TBL1XR1-Related Disorders (Pierpont Syndrome)

Allelic class of autosomal dominant neurodevelopmental disorders caused by germline variants in the TBL1XR1 gene (3q26.32): Pierpont syndrome, associated with the recurrent variant p.(Tyr446Cys); Pierpont-like presentations due to other substitutions on the inner face of the WD40 ring; autosomal dominant intellectual disability (ID) 41 (MRD41), due to loss of function or other missense variants; and microduplication of the gene, whose pathogenicity has not been established.

Literature and regulatory information updated: 18 October 2026.

0. Reference Summary Table

1. Introduction

1.1 Original clinical description and pre-molecular period

In 1998, Mary Ella Pierpont, Fiona Stewart and Robert Gorlin, of the University of Minnesota (Minneapolis, United States), described two unrelated boys with a presentation they regarded as a new multiple congenital anomalies/mental retardation (MCA/MR) syndrome: global developmental delay, microcephaly, midface hypoplasia, large fleshy ears, depressed nasal bridge, anteverted nares, central palatal ridge and high forehead, together with bilateral congenital anteromedial fat pads of the heels, fetal pads on the fingers and toes, and deep palmar and plantar creases with «padding» of the soft tissues between them [1, 32]. The authors found no similar patients in the literature, and OMIM notes that isolated congenital fat pads of the heel are rare [1]. In 2005, Oudesluijs and colleagues (Groningen, the Netherlands) reported a 2.5-year-old boy with axial hypotonia in the first months, prolonged feeding problems, moderate delay without speech, deep palmar and plantar creases and anteromedial heel pads, with a phenotype «almost identical» to that of the two original patients, and proposed the name «Pierpont syndrome» [1, 33]. In 2013, Vadivelu and colleagues (New York) described the fourth published child, with hydrocephalus and an atypical intraventricular choroid plexus papilloma, the first tumour associated with the syndrome [34].

In 2011, the British collaborative study by Burkitt Wright and colleagues brought together seven new patients considered possible cases (including a pair of monozygotic twins) and updated the three already published, excluding four patients with typical hands and feet but without the characteristic facies; the 250K SNP array and the karyotype did not reveal the cause [23]. The group proved recognisable by the facies, especially on smiling, and by the hand and foot findings, and advanced paternal age in the three original patients (58, 37 and 37 years) and in several of the new ones led to the hypothesis of a dominant de novo variant; the inclusion of a girl made the X-linked recessive inheritance suggested by the initial male predominance less likely [1, 23]. Around the same time, several patients published as «Pierpont-like» were reclassified, after clinical and molecular reassessment, as Coffin–Siris or Wiedemann–Steiner syndrome, which created uncertainty about the boundaries of the phenotype [5]. In 2016, O'Keefe and colleagues described the first Hispanic patient (the second female), with a clinical diagnosis confirmed from photographs by Dr Pierpont herself, and interpreted 118 regions of homozygosity (8% of the genome) as suggesting recessive inheritance, a hypothesis superseded by the discovery of the dominant de novo mechanism in the same year [35].

1.2 Molecular discovery and broadening of the spectrum

In 2016, Heinen and colleagues (Amsterdam) sequenced the exome of four unrelated patients (one as a trio) and confirmed by Sanger sequencing in two more: all six had the same heterozygous TBL1XR1 missense variant, absent in the parents, at a conserved position and absent from the dbSNP, 1000 Genomes, NHLBI ESP and GoNL databases [5]. The article described the variant as c.1337A>C in the abstract and results; an erratum published in the same year corrected the notation to c.1337A>G p.(Tyr446Cys), which is the form used in this article [11]. The cohort included four of the patients already published (the two of Pierpont 1998, that of Oudesluijs 2005 and that of Vadivelu 2013) and showed that none of the six had ASD, in contrast with the deletions and other TBL1XR1 variants already associated with autism [5]. Reports with the same variant followed from Germany (Kahlert 2017, with microphthalmia, pendular nystagmus, cryptorchidism, dermal sinus and joint laxity), the United States (Slavotinek 2017, with submucous cleft palate, bilateral cryptorchidism, hydronephrosis and Chiari malformation), Czechia (Tesarova 2022), Kosovo (Ismaili-Jaha 2021), Portugal (Pereira-Nunes 2023, with arthrogryposis multiplex congenita) and Hong Kong (Wong 2026, with bilateral renal dysplasia and renal failure) [19, 21, 36–39]. Kahlert and colleagues concluded that the syndrome was caused exclusively by p.(Tyr446Cys), a conclusion revised in 2018 by Lemattre and colleagues (Montpellier and Dijon), who described two patients with a typical presentation and different de novo variants, p.(Cys325Tyr) and p.(Tyr446His), located on the same inner face of the WD40 ring [3, 36]. In 2023, Tamma and colleagues (Baylor College of Medicine, Houston) proposed p.(Ser326Asn), adjacent to p.(Cys325Tyr), as a new cause of Pierpont [12].

The association of TBL1XR1 with neurodevelopmental disorders without Pierpont features preceded the 2016 discovery. Exome sequencing of 209 trios with sporadic ASD identified a girl with ASD and a non-verbal intelligence quotient (IQ) of 47 carrying de novo p.(Leu282Pro), and targeted sequencing of 44 candidate genes in 2446 probands with ASD identified a boy with a de novo truncating variant (Heinen 2016 gives 2494 cases for this cohort, a discrepancy between secondary sources) [4, 5, 40, 41]. In 2014, Saitsu and colleagues described a Japanese girl with West syndrome, autistic traits and de novo p.(Gly70Asp) in the F-box-like domain, and Tabet and colleagues described a 1.6 Mb de novo deletion at 3q26.31-q26.32 in a child with non-specific ID without autism [13, 42]. In 2015, Pons and colleagues described a girl and her mother with the same 708 kb deletion confined to TBL1XR1, both with mild to moderate ID and similar dysmorphism, and proposed an ID-with-dysmorphism syndrome due to TBL1XR1 deletion [14]. OMIM created entry #616944 (MRD41) in May 2016 [4]. In 2016, Armour and colleagues reinterpreted the «Fitzsimmons syndrome» of a patient with de novo p.(Tyr245Cys) as the co-occurrence of several events, concluding that the spastic paraparesis, brachydactyly and dysmorphism might not be caused by TBL1XR1 [4, 43, 44]. In 2017, Riehmer and colleagues described the microduplication confined to the gene as a «sister» disorder of the 3q26.32 microdeletion [6]. The hypothesis of a relationship with Rett syndrome, based on the loss of MeCP2 binding by some missense variants, was not supported by the clinical review of Zaghlula and colleagues in 2018 [9, 45].

From 2020 onwards, research moved from case description to genotype–phenotype correlation: Quan and colleagues curated 38 variants in 50 individuals, the ClinGen ID and autism panel classified the gene–disease relationship as definitive for a single lumped entity, Nagy and colleagues published in 2024 a caregiver survey of 41 patients, and in 2025–2026 reports appeared of renal dysplasia with renal failure, of generalised dystonia in an adult and of non-canonical intronic variants with an effect demonstrated by minigene assay [9, 10, 15, 19, 25, 46].

1.3 Current nomenclature and classifications

OMIM maintains two phenotype entries for the gene *608628: Pierpont syndrome (#602342, PRPTS; mapping key 3, autosomal dominant, AD) and MRD41 (#616944), included in the phenotypic series of autosomal dominant IDs [1, 4, 7]. Orphanet classifies Pierpont syndrome (ORPHA:487825) as a malformation syndrome, with the ICD-10 code Q87.8 and no ICD-11 mapping returned, within the classifications of rare developmental anomalies during embryogenesis, rare genetic diseases and rare neurological diseases; no specific Orphanet code for MRD41 was identified [2]. ClinGen adopted lumping: a single entity, «complex neurodevelopmental disorder» (MONDO:0100038), autosomal dominant, which brings together Pierpont syndrome, West syndrome and the remaining phenotypes, classified as Definitive on 7 July 2020 with the maximum genetic score of 12 points [15]. GenCC keeps separate classifications by phenotype: Definitive (G2P, February 2025) for Pierpont and for MRD41, Strong (Labcorp/Invitae and PanelApp Australia) and Moderate (Ambry) [16]. The clinical literature uses a four-group genotypic classification, which does not correspond to published consensus criteria: classic Pierpont (p.(Tyr446Cys)), Pierpont-like presentation (other missense variants on the inner face of the WD40 ring), MRD41 (deletions, truncations and various missense variants) and microduplication [3, 6, 10, 12].

1.4 Types within the class

1.5 Definition of each entity within the scope

Pierpont syndrome is defined, in the discovery cohort, by the combination of the facial features, the palmar and plantar fat pads and global developmental delay, with the heterozygous TBL1XR1 variant p.(Tyr446Cys) [5]. Pierpont-like presentation designates patients with an overlapping phenotype and other missense variants on the inner face of the WD40 ring, whom OMIM and Orphanet include under Pierpont syndrome [1, 3]. MRD41 is the non-syndromic to mildly syndromic neurodevelopmental disorder caused by TBL1XR1 loss of function or by missense variants outside that group, with ID of variable severity and, in a subgroup, autistic traits [4, 18, 24]. TBL1XR1 microduplication is a copy-number gain of the gene associated with ID, ASD and hearing loss in isolated families, classified as a variant of uncertain significance (VUS) in the curation of Quan et al. 2020 [6, 10]. The somatic TBL1XR1::RARA and TBL1XR1::RARB fusions of acute promyelocytic leukaemia (APL) do not belong to this class and are addressed in the differential diagnosis as a matter of interpretation [48, 49].

2. Molecular Genetics and Pathophysiology

2.1 The gene and the protein

The TBL1XR1 gene (transducin beta-like 1 X-linked receptor 1; synonyms TBLR1, IRA1, C21) lies at 3q26.32, on the minus strand, at GRCh38 coordinates 3:177,019,344–177,201,800 according to NCBI [7, 8]. The MANE Select transcript is NM_024665.7, which encodes the 514-amino-acid protein NP_078941.2 (55,595 Da); earlier literature used NM_024665.4, NM_024665.5 and NM_024665.6, and for the variants discussed in this article the c. numbering is the same in versions .4 and .7 [5, 8]. The number of exons varies with the annotation: Heinen et al. 2016 describe 18 exons, the canonical Ensembl transcript ENST00000457928.7 has 16 exons and Löw et al. 2026 refer to 14 coding exons, so the exonic location of a variant should be read with the transcript stated in the report [5, 8, 25]. Zhang and colleagues cloned the gene in 2000 from CD34+/CD38− haematopoietic progenitors; the 4.3 and 7.8 kb transcripts are ubiquitously expressed [7]. The mRNA was detected in the pituitary and the paraventricular nucleus of the hypothalamus (three post mortem brains), in liver, muscle and white and brown adipose tissue; two patients with Pierpont (aged 13 and 20 years) had lower whole-blood expression than four controls aged 25–30 years, with no statistical analysis possible given the sample size [5].

The protein has an amino-terminal LisH domain (amino acids 4–36), which mediates tetramerisation and interactions with NCoR/SMRT (nuclear receptor corepressor/silencing mediator of retinoid and thyroid hormone receptors) and GPS2, an F-box-like domain (amino acids 41–86) and eight carboxy-terminal WD40 repeats (amino acids 167–513) that form a ring [5, 10]. TBL1XR1 is a component of the NCoR/SMRT corepressor complex, together with histone deacetylase 3 (HDAC3) and GPS2 [5, 18]. Bound to unliganded nuclear hormone receptors, the complex silences transcription by recruiting chromatin-modifying enzymes; in the presence of ligand the corepressors dissociate, and at negatively regulated genes the corepressors are required to activate transcription [5]. Yoon et al. 2003 showed that TBL1 and TBLR1 bind NCoR through two independent routes (amino-terminal region with RD1; WD40 with RD4), bind histones H2B and H4, and that repression correlates with this binding; Perissi et al. 2004 showed that activation by liganded nuclear receptors requires TBL1 and TBLR1 as adaptors for the 19S ubiquitin/proteasome complex, which mediates the exchange of NCoR/SMRT for coactivators, a mechanism shared by JUN and NF-κB [7]. TBL1XR1 also takes part in the NF-κB pathway (IKKα phosphorylates SMRT on chromatin and recruits TBL1XR1) and in Wnt transcription, by recruiting β-catenin to the promoters of target genes [5]. TBL1 (TBL1X, Xp22) and TBLR1 are partly redundant in repression and have specific roles: TBL1 in CTBP degradation, TBLR1 in NCoR/SMRT exchange [7]. TBL1X shares 86% sequence similarity with TBL1XR1 [50].

2.2 Mechanisms: dominant-negative, loss of function and dosage gain

The clinical division of the class results from the type of variant and not only from gene dosage [18]. Gene deletions, frameshift variants and truncations cause loss of function through haploinsufficiency, with ID and, frequently, ASD, without resemblance to Pierpont; ClinGen gives them a haploinsufficiency score of 3 [5, 15]. Constraint of the gene against loss of function is high, but the values depend on the gnomAD version: pLI 1 and LOEUF 0.17 in gnomAD v4.0 (ENST00000457928) according to ClinGen, LOEUF 0.11 with no loss-of-function variants in an earlier version according to Nagy et al. 2024, and pLI 1 with an observed/expected ratio of 0.075 and a small number of loss-of-function variants according to Löw et al. 2026; the DECIPHER %HI is 6.88 [9, 15, 25].

Residue Tyr446 lies on the inner face of the WD40 ring, exposed to solvent; substitution by cysteine is not expected to disturb the structure, because the equivalent residue of Saccharomyces cerevisiae Sif2 is a phenylalanine of similar conformation [5]. The p.(Tyr446Cys) protein was expressed, purified and assembled correctly into the TBL1XR1:GPS2:SMRT:HDAC3 complex in HEK293F cells, which points to an altered protein–protein interaction with an unidentified partner rather than to misfolding [5]. Because the mutant protein can form heterotetramers with the normal protein and be present in most HDAC3 complexes, the authors proposed a dominant-negative mechanism, which has not been demonstrated experimentally [5]. Lemattre et al. 2018 considered a dominant-negative effect «strongly suspected» because deletions and loss-of-function variants do not give the same phenotype, and Quan et al. 2020 allowed that missense variants at Tyr446 may have novel (neomorphic) properties [3, 10]. Three of the four microduplications curated by Quan et al. included the whole gene, which suggests gain of function through increased expression, with a phenotype similar to that of loss of function [10]. Some TBL1XR1 missense variants prevent binding to MeCP2, an observation that prompted the hypothesis of a relationship with Rett syndrome, not supported clinically [9, 45]. The missense variant c.30C>G p.(Phe10Leu), identified de novo in one of 18 trios with sporadic schizophrenia in Japan, altered the interaction with N-CoR and β-catenin and increased Wnt pathway activation in vitro; its clinical relevance to psychiatric disorders remains unclear [51]. Molecular docking of a non-canonical intronic variant suggested reduced interaction with NCOR1, a finding obtained only in silico [46].

2.3 Animal models

In mice with the Tbl1xr1 Y446C variant introduced by CRISPR-Cas9 into exon 14 (C57BL/6J background), only homozygotes have a phenotype; the murine heterozygote has no detectable abnormalities, unlike the human heterozygote [50]. Homozygotes have lower weight in males between weeks 4 and 10 (6–7 animals per group), a higher percentage of lean mass and a lower percentage of fat mass (12–14 per group), lower bone mineral density in both sexes and moderately raised auditory brainstem response thresholds at 3–5 months (11 per group) without histological changes in the cochlea; locomotor activity, T4, T3, TSH and hypothalamic Trh expression did not differ from controls, and no fat pads formed [50]. In white adipose tissue, expression of Ppara, Ucp1 and Fasn increased, which the authors interpret as a tendency towards browning, and they proposed that fat pad formation requires additional local factors and that bone parameters be measured in patients, for whom no published data existed [50]. In the same model, Hu et al. 2023 described minor changes in thyroid hormone metabolism and tissue action (lower pituitary TRα1; increased pituitary Tshβ and Nmb; increased Mct8 in white adipose tissue and kidney; lower Dio2 and Tshr in brown adipose tissue) and, in HepG2 cells, reduced DIO1 induction by T3 after TBL1XR1 knockdown; the creation of a model with the identical mutation in Tbl1x failed [52]. Hu et al. 2023 refer to «six male patients» in the Heinen 2016 cohort, which had four boys and two girls; the error lies in the secondary source [5, 52].

2.4 Variant spectrum and nomenclature

The following conversions were confirmed in VariantValidator (GRCh38, MANE Select transcript) and in ClinVar; the variants in the last part of the table are given with the transcript stated in the source, without independent normalisation [8, 53–55].

In the curation by Quan et al. 2020 (literature, ClinVar and HGMD, classification of the American College of Medical Genetics and Genomics, ACMG), the 38 variants in 50 patients comprised 8 frameshift (7 de novo), 1 nonsense, 22 missense (20 de novo) and 7 copy-number variants (CNV; 3 de novo and 4 inherited) [10]. Seventeen of the 22 missense variants lay in the WD40 domain, with five clusters, three recurrent loci (Asp370, Tyr446 and Gly460) and a hotspot of 12 variants in the seventh WD40 repeat; all had a CADD score above 20 and all were absent from gnomAD, except one VUS; of the 31 point variants or small insertions/deletions, 22 were classified as pathogenic, 7 as likely pathogenic and 2 as VUS [10]. In the survey by Nagy et al. 2024, the 20 missense variants and the 3 in-frame deletions reported lay in the WD40 regions, and 48 TBL1XR1 missense variants had been published by 2025 according to Wei et al. [9, 58].

2.5 Genotype–phenotype correlations, penetrance and expressivity

At the Tyr446 locus in the 2020 curation there were 12 patients (9 p.(Tyr446Cys), 2 p.(Tyr446Asp) and 1 p.(Tyr446His), on NM_024665.7), of whom 10 had a diagnosis of Pierpont (8 p.(Tyr446Cys), 1 p.(Tyr446Asp), 1 p.(Tyr446His)) and 2 a primary diagnosis of ID (1 p.(Tyr446Cys), 1 p.(Tyr446Asp)) [10]. In the comparison between variants at Tyr446 and the remaining missense variants, hearing impairment (7/11), skeletal deformity (5/11) and hypertonia (2/11) occurred only at Tyr446, and ASD (5/9) and congenital heart disease (2/9) only in the others; ID was recorded in 9/11 versus 2/9, ocular deformity in 5/11 versus 1/9 and hypotonia in 8/11 versus 4/9 [10]. The same class of variant can give different phenotypes: the frameshift p.(Gly267AlafsTer6) was associated with ADHD and gastrointestinal and sleep disorders, absent in the patient with p.(Thr130SerfsTer14) [10]. In the 2024 survey, 18 of 41 patients had a self-reported diagnosis of Pierpont associated with diverse variants (missense, truncations and gene duplication), and only 3 had the classic variant; in-frame deletions, intronic variants and gene deletions occurred only in patients without a diagnosis of Pierpont [9]. Without in-person examination or photographs, some of these diagnoses may have been assigned on the genetic finding alone [9].

For the de novo variants of Pierpont syndrome, penetrance cannot be measured by segregation, because no transmission has been documented [5]. In MRD41 due to deletion, the mother and daughter with the same 708 kb deletion both had mild to moderate ID [14]. In the microduplication, ASD showed incomplete penetrance in a family with three carriers over two generations [6]. Modifier factors have not been identified; in the 2024 survey, 15 of 41 patients (36.6%) reported another genetic alteration in addition to TBL1XR1, including a 47,XYY karyotype, which is a confounding factor in interpreting the phenotypes [9].

2.6 Somatic alterations and non-germline diseases

TBL1XR1 has recurrent somatic variants in lymphoid neoplasms (primary central nervous system lymphoma, acute lymphoblastic leukaemia, Sézary syndrome), and has been proposed as a tumour suppressor in the lymphoid system and as an oncogene in breast cancer, with a tissue-dependent role [5, 59]. In diffuse large B-cell lymphoma (DLBCL), the variant profile is similar to that of the neurological phenotype, and the somatic variant p.(Asp370Tyr) (published designation D370Y; nucleotide change not stated in the source) alters interactions with the SMRT/HDAC3 complex; cancer and TBL1XR1 neurodevelopmental disorder have not been described as co-occurring [9]. The somatic TBL1XR1::RARA and TBL1XR1::RARB fusions define variant forms of APL, and TBL1XR1 is listed in Orphanet as a fusion gene partner in APL (ORPHA:520) [48, 49, 60]. These events are acquired and confer no oncological significance on a germline variant of the same gene, and it has not been established that germline variants increase the risk of neoplasia [18, 19].

3. Clinical Spectrum and Manifestations by System

3.1 Common syndromic description of the class

TBL1XR1-related disorders share a core neurodevelopmental disorder with onset in the first year of life: language and motor delay, ID, hypotonia and feeding difficulties, to which are added, with frequencies that differ by group, microcephaly, facial dysmorphism, hearing impairment, ASD, ADHD and epileptic seizures [9, 10, 18]. In the curation of 31 patients with clinical data (male:female ratio 1:1), the frequencies were: speech delay 29/31, motor delay 23/31, ID 19/31, facial dysmorphism 17/31, hypotonia 15/31, microcephaly 14/31, hearing impairment 12/31 and ASD 10/31 (10 of the 15 with information on ASD had ASD or autistic traits); the overlapping facial features were midface hypoplasia, bilateral epicanthus, bulbous nose, depressed nasal bridge and frontal bossing [10]. In the aggregation of 51 cases by Ren et al. 2023 (4 new and 47 published), with denominators equal to the cases with information, speech impairment was recorded in 38/39, ID in 28/28, global delay in 42/42, hypotonia in 24/27, epilepsy in 10/22, ASD in 13/25 and regression in 4/13 [20]. These series are compilations of published reports, with ascertainment through severe cases and variable denominators, and do not describe the frequency of the findings in the carrier population.

The phenotype depends on the genotypic group. Pierpont syndrome adds to the common core the characteristic facies, the abnormal distribution of fat in the distal extremities, hearing loss, short stature and scoliosis, and in the discovery cohort none of the six patients had ASD [5, 23]. MRD41 is non-syndromic to mildly syndromic, with ASD or autistic traits in a subgroup [18, 24]. The presence of autism does not, however, exclude a variant in the Pierpont region: Arroyo Carrera et al. 2021 (Spain) described a de novo missense variant with features overlapping those of Pierpont and autism, and in the 2024 survey self-reported ASD reached 39.0% in a group in which 43.9% reported a diagnosis of Pierpont [9, 61].

3.2 Classic Pierpont syndrome (p.(Tyr446Cys))

Facies and extremities. The facies includes a broad face, high forehead and high anterior hairline, narrow palpebral fissures that take on a «crescent-moon» shape on smiling because of the fullness of the cheeks, deep-set eyes, a broad nose with a broad tip and hypoplastic alae, a prominent premaxilla with a long smooth philtrum, thin upper vermilion and full lower lip, large fleshy ears, brachycephaly and small widely spaced teeth [23]. The resemblance between patients becomes more apparent on smiling (figure 5 of the collaborative study) [23]. The hands and feet are short and broad, with «padding» of the palmar tissues, deep palmar and plantar creases, persistent fetal pads and anteromedial fat pads of the heels (figures 3 and 4 of the same study) [23]. The fat pads become less prominent with time: they had disappeared by the age of 12 years in the first patient described and also in some of the patients with longer follow-up [2, 23]. In Orphanet, the craniofacial dysmorphism also includes mild midface hypoplasia, anteverted nares, flat occiput, microcephaly and brachycephaly [2].

Sources: collaborative study of 10 patients, three published previously and seven new, without molecular confirmation [23]; molecular cohort of 6 patients (4 male, 5.7–28 years) [5].

Growth and feeding. In the collaborative study, height ranged from <0.4th to 9th centile, weight from <0.4th to 50th centile and head circumference from <0.4th to 10th centile, with microcephaly in most (proportionate in 4, disproportionate in 3 and normal head circumference in 2); four patients were fed by nasogastric tube, three had a gastrostomy and three had severe vomiting [23]. The authors regarded the severe and persistent feeding difficulties, disproportionate to the other problems, as a marker of the condition; the three original patients had constipation [23]. In the molecular cohort, final or current height was below the 3rd centile in all six patients (147, 147, 128, 100, 109 and 144 cm) and birth length below the 3rd centile in two of five [5].

Neurodevelopment and nervous system. No patient in the collaborative study had normal intellectual function: 9 had moderate ID and 1 severe ID, 4 did not speak and 6 used single words, and walking was achieved between 18 months and 2 years in the new patients (at 4 years in the first patient) [23]. The authors identified no characteristic behavioural features [23]. Seizures, in particular absences (3 of 10 patients), were considered part of the syndrome; the first patient had myoclonic and generalised tonic-clonic seizures from the age of 5 years [23]. Magnetic resonance imaging (MRI) of the Oudesluijs patient showed relatively small frontal lobes, enlargement of the lateral ventricles, the third ventricle and the subarachnoid space, a relatively large cerebellum and delayed myelination; MR spectroscopy showed increased choline in the frontal white matter [23, 33]. Chiari malformation (Slavotinek 2017, with Chiari also reported in a maternal uncle), atypical choroid plexus papilloma with hydrocephalus, and cortical hypoplasia with small frontal lobes have been described [34, 37, 39].

Hearing and eyes. Hearing loss is sensorineural or conductive; it was documented by audiometry in the five assessed patients of the molecular cohort, and one patient in the collaborative study had conductive hearing loss [5, 18, 23]. Ocular findings include microcornea (3/6), strabismus (6/10), astigmatism, hypermetropia, unilateral retinal coloboma, microphthalmia and pendular nystagmus, congenital cataract and subcapsular cataract [5, 21, 23, 36, 39].

Musculoskeletal system. Scoliosis is frequent (5/6 in the molecular cohort) and may be progressive, with instrumentation at 10 years in one patient; bilateral hip dislocation, hip subluxation with repeated surgery, bilateral clubfoot, pectus excavatum, joint laxity, multiple epiphyseal dysplasia and arthrogryposis multiplex congenita have been described [5, 21, 23, 36, 39].

Genitourinary tract, heart and other systems. The original patients had inguinal hernias, hydroceles, a small penis and hypoplastic scrotum; cryptorchidism (Kahlert 2017; Slavotinek 2017, bilateral; Pereira-Nunes 2023, bilateral), hydronephrosis, mild pyelectasis, duplex kidney and bilateral renal dysplasia progressing to renal failure have been described [19, 21, 23, 36, 37]. Among eight children with the variant reviewed by Wong et al. 2026, only one had mild hydronephrosis, with preserved renal function in all, so a causal relationship between renal dysplasia and the syndrome has not been established [19]. Also described are unexplained pericardial effusion treated with corticosteroids, submucous cleft palate, dermal sinus, recurrent tonsillitis and respiratory infections, sialorrhoea, an air-swallowing breathing pattern with near-collapse on vomiting, and obstructive and central sleep apnoea [19, 23, 36, 37].

OMIM synopsis. The OMIM clinical synopsis (updated 17 November 2017) also records height below the 10th centile, weight below the 50th centile, truncal hypotonia with hypertonia in some patients, hypoplastic areolae, small penis in some, dermal sinus in one patient and attenuation of the fat pads with time [62].

Orphanet frequencies. Orphanet describes axial hypotonia after birth, prolonged feeding difficulties, moderate to severe global delay and seizures (mainly absences), and assigns frequencies to Human Phenotype Ontology (HPO) terms [2].

Orphanet includes the high anterior hairline and thin upper vermilion in the definition of the syndrome but classifies them as occasional in the HPO table, whereas the molecular cohort recorded them in 6/6; seizures appear in the definition without a corresponding HPO term in the list [2, 5].

3.3 Pierpont-like presentation

The two patients of Lemattre et al. 2018, with p.(Tyr446His) (24-year-old girl) and p.(Cys325Tyr) (14-year-old boy), had typical facies, growth restriction and severe ID; one had Chiari malformation and the other a gyration disorder with delayed myelination, and the palmar and plantar creases were less prominent than in the classic form [1, 3, 7]. The patient of Tamma et al. 2023, with p.(Ser326Asn), had short stature, developmental delay, craniofacial dysmorphism and plantar fat pads [12]. The intronic variant c.865-7A>G was described by Xie et al. 2025 as a cause of Pierpont in a child with facial dysmorphism and ASD, and by Nagy et al. 2024 in a patient without that diagnosis, which shows that assignment to this group depends on clinical assessment [9, 46].

3.4 MRD41

The OMIM clinical synopsis records psychomotor delay, ID of variable severity, language delay, non-specific facial dysmorphism in some, autistic traits in some, seizures in one patient and a variable phenotype, with de novo mutations [24]. Among deletions, the child of Tabet et al. 2014 (1.6 Mb deletion) had mild to moderate non-specific ID with normal MRI and electroencephalogram (EEG) and no autistic traits; the 8-year-old girl and her mother in Pons et al. 2015 (708 kb deletion confined to TBL1XR1) had mild to moderate ID, language delay, synophrys, mild hypotelorism, depressed nasal bridge, short nose with anteverted nares, long philtrum, pointed chin, low-set ears, dental crowding, clinodactyly and a gap between the 1st and 2nd toes, without autistic traits [4, 14, 42]. Vaqueiro et al. 2018 (University of Brasília) described a Brazilian patient with a TBL1XR1 deletion detected by CMA, ID, dysmorphism, multiple cardiac malformations and a brain malformation, the third family with a deletion at the time [63]. García-Payá et al. 2023 (Alicante) described an 18-month-old boy with Klinefelter syndrome and a 202 kb de novo deletion of the first two exons, with motor delay, gait abnormality, mild hypotonia, minor dysmorphism and growth delay, overlapping with Pierpont [64]. In the 2020 curation, the four patients with a microdeletion were all female and had speech delay in childhood, ID and ADHD, with recurrent congenital anomalies, microcephaly and hearing impairment, and had more ADHD, congenital anomalies and hearing impairment than patients with point variants [10].

Among point variants, the index patient of Quan et al. 2020 (a Chinese boy from the ACGC cohort, Autism Clinical and Genetic Resources in China), with de novo p.(Thr130SerfsTer14), was born with normal parameters, had hypotonia and eczema in infancy, at 18 months did not communicate or make eye contact, walked at 20 months, said single words at 60 months and short sentences at 66, and was diagnosed with ASD by DSM-5 criteria at 87 months, with repetitive and stereotyped behaviours, aggression, toe walking, weight at the 94.5th centile, normal MRI and EEG, and no regression, gastrointestinal or sleep problems or ADHD [10]. Variants in the F-box-like domain and the amino-terminal region are associated with West syndrome: the girl of Saitsu et al. 2014, with p.(Gly70Asp), had normal early development until infantile spasms at 5 months, an EEG with hypsarrhythmia at 7 months, absent visual fixation, stereotyped hand movements at 8 months and a developmental quotient of 13 at 5 years, with supported walking [4, 13]. The girl of Shen et al. 2022, with p.(Glu63Lys), had no social smile at 3 months, had spasms 3–4 times a day at 4 months with loss of head control, hypotonia, four small café-au-lait macules, atypical hypsarrhythmia and slightly delayed myelination, and was the third published patient with West syndrome associated with TBL1XR1 [22]. The girl of Wu et al. 2023, with p.(Gly29Asp), had episodic limb «tremors» for more than a month at 5 months, motor delay and atypical hypsarrhythmia [56]. Ren et al. 2023 described easy startle, hypovitaminosis D, short stature, hyponatraemia and ASD in four new patients [20]. Wei et al. 2025 described global delay, ID, language delay and seizures with p.(Val314Phe), and mild dysmorphism, marked delay, feeding difficulties and hypertonia with p.(Asp463Tyr) [58].

The patient of Armour et al. 2009, then described as «Fitzsimmons syndrome» (a 15-year-old boy with global delay, early spastic paraparesis, brachydactyly, bladder dysfunction and Tourette syndrome, also present in his brother), had de novo p.(Tyr245Cys); exome reanalysis concluded that the paraparesis, brachydactyly and dysmorphism might result from other genetic events [43, 44].

3.5 TBL1XR1 microduplication

Riehmer et al. 2017 (Cologne) described four patients from two families with a microduplication confined to TBL1XR1 by array-CGH and qPCR, de novo in one patient and inherited over two generations in the other three, with ID or learning difficulty, ASD with incomplete penetrance, hearing loss and delayed puberty [6]. In the 2020 curation, the five patients with a microduplication had speech delay in childhood (4/5), ID (3/5) and autism (3/5), with no malformations reported; there were no marked phenotypic differences between deletions and duplications or between CNVs and point variants [10]. In the 2024 survey, two individuals with a 3q26.32 duplication reported a diagnosis of Pierpont [9].

3.6 2024 cross-sectional cohort: manifestations by system and trajectory

The survey by Nagy et al. 2024 (Massachusetts General Hospital, USA) was distributed in two closed family groups on a social network between January 2021 and January 2023, in English only: of 132 surveys started, 41 complete ones were included, 9 (21.9%) without genetic information and included on the basis of a self-reported diagnosis; the median age was 8 years (1–25), 53.7% were male, and the genetic diagnosis was made at a median age of 5 years (3 months–16.5 years) [9]. Pregnancy complications were recorded in 16/41 (39.0%), with fetal problems in 8 (19.5%: poor growth, bilateral clubfoot, renal anomalies, reduced fetal movements, bradycardia, abnormal nuchal translucency), preterm birth in 9 (22.0%) and perinatal complications in 24 (58.5%), including admission to a neonatal intensive care unit (NICU) in 15 (36.6%) [9]. The symptoms that prompted genetic testing were failure to achieve milestones (87.8%), hypotonia (78.0%), feeding difficulties (68.3%), poor fine motor skills (63.4%), growth delay (56.1%) and sleep disturbance (48.8%); 30/41 (73.2%) had a neurological diagnosis before the genetic one, mainly ASD (31.7%), Chiari malformation (19.5%) and epilepsy (14.6%) [9].

Regression in any domain occurred in 14/41 (34%): language in 10, motor in 5 and social in 3, with onset from the first year to the end of the second decade; regression was not explained by perinatal complications (50% in those who regressed versus 58.5% in the cohort) [9]. Epileptic seizures occurred in 14/41 (34.1%), with a median age at onset of 2.5 years (0.4–23.2) and most before 10 years; the types were absences, tonic-clonic, focal, tonic and epileptic spasms; most reported partial to complete control with medication, but all but one of the patients with data had had seizures in the previous two years, and half of the patients with seizures had language regression, with no relationship between seizure type and regression [9]. Chiari malformation was reported in 9 (22.0%), spinal problems including scoliosis in 8 (19.5%), ataxia in 4 (9.8%), dyskinesia in 1, ASD in 16 (39.0%), ADHD in 12 (29.3%), impulsivity and repetitive behaviours in 20 (48.8%) each, climbing or standing on objects in 18 (43.9%), sensory hypersensitivity in 15 (36.6%) and self-injury in 15 (36.6%) [9]. Feeding difficulties affected 36 (87.8%), with a median onset at 1 month; 16 (39.0%) required thickened feeds, 17 a nasogastric tube and 10 remained on partial or total tube feeding; there was gastro-oesophageal reflux disease (GORD) in 18 (43.9%), constipation in 4 (9.8%), dysmotility or gastroparesis in 3 (7.3%), growth problems in 26 (63.4%) and weight loss in 10 (24.4%) [9]. The authors describe renal and cardiac anomalies and anal malformation as systemic involvement [9].

The limitations of this cohort are the cross-sectional design, information provided by caregivers without in-person examination, the small sample, selection bias from the family groups, the young ages (which underestimate late events) and the few ages at achievement reported [9].

3.7 Adulthood, natural history and treated disease

Data in adults are limited to isolated cases: in the 2016 molecular cohort, the patients aged 19, 20 and 28 years had height below the 3rd centile and ID, and the 19-year-old woman never developed speech or sphincter control, with an estimated IQ below 35 at 18 years, a relatively large head, low weight, little subcutaneous tissue, pectus excavatum and thoracic scoliosis [5]. Löw et al. 2026 described a 61-year-old Caucasian man, followed in a German movement disorders clinic, with p.(Ser400ThrfsTer4), diagnosed for 40 years as having cerebral palsy: delayed milestones from infancy, special education and sheltered workshop, cervical dystonia at 18 years that generalised over several years (spasmodic dysphonia, oromandibular, axial and appendicular dystonia), mild ataxia, broad-based gait, saccadic ocular pursuit, normal head circumference, absence of fat pads and of Pierpont dysmorphism, an MMSE (Mini-Mental State Examination) score of 16/30 and mild axonal sensorimotor polyneuropathy [25]. Chorea, stereotypies and ataxia had been described occasionally in children, but not generalised dystonia in adulthood, and the authors conclude that these syndromes may not be static childhood conditions [25].

The series described mix natural history and the effects of care provided: gastrostomy, spinal instrumentation, clubfoot correction, orchidopexy and antiseizure treatment modified the course of several patients, and no source consulted compares treated and untreated groups [5, 9, 21]. The sources consulted describe no data on life expectancy or mortality.

4. Clinical Recognition and Red Flags

4.1 When to suspect, by age

Prenatal period. The findings described are non-specific: intrauterine growth restriction, microcephaly, bilateral clubfoot, oligohydramnios, renal anomalies, reduced fetal movements and abnormal nuchal translucency [9, 19, 21]. In the Portuguese case, the second-trimester ultrasound showed growth restriction, microcephaly below the 3rd centile and bilateral talipes equinovarus, and the prenatal karyotype and array-CGH were normal [21].

Newborn and infant. The combination of axial hypotonia, weak suck and prolonged feeding difficulties with deep palmar and plantar creases, fat pads near the heels and fetal finger pads should raise consideration of Pierpont syndrome; the face and creases may be evident at birth [2, 5, 21]. The facies becomes more pronounced during the first year, as in the Portuguese case at 12 months [21]. In infants with global delay, infantile spasms and hypsarrhythmia without a structural cause, TBL1XR1 is among the genes to consider [13, 22, 56].

Childhood. Disproportionate language delay, ID, ASD, ADHD, absence seizures, Chiari malformation, scoliosis and hearing loss are the manifestations that most often prompt assessment; in the 2024 survey, 73.2% of patients had a neurological diagnosis before the genetic diagnosis [9, 10]. The «crescent-moon» facies on smiling is a recognition sign of Pierpont syndrome [23].

Adulthood. An adult with a neurodevelopmental disorder and generalised dystonia of adolescent onset, labelled as cerebral palsy, may have a TBL1XR1 loss-of-function variant [25].

4.2 Red flags and emergency signs

The signs that require urgent assessment are infantile spasms in a child under 2 years, which under NICE NG217 should lead, within the following 24 hours, to seeking advice and referral to tertiary paediatric neurology, with a sleep EEG and prompt treatment [29]. Other red flags are language, motor or social regression, described in about one third of the patients in the 2024 survey and which prompts a search for seizures; loss of head control with spasms; signs compatible with Chiari malformation or hydrocephalus (including choroid plexus papilloma); poor weight gain with dysphagia; sleep apnoea; and deterioration of renal function [9, 19, 22, 34]. The near-collapses on vomiting and the intractable vomiting described in patients of the collaborative study require gastrointestinal assessment [23].

4.3 Signs that do not justify suspicion on their own

Persistent fetal finger pads are non-specific (they occur in Kabuki syndrome and in individuals without disease), and anteromedial fat pads of the heels have been described in neurofibromatosis type 1, in the 8q24 microdeletion with a Langer–Giedion phenotype and in individuals without disease; on their own, they do not justify suspicion of Pierpont [23]. The collaborative study excluded four girls with suggestive hands and feet but without the characteristic facies, who had divergent presentations [23].

4.4 Newborn screening

There is no newborn screening for these disorders, because there is no measurable biochemical marker and the diagnosis is molecular [18].

5. Diagnosis: Criteria, Testing and Algorithms

5.1 Clinical criteria

There are no published consensus diagnostic criteria for Pierpont syndrome or for MRD41, and the boundary between Pierpont and the other forms has not been validated by formal clinical criteria [3, 9, 12]. In the discovery cohort, the clinical diagnosis required the combination of the facial features, the palmar and plantar fat pads and global developmental delay, and the collaborative study required the facies in addition to the hand and foot findings [5, 23]. The diagnosis rests on the identification of a heterozygous pathogenic or likely pathogenic TBL1XR1 variant, or of a CNV including the gene, in a patient with a compatible phenotype [10, 15].

5.2 Genetic tests and order of requesting

The 2014 AAP recommended CMA and fragile X testing as first line in ID of unknown aetiology, consideration of inborn errors of metabolism and MRI in selected patients, and treated the exome as an emerging technology; the 2021 ACMG guideline went on to recommend the exome or genome as a first- or second-tier test, with a higher diagnostic yield than standard tests and possible cost-effectiveness when requested early [26, 65]. The divergence is temporal and results from the evidence accumulated between the two publications. In practice, clinical suspicion of Pierpont directs the request towards exome, genome or a panel, because karyotype, array-CGH and SNP array were normal in all patients with Pierpont studied, except for a 3.17 Mb maternal deletion at 10q21.3 in the monozygotic twins with no established causal relationship [1, 23]. In a patient with non-syndromic ID or ASD, CMA detects MRD41 due to deletion, but a normal result does not exclude a TBL1XR1 point variant [10, 27].

5.3 Practical algorithm

5.4 Test limitations and interpretation

A negative result does not exclude the diagnosis: CMA does not detect point variants or balanced rearrangements, and low-level mosaicism generally escapes the array [27]; non-canonical intronic variants require functional demonstration, such as the minigene assay that showed the 6 bp insertion produced by c.865-7A>G [46]; and the CNVs in the 2020 curation were detected by CMA without exome, which prevents comparison of the performance of the two methods in those patients [10]. Inconsistent inclusion of TBL1XR1 in the panels of different laboratories may also bias the apparent natural history, and exome and genome require phenotyping and reanalysis over time [9]. The proportion of patients with variants detectable by each method does not correspond to the clinical sensitivity of a test, and the sources consulted do not estimate the clinical sensitivity of any method for these disorders.

Interpretation requires attention to three points of nomenclature. The Pierpont variant is NM_024665.7:c.1337A>G, and the c.1337A>C form in the discovery article is an error corrected in an erratum [11]. Reports using non-MANE transcripts describe the same variant with another reference (for example, NM_001321194.1:c.1337A>G in the Portuguese case), so comparison should be made by genomic position [8, 21]. Reports using the .4, .5 or .6 transcripts should be reviewed with the MANE transcript before comparison with other databases [8]. Conditions submitted to ClinVar may also differ from those of OMIM, such as p.(Tyr446His) recorded as MRD41 by one submitter [54]. A somatic TBL1XR1 variant identified in a tumour or in a leukaemic fusion does not imply a germline disorder [18].

The report should state the gene, the transcript and its version (NM_024665.7), the HGVS c. and p. nomenclature, the genomic coordinate with the genome build, the zygosity (heterozygous), the origin when known (de novo or inherited) and the ACMG/AMP class. VUS, which included 2 of the 31 point variants in the 2020 curation and all the microduplications in that curation, benefit from parental testing and from comparison of the phenotype with the expected genotypic group [10]. Reassessment of variants at position Tyr446 and on the inner face of the WD40 ring should take the Pierpont phenotype into account, and that of truncating variants the haploinsufficiency mechanism [3, 15].

5.5 Other investigations

There is no biochemical biomarker [18]. Metabolic investigations (carnitine, 7-dehydrocholesterol, transferrin isoelectric focusing, urinary mucopolysaccharides) were normal in the patients of the collaborative study in whom they were performed; in the monozygotic twins, a muscle biopsy showed suboptimal oxidation and urinary ethylmalonic acid and fumarate/succinate were raised, of uncertain significance [23]. Brain MRI may show central atrophy, enlarged ventricles, small frontal lobes, delayed myelination, Chiari malformation, abnormal gyration and choroid plexus papilloma [3, 5, 23]. Thyroid function was normal in the patients in whom it was reported, and no hypothyroidism has been described in Pierpont syndrome [23, 52].

5.6 Prenatal and preimplantation diagnosis

In the Portuguese case, amniocentesis at 20 weeks with a 46,XY karyotype and normal prenatal array-CGH did not identify the cause, which was found only by clinical exome after birth [21]. The sources consulted do not describe targeted prenatal diagnosis or preimplantation genetic testing in families with TBL1XR1 variants; the general principles are given in section 8.

6. Differential Diagnosis

6.1 Comparative table

The frequencies for the syndromes with ASD reproduce the classes of the comparative table of Nagy et al. 2024 (+ <25%; ++ 25–49%; +++ 50–74%; ++++ ≥75%), in which TBL1XR1 showed ASD, regression, seizures and self-injury in the 25–49% class and gastrointestinal and sleep symptoms in the 50–74% class [9].

6.2 Differential within the class

Pierpont syndrome and MRD41 are separated by the facies and the distal fat and crease findings, present in Pierpont, and by autism, frequent in a subgroup of MRD41 and absent in the six patients of the discovery cohort [5, 18]. This rule has exceptions: a patient with a de novo missense variant, features overlapping those of Pierpont and autism was described in Spain, and in the 2024 survey self-attribution of a diagnosis of Pierpont covered truncating variants and duplications [9, 61]. In the comparison by Quan et al. 2020, hearing impairment, skeletal deformity and hypertonia occurred only with variants at Tyr446, and ASD and congenital heart disease only with the remaining missense variants [10]. The distinction is therefore both genotypic and clinical: the position of the variant guides expectation, and dysmorphological examination confirms the group.

6.3 The TBL1X paralogue and the thyroid question

TBL1X is the X-linked paralogue of TBL1XR1, and a variant at the identical position of the TBL1X WD40 domain gives a different phenotype, isolated central congenital hypothyroidism [50, 67]. In the index series of Heinen et al. 2016 (six Dutch families), three probands were identified by Dutch newborn screening and three in adolescence (short stature, macrocephaly, weight gain, fatigue, difficulty concentrating, secondary amenorrhoea); of the 19 carriers, 9 had central hypothyroidism, including 3 women, and 10 unaffected carriers had free T4 in the lower half of the range; 12 carriers had mild to profound hearing loss, with worse thresholds at high frequencies, and the other pituitary axes and hypothalamic-pituitary MRI were normal [67, 69]. A 10-year-old Spanish boy with a de novo TBL1X nonsense variant p.(Arg339Ter) (published designation R339X; transcript not stated in the source) had refractory constipation and encopresis, low free T4 with normal TSH, a mildly hypoplastic thyroid, Chiari type 1 malformation, ADHD and high-frequency hearing loss [67]. In a Dutch newborn screening cohort, 16% of genetically tested children with isolated congenital central hypothyroidism had a TBL1X variant, after IGSF1 (53%), and treatment is standard levothyroxine replacement according to the 2021 ENDO-ERN/ESPE/ESE consensus [68]. No hypothyroidism has been described in Pierpont syndrome, and the Tbl1xr1 Y446C mouse model has no serum thyroid hormone abnormalities, only minor changes in metabolism and tissue action [50, 52].

6.4 Somatic findings: acute promyelocytic leukaemia and lymphomas

Somatic TBL1XR1 fusions are a problem of report interpretation and not a clinical differential diagnosis of the neurodevelopmental disorders. Osumi et al. 2018 (Tokyo) studied by genome sequencing, PCR and FISH five APLs without RARA translocation: four had RARB translocations and three had the in-frame TBL1XR1::RARB fusion, whose protein homodimerises, reduces in a dominant-negative manner the transcriptional activity of the retinoic acid pathway, increases the replating capacity of murine marrow and inhibits myeloid maturation, with an attenuated response to retinoids, consistent with the clinical resistance of these APLs to all-trans retinoic acid (ATRA) [48]. Osumi et al. 2019 described a 3-year-old girl with morphological APL and negative conventional RARA tests, in whom genome sequencing revealed a cryptic insertion of RARA into TBL1XR1; she did not respond to ATRA, achieved complete remission with chemotherapy, had an extramedullary relapse at 2 years and received a cord blood transplant in second remission; the authors recommend next-generation sequencing (NGS) in variant APLs, which account for less than 5% of APLs [49]. Halloran et al. 2025 (Chicago) described a 54-year-old woman with TBL1XR1::RARA, without Auer rods, with granulocytic dysplasia, monocytosis, CD117-negative blasts, negative PML::RARA and a positive RARA break-apart probe, with no response to ATRA and death 24 days after presentation [70]. In the review by Du et al. 2025 of TBL1XR1::RARB APLs, with a paediatric case with KRAS p.G12D, the paediatric age group predominated (median 2.7 years), response to ATRA or arsenic trioxide occurred in 55% and relapse in 44%; Jiang et al. 2022 described a child with early onset, without haemorrhage or coagulopathy, resistant to ATRA and arsenic trioxide [71, 72]. TBL1XR1 also appears in lymphomas (DLBCL and central nervous system lymphoma) and as a rare RET fusion partner, a context in which trials of RET inhibitors include it [9, 28, 59].

7. Treatment and Risk Management Strategies

7.1 Principles

There is no specific treatment, authorised medicine, management guideline or clinical trial for the germline TBL1XR1-related disorders, and ClinGen has no actionability curation for the gene [15, 18, 28]. Treatment is symptomatic and multidisciplinary and relies on general guidelines (assessment of ID, ASD, hearing loss and infantile spasms) and on the suggestions of the authors of the published series and cases, which are opinion and not formal recommendation [9, 29, 65, 73, 74]. The 2014 AAP recommends co-management between the family, the primary care physician and genetics, and the 2020 AAP recommends behavioural interventions in ASD, with growing evidence, and shared decision-making with families [65, 73].

7.2 Neurodevelopment, behaviour and rehabilitation

Nagy et al. 2024 recommend careful screening for ASD and ADHD in all patients and attention to sleep disorders, Chiari malformation and spinal problems, which they consider amenable to intervention [9]. The 2020 AAP recommends standardised ASD screening at 18 and 24 months with continuous developmental surveillance, aetiological assessment and attention to comorbidities (sleep, feeding, gastrointestinal symptoms, obesity, seizures, ADHD, anxiety and elopement) [73]. Physiotherapy, occupational therapy and speech therapy were used in the adult with dystonia, and physiotherapy, the developmental clinic and paediatric palliative care formed part of the follow-up of the Portuguese newborn [21, 25]. Self-injurious behaviour (36.6% in the 2024 survey) and sensory hypersensitivity require a behavioural approach [9, 73].

7.3 Feeding, growth and the digestive system

Feeding difficulties are frequent and severe: in the collaborative study, four patients needed a nasogastric tube and three a gastrostomy; in the molecular cohort, one patient had a gastrostomy in infancy; and in the 2024 survey, 16 patients needed thickened feeds, 17 a nasogastric tube and 10 remained on partial or total tube feeding [5, 9, 23]. The authors of the survey recommend close monitoring of feeding and growth, with referral for specialised nutritional and feeding support [9]. GORD (43.9%), constipation, dysmotility and intractable vomiting suggestive of primary gastrointestinal dysmotility (which led to gastrostomy in the twins of the collaborative study) require gastroenterological assessment [9, 23]. Persistent sialorrhoea was treated in one patient with transdermal scopolamine (hyoscine) patches, in a single-case experience [23].

7.4 Epilepsy and West syndrome

Seizures in TBL1XR1-related disorders are treated according to seizure type and epilepsy syndrome, and the sources consulted describe no preferred antiseizure medicine for the gene. In West syndrome, the current guideline consulted is NICE NG217 (published 27 April 2022 and updated 5 August 2026), section 6.3 [29].

The 2012 update of the American Academy of Neurology and the Child Neurology Society (AAN/CNS), now marked as retired, concluded that low-dose adrenocorticotrophic hormone (ACTH) was probably as effective as high-dose ACTH, that ACTH was more effective than vigabatrin in the short term (excluding tuberous sclerosis), that the evidence was insufficient for other corticosteroids and combination therapies, and that a shorter time to treatment would improve long-term development [75]. The divergence from NICE NG217, which prefers the combination of prednisolone with vigabatrin, reflects later evidence, and NICE is the current guideline used in this article [29, 75].

7.4.1 Dosing in infantile spasms and seizures

There are no specific doses for TBL1XR1-related disorders. The doses in the following table are those of the official labels for infantile spasms or for seizures of other aetiologies and those of the UKISS and ICISS randomised trials in infantile spasms, and they apply to TBL1XR1 patients by extrapolation; uses outside the approved indication are flagged. Vigabatrin is indicated for infantile spasms in the United States (Sabril® and Vigadrone®, 1 month to 2 years), in the European Union through the centralised authorisation of Kigabeq® (1 month to less than 7 years) and through national authorisations of Sabril®, as in Portugal and the United Kingdom [76–80]. Repository corticotropin (Acthar Gel®) is FDA-approved as monotherapy for infantile spasms under 2 years [81]. Prednisolone and depot tetracosactide do not have this indication in the labels consulted, and the doses come from the UKISS (107 infants) and ICISS (377 infants) trials, in which they were minimum doses, with increases allowed by the investigators between days 7 and 14 in non-responders [82–84]. The vigabatrin dose used in the girl of Shen et al. 2022 (100 mg/kg/day) matches the minimum dose of the two trials [22, 82, 83].

Ages and doses differ between jurisdictions: the FDA authorises vigabatrin for spasms up to 2 years and Kigabeq® up to before 7 years, titration is every 3 days in the FDA and Kigabeq® labels and over 1 week in the Portuguese Sabril® SmPC, and the frequency of visual assessment is at least every 3 months at the FDA, every 3–6 months in the Portuguese and UK Sabril® SmPCs and at least every 6 months in the Kigabeq® SmPC [76, 78–80]. The Portuguese SmPC flags dystonia, dyskinesia and hypertonia in infants treated for infantile spasms, which is relevant to TBL1XR1 forms with a movement disorder, because motor worsening on vigabatrin should prompt consideration of dose reduction [25, 79]. In TBL1XR1 patients with prior ophthalmological abnormalities (microcornea, strabismus, coloboma, nystagmus, cataract), baseline visual assessment before vigabatrin has added reference value, because the Kigabeq® SmPC advises against vigabatrin in clinically significant pre-existing visual field defects [5, 21, 23, 36, 78].

Published experience with TBL1XR1 is limited to single cases. In the girl of Shen et al. 2022, ACTH for 28 days with high-dose pyridoxine did not reduce the spasms and topiramate alone was ineffective; the combination of vigabatrin (100 mg/kg/day) with topiramate (8 mg/kg/day) led to seizure freedom after one month, maintained for more than 20 months up to 28 months of age, with a much improved EEG, but with limited development (sitting without support, no words, Gesell quotient 30) [22]. In the girl of Wu et al. 2023, topiramate for 6 months did not control the episodes and the addition of vigabatrin brought no significant improvement, with episodes up to 15 months [56]. In the patient of Cao et al. 2026, with p.(Asp463GlyfsTer6), valproate up to 20 mg/kg/day controlled the seizures, which disappeared at 5 and 6 months of age, with persisting hyperactivity, attention deficit and global delay [57]. These doses are those of the reports and do not constitute a recommendation.

7.5 Dystonia and movement disorders

In the adult of Löw et al. 2026, trihexyphenidyl 4 mg/day slightly improved the axial dystonia, and increasing the dose caused confusion and worsening dysarthria, leading to discontinuation; botulinum toxin was used for the cervical and vocal symptoms, and deep brain stimulation was discussed as an option [25]. This is single-case experience of symptomatic use.

7.6 Hearing, vision and the musculoskeletal system

The clinical and aetiological assessment of hearing loss and linguistically and culturally sensitive counselling follow the 2022 ACMG clinical practice resource, which is not specific to TBL1XR1 [74]. Hearing loss in Pierpont may be sensorineural or conductive, which determines audiological management [18, 23]. The orthopaedic interventions described include instrumentation of progressive thoracolumbar scoliosis at 10 years, repeated surgery for hip subluxation, correction of talipes equinovarus by the Ponseti method and physiotherapy for the contractures of arthrogryposis, which improved without limitation of movement in the Portuguese case [5, 21, 23]. Arthrogryposis multiplex congenita enters the differential.

7.7 Genitourinary tract, kidney and kidney replacement therapy

Bilateral orchidopexy, inguinal hernia repairs and hydrocele surgery have been described [21, 23]. In the child of Wong et al. 2026 with bilateral renal dysplasia, renal failure at 4 years required peritoneal dialysis; the bilateral indirect inguinal hernias recurred despite herniorrhaphy and there was dialysate leakage with a fill volume of 550 mL (800 mL/m²); haemodiafiltration was difficult because of the small vascular calibre and the need for sedation associated with severe ID; peritoneal dialysis was resumed with 10 cycles over 12 hours and a fill volume of 500 mL (700 mL/m²), with a Kt/V of 1.89, normotension and euvolaemia, and the child was on the waiting list for kidney transplantation [19]. The authors attribute the recurrent hernias and the dialysate leakage to hypotonia and connective tissue laxity, and point to wound healing, fragility of anastomoses, uncertain prognosis and a theoretical oncogenic potential under chronic immunosuppression, which has not been established for germline variants, as concerns for transplantation [19]. The recommendations for renal surveillance, individualised dialysis regimens, multidisciplinary perioperative planning and open discussion with families before transplantation are the opinion of the authors of a single case [19].

7.8 Other interventions

An unexplained pericardial effusion was treated with corticosteroids in the Oudesluijs patient [23]. The obstructive and central sleep apnoea of the child of Wong et al. was treated with tonsillectomy and nocturnal non-invasive ventilation [19]. The atypical choroid plexus papilloma with hydrocephalus was reported by a paediatric neurosurgery team, and the abstract consulted does not detail the intervention [34].

7.9 Comparative regulatory status

7.10 Clinical trials and available therapeutic evidence

There are no controlled trials, and confidence intervals do not apply to single-case reports. The reports cannot be compared with one another, because they differ in variant, age, epilepsy syndrome and prior treatments, and a favourable result in one case does not estimate the probability of response in another patient. Reports with a negative result (ACTH, pyridoxine and topiramate in the Shen case; topiramate and vigabatrin in the Wu case) should be read with the same weight as the positive ones [22, 56]. The oncology trials with RET inhibitors concern somatic fusions and have no application to the neurodevelopmental disorders [28].

7.11 Developments from April 2025 to October 2026 and research

In the window from April 2025 to October 2026, no medicine, trial, regulatory application, opinion of the Committee for Medicinal Products for Human Use (CHMP) or authorisation was identified for the germline TBL1XR1 disorders [28]. The published developments are human case reports, with a low level of evidence: renal failure due to bilateral renal dysplasia in a child with p.(Tyr446Cys), published on 27 June 2026 [19]; generalised dystonia in a 61-year-old adult with p.(Ser400ThrfsTer4) [25]; and a frameshift p.(Asp463GlyfsTer6) with seizures controlled with valproate, published in June 2026 [57]. In 2025, the intronic variant c.865-7A>G with an effect demonstrated by minigene assay and the missense variants p.(Val314Phe) and p.(Asp463Tyr) were published [46, 58]. In the somatic context, a case of TBL1XR1::RARA APL without response to ATRA and a review of TBL1XR1::RARB APLs were published [70, 71]. In the curations, PanelApp Australia re-rated the gene as Strong on 31 March 2026, ClinVar re-evaluated VCV000225874 on 11 December 2025, and NICE NG217 was updated on 5 August 2026 [16, 29, 53]. At the preclinical level, the Tbl1xr1 Y446C mouse model (2022–2023) is the only published model of Pierpont syndrome [50, 52]. The Fly Little Bird Foundation states its mission as collaborating with the scientific and medical communities to identify and develop treatments [31]. A negative search does not prove the absence of ongoing studies.

7.12 Agents to avoid, pregnancy, perioperative care and transition

The sources consulted identify no medicines contraindicated specifically because of TBL1XR1; in the only adult with dystonia, increasing the trihexyphenidyl dose caused confusion and worsening dysarthria [25]. In infantile spasms, corticosteroids require the NICE precautions (varicella-zoster serology, steroid card, weekly monitoring of blood pressure and glycosuria) [29]. There are no published data on pregnancy in women with TBL1XR1-related disorders; the mother with the 708 kb deletion in Pons et al. 2015 had an affected daughter, but the abstract consulted does not describe the pregnancy [14]. Pregnancies with affected fetuses had complications in 39.0% in the 2024 survey [9]. In the perioperative setting, hypotonia and connective tissue laxity were associated with recurrent hernias and dialysate leakage, and severe ID required sedation for haemodiafiltration procedures [19]. Transition to adult care is constrained by the scarcity of data: the syndromes may not be static and one patient developed progressive generalised dystonia over more than four decades [25].

7.13 Guideline recommendations and divergences

8. Reproductive Options and Family Counselling

8.1 Inheritance and risks by scenario

All disorders in the class have autosomal dominant inheritance [1, 4]. In Pierpont syndrome, all molecularly confirmed cases with tested parents had a de novo variant: the six patients of Heinen et al. 2016 and the patients of Ismaili-Jaha 2021, Tesarova 2022, Pereira-Nunes 2023 and Wong 2026 [1, 5, 19, 21, 39]. In the pre-molecular period, the collaborative study found no affected non-twin sibling pairs or children of consanguineous parents, and paternal age was advanced in several cases (median 37 years; mean 42; range 27 to 58, with data in 6) [23]. In MRD41, vertical transmission has been documented: the mother with a 708 kb de novo deletion transmitted it to her daughter, both affected [4, 14]. In the microduplication, three carriers belonged to two generations of one family, with ASD of incomplete penetrance [6].

8.2 Cascade testing and carriers

Parental testing by targeted Sanger sequencing establishes de novo occurrence and was the basis of confirmation in all series [5, 39]. In MRD41 due to deletion and in the microduplication, parental testing by CMA or qPCR identifies carriers with milder expression, such as the mother with mild to moderate ID [6, 14]. In the family of Pons et al. 2015, the mother of the girl studied had the same deletion and also mild to moderate ID [14].

8.3 Prenatal and preimplantation diagnosis

The sources consulted do not describe targeted prenatal diagnosis or preimplantation genetic testing in families with TBL1XR1 variants. The ultrasound findings described (growth restriction, microcephaly, clubfoot, oligohydramnios, renal anomalies) are non-specific, and prenatal karyotype and array-CGH do not detect the Pierpont variant [9, 19, 21]. When the familial variant is known, reproductive options are discussed in the genetics clinic.

8.4 Content of counselling

Counselling includes explanation of the genotypic group (Pierpont, Pierpont-like presentation, MRD41 or microduplication) and of the uncertainty of the genotype–phenotype correlation, the absence of specific treatment, the frequency of the comorbidities that require surveillance, the possibility of regression in one third of the patients in the 2024 survey and the scarcity of data in adulthood [9, 10, 25]. A germline TBL1XR1 variant does not have the oncological significance of somatic alterations of the same gene, and no increased tumour risk has been established [18, 19]. Families can be directed to ERN-ITHACA and to patient organisations [30, 31].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Prevalence and what each number measures

There is no validated population estimate of prevalence or incidence for any of the forms. Orphanet places Pierpont syndrome in the prevalence class <1/1,000,000 and records 7 cases or families, a count of cases published at the date of the source used (Kahlert 2017) and not a prevalence [2]. Wong et al. 2026 refer to fewer than 20 published cases of Pierpont worldwide [19]. The compilations of 50 patients (Quan 2020) and of 51 cases (Ren 2023), and the survey of 41 patients (Nagy 2024), bring together all forms and measure only the number of patients described or recruited [9, 10, 20]. In the Simons Simplex Collection, a de novo loss-of-function variant was identified among 2446 probands with ASD, and SFARI Gene records 15 reports of autism out of 37 [17, 41]. These proportions do not estimate the frequency of MRD41 in the population with ASD.

9.2 Geography and ancestry

Published cases come from the United States (Pierpont 1998 in Minnesota; Vadivelu 2013 in New York; Slavotinek 2017 in San Francisco; Tamma 2023 in Houston; the Hispanic patient of O'Keefe 2016; the English-language international survey from Massachusetts General Hospital), Europe (the Netherlands, United Kingdom, France, Germany, Spain, Czechia and Kosovo) and Asia (China, Japan and Hong Kong) [3, 5, 9, 10, 12, 13, 19, 23, 32, 34–39, 61]. In Portugal, Pereira-Nunes et al. 2023 (Centro Hospitalar Universitário de São João and University of Porto) described a newborn with de novo p.(Tyr446Cys) and arthrogryposis multiplex congenita [21]. In Brazil, Vaqueiro et al. 2018 (University of Brasília) described a patient with a TBL1XR1 deletion and cardiac and cerebral malformations [63]. No founder variants or populations with increased frequency have been described, which is consistent with the predominance of de novo variants. The facies has been recognised in patients of European, Hispanic, Albanian and Chinese ancestry, and the first non-white patient was only published in 2016 [19, 35, 39]. The absence of data in the sources consulted does not demonstrate the absence of cases in other populations.

9.3 Special populations

The sex distribution is balanced in the molecular series (4 boys and 2 girls in the discovery cohort; ratio 1:1 in the 2020 curation; 53.7% male in the 2024 survey), and the male predominance of the first three cases was not sustained [5, 9, 10, 23]. The four patients with a microdeletion in the 2020 curation were all female [10]. In adults, data are limited to isolated cases, and the oldest adult described was 61 years old [25]. In the child with renal failure, severe ID determined the choice of kidney replacement technique [19].

9.4 Reference networks and patient organisations

ERN-ITHACA (European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders; https://ern-ithaca.eu) includes working groups on neurodevelopmental disorders and on fetal medicine and pathology, maintains the list of specialised centres and the ILIAD registry; the home page consulted does not mention Pierpont or TBL1XR1 [30]. For epilepsy, the relevant network is ERN EpiCARE [30]. The Fly Little Bird Foundation (Excelsior, Minnesota) is dedicated to TBL1XR1 variants and covers ID, ASD, epilepsy and brain, heart and kidney defects [31]. The closed, English-language family groups «TBL1XR1 Gene Mutation Forum» and «Pierpont Syndrome» formed the basis of the 2024 survey [9].

10. Illustrative Clinical Case

10.1 Portuguese newborn with Pierpont syndrome and arthrogryposis multiplex congenita

Pereira-Nunes and colleagues, of the Centro Hospitalar Universitário de São João and the University of Porto, described in 2023 a male newborn, the first child of healthy non-consanguineous parents, with no relevant family history [21]. The second-trimester ultrasound showed intrauterine growth restriction, microcephaly below the 3rd centile and bilateral talipes equinovarus; amniocentesis at 20 weeks revealed a 46,XY karyotype and normal prenatal array-CGH [21]. Delivery occurred at 41 weeks and 1 day, by vacuum extraction, with Apgar scores of 7/9/10, weight 3145 g (3rd–10th centile), length 51 cm (10th–50th centile) and head circumference 31.5 cm (below the 3rd centile) on the Fenton charts [21]. He was admitted to the NICU in the first hour of life for feeding difficulties and hypoglycaemia, with axial hypotonia, hypoactivity and weak suck [21].

Examination showed a broad nasal bridge and tip with anteverted nares, thin upper vermilion, a right preauricular sinus with lobule indentation, flat occiput, bifid uvula, widely spaced nipples and bilateral cryptorchidism [21]. The dominant finding was bilateral flexion deformities of the wrists, elbows and knees and clubfoot, compatible with arthrogryposis multiplex congenita (AMC), with apparently large hands and feet, deep palmar and plantar creases and calcaneoplantar fat pads (Figure 1 of the article: facies, bilateral talipes equinovarus, flexion of the wrists and elbows with large hands and deep creases, preauricular sinus; https://pmc.ncbi.nlm.nih.gov/articles/PMC9880567/figure/fig1-23247096221150637/) [21]. Whole-body radiography showed only the clubfoot; renal ultrasound showed a right duplex kidney; ophthalmological examination, otoacoustic emissions, creatine kinase, electromyography and brain MRI were normal; spinal MRI showed incipient left-convex scoliosis with inversion of the configuration of the T8 and L2 vertebral bodies [21]. An 87-gene AMC panel was negative, and the clinical exome identified de novo NM_001321194.1:c.1337A>G p.(Tyr446Cys), which corresponds to NM_024665.7:c.1337A>G p.(Tyr446Cys) on the MANE transcript (genomic position NC_000003.12:g.177033050T>C) [8, 21].

The child spent 35 days in the NICU, fed by gastric tube, and was followed by a multidisciplinary team with physiotherapy, a developmental clinic and paediatric palliative care [21]. At 12 months he had global delay with marked hypotonia, could not sit without support, accepted only soft foods orally, babbled and had normal hearing; at 11 months a small subcapsular cataract was detected in the right eye; he underwent bilateral orchidopexy; the talipes equinovarus was corrected by the Ponseti method, and the remaining contractures improved with physiotherapy, without limitation of movement [21]. The facies was more pronounced at 12 months (broad face, midface hypoplasia, high forehead, high anterior hairline, deep-set eyes with narrow fissures, broad nasal bridge and tip, long smooth philtrum, thin upper vermilion), with abnormal fat distribution in the hands and feet, fetal pads and deep palmar and plantar creases (Figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9880567/figure/fig2-23247096221150637/) [21]. It was the first report of AMC and of subcapsular cataract in the syndrome [21].

The case illustrates three points of general application: the prenatal findings are non-specific and a normal prenatal array-CGH does not exclude the syndrome; a panel targeted at AMC may not include TBL1XR1, and the exome resolved the diagnosis; and the facies becomes more marked over the first year, whereas the creases and distal fat are already present at birth [21]. The management described (Ponseti method, orchidopexy, physiotherapy) is that of the case and not a syndrome-specific protocol. Normal hearing at 12 months does not exclude later hearing loss, which was documented in all patients assessed by audiometry in the 2016 cohort [5].

10.2 Complementary case: renal failure in a child with p.(Tyr446Cys)

Wong et al. 2026 (Hong Kong) described an 8-year-old girl, the only child of non-consanguineous parents, with oligohydramnios and growth restriction in the second trimester, caesarean section at 35 weeks (2.13 kg, 10th centile; length 41 cm, below the 3rd centile), central hypotonia and non-specific dysmorphism at birth (prominent forehead, macrotia, upslanting deep-set eyes, anteverted nares, thick fingers) [19]. On day 5, serum creatinine reached 370 µmol/L (reference 44–80) and urea 27 mmol/L (reference 1.4–6.8); ultrasound showed small bilateral kidneys of 2 cm without corticomedullary differentiation, and at 1 year the estimated clearance was 14 mL/min/1.73 m² [19]. She had global delay from 4 months, moderate to severe sensorineural hearing loss, a gastrostomy for oropharyngeal dysphagia, a developmental age equivalent to 1 year at 5 years, and obstructive and central sleep apnoea [19]. The exome identified de novo p.(Tyr446Cys), with no other variants associated with congenital anomalies of the kidney and urinary tract; renal failure at 4 years led to peritoneal dialysis, with the complications described in section 7.7, and the child was on the waiting list for kidney transplantation (Figure 1 of the article: short palpebral fissures, deep-set eyes, broad nasal bridge, thin vermilion, prominent ears, short broad hands and feet; https://pmc.ncbi.nlm.nih.gov/articles/PMC13576176/figure/Fig1/) [19]. The authors do not establish causality between the syndrome and the renal dysplasia [19].

11. Prognosis and Long-Term Follow-up

11.1 Prognosis

In the Pierpont forms, no patient described had normal intellectual function: ID was moderate or severe in the 10 patients of the collaborative study and in 6/6 in the molecular cohort, four of the ten did not speak, and final or current height was below the 3rd centile in all six patients of the molecular cohort [5, 23]. In the 2024 survey, which mixes the forms, 61% said their first words, 46% 2–3-word phrases and 71% walked without support, with outcomes ranging from almost normal development to severe delay, regression in 34% and seizures in 34.1%, almost all with seizures in the two years before responding [9]. In MRD41 due to deletion, ID is mild to moderate in the cases described, and in the forms with West syndrome development was limited (developmental quotient of 13 at 5 years in one case; Gesell quotient of 30 at 28 months in another) [13, 14, 22, 42]. The fat pads attenuate or disappear with age, and scoliosis may progress [2, 23]. Adulthood is poorly described and may include progressive generalised dystonia [25]. The sources consulted provide no data on life expectancy or mortality.

11.2 Surveillance

No source consulted proposes surveillance intervals specific to TBL1XR1. The intervals in the table come from general guidelines; where these do not define an interval, the table states the clinical rationale for the assessment and the absence of a published interval, without replacing it with a value of its own.

12. Summary and Concluding Remarks

TBL1XR1-related disorders form an autosomal dominant allelic class in which the type and position of the variant determine the phenotype. The recurrent variant NM_024665.7:c.1337A>G p.(Tyr446Cys), and other substitutions on the inner face of the WD40 ring such as p.(Tyr446His) and p.(Cys325Tyr), cause Pierpont syndrome, with «crescent-moon» facies on smiling, anteromedial fat pads of the heels, deep palmar and plantar creases, hearing loss, short stature, scoliosis, moderate to severe ID and severe feeding difficulties; the proposed mechanism is dominant-negative, because the mutant protein assembles normally into the NCoR/SMRT–HDAC3 complex. Deletions, truncations and other missense variants cause MRD41 through haploinsufficiency, with ID of variable severity, ASD or autistic traits in a subgroup, ADHD and, with amino-terminal variants, West syndrome. Microduplication of the gene is associated with ID, ASD and hearing loss, with pathogenicity not established.

ClinGen classifies the gene–disease relationship as definitive for a lumped entity, and the clinical boundary between Pierpont and the other forms has no consensus criteria. The diagnosis is molecular: exome, genome or a panel identify point variants, and CMA identifies only CNVs, so a normal CMA does not exclude any of the point-variant forms. The c.1337A>C notation in the discovery article is an error corrected in an erratum, and comparison between reports requires the MANE transcript and the genomic position.

There is no specific treatment, authorised medicine, guideline or trial for these disorders. Management is symptomatic and multidisciplinary, with general guidelines for the assessment of ID, ASD screening, hearing loss and infantile spasms, and with attention to the comorbidities that the series show to be frequent: feeding difficulties, seizures, regression, Chiari malformation, scoliosis, ocular abnormalities and renal anomalies. The variants are as a rule de novo, with vertical transmission documented in the deletion and the microduplication, and parental mosaicism has not been quantified. The available data come from a few dozen described patients (50 in the 2020 curation, 51 in the 2023 aggregation and 41 in the 2024 survey, with overlap), including one Portuguese and one Brazilian case, and adulthood remains poorly understood. The somatic TBL1XR1::RARA and TBL1XR1::RARB fusions of acute promyelocytic leukaemia and the somatic variants of lymphomas belong to another clinical context and do not alter the counselling for a germline variant.

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