differential of SMS and the discriminating test is sequencing: when the presentation suggests SMS but CMA and RAI1 sequencing are normal, the exome or genome should include TCF20 [2, 6]. Clinically, TAND has less documented circadian inversion, less stereotyped self-injury (onychotillomania, polyembolokoilamania) and more movement disorders (ataxia, tremor, dystonia) than SMS, and has no consistent facial gestalt [6, 11]. The differential of TAND itself includes:

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

Neither syndrome has a curative treatment. Objectives are to improve quality of life, maximise function and prevent complications through multidisciplinary care coordinated by a clinical geneticist, paediatrician or paediatric neurologist affiliated with a referral centre [2, 3, 25]. The French PNDS defines roles for specialties (genetics, paediatric neurology, child psychiatry, gastroenterology, endocrinology, surgery and urology, orthopaedics, ENT, ophthalmology, nephrology, dentistry and orthodontics, physical and rehabilitation medicine) and therapists (physiotherapy, psychomotor therapy, speech and language therapy, occupational therapy, psychology, dietetics, orthoptics, specialist education and social work) [25]. Early intervention, structured individualised education and routines, augmentative and alternative communication (which does not impair speech), applied behaviour analysis for ASD features and vocational training apply to both conditions [2, 3].

7.2. Sleep disturbance in SMS: non-pharmacological measures

The PNDS notes a lack of treatment consensus and recommends starting with a sleep diary and actigraphy, sleep-centre assessment and polysomnography for suspected obstructive apnoea, treated conventionally (including tonsillectomy and adenoidectomy when indicated) [25]. Sleep–wake hygiene includes short naps, regular schedules, limiting evening screen use and avoiding bed-sharing with parents. Night-time safety includes a room free of dangerous objects, a closed door to prevent wandering, an enclosed bed (tent-style or “safe space”) and locks on food cupboards [2, 25]. In 2026, Wiater and colleagues published paediatric recommendations with an appendix advising parents on diagnostic and therapeutic pathways, based on sleep–wake rhythm dysfunction and daytime melatonin secretion [40].

7.3. Sleep disturbance in SMS: medications

Tasimelteon is an MT1 and MT2 melatonin receptor agonist with greater MT2 affinity. In the United States, Hetlioz® capsules (20 mg) are indicated for night-time sleep disturbances in SMS from age 16, and Hetlioz LQ® oral suspension (4 mg/mL) for ages 3–15 [21]. Melatonin-based treatment aims to restore a nocturnal signal; beta-1 blockade aims to suppress the inappropriate daytime melatonin peak [2, 25].

Off-label melatonin doses depend on formulation and product. GeneReviews and PRISMS low-dose recommendations (<3 mg) differ from 2021 French practice with prolonged-release melatonin up to 6 mg. The PNDS predates extension of Slenyto’s indication to neurogenetic disorders, and the RTU was time-limited; current authorised European dosing is therefore specified in Slenyto’s Summary of Product Characteristics [2, 25, 90]. Braam and Smith’s observation that exogenous melatonin may further increase daytime levels and worsen sleep supports measuring levels before and during treatment. This was a retrospective analysis without a randomised control group [39].

7.4. Comparative regulatory status

Authorisation does not guarantee marketing, reimbursement or access in each country. No indication-specific reimbursement decisions for Portugal or Brazil were identified in the sources consulted.

7.5. Trials and intervention studies

These studies cannot rank treatments through indirect comparisons: populations, formulations, outcomes (parental diaries for the worst nights, actigraphy, total sleep time) and durations differ. In the tasimelteon trial, the 0.4-point difference on a 5-point scale concerns the mean of the worst nights rather than each patient’s response, and sleep-time improvement did not reach significance for the primary outcome. The Slenyto study included few children with SMS, while acebutolol studies are small and open-label.

7.6. Behaviour, mental health and psychotropic medication

Behavioural support at home and school should begin when disruptive behaviour emerges, usually at school entry, using a structured programme, individual support, a curriculum adapted to cognitive and behavioural profiles, and attention to sensory processing [2]. Behavioural change should prompt investigation of an underlying cause (pain, infection, sleep disturbance, seizures) before medication changes [2, 25]. In 2024, PRISMS published strategies for emotional and behavioural difficulties, cited by GeneReviews [2]. The PNDS prioritises speech and communication therapy, parental guidance and, in selected cases, residential schooling. Protective or restrictive measures (helmet, secured exits, refrigerator lock) may be necessary [25].

No medication regimen has demonstrated consistent efficacy. In a retrospective caregiver survey concerning 62 people, none of seven classes (stimulants, antidepressants, antipsychotics, hypnotics, mood stabilisers, alpha-2 agonists and benzodiazepines) differed substantially from “no change”, and benzodiazepines had a slightly harmful effect. Medication began at a mean age of 5, with frequent polypharmacy and successive trials of low efficacy [2, 93]. Without controlled trials, each new drug requires sleep and behaviour recording over days to weeks and monitoring for increased appetite and weight; pharmacogenetic testing may help predict interactions [2].

As expert opinion and in monotherapy, the PNDS proposes: low-dose divided hydroxyzine (1 mg/kg/day; 10–50 mg/day), usable before age 6, with monitoring for daytime somnolence; risperidone from age 6, starting at 0.25–0.5 mg/day and increasing in 0.25–0.5 mg steps until symptoms are controlled, usually effective at 0.25–0.75 mg/day in children, with a usual dosage of 2–6 mg/day in adults (no maximum dose defined in the source), with prior ECG and monitoring of weight, glucose and lipids; clozapine in adults at moderate doses (25–200 mg), with weekly haematological monitoring for 19 weeks and then monthly throughout treatment (PNDS schedule); methylphenidate after treatment of anxiety, with possible reversible withdrawal; and antiandrogen treatment, discussed with endocrinology, for inappropriate sexual behaviour [25]. The clozapine haematological schedule given in the PNDS does not match the current SmPC: the absolute neutrophil count is measured weekly for the first 18 weeks and monthly for the following 34 weeks; after 12 months without neutropenia it moves to every 12 weeks and, after 24 months without neutropenia in the previous two years, to annual, with initiation requiring a baseline count ≥1500/mm³ [94]. These indications constitute off-label use in SMS and must be checked against each country's label, age and comorbidity; the PNDS recommends cardiological assessment before neuroleptics, beta-blockers or methylphenidate [25]. Antipsychotics increase the risk of weight gain [2]. On the labels, hydroxyzine in the European Union, since the 2015 Article 31 referral, has a maximum daily dose of 2 mg/kg/day in children up to 40 kg, 100 mg/day in adults and children over 40 kg and 50 mg/day in older people, should be used at the lowest effective dose for the shortest possible time, and is contraindicated in congenital or acquired QT prolongation and in the presence of risk factors for such prolongation [95]. The US Risperdal® label indicates risperidone for irritability associated with autistic disorder at ages 5 to 17: starting at 0.25 mg/day below 20 kg or 0.5 mg/day from 20 kg; after at least 4 days, 0.5 mg/day or 1 mg/day, respectively, maintained for at least 14 days; then increments of 0.25 mg/day or 0.5 mg/day at intervals of 2 weeks or more; effective range 0.5 to 3 mg/day, with no dosing data below 15 kg [96]. The paediatric doses in the PNDS do not exceed these upper limits [25, 95, 96]. In the EU, risperidone is authorised from age 5 only for short-term (up to 6 weeks) symptomatic treatment of persistent aggression in conduct disorder, in children and adolescents with below-average intellectual functioning or intellectual disability, with a starting dose of 0.25 mg/day below 50 kg (optimum 0.5 mg/day; maximum 0.75 mg/day) and 0.5 mg/day from 50 kg (optimum 1 mg/day; maximum 1.5 mg/day); autism spectrum disorder is not a European indication [97]. Thus, the PNDS threshold of 6 years is more restrictive than the European SmPC, and the paediatric range of 0.25 to 0.75 mg/day matches that of the SmPC below 50 kg.

7.7. Epilepsy

Seizures are treated with antiseizure medications selected for seizure type; none has demonstrated SMS-specific efficacy [2]. GeneReviews recommends considering somnolence and administration timing because of circadian disturbance, and avoiding weight-gain-associated agents such as valproic acid [2]. The PNDS advises caution with levetiracetam, topiramate, lamotrigine and zonisamide because they may worsen behaviour. It lists drugs associated with higher aggression rates (topiramate, tiagabine, clobazam, levetiracetam, vigabatrin, perampanel) and hyperactivity (phenobarbital, clobazam, vigabatrin), without SMS-specific studies [25]. Unexplained mood or behavioural change should prompt reassessment for seizures [25].

7.8. Feeding, obesity, lipids and endocrinology

Infant oromotor dysfunction requires swallowing assessment, feeding therapy and, when severe, nasogastric feeding or gastrostomy [2]. For obesity, GeneReviews recommends portion control, nutritional counselling, physical activity, less sedentary behaviour and nocturnal intake, and strategies limiting food access because of the biological intensity of eating behaviour [2]. Setmelanotide did not reduce weight in SMS [56]. In 2026, two individual reports described weight loss with the glucagon-like peptide 1 receptor agonist liraglutide and with tirzepatide (a dual GIP/GLP-1 agonist), the latter in a 31-year-old woman with a deletion. These isolated uncontrolled observations do not establish efficacy or safety in this population. SMS is not an authorised indication for these agents; use depends on each label’s obesity and age criteria [98, 99].

Hypercholesterolaemia is treated with diet and, if necessary, medication according to general recommendations. The PNDS suggests fasting glucose and glycated haemoglobin when overweight is present and reducing neuroleptics where possible [2, 25]. Hypothyroidism is treated with levothyroxine; growth hormone treatment has been described for proven deficiency, without controlled studies [2].

7.9. Sensory organs, mouth, immunity, heart, kidneys, spine and skin

Recurrent otitis is treated conventionally, with ventilation tubes when indicated; hearing aids may help, and velopharyngeal insufficiency and palatal abnormalities benefit from a cleft team [2]. The PNDS recommends ophthalmological examination with cycloplegia in the first week, at 12 months and ages 3, 6 and 10, helmets to reduce eye and head trauma, and dental care from the first dentition, with supervised brushing, fluoride, 2–4 annual visits and conscious sedation or general anaesthesia when needed [25]. For recurrent infections, immunology may propose antibiotic prophylaxis or immunoglobulin replacement; infection prevention may also improve behaviour [2, 75]. Heart and renal abnormalities are treated conventionally, with endocarditis prophylaxis when indicated; unexplained fever should prompt urinalysis [2, 25]. Scoliosis is monitored clinically. The PNDS recommends orthopaedic referral for progressive curves or >20°, a night-time brace before adolescence, and surgery, usually towards the end of growth, for curves >45° [25]. Emollients, long sleeves and nail care limit the consequences of skin self-injury [25].

7.10. Birt-Hogg-Dubé surveillance in deletions including FLCN

Sources agree on beginning renal surveillance in adulthood but differ in interval and method.

The difference reflects population: European guidance concerns BHDS due to an FLCN variant, whereas SMS GeneReviews adapts it to people with intellectual disability, for whom MRI may require sedation and only a few renal tumour cases have been documented [2, 27]. In practice, the interval should be chosen individually and explicitly, weighing BHDS risk (confirmed FLCN inclusion), MRI feasibility and patient and family preferences.

7.11. Perioperative circumstances, pregnancy and transition

Before open-heart surgery in adolescence or adulthood, assessment for premature cerebrovascular disease is recommended because of postoperative stroke reported in an adult with severe intracranial atherosclerosis [2, 25]. Sudden death after palatoplasty in an infant with adrenal hypoplasia supports adrenal screening before procedures for deletions extending into 17p12 [2, 25]. The PNDS recommends anaesthetic consultation before any adult surgery [25].

SMS fertility has not been studied; women with SMS have had affected children, and gynaecological assessment (contraception, possible hormonal treatment) is part of adult follow-up [2, 25]. In pregnancy, tasimelteon data are insufficient to assess risk, and no human data exist for prolonged-release melatonin; neither use is authorised in pregnancy [21, 90]. Transition to adult care should be discussed from ages 12–14 in SMS and from age 12 in PTLS, including guardianship, funding, employment and care organisation [2, 3]. When there is intellectual disability, the PTLS PNDS recommends preparing a legal protection measure for the age of majority, adjusted to severity (in France, sauvegarde de justice, curatelle, tutelle or habilitation familiale), and directing the adult to adapted facilities (medico-social residential home, day care) or, in mild to moderate disability, to sheltered or mainstream employment with recognition of disabled worker status; the anaesthetic precautions for PTLS are described in section 7.12 [19].

7.12. Potocki-Lupski syndrome

PTLS management follows conventional practice for each manifestation, coordinated by a team potentially including audiology, cardiology, dentistry, developmental paediatrics, endocrinology, feeding services, gastroenterology, genetics, ophthalmology, orthopaedics, ENT, physical and rehabilitation medicine, psychiatry, sleep medicine, speech and language therapy and urology [3].

The 2026 French PNDS identifies no specific or consensus pharmacological treatment and organises management by problem [19].

For neurodevelopment, screening and referral follow the general HAS recommendations for children at risk of a neurodevelopmental disorder. At diagnosis, the child is referred to a comprehensive support structure (in France, an early medico-social action centre up to age 6 and a special education and home care service from age 3), using, when there is a waiting list, the departmental coordination and referral platform for neurodevelopmental disorders. Muscle-strengthening physiotherapy aims to maximise strength and mobility and to reduce the risk of scoliosis; hydrotherapy, music therapy and hippotherapy are options; occupational therapy addresses fine motor skills (feeding, hygiene, dressing, writing); oral-motor rehabilitation, by a physiotherapist or speech and language therapist, applies when oral feeding is safe; and speech and language therapy, started early and combined with augmentative and alternative communication (signs, pictograms, speech-generating devices, comprehension and expression tools), addresses verbal apraxia and receptive and expressive deficits. Improvement in verbal abilities with age and therapy is a clinical observation, without formal studies in adolescents and adults. A comprehensive neuropsychological assessment guides schooling and educational adaptations, with regular reassessment [19]. Neurological follow-up (paediatric neurology in childhood) looks for hypotonia or hypertonia and signs of epilepsy, with no surveillance beyond that recommended for any child; assessment in physical and rehabilitation medicine and assistive equipment (orthoses, adapted pushchairs) are decided case by case [19].

For behaviour, assessment is performed at diagnosis and repeated periodically, with formal ASD assessment, interventions based on applied behaviour analysis and child psychiatric follow-up. When behaviour changes, a somatic cause (pain, constipation, infection) is sought first. For severe aggression and impulsivity, the PNDS accepts antipsychotics, possibly combined with psychostimulants, on the basis of a case report, and draws attention to adverse and metabolic effects in children [19]. ASD diagnosis and interventions follow the general HAS recommendations for children, adolescents and adults, with autism resource centres as the diagnostic reference in France [19]. The PNDS gives no doses for PTLS; by extrapolation, the references are those of the labels in analogous conditions: risperidone for irritability associated with autistic disorder at ages 5 to 17 (0.25 mg/day below 20 kg or 0.5 mg/day from 20 kg, increased to 0.5 or 1 mg/day after at least 4 days, maintained for at least 14 days, then increments of 0.25 or 0.5 mg/day at intervals of at least 2 weeks, up to the maximum of the effective range of 0.5 to 3 mg/day; no data below 15 kg) and immediate-release methylphenidate for ADHD from age 6 (5 mg twice daily, before breakfast and lunch, with weekly increments of 5 to 10 mg, not exceeding 60 mg/day; in adults, 20 to 30 mg/day in 2 or 3 doses, maximum 60 mg/day), with prior cardiovascular assessment [96, 100]. These regimens are off-label in PTLS, and the choice must take into account heart disease, which is frequent in this syndrome.

For sleep, ENT assessment for an obstructive cause precedes treatment; apnoea is treated according to the usual standards, and excessive periodic limb movements prompt a search for iron deficiency. Once an organic cause has been excluded, bedtime routines and melatonin may be effective; in France, prolonged-release melatonin (Slenyto®) is reimbursed at 100% from ages 2 to 18 in people with ASD covered by the long-term illness scheme, and access in adults was under evaluation at the time of the PNDS [19]. In the absence of a PTLS-specific dose, the dosage in the Slenyto Summary of Product Characteristics applies (starting at 2 mg, increasing to 5 mg, maximum 10 mg, once daily, 0.5–1 hour before bedtime), whose European indication covers insomnia in ASD and neurogenetic disorders at ages 2 to 18 (section 7.3) [90].

For cardiology, the PNDS recommends echocardiography and ECG at diagnosis and treatment according to the usual recommendations, given the variety of presentations (malformation, aortic root dilatation or aortopathy, ECG abnormality). For orthopaedics, foot position and spinal alignment are examined at each visit, with full-length spinal radiography if scoliosis is suspected; management is that of the general population, except with marked hyperlaxity. For feeding, treatment of poor weight gain combines swallowing and speech therapy, nutritional support and, if necessary, gastrostomy, with a food diary and calorie counting; however, in the Soler-Alfonso series of 24 patients, nasogastric tube or gastrostomy feeding did not correct the weight deficit in the long term. Constipation is treated with stool softeners, prokinetics, osmotic laxatives or other laxatives. No calcium abnormalities have been described in PTLS; correcting vitamin D deficiency, ensuring calcium intake and promoting physical activity follow general paediatric recommendations, particularly with reduced mobility. Audiometry is repeated so that hearing loss is treated early, and strabismus may require surgery. Oral hygiene begins with the eruption of the first teeth, and dental care may require conscious sedation with an equimolar mixture of oxygen and nitrous oxide, in authorised practices or in hospital centres for people with disabilities [19, 78].

Anaesthesia requires specific preparation because of possible micrognathia and a high-arched palate, heart disease, sleep apnoea, hypotonia and dysphagia. The PNDS recommends a cardiology consultation with echocardiography and ECG in the pre-anaesthetic assessment; preparation for difficult intubation with videolaryngoscopy, according to the Société Française d'Anesthésie et de Réanimation (SFAR) recommendations for the paediatric airway; screening for sleep apnoea, which contraindicates day-case anaesthesia; choice of induction mode (inhalational or rapid sequence) and airway device according to aspiration risk; monitoring of neuromuscular blockade and mandatory reversal of neuromuscular blockade at the end of surgery; and close postoperative monitoring for upper airway obstruction and aspiration. Hypotonia in PTLS is of central origin and there is no known association with malignant hyperthermia, so, in the absence of a personal or family history, halogenated anaesthetics may be used; there are no data on suxamethonium; an associated neuropathy (duplication including PMP22) should be considered, although it changes the technique little [19].

Vaccination follows the general schedule, with no contraindications. In congenital heart disease, the PNDS indicates, after age 2, the 23-valent pneumococcal polysaccharide vaccine in addition to the conjugate vaccine [19]. This position has been superseded by the HAS recommendation validated on 23 July 2026, which provides for PCV20 in infants (3+1 schedule) and as a single dose in at-risk children and adolescents from 15 months to 18 years, abandoning PCV13, PCV15 and PPSV23, and preferential PCV21, as a single dose, in at-risk adults aged 18 to 64 and in all adults aged 65 or over [101]; in the USA, the CDC recommends PCV15 or PCV20 in at-risk children aged 2 to 18, with PCV20 or PPSV23 at least 8 weeks later if the series was completed without PCV20 [102]. The PNDS also indicates vaccination against influenza (from 6 months, two doses one month apart for primary vaccination and then one annual dose) and against COVID-19 in infants older than 6 months with heart disease, in household contacts of at-risk infants younger than 6 months and in institutionalised people; and, at the date of the document, COVID-19 primary vaccination with three doses of the 3 µg paediatric formulation from 6 months to 4 years (10 µg per dose from 5 to 11 years) [19]. The two-dose influenza primary vaccination applies only to children aged 6 months to 8 years without previous vaccination, and the seasonal vaccines available since the 2024–2025 season are trivalent, not the quadrivalent vaccines referred to by the PNDS [103]. In children with congenital heart disease, the PNDS proposes prophylaxis of respiratory syncytial virus bronchiolitis with palivizumab (Synagis®) [19]; in this context, the Summary of Product Characteristics reserves it for children younger than 2 years with haemodynamically significant congenital heart disease, at a single monthly dose of 15 mg/kg intramuscularly (volume in millilitres equal to weight in kilograms multiplied by 0.15), with no higher dosage, during the risk period and, if possible, with the first dose before the start of the season, with an additional dose as soon as the child is stable after cardiopulmonary bypass [104]. The PNDS does not mention nirsevimab (Beyfortus®), authorised in the European Union since 31 October 2022 for all newborns and infants in their first RSV season (single intramuscular dose of 50 mg below 5 kg and 100 mg from 5 kg) and for children up to 24 months who remain vulnerable to severe disease in their second season (200 mg, as two 100 mg injections), with an additional dose after cardiac surgery with cardiopulmonary bypass; in countries that have adopted it, it replaces palivizumab as the reference immunisation, according to national recommendations; the second-season extension dates from the decision of 1 August 2024 [105]. Clesrovimab (Enflonsia®), as a single fixed dose of 105 mg IM, was approved by the FDA on 9 June 2025 and authorised in the EU on 15 April 2026, for the first season only, with an additional 105 mg after cardiac surgery with cardiopulmonary bypass in the EU [106, 107]. Vaccination schedules and respiratory syncytial virus immunisation options differ between countries and change frequently, so the current national programme prevails.

The PNDS includes an emergency card (Orphanet ORPHA:1713) recording epilepsy, heart disease, hypotonia, sleep apnoea, laryngopharyngeal spasm, constipation, feeding disorders (reflux, gastrostomy, nasogastric tube), brain involvement or peripheral neuropathy (including CMT1A), orthopaedic involvement, behavioural disorders (ASD, attention deficit, self-harm), mode of communication (level of comprehension and expression; oral, gestural, pictograms or tablet), sensory deficits, allergies and treatments; orthopaedic involvement distinguishes scoliosis, hernia and arthrodesis, and the card highlights, as priority information for the emergency team, epilepsy, heart disease, gastrostomy, laryngopharyngeal spasm, peripheral neuropathy, behavioural disorders and ASD. Therapeutic education begins when the diagnosis is disclosed and aims to ensure that the family understands the disease and its treatments, knows how to respond to seizures, discomfort or pain, prevents complications and masters technical procedures (tube feeding, oral hygiene); in a cohort cited by the PNDS, the psychosocial impact on parents was associated with the severity of feeding difficulties and cardiovascular anomalies [19].

7.13. Updates during the past 12 months and research

Between October 2025 and October 2026, new evidence was mainly observational: SMS-specific growth charts (published October 2025 and incorporated into GeneReviews April 2026), French genotype-specific neuropsychiatric and actigraphic sleep studies, the systematic review of neurodevelopmental disorder prevalence, melatonin analysis in 89 patients, paediatric sleep recommendations, the French PTLS series, mirror-image episignatures and descriptions of 17p11.2 gains sparing RAI1 [2, 14, 36–40, 54, 68, 71]. Regulatively, tasimelteon’s SMS indication has not changed. The current US label is dated 4 August 2026, Hetlioz’s European orphan designation was removed in July 2025 after market exclusivity, and Slenyto’s European ADHD extension occurred in March 2025 [21, 23, 91]. On 29 September 2026, tasimelteon’s holder announced preliminary phase III delayed sleep phase disorder results (press release, not peer-reviewed publication; NCT04652882; 20 patients per arm), showing sleep onset advanced by 37.1 minutes versus placebo. These findings do not concern SMS [108].

RAI1-directed therapeutic research remains preclinical. CRISPRa-mediated transcriptional activation of the intact allele, delivered by adeno-associated virus into the hypothalamic paraventricular nucleus, reduced repetitive behaviour, delayed obesity and partly reduced hyperphagia in haploinsufficient mice [109]. In 2026, a CRISPR screen in human cells identified TRIM27 as a destabiliser of RAI1 protein, suggesting protein stabilisation as a target [110]. A 2025 review summarises proposed strategies, including the BDNF pathway [111]. A ClinicalTrials.gov search on 6 October 2026 found no active therapeutic SMS or PTLS trials. Registered studies include clinical and molecular biomarkers in RAI1-related disorders (NCT06274164, Baylor College of Medicine, recruiting, 90 participants, expected completion 2027), a National Human Genome Research Institute natural history study (NCT00013559, completed, 593 participants) and a sleep database sponsored by tasimelteon’s holder (NCT03154697) [112]. Absence of active trials in this search does not prove that unregistered programmes do not exist.

7.14. TCF20-related disorder

There is no targeted treatment or clinical guideline, and GeneReviews has no chapter on TAND; management is symptomatic and follows the standards for each manifestation, with the multidisciplinary organisation described for SMS [2, 11]. The mainstays are early developmental intervention, speech and language therapy (including verbal dyspraxia), occupational therapy and physiotherapy for coordination and dyspraxia, special education and behavioural support [11, 24]. ASD and ADHD are treated according to general standards; in the elder sister of the Poquérusse family, ADHD responded to methylphenidate [18]. Dosages of methylphenidate and other psychotropic drugs have not been studied in TAND and follow the label and ADHD standards, with the prior cardiological assessment referred to in section 7.6 [25].

Sleep disturbance may respond to melatonin, as in the same patient, whose circadian rhythm disorder was controlled [18]. There are no dose studies in TAND and no demonstration of inverted melatonin secretion, unlike SMS. In the European Union, prolonged-release melatonin (Slenyto®) is authorised from ages 2 to 18 for insomnia in ASD and/or neurogenetic disorders with aberrant daytime melatonin secretion and/or nocturnal awakenings, after failure of sleep hygiene measures; the dosage in the Summary of Product Characteristics — 2 mg, increasing to 5 mg if the response is insufficient, up to a maximum of 10 mg, once daily 0.5 to 1 hour before bedtime, with reassessment at 3 months and then at least every 6 months — is the reference for children with TAND and ASD, by extrapolation from the label and without a specific guideline (section 7.3) [90]. Above age 18, use is off-label.

Movement disorders require assessment by a movement disorders neurologist. Published reports show a limited response to first-line drugs for dystonia: in Kilic's patient, levodopa up to 250 mg/day for 3 months and trihexyphenidyl up to 18 mg/day were of no benefit, and periodic botulinum toxin injections gave partial relief of cervical and mandibular dystonia; in one of Svorenova's patients, dystonia did not respond to levodopa [82]; in Magistrelli's patient, clonazepam, piracetam and levetiracetam did not improve the myoclonus [60, 84]. These data come from isolated cases and do not constitute a recommendation, but they justify a therapeutic trial of levodopa before excluding dopa-responsive dystonia, because lack of response in one person does not predict the response in another. Deep brain stimulation has not been described in TAND.

Seizures are treated with antiseizure medications chosen according to seizure type, with the behavioural precautions referred to in section 7.7 [11, 25]. Constipation, reflux and feeding difficulties are treated according to paediatric standards, and severe constipation from the neonatal period justifies considering Hirschsprung disease [11, 61]. Correction of refractive errors and strabismus, surveillance for keratoconus in adolescence, orthopaedic treatment of flat feet and scoliosis and management of eczema complete the plan [11].

ClinicalTrials.gov lists no therapeutic trials for TAND; the gene is included in the Simons Searchlight natural history registry (NCT01238250, recruiting), which collects data from people with genetic changes associated with autism [113]. No gene or molecular therapy is in clinical development; evidence on the reversibility of Tcf20 loss is only indirect, from mouse models in which reducing Tcf20 modified the MeCP2-excess phenotype [59]. Between 2025 and 2026, publications were case descriptions that broadened the phenotype (predominantly cervical dystonia, Chiari type I malformation, Hirschsprung disease), duplication series and the confirmation of paternal germline mosaicism [15, 18, 24, 60, 61].

8. Reproductive Options and Family Counselling

8.1. Smith-Magenis syndrome

SMS is autosomal dominant and almost always results from a de novo alteration [2]. Rare causes include deletion or variant inheritance from a mosaic parent with absent or mild features, a parental structural rearrangement (for example, a paracentric 17p inversion), or an RAI1 variant inherited from an affected parent [2, 114]. Both parents should be tested using the method that detected the proband’s alteration, with parental karyotyping in all deletion cases [1, 2]. If neither parent carries the alteration, karyotypes are normal and parentage is confirmed, sibling risk is probably below 1%, attributed to gonadal mosaicism. A parental balanced rearrangement makes risk rearrangement-dependent; a parent carrying the alteration confers a 50% risk [2, 47]. Parental somatic mosaicism is underrecognised in genomic disorders, and leucocyte DNA cannot detect mosaicism confined to the gonads [2, 115]. Recurrence in two siblings due to maternal mosaicism (62% in lymphocytes) and mother-to-daughter transmission of an RAI1 variant are described [2, 114]. Parents carrying the alteration should be assessed for neuropsychiatric manifestations [2].

An affected individual’s offspring have a 50% risk [2]. The PNDS proposes prenatal diagnosis in every subsequent parental pregnancy, even with unaffected parents, through chorionic villus sampling at 11–13 weeks or amniocentesis from 16 weeks [25]. Prenatal diagnosis and preimplantation genetic testing are possible when the familial alteration is known. Prenatal detection should use CMA and sequencing because G-banded karyotyping frequently misses the deletion [2]. Unexpected detection may occur in low-risk pregnancies: a Chinese series identified 10 affected fetuses in 455,121 consecutive prenatal cytogenetic studies, and diagnoses have followed amniocentesis prompted by low maternal serum alpha-fetoprotein [2]. No specific ultrasound signs exist; heart or renal abnormalities may lead to fetal CMA [25].

8.2. Potocki-Lupski syndrome

PTLS is autosomal dominant; most duplications are de novo, but parent-to-child transmission occurs, and parents with only cognitive and behavioural manifestations may be diagnosed only after an affected child is born [3, 88]. The French series found no inherited duplications among the 43 patients with parental information; a family with an affected mother and two affected children illustrates intrafamilial variability [14, 116]. If neither parent carries the duplication, the empirical sibling risk is approximately 1% because of possible germline mosaicism; if a parent is a carrier, the risk is 50%, and the carriers' phenotype is not predictable; a carrier's offspring have a 50% risk [3]. Prenatal and preimplantation diagnosis by CMA are available once the duplication is known, without the ability to predict phenotype; prenatal CMA may detect the duplication without a prior risk [3]. GeneReviews inadvertently refers to “17q11.2” in these paragraphs; the region is 17p11.2 [3]. The PNDS recommends offering a genetics clinic appointment from the time of suspicion and again after confirmation; testing parental blood to exclude a balanced rearrangement or mosaicism, which alter the risk (up to 50%); with unaffected parents, it considers the recurrence risk to be of the order of 1%, because of germline mosaicism, and proposes prenatal diagnosis in all subsequent pregnancies the couple wishes, by chorionic villus sampling from 11 weeks of gestation (preferred, between 11 weeks and 14 weeks and 6 days, when a parent has a balanced rearrangement or mosaicism) or by amniocentesis from 16 weeks. There are no specific ultrasound signs: intrauterine growth restriction or cardiac or renal anomalies may lead to fetal CMA. Siblings are tested only if they have symptoms or if there is a parental rearrangement [19].

8.3. Shared considerations

Genetic risk and reproductive options should be discussed before pregnancy, including with young adults from families with chromosomal rearrangements [2, 3]. Banking proband DNA may be useful as methods evolve [3]. Professional and family views on prenatal and preimplantation diagnosis differ, and the decision is personal [2, 3]. For 17p11.2 gains sparing RAI1, four of 11 families had inherited variants; counselling should reflect the specific alteration rather than the PTLS model [54].

8.4. TCF20-related disorder

TAND is autosomal dominant and the risk to the offspring of an affected person is 50% [6, 11]. Most variants are de novo (20 of the 25 families with parental testing in the Vetrini cohort and 17 proven de novo variants in the Torti cohort), but the variant was inherited from a symptomatic parent in four families of the Vetrini cohort, which makes testing the parents and clinically examining carriers mandatory [6, 11]. Germline mosaicism is documented: affected siblings with parents who were non-carriers in blood (Babbs, pericentric inversion; Torti, two siblings), confirmation of maternal mosaicism by Schneeweiss and colleagues and detection of 3.2% variant allele in the urothelial cells of a father whose blood was negative by three sequencing methods [11, 18, 41]. Thus, even with parents negative in blood, the recurrence risk is higher than that of the population and should not be presented as zero; the sources provide no empirical estimate, and the figure of about 1% used in other de novo disorders is only an approximation [18]. Prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are options in subsequent pregnancies. With 22q13.2 duplications, transmission from mothers with a mild or absent phenotype and uncertain penetrance make prenatal counselling more difficult and require that this uncertainty be explained [15]. Testing asymptomatic minor siblings has no immediate medical benefit and is justified only when there are signs of developmental delay.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and quality of estimates

The SMS incidence of 1:25,000 births proposed by Greenberg and colleagues in 1991 is the most frequently cited estimate. Smith and colleagues suggested that actual prevalence may approach 1:15,000, allowing for underdiagnosis [2, 31, 117]. Smith’s Recognizable Patterns and the Brazilian textbook reproduce approximately 1:25,000; the PNDS gives 1:15,000–1:25,000 [1, 25, 47]. Orphanet records a European point prevalence of 5.35 per 100,000 (validated expert estimate) and a worldwide and US category of 1–9 per 100,000 with sources awaiting validation [7]. GeneGuidance uses 6.7 per 100,000, corresponding to 1:15,000, and emphasises that the figure excludes PTLS [9]. A Chinese series identified 10 affected fetuses in 455,121 consecutive prenatal cytogenetic studies. This measures karyotype detection in a prenatal diagnostic population and should not be converted into birth prevalence [2].

For PTLS, the frequency of approximately 1:25,000 derives from the reasoning that the reciprocal duplication should occur at a similar rate to the deletion; Orphanet classifies prevalence as unknown and records 170 cases or families [3, 4]. The 2026 French PNDS gives 1:25,000 as the incidence, citing a prenatal diagnosis report, which does not change the theoretical nature of the estimate [19]. The discrepancy between theoretical frequency and the number of reported cases suggests underdiagnosis of a less distinctive phenotype, as does the late identification of carrier parents [3, 88]. For YUHAL syndrome, Orphanet records 23 cases and prevalence below 1 per million [46].

9.2. Population distribution and absence of a founder effect

SMS occurs in all ethnic groups without predominance by sex, ancestry or region [47]. Because recurrent deletions and duplications arise through de novo NAHR governed by genomic architecture, neither syndrome has a described founder effect; rare vertical transmission prevents familial concentration in isolated populations [2, 3]. Edelman and colleagues’ meta-analysis of 105 cases found sex differences: girls more often had myopia, feeding and appetite problems, cold hands and feet, and communication-related frustration [118]. Impulsivity may increase with age, particularly in girls [2].

9.3. American and European data

Large North American cohorts—the multidisciplinary Baylor College of Medicine protocols (58 SMS patients during 1990–1999; 35 and subsequently 74 PTLS patients), the National Human Genome Research Institute natural history study (593 participants), and the international PRISMS registry—underpin most clinical frequencies [10, 20, 67, 112, 119]. Recent European series come from France (national PNDS; 52 SMS patients at Lyon’s GénoPsy referral centre; 20 children studied by actigraphy; 56 PTLS carriers assembled through French genetics centres), the Netherlands (66 patients at a specialist clinic), Italy (the metabolic cohort cited by GeneReviews) and Southern Europe [2, 14, 25, 38, 65, 66, 71].

9.4. Portugal and Brazil

The principal Portuguese contribution in the sources consulted is Osório and colleagues’ University of Minho cognitive study of Southern European children and adults assessed using Wechsler scales, described by its authors as the region’s first systematic SMS cognitive-profile study [66]. In Brazil, Síndromes Genéticas: Reconhecer para Tratar, published in Fortaleza, devotes a section to SMS, with system-specific clinical findings, diagnostic methods (FISH, MLPA, quantitative PCR and RAI1 sequencing) and genetic counselling [47]. In a Southern Brazilian cohort of 1012 patients, mainly children with neurodevelopmental disorders and/or congenital anomalies assessed by CMA, one patient had a 3.07 Mb 17p11.2 deletion compatible with SMS (with ventricular septal defect and microtia), and one female patient had a 3.88 Mb 17p11.2 duplication compatible with PTLS (with ASD and moderate intellectual disability) [120]. These figures describe diagnostic yield in a hospital series rather than population prevalence. No Portuguese or Brazilian population estimates were found in the sources consulted.

9.5. Special populations

Adults are underdiagnosed and understudied. Many neuropsychiatric manifestations persist, and assessment should include sleep, anxiety, aggression and epilepsy [69]. In PTLS, parents diagnosed only after an affected child is born demonstrate that the adult phenotype may consist solely of cognitive and behavioural difficulties [88, 116]. Sleep deprivation, parental depression and anxiety, and family stress exceed those in families of children with other developmental disabilities, and siblings should be included in support [2, 25].

9.6. TCF20-related disorder

There is no estimate of the prevalence or incidence of TAND: cases come from exome cohorts rather than population-based studies, so the number of published individuals (91 from 83 families up to 2025, and more than 100 according to Ziveri and colleagues) measures diagnostic activity and not frequency [18, 24]. The meta-analysis of 2104 intellectual disability trios by Lelieveld and colleagues and the DDD study included four and seven people with TCF20 variants, respectively, which shows that TAND recurs in large sequencing series of neurodevelopmental disorders [6, 11]. Published patients come mainly from the United States and the United Kingdom, with contributions from France, Italy, Israel, Turkey and New Zealand (one family of Polynesian ancestry), with no founder effect [6, 11, 15, 18, 24, 60]. The sources consulted include no patients from Portugal or Brazil. In Europe, follow-up falls within ERN ITHACA [24, 26].

10. Illustrative Clinical Case

10.1. Adolescent with deletion-associated SMS, polysomnography and EEG showing Rolandic-type spikes

In 2026, Shevchenko described a 16-year-old girl followed at a German paediatric centre [87]. Pregnancy and delivery were normal, with birth at 41 weeks, weight 3800 g (percentile 70), length 52 cm, a nuchal cord without asphyxia and early discharge. She first walked at 11 months, with fine motor difficulties. At 16, she weighed 49.6 kg (percentile 16), measured 163.5 cm (percentile 35), had a head circumference of 55 cm and body mass index of 18.6 kg/m² (percentile 21), with a slender build. She had prognathism, oligodontia, a broad nose and malocclusion requiring dental extractions, short broad fingers and bilateral second–third toe syndactyly. Marked adolescent idiopathic scoliosis required thoracolumbar spinal fusion in 2022 and extensive T2–L5 fusion in 2024. Recurrent pulmonary infections were attributed to restrictive respiratory impairment. Grade 1 hypertension was treated with valsartan from 2024 (40 mg morning, 20 mg evening), and she had a history of pulmonary hypertension; echocardiography showed normal biventricular and valvular function without current pulmonary hypertension. She had left amblyopia (30% acuity) and normal hearing (orientation at 35–40 dB, present otoacoustic emissions). Full-scale IQ was 60, with expressive and receptive language impairment, dysarthria and limited sentence formation. She attended special education and reportedly had no behavioural abnormalities [87].

She woke very early (4–5 h), without epileptic seizures. Pittsburgh Sleep Quality Index was 10 (poor quality), and the paediatric breathing questionnaire did not suggest apnoea (0.25). Polysomnography showed total sleep time 330 minutes, latency 65 minutes, wakefulness after sleep onset 95 minutes, efficiency 69%, REM latency 150 minutes, REM 16%, N3 14%, three incomplete cycles and an arousal index of 22/h, with normal respiratory parameters. Serum melatonin at 7 h was 57 pg/mL (daytime reference <30 pg/mL), and urinary melatonin sulphate was 18 µg/L. Wake EEG showed Rolandic-type pentaphasic spike-wave complexes in bilateral posterior temporal and central regions without a clinical correlate on video (article figure 1: patient EEG) [87]. Exome, microarray and karyotype identified a heterozygous de novo 3.2 Mb deletion described as 17p12–p11.2; her parents and two siblings were healthy. Sleep hygiene advice and prolonged-release melatonin (Mellozzan®) 2 mg approximately 30 minutes before bedtime were prescribed with reassessment. Valsartan, physiotherapy, speech and language therapy and parental social support continued [87].

The case illustrates several points of this article and some caveats. It shows that the adolescent phenotype may include scoliosis requiring surgery, dental abnormalities, syndactyly of the toes and early waking, but without obesity and without reported self-injury, which confirms the variability described in the series [2, 25]. Polysomnography documents sleep fragmentation without apnoea, in keeping with descriptions of reduced REM sleep and sleep efficiency [2]. The interpretation of the EEG as an expression of cerebral immaturity and the claim that this is the first description of these complexes in SMS are the author's and rest on a single patient; GeneReviews records an abnormal EEG without seizures in about 25% [2, 87]. Melatonin was measured at a single time point, which is insufficient to define the circadian profile, and exogenous melatonin was prescribed without prior determination of the profile, which Braam and Smith recommended avoiding [39]. The 17p12–p11.2 designation makes the gene content of the deletion decisive, and it should appear in the report: inclusion of PMP22 implies a risk of HNPP, inclusion of FLCN surveillance for BHDS from age 20 years, and extension into 17p12 the recommended adrenal screening; the case report does not describe the gene content or these assessments [2, 25]. The 2 mg dose corresponds to the initial dose of Slenyto in the EU for this age group, although the product prescribed was of a different brand [90].

10.2. Family with inherited PTLS

Kolbasin and colleagues described a mother and her two children with PTLS in Russia’s Yugra region [116]. The children had speech delay, mild intellectual disability, motor abnormalities and craniofacial dysmorphism (microcephaly, dolichocephaly, triangular face, broad prominent forehead, long chin, downslanting palpebral fissures and “elf-like” ears). One child, referred for rehabilitation at 20 months, had an 8–10-word vocabulary and interaction difficulties at age 4. The mother, diagnosed at 28, had cognitive impairment and behavioural abnormalities. MLPA showed duplication of DRC3, LLGL1 and RAI1, and microarray a 2.9 Mb duplication, arr[GRCh37] 17p11.2(17019267_19947934)x3, in all three; a 450-band karyotype showed dup(17)(p11.2) (article figure 5: cytogenetic and molecular results) [116]. The case documents autosomal dominant transmission with a 50% risk per pregnancy, intergenerational variability and parental diagnosis only after assessment of the children [3, 88]. The 2.9 Mb duplication is smaller than the recurrent 3.7 Mb duplication, without altering diagnosis because it includes RAI1 [10].

10.3. Woman with generalised dystonia and a de novo TCF20 variant

In 2026, Kilic and colleagues described a 23-year-old Turkish woman, born to non-consanguineous parents and with no family history [60]. She had had unclear speech since early childhood; at age 8, a semi-flexed posture of the right wrist and elbow and dragging of the right foot appeared, and assessment for learning difficulties showed mild intellectual disability; at age 9 the left side became affected; from age 15 she needed support to walk and developed cervical dystonia; at age 17 mandibular dystonia prevented her from chewing solids; and from age 19 her speech deteriorated until it became unintelligible [60]. Examination showed severe dysarthria, hypophonia, predominantly cervical dystonia (anterocollis and right laterocollis), truncal and mandibular dystonia, rest and postural tremor, bradykinesia, lower-limb spasticity with clonus, cogwheel rigidity in the upper limbs and mild dysmetria; cognitive assessment showed deficits in sustained attention, executive function and working memory, with 23/30 on the Mini-Mental State Examination [60]. Laboratory tests, cerebrospinal fluid, EEG, electromyography, fundoscopy and optical coherence tomography were normal; 3 tesla MRI showed relative hypointensity of the globi pallidi on T2 and susceptibility imaging, and quantitative analysis compared with five controls showed numerically greater susceptibility and smaller volume, without statistical inference [60].

Research genome sequencing, filtered for dystonia-associated genes, identified NM_001378418.1:c.932_933del p.(Gln311ArgfsTer22), absent from the parents by Sanger sequencing (parentage not formally confirmed), classified as pathogenic and previously described in two unrelated women, in one of whom dystonia had not been recorded because the information was collected by questionnaire [11, 60]. Levodopa up to 250 mg/day for 3 months and trihexyphenidyl up to 18 mg/day were of no benefit; botulinum toxin gave partial relief [60]. The case illustrates three points: TAND may present in adults as progressive dystonia and not only as a neurodevelopmental disorder; questionnaire-based characterisation underestimates movement disorders; and pallidal imaging does not, by itself, allow an iron accumulation mechanism to be assumed. The therapeutic measures in the report correspond to individual trials, not to a validated protocol.

11. Prognosis and Long-Term Follow-up

11.1. Natural history and prognosis

Longitudinal data are insufficient to estimate SMS life expectancy. Without severe organ involvement, it is expected to resemble that of people with intellectual disability generally; the PNDS considers it normal without cardiac complications [2, 25]. The oldest known person with SMS lived to 88 (anecdotal information) [2]. There is no evidence of global cognitive decline with age, although behaviour changes into adulthood and anxiety increases in adolescence [1, 2, 66]. Functional prognosis depends on age at diagnosis, severity, complications, deletion type and multidisciplinary intervention quality [47]. Late risks requiring surveillance include obesity and metabolic complications, retinal detachment, progressive sensorineural hearing loss, scoliosis, BHDS manifestations in FLCN-containing deletions and vascular complications described in isolated cases [2, 72].

PTLS has complete penetrance with variable expressivity. Language and articulation improve with age and therapy, but assessed adults retain cognitive difficulties. Cardiovascular natural history data, particularly concerning the aortic root, are limited [3, 81].

11.2. Surveillance in Smith-Magenis syndrome

11.3. Surveillance in Potocki-Lupski syndrome

11.4. Networks and resources

In Europe, SMS and PTLS patients fall within the European Reference Network ERN ITHACA, dedicated to intellectual disability, neurodevelopmental disorders and rare congenital anomalies, and BHDS manifestations within ERN GENTURIS; in France, follow-up is organised through the reference centres of the AnDDI-Rares and DéfiScience networks [25–27]. Patient organisations cited by the sources include PRISMS (United States, with multidisciplinary SMS clinics and an international registry), Association Smith-Magenis France (ASM17), SIRIUS e.V. (Germany), SMS Foundation UK and Smith-Magenis Syndrome Australia; for PTLS, the Potocki-Lupski Syndrome Outreach Foundation and PTLS Hope Research Foundation [2, 3, 25]. For PTLS, the PNDS was coordinated by the western France reference centre for developmental anomalies and malformation syndromes (CLAD-Ouest, Angers University Hospital), and follow-up takes place in the reference and competence centres of the AnDDI-Rares and DéfiScience filières, with support from the regional rare disease expertise platforms and the liaison teams for rare disabilities. In France, PTLS gives access to 100% coverage as an off-list long-term illness, under a care protocol, and to recognition of disability by the departmental house for disabled people, which opens entitlement to benefits (education allowance for a disabled child, disability compensation benefit, daily parental presence allowance and, from age 20, disabled adult allowance). At the time of the PNDS there was no PTLS-specific French association; the reference associations were Valentin APAC (chromosomal anomalies) and Mon Chromosome à moi, c'est toi, and the PNDS lists the European collaborative resources GenIDA and Human Disease Genes [19]. French benefits are combined according to specific rules: up to age 20, the daily parental presence allowance can be combined with the basic education allowance but not with its supplements, and the family chooses between the supplement to this allowance and the compensation benefit, except for the part intended for adapting the home and vehicle and for transport costs; the coordination and referral platform for neurodevelopmental disorders funds assessments up to age 12, without replacing the application to the departmental house; in adults, the mobility inclusion card may be requested when mobility is limited, and since 1 January 2023 the compensation benefit has included supervision hours for psychological or cognitive disability, even with the disabled adult allowance. The PNDS also lists the coordination support schemes, the competence hubs and outsourced services, the free national number Communautés 360, the liaison teams for rare disabilities (aimed at rare combinations of deficits in a population with a prevalence below 1 per 10,000), the networks for adapted dental care and the associations supporting gastrostomy feeding (La vie par un fil, Réseau Lucioles) [19].

11.5. TCF20-related disorder: prognosis and surveillance

Outcome data for TAND are cross-sectional. Developmental delay persists, but the spectrum ranges from adults living independently and having affected children to adults in supported housing; the oldest published adult was 70 years old, with myoclonus-dystonia stable for decades, and a man in his sixties was being evaluated for possible cognitive decline, with no data to attribute that decline to the disorder [6, 11, 84]. Dystonia may progress in adolescence and early adulthood, as in the case in section 10.3 [60]. There are no data on life expectancy. In the absence of a guideline, the following surveillance derives from the manifestations described in the cohorts and applies general paediatric standards.

12. Summary and Final Considerations

SMS and PTLS are opposite consequences of altered RAI1 dosage, involving a transcriptional regulator controlling circadian clock and satiety genes. The recurrent approximately 3.7 Mb deletion and reciprocal duplication arise through the same recombination mechanism between low-copy repeats, and CMA detects both. In SMS, approximately 10–20% of cases involve intragenic variants, almost all in exon 3, identified only by sequencing; normal microarray therefore does not exclude diagnosis [2, 3, 32].

SMS is recognised through circadian melatonin inversion, self-injury with onychotillomania and polyembolokoilamania, self-hugging, attention seeking, hoarse voice, a square face that becomes coarser, and abdominal obesity from school age. Deletions add greater cognitive impairment, short stature, hearing loss, heart disease, renal abnormalities and, when FLCN is included, adult Birt-Hogg-Dubé manifestations [2, 38, 57]. PTLS has a less distinctive phenotype—hypotonia with dysphagia and growth delay, moderate intellectual disability, autistic features, heart disease and aortic root dilatation—and is almost always diagnosed through CMA [3, 20, 81].

Management is supportive and multidisciplinary. In the United States, tasimelteon is the only drug specifically approved for SMS (night-time sleep disturbances, from age 3), with a modest effect on sleep quality during the worst nights. It lacks this EU indication, while prolonged-release melatonin (Slenyto®) is authorised up to age 18 for neurogenetic disorders involving aberrant daytime melatonin secretion [21, 23, 90, 92]. Acebutolol, melatonin doses exceeding authorised doses and psychotropic medications for behaviour are off-label, supported by uncontrolled studies or expert opinion, and exogenous melatonin requires monitoring [2, 25, 39]. Setmelanotide did not reduce weight, and RAI1-directed treatments remain preclinical [56, 109, 110].

For PTLS, the 2026 French PNDS adds an age-based surveillance schedule that differs from GeneReviews in several intervals, anaesthetic precautions (difficult airway, apnoea, aspiration, reversal of neuromuscular blockade) and the offer of prenatal diagnosis in all subsequent pregnancies of a couple with an affected child [19].

Genetic counselling begins with recurrence risk usually below 1% (SMS) or approximately 1% (PTLS) when parents are unaffected, a 50% risk for affected individuals’ offspring, and the possibility of parental mosaicism and undiagnosed adult carriers [2, 3, 115]. Surveillance should cover sleep, behaviour, hearing, vision, teeth, spine, lipids, thyroid and, in FLCN-containing deletions, kidneys, lungs and skin from age 20, with intervals differing between SMS and BHDS recommendations [2, 25, 27]. Support for families experiencing sleep deprivation and high stress is integral to treatment [2].

TCF20-related disorder completes the picture of dosage alterations of transcriptional regulators of the RAI1 family. Haploinsufficiency of the paralogue at 22q13.2, almost always due to a de novo truncating variant, causes developmental delay with variable intellectual disability, ASD, ADHD, hypotonia and movement disorders ranging from ataxia to generalised dystonia, with SMS-like features in a subgroup and no recognisable facial gestalt; diagnosis depends on exome or genome sequencing, management is symptomatic and counselling must take into account transmission from mildly affected parents and germline mosaicism [6, 11, 18, 60].

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