ATRX Syndrome (Alpha-Thalassaemia X-linked Intellectual Disability)

An X-linked neurodevelopmental disorder caused by hypomorphic variants of the chromatin remodeller ATRX, combining intellectual disability, characteristic hypotonic facies, genital anomalies in 46,XY individuals, gastrointestinal dysfunction and, in some patients, a mild form of alpha-thalassaemia with haemoglobin H inclusions.

Literature and regulatory information updated: 9 October 2026; integration of the French National Diagnosis and Care Protocol (PNDS): 2 November 2026.

0. Initial Reference Table

1. Introduction

1.1. From haematological coincidence to syndrome

The history of ATR-X syndrome begins in a haematology laboratory. In 1981, Weatherall and colleagues described in the New England Journal of Medicine three Northern European families in which one child had intellectual disability and haemoglobin H (HbH) disease, although only one parent carried mild alpha-thalassaemia and the other was haematologically normal. The authors considered two explanations, a new mutation on chromosome 16 or a chance coincidence, and already raised the possibility that the association between HbH and intellectual disability constituted a new syndrome [21].

In 1990, Wilkie and colleagues published two complementary series in the American Journal of Human Genetics that separated the two entities previously confused. In the first, eight patients with alpha-thalassaemia unexplained by Mendelian inheritance of alpha-globin alleles, mild to moderate intellectual disability and variable dysmorphism had deletions of variable extent in band 16p13.3, at least four resulting from unbalanced translocations; this form was named ATR-16 [22]. In the second, five unrelated patients, also from Northern Europe, had HbH disease with a molecularly normal alpha-globin complex and a uniform phenotype, with severe intellectual disability, microcephaly, relative hypertelorism, distinctive facies and genital anomalies; HbH was subtly but distinctly milder than in Mendelian forms, and the authors proposed a factor acting in trans, unlinked to the alpha cluster, as the cause of this “non-deletion” form [3].

In 1991, three consecutive publications in the Journal of Medical Genetics established X-linked inheritance. Gibbons and colleagues defined a new X-linked mental retardation syndrome associated with alpha-thalassaemia [23]; Wilkie and colleagues described the clinical spectrum in three related men, in a pedigree with many miscarriages and male stillbirths according to the later description by Noordhuis-Zijderveld and colleagues [14, 24]; and Donnai and colleagues reported four brothers with the non-deletion form, suspected clinically and confirmed by HbH inclusions in a fraction of erythrocytes, with very rare inclusions in the mother and one sister, both probable carriers [25]. In 1995, Gibbons and colleagues identified diverse mutations in the gene then called XH2, a member of the SNF2 helicase subfamily (with RAD16, RAD54, ERCC6, SWI2/SNF2, MOT1 and brahma), and proposed that its product was a global transcriptional regulator whose dysfunction reduced the expression of several genes, including those encoding alpha-globin [26]. In the same year, the description of 15 new cases established the syndrome's clinical hallmarks and stressed that repeated examinations may be required to detect HbH inclusions [27]. In 1996, the review by Gibbons and Higgs consolidated the distinction between ATR-16, a contiguous gene syndrome caused by truncation, interstitial deletion or unbalanced translocation of 16p13.3, and ATR-X, caused by mutation of a regulatory factor acting in trans [28].

1.2. Nomenclature and reclassifications

Following identification of the gene, ATRX (historical synonyms XNP and XH2) was found to explain several “named” forms of syndromic X-linked intellectual disability, including Carpenter(-Waziri) syndrome, Smith-Fineman-Myers syndrome and X-linked intellectual disability with spastic paraplegia [29]. GeneReviews adds Holmes-Gang and Chudley-Lowry syndromes, XLID with arch dermatoglyphics and hypotonia, XLID with epilepsy and non-syndromic XLID, and concludes that there are no compelling reasons to retain the syndromic names, which should be understood as part of the ATR-X phenotypic spectrum [1]. Orphanet implemented this decision by merging into ORPHA:847 the entries for XLID syndrome with hypotonic facies (ORPHA:73220), Holmes-Gang (ORPHA:93970), Chudley-Lowry-Hoar (ORPHA:93971), Carpenter-Waziri (ORPHA:93973) and Smith-Fineman-Myers (ORPHA:93974), and making the entry “ATR-X-related syndrome” (ORPHA:263355) obsolete [2]. In OMIM, entry 309580 (MRXHF1, XLID syndrome with hypotonic facies 1) remains separate from 301040, although it corresponds to the same gene and the same clinical continuum, generally without demonstrable alpha-thalassaemia [1, 30, 31].

Two reclassifications require attention. Juberg-Marsidi syndrome was attributed to ATRX after a family so designated was found to have a variant in this gene; however, Friez and colleagues found the HUWE1 variant c.12928G>C p.(Gly4310Arg) in an affected man from the original Juberg and Marsidi family and concluded that this syndrome does not result from an ATRX mutation, but is, like Brooks syndrome, allelic to HUWE1; the previously published family with an ATRX variant represented a diagnostic error [1, 5]. In Smith-Fineman-Myers syndrome, two families labelled as such have ATRX variants, but the original family has not been re-examined, so the relationship remains uncertain [1]. The gene designation has also changed: the Oxford Desk Reference still refers to the “XNP gene at Xq13” and Smith's Recognizable Patterns uses “X-linked α-thalassemia/mental retardation (ATRX) gene”, historical terminology in which intellectual disability now replaces mental retardation [12, 32]. Some families and international registries propose the genetic name “ATRX-Related Syndrome”, justified by the fact that approximately a quarter of patients do not have alpha-thalassaemia [4].

1.3. Definition and scope

According to GeneReviews, ATR-X syndrome is defined in a male proband with suggestive clinical findings, a 46,XY karyotype and a hemizygous pathogenic or likely pathogenic variant in ATRX [1]. The systematic analysis by León and Harley showed that intellectual disability is the only manifestation shared by all affected individuals, with the others varying even within the same family, and proposed a shift from a clinical diagnosis to a molecularly based diagnosis [33]. Alpha-thalassaemia, which gave the syndrome its name, is no longer a necessary condition: it was documented in approximately 75% of males in the GeneReviews synthesis and in only 3 of 9 individuals tested in the Dutch cohort published in 2025 [1, 14]. The scope addressed here is germline disease, including the MRXHF1 phenotype and the absorbed syndromic names. Somatic ATRX variants in neoplasia, including acquired ATMDS, are addressed only as a differential diagnosis and as context, because a somatic variant in tumour tissue does not have the significance of a germline variant and should not be counselled as such [6].

2. Molecular Genetics and Pathophysiology

2.1. Gene, transcripts and location

The ATRX gene (HGNC:886; OMIM 300032; Entrez 546; Ensembl ENSG00000085224; UniProt P46100) is located at Xq21.1 according to GeneReviews, Orphanet and GeneGuidance [1, 2, 6]. Smith's Recognizable Patterns (Xq13.3), Gibbons' 2006 review (Xq13.3) and the Oxford Desk Reference (Xq13) retain the cytogenetic designation from the time of cloning, which should be understood as historical [7, 12, 32]. The aliases XH2, XNP, RAD54, JMS and MRX52 appear in the literature and older databases [6]. The gene spans approximately 300 kb and has 36 exons; it produces two transcripts of approximately 10.5 kb encoding proteins of 265 and 280 kDa, and a transcript of approximately 7 kb that retains intron 11 and gives rise to a truncated isoform, ATRXt, lacking the central and C-terminal motifs [7, 34]. The MANE Select reference transcript is NM_000489.6 (ENST00000373344.11), with protein NP_000480.3; earlier literature uses versions NM_000489.3 and NM_000489.4, requiring confirmation of numbering before variants are compared [8].

2.2. Protein architecture

ATRX is a chromatin-remodelling ATPase of the SWI/SNF family (SNF2 subfamily) [6, 26]. Near the N-terminus lies the ADD domain (ATRX-DNMT3-DNMT3L), composed of a GATA-like module and a PHD module; older descriptions call this domain “PHD-like” or a “zinc-finger domain”, and its similarity to DNMT3 gave it its name [1, 7, 34]. Both isoforms contain the ADD domain and the HP1a- and EZH2-binding motifs; the central region contains the DAXX-binding motif; the C-terminal helicase/ATPase domain contains the MeCP2 interaction region and a motif targeting PML nuclear bodies [34]. The protein is nuclear and concentrates in pericentromeric heterochromatin and beside the ribosomal DNA (rDNA) arrays on the short arms of acrocentric chromosomes, where it colocalises with UBF [7, 35]. ATRX forms with DAXX a remodelling complex located in PML bodies and associates with cohesin and MeCP2, an interaction disrupted by intellectual disability-causing mutations, according to the studies by Xue (2003), Nan (2007) and Kernohan (2010) cited in GeneReviews [1].

2.3. Molecular mechanisms

With DAXX, ATRX deposits the histone variant H3.3 in pericentromeric heterochromatin, telomeres and other guanine-rich repetitive loci, where it resolves G-quadruplex (G4) structures and allows replication and transcription of these regions [6]. Loss of function destabilises heterochromatin at repetitive loci and alters DNA methylation. Gibbons and colleagues demonstrated in 2000 that ATRX mutations alter the methylation pattern of repetitive sequences, including rDNA, a Y-specific satellite and subtelomeric repeats [35]. In controls, approximately 20% of transcribed rDNA units are methylated, whereas in patients many are not; Y DYZ2 repeats are almost all methylated in patients, compared with approximately 6% unmethylated in controls; methylation is unchanged at the alpha-globin cluster itself [7]. These widespread changes produce a reproducible leucocyte methylation episignature, with differentially methylated regions preferentially located in pericentromeric and telomeric regions, now used as a diagnostic biomarker [6, 15].

The link between ATRX and alpha-globin became clearer in 2026. Shen and colleagues showed that ATRX deficiency reduces alpha-globin expression only in a subpopulation of cells with DNA damage: a G-rich repeat at the alpha-globin locus, potentially forming a G-quadruplex, is the site of damage; ATRX binds to this repeat co-transcriptionally, and its loss increases DNA–RNA hybrids (R-loops), causing local damage and transcriptional disruption in cis; deletion of the repeat abolishes the effect and targeted induction of damage reinstates it [36]. This model links ATRX's role in genome stability to transcriptional regulation and explains cell-to-cell variability, with HbH inclusions present in a fraction of erythrocytes. Underexpression of the subtelomeric alpha-globin genes at 16p results in mild alpha-thalassaemia, with excess beta chains precipitating as β4 tetramers (HbH) [6]. HbH inclusions become visible only when alpha synthesis falls by 30–40% [7].

In the nervous system, loss of murine ATRX is lethal early in development, and conditional inactivation in the forebrain causes apoptosis during cortical neuronal differentiation and reduces forebrain size [7]. In a mouse model, ATRX binds G-quadruplexes in the CpG islands of the imprinted gene Xlr3b and recruits DNA methyltransferases; mutation of Atrx causes overexpression of Xlr3b, which inhibits dendritic transport of CaMKII-α mRNA and causes synaptic dysfunction [12, 37]. ATRX loss also causes defects in cohesion and chromosome congression during mitosis and participates in silencing imprinted genes in the brain, according to Ritchie (2008) and Kernohan (2010), cited in GeneReviews; the protein also participates in meiosis and DNA repair [1, 12]. A 2025 preprint, not yet peer-reviewed, described two unrelated patients with white matter disease, learning difficulties and persistent overexpression of interferon-stimulated genes in the blood, both with the substitution p.(Tyr1758Cys); in patient cells, edited fibroblasts and neuronal models, this and other ATRX loss-of-function variants increased type I interferon signalling through a cGAS-dependent but DNA-sensing-independent mechanism, with redistribution of DAXX and H3.3 in chromatin [38]. The work was highlighted in Nature Reviews Immunology in 2026 as type I interferonopathy in ATR-X syndrome [39]; this is preliminary translational evidence with no established therapeutic implication.

2.4. Variant spectrum and hypomorphic loss of function

The mechanism is loss of function [1]. Intragenic deletions, insertions and duplications and nonsense and splice variants have been described, but a disproportionate fraction are missense, and more than 90% of reported variants lie in the regions encoding the ADD and helicase domains [1]. In 2008, the report of 127 mutations (32 new) confirmed the clustering of missense variants in these two domains and observed that truncating variants appear to be “rescued” to some degree, leading all constitutional mutations compatible with life to be considered hypomorphic [40]. In 2006, with more than 60 mutations described, a single recurrent variant accounted for approximately 20% of all recorded mutations and the remainder were private; there was one major hotspot in the PHD-like domain and two minor hotspots in the helicase domain (exons 18–20 and 26–29), accounting for 33% of mutations [41]. Gibbons' review estimated that 50–60% of mutations lie in the ADD domain and approximately 20% correspond to the common variant 736C>T (R246C), followed by the helicase domain [7]. The systematic review by Wang and colleagues (literature up to 1 August 2023; 43 articles, 63 patients, 50 variants) counted 35 missense variants in 43 patients, 7 frameshift variants, 4 nonsense variants in 9 patients and 5 splice variants; p.(Arg246Cys) and p.Arg37Ter each occurred in 7 patients [31]. The figure quoted by Smith's Recognizable Patterns, “more than 127 mutations, only 8 nonsense”, is an undated historical count matching the total in the 2008 report [12]. In 2021, León and Harley counted more than 190 different germline variants in approximately 200 patients analysed [33]. In October 2026, ClinVar contained 301 ATRX records classified as pathogenic or likely pathogenic, a figure counting records rather than patients and potentially including variants from other contexts [42].

Rescue of N-terminal truncating variants has a known molecular basis. Howard and colleagues demonstrated that an amino-terminal premature termination codon is attenuated by alternative translation initiation [43]. In Guerrini's Italian family and the Chudley-Lowry group, the same N-terminal truncating mutation coexists with small amounts of full-length protein, explained by reinitiation at a downstream methionine or by alternative splicing, without a correlation between protein quantity and degree of intellectual disability [7, 44]. The extreme case is ATRX c.21-1G>A, which destroys the intron 1 acceptor and causes exon 2 deletion (NM_000489.6:c.21_133del, p.Ser7Argfs*1): initiation at the exon 3 codon produces a slightly shorter functional protein, and the variant was found without a phenotype in a patient whose Cockayne syndrome was explained by ERCC6 [45]. This example shows that automatically classifying an N-terminal truncating variant as causing complete loss of function can be incorrect.

Copy number changes require quantitative methods. Partial intragenic duplications cause ATR-X with absent mRNA and protein [46]. Whole-gene duplications have been described, but not whole-gene deletions; large duplications encompassing ATRX and adjacent genes, such as the Xq13.2q21.1 duplication reported by Lugtenberg (2009) or concomitant MECP2 and ATRX microduplications, have distinct phenotypes and breakpoints that targeted methods may fail to capture [1, 47]. An intragenic deletion of 78.6 kb (exons 2–5 of 35) was transmitted to two brothers by a mother with gonosomal mosaicism below 1% in blood [48]. Intronic splice variants also cause the disease, such as c.5786+4A>G, which causes exon 24 skipping [30].

2.5. Normalised reference variants

The reference variants were normalised in VariantValidator against NM_000489.6 (GRCh38) and cross-checked against ClinVar on 9 October 2026 [8, 42].

A Jordanian missense variant was published as c.7365C>T p.(Arg2465Cys), but the reference base at position c.7365 is T and the protein change could not be validated; it is therefore not reproduced as a normalised variant [8, 52]. The variants in the Dutch cohort were published against NM_000489.3 and retain the authors' nomenclature here: c.787T>C p.Trp263Arg and c.736C>T p.Arg246Cys in the zinc-finger domain; c.6573T>A p.Asp2191Glu, c.6532C>T p.Arg2178Trp, c.6253C>A p.Arg2085Ser and c.6254G>A p.Arg2085His in the C-terminal helicase domain; c.5321A>G p.Lys1774Arg (variant of uncertain significance with strong clinical evidence, typical facies and HbH inclusions); c.4721G>A p.Cys1574Tyr and c.4492_4497del p.Lys1498_Glu1499del, both de novo; splice variants c.6327-6T>A and c.5957-1G>A; c.5387A>G p.Asp1796Gly, arising de novo in the mother; and c.1732del p.Thr578fs. There were 13 different variants in 14 families, and family 14 had no detected variant but showed the ATR-X episignature and a mother with 100% skewed X-inactivation [14]. In the Italian cohort, the 10 germline variants included c.187G>T p.(Glu63Ter) outside the hotspots, c.536A>G (which creates a cryptic donor and removes 21 amino acids from the ADD domain), c.658T>A p.(Cys220Ser), c.1727C>A p.(Ser576Ter), c.5273-5C>G in the helicase domain, c.6508A>G p.(Thr2170Ala) and the C-terminal c.7376del p.(Met2459SerfsTer21), in addition to R246C and the two codon 2085 variants [34]. Other recently published variants are p.(Arg2131Gln), in the first Tunisian family [53], and p.(Arg246Cys) in a 36-year-old man with epilepsy and ictal apnoea [54].

2.6. Genotype–phenotype correlations

Badens and colleagues, in a French series of 22 patients from 16 families, associated PHD-like domain mutations with severe permanent psychomotor impairment, usually without walking, and invariably present urogenital anomalies, and helicase-domain mutations with delayed but achieved psychomotor milestones and mild or absent urogenital anomalies; rare C-terminal truncating variants were consistently associated with severe urogenital anomalies [41]. In Gibbons' review, eight mutations were associated with the most severe urogenital anomalies, five truncating the C-terminal domain (conserved element and polyglutamine tract) [7]. The review by Wang and colleagues found more epilepsy, congenital heart disease, urogenital anomalies and hearing and ocular defects with frameshift than with missense variants, and more urogenital anomalies with C-terminal than N-terminal frameshift variants [31]. GeneReviews and Smith's Recognizable Patterns summarise these observations: zinc fingers with severe psychomotor delay and urogenital anomalies, helicase with milder phenotypes [1, 12].

The Italian cohort of Vaisfeld and colleagues showed a less clear-cut picture. Overall, there was no difference in psychomotor or urogenital severity by domain, and the authors consider that phenotypic differences by domain are not established and should not be used for individual prognosis [34]. They recognise two exceptions: variants with an early stop codon, such as p.(Arg37Ter), in which initiation at an alternative methionine produces a smaller, less abundant protein, and variants at residue 2085 [34]. The only two Italian patients with moderate to mild intellectual disability had codon 2085 variants, and in the Dutch cohort all four individuals with moderate disability had helicase-domain variants, with fewer health problems and less dysmorphism [14, 34]. In five families with p.(Arg37Ter), Basehore and colleagues described variable but overall milder phenotypes, with characteristic facies present in only 1 of 18 males assessed after puberty, although suggestive in several during childhood [49]. Divergence between series reflects small sample sizes and intrafamilial variability; the affected domain therefore guides expectations but does not replace clinical observation.

The 2026 French PNDS systematises these correlations with explicit domain boundaries: the ADD between amino acids 161 and 293 and the helicase domain between amino acids 1581 and 2205 [13]. Missense variants in the ADD tend to be associated with more severe impairment, often without independent walking, almost constant urogenital anomalies, more heart defects and more digestive problems, more marked dysmorphism and, on MRI, grey matter changes; those in the helicase domain are associated with milder neurodevelopmental phenotypes and more white matter signal changes [13, 41, 55]. Within the helicase domain, the protocol highlights the recurrent variant NM_000489.6:c.4862C>T p.(Thr1621Met) (NC_000023.11:g.77633660G>A; ClinVar VCV000011739, pathogenic/likely pathogenic, last evaluated on 21 August 2026), described with apparently isolated mild to moderate intellectual disability and with autism spectrum disorder, and the codon 2085 variants (exon 28), with subtle dysmorphism and without epilepsy or urogenital anomalies [8, 13, 34, 42]. Among truncating variants, the PNDS associates C-terminal variants with severe genital anomalies with micropenis or atypical sex development, allows that the milder phenotype of c.109C>T p.(Arg37Ter) results from alternative splicing with two isoforms (a hypothesis that coexists with that of alternative translation initiation described in section 2.4), and cites two extremes from the Japanese neuroimaging series: a substitution in the 5' untranslated region, in a boy with hypospadias and 5% of erythrocytes with inclusions, with normal development at 1 year, and the splice variant NM_000489.6:c.7200+4A>G (g.77520784T>C; designated p.L2401fs in the original publication), with progressive cerebral atrophy and drug-resistant epilepsy preceded by West syndrome [8, 13, 55]. The 5' untranslated variant is not identified in the protocol and is not reproduced here as a normalised variant.

Modifying factors clearly act on the haematological phenotype: in 32 cases from 26 pedigrees with the same 736C>T variant, the frequency of cells with HbH inclusions ranged from 0% to 14% [7]. Genital anomalies tend to recur within a family (“breed true”), whereas the degree of intellectual disability may vary between relatives with the same variant [1, 7].

2.7. Inheritance and heterozygous women

Inheritance is X-linked recessive, and ATR-X syndrome is an example of an X-linked disease almost never expressed in women [1, 9]. Heterozygotes typically show marked skewing of X-inactivation (>90:10), with preferential inactivation of the X carrying the variant [1]. In a study of nine Japanese carriers using methylation at the HUMARA locus, six had skewed inactivation, one had an unskewed pattern (72:28) and two were uninformative; only the mother with the unskewed pattern had moderate intellectual disability [56]. A five-generation pedigree with three women showing signs of ATR-X has been described, as has a 4-year-old girl with a typical phenotype carrying p.(Arg246Cys) inherited from her mother, with completely skewed inactivation but an active mutant X; she was born following in vitro fertilisation (IVF), leading the authors to hypothesise a link to assisted reproduction techniques, whose role remains unknown [1, 57].

2.8. Allelic, somatic and associated diseases

Beyond the ATR-X/MRXHF1 continuum, there is a family with severe X-linked intellectual disability, multiple anomalies and 46,XY gonadal dysgenesis with female sex assignment, without alpha-thalassaemia, with partial optic atrophy and partial ocular albinism, caused by a 4 bp deletion at the intron/exon boundary that removes 8 coding bp [58]. Combined dysfunction of ATRX and MAGT1, with generalised pruritus and immunodeficiency, has been described as “variant ATRX syndrome” [59].

Somatic ATRX variants form a distinct domain. An acquired mutation in a myeloid clone causes ATMDS, a presentation of acquired HbH in adulthood, particularly in older men with myelodysplastic syndrome, with a more severe haematological phenotype than that of germline variants [10, 60, 61]. Somatic truncating variants are common in diffuse gliomas; IDH-mutant astrocytoma (World Health Organization grades 2–4) is characterised by IDH1/IDH2 mutations, often with ATRX mutations, and ATRX alteration forms part of the integrated diagnosis of gliomas [11]. ATRX is included in the myeloid panels recommended for haematological neoplasms [62], and somatic alterations are also common in pancreatic neuroendocrine tumours (Jiao 2011) and osteosarcomas, where frameshift, nonsense and intragenic deletions are described (Chen 2014) [1, 6]. Orphanet associates somatic ATRX with grade 4 astrocytoma, ATMDS and Cushing disease, lists it as a biomarker in high-grade astrocytoma with piloid features and as a candidate gene in gastric neuroendocrine tumour [2]. Somatic mutations are distributed throughout the gene and cause complete loss of function, presumably incompatible with embryonic development when constitutional [34].

3. Clinical Spectrum and Manifestations by System

3.1. The series and what they measure

Published frequencies vary widely, largely because of the method of ascertainment. Historical series assembled patients identified by HbH inclusions, overestimating alpha-thalassaemia and classical phenotypes; recent cohorts recruit through molecular diagnosis and family associations, and include adults and milder forms. The main sources differ in population and design.

The following table brings together the main frequencies by source; interpretation of each column depends on the denominator stated.

3.2. Pregnancy, birth and the neonatal period

In the Italian cohort, 10 of 17 mothers (59%) reported reduced fetal movements; 6 children (35.5%) were born before 37 weeks, compared with 7% in the Italian population; 8 (47%) were born by caesarean section; head circumference was below the 5th centile at birth in 7 (41%) and length in 4 (23.5%) [34]. The French PNDS summarises reduced fetal movements as present in approximately a third of patients, citing this same cohort, whose published figure is 59%; there is no specific fetal presentation, but the diagnosis may be made prenatally by exome in the presence of genital or, more rarely, cerebral anomalies [13, 34]. In the Dutch cohort, pregnancy was complicated in 7 of 18 (39%) and delivery in 9 of 20 (45%); 3 of 21 were born preterm, 17 at term and 1 post-term; mean birth weight at term was 3,347 g [14]. Neonatal problems occurred in 18 of 21 (86%), mainly feeding, thermoregulation and respiratory problems, with one case of hypoglycaemia and two of congenital heart disease [14]. The first signs appeared at a median of 3 months (0–36): feeding difficulties in 76%, motor delay in 57%, hypotonia in 48%, growth delay in 29%, lack of eye contact in 24% and dysmorphism in 24% [14]. Microcephaly and short stature are often present at birth according to GeneReviews, whereas Gibbons described normal head circumference at birth with postnatal microcephaly [1, 7].

3.3. Development and cognition

Global delay is marked from the outset; speech and walking appear late, and some patients never walk independently or develop meaningful speech [1]. Smith's Recognizable Patterns describes as the rule severe intellectual disability without expressive speech, with limited receptive language and only partial bladder and bowel control; some walk only in late adolescence [12]. In the Dutch cohort, the median age for sitting without support was 2 years (9 months to 7 years); 12 individuals achieved independent walking, at a median of 3 years (1.5–5); on the Vineland Adaptive Behavior Scale, the median developmental age was 10 months in the communication domain and 1 year and 5 months in the motor domain; 16 never spoke, 4 used single words and gestures and 2 formed sentences; at the time of the study, 10 walked alone, 3 with support, 2 had lost walking with a walking frame and 7 had never walked; 6 were continent during the day [14]. Patients continue to acquire skills throughout childhood; brief episodes of neurological deterioration have been described in three cases, one with an electroencephalogram compatible with encephalitis [7]. The spectrum has broadened with molecular testing, especially at the mild end: there is mild, moderate or profound impairment, even within the same family, and adults from a family with apparent non-syndromic XLID had hypotonic facies in childhood photographs [1]. In an Italian family with four affected members and an N-terminal nonsense variant, two had moderate to profound impairment and typical facies and two had mild impairment and epilepsy without characteristic dysmorphism, which justifies considering ATRX in males with mild impairment without specific signs [44]. The French PNDS estimates severe to profound impairment in 80–90% of patients, states that expressive language is generally limited to a few words or gestures, although some patients form sentences, and emphasises that there is no intellectual deterioration over time [13].

3.4. Tone, motor function and neurological course

Hypotonia is a hallmark of the syndrome and contributes to the facies, drooling, motor delay and possibly gastrointestinal manifestations [1]. Initial hypotonia often gives way to spasticity with age, and there is a family with spastic paraplegia from birth [7, 12]. In those who walk, a short-stepped gait with flexed knees and hyperlordosis is described [20]. Choreoathetoid movements and myoclonic jerks without epileptiform activity on the electroencephalogram (EEG), reported by parents, form part of the presentation [7]. In adulthood, the five Dutch individuals aged 45–69 years experienced motor deterioration, with a slower, shuffling gait; one lost the ability to stand unsupported and one had neuropathy of the feet; three of these five were brothers, which may reflect a familial effect [14].

3.5. Epilepsy and apnoea

Seizures, of various types, occur in approximately a third of patients and are not defining [1]. The Italian review by Aiello and colleagues recorded epilepsy in approximately 30%, with clonic, tonic and myoclonic seizures and myoclonic absences, and described in seven new patients a peculiar EEG pattern of diffuse slowing of the background rhythm with superimposed low-voltage fast activity [63]. In the Italian cohort of Vaisfeld, seizures occurred in 9 of 17, were often sporadic and clustered over a short period, without the need for chronic treatment; only two patients had drug-resistant epilepsy, one with epileptic spasms and the other with early tonic-clonic seizures [34]. In the Dutch cohort, seven of 22 had epilepsy (absences, tonic-clonic and myoclonic seizures), with onset before 1 year in two, between 12 and 20 years in four and at 37 years in one; one patient went into remission at 12 years and relapsed at 63; all were controlled with medicines or a ketogenic diet [14]. Two brothers with a C-terminal truncating variant had epileptic encephalopathy, myoclonus-dystonia and precocious pubarche, according to Giacomini (2019) cited in GeneReviews [1]. Episodes of apnoea and cyanosis and cold or bluish extremities are frequent [12]. In a 36-year-old man with p.(Arg246Cys), video-EEG showed seizures of left frontocentral origin and apnoea episodes without an electroencephalographic correlate, documenting the coexistence of ictal and non-ictal apnoea [54]. The French PNDS places epilepsy at between a third and a half of patients, with seizures sometimes in a febrile context and onset between the first year and the first decade; seizures generally respond to antiepileptic medicines, most patients remain stable on monotherapy and the proportion with drug resistance is not known [13, 63]. The protocol draws attention to episodes of myoclonic dystonia, aggravated by pain or sadness, which may be mistaken for seizures, and to severe phenotypes of epileptic encephalopathy with polymorphic and tonic seizures, spasms or West syndrome [13].

3.6. Neuroimaging

In a series of 27 Japanese patients with an ATRX variant, magnetic resonance imaging (MRI) showed non-specific cerebral atrophy in 17, white matter abnormalities, mainly peritrigonal, in 11, diffuse white matter abnormalities in 1, delayed myelination in 4 and severe, rapidly progressive cortical atrophy in 1 [55]. Smith's Recognizable Patterns converts these figures into percentages (atrophy 63%, white matter 41%, delayed myelination 15%) and adds hypoplasia of the cerebellar vermis and of the corpus callosum [12]. In the Italian cohort, 10 of 17 had neuroimaging findings, including mild atrophy, agenesis of the corpus callosum, white matter changes and hypoplasia of the brainstem or olfactory bulbs [34]. Partial or complete agenesis of the corpus callosum has been described in two cases, and three autopsies showed a small brain, one of them with indistinct right temporal gyri and white matter hypoplasia [7]. The French PNDS points out that MRI may be normal and that the combination of non-specific abnormalities supports the diagnosis: white matter changes in approximately 40% (cortico-subcortical, deep and around the posterior horns of the lateral ventricles), delayed myelination, sometimes marked, and, more rarely, cerebellar or pontocerebellar hypoplasia and a thin or absent corpus callosum [13, 55].

3.7. Behaviour and sleep

Most patients appear affable and close to their caregivers; some are emotionally labile, with tantrums and prolonged episodes of crying or laughing for no apparent reason [1, 7]. Crying may be associated with gastrointestinal pain [7]. Reported features include autistic-like behaviour with gaze avoidance, persistent unusual postures, putting hands in the mouth to induce vomiting, self-injury (biting, hitting), squeezing the neck until cyanotic, voluntary apnoea, spinning while looking at light and stereotypies such as “pill-rolling” and “flapping”, a constellation similar to that of Angelman syndrome [7, 20]. In the Dutch cohort, 19 of 22 (86%) had behavioural problems, with median onset at 2 years: aggression, compulsiveness, hyperactivity, self-injury and motor tics in five; triggers were illness, pain, overstimulation and frustration; problems decreased with age in 47% but never disappeared [14]. Sleep problems affected 14 of 22 (64%), with difficulty falling asleep and night waking with hyperactivity (laughing, shouting, kicking); they improved with age in five and disappeared at 6 and 12 years in two; in one individual, altered salivary melatonin production was demonstrated [14]. In the Italian cohort, severe behavioural problems requiring medication were rare [34]. The French PNDS gives higher summary frequencies, 80–90% for behavioural disorders (self- and other-directed aggression, hyperactivity, autistic traits, motor tics) and 60–70% for sleep disorders, and describes obstructive, central or mixed sleep apnoeas, in addition to ictal apnoeas; sleep and behaviour tend to improve with age, behaviour in approximately half of patients [13, 14].

3.8. Facies and growth

The craniofacial pattern includes microcephaly, an upswept frontal hair whorl, telecanthus or hypertelorism, epicanthic folds, a flat nasal bridge, midface hypoplasia, a small, triangular, upturned nose with anteverted nares and alae below the columella, a tented upper lip, a full, everted lower lip, an open mouth, widely spaced incisors, tongue protrusion and copious drooling; the ears are simple, slightly low-set and posteriorly rotated, sometimes with a preauricular pit [1, 7, 12]. The facies is generally present from birth and becomes coarser with age, although it may become less distinctive in adults [1, 27]. Figure 1 of the Gibbons review shows an 8-year-old child with the characteristic facies (https://pmc.ncbi.nlm.nih.gov/articles/PMC1464382/), and Figure 1 of Smith's Recognizable Patterns shows a boy at 12 and 15 years, with telecanthus, epicanthus, a low nasal bridge, a large mouth and thick lips, tapering fingers and 5th finger clinodactyly [7, 12]. The tented upper lip with a small triangular nose and flat nasal bridge is the feature that the Oxford Desk Reference highlights on examination [64, 65]. In the Italian cohort, the facies was always detectable to some degree, but highly suggestive in only 53% [34]. The French PNDS adds irregularly shaped pinnae, diastema and tongue protrusion to the list; places microcephaly, generally mild and often congenital, at between 40% and 80% of patients, with low-normal head circumference in the rest; and describes, in the extremities, brachydactyly, clinodactyly, tapering fingers and short, broad, low-set halluces [13].

Height is below −2 standard deviations in 67% (general growth charts; there are no syndrome-specific charts), and above-average growth is exceptional [1]. Short stature may become evident only during the pubertal growth spurt, and bone age is delayed [7, 12]. Macrocephaly has never been described [7].

3.9. Gastrointestinal tract

Gastrointestinal manifestations are the main source of morbidity. GeneReviews estimates gastro-oesophageal reflux in approximately three quarters and chronic constipation in approximately one third [1]. The review by Martucciello and colleagues, covering 128 cases, described feeding difficulties, regurgitation and vomiting, abdominal pain and distension and chronic constipation, and noted that prolonged food refusal with distress was rarely investigated [66]. Uncoordinated swallowing, drooling, frequent belching, rumination and self-induced vomiting occur [7, 12]. Gastric pseudo-obstruction results from abnormal suspension of the stomach, without the normal peritoneal ligaments, allowing torsion (episodic gastric pseudovolvulus, described in dizygotic twins), with gastric outlet obstruction and secondary reflux [1, 7]. Ultrashort-segment Hirschsprung disease and colonic hypoganglionosis have been described [66]. In the review of 128 cases, two patients had admissions for recurrent ileus, four had radiologically reduced motility, two underwent ileal resections for ischaemia (one due to volvulus), another had volvulus and one underwent right hemicolectomy for necrotising enterocolitis at 13 days of life; peptic ulcer, oesophagitis, oesophageal stenosis and upper gastrointestinal bleeding were also described in five, one of whom was transfused with haemoglobin of 5 g/dL [7]. A Japanese child with refractory periodic vomiting had oesophagogastric dysmotility and severe gastric volvulus [67]. A 19-year-old man had recurrent colonic volvulus with intestinal necrosis and septic shock, followed the next year by four readmissions for low intake, dehydration and distension and a partial small bowel volvulus that resolved without surgery; small bowel or colonic volvulus is an uncommon, potentially fatal complication that may contribute to food refusal [68].

In the Italian cohort, dysphagia affected 70.5%, reflux 82.5%, gastric pseudovolvulus 12%, oesophagitis or peptic ulcer 12% and colonic hypoganglionosis 23.5% [34]. In the Dutch cohort, chronic constipation affected 73%, dysphagia 67%, drooling 64%, reflux 59%, allergy or intolerance 27% and gastrointestinal bleeding 19%; 7 individuals were tube-fed (5 partly, 2 exclusively), 1 had a jejunostomy for severe gastroparesis and 2 had dolichocolon; in 54%, gastrointestinal problems decreased around 7 years of age [14]. Episodes of anorexia and adipsia, mainly in early childhood and averaging one every three months, occurred in 45% [14], and the Japanese criteria include periodic episodes of complete food refusal [20]. Aspiration, presumably related to reflux, is a significant cause of morbidity and mortality [1, 12]; 8 of 21 Dutch individuals (38%) had aspiration pneumonia [14].

The French PNDS brings these series together in summary figures: gastro-oesophageal reflux in approximately three quarters, with Nissen fundoplication in approximately 10%; constipation in approximately three quarters, multifactorial (hypotonia, immobility, low fluid intake), to which a primary digestive dysfunction due to short-segment colonic hypoganglionosis or dolichocolon is added in approximately a third; prolonged enteral feeding in 9%; sialorrhoea in approximately 90%, with drooling in approximately a third [13, 27, 66]. The protocol includes rectal prolapse among the complications of constipation, describes cases of chronic intestinal pseudo-obstruction, pseudovolvulus and volvulus, and considers aspiration a frequent cause of premature death [13, 68].

3.10. Genitalia, gonads and urinary tract

Genital anomalies range from minor forms, such as 1st-degree hypospadias, undescended testes and an underdeveloped scrotum, to severe forms due to gonadal dysgenesis with insufficient testosterone production: 2nd- and 3rd-degree hypospadias, micropenis, ambiguous genitalia or normal-appearing female external genitalia in a 46,XY individual [1]. In the latter, generally raised as girls, there are no Müllerian structures, and the gonads are intra-abdominal dysgenetic testes or streak gonads [7]. The type of anomaly is consistent within each family [1]. Puberty is frequently delayed or arrested, and premature adrenarche has been described in two patients [7]. In the Italian cohort, there was cryptorchidism in 70.5%, micropenis in 17.5%, and hypospadias and shawl scrotum in 12% each [34]; in the Dutch cohort, cryptorchidism in 8 (4 operated on), retractile testis, hypospadias, micropenis and inguinal or umbilical hernias [14]. Renal anomalies include hydronephrosis, renal hypoplasia or agenesis, polycystic kidney and vesicoureteric reflux with recurrent urinary tract infections [7]; they affected 23.5% of the Italian patients [34]. In the Dutch cohort, four had recurrent urinary tract infections, one chronic cystitis, one post-renal failure due to an overflow bladder and one renal failure with 30% function [14]. A Jordanian boy had progressive bilateral cystic kidneys [52]. The French PNDS estimates genital anomalies at approximately 70%, attributed to inadequate testosterone production, and notes that some uropathies are progressive, complicated by repeated infections and, exceptionally, by renal failure [13].

3.11. Haematology

Evidence of alpha-thalassaemia is present in approximately 75% of males according to GeneReviews and in 90% in the historical series of Gibbons [1, 7]. The proportion of erythrocytes with HbH inclusions varies between 0.01% and 30%; inclusions are absent in a quarter of affected individuals and rare (≤1% of erythrocytes) in a further 40% [1]. Some patients have mild hypochromic microcytic anaemia, but many have normal indices; haemoglobin and mean corpuscular haemoglobin concentration are less affected than in the cis thalassaemias [1, 7]. The anaemia does not require treatment [6, 7]. Recent cohorts, recruited through molecular diagnosis, find less alpha-thalassaemia: 3 of 9 tested (38%) and HbH inclusions in 3 of 10 in the Dutch cohort, and 41.9% of missense carriers in the 2024 review [14, 31]. The French PNDS adopts the figure from the Dutch cohort (approximately a third with laboratory signs of alpha-thalassaemia), states that the presence of alpha-thalassaemia appears independent of the degree of cognitive impairment and that the anaemia, generally mildly symptomatic, was more marked in some patients [13]. It also suggests that the inclusions, testing for which is increasingly less available, remain of interest as a biomarker when the genetic diagnosis arises in a setting of isolated intellectual disability without a suggestive phenotype; the French text calls them “Heinz bodies”, but they are the HbH inclusions revealed by incubation with brilliant cresyl blue [7, 13].

3.12. Skeleton, bone and teeth

In a series of 45 cases, fixed flexion deformities of the fingers were common, together with clinodactyly, brachydactyly, tapering fingers, clubbed terminal phalanges, cutaneous syndactyly and overlapping fingers; the feet were deformed in 29% (pes planus, talipes equinovarus, calcaneovalgus); almost a third had kyphosis or scoliosis; there was a chest wall deformity in 10, sacral dimples in 3 and radiological spina bifida in 2; delayed bone age and coxa valga were the most common radiological findings [7]. Smith's Recognizable Patterns adds hemivertebrae, ovoid vertebral bodies, a short sternum, an absent rib and absent frontal sinuses [12]. In the Dutch cohort, hand and foot deformities affected 81% and scoliosis or kyphosis 48% (scoliosis only 1, kyphosis only 3, both 6) [14]. Osteoporosis was confirmed in five Dutch individuals (four adults), three with spontaneous fractures; three of these were taking antiepileptic medicines and four vitamin D; because densitometry was not performed in most, the prevalence may be underestimated [14]. In the Italian cohort, there was osteoporosis in 3 (17.5%), all from the older group [34]. Dental problems affected 68% of the Dutch individuals [14]. The French PNDS places spinal alignment disorders at 40–50%, mainly kyphoscoliosis, sometimes severe, and considers bone fragility probably underdiagnosed and multifactorial (reduced mobility, prolonged antiepileptic medicines); it adds genu valgum, hip malrotation, foot deformities in approximately a third (varus, valgus, pes planus) and finger anomalies in approximately two thirds; for the teeth, it describes early dentition, agenesis, supernumerary teeth and persistence of deciduous teeth [13, 14, 34].

3.13. Heart, vision, hearing and other organs

The congenital heart defects described in the historical series include septal defects (10), patent ductus arteriosus (6), pulmonary stenosis (3), aortic stenosis (2), tetralogy of Fallot (2), transposition, dextrocardia with situs solitus and aortic regurgitation [7]. In the Dutch cohort there was secundum atrial septal defect in two, cardiomyopathy with atrial septal defect, tetralogy of Fallot and a complex heart defect with atrioventricular septal defect, aortic and mitral regurgitation, patent ductus and coarctation; in adults, a myocardial infarction at 64 years [14]. Uncommon major malformations include coloboma, cleft palate, inguinal hernia, heterotaxy and asplenia [1, 12]. The French PNDS adds cardiomyopathy, aortic dilatation and stenoses and complex malformations to the cardiac list and, to the ocular list, optic nerve dysplasia, ocular albinism, severe myopia, astigmatism and persistent primary vitreous [13].

Vision generally appears normal, but optic atrophy, pale optic discs and myopia are common, and two patients were blind [7]. In the Dutch cohort, 63% had visual impairment (myopia, reduced contrast sensitivity and depth perception, reduced visual field), nine had strabismus, one developed severe cataract at 64 years and another glaucoma at 66 [14]. Sensorineural deafness was documented in 13 cases in the historical series, 7 with alpha-thalassaemia [7], and affected 41% of the Dutch individuals, generally without a clear cause, with frequent otitis in childhood [14]. Recurrent respiratory infections, blepharitis and conjunctivitis are common [12]. Respiratory problems include obstructive sleep apnoea, episodes of hyperventilation and chronic atelectasis [14]; 23.5% of the Italians had obstructive sleep apnoea syndrome [34].

Endocrine findings in the Dutch cohort included one case of low testosterone and two of hypothyroidism, while the Italian cohort recorded thyroid dysfunction in 17.5% [14, 34]. One Dutch individual had episodes of sweating, hypotension, bradycardia, desaturation and hypoglycaemia of unexplained aetiology [14]. A 2026 preprint proposes diabetes mellitus as a new endocrine manifestation in a case report, but only the title is available in the sources consulted and the text has not been peer-reviewed [69].

3.14. Neoplasia

Tumour predisposition from germline variants is not confirmed, but four patients with ATR-X developed five osteosarcomas [1]. Ji and colleagues described two North American brothers with dysmorphism, microcephaly, severe non-verbal intellectual disability, mild anaemia and cryptorchidism, both with osteosarcoma and carrying the nonsense variant p.(Arg2386Ter) inherited from a healthy mother, with no family history of cancer; the tumours had complex copy-number alterations [50]. Masliah-Planchon and colleagues reported three osteosarcomas in two French boys: one had an osteosarcoma of the tibia at 9 years and another of the humerus at 20, both successfully treated; the other had an osteosarcoma of the femur with pulmonary nodules at 4 years and died 18 months later [1, 70]. Interpretations diverge: León and Harley consider that osteosarcoma suggests an increased cancer risk; Vaisfeld and colleagues refer to a “reported” risk for C-terminal variants with a limited number of cases; a 2025 institutional text from the University of Edinburgh with the ATRX Research Alliance states that five cases are too few to conclude a causal relationship [4, 33, 34]. There was no osteosarcoma in the Italian and Dutch cohorts [14, 34]. The French PNDS counts six patients with osteosarcoma, two of them before 10 years, adding to the two North American brothers and the two French boys an Austrian report from 2017 (Smolle and colleagues) and a case from a series of germline variants in patients with osteosarcoma (Mirabello and colleagues, 2020); the two brothers with p.(Arg2386Ter) had multiple tumour involvement [13, 50, 70]. The protocol concludes that there is a particular predisposition, especially with C-terminal variants, but considers the data insufficient to quantify the risk or propose screening; an oesophageal cancer has also been described, without a suggested predisposition [13, 33]. The difference in count from GeneReviews (four patients) results from the dates of the two sources and the inclusion of these two reports.

3.15. Heterozygous women

Carriers generally have neither physical nor intellectual manifestations, in contrast to carriers of Coffin-Lowry syndrome [64]. They may have some HbH inclusions: approximately one quarter of obligate carriers have rare cells with inclusions [7]. The clinical exceptions (a carrier with moderate disability and unskewed inactivation, a girl with a typical phenotype and an active mutant X, a family with three affected women) are described in section 2.7 [1, 56, 57].

3.16. Adulthood and ageing

The Dutch cohort provided the first description of adults over 50 years [14]. Between 45 and 69 years, motor decline, osteoarthritis and low back pain, osteoporosis with fractures, cataract, glaucoma, myocardial infarction and mitral and tricuspid regurgitation without consequences were observed [14]. The Gibbons review had already noted that several individuals were well in their 30s and 40s [7]. The French PNDS, based on the same cohort, emphasises that no developmental regression, dementia or acquired psychiatric disorder has been described with ageing and that adults are at risk of fragility fractures due to osteoporosis [13, 14].

4. Clinical Recognition and Warning Signs

4.1. When to suspect the diagnosis

In the newborn and infant, suspicion arises with hypotonia and feeding difficulty requiring tube feeding, microcephaly or short length at birth and genital anomalies in a boy, especially hypospadias, cryptorchidism, micropenis or ambiguous genitalia [1, 20, 34]. A child with female external genitalia and a 46,XY karyotype, together with hypotonia and delay, should prompt consideration of the syndrome [1, 6]. In childhood, the pattern of severe global delay with absent speech, hypotonic facies (telecanthus, small triangular nose with anteverted nares, tented upper lip, open mouth, widely spaced incisors), reflux, vomiting and constipation is the most typical [1, 7]. The Oxford Desk Reference recommends looking for HbH inclusions in males with intellectual disability and abnormal genitalia, when the special stain is available locally [64, 71]. Persistent microcytic anaemia with negative haemoglobin electrophoresis and alpha-deletion testing in a boy with delay should suggest the diagnosis, but the absence of alpha-thalassaemia does not exclude it [52]. In adults with mild or moderate intellectual disability without obvious dysmorphism, an X-linked family history, epilepsy or childhood photographs with hypotonic facies justify including ATRX in the work-up [1, 44, 49]. Rarely, the diagnosis begins with the detection of HbH on newborn screening for haemoglobinopathies [1]. The French PNDS adds two points of entry: thalassaemia minor discovered incidentally, especially with a suggestive family history, and a prenatal exome requested for fetal genital or cerebral anomalies; it stresses taking a history of boys with intellectual disability in the maternal line, pointing out that its absence does not exclude the diagnosis, and the role of the general practitioner, who refers to paediatric neurology or genetics and starts rehabilitation without waiting for the aetiological diagnosis [13].

The median age at definitive diagnosis was 4.5 years in the Dutch cohort (6 months to 58 years), and only three were diagnosed in the first year, two with an already affected relative [14]. In the Italian cohort, age at diagnosis ranged from 1 to 23 years, with a median of 1 to 5 years (2.25) among those born after identification of the gene [34].

4.2. Warning signs and emergencies

5. Diagnosis: Criteria, Tests and Algorithms

5.1. GeneReviews criterion

The diagnosis is established in a male proband with suggestive findings and a hemizygous pathogenic or likely pathogenic variant in ATRX; the two categories are clinically equivalent according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [1]. A hemizygous variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [1]. The 46,XY karyotype is part of the diagnosis, because the child may have female-appearing external genitalia [1, 6]. A family history compatible with X-linked inheritance, without male-to-male transmission, supports the diagnosis, but its absence does not exclude it [1]. The French PNDS adopts the same definition (hemizygous pathogenic or likely pathogenic variant), accepts as routes of identification targeted testing, an intellectual disability gene panel when the clinical picture is suggestive or a genome-wide test (exome or genome), and proposes the leucocyte episignature for a class 3 variant [13, 15].

5.2. Japanese criteria

The only formal set of criteria is that of Japan's Ministry of Health, Labour and Welfare (MHLW), for designated intractable disease no. 180, prepared by the Japanese ATR-X syndrome research network (Kyoto University) [20].

The Japanese document notes that symptoms change with age and recommends serial observation [20]. The criteria were designed for the severe classical phenotype; patients with mild or moderate disability, such as carriers of codon 2085 variants or p.(Arg37Ter), do not fulfil the mandatory sign of severe delay and fit only the doubtful category, explaining why the 2026 Japanese trial in adults with mild to moderate disability accepted the definite criteria “except that of severe disability” [17, 34, 49]. The paediatric form for the Japanese programme for specific chronic diseases lists the investigations to be recorded: brilliant cresyl blue smear, echocardiogram, radiography, computed tomography (CT) or MRI, developmental testing, EEG, brainstem auditory evoked potentials (BAEP), karyotyping and ATRX genetic testing [72].

5.3. Haemoglobin H inclusions

The classical test consists of incubating fresh venous blood with 1% brilliant cresyl blue in isotonic saline for 4 to 24 hours at room temperature and looking under a light microscope for erythrocytes with “golf-ball” inclusions; older samples are less reliable, testing should be repeated and HbH is generally undetectable by electrophoresis [7]. In the Dutch cohort, inclusions appeared only on the second test in two individuals [14]. The test is inexpensive, available in any haematology laboratory and frequently overlooked [6]. Its limitations are substantial: inclusions are absent in one quarter of affected individuals and rare in a further 40%, so usefulness is limited in most settings; a negative result does not exclude the diagnosis [1, 12]. HbH also occurs in acquired ATMDS, so it is not specific to germline disease [6]. The approximately 80% positivity cited in the Japanese criteria and the 90% in Gibbons' series contrast with the 30% (3 of 10) in the Dutch cohort, a difference reflecting the change in ascertainment [7, 14, 20].

5.4. Molecular testing

Possible approaches are targeted testing (single gene or panel) and genomic testing (exome, exome with CNV analysis, genome) [1]. An XLID panel, or another panel including ATRX and the differential diagnosis genes, is the approach most likely to identify the cause while limiting VUS; composition and sensitivity vary between laboratories [1]. Single-gene testing starts with sequencing (small indels, missense, nonsense and splice variants), followed, if negative, by targeted deletion and duplication analysis [1]. If exome sequencing is non-diagnostic, an “exome array” can be considered for deletions or duplications of one or more exons [1]. In the Italian cohort, diagnosis resulted from targeted ATRX analysis in 10 of 14 independent cases and next-generation sequencing (exome or panels) in 4; among those born after 2015, only 1 of 5 was diagnosed through targeted analysis [34]. The Oxford Desk Reference includes FMR1 testing in all males with XLID, genomic testing as appropriate and DNA banking with consent [64].

These percentages describe the distribution of variant types among already diagnosed patients and do not equate to the clinical sensitivity of testing in a patient with suspected disease [1]. Several limitations need to be understood. Intragenic duplications require quantitative analysis [46]. Breakpoints of large duplications and duplications of adjacent genes may escape targeted methods [1, 47]. Low-level maternal mosaicism (<1% in blood) was not detected by quantitative exon PCR and was revealed only with breakpoint primers [48]. Intronic splice variants outside the canonical dinucleotides, such as c.5786+4A>G, which causes exon 24 skipping, can be interpreted only by demonstrating their effect on RNA processing [30]. One Dutch family with a typical phenotype and episignature had no detected variant [14]. Variants outside the ADD and helicase domains found on panels in atypical patients should be interpreted cautiously [34], and N-terminal truncating variants may be hypomorphic or even benign [45].

The report should state the gene, transcript with version (NM_000489.6), HGVS c. and p. descriptions, zygosity (hemizygous in males, heterozygous in females), ACMG/AMP class and, where possible, parental origin. Conversion between older transcript versions and the current version is necessary for comparison with the literature, as illustrated by the nomenclature discrepancy in c.399_400dup and the reference error in the Jordanian variant [8, 31, 52]. Family segregation (maternal carrier status and X-inactivation), HbH inclusions and the methylation episignature contribute to VUS reclassification [1, 14].

5.5. Methylation episignature

The leucocyte epigenetic signature was described in 18 patients compared with 210 controls: differentially methylated regions were preferentially pericentromeric and telomeric, and 14 loci formed a signature proposed as a highly sensitive and specific biomarker [15]. Aref-Eshghi's studies broadened the approach to 14 and then 42 syndromes (34 robust episignatures) and showed that a multiclass model is needed to avoid confusion between similar episignatures [73, 74]. GeneReviews recommends the episignature as a first-line test in an atypical phenotype or second-line testing when molecular analysis identifies a VUS in ATRX [1]. Smith's Recognizable Patterns describes it as unique and highly specific, useful for confirming the pathogenicity of previously unreported variants [12]. Neither the episignature nor HbH inclusions alone establish the diagnosis [6].

5.6. Other investigations

Karyotyping is necessary to confirm chromosomal sex [6]. MRI is indicated in the presence of microcephaly, neurological signs or seizures, and EEG when seizures are suspected [64]; video-EEG distinguishes non-epileptic jerks from seizures and documents apnoeas [7, 54]. The full blood count may show microcytosis and hypochromia in some patients, but is often normal [1]. Historical investigation included ATRX protein studies (Western blot may reveal truncation, and protein is reduced in ADD missense variants) and X-inactivation studies [7]. ClinGen has not included ATRX in either its adult or paediatric actionability tables [6].

5.7. Practical algorithm

The pathway proposed from the sources is as follows. In a boy with severe global delay, hypotonia and suggestive facies, especially with genital anomalies or marked feeding difficulties, request karyotyping and, in parallel, an XLID panel or exome sequencing with CNV analysis; testing for HbH inclusions with brilliant cresyl blue, repeated if negative, may raise suspicion earlier and guide the laboratory [1, 6, 64]. If testing shows a hemizygous P or LP variant, the diagnosis is established and maternal testing follows [1]. If it shows a VUS, use segregation, maternal X-inactivation, HbH and the episignature [1, 15]. If testing is negative with strong suspicion, investigate intragenic CNV, splice variants and mosaicism, and the episignature may be requested as a guiding test [1, 14]. In an atypical phenotype with negative genomic testing, the episignature may be the first sign of a hidden variant [1].

5.8. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal testing of an at-risk XY fetus and preimplantation genetic testing (PGT) are possible [1, 30]. The French pathway, with prior determination of fetal sex on maternal blood, is described in section 8.3 [13]. Counselling aspects and recurrence risk are developed in section 8.

6. Differential Diagnosis

6.1. Comparative table

6.2. Main differential diagnoses

The first differential diagnosis is haematological. Classical HbH disease results from loss of three of the four alpha-globin genes and is not accompanied by intellectual disability; in ATR-X syndrome, the alpha-globin genotype is normal [1]. ATR-16 also combines alpha-thalassaemia and intellectual disability, but through deletion of alpha genes on the distal short arm of chromosome 16; deletions and rearrangements are large and variable, so there is no specific phenotype, unlike the more predictable phenotype of ATR-X [1, 22]. The first ATR-16 translocation was detected by molecular analysis and escaped conventional cytogenetics [28]; an 8-year-old girl with a de novo terminal deletion of approximately 1 Mb, including SOX8, had HbH [75], and a 45,X man with a submicroscopic unbalanced Y;16 translocation had the alpha-thalassaemia/intellectual disability phenotype [78]. ATMDS is the third haematological differential diagnosis: in a French multicentre registry of 2,980 myelodysplastic syndromes, ATRX mutations were found in 0.2–0.8%, but in 43% of patients with unexplained microcytosis; in a trial cohort of 80 low-risk myelodysplastic syndromes, none were found [76].

Among the genetic causes of intellectual disability, Coffin-Lowry syndrome is the one most frequently confused on the basis of the facies. It is distinguished by downslanting palpebral fissures, a broad nose, tapering, padded fingers, the absence of genital anomalies and frequent manifestations in female carriers [7, 64]. MECP2 duplication syndrome shares hypotonia, spasticity, absent speech, epilepsy and gastrointestinal dysfunction; the face lacks the typical hypotonic appearance and microcephaly is less common [1]. There are males with concomitant MECP2 and ATRX microduplications and severe intellectual disability [47]. Angelman syndrome shares profound impairment without speech or walking, seizures, a happy disposition and stereotypies [7]. Smith-Lemli-Opitz syndrome combines dysmorphism with skeletal and genital anomalies [7]. The original Juberg-Marsidi family has a variant in HUWE1, and a diagnosis of Juberg-Marsidi should be investigated through that gene [5]. An Indian case mimicking Down syndrome has been reported, illustrating the possibility of confusion with trisomy 21 in the absence of a karyotype [77]. The French PNDS restricts the differential diagnosis to six entities (Coffin-Lowry, Börjeson-Forssman-Lehmann, MECP2 duplication, ATR-16, Smith-Lemli-Opitz and, exceptionally, trisomy 21) and emphasises that three of them, all X-linked, may be expressed in a milder form in female carriers, unlike ATR-X [13].

In the Oxford Desk Reference's list for XLID, ATRX appears under several examination findings: absent speech (with SLC16A2, SLC6A8 and SLC9A6), abnormal genitalia, microcephaly (with MECP2, PQBP1 and SMCX), scoliosis (with RPS6KA3 and SLC9A6), seizures (with AGTR2, SYN1, SLC6A8, ARX and PQBP1) and spastic paraplegia (with SLC16A2, SMCX and MECP2) [64]. XLAG also produces female external genitalia in a male, but with lissencephaly [64]. Two molecular situations warrant mention: the double variant ATRX + MAGT1, with pruritus and immunodeficiency [59], and the ATRX variant c.21-1G>A found incidentally in a patient with Cockayne syndrome, unrelated to the phenotype [45].

7. Treatments and Risk Management Strategies

7.1. Framework of recommendations

There is no approved disease-modifying therapy [6]. The first specific national protocol is the French PNDS published by the Haute Autorité de Santé on 1 October 2026, developed by the “Déficiences intellectuelles de causes rares” reference centre (coordinated at the Pitié-Salpêtrière, Paris) with the DéfiScience filière, according to the 2012 HAS method for rare diseases; it is an expert consensus with multidisciplinary review and the participation of a patient association, without formal grading of the evidence [13]. The search for guidelines and consensus documents from 2024–2026, including the ERN ITHACA page, identified no other specific documents, which does not demonstrate that none exist [19]. The PNDS does not propose curative treatment: management is symptomatic, medicines are used within the terms of their marketing authorisation and off-label use is accepted only in particular situations, after specialist assessment and weighing of benefit and risk [13]. The other sources of recommendations are of a different nature: GeneReviews (Stevenson, updated in 2020) is an expert recommendation and not a formal consensus [1, 6]; the 2006 Gibbons review provides system-based management recommendations grounded in the experience of the Oxford group [7]; the Japanese MHLW document describes symptomatic treatment and the severity criteria for public support [20]; and the 2025 Dutch cohort adds authors’ recommendations for adulthood [14]. Management is supportive, multidisciplinary and lifelong [1, 13, 20]. There are no controlled trials of any intervention in the disorder [6].

7.2. Evaluation following diagnosis

The initial assessment table of the French PNDS details some investigations. For the digestive system, a gastroenterology consultation and, according to symptoms, 24-hour pH monitoring, upper gastrointestinal contrast study and motility studies; in severe or refractory constipation, investigation for faecal impaction, pseudo-obstruction, dolichocolon or malrotation. Abdominopelvic and renal-bladder ultrasound is performed at diagnosis, with endocrinology and urology consultation if there is an anomaly. Spinal radiography and densitometry are requested according to the clinical examination. Echocardiography should be performed by a cardiologist experienced in malformations. In ENT, behavioural audiometry, audiogram or auditory evoked potentials are used according to the age and abilities of the patient, with otoscopy and screening for otitis media with effusion. Head circumference and neurodevelopment are assessed with age-appropriate scales, including neuropsychological assessment, and EEG is requested when seizures, regression, paroxysmal movements or unexplained apnoeas are suspected [13].

7.3. Development, education and communication

Developmental assessment should begin in childhood, with early stimulation and special education; socialisation improves with individual therapy [7]. GeneReviews describes the North American model, which varies between countries: early intervention from 0 to 3 years (occupational therapy, physiotherapy, speech and feeding therapy, infant mental health, special educators and sensory specialists), developmental preschool with an individualised education plan from 3 to 5 years, follow-up by a developmental paediatrician at all ages, annual review of the education plan, the least restrictive environment possible and a transition plan in adolescence [1]. Augmentative and alternative communication (AAC), from picture exchange to speech-generating devices, should be assessed by a speech and language therapist; AAC does not hinder speech development and indeed supports it [1]. The Japanese document includes physiotherapy, occupational therapy and speech and language therapy in standard treatment [20].

The French PNDS refers screening and guidance for neurodevelopmental disorders to the general HAS recommendations and proposes physiotherapy, psychomotor therapy from the first signs (hypotonia, postural delay) and speech and language therapy from the onset of sucking-swallowing disorders or language delay, with early hearing assessment so as not to delay rehabilitation of an associated hearing loss [13]. AAC should be introduced early and may be low-tech, such as picture exchange (PECS) or Makaton, or high-tech, with speech-generating devices; used multimodally, alongside work on oral language, it improves receptive skills and reduces frustration and behavioural disorders [13]. In the French model, rehabilitation is concentrated up to 6 years in an early medico-social action centre (CAMSP), followed by transfer to special education and home care services (SESSAD) or medico-psychological centres; inclusion in mainstream school is possible in some cases at pre-school level and rare in primary school, with a support assistant for pupils with disabilities (AESH) and a personalised schooling plan, and most boys are directed to a medico-educational institute (IME), inclusion units (ULIS) or facilities for profound multiple disabilities [13]. Rehabilitation needs and educational adaptations are reassessed throughout childhood, adolescence and adulthood [13].

7.4. Feeding and gastrointestinal tract

The gastrointestinal burden warrants specific attention because reflux, constipation, pseudo-obstruction and aspiration explain much of the morbidity and part of the mortality [6]. Sucking difficulties in the neonate may require tube feeding for weeks [7]. GeneReviews recommends feeding therapy, high-calorie formula and gastrostomy when problems persist, with conventional treatment of reflux and constipation and management of gastric pseudo-obstruction by the gastroenterologist or paediatric surgeon [1]. Gibbons' review details the pathway: reflux and vomiting are assessed with 24-hour pH monitoring and an upper gastrointestinal barium study; initial treatment is conservative and follows usual practice, with nutritional consultation; in severe cases, fundoplication and gastrostomy are considered; gastric pseudovolvulus requires surgical correction [7]. In a Japanese child with gastric volvulus and oesophagogastric dysmotility, anterior gastropexy with jejunal feeding through a gastrostomy brought relief and good weight gain [67]. The Japanese document provides for swallowing physiotherapy, tube feeding, gastrostomy and reflux surgery [20]. In the Dutch cohort, seven individuals were tube-fed and one required jejunostomy for severe gastroparesis [14].

Prolonged food refusal should prompt investigation for peptic ulcer, oesophagitis, ileus and intestinal obstruction, including gastric or intestinal volvulus and malrotation [7, 12, 68]. For constipation, Gibbons' review recommends hydration, fibre and regular osmotic laxatives, such as lactulose, and, if refractory, rectal biopsy to exclude ultrashort-segment Hirschsprung disease or hypoganglionosis [7]. The sources consulted do not give syndrome-specific laxative doses.

Pyridostigmine was used off-label in a 10-year-old boy with c.736C>T and severe dysmotility (gastroparesis, marked bowel loop distension and a substenotic rectosigmoid area) who had not responded to macrogol or enemas. Following cardiac assessment, oral pyridostigmine was started at 30 mg/day (1.6 mg/kg/day), gradually increased to 60 mg/day (3.2 mg/kg/day) over 20 days, with maintenance at 45 mg/day; surgery was avoided and, after one year, gastrointestinal symptoms had resolved without significant adverse effects [79]. The review included in the same article assembled nine paediatric cases of dysmotility from other causes treated at doses of 0.3 to 30 mg/kg/day, one with abdominal pain and cramps [79]. The authors stress that the optimal dose, efficacy and long-term safety are unknown and propose the drug only as an alternative when first-line treatment fails [79]. This is a single uncontrolled case and does not establish a dosing regimen.

The French PNDS, based on the same series, accepts a systematic assessment in a specialist centre, with 24-hour pH monitoring, barium contrast study and investigation for Hirschsprung disease according to symptoms [13, 66, 67]. Reflux may reveal pseudovolvulus, to be sought at the slightest doubt because of the risk to life, and should prompt study of oesophagogastric motility and swallowing safety, adapting the mode of feeding [13, 68]. Recurrent constipation requires exclusion of intestinal malrotation and volvulus, whose early diagnosis and surgery determine survival, and of pseudo-obstruction, entrusted to the gastroenterologist or the paediatric surgeon; outside these situations, it is treated by the usual means, starting with sufficient hydration, a high-fibre diet, regular mobilisation and standing, and abdominal massage, and a specialist opinion is sought for unusual refractory symptoms, such as distension or vomiting [13]. Oral feeding disorders in the first months require monitoring of weight gain and rehabilitation, and the protocol provides for assessment of the indications for enteral feeding, gastrostomy or jejunostomy by the gastroenterologist or the visceral surgeon [13]. For severe refractory dysmotility, the PNDS accepts pyridostigmine on an exceptional, off-label basis, in an expert centre, with a gastroenterological opinion and prior cardiological assessment, acknowledging that the efficacy rests on a single paediatric case and that the optimal dosage, long-term efficacy and tolerability are not established [13, 79]. The protocol gives no dose; the only dosage published in the syndrome is that of the case of Comisi and colleagues described above.

7.5. Drooling

When sialorrhoea is a serious problem, GeneReviews proposes anticholinergics, botulinum toxin type A into the salivary glands or surgical rerouting of the submandibular ducts [1]. The Gibbons review starts with oral feeding and speech and language therapy; it warns that anticholinergics reduce gastrointestinal motility, already abnormal in the syndrome, and may worsen constipation or cause ileus; it states that botulinum toxin A has scarce data and needs to be repeated; and it includes surgery (rerouting or excision of the submandibular ducts) [7]. In the Dutch cohort, three individuals were treated with botulinum toxin or radiotherapy, with a generally unsatisfactory result [14]. In the Chinese case described in section 10, speech and language therapy and occupational therapy reduced sialorrhoea [31]. The French PNDS takes up the three GeneReviews options for excessive hypersalivation, which aggravates the oral feeding disorder, but requires that the benefit be weighed against constipation and the risk of pseudo-obstruction, a position that coincides with Gibbons’ reservation [1, 7, 13].

No drug is approved for drooling in ATR-X syndrome. Labels for oral glycopyrronium approved for children with chronic neurological conditions provide the available dosing reference, but use in the syndrome is an extrapolation, and a history of intestinal obstruction (volvulus, pseudo-obstruction), common in this disease, is a contraindication in the European label [7, 68, 80].

7.6. Epilepsy, apnoea and sleep

Seizures are treated with standard antiepileptic medicines, chosen by an experienced neurologist; many may be effective, but none has been studied specifically in this disorder, and parents and caregivers should receive education about seizures [1]. Seizures respond well to standard therapy according to Gibbons, and in the Dutch cohort all patients with epilepsy were controlled with medicines or a ketogenic diet [7, 14]. In the Italian cohort, many seizures were sporadic and clustered over a short period, without the need for chronic treatment [34]. Refractory epilepsy, defined in Japan as lack of control for at least one year despite two to three main antiepileptic medicines at sufficient doses for at least two years, is one of the severity criteria in adults [20]. Video-EEG distinguishes non-epileptic jerks from seizures and is useful in documenting apnoeas [7, 54]. Respiratory failure is treated with oxygen, tracheostomy or ventilation as appropriate [20].

The French PNDS asks for epilepsy to be investigated in paediatric neurology or neurology and recommends an EEG before confirming the diagnosis, because myoclonic dystonia may mimic seizures; treatment follows the seizure type, without specificity in the syndrome [13, 63]. Motor or cognitive regression, or new behaviour, should prompt consideration of seizures even in a patient who has never had them, and worsening of a stable epilepsy requires a search for a trigger: pain (constipation, orthopaedic or dental pain, reflux), urinary tract infection or otitis, sleep disturbance, change in bowel habit, recent weight gain or non-adherence [13]. Parent education should include what to do during a seizure [1, 13].

For sleep, the French PNDS proposes bedtime routines, possibly with prolonged-release melatonin (Slenyto®), and screening for apnoeas by history, with referral to a sleep centre; central or obstructive apnoea and alveolar hypoventilation are decided case by case and by the team, with ENT treatment, non-invasive ventilation or oxygen therapy according to the mechanism [13]. The protocol gives no dose. The reference dosage is that of the European SmPC for Slenyto® (melatonin 1 mg and 5 mg prolonged-release tablets), authorised for insomnia from 2 to 18 years in autism spectrum disorder or in neurogenetic disorders with aberrant daytime melatonin secretion or nocturnal awakenings, when sleep hygiene measures have been insufficient, an indication into which ATR-X fits because of the pattern of nocturnal awakenings and the melatonin abnormality documented in one patient [14, 84]. The starting dose is 2 mg once daily, 30 to 60 minutes before bedtime, with or after food; if the response is insufficient, it is increased to 5 mg, with a maximum of 10 mg per day; the effect is assessed after at least 3 months, considering discontinuation if there is no benefit, and the indication is reviewed at least every 6 months; data are available for up to 2 years of treatment [84]. The tablets are swallowed whole, without breaking, crushing or chewing, because they lose their prolonged release; they may be mixed with yoghurt, orange juice or ice cream and taken immediately, which limits administration by tube or gastrostomy, frequent in this disorder [84]. The SmPC advises against use in hepatic impairment, asks for caution in renal impairment and does not provide for use below 2 years or in adults, so prescription in adults with ATR-X is an extrapolation [84].

7.7. Behaviour

The developmental paediatrician guides behavioural strategies or medication (for example, for attention deficit hyperactivity disorder) when necessary, and severe aggressive or destructive behaviour should be referred to child and adolescent psychiatry [1]. The Gibbons review states that an antipsychotic such as prochlorperazine may be effective for severe behavioural problems, without giving a dose; this is expert opinion, without a supporting study [7]. Because crying and agitation may be an expression of gastrointestinal pain, assessment for somatic causes precedes psychotropic medication [7, 14]. The French PNDS asks for behaviour to be assessed at every visit; in the event of an acute change, a painful somatic cause is sought first (reflux, dental pain, otitis, faecal impaction), with observer-rated pain scales for patients without language, such as the Pédiadol or the San Salvadour scale [13]. Depending on the age of onset, nature and severity, an opinion may be requested from the reference centre for early-onset psychiatric manifestations of the same filière, and behavioural interventions, cognitive behavioural therapies and cognitive remediation may help; problem behaviour is referred to child and adolescent psychiatry or adult psychiatry according to age [13].

7.8. Genitalia, gonads and urinary tract

Cryptorchidism should be assessed and treated by orchidopexy at the standard age [7]; the Japanese document includes cryptorchidism surgery in symptomatic treatment [20]. Intra-abdominal testes, usually dysgenetic, should be removed because of the risk of malignancy, according to the Gibbons review [7]. The remaining decisions, including hypospadias repair and the management of ambiguous genitalia, are the responsibility of paediatric urology [1]. The French PNDS gives a hormonal timetable: in variations of genital development, an endocrine study at 2 months of age, during minipuberty, to demonstrate gonadal dysgenesis, and another at around 13–14 years, to decide on pubertal induction, the aim of which is to preserve bone mass [13]. The assessment is carried out in a multidisciplinary expert centre, with paediatric endocrinologist and urologist (in France, the reference centres for variations of genital development); orchidopexy, when necessary, has no particular features [13]. The French legal framework (bioethics law no. 2021-1017 of 2 August 2021 and decree of 15 November 2022) authorises genital interventions only for medical necessity, after discussion of the case at a national multidisciplinary consultation meeting, and requires the child’s participation in the decision according to their maturity; in a patient with intellectual disability, expressions of agreement or refusal are sought and respected [13]. This framework is national; Gibbons’ recommendation to remove intra-abdominal testes, which predates these texts, should now be discussed at the same type of meeting [7, 13]. Renal and urinary tract ultrasound should be performed at diagnosis; urine culture is required in the presence of fever or dysuria; and antibiotic prophylaxis is considered when there are urinary anomalies [7]. The delayed or arrested puberty and low testosterone described justify endocrine assessment [7, 14]. According to the PNDS, renal and urinary anomalies are screened for at diagnosis and then monitored according to the finding and the nephrology or urology opinion; a fall-off in the height and weight growth curve leads to a search for the cause, starting with the oral feeding disorder, and, as there are no data on growth hormone in the syndrome, its indication is decided by individual endocrinological assessment [13].

7.9. Musculoskeletal system and bone health

The musculoskeletal examination should be carried out at diagnosis and throughout childhood, because kyphosis and scoliosis increase with age [7]. Spasticity also increases with age and requires regular physiotherapy [7]. GeneReviews recommends orthopaedics, physical medicine and rehabilitation, physiotherapy and occupational therapy, with positioning and mobility equipment (wheelchairs, walking frames, bath chairs, orthoses, adapted pushchairs) [1]. The authors of the Dutch cohort propose early screening for spinal deformities to allow early conservative treatment and assessment of vitamin D and bone mineral density to prevent fractures, taking into account antiepileptic medicines, immobility, falls and vitamin D deficiency as risk factors [14]. The French PNDS converts these proposals into a protocol recommendation: regular screening for spinal alignment disorders, for conservative treatment that limits progression and reduces the need for surgery, and regular assessment of bone status with densitometry and calcium-phosphate studies including testing for vitamin D deficiency, without setting an age or interval [13]. Spasticity, contractures and joint stiffness, which may cause pain, positioning difficulties and loss of motor skills, are prevented with physiotherapy and splints; they may require muscle relaxants or local botulinum toxin injections, with a physical medicine and rehabilitation or orthopaedic consultation and environmental adaptation by occupational therapy [13]. The protocol does not name the muscle relaxant or give doses.

7.10. Haematology

The alpha-thalassaemia of the syndrome is mild, not transfusion-dependent and should not be managed as a transfusion-dependent thalassaemia [1, 6]. The mild anaemia does not require treatment, and iron is given only when stores are low [7]. The French PNDS concurs: the baseline haemoglobin should be known, microcytosis does not justify iron without laboratory confirmation of deficiency, and a haematology opinion is reserved for significant, symptomatic or unusual anaemia [13].

7.11. Heart, vision, hearing and oral health

Congenital heart defects follow the guidance of cardiology, with surgery or medical treatment according to the defect [1, 20]. The French PNDS specifies that treatment does not differ from that applied to the same heart defect in the general population and that, if the echocardiogram at diagnosis is normal, systematic cardiological follow-up is not necessary in the absence of symptoms [13]. Formal ophthalmological assessment is carried out at diagnosis and regularly [7]. Hearing is assessed with distraction tests and, when there is suspicion, with auditory evoked potentials [7]; the frequent otitis of childhood led to the insertion of tympanostomy tubes in part of the Dutch cohort [14]. The French PNDS requests an ophthalmological examination at diagnosis, targeting oculomotor disorders and anomalies of ocular development, and a systematic ENT examination at diagnosis, repeated as necessary, with screening and treatment of otitis, audiogram or auditory evoked potentials [13].

Oral health is not included in the GeneReviews recommendations. The French PNDS considers regular dental care indispensable, with a stomatologist or dentist used to children with disabilities: toothbrushing from the eruption of the first tooth, systematic follow-up (annual in the visit table) for caries, crowding and malpositioned teeth, bruxism and sialorrhoea, and orthodontics if necessary [13]. Follow-up can take place in an ordinary practice; some patients need professionals used to disability and conscious sedation with an equimolar mixture of oxygen and nitrous oxide, which may require care in hospital or in an approved practice [13].

7.12. Drugs and situations requiring caution

Anticholinergics require caution because they reduce gastrointestinal motility, with a risk of exacerbating constipation or causing ileus; the European glycopyrronium label contraindicates use in those with a history of intestinal obstruction or paralytic ileus [7, 80]. Antiepileptic drugs, alongside immobility and vitamin D deficiency, were identified as risk factors for osteoporosis and fractures [14]. Mild alpha-thalassaemia does not justify transfusions or chelation [6]. Attributing food refusal, crying or agitation to behaviour without investigating a gastrointestinal cause is a documented management error [7, 66].

7.13. Perioperative care, pregnancy and transition

The sources consulted do not describe specific anaesthetic recommendations for the syndrome. The risks to be considered result from the manifestations described: aspiration due to reflux and uncoordinated swallowing, apnoea, congenital heart disease and recurrent respiratory infections [1, 12, 54]. The French PNDS, without anaesthetic recommendations of its own, asks that major surgery be weighed with the parents, as in any patient with severe intellectual disability or profound multiple disabilities, making explicit the expected benefit and the risks, that the postoperative period be anticipated and that the risk of osteoporosis be taken into account (immobilisation, handling, positioning) [13]. For dental care, it accepts conscious sedation with an equimolar mixture of oxygen and nitrous oxide [13]. Affected males do not reproduce, and female carriers are as a rule asymptomatic; the only reproductive observation concerning carriers is the frequency of miscarriages discussed in section 8 [1, 14]. Transition to adult care is based on the educational transition plan and on continuity of gastrointestinal, orthopaedic, bone, visual and neurological surveillance; the ageing described in the Dutch cohort (motor decline, osteoporosis, cataract, glaucoma, cardiovascular events) defines the topics to be added to adult follow-up [1, 14]. The French PNDS asks that the child–adolescent–adult transition be anticipated and supported by the reference centre, often with its own protocol, and that it cover medical follow-up, rehabilitation and medico-social support; updating of investigations and preparation of a complete clinical record for the new team should be done well in advance [13]. In the French system, placement in an IME may be extended beyond 20 years (the “Creton” provision) until a place is available in an adult facility, such as a medicalised residential home or a specialised residential home; at 18 years, a legal protection measure for the vulnerable adult (curatorship, guardianship or family authorisation) is discussed with the family [13].

7.14. Investigational therapies

The most advanced research builds on the G-quadruplex mechanism. In a mouse model, 5-aminolevulinic acid (5-ALA), converted to porphyrin metabolites that bind G-quadruplexes, reduced RNA polymerase II recruitment, repressed Xlr3b and rescued synaptic plasticity and cognitive deficits [37]. In 2020, Wada and colleagues published a letter entitled “5-ALA may improve language dysfunction in patients with ATR-X syndrome”, whose content is unavailable in the sources consulted [85]. This was followed by an investigator-initiated trial at Kyoto University (jRCT2051220062, IACT21003), registered on 14 July 2022: a single-arm, open-label, uncontrolled exploratory study targeting 5 boys over 2 years old, weighing ≥10 kg and diagnosed as definite according to the Japanese criteria, receiving NPJ005 tablets (25 mg 5-ALA hydrochloride and 39.2 mg sodium ferrous citrate per tablet) for 24 weeks; the registry does not state the daily dosing regimen [16]. Primary outcomes are safety, development assessed by the new version of the Kyoto Scale of Psychological Development and social competence by the S-M test; secondary outcomes include M-CHAT, gaze patterns (Gazefinder), gastrointestinal symptoms, weight and blood levels of 5-ALA and protoporphyrin IX; photosensitivity, porphyria, hypersensitivity to 5-ALA, porphyrins or iron and haemochromatosis are exclusion criteria [16]. Status is “not recruiting”, the registry does not state the phase in the English version, and no published results were found [16]. A second study, at Nagoya University (jRCTs041250198), was registered on 6 March 2026 and is recruiting: single-arm, open-label, targeting 4 adult males with a hemizygous pathogenic variant and mild to moderate intellectual disability, receiving 5-ALA phosphate 200 mg once daily for 12 weeks; the primary outcome is the Vineland-II Adaptive Behavior Composite at 12 weeks [17].

Cutamesine (SA4503), a sigma-1 receptor agonist, reversed axonal and dendritic spine abnormalities in cortical neurons, rescued cognitive deficits and normalised BDNF in the medial prefrontal cortex in ATR-X mice lacking Atrx exon 2 [86]. It received European Commission orphan medicinal product designation EU/3/23/2883 for alpha-thalassaemia X-linked intellectual disability syndrome caused by ATRX variants, dated 12 January 2024 and published on 11 April 2024 [18]. Orphan designation is not a marketing authorisation, and the EMA page does not identify the sponsor; no clinical trial of cutamesine in the syndrome was found in ClinicalTrials.gov [18, 87]. The ClinicalTrials.gov search in October 2026 found no syndrome-specific therapeutic trial; studies including it cover multiple conditions, such as the Simons Searchlight registry (NCT01238250, recruiting) [87]. Academic research pursues drug repurposing and gene therapies in cellular and mouse models with CRISPR-edited patient variants and in induced pluripotent stem cells, with no gene therapy trial identified [4]. The cGAS-dependent type I interferon mechanism suggested by the 2025 preprint opens a line of investigation, without therapeutic translation [38, 39].

These data do not permit conclusions about efficacy. The human studies are single-arm, open-label and have four or five participants, without a control group, in patients whose development progresses spontaneously and whose severity varies with genotype; developmental and behavioural outcomes are sensitive to expectancy effects; there are no confidence intervals or published results; and the pyridostigmine case cannot be generalised. Nor is there a basis for comparing effects between the two mouse models.

7.15. Comparative regulatory status

The sources consulted do not include INFARMED or ANVISA data on access to oral glycopyrronium in Portugal and Brazil.

7.16. Developments over the past twelve months

Between October 2025 and October 2026, developments were as follows, by level of evidence. Mechanistically, a study published in 2026 demonstrated that ATRX loss couples genomic instability at a G-rich repeat to human alpha-globin dysregulation [36]. A November 2025 preprint, highlighted in a review journal in 2026, proposed a cGAS-dependent type I interferonopathy [38, 39]. Clinically, the 2025 Dutch cohort described adults over 50 years for the first time [14], and a 2026 preprint proposed diabetes mellitus as an endocrine manifestation, without peer review [69]. The first cases from Jordan, without alpha-thalassaemia, and Tunisia were published [52, 53], as was an Indian case mimicking Down syndrome [77]. In trials, the Nagoya University adult 5-ALA study was registered in March 2026 [17]. In regulation, no new authorisation or new application was identified; European orphan designation for cutamesine dates from 2024 [18].

7.17. Source recommendations and divergences

The main divergence concerns the weight given to alpha-thalassaemia in diagnosis: historical sources and the Japanese document treat it as an almost constant finding, whereas recent molecular cohorts treat it as a minority finding [7, 14, 20]. The second concerns anticholinergics, proposed by GeneReviews and viewed with caution by Gibbons because of gastrointestinal risk [1, 7]. The third concerns osteosarcoma risk, discussed in section 11.

The French PNDS adds divergences of its own, which are made explicit. For the proportion of de novo variants, it adopts approximately 10%, at the lower limit of the 10–20% of GeneReviews and far from the third of the Japanese document [1, 13, 20]. For alpha-thalassaemia, it takes up the third from the Dutch cohort, versus the 75% of GeneReviews and the 90% of Gibbons, and assigns the inclusions a role as a biomarker in isolated intellectual disability that GeneReviews considers of limited utility [1, 7, 13]. For reduced fetal movements, the third cited does not match the 59% published in the Italian cohort that serves as its source [13, 34]. For osteosarcoma, it counts six patients versus the four of GeneReviews and speaks of a particular predisposition, although, like GeneReviews, it does not propose screening [1, 13]. For pyridostigmine, it is the only management source that accepts it, on an exceptional basis and without a dose [13, 79]. For bone, it turns into a protocol recommendation, without age or interval, what the Dutch cohort proposed as an authors’ suggestion [13, 14]. For follow-up, it is the only source with an explicit visit frequency and the only one that dispenses with cardiological follow-up when the initial echocardiogram is normal [1, 13]. For the gonads, the systematic removal of intra-abdominal testes proposed by Gibbons gives way to a case-by-case decision at a national multidisciplinary meeting, imposed by French law [7, 13]. For preimplantation diagnosis, the protocol reserves it for inherited variants, whereas GeneReviews presents it as possible whenever the familial variant is known [1, 13]. For doses, the PNDS gives no dosages; those of glycopyrronium and melatonin come from the European and US labels, and that of pyridostigmine from a single case, so none has the status of a guideline dose in the syndrome [79, 80, 82, 84].

7.18. Therapeutic education

The French PNDS is the only source that structures therapeutic education [13]. It is aimed at the parents and at the patient themself, child or adult, whatever their degree of autonomy, and begins at the time the diagnosis is disclosed, with information about the disease, the possible medical consequences, the care plan and the implications of genetic counselling for each relative [13]. The aims are to help the family understand the disease and the treatments, with their adverse effects and precautions, to act in daily life in particular situations, such as an epileptic seizure or discomfort that the patient cannot verbalise, to avoid complications and to master the technical procedures of care [13]. It is based on an educational diagnosis, individual interviews during visits, group sessions and telephone follow-up, and extends to life-plan choices, orientation, transition and applications for technical and social assistance [13]. The protocol points out that early treatment of some symptoms may avoid hospital admissions [13].

8. Reproductive Options and Family Counselling

8.1. Risks by scenario

The father of an affected 46,XY male does not have the disorder, is not hemizygous for the variant and does not need to be assessed [1]. When there is more than one affected individual in the family, the mother is an obligate heterozygote [1]. In a simplex case, the mother may be a carrier or the variant may have arisen de novo; estimates of the proportion of de novo variants diverge: 10–20% of affected males according to GeneReviews, approximately 15% indirectly from the Gibbons series (17 of 20 mothers of sporadic cases were carriers, i.e. 85%), 2 of 14 families (14%) in the Italian cohort, approximately 10% in the French PNDS, which cites León and Harley, and approximately a third according to the Japanese document [1, 7, 13, 20, 33, 34]. In practice, most mothers of isolated cases are carriers, and maternal testing is always indicated. The French PNDS adds that the carrier mother usually shows skewed X inactivation and that X-linked inheritance makes testing of the father unnecessary [13].

8.2. Mosaicism and cascade testing

Maternal somatic and germline mosaicism caused recurrence in two Japanese brothers with an intragenic deletion: their mother, an obligate carrier, tested negative by quantitative exon PCR, and only breakpoint primers revealed a mosaic frequency below 1% in blood; the diagnosis of mosaicism rendered the risk of the mother's sisters being carriers negligible [48]. Other families with presumed germline and gonosomal mosaicism have been described [1]. Gibbons' review therefore recommended offering prenatal diagnosis to all mothers of affected individuals, even with negative testing [7]. Molecular testing also allows identification of the generation in which the variant arose, as in the Dutch mother with de novo p.Asp1796Gly [1, 14].

Testing at-risk female relatives is most informative when the proband's variant is known; without an affected individual available, sequencing is performed, followed, if negative, by targeted deletion and duplication analysis [1]. HbH inclusions are not a reliable carrier detection method: only approximately one quarter of obligate carriers have rare cells with inclusions [7, 64]. X-inactivation studies serve only as supportive evidence when there is almost complete skewing (>95%) consistent across all obligate carriers in a large family; there are false negatives (carriers with a balanced pattern) and false positives, because approximately 10% of normal women have skewed inactivation [7, 64]. When the variant is unknown, linked markers may be used [7].

The French PNDS organises cascade testing based on the mother’s status [13]. If the variant arose de novo in the proband (approximately 10%), the recurrence risk for the couple is limited to maternal mosaicism, rare but described, and for this reason the sisters of sporadic cases should be informed and testing should be offered to them from the age of majority [13, 48]. If the mother is a carrier (approximately 90%), testing is offered to the maternal grandmother; if this is not possible or not wanted, the women on the maternal side should be informed of their risk and testing may be offered to them after a genetics clinic consultation [13]. Even when the variant arose de novo in the mother, her sisters may be carriers because of mosaicism in one of the grandparents, so the maternal result does not close the investigation of that branch [13].

8.3. Prenatal and preimplantation diagnosis

With the familial variant identified, prenatal testing in an at-risk XY fetus and PGT are possible [1, 30]. Requests for prenatal diagnosis for a disease such as this elicit differing perspectives among professionals and families; the decision is personal [1]. GeneReviews recommends determining risk and discussing prenatal testing and PGT ideally before pregnancy, offering counselling to young adults who are carriers or at risk and banking DNA from probands without a confirmed molecular diagnosis [1]. In the Dutch cohort, 12 confirmed carrier mothers had 8 spontaneous miscarriages in 46 pregnancies (17%), compared with 13.5% in the general population; numbers are small and the difference was not formally tested [14]. Wilkie's 1991 pedigree had many miscarriages and male stillbirths [14, 24]. One affected girl was born after IVF, and the authors hypothesised a link between assisted reproduction and aberrant X-inactivation, without demonstrating it [57].

The French PNDS describes the prenatal pathway applied in France [13]. With an inherited or de novo variant, invasive prenatal diagnosis may be offered to the couple who wish it when the fetus is male: determination of fetal sex on maternal blood precedes sampling, and chorionic villus sampling (from 11 weeks of gestation) or amniocentesis (from 16 weeks) is performed only if the fetus is male [13]. Preimplantation diagnosis is offered only when the variant is inherited, in authorised centres, after the opinion of a multidisciplinary prenatal diagnosis centre [13].

8.4. Counselling minors and the family

Counselling should explain the nature, inheritance and implications of the disease [1]. Carrier testing in asymptomatic underage sisters and cousins has no immediate clinical utility, because heterozygotes are generally asymptomatic and its principal purpose is reproductive; GeneReviews directs reproductive counselling towards young adults [1]. In the rare girls with manifestations, testing has a diagnostic indication [56, 57]. Contact with family associations forms part of support (section 9.4).

The French PNDS separates three stages [13]. The disclosure of the diagnosis takes place in a dedicated consultation, in a suitable setting and with both parents or the legal representatives, and covers the disease and its complications, the genetic results, multidisciplinary follow-up and inheritance; this is followed by the systematic offer of a psychology consultation, at a time chosen by the parents and extendable during follow-up, and a medical consultation soon afterwards [13]. The genetic counselling consultation, by a geneticist or genetic counsellor, is indispensable and distinct from the disclosure, but should take place shortly afterwards: it completes the information, re-explains the inheritance and the recurrence risk, identifies the people at risk in the family and provides information on prenatal and preimplantation diagnosis [13]. In France, the patient or the parents (or the guardian of an adult) have a legal obligation to inform potentially at-risk relatives, under Decree no. 2013-527 of 20 June 2013; if they do not wish to do so personally, they may ask the doctor to tell the relatives that there is information concerning them, and they must be informed of the risk that failure to inform entails [13]. Patient associations are presented to the family, who decide whether to contact them [13].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

None of these estimates is prevalence measured in a population study. Case numbers are counts of published or diagnosed patients and should not be converted into rates [6]. Underdiagnosis is likely, particularly in mild phenotypes, and a 2025 institutional blog describes the syndrome as affecting “at least 200 families” and probably being greatly underdiagnosed [1, 4].

9.2. Geography and ancestry

No racial or ethnic clustering or founder populations have been described [1]. The first series were from Northern Europe and the United Kingdom [3, 21, 25]. In Europe, there are molecular cohorts in France (22 patients from 16 families), Italy (17 patients from 14 families) and the Netherlands and Flanders (22 individuals from 14 families, mainly of Dutch ancestry, but also Belgian, Spanish, Moroccan and mixed Filipino/English) [14, 34, 41]. In the United States, data come from laboratory series and isolated families, such as that of the two brothers with osteosarcoma and the five families with p.(Arg37Ter) [1, 49, 50]. Japan has its own research network, more than 70 patients diagnosed by 2013 and national criteria [20, 55]. In 2025 the first cases from Jordan and Tunisia and a case from India were published [52, 53, 77]. The variant p.(Arg246Cys) is the most frequent in all series with data, recurrent in unrelated families, with no founder effect described [7, 34]. In France, in addition to the Badens series and the two boys with osteosarcoma, the 2026 PNDS organises follow-up in a national network of centres, without publishing a national patient count [13, 41, 70]. The sources consulted do not include data from Portugal or Brazil, which does not mean that there are no patients or publications in those countries.

9.3. Special populations

Heterozygous women are generally asymptomatic, with the exceptions described in section 2.7 [1, 56, 57]. The 46,XY individuals with female external genitalia were generally raised as girls and have intra-abdominal dysgenetic gonads, whose removal is recommended because of malignancy risk [7]. Adults over 45 years have problems associated with early ageing of the musculoskeletal system and sensory organs [14]. Patients with a mild phenotype may reach adulthood without a diagnosis, labelled as having non-syndromic XLID [1, 49].

9.4. Reference networks and patient associations

In Europe, the relevant network is ERN ITHACA (European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders), with working groups on neurodevelopmental disorders and guidelines, the ILIAD registry and the CPMS patient consultation system [19]. The ATRX Research Alliance is a global family-led organisation, with country groups and scientific advisory board meetings, associated with the Simons Searchlight registry, which includes ATRX under the designation “ATRX-Related Syndrome” [4, 87]. In the Netherlands, Stichting ATR-X Syndroom Nederland was a co-author and recruitment route for the Dutch cohort [14]; in Italy, the ATRX Italia family group supported the Italian cohort [34]. In Japan, the ATR-X syndrome research network is based at Kyoto University [20]. EURORDIS serves as a generic contact for patient associations in the European Union [18]. GeneReviews also lists AAIDD, the MedlinePlus page on intellectual disability and the Parent to Parent network [1].

In France, the 2026 PNDS describes a three-level organisation [13]. Diagnosis and coordination are the responsibility of the “Déficiences intellectuelles de causes rares” reference centres of the DéfiScience filière (the national rare disease network for neurodevelopmental disorders), with a coordinating centre at the Pitié-Salpêtrière Hospital (Paris), plus 11 reference centres (Trousseau, Necker, Robert-Debré and Jean-Verdier in the Paris region; Bordeaux, Dijon, Lille, Lyon, Nantes, Rennes and Strasbourg) and 11 competence centres (Bicêtre, Institut Jérôme Lejeune, Besançon, Montpellier, Nancy, Nice, Pointe-à-Pitre, Reims, Rouen, Saint-Malo and Toulouse), in liaison with the AnDDI-Rares filière for developmental anomalies [13]. The general practitioner or paediatrician refers when warning signs appear, deals with medico-administrative measures, starts rehabilitation before the aetiological diagnosis, ensures general follow-up (vaccination, prevention and general population screening) and coordinates with the reference centre [13]. Medico-social structures (CAMSP, SESSAD, IME, medicalised residential homes and adult support services) provide rehabilitation and daily support [13].

The protocol serves as the basis for the application for exemption from patient co-payments as an “off-list” long-term condition, with 100% coverage by the Caisse Primaire d'Assurance Maladie, and for the medical certificate in the application to the Maison Départementale des Personnes Handicapées (MDPH) [13]. Up to 20 years, parents may apply for the allowance for the education of a disabled child (AEEH, basic allowance and supplements), the disability compensation benefit (PCH), the daily parental presence allowance (AJPP, combinable with the basic AEEH but not with the supplement) and the mobility-inclusion card (priority; parking from 50% disability; invalidity from 80%); the family chooses between the AEEH supplement and the PCH [13]. The transition to adulthood at the MDPH, set at 20 years, is prepared 9 to 12 months in advance (disabled adult allowance, PCH, mobility card) and opens up referral to sheltered employment or to residential homes, medicalised residential homes or specialised residential homes; applications are renewed 6 months before the rights expire [13]. The social worker is considered indispensable in this process [13].

In an emergency, the PNDS recommends the rare disease emergency card, created by the Directorate-General for Health Care Provision under the national rare diseases plan: personal, subject to medical confidentiality, credit-card sized, sometimes bilingual, completed and issued by the doctor of the reference or competence centre, with contact details of the family and the reference doctors, actions to avoid and to recommend and useful links; in its absence, a record for patients with specific needs is used [13]. The protocol does not describe specific content for ATR-X on this card.

There is no association in France specific to ATR-X syndrome; the PNDS refers to associations dealing with common problems, which collaborate with the DéfiScience and AnDDI-Rares filières, and the association XTRAORDINAIRE took part in the review of the protocol [13]. As sources of information, it lists Orphanet, the websites of the two filières, the UNAPEI federation, the Alliance Maladies Rares and the Maladies Rares Info Service telephone platform [13].

10. Illustrative Clinical Case

10.1. A 3-year-old boy with a frameshift variant and a phenotype without alpha-thalassaemia

Wang and colleagues, from Anhui Provincial Children's Hospital in China, published in 2024 the case of a 3-year-old boy, the third child of non-consanguineous parents, with two older brothers aged 13 and 10 years with normal development and no family history of neuromuscular disease [31]. He was born vaginally at 41 weeks, weighing 3,150 g, and was admitted during the neonatal period for feeding difficulties and poor weight gain. Echocardiography showed a 0.16 cm atrial septal defect, which decreased by 3 years. Before that age he had recurrent severe respiratory infections. Global delay was profound: he walked only at 2 years, said no meaningful words and barely understood language; he had unprovoked screaming, hyperactivity and sleep disturbance [31].

At 3 years, he was admitted for severe intellectual disability. He was 90 cm tall (−2 standard deviations), weighed 16 kg (+1 standard deviation) and had a head circumference of 48 cm (−2 standard deviations). Examination showed overfolded ears, a flat nasal root, an open mouth with drooling, a triangular tented upper lip and widely spaced upper incisors, with mild lower limb hypotonia. Figure 2 of the article shows the frontal view, with an open mouth, full everted lower lip, tented upper lip and small nose with anteverted nares, and the profile with hypotonic facies (https://pmc.ncbi.nlm.nih.gov/articles/PMC11448441/figure/Fig2/) [31]. Urogenital ultrasound revealed unilateral cryptorchidism and bilateral pelvic dilatation; brain MRI showed thickening of the frontal calvarium and poor mastoid pneumatisation; fundoscopy showed optic nerve dysplasia; BAEP showed bilaterally elevated thresholds (70 dB on the left, 65 dB on the right). Scores on the Binet-Simon scale and the Peabody Picture Vocabulary Test were 0, and assessment of activities of daily living showed severe impairment. Full blood count, thyroid function and biochemistry were normal; haemoglobin electrophoresis showed normal HbA, HbF and HbA2, brilliant cresyl blue staining showed no HbH inclusions and the blood smear was normal [31].

Exome sequencing identified the ATRX duplication c.399_400dup in exon 6, published as p.Leu134Cysfs*2 against NM_000489.6 and classified as likely pathogenic (PVS1 and PM2_Supporting criteria), with no other explanatory variant; the protein description validated in VariantValidator is p.(Leu134ArgfsTer2) [8, 31]. The variant lies immediately before the ADD domain. Sanger sequencing showed the mother to be heterozygous and the father without the variant; parentage confirmation was declined. Figure 1 presents the pedigree, with the carrier mother, affected proband and two unaffected brothers, and the electropherograms of the three (https://pmc.ncbi.nlm.nih.gov/articles/PMC11448441/figure/Fig1/) [31]. The authors assigned a diagnosis of MRXHF1 (OMIM 309580). The patient received speech and language therapy and occupational therapy; drooling decreased, without evident cognitive progress [31].

10.2. Clinical interpretation of the case

The case combines almost all features of the classical presentation (neonatal feeding difficulties, profound delay, hypotonic facies, microcephaly, short stature, cryptorchidism, septal heart defect, hearing loss, respiratory infections), but without any haematological sign, and received the OMIM label MRXHF1. It illustrates that absence of HbH inclusions does not rule out the diagnosis and that the distinction between “ATR-X” and “MRXHF1” is nosological rather than biological, as argued by GeneReviews and Orphanet [1, 2]. It also illustrates the need to normalise nomenclature: the published protein description differs from the validated description. The management described (rehabilitation therapies) is consistent with GeneReviews; the report does not mention the gastrointestinal, follow-up ophthalmological and renal assessments included in the surveillance in section 11 [1, 7].

10.3. Complementary case: gastrointestinal dysmotility

Comisi and colleagues described a 10-year-old Caucasian boy, born at 39 weeks after a pregnancy complicated by oligohydramnios, with perinatal hypotonia and a molecular diagnosis of hemizygous c.736C>T at 1 year [79]. He had microcephaly, a low hairline, telecanthus, a small triangular nose with anteverted nares, a carp-shaped mouth, psychomotor delay, epilepsy, moderate bilateral hearing loss and laryngomalacia. He was admitted for chronic reflux, dysphagia and severe persistent constipation, after three recent admissions; the abdominal radiograph showed gastroparesis and severe bowel loop distension (Figure 1 of the article, known from its legend), and the barium enema showed a rectosigmoid substenotic zone. Macrogol and enemas were ineffective, and the pain and distension caused agitation. The pyridostigmine treatment described in section 7.4 avoided surgery and led to resolution of symptoms after one year [79]. Pyridostigmine is not part of the GeneReviews recommendations; the 2026 French PNDS, based on this case, accepts it only on an exceptional, off-label basis, in an expert centre and after cardiological assessment; the case documents a rescue option, not a routine [1, 13, 79].

11. Prognosis and Long-Term Follow-up

11.1. Survival and causes of death

There are no longitudinal survival studies [7]. In Gibbons' series of 168 patients, there were 25 deaths, 19 before 5 years of age; the cause was known in just over half: pneumonia in 6, aspiration of vomit in 4 and renal failure in 2, possibly related to recurrent urinary tract infections [7]. Early childhood deaths from aspiration of vomit or aspiration pneumonia recur across series [1, 66]. In the Dutch cohort, 3 of 22 individuals died: at 2 years from pneumococcal sepsis, at 29 from aspiration pneumonia and at 36 from streptococcal sepsis [14]. In the Italian cohort, one patient died of pneumonia at 8 years [34]. At the same time, several individuals were doing well in their 30s and 40s, and the Dutch cohort included adults up to 69 years [7, 14]. The Japanese document estimates life expectancy below that of the general population, but acknowledges the lack of data, and indicates that prognosis depends mainly on heart disease, respiratory compromise and nutritional status [20]. Death figures are counts in small series with heterogeneous follow-up; they do not allow life expectancy to be calculated.

11.2. Functional course

Most patients continue to acquire skills; gastrointestinal problems decreased around 7 years of age in 54% of the Dutch individuals, and behavioural problems decreased with age in 47% [7, 14]. Spasticity, kyphosis and scoliosis increase with age [7]. After 45 years, the Dutch cohort described motor decline, osteoporosis with fractures, cataract, glaucoma and cardiovascular events [14]. Genotype modifies expectations: codon 2085 variants and p.(Arg37Ter) are associated with milder phenotypes, with independent walking, and C-terminal truncating variants with severe urogenital anomalies, but intrafamilial variability prevents individual predictions [34, 41, 49].

11.3. Oncological risk

The risk of osteosarcoma remains uncertain. Four patients with five osteosarcomas have been described in two reports, and interpretations range from a probably increased risk to an undemonstrated causal relationship [4, 33, 50, 70]. No source consulted proposes an oncological surveillance protocol, and GeneReviews does not recommend surveillance [1]. The French PNDS, which counts six patients with osteosarcoma, reaches the same conclusion: the data are insufficient to define the level of risk or propose screening, and the oncologist intervenes when a tumour is suspected or diagnosed [13]. In practice, persistent bone pain or swelling of a limb in a patient with ATR-X justifies targeted imaging, without systematic screening.

11.4. Surveillance table

The GeneReviews “at each visit” intervals do not set a frequency, which depends on age and severity [1]. The frequency of the coordination and paediatric visits comes from the French PNDS, which provides, for the other specialties (neurology, gastroenterology, ophthalmology, orthopaedics, physical medicine and rehabilitation, psychiatry, sleep medicine, urology and nephrology), for a schedule adjusted to the symptoms, with grouping of hospital visits [13]. The bone recommendations, proposed by the authors of the Dutch cohort, have been adopted by the PNDS without a defined interval [13, 14].

12. Summary and Final Considerations

ATR-X syndrome results from hypomorphic variants in ATRX, an SNF2-family chromatin remodeller that, with DAXX, maintains heterochromatin at G-rich repetitive loci. Its loss alters methylation of repetitive sequences, produces a leucocyte episignature and reduces alpha-globin expression in a fraction of cells through DNA damage at a G-rich repeat within the locus itself. The classical phenotype combines severe intellectual disability, hypotonia, characteristic facies, microcephaly, short stature, genital anomalies in a 46,XY individual, gastrointestinal dysfunction and HbH inclusions; molecular diagnosis has revealed a broader spectrum, with mild forms, older adults and patients without alpha-thalassaemia, such that intellectual disability is the only constant manifestation.

Diagnosis rests on a hemizygous pathogenic variant, ideally identified by panel, exome or genome sequencing with CNV analysis, with HbH inclusion testing and the methylation episignature as supportive tools, particularly in the presence of VUS or negative studies. The ADD-domain variant p.(Arg246Cys) is the most frequent; codon 2085 variants and p.(Arg37Ter) tend towards milder phenotypes, but intrafamilial variability limits individual prognosis. Female carriers are almost always asymptomatic, most mothers of isolated cases are carriers and germline mosaicism justifies offering prenatal diagnosis even with negative maternal testing.

Management is supportive and focuses on the digestive system, because reflux, dysphagia, constipation, pseudovolvulus, volvulus and aspiration account for much of the morbidity and early mortality; food refusal should be investigated as an organic symptom. Sialorrhoea, seizures, behaviour, dysgenetic gonads, the spine and bone complete the follow-up, and anticholinergics require caution because of the risk of ileus. There is no approved therapy: 5-ALA is in exploratory Japanese studies and cutamesine has only a European orphan designation and preclinical data. The 2026 French PNDS is the first national protocol and sets a follow-up schedule, an endocrine timetable and the counselling pathway, but adds no new quantitative data or doses of its own. The main gaps are the absence of guidelines with graded evidence, of survival data and of population-based prevalence estimates, the uncertainty about osteosarcoma risk and the scarcity of data on adults, which the Italian and Dutch cohorts have begun to fill.

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