ASXL Syndromes (Bohring-Opitz, Shashi-Pena and Bainbridge-Ropers)

Developmental disorders caused by germline variants in the ASXL1, ASXL2 and ASXL3 genes, Polycomb regulators of the PR-DUB complex

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

Sources for the table: GeneReviews [1–4], Orphanet [5–7], OMIM [8–13], VariantValidator [14], tumour surveillance and hyperinsulinism guidelines [15, 16], trial registry [17], 2026 cohort [18] and, for PERCHING syndrome, Orphanet, OMIM and published series [19–24].

1. Introduction

1.1 One gene family, three syndromes

The ASXL1, ASXL2 and ASXL3 genes (from additional sex combs-like) are the human homologues of the Drosophila asx gene and encode Polycomb group proteins involved in the epigenetic regulation of embryonic development [3]. Germline truncating variants in each of these genes cause a distinct syndrome: Bohring-Opitz syndrome (BOS), associated with ASXL1; Shashi-Pena syndrome (SHAPNS), associated with ASXL2; and Bainbridge-Ropers syndrome (BRPS), also called ASXL3-related disorder [25, 26]. All three share global developmental delay, hypotonia, feeding difficulties in infancy and some facial features, but differ in growth, head circumference, severity of intellectual disability and systemic complications, to the extent that they constitute clinically distinct entities within a single gene family [25, 26]. This article covers the whole class, including Shashi-Pena syndrome, and examines each entity in depth in the sections where the differences have clinical consequences.

1.2 Bohring-Opitz syndrome: from clinical description to gene

In 1975, Oberklaid and Danks described a child whom they interpreted as having Opitz trigonocephaly syndrome (C syndrome) [8]. In 1999, Bohring and colleagues reported four unrelated sporadic cases that resembled C syndrome but were distinguished from it by intrauterine growth restriction, cleft lip or palate, exophthalmos, retinal involvement, flexion deformities of the upper limbs, dislocation of the radial heads and frontal hirsutism; they also identified two previously published cases with the same picture (Addor 1995 and Oberklaid and Danks 1975) and proposed that this was either the severe end of C syndrome or a new entity [8, 27]. The description of four further patients and a critical review in 2006 consolidated the main criteria [8], and in 2011 Hastings and colleagues proposed clinical diagnostic criteria, before the gene had been identified; only five of the patients used in that proposal were later molecularly confirmed [1, 28]. Smith's textbook, in its 2022 edition, also lists the syndrome under the eponym Oberklaid-Danks and reports about 50 patients described, slightly fewer than half with molecular confirmation [29].

The molecular cause was identified in 2011 by Hoischen and colleagues, who sequenced the exome of three patients and found in each a heterozygous de novo nonsense variant in ASXL1; in total, 7 of 13 individuals with a BOS phenotype had de novo variants in the gene, suggesting genetic heterogeneity [30]. Of the seven patients with a variant, six were female and one male, aged between 2.5 and 24 years, and two had died (at 6 years and at 23 hours of life); the two oldest showed that the face, the prominent eyes and the facial nevus become less marked with age [8]. In parallel, Kaname and colleagues identified variants in CD96 in one form of C syndrome, including a patient previously described as "C-like", which left open whether C syndrome and BOS form a clinical gradient or a set of genetically distinct entities [8, 31]. The 2026 GeneReviews adopts the dyadic nomenclature "ASXL1-related Bohring-Opitz syndrome", following the proposal of Biesecker and colleagues to name Mendelian disorders by gene-phenotype association, and includes in the clinical description only patients with molecular confirmation [1, 32].

1.3 Bainbridge-Ropers syndrome

In 2013, Bainbridge and colleagues used genome and exome sequencing in four individuals with an undiagnosed syndrome and found heterozygous de novo truncating variants in ASXL3; the patients shared severe feeding difficulties, faltering growth and neurological abnormalities with significant developmental delay, with similarities to BOS but less phenotypic overlap than among patients with ASXL1 variants [33]. The entity is called Bainbridge-Ropers syndrome or, in dyadic terminology, ASXL3-related disorder [3]. The 2017 series delineated the phenotype and showed that it is a recognisable condition [34, 35], and the international cohorts of 2021, 2025 and 2026 extended it to mild, inherited and mosaic forms [18, 36, 37]. In the original description, three of the four patients had severe psychomotor delay, feeding difficulties, severe postnatal growth restriction, arched eyebrows, anteverted nares and ulnar deviation of the hands; the fourth had less severe delay and normal growth; none had the BOS posture, myopia or trigonocephaly, and one child born small for gestational age died at 9 months [12, 13]. In 2016 three further patients were described, all dependent on tube feeding, without speech and with absent or unsteady independent walking [12]. In the 2017 series, recruited through the Deciphering Developmental Disorders study, the 12 patients were aged between 4 and 22 years and had moderate to profound intellectual disability; two did not walk, nine did not speak, 11 attended special education, three had controlled epilepsy and three a marfanoid habitus with arachnodactyly, tall stature, flat feet and scoliosis [12, 34].

1.4 Shashi-Pena syndrome

In 2016, Shashi, Pena and colleagues, with support from the Undiagnosed Diseases Network, sequenced the exome of six unrelated probands with developmental delay, macrocephaly and dysmorphism and found in all of them de novo truncating variants in ASXL2, a gene with no Mendelian disorder associated until then [25]. The phenotype included macrocephaly, prominent eyes, arched eyebrows, hypertelorism, glabellar nevus, neonatal feeding difficulties, hypotonia and developmental disabilities; it was distinguished from the ASXL1- and ASXL3-associated syndromes by macrocephaly, the absence of growth restriction and the greater variability in the degree of intellectual disability [25]. The six patients were aged between 11 months and 31 years; all had macrocephaly, present at birth in three; four had deep palmar creases and two capillary malformations outside the glabella; three had an atrial septal defect, three episodic hypoglycaemia and several skeletal abnormalities (kyphosis, scoliosis, advanced bone age, reduced bone mineral density and fractures); three had febrile seizures in childhood and one developed generalised epilepsy at 21 years; neuroimaging showed enlarged extra-axial spaces, ventriculomegaly and white matter volume loss in five, and was normal in the oldest patient [10]. The probands came from cohorts totalling 12 030 individuals with neurodevelopmental disorders, and the probability of six de novo truncations in the same gene occurring by chance was estimated at 1.47 × 10⁻¹⁰; the ExAC database contained only six putative loss-of-function variants in ASXL2, fewer than expected, indicating that the gene is intolerant of such variants [10, 11]. The original article described ASXL2 as having 12 exons; the current transcript annotation has 13 exons, without altering the observation that all pathogenic variants lie in the last two exons [2].

1.5 Definitions used in this article and framework

Bohring-Opitz syndrome is defined as a suggestive clinical picture with a constitutional heterozygous pathogenic or likely pathogenic variant in ASXL1; Shashi-Pena syndrome as a suggestive picture with a heterozygous pathogenic or likely pathogenic variant in ASXL2, so far always truncating and located in the last two exons; and ASXL3-related disorder as the presence of a heterozygous pathogenic or likely pathogenic variant in ASXL3, as there are no formal clinical criteria [1–3]. In all of them, a variant of uncertain significance neither establishes nor excludes the diagnosis [1–3]. In a broader context, these syndromes belong to the developmental conditions associated with the Polycomb and Trithorax complexes; an analysis of 462 patients from the DECIPHER database showed enrichment of integumentary, growth, head and neck, limb and digestive manifestations, and gene clusters differentiated by microcephaly, limb and digit dysmorphism, growth abnormalities and behaviour, although individual patient clusters did not coincide with the genetic diagnosis [38]. Somatic ASXL1 variants, on the other hand, are among the most frequent alterations in clonal haematopoiesis and myeloid neoplasms, which has direct consequences for laboratory interpretation [39, 40].

1.6 PERCHING syndrome (KLHL7): a grouped differential entity

PERCHING syndrome is an autosomal recessive multisystem disorder caused by biallelic variants in KLHL7, and is included in this article because it reproduces the face and posture of BOS and is, after the ASXL syndromes, the most frequent genetic cause of "Bohring-Opitz-like" presentations without an ASXL1 variant [19, 22]. The first description appeared in 2016, from a European reference centre for Crisponi syndrome and cold-induced sweating syndrome type 1 (CS/CISS1): of 64 patients from 60 families referred between 2007 and 2014 with a clinical suspicion of CS/CISS1, 25 had no CRLF1 variant; exome sequencing of the five patients with the most typical phenotype, from four consanguineous Turkish families, revealed four homozygous variants in KLHL7, corresponding to about 6.7% of the cohort [23]. OMIM catalogued the entity as Crisponi/cold-induced sweating syndrome type 3 (CISS3) [22]. In 2017, exome sequencing in two families with suspected recessive inheritance and data sharing through the Matchmaker Exchange identified six patients from four families with biallelic truncating variants, microcephaly, exophthalmos, glabellar nevus flammeus and contractures, five of them with BOS posture, and the phenotype came to be described as "Bohring-Opitz-like" [24]. In 2019, the description of two siblings of Guatemalan origin, whose features overlapped inconsistently with both phenotypes, led to the proposal of the acronym PERCHING for the recessive KLHL7 spectrum, and in the same year an Indian child with overlap of both pictures and cold-induced sweating confirmed the continuity between them [41, 42]. OMIM dropped the designation CISS3 because cold-induced sweating is rare with KLHL7 variants [22]. Orphanet maintains three entries: KLHL7-related "Bohring-Opitz-like" syndrome (ORPHA:603689), KLHL7-related Crisponi/CISS-like syndrome (ORPHA:603694) and the overlap syndrome between the two (ORPHA:603684) [19–21]. In this article, PERCHING syndrome is defined as a picture compatible with biallelic pathogenic or likely pathogenic variants in KLHL7, regardless of whether BOS or CS/CISS features predominate; retinitis pigmentosa 42 (RP42), caused by heterozygous KLHL7 variants, is treated as an allelic disorder [22, 43].

2. Molecular Genetics and Pathophysiology

2.1 The ASXL genes and proteins

ASXL1 is located at 20q11.21 and encodes the Polycomb group protein ASXL1; ASXL2 is located at 2p23.3 and encodes the putative protein ASXL2; ASXL3 is located at 18q12.1 and encodes the putative protein ASXL3 [1–3]. The MANE Select transcripts confirmed in VariantValidator are NM_015338.6 (NP_056153.2) for ASXL1, NM_018263.6 (NP_060733.4) for ASXL2 and NM_030632.3 (NP_085135.1) for ASXL3 [14]. The three genes take part in establishing the body plan during embryogenesis and encode proteins involved in epigenetic regulation and in the assembly of transcription factors at specific genomic sites [25]. ASXL3 is expressed in the same tissues as ASXL1 (brain, spinal cord, kidney, liver and bone marrow), albeit at a lower level, and the correlation of expression patterns is one proposed explanation for the phenotypic overlap between BOS and BRPS [3].

ASXL1 is an epigenetic scaffold protein without catalytic activity of its own that organises chromatin modifications through several protein complexes [1]. It acts through two main mechanisms: with the deubiquitinase BAP1 (Küry-Isidor syndrome and BAP1 tumour predisposition) it forms the PR-DUB complex (Polycomb repressive deubiquitinase), which removes monoubiquitin from lysine 119 of histone H2A (H2AK119Ub), and it interacts with Polycomb repressive complex 2 (PRC2), regulating trimethylation of lysine 27 of histone H3 (H3K27me3) [1]. Structural studies show that the DEUBAD domain of ASXL1 binds the catalytic domain of BAP1 and stimulates deubiquitination specifically on nucleosomal substrates; through these interactions, ASXL1 regulates the expression of the HOX genes and other regulators of embryonic patterning [1]. Constitutional loss of Asxl1 in the mouse causes anophthalmia, microcephaly, cleft palate and mandibular malformations, with 80% embryonic lethality [1]. In 2025, Asxl1 deletion in the mouse was shown to cause microcephaly through reduced size and number of cortical neurons, with lower proliferation and greater apoptosis of neural stem cells, by a mechanism dependent on Ezh2 and PRC2 [44].

Multi-omic studies in primary cells from 18 patients with BOS and 49 controls (ATAC-seq, DNA methylation, histone methylation binding and transcriptome, in peripheral blood and fibroblasts) showed that ASXL1 variants produce cross-tissue effects across several layers of the epigenome, with activation of the canonical WNT pathway at transcriptional and protein level and increased VANGL2, a planar cell polarity pathway protein that acts through non-canonical WNT signalling [45]. ASXL2 functions redundantly with ASXL1 and ASXL3 in the PR-DUB complex; in the mouse, Asxl2 regulates skeletal, lipid and glucose homeostasis and cardiac development, and Asxl2-null mice show glucose intolerance, insulin resistance and lipodystrophy, mediated by interaction with the PPARγ receptor [2, 46]. These mice also have osteopetrosis, and in another knockout line they show lower weight, skeletal and vertebral anomalies, congenital heart disease with cardiomegaly and cardiac dysfunction, and premature death [11]. In adipocyte cell lines, ASXL1 and ASXL2 have opposing roles on PPARγ: ASXL1 acts as a corepressor, through its HP1-binding domain and in association with HP1α and methylated H3K9, and ASXL2 as a coactivator, in association with MLL1 and active chromatin marks [9, 11].

The three proteins share an N-terminal domain (ASXN) and a middle domain (ASXM), which in ASXL1 includes the Asx homology domain, and end in a PHD-type zinc finger (plant homeodomain) [9, 11, 13]. ASXL1 has 1 541 amino acids (about 165.5 kDa), with a serine-rich region, three nuclear localisation signals, PEST motifs and a nuclear receptor-binding motif; the gene has 13 exons spanning 81 kb, exon 3 being only 3 bp long and exon 13 containing the entire 3′ untranslated region, of about 5 kb [9]. ASXL2 has 1 435 amino acids, with 29.8% identity to ASXL1, encoded by 13 exons spanning about 139 kb; ASXL3 is the largest of the family, with 2 248 amino acids encoded by 12 exons, and is distinguished by a proline-rich region immediately before the PHD [11, 13]. The loci are paralogous: DNMT3B–ASXL1–KIF3B on 20q corresponds to DNMT3A–ASXL2–KIF3C at 2p23.3, and ASXL3–DTNA at 18q12.1 corresponds to ASXL2–DTNB [9, 11, 13].

2.2 Disease mechanism: loss of function, dominant-negative effect or gain of function

The variants associated with BOS and SHAPNS are truncating and cluster in the last two coding exons, which allows them to escape nonsense-mediated mRNA decay (NMD) and produce truncated proteins [1, 2]. For BOS, GeneReviews regards the mechanism as unknown, with data in favour of either loss of function or toxic gain of function [1]. In SHAPNS, the mRNA studies of the original work showed expression of both alleles in blood and no reduction of the mutant transcript, supporting a dominant-negative effect; no exonic deletions of ASXL2 have been described in patients with the phenotype and there is no evidence that haploinsufficiency contributes to it [2, 25]. A family with a balanced translocation t(2;11)(p23;q23) disrupting ASXL2, studied by nanopore sequencing, showed reduced mRNA of the gene; the proband had developmental delay without the facial gestalt or macrocephaly, and the carrier father and paternal grandmother had normal development, an observation incompatible with the dominant-negative mechanism that distinguishes this scenario from classic SHAPNS [2, 47]. For ASXL3, the 2020 GeneReviews indicates loss of function, and all causal heterozygous variants described were truncating or splicing variants [3]. In fibroblasts from a patient with NM_030632.3:c.1448dup p.(Thr484AsnfsTer5), in the 5′ cluster region, mRNA and protein were reduced to about 50%, with increased H2AK119Ub1, normal H3K27me3 and dysregulation of genes linked to transcriptional regulation, proliferation and gut development, data compatible with haploinsufficiency for this variant [13, 14]. Population databases contain ASXL1 and ASXL3 truncations located upstream and downstream of the disease-associated regions in individuals with no described phenotype, which limits the interpretation of truncations outside those regions [13].

Data from 2025 and 2026 are changing this framework. In cells of clonal haematopoiesis and chronic myelomonocytic leukaemia, truncated ASXL1 proteins increase the deubiquitinase activity of PR-DUB, interact with the EHMT1-EHMT2 complex and reduce H3K9me2, H3K9me3 and H2AK119Ub, with increased expression of transposable elements and interferon-induced genes [48]. Four 2026 preprints, not yet peer-reviewed and preclinical in level, point in the same direction for the developmental syndromes: in isogenic embryonic stem cells, BOS variants reduce (without abolishing) H2AK119ub1 through a hyperstable truncated ASXL1 protein, which shifts PR-DUB assembly away from ASXL2-containing complexes and reduces PRC2 binding and H3K27me3 deposition [49]; in fibroblasts from patients with BOS, ASXL1 truncations induce a Warburg-like metabolic state by repressing the mitochondrial pyruvate carrier, upstream of WNT pathway activation [50]; and, in BRPS, patients' ASXL3 truncations escape NMD and Cullin 4-dependent degradation, accumulate protein and cause transcriptional dysregulation that forced expression of the full-length protein does not correct, but which antisense oligonucleotides targeting ASXL3 largely normalise [51]. A knock-in mouse model of a BRPS patient variant reproduced NMD escape and PRC2-linked dysregulation, whereas heterozygous knockout mice had no phenotype [52]. These results support the hypothesis that distal truncations of the three genes act through gain of function or a dominant-negative effect, which underpins the allele-reduction strategies described in section 7, but they do not yet change variant classification criteria.

2.3 Variant spectrum

In BOS, sequencing detects more than 99% of known pathogenic variants and targeted deletion/duplication analysis less than 1%, according to HGMD data; all variants described are loss-of-function, mostly in the last two exons [1]. Illustrative variants normalised in VariantValidator are NM_015338.6:c.1210C>T p.(Arg404Ter) (NC_000020.11:g.32433408C>T), described in a 71-year-old man with a neuromuscular phenotype, and NM_015338.6:c.1720-2A>G, a splicing variant from a mild case of BOS whose protein consequence, demonstrated by mRNA study in fibroblasts and published as p.I574VfsX22, can only be predicted as p.? by the tool [14, 53, 54]. Variants from the 2011 description include NM_015338.6:c.2197C>T p.(Gln733Ter), in a newborn girl who died at 23 hours of life, c.2773C>T p.(Gln925Ter), in a patient who died at 6 years, c.3083C>A p.(Ser1028Ter) and c.2893C>T p.(Arg965Ter); the deletion c.2407_2411del p.(Gln803ThrfsTer17) was described in a 3-year-old child with a typical phenotype [9, 14]. In SHAPNS, all variants associated with the classic picture are deleterious de novo frameshift, nonsense or splicing variants in the last two exons; sequencing detects 100% and no deletion or duplication has been described [2]. The variant in the clinical case in section 10 is NM_018263.6:c.1792C>T p.(Gln598Ter) (NC_000002.12:g.25749764G>A) [14, 55]. A review of 11 patients compiled, in the authors' notation on NM_018263.6, variants such as c.1225_1228delCCAA p.Pro409Asnfs*13, c.1288G>T p.Glu430*, c.2081dupG p.Gly696Argfs*11, c.2485C>T p.Gln829*, c.2971_2974delGGAG p.Gly991Argfs*3, a missense c.4228T>G p.Cys1410Gly and the translocation t(2;11)(p23;q23); eight of the 11 had de novo truncations [55]. The six variants of the original description, annotated on NM_018263.4 and confirmed on the MANE transcript, were c.2424del p.(Thr809ProfsTer32), c.2081dup p.(Gly696ArgfsTer11), c.2472del p.(Ser825ValfsTer16) and c.2971_2974del p.(Gly991ArgfsTer3) in the last exon, and c.1225_1228del p.(Pro409AsnfsTer13) and c.1288G>T p.(Glu430Ter) in the penultimate exon; in three of them the mutant transcript escaped NMD [11, 14]. Missense variants in ASXL2 have been reported as pathogenic and as of uncertain significance in individuals with delay or intellectual disability without the classic features, often inherited from an unaffected parent, so the evidence is insufficient to assign them a phenotype [2, 26].

In ASXL3-related disorder, sequencing detects 98–99% of variants, targeted deletion/duplication analysis 1–2% and microarray rare intragenic deletions; heterozygous missense variants are not considered causal [3]. The 2026 cohort of 204 individuals distinguished NMD-subject variants (n = 87) from truncations escaping it (n = 117) and two mutational cluster regions, MCR1 (c.1095_2237, exon 11; n = 66) and MCR2 (c.3043_4906, exon 12; n = 101) [18]. These two regions correspond to those described earlier: the 2013 variants clustered at the start of exon 11, between codons 404 and 659, between the N-terminal scaffold domains and the C-terminal chromatin-binding domain, and the 2017 series identified a second region between codons 1045 and 1444 [13]. Recurrent variants include NM_030632.3:c.4330C>T p.(Arg1444Ter) and the p.(Arg1036Ter) variant shared by two sisters, which corresponds to c.3106C>T on the MANE transcript [14, 56, 57].

2.4 Genotype-phenotype correlations, penetrance and expressivity

GeneReviews identifies no clinically relevant correlations in BOS or SHAPNS, and the registry of 39 patients with BOS did not find any either [1, 2, 58]. In BRPS, the 2017 series found no phenotypic differences between patients with variants in the two cluster regions [12]; the 2026 analysis, with a larger number of patients, showed microcephaly, sleep apnoea, hyperventilation and gastrostomy tube use more frequently in the NMD and MCR1 groups, more severe intellectual disability and global delay in MCR1 than in MCR2 (P = 0.0031 and P = 0.0183) and more formal autism diagnoses in the non-NMD and MCR2 groups [18]. In the Spanish cohort of 22 patients, variants in the 3′ region of exon 12 were associated with more perinatal feeding problems and those in the 5′ region of exon 11 with lower height and head circumference centiles and arched eyebrows [59]. Penetrance of typical truncating variants is considered complete in de novo forms, but BRPS includes families with inherited variants and wide intrafamilial variability, which may reflect as yet unidentified modifying factors or uncertainty about the pathogenicity of some inherited variants [18, 36]. Two siblings with the same ASXL3 genotype illustrate this variability: one had childhood apraxia of speech with largely preserved cognition and the other intellectual disability, autism and non-verbal communication [60].

2.5 Methylation signature

DNA methylation profiling in blood from 17 patients with ASXL1 variants and 35 matched controls (EPIC array) identified 763 differentially methylated CpGs in 323 genes, including HOXA5 and HOXB4 [61]. A classification model based on this signature allowed reclassification of ASXL1 variants of uncertain significance; the profile of a patient with an ASXL2 variant was similar to that of BOS and those of three patients with ASXL3 variants were similar to controls, and the Horvath epigenetic clock showed accelerated methylation age in the patients with ASXL1 variants and in the patient with an ASXL2 variant, but not in those with ASXL3 variants [61]. GeneReviews mentions this signature as a variant classification tool [1].

2.6 Clonal haematopoiesis and ASXL1 allelic disorders

ASXL1 is one of the three most frequently mutated genes in age-related clonal haematopoiesis, together with DNMT3A and TET2 [1, 48]. Somatic ASXL1 truncations are associated with a higher risk of progression to myeloid neoplasia and of cardiovascular disease, and the excess mortality is mainly due to cardiovascular complications; this clonal haematopoiesis is more frequent in obesity, smoking, autoimmune diseases and HIV infection, although the association is not understood [1, 40, 62]. The ESMO handbook lists ASXL1 among the driver genes whose somatic detection defines clonal haematopoiesis of indeterminate potential and clonal cytopenia of undetermined significance, among the additional mutations of worse prognosis in mastocytosis and among the genes of the minimum recommended set for chronic myelomonocytic leukaemia; ASXL1 and ASXL2 are included in myeloid panels as chromatin modifiers [63]. Sporadic neoplasms containing somatic variants in ASXL1, ASXL2 (liver, myeloid, pancreas) or ASXL3 (parathyroid adenomas, pancreatic and prostate cancers) do not imply hereditary predisposition [1–3].

This has a direct interpretive consequence. A 6-year-old child with seizures, developmental delay, dysmorphism and faltering growth had an ASXL1 variant previously described as causing BOS, but observed seven times in the ExAC database; analysis of all ASXL1 truncations in that database indicated that most are probably somatic, acquired through age-related clonal haematopoietic expansion [39]. Ignoring somatic mosaicism may lead to assuming reduced penetrance of BOS or to classifying pathogenic variants as benign [1, 39]. Distinguishing a constitutional variant from one acquired through clonal expansion relies on context (a child with the phenotype and a heterozygous de novo variant, or an adult without the phenotype with a variant confined to the haematopoietic lineage) and on demonstrating the variant in a non-haematopoietic tissue, the criterion used to prove the germline nature of the variant in the leukaemia family described below [39, 64].

Germline allelic forms outside BOS are rare. A father and son developed myelodysplastic syndrome progressing to acute myeloid leukaemia and had the same ASXL1 missense variant in haematological and non-haematological tissue, NM_015338.6:c.2957A>G p.(Asn986Ser) [1, 14, 64]. Biallelic ASXL1 missense variants have been described in a patient with an inborn error of immunity: chronic macrocytosis, persistent granulomas due to rubella vaccine virus and Epstein-Barr virus-associated Hodgkin lymphoma, with B-cell loss, hypogammaglobulinaemia, cytotoxic T-cell and NK-cell deficiency, a T-cell exhaustion phenotype, global loss of methylation and accelerated epigenetic ageing, corrected in vitro by transduction of wild-type ASXL1 [65]. The last-two-exon truncations typical of BOS have not been described as constitutional in patients with haematological neoplasms [1]. For ASXL3, biallelic missense variants have been reported in four individuals from two families with tetralogy of Fallot or transposition of the great arteries, an association that requires confirmation [3, 66].

2.7 Inheritance pattern

All three syndromes are autosomal dominant [1–3]. The sibship with BOS described in 2003 led to consideration of autosomal recessive inheritance [8]; the later demonstration of transmission from parents with germline mosaicism explains this type of recurrence within the dominant model [58, 67]. The immunodeficiency due to biallelic ASXL1 missense variants and the possible heart disease due to biallelic ASXL3 missense variants constitute a second, recessive pattern, associated with mechanisms and phenotypes different from the developmental syndromes [65, 66].

2.8 KLHL7 and PERCHING syndrome

KLHL7 is located at 7p15.3; the MANE transcript is NM_001031710.3, and the protein, of 586 amino acids, has a BTB domain (bric-a-brac, tramtrack and broad complex), a BACK domain (BTB and C-terminal Kelch) and a Kelch domain formed by six Kelch motifs, which adopts a β-propeller structure [23, 68]. KLHL7 forms dimers and binds cullin 3 (CUL3) through the BTB and BACK domains, functioning as the substrate-recognition subunit of a BTB-CUL3-RBX1 E3 ubiquitin ligase complex that polyubiquitinates proteins destined for proteasomal degradation; the Kelch domain is the presumed substrate-binding site [23, 42]. Expression is widespread, including retinal rods, and the physiological substrates remain unknown [23]. In the prevailing hypothesis, biallelic loss of function prevents substrate ubiquitination, so that substrates accumulate and damage the cells with the highest metabolic activity, including photoreceptors [23, 68].

Functional data support loss of function. The protein encoded by the NM_001031710.3:c.1022del p.(Leu341TrpfsTer9) allele was not detected by Western blot in transfected cells, compatible with nonsense-mediated mRNA decay [23]. The three original missense variants in the Kelch domain retained perinuclear localisation and colocalisation with CUL3, and structural modelling showed that NM_001031710.3:c.1258C>T p.(Arg420Cys) and NM_001031710.3:c.1115G>A p.(Arg372Gln) disrupt internal salt bridges (Arg420–Glu452 and Arg372–Glu401) that stabilise Kelch domain loops involved in substrate recognition; the authors concluded that these variants prevent substrate binding without preventing complex assembly, without excluding effects on stability or catalytic activity [23]. The in-frame deletion NM_001031710.3:c.181_183del p.(Val61del), in the BTB domain, disrupts a hydrogen bond with Ala65 and alters an α-helix in the homology model, suggesting interference with CUL3 binding [42]. In 2026, long-read RNA sequencing showed that the homozygous variant NM_001031710.3:c.936+3_936+22del causes skipping of exons 6 and 7 (r.619_936del, p.(Val207_Lys312del)), but also leaves normal transcript, a partial splicing effect that may contribute to clinical variability [69].

The allelic disorder RP42 results from heterozygous missense variants in the BACK domain, such as NM_001031710.3:c.449G>A p.(Ser150Asn), NM_001031710.3:c.457G>A p.(Ala153Thr) and NM_001031710.3:c.458C>T p.(Ala153Val), first described in a six-generation Scandinavian family [23, 43]. Variants at residue Ala153 reduce interaction with CUL3 and E3 activity through a dominant-negative effect, whereas the Ser150 substitution preserves CUL3 binding [23]. RP42 has late onset, often after 50 years of age, slow progression, preservation of foveal function and concentric constriction of the visual fields with sparing of the far periphery [23, 68]. Heterozygous parents of patients with PERCHING examined at 30 and 34 years, and a couple examined at 60 years, had no signs of retinopathy; haploinsufficiency due to a truncating allele does not appear sufficient to cause retinal disease, which in the dominant forms depends on the dominant-negative mechanism [23, 68].

There is no stable genotype-phenotype correlation. The first variants associated with the CS/CISS-like phenotype were missense variants in the Kelch domain, and those in the "Bohring-Opitz-like" series were truncating variants in the BACK or Kelch domains, none in the BTB domain [22–24]; the later description of variants in the BTB domain, of mixed phenotypes and of siblings with clinical differences between them showed that the type and position of the variant do not predict the picture [41, 42, 70]. The published variants are normalised below on the MANE transcript; the numbering in publications on NM_001031710.2 coincides with that of NM_001031710.3 for all variants reviewed [14].

Variants confirmed in VariantValidator (GRCh38) and, where indicated, in ClinVar [14, 71]. The homozygous missense variant described in an Iranian patient in 2024 was published on the non-MANE transcript NM_018846 and classified by the authors as of uncertain significance, so it is not included in the table [74].

3. Clinical Spectrum and Manifestations by System

3.1 Comparative overview

The three syndromes share hypotonia and feeding difficulties early in life, global developmental delay and some facial features (glabellar nevus simplex, prominent eyes, hypertelorism, synophrys or arched eyebrows), but they are arranged along a clinical gradient. BOS combines growth restriction, microcephaly or trigonocephaly, the characteristic upper-limb posture, cyclic vomiting, high myopia, severe to profound intellectual disability and an increased risk of Wilms tumour and hepatoblastoma; SHAPNS combines overgrowth, macrocephaly, hypoglycaemia, dental anomalies and greater cognitive variability; BRPS combines intellectual disability with absent or minimal speech, autism, marfanoid habitus and a less specific face [1–3, 26]. The frequencies that follow come from small series, with denominators that vary from feature to feature because each was assessed in a subset of patients, and partly reflect the ascertainment bias of the first descriptions.

Table built from the GeneReviews and the cohorts cited in the text [1–3, 18, 37, 55, 58, 59].

3.2 Bohring-Opitz syndrome

The 2026 GeneReviews is based on more than 70 individuals with BOS and a pathogenic ASXL1 variant published between 2011 and 2024 [1]. The following table reproduces the compiled frequencies, with the denominators of patients assessed for each feature.

ASD, atrial septal defect; VSD, ventricular septal defect; ID, intellectual disability; IUGR, intrauterine growth restriction; MRI, magnetic resonance imaging. Source: GeneReviews [1].

Face and skull. The face includes microcephaly or trigonocephaly with a prominent metopic ridge (not necessarily fused), prominent glabellar and eyelid nevus simplex that fades with age (often incorrectly called nevus flammeus), prominent or proptotic eyes, cleft lip, palatal anomalies (cleft, high-arched palate or prominent palatal ridges), micrognathia or retrognathia, synophrys that becomes more marked with age, a hypotonic face with full cheeks, and hypertrichosis with rapid growth of hair and nails [1]. Smith's textbook adds bitemporal narrowing, hypoplastic supraorbital ridges, upslanting palpebral fissures, a broad nasal bridge, anteverted nares, a broad secondary alveolar ridge, posteriorly rotated ears with overfolded helices and thick lobes, a short neck with redundant skin and a low posterior hairline [29]. Three patients required craniosynostosis surgery, and the 2023 registry identified craniosynostosis and hernias as new findings [1, 58]. Of the ten patients described with clefting, three had isolated cleft lip, three isolated cleft palate and four cleft lip and palate [1].

Posture. The BOS posture consists of flexion of the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints, with external rotation or adduction of the shoulders and camptodactyly; it is most evident in early childhood and becomes less apparent with age [1, 29]. Congenital contractures, dislocations (including of the radial heads), hip dysplasia, valgus and foot deformities and pectus excavatum have been described, and progressive neuromuscular scoliosis or kyphosis is frequent and often requires surgery [1, 8]. Fractures have been recorded in three patients [1].

Growth and feeding. Intrauterine growth restriction, usually mild, occurs in some patients, but many are born after uneventful pregnancies with average or low-average weight; the 2023 registry confirmed birth weight within the normal range in most participants [1, 58]. Faltering height and weight gain appears in the first year and is attributed to chronic vomiting, but even patients without feeding intolerance grow poorly in the long term; some reach typical adult height [1]. Feeding difficulties begin in infancy and improve or resolve in early childhood. They were long attributed to severe gastro-oesophageal reflux, but studies have documented neither reflux nor response to antireflux treatment, and neurogenic causes such as cyclic vomiting and poor gastric motility have been proposed; the frequency of vomiting causes a high risk of aspiration and dehydration and multiple hospital admissions [1]. One case of pharyngeal dysphagia, two cases of annular pancreas and two intestinal obstructions have been described; chronic constipation is frequent [1]. In the 2015 compilation (17 patients with an ASXL1 variant, 6 without a variant and 43 with a clinical diagnosis), faltering growth and feeding difficulties occurred in all, frequent vomiting in 23/25 (92%), gastrostomy was placed in 23/43 (53%) and Nissen fundoplication performed in 8/43 (19%) [75].

Neurology and development. Most patients have severe to profound intellectual disability; few speak, but many communicate basic needs with augmentative and alternative communication devices, gestures and vocalisations, and most do not walk independently, although some use a walker and orthoses by late childhood [1]. Seizures are frequent and generally respond to the usual antiseizure medications; tone combines axial hypotonia with hypertonia or spasticity of the extremities [1]. Standardised assessment of eight patients with BOS and seven with BRPS showed first developmental concerns at a mean of 4 months in BOS and 9 months in BRPS, criteria for developmental coordination disorder in all who completed the questionnaire, motor difficulty interfering with learning in 71% of children with BOS and in none with BRPS, and a combination of hypotonia and hypertonia throughout life in BOS [76]. On brain imaging, corpus callosum anomalies (from hypoplasia to agenesis) predominate, followed by Dandy-Walker malformation, delayed myelination and ventriculomegaly; Smith's textbook also describes tortuous carotid and vertebral arteries and an enlarged, hyperechoic pancreas [1, 29].

Behaviour. Patients often have a happy, interactive and curious temperament, recognise their caregivers and are sociable; self-injury, severe behavioural crises and breath-holding spells have been described and are probably under-reported [1, 75].

Respiratory system, ear, nose and throat, and sleep. Transient apnoea and bradycardia, recurrent respiratory infections and aspiration pneumonia are frequent, especially in infancy, and decrease when vomiting is treated or improves with age; some patients have needed a tracheostomy, and laryngomalacia and tracheomalacia have been described [1]. Recurrent otitis media is common (myringotomy in 14 published patients), with sensorineural or conductive hearing loss, and adenoidectomy, tonsillectomy and supraglottoplasty are frequent [1]. Obstructive and central sleep apnoea and disorders of sleep onset and maintenance are frequent; micrognathia may cause tongue-base obstruction, and some patients have periods of several days without sleep alternating with exhaustion and excessive sleep [1].

Heart. In addition to idiopathic and transient bradycardia, septal defects and cardiac hypertrophy have been described in a small number of patients [1]. Persistent pulmonary hypertension was the cause of death in two patients, one of them with abnormal alveolar formation [1].

Eyes. Myopia, often severe, worsens in the first years and requires optical correction from infancy in most; there are colobomas, retinal and optic nerve atrophy, abnormal retinal pigmentation, strabismus and probably under-reported cortical visual impairment [1]. Smith's textbook also mentions persistent tunica vasculosa lentis, pale choroid and pigmentary retinopathy [29].

Kidney and urinary tract. Cryptorchidism, hypospadias, pyelectasis, vesicoureteric reflux, neurogenic bladder, urinary retention and recurrent urinary tract infections have been described, and there is a clinical impression of an increased risk of nephrolithiasis [1].

Immunity and puberty. Recurrent infections are frequent in the first years, without demonstrated immunodeficiency, and decrease with age [1]. Precocious pubarche has been reported in both sexes; a cross-sectional survey of caregivers of adolescents with ASXL syndromes documented parental and medical concern about premature pubarche and possible precocious puberty in BOS, with pubertal profiles different from those in BRPS, and suggested a low threshold for referral to paediatric endocrinology [1, 77].

Neoplasms. As of 2026, three cases of Wilms tumour in BOS have been published and four unpublished cases are known to the GeneReviews authors, corresponding to seven cases in 74 patients in the literature, compared with a paediatric incidence of 7 per million [1]. The first two cases, of bilateral Wilms tumour at 6 and 2 years, were described in 2015, without loss of heterozygosity of ASXL1 in the tumour analysed [75]. Hepatoblastoma, with an incidence of 0.5–1.5 per million children, has been described in three patients [1, 58, 78]. The 2024 American Association for Cancer Research (AACR) guideline summarises three Wilms tumours (two bilateral, at 1.5 and 5 years, and one unilateral at 4 years), one nephroblastomatosis found at autopsy at 5 months and three hepatoblastomas at 15 months, 18 months and 2 years, and estimates a risk above 1% for each tumour [15]. The true frequency is not known, because the prevalence of the syndrome is not known either [1].

Natural history and atypical forms. Mortality was high in the early series: 17 of the 43 patients published up to 2015 (40%) had died between 23 hours and 6 years of life, 11 (26%) before 1 year; of the 12 deaths with a known cause, 5 were due to respiratory infection, 4 to cardiovascular causes, apnoea or bradycardia, 1 to seizure, 1 to medulloblastoma (in a patient without an ASXL1 variant) and 1 to sepsis [75]. The 2026 GeneReviews lists nine deaths with a confirmed variant (status epilepticus 2, pneumonia 2, respiratory failure 1, persistent pulmonary hypertension 2, heart failure 1, meningoencephalitis 1) and mentions several patients in the natural history study alive at the end of their fourth decade [1]. Not all patients have the complete picture: a 5-year-old girl with a de novo splicing variant had the typical face, but no faltering growth, posture, severe intellectual disability, microcephaly or trigonocephaly; she walked at 20 months, communicated by sign language and was diagnosed with autism at 4 years and 3 months [8, 54]. In 2026 a 71-year-old man was described with congenital muscle weakness and atrophy (facial, extraocular, proximal upper limb and distal lower limb), dysphagia, motor delay in childhood, tremor and pes cavus, with some BOS features without the posture, carrying ASXL1 p.(Arg404Ter) identified by a neurodevelopmental panel after negative initial sequencing [53].

3.3 Shashi-Pena syndrome

The GeneReviews is based on at least 23 patients with truncating ASXL2 variants, 12 published and 11 unpublished [2].

Source: GeneReviews [2].

Face, skin and teeth. The face includes glabellar nevus simplex, widely spaced and prominent eyes with epicanthic folds, ptosis, arched eyebrows, a broad nasal tip and low-set or posteriorly rotated ears, and is most evident in infancy [2]. In the 2023 review of 11 patients, hypertelorism was present in all, a broad nasal tip in 10, arched eyebrows and a large V-shaped glabellar nevus in 9, low-set ears in 8 and posteriorly rotated ears in 7, and proptosis and deep palmar creases in 6 [55]. Teeth erupt early, are small with weak enamel, and primary teeth are lost early, with early eruption of the permanent dentition; gingival hyperplasia, microdontia, sialorrhoea and increased alveolar bone density have also been described [2, 79].

Growth. At least two thirds of patients have macrosomia, sometimes with advanced bone age, and about three quarters macrocephaly, present at birth or acquired [2]. In the 2023 review, median birth weight was 3 000 g (2 071–4 860 g), median head circumference 35.5 cm and only 2 of the 11 patients had macrocephaly at birth, a number that rose to 8 during follow-up, suggesting progressive macrocephaly [55].

Neurology, development and behaviour. Almost all have some degree of delay; walking was achieved between 18 months and after 4 years, and speech between 2 years and absent at 4 years [2]. Hypotonia improves from childhood to adolescence. Seizures occur in about two thirds, one third febrile only, one third afebrile only and one third both; afebrile seizures include generalised tonic-clonic, focal and absence seizures, with no specific electroencephalographic pattern and good pharmacological control [2]. In the 2023 review, two patients with normal early MRI developed afebrile seizures at 13 and 23 years, and the authors raised the possibility of regression [55]. Brain MRI is abnormal in 15/17 (88%), with white matter volume loss and increased extra-axial space, without a specific pattern [2]. Temper outbursts and aggression are frequent and difficult to control; anxiety, attention deficit hyperactivity disorder and autism spectrum disorder have been observed in a few patients [2]. Several patients overheat easily and have a higher baseline temperature [2].

Feeding. Most have feeding difficulties from infancy, attributed to hypotonia, with uncoordinated sucking and latching that may progress to oral apraxia; dysphagia and aspiration are uncommon, and patients generally eat by mouth in childhood and adulthood, sometimes with sensory aversions [2]. In the 2023 review, 8 of the 10 feeding difficulties were transient and one patient required parenteral nutrition and lifelong gastrojejunal feeding because of severe reflux [55].

Endocrine and metabolism. More than half of patients have hypoglycaemia at some point: neonatal only, episodic or, in one case, severe and requiring continuous feeding; hyperinsulinism has been documented in at least two patients [2]. In the 2023 review, four of six patients with hypoglycaemia had persistent forms, two with inappropriate insulin (treated with octreotide or continuous tube feeding), one with ketotic hypoglycaemia and central adrenal insufficiency between 12 and 24 months and one of unknown cause [55]. An 8-year-old prepubertal boy with SHAPNS developed type 2 diabetes without a family history, with dyslipidaemia and fatty infiltration of the liver; the authors relate the picture to the interaction of ASXL2 with PPARγ and to the insulin resistance of Asxl2-null mice [46].

Heart, hearing, eyes and other systems. Heart defects occur in about 80%, mainly atrial septal defect and patent ductus arteriosus, and more rarely ventricular septal defect, coarctation of the aorta and pulmonary valve and artery abnormalities; several atrial septal defects have been closed surgically [2]. A patient in the 2023 review with patent ductus arteriosus, patent foramen ovale and pulmonary hypertension died of heart disease at 16 months [55]. Hearing loss, usually conductive, affects about half and may normalise with ventilation tubes; one patient with sensorineural hearing loss received cochlear implants [2]. About three quarters have ophthalmological abnormalities, mainly strabismus and amblyopia; pigmentary retinal dystrophy with optic atrophy, ovoid corneas and presenile cataracts have also been described [2, 55]. Scoliosis or kyphosis (11/16) and joint hypermobility (9/14) are frequent, the former sometimes requiring extensive surgery; fracture predisposition (5/17) and hip dysplasia affect fewer than one third [2]. Sleep apnoea, obstructive or mixed, affects almost half [2]. Immunological involvement has been described in an adolescent with late-onset hypogammaglobulinaemia and autoimmune cytopenia, and granulocytopenia with thrombocytopenia in another patient [2, 80]. No cancer has been reported during follow-up of patients with SHAPNS [55].

3.4 ASXL3-related disorder (Bainbridge-Ropers syndrome)

The 2020 GeneReviews describes 89 patients (44 published and 45 from a cohort of the authors, later published in 2021) [3, 36].

ASD, autism spectrum disorder. Source: GeneReviews [3].

Language and cognition. Only 32% of patients said their first word, at a mean age of 28.8 months; comprehension is better than expression, which justifies communication devices with specialised speech and language therapy [3]. The first descriptions, of profound intellectual disability, reflected ascertainment bias, and as the case series expanded mild forms emerged, including a father and son with an inherited truncating variant, compatible with normal cognition in some carriers; most children need special education and most adults live in assisted settings with some independence [3]. The international natural history study of 64 patients described improvement over time in feeding, hypotonia, verbalisation and motor skills and the first qualitative descriptions of mildly affected probands [37].

Face. Prominent forehead, highly arched eyebrows, synophrys, widely spaced eyes, downslanting palpebral fissures, long tubular nose with a prominent bridge, low columella, wide mouth with a full, everted lower lip and crowded teeth [3, 36].

Behaviour. More than three quarters have behavioural, social and communication difficulties; about half meet criteria for autism and others have autistic traits, while some are described as placid and friendly [3]. Hand stereotypies, agitation, motor and vocal tics, episodes of hyperventilation, bruxism, attention deficit, pica and self-injury (self-biting, scratching the face, head-banging) from 2 years of age have been described [3]. In the Spanish cohort, 75% had autism [59].

Growth and feeding. Birth weight is normal in most, and postnatal faltering growth, sometimes down to −2 standard deviations, is due to the feeding difficulties and normalises with their treatment; short stature is not a primary feature [3]. Swallowing studies show an oral-phase deficit, oromotor weakness, reduced chewing and oral hypersensitivity; some patients need prolonged gastrostomy feeding and others improve with slow-flow teats, and food aversions may persist [3]. In the Spanish cohort, intrauterine growth restriction occurred in 35%, feeding difficulties in 90.5%, hypotonia in 85.7% and gastro-oesophageal reflux in 82.4% [59]. The 2025 study described obesity later in childhood, a new finding, and specific growth charts have been published [37].

Neurology, skeleton and other systems. Hypotonia predominates in the neonatal period; later, some children develop a posture with flexed elbows, wrists and fingers and contractures due to spasticity [3]. Seizures occurred in about one third in the 2020 series, but less frequently than expected in the 2025 natural history study, and MRI is usually normal [3, 37]. More than two thirds have skeletal abnormalities: marfanoid habitus, pectus excavatum, hypermobility (laxity in 73.7% in the Spanish cohort), flat feet, arachnodactyly, syndactyly, clinodactyly, tapering fingers, postural scoliosis and delayed bone age [3, 59]. Sleep disturbance is frequent, with apnoea, breath-holding spells and irregular nocturnal breathing; strabismus affects more than half and may be associated with myopia, hypermetropia, astigmatism and ptosis; dental abnormalities (crowding, malocclusion, large teeth or severe hypodontia) affect almost half; and there are disturbances of thermoregulation and, inconsistently, of pain perception [3]. The 2025 study described more prenatal and neonatal structural anomalies and an emerging renal phenotype [37]. In 2026 new isolated findings were described, such as long eyelashes, laryngeal cartilage hypoplasia and dextrocardia, and a fetus with complete agenesis of the corpus callosum and increased nuchal fold [56, 81].

3.5 PERCHING syndrome (KLHL7)

Clinical information comes from reports and small series published between 2016 and 2026, totalling just over twenty patients with confirmed biallelic variants, including one fetus; the two adult siblings from Bristol described in 2019 have an age and origin compatible with the surviving siblings of the 2017 series, so the count may include overlap [23, 24, 68]. There are no natural history studies or cohorts with a population denominator, and all patients described have received only supportive treatment.

Sources: [22–24, 41, 42, 68, 70, 72, 73, 82].

Prenatal and neonatal period and feeding. IUGR is frequent, and the only published prenatal diagnosis identified, at 31 weeks, mild polyhydramnios, borderline ventriculomegaly, possible delayed sulcation, an enlarged cisterna magna and a small calcification near the posterior horns [24, 82]. Sucking and swallowing difficulties, with paroxysmal contractions of the oropharyngeal muscles and choking, are almost constant and lead to nasogastric tube or gastrostomy feeding; gastro-oesophageal reflux may require fundoplication [22, 23, 68]. Dependence on enteral feeding corresponds to the letter E of the acronym [22].

Breathing and thermoregulation. Neonatal respiratory distress may require intubation, and there are reports of sleep apnoea and recurrent respiratory infections [22, 41, 68]. Hyperthermia without infection in the first months was the feature that prompted the initial classification as CS/CISS-like, but it is absent in several series, including that of 2017 [23, 24]. Paradoxical sweating with cold, characteristic of CISS due to CRLF1 or CLCF1, is rare: the clinical table of the 2016 series records it in one of the five children, the first detailed description dates from 2019, and altered sweating was noted in one of the four Turkish patients of 2022 [23, 42, 72].

Face and skin. The gestalt includes microcephaly, exophthalmos, hypertelorism, anteverted nares, micrognathia or retrognathia, a high narrow palate or cleft palate, broad alveolar ridges, a thin upper lip, low-set dysplastic ears, hirsutism and glabellar or frontal nevus flammeus (nevus simplex); blepharophimosis and gingival hypertrophy have been described in isolated cases [24, 42, 68, 72]. The grimacing and the facial gestalt correspond to the letter G of the acronym [22].

Nervous system. Global developmental delay and intellectual disability are severe to profound in the published series [24, 68, 70]. Axial hypotonia often coexists with peripheral hypertonia or spasticity, and absent tendon reflexes have been described [41, 42]. Neuroimaging shows a thin or hypoplastic corpus callosum, ventriculomegaly, white matter volume loss, delayed myelination and, in some patients, periventricular nodular heterotopia; epileptic seizures occur in some patients [22, 24, 42]. Nodular heterotopia due to KLHL7 is now included in genetic reviews of this cortical malformation [83].

Eyes and vision. Retinopathy is the feature that separates PERCHING from BOS and from classic CS/CISS. In the two surviving children of the 2016 series there was retinitis pigmentosa before 6 years of age: in one of them, at 6 years, bilateral subclinical chorioretinal atrophy, pale optic discs, pigmentary changes, attenuated arterioles and visual acuity estimated by sweep visual evoked potentials between 0.11 and 0.41 [23]. In the two British siblings, at 19 and 21 years, there were confluent hypopigmented or pale yellow lesions in the mid-periphery with sparing of the far periphery, pale discs with a ring of peripapillary atrophy, attenuated arterioles and maculopathy, bull's-eye in the younger sister and with a perifoveal fibrotic ring in the older brother, without bone spicules; functionally, difficulties with depth perception and the peripheral field [68]. Peripheral retinal and optic disc atrophy was described in the Iranian siblings of 2020 [70]. The high myopia and optic atrophy typical of BOS are not part of the usual picture [19].

Musculoskeletal system. Joint contractures, fixed flexion of the elbows, camptodactyly and the BOS posture, with internal rotation of the shoulders, flexion of the elbows and ulnar deviation of the wrists and metacarpophalangeal joints, are present in most [23, 24, 42]. The scoliosis of CISS was not recorded in the 2016 children [23].

Other systems and growth. Cardiac septal defects, hypospadias, cryptorchidism, vesicoureteric reflux and profound sensorineural deafness have been described, and postnatal faltering of weight and height may be extreme, as in the 3-year-old child with length at −5, head circumference at −7 and weight at −6 standard deviations [24, 42, 70]. Death in infancy or early childhood is frequent, but there are survivors into the third decade [22].

4. Clinical Recognition and Warning Signs

4.1 Prenatal and neonatal period

In the prenatal period, BOS may present with polyhydramnios, intrauterine growth restriction, oligohydramnios and short femurs [29]. In BRPS, prenatal structural anomalies have been reported, including agenesis of the corpus callosum with increased nuchal fold [37, 81]. In the newborn, the combination of trigonocephaly or microcephaly, glabellar nevus simplex, prominent eyes, micrognathia, clefting and the flexed posture of the upper limbs with ulnar deviation should suggest BOS [1, 29]. The combination of macrocephaly or macrosomia, V-shaped glabellar nevus simplex, hypertelorism, deep palmar creases and neonatal hypoglycaemia should suggest SHAPNS; in recurrent hypoglycaemia requiring glucose above 8 mg/kg/min, the international hyperinsulinism guideline recommends biochemical diagnosis of hyperinsulinism and screening for multisystem syndromes [2, 16]. Hypotonia with feeding difficulties and faltering growth is the most frequent reason for referral in BRPS [3].

4.2 Infant and child

In the older child, the guiding signs are recurrent or cyclic vomiting with high myopia and severe intellectual disability in BOS; overgrowth with macrocephaly, early tooth eruption, heart disease and febrile and afebrile seizures in SHAPNS; and intellectual disability with absent speech, autism, strabismus, hypotonia progressing to flexion contractures and marfanoid habitus in BRPS [1–3]. The facial features of BOS and SHAPNS become less marked with age, and the glabellar nevus may disappear, so the face of an adolescent is less informative than that of an infant [1, 2]. The identification of an adult with a congenital neuromuscular picture and an ASXL1 variant shows that the diagnosis may be made late when the phenotype is atypical [53].

4.3 Warning signs and emergencies

Emergencies include recurrent neonatal hypoglycaemia in SHAPNS, because of the risk of brain injury; intractable vomiting with dehydration, aspiration and pneumonia, apnoeas and bradycardia in BOS; status epilepticus; and pulmonary hypertension, a cause of death in patients with BOS and SHAPNS [1, 16, 55]. In BOS, a renal or hepatic lesion on surveillance ultrasound or a rise in alpha-fetoprotein (AFP) requires immediate investigation, because of the predisposition to Wilms tumour and hepatoblastoma [15]. There is no newborn screening for these syndromes; neonatal genomic sequencing enabled the diagnosis of SHAPNS at 21 days in the case in section 10 [55].

4.4 When to suspect PERCHING syndrome

PERCHING syndrome should be considered in a newborn or infant with a face and posture suggestive of BOS without an ASXL1 variant, especially if the parents are consanguineous or there are affected siblings; in an infant with a CS/CISS picture without variants in CRLF1 or CLCF1; in hyperthermia without infection associated with oropharyngeal contractions and camptodactyly; and in a child with syndromic intellectual disability and early-onset pigmentary retinopathy [4, 23, 24]. Prenatally, polyhydramnios with ventriculomegaly and sulcation anomalies justifies rapid exome sequencing when other signs are present [82]. Emergencies include hyperthermic crisis, laryngospasm with respiratory distress, aspiration and epileptic seizures [4, 22].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria

None of the three syndromes has current consensus clinical criteria. For BOS, the clinical criteria proposed before the gene was identified included microcephaly, trigonocephaly, palatal anomalies, prominent eyes with hypoplastic supraorbital ridges, upslanting palpebral fissures, a depressed nasal bridge and anteverted nares, facial nevus, low-set posteriorly angulated ears, faltering growth, severe delay and the characteristic upper-limb posture [8, 28]. As only five of the patients used to construct them had molecular confirmation, they serve to guide suspicion and not to establish the diagnosis [1]. Diagnosis of all three entities requires the identification of a heterozygous pathogenic or likely pathogenic variant in the respective gene, constitutional in the case of ASXL1, in a patient with compatible findings [1–3]. According to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) standards, pathogenic and likely pathogenic variants are equivalent for clinical decision-making [1].

5.2 Testing strategy

The 2026 GeneReviews recommends, in a child with developmental delay or an individual with intellectual disability, with or without dysmorphism or multiple congenital anomalies, starting with exome or genome sequencing and using chromosomal microarray as second line if the exome is negative; single-gene ASXL1 testing (sequencing followed by deletion/duplication analysis) is useful only when clinical suspicion is strong, and multigene panels limit incidental variants [1]. For SHAPNS, GeneReviews accepts targeted testing when the phenotype is suggestive, by ASXL2 sequencing or by intellectual disability, overgrowth, macrocephaly or hypoglycaemia panels that include the gene, and exome or genome sequencing when the syndrome has not been considered [2]. The 2020 ASXL3 GeneReviews proposed starting with microarray and proceeding to a panel or exome, advising against single-gene testing because of the non-specific phenotype [3]. The difference reflects the dates of the documents: the most recent guidance places genomic sequencing first-line [1].

Sources: GeneReviews [1–3]. These proportions describe the distribution of known variants by method, not the clinical sensitivity of the test in a patient with suspected disease, which also depends on genetic heterogeneity (seven of the 13 patients in the original BOS series had an ASXL1 variant) [30].

5.3 Test limitations and interpretation

A negative exome does not exclude the syndrome. Sequencing does not usually detect exonic deletions, deep intronic variants escape the exome, and low-fraction mosaic variants may not be called; an ASXL3 variant mosaic at 30–35% in blood and saliva caused the full phenotype [1, 84]. In interpreting ASXL1, the presence of truncating variants in population databases does not exclude pathogenicity, because most result from age-acquired clonal haematopoiesis; the variant should be assessed in the clinical context and, if necessary, confirmed in another tissue and studied in the parents [1, 39]. In 2026, structural modelling of an ASXL1 missense variant classified as benign in a patient with a BOS picture and of three variants of uncertain significance was proposed as complementary support for interpretation, without the value of functional evidence [85]. The DNA methylation signature allows reclassification of ASXL1 variants of uncertain significance [1, 61]. Heterozygous missense variants in ASXL2 and ASXL3 are not established as causal, and large contiguous deletions including ASXL2 do not allow the phenotype to be attributed to the gene [2, 3].

The laboratory report should state the gene, the transcript with version (NM_015338.6, NM_018263.6 or NM_030632.3), the HGVS designation of the variant at DNA and protein level, zygosity, allele fraction when relevant, origin (de novo, inherited or undetermined) and the ACMG/AMP classification [1, 14]. A variant is designated de novo only when absent in both parents with confirmed parentage; otherwise it is "presumed de novo" [3].

5.4 Ancillary investigations

There is no diagnostic biomarker. Investigations serve to characterise the manifestations: echocardiogram and electrocardiogram, abdominal and renal ultrasound, brain MRI and electroencephalogram as clinically indicated, ophthalmological assessment with electroretinogram and visual evoked potentials in BOS, swallowing and gastric emptying studies, polysomnography and radiographs of the spine and hips [1–3]. In SHAPNS with hypoglycaemia, hyperinsulinism is diagnosed at the time of hypoglycaemia (plasma glucose below 50 mg/dL, 2.8 mmol/L), with inappropriately detectable insulin, low beta-hydroxybutyrate and free fatty acids and a glycaemic response to glucagon; a glucose requirement above 8 mg/kg/min in a newborn (normal 4–6 mg/kg/min) is a sign of excessive insulin action [16]. In the patient in section 10, with glucose of 2.1 mmol/L, insulin was 2.1 µU/mL, free fatty acids 0.34 mmol/L and beta-hydroxybutyrate 0.06 mmol/L [55].

5.5 Practical algorithm

In a child with global delay, hypotonia and feeding difficulties, exome or genome sequencing, ideally as a trio, is the first step; if the phenotype specifically suggests one of the syndromes, a panel including the three ASXL genes and the differentials is an alternative [1, 2]. A truncating variant in the last two exons of ASXL1 or ASXL2, or a truncating variant in ASXL3, confirms the diagnosis in the appropriate clinical context; a variant of uncertain significance can be reassessed by segregation, methylation signature (for ASXL1) and review of the phenotype; a negative result with strong suspicion justifies reanalysis, deletion testing and consideration of the differentials in section 6 [1, 61]. Detection of a truncating ASXL1 variant on a myeloid panel in an adult without the phenotype should be interpreted as probable clonal haematopoiesis, and not as BOS [1, 39].

5.6 Prenatal and preimplantation diagnosis

When the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible [1–3]. In a couple with paternal ASXL3 mosaicism (allele fraction of 8.17% in blood and 15.03% in semen, detected by ultra-deep sequencing), amniocentesis at 18 weeks excluded the variant in the next pregnancy [86]. The ultrasound findings that lead to fetal sequencing, such as growth restriction, polyhydramnios or agenesis of the corpus callosum, are non-specific [29, 81].

5.7 Diagnosis of PERCHING syndrome

There are no formal clinical criteria; diagnosis rests on the identification of biallelic pathogenic or likely pathogenic variants in KLHL7 in a compatible picture [22]. The first diagnoses came from exomes in patients with suspected CS/CISS or BOS who were negative for the known genes, and reanalysis of exomes from patients with a CS/CISS-like phenotype without an identified variant also revealed alternative diagnoses in NALCN, MAGEL2 and SCN2A, which favours exome or genome sequencing over restricted panels [23, 24, 87]. The report should state the transcript NM_001031710.3, the HGVS nomenclature, the zygosity and the ACMG/AMP class of each variant, and the phase of the two alleles should be confirmed in the parents: in the Congolese patient of 2022, the truncating variant had no determined origin and the intronic variant NM_001031710.3:c.793+5G>C, inherited from the mother, was classified as of uncertain significance [73].

Test limitations have practical consequences. ClinVar includes intragenic deletions and duplications of KLHL7, which require copy-number analysis, and intronic and splicing variants whose interpretation depends on RNA studies; the variant NM_001031710.3:c.936+3_936+22del was only reclassified after RT-PCR, and long-read RNA sequencing also revealed residual normal transcript [69, 71]. In children of consanguineous parents, the variant is usually found in a region of homozygosity, such as the 13.6 Mb block on chromosome 7 in the Indian child [42]. A negative exome does not exclude the diagnosis. Fundoscopy and, where possible, electroretinography and visual evoked potentials help support the classification of a variant of uncertain significance, because retinopathy is rare in the other differentials [23, 68]. Brain magnetic resonance imaging documents the corpus callosum anomalies and nodular heterotopia [42]. Rapid trio exome sequencing from amniotic fluid enabled prenatal diagnosis at 31 weeks, and with both familial variants known, early prenatal diagnosis and preimplantation genetic testing are possible [82].

6. Differential Diagnosis

6.1 Differential between the ASXL syndromes and with other entities

The differential depends on the dominant axis of the picture: growth restriction with flexed posture and trigonocephaly (BOS), overgrowth with macrocephaly and hypoglycaemia (SHAPNS) or intellectual disability with autism and absent speech without specific features (BRPS).

AD, autosomal dominant; AR, autosomal recessive; ID, intellectual disability; ASD, autism spectrum disorder; IUGR, intrauterine growth restriction. Sources: GeneReviews [1–3], OMIM [8], KLHL7 report [73] and CD96 report [31].

6.2 Comments on the main differentials

The three ASXL syndromes are distinguished mainly by growth and head circumference: BOS presents with faltering growth and microcephaly, SHAPNS with macrosomia and macrocephaly without growth restriction, and BRPS with growth that normalises after treatment of the feeding difficulties [1, 3, 25]. BOS is distinguished from BRPS by its characteristic dysmorphism, and SHAPNS by macrocephaly and abnormal MRI [3]. Opitz C syndrome was the historical starting point of BOS: the 1999 patients differed from it by growth restriction, clefting, exophthalmos, retinal involvement, upper-limb flexion, dislocation of the radial heads and hirsutism; one patient with a "C-like" picture had a CD96 variant, and one original BOS series had six patients without an ASXL1 variant, so exome sequencing should be preferred to single-gene testing when the picture is suggestive but atypical [8, 30, 31].

The syndrome associated with biallelic KLHL7 variants (called PERCHING, and in Orphanet KLHL7-related "Bohring-Opitz-like" syndrome, ORPHA:603689) reproduces the BOS posture, but has recessive inheritance, retinitis pigmentosa instead of high myopia and optic atrophy, hyperthermia and oropharyngeal contraction [1, 19, 73]. Cornelia de Lange syndrome is the traditional clinical differential of BOS in the Brazilian textbook of genetic syndromes, which includes BOS in its differential diagnosis table, with microcephaly, strabismus, hypertelorism, anteverted nares, micrognathia, growth restriction, trigonocephaly, exophthalmos and the typical position of the shoulders in external rotation with ulnar deviation and flexion of the wrists and metacarpophalangeal joints [88]; the HDAC8 form approaches BOS in its glabellar nevus and widely spaced eyes [1]. The mild 2020 case of BOS had initially been published as a Cornelia de Lange-like phenotype in a cohesinopathy series [8, 54]. For SHAPNS, macrosomia and the glabellar nevus suggest Beckwith-Wiedemann syndrome, and hypoglycaemia due to hyperinsulinism places SHAPNS in the differential of syndromic hyperinsulinism, which the international guideline requires to be screened for in all infants with hyperinsulinism [2, 16]. For BRPS, as the picture is often intellectual disability without distinguishing features, the differential covers all autosomal and X-linked intellectual disabilities, and genomic sequencing is the discriminating test [3]. A brief mention of phenotypic overlap between the conorenal dysplasias and Opitz trigonocephaly syndrome appears in the atlas of skeletal dysplasias [89]. The entity was initially called Crisponi/cold-induced sweating syndrome type 3 (CISS3), a name dropped because cold-induced sweating was confirmed in only one patient; the acronym PERCHING summarises the postural and palatal anomalies, exophthalmos and dependence on enteral tube feeding, respiratory distress and retinitis pigmentosa, contractures and camptodactyly, hypertelorism and hirsutism, growth restriction and intellectual disability, nevus flammeus and neurological malformations, and the facial gestalt with grimacing and the genitourinary anomalies [22]. Death in infancy or early childhood is frequent, but there are survivors into the third decade; neuroimaging shows a thin corpus callosum, ventriculomegaly and, in some patients, periventricular nodular heterotopia, and recurrent infections, sensorineural deafness and septal heart disease may occur [22]. Heterozygous KLHL7 variants cause adult-onset autosomal dominant retinitis pigmentosa (RP42) [22]; the parents carrying truncating alleles who were examined had no retinopathy, and the detailed differential of PERCHING is given in section 6.3 [23, 68].

6.3 Differential of PERCHING syndrome

In the neonatal period, PERCHING overlaps with the ciliary neurotrophic factor receptor (CNTFR)-related disorders and other causes of a CS/CISS-like picture, and in childhood with BOS.

AD, autosomal dominant; AR, autosomal recessive; CNV, copy-number variation. Sources: [1, 4, 19, 23, 87].

The distinction between PERCHING and CS/CISS has prognostic consequences: in CS/CISS, most problems of infancy regress in the first two years with attentive care, whereas in PERCHING few patients survive childhood, none of those described in the GeneReviews differential table had cold-induced sweating, and retinopathy and severe intellectual disability are expected [4, 21]. Compared with BOS, recessive inheritance, pigmentary retinopathy, hyperthermia and oropharyngeal contractions point to KLHL7, whereas trigonocephaly, synophrys, high myopia and cyclic vomiting are rare in PERCHING [19, 42].

7. Treatments and Risk Management Strategies

7.1 General principles

There is no curative therapy or approved drug for any of the ASXL syndromes, and there are no specific clinical practice guidelines; the GeneReviews recommendations are expert consensus based on case series [1–3]. Treatment is supportive, multidisciplinary and directed at the manifestations, with two elements based on guidelines for other conditions: surveillance for embryonal tumours in BOS, covered by the 2024 AACR guideline, and treatment of hyperinsulinism in SHAPNS, according to the 2024 international hyperinsulinism guideline [15, 16]. The doses of the symptomatic drugs cited in the GeneReviews come from guidelines or official labels and, when applied to these syndromes, constitute off-label use.

7.2 Initial evaluation after diagnosis

AFP, alpha-fetoprotein; ECG, electrocardiogram; EEG, electroencephalogram; ERG, electroretinogram; PRM, physical and rehabilitation medicine; HC, head circumference; ASD, autism spectrum disorder; VEP, visual evoked potentials; MRI, magnetic resonance imaging. Sources: GeneReviews and the ASXL3 natural history study [1–3, 37], report of immunodeficiency in SHAPNS [80].

7.3 Bohring-Opitz syndrome: treatment of manifestations

Cyclic vomiting and feeding. GeneReviews recommends identifying and avoiding triggers, instituting daily maintenance medication and treating each episode early; cyproheptadine has been used for maintenance, and abortive treatment includes lorazepam, ondansetron and paracetamol, or a combination of an antiemetic, an analgesic and a sedative; antiemetic prophylaxis before a known exposure (vaccines, infections, anaesthesia) has been beneficial [1]. These triggers do not justify avoiding vaccination or anaesthesia, and all children should complete the vaccination schedule [1]. Gastrostomy or gastrojejunostomy reduces aspiration and improves nutrition, and thickening of feeds helps; fundoplication and antacids are not usually beneficial when reflux is not the cause [1]. When vomiting is controlled, growth improves and admissions for dehydration and aspiration decrease, although growth remains poor; most patients with feeding difficulties need a permanent tube, but the need should be reassessed periodically [1]. The consensus statement of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) for cyclic vomiting syndrome, not specific to BOS, recommends cyproheptadine as prophylaxis up to 5 years and amitriptyline above that age, triptans as abortive agents and, in patients requiring intravenous hydration, 10% dextrose-containing fluids and ondansetron [90]. Constipation is treated with hydration, pelvic floor physiotherapy, exercise, laxatives and stool softeners [1].

Breathing, aspiration and infections. Tracheostomy may be needed to secure the airway, treat aspiration or treat severe obstructive apnoea that does not respond to positive pressure (CPAP, BiPAP) or surgery (adenoidectomy, mandibular distraction); salbutamol and inhaled corticosteroids improved the respiratory status of some patients without typical findings of bronchial hyperreactivity [1, 75]. In the 2015 series, prophylactic inhaled corticosteroids started at 2.5 years reduced infections in one patient, and in another, control of cyclic vomiting with daily inhaled corticosteroids and beta-agonists reduced the frequency and severity of infections [75]. Descending aspiration of saliva can be treated with glycopyrronium or with botulinum toxin injected into the salivary glands, and post-pyloric feeding reduces aspiration [1]. Airway clearance (inhaled corticosteroids, saline nebulisation, intrapulmonary percussive ventilation or vest, cough assistance, suctioning), avoidance of infectious exposures, seasonal vaccination against influenza, COVID-19 and respiratory syncytial virus and prompt assessment of symptoms are recommended, considering admission with intravenous fluids and a pause in feeding because of the risk of aspiration [1]. In the event of fever or increased vomiting, urinalysis and urine culture should be performed and other sources of infection, pain or exposure sought; appropriate treatment of urinary retention, urinary tract infections and nephrolithiasis improves vomiting and reduces admissions [1].

Clefts, sleep, vision and motor function. Cleft lip is repaired on the usual schedule; cleft palate repair may be delayed or omitted when there is no oral language, because it may increase the risk of obstructive apnoea, and the decision should take language and mobility into account [1]. Sleep disturbance is treated with melatonin and behavioural interventions; the dysregulated pattern may be sporadic or cyclic and self-limiting [1, 29]. In the 2015 series, treatment of anaemia improved the sleep of two patients, and mandibular distraction with tongue-lip adhesion resolved obstructive apnoea in one patient [75]. Myopia is corrected with glasses from infancy, with support from a teacher of the visually impaired and occlusion or strabismus surgery [1]. Spasticity is managed by orthopaedics, physical and rehabilitation medicine, physiotherapy and occupational therapy, with stretching and positioning and mobility devices [1].

Epilepsy and drug response. Most patients respond to antiseizure monotherapy, with no drug of specifically demonstrated efficacy [1]. Patients frequently have atypical or paradoxical responses to medicines, especially psychotropics, benzodiazepines and antihistamines, and the GeneReviews authors suggest trying microdoses when a paradoxical reaction occurs [1].

7.4 Shashi-Pena syndrome: treatment of manifestations

Hypoglycaemia is treated with dextrose, avoidance of fasting, continuous feeding and, where appropriate, octreotide, with referral to endocrinology [2]. The 2024 international hyperinsulinism guideline sets the glycaemic target at 70–100 mg/dL (3.9–5.6 mmol/L) (strong recommendation, low evidence), allowing individually a threshold of 63 mg/dL (3.5 mmol/L) in severe forms; it recommends intravenous glucose as initial treatment in the newborn, continuous glucagon infusion when the glucose requirement carries a risk of fluid overload, diazoxide as first line and somatostatin analogues as second line [16]. The guideline also recommends referring all children with hyperinsulinism for developmental surveillance, feeding assessment and early intervention [16]. In an 8-year-old boy with SHAPNS and type 2 diabetes, the association with dyslipidaemia and hepatic steatosis suggests that metabolic assessment should continue beyond infancy [46]. In obesity, GeneReviews recommends reviewing eating habits, monitoring blood glucose, lipids and blood pressure and referring to nutrition [2].

The remaining manifestations have standard treatment: feeding therapy with nasogastric tube or gastrostomy when difficulties persist; antiseizure medications prescribed by an experienced neurologist, with no drug shown to be superior; dental and orthodontic treatment; orthopaedic treatment of scoliosis, kyphosis and hip dysplasia, which may require major surgery; cardiac surgery when indicated (several atrial septal defects have been closed); ophthalmological treatment of ptosis, strabismus and refractive errors; prompt treatment of recurrent otitis media with ventilation tubes and hearing aids (one patient with cochlear implants); and treatment of sleep apnoea by ear, nose and throat or sleep medicine specialists [2]. Aggressive behaviour may benefit from interventions used in autism, such as applied behaviour analysis, from medication for hyperactivity when needed and from child psychiatry in severe cases [2]. The detection of hypogammaglobulinaemia and autoimmune cytopenia in an adolescent with SHAPNS justifies studying immunity in patients with recurrent infections or autoimmune manifestations [80].

7.5 ASXL3-related disorder: treatment of manifestations

GeneReviews recommends feeding therapy with a low threshold for clinical or radiological swallowing assessment and gastrostomy when difficulties persist; antireflux medication, with fundoplication or percutaneous endoscopic gastrostomy in severe cases; standard antiseizure medications; orthopaedic treatment of flat feet, contractures and scoliosis; treatment of sleep apnoea; dental treatment of malocclusion and hypodontia; and ophthalmological treatment of strabismus and refractive errors [3]. As comprehension exceeds expression, augmentative communication devices with specialised speech and language therapy are central, and speech motor learning therapy enabled verbal communication in a patient with apraxia of speech [3, 60]. A 2026 proposal suggests adapting to BRPS the neuromotor assessment and rehabilitation methods used in cerebral palsy and spina bifida, given the lack of specific evidence [91]. The 2025 natural history study recommends baseline renal imaging after diagnosis and dental and ophthalmological follow-up for all patients [37].

7.6 Development and communication in the three syndromes

General recommendations include early intervention (occupational therapy, physiotherapy, speech and feeding therapy) from 0 to 3 years, preschool education with an individualised education plan from 3 to 5 years and follow-up by a developmental paediatrician throughout life, with a transition plan in adolescence [1–3]. Augmentative and alternative communication does not hinder speech development, and children may benefit from interventions used in autism [1, 2]. References to North American programmes (individualised education plans, services up to 21 years, federal support) describe the United States context and should be transposed to the special education and social support systems of each country [1].

7.7 Dosing of the drugs cited

None of the following drugs has an approved indication for the ASXL syndromes. The reference dose is that of the guideline, where one exists for the condition treated (hyperinsulinism); in the remaining cases the dose given is that of the official label for the closest approved indication, with the extrapolation stated.

INN, international nonproprietary name; IV, intravenous; HI, hyperinsulinism; ASD, autism spectrum disorder; EU, European Union.

7.8 Surveillance for Wilms tumour and hepatoblastoma in BOS

Tumour surveillance is the specific element of BOS management. The 2024 AACR guideline considers that the risk of Wilms tumour and hepatoblastoma in BOS exceeds 1%, the threshold above which North America recommends surveillance (Europe typically adopts 5%), and recommends renal ultrasound every 3 months from birth or diagnosis until the 7th birthday and, because of the risk of hepatoblastoma, complete abdominal ultrasound with AFP measurement every 3 months until the 3rd birthday, followed by quarterly renal ultrasound until 7 years [15]. This window covers the age at which 95% of Wilms tumours arise; hepatoblastoma surveillance was shortened from 48 months (2017 guideline) to 36 months, based on the age at presentation in Beckwith-Wiedemann syndrome [15, 99]. The guideline recommends a six-monthly physical examination by a specialist with education about tumour signs; a rise in AFP above 50–100 ng/mL requires review of the last ultrasound and repeat measurement after 6 weeks, two successive rises MRI or contrast-enhanced ultrasound, and values above 1 000 ng/mL urgent confirmation and imaging [15]. It does not recommend surveillance for other tumours in BOS and emphasises shared decision-making with the family [15]. The 2026 GeneReviews recommends abdominal ultrasound and AFP every 3 months until 4 years and then quarterly renal ultrasound until 7 years, that is, one more year of hepatoblastoma surveillance than the AACR [1]. Before these recommendations, the 2015 series proposed abdominal ultrasound every 3–4 months until 8 years, by analogy with Beckwith-Wiedemann syndrome [75]. This article adopts the AACR guideline as the reference, noting the GeneReviews divergence. For SHAPNS and BRPS there is no tumour surveillance recommendation, and somatic ASXL2 and ASXL3 variants in sporadic tumours do not support any screening [2, 3].

7.9 Regulatory status

Sources: hyperinsulinism guideline [16], labels [92, 95–98] and trial registry [17].

7.10 Clinical trials, natural history studies and recent developments

CSF, cerebrospinal fluid. Sources: ClinicalTrials.gov [17, 100] and publications [18, 37, 58, 77].

These studies do not allow interventions to be compared: the only therapeutic trial has one participant, without a control group, and the others are observational. No negative, suspended or withdrawn trials for these syndromes were found on ClinicalTrials.gov on 1 November 2026, which does not exclude unregistered studies.

Antisense oligonucleotides and gene therapy. The most advanced therapeutic approach is reduction of mutant allele expression with antisense oligonucleotides (ASOs), classified as RNA-modulating therapy and not as replacement gene therapy. The strategy rests on the hypothesis that distal truncations produce stable proteins with gain of function or a dominant-negative effect; in that case, restoring the normal protein does not correct the disease, as forced expression of full-length ASXL3 in patient cell lines showed, whereas reduction of ASXL3 RNA with ASOs largely normalised the transcriptional signature [51]. In a second set of studies, allele-specific ASOs reduced expression of the mutant allele in patient cells and partially restored the proteomic profile, and the knock-in mouse model reproduced the molecular changes, whereas heterozygous knockout mice had no phenotype [52]. These results are preclinical and come from 2026 preprints without peer review. Clinical translation is limited to study NCT07197268, declared phase 1/2, which administers a personalised ASO to a single participant with BRPS; the registry does not state the route, target or dose, and the risks it assesses (adverse events, neurological and CSF changes) are those inherent to ASO administration in the central nervous system; there are no efficacy results [17]. For BOS, the 2026 studies identify potential targets (stability of the truncated ASXL1 protein, PRC2 displacement, mitochondrial pyruvate carrier, WNT pathway), without human studies [45, 49, 50]. There is no replacement gene therapy in clinical development for any of the syndromes, and the gain-of-function hypothesis makes that approach unlikely.

Other developments in the last 12 months. Between November 2025 and October 2026 the following were published: the survey on puberty in the ASXL syndromes [77], the genotype-phenotype review of 204 patients with ASXL3 variants [18], familial cases of BRPS due to maternal mosaicism [101], new BRPS cases and findings [56, 81], the congenital-onset neuromuscular phenotype diagnosed at 71 years [53] and the structural reinterpretation of ASXL1 missense variants [85]. In 2025 the ASXL3 natural history study with recommendations [37], immunodeficiency due to biallelic ASXL1 variants [65], the first report of immunological involvement in SHAPNS [80] and the AACR update on emerging Wilms tumour predisposition syndromes [102] had been published. The BOS GeneReviews underwent a comprehensive update on 30 June 2026 [1].

7.11 Agents and circumstances to avoid

In BOS, known vomiting triggers should be avoided and prophylactic antiemetics used before unavoidable exposures, such as anaesthesia, without postponing necessary vaccines or surgery [1]. Paradoxical responses to psychotropics, benzodiazepines and antihistamines justify starting at low doses [1]. In SHAPNS with hypoglycaemia, prolonged fasting should be avoided, which includes planning for preoperative fasting and intercurrent illness [2]. In ASXL1 clonal haematopoiesis, which is not part of these syndromes, management focuses on cardiovascular and haematological risk [40].

7.12 Pregnancy, perioperative care and transition

People with BOS have no known offspring [1]. For women with epilepsy, including those with SHAPNS or BRPS, GeneReviews notes that antiseizure medications reduce maternal mortality, that fetal risk depends on the drug, dose and stage of pregnancy and is generally lower than that of untreated maternal epilepsy, so discussion and any switch to a lower-risk drug should take place before conception [2]. Perioperatively, BOS requires airway planning (micrognathia, laryngomalacia, obstructive apnoea), antiemetic prophylaxis and prevention of aspiration, and SHAPNS prevention of hypoglycaemia during fasting [1, 2]. Patients with BOS and SHAPNS with scoliosis may need extensive spinal surgery [1, 2]. Transition to adult medicine should include supportive care, augmentative communication, assisted living (frequent in adults with BRPS) and, in BOS, monitoring of skeletal and respiratory function, which worsens with immobility [1, 3].

7.13 PERCHING syndrome: management

There is no targeted treatment, gene therapy or clinical trial for PERCHING syndrome or for RP42; a ClinicalTrials.gov search for KLHL7 and for PERCHING returned no studies in November 2026 [103]. There are no dedicated guidelines or consensus statements, and supportive measures are based on the published series and, by stated extrapolation, on the GeneReviews recommendations for CS/CISS, which shares the neonatal pathophysiology of oropharyngeal contractions, respiratory distress and hyperthermia [4, 23].

In the neonatal period, GeneReviews recommends for CS/CISS continuous cardiorespiratory monitoring with oxygen available, a constant room or incubator temperature of 20 °C, a calm, dimly lit environment, gentle handling, reduction of painful stimuli and preparation for hyperthermic and convulsive crises [4]. Laryngospasm with respiratory distress is treated with oxygen without delay and justifies an apnoea monitor; hyperthermic crises, which in CS/CISS reach 42 °C, are treated with cooling blankets, because antipyretics are not effective; acute seizures are treated with antiseizure medications [4]. In CS/CISS, seizures are secondary to hyperthermia and rarely require prolonged therapy, but in PERCHING the coexistence of brain malformations requires neurological and electroencephalographic assessment before deciding the duration of treatment [4, 22]. Respiratory distress at birth may require intubation and surfactant [68].

Nasogastric tube or gastrostomy feeding is needed in most, and severe gastro-oesophageal reflux may require fundoplication [22, 68]. Contractures and camptodactyly are treated with orthoses, physiotherapy and occupational therapy, as in CS/CISS [4]. An initial ophthalmological assessment is recommended by the authors who described the maculopathy, and visual loss requires low-vision support and adaptation of educational programmes [68]. Audiology, echocardiography and urological assessment follow from the sensorineural deafness, septal defects, hypospadias, cryptorchidism and vesicoureteric reflux described [22, 24]. Recurrent infections and sleep apnoea justify respiratory surveillance and polysomnography when there are symptoms [41]. Decisions about life-sustaining measures should be shared with the family, with early involvement of paediatric palliative care, given the mortality in infancy [22]. The drugs used (antiseizure medications, antireflux agents) follow the paediatric doses of their respective indications; none has a specific indication in this syndrome.

8. Reproductive Options and Family Counselling

8.1 Mechanisms of occurrence and recurrence risk

All three syndromes are autosomal dominant and, in most families, result from a de novo variant, so the proband is usually the only affected individual [1–3]. Molecular testing of both parents is recommended to calculate the recurrence risk [1–3].

Sources: GeneReviews [1–3] and family series [18, 57, 58, 67, 84, 86, 101].

In BOS, transmission from a healthy mother with germline mosaicism was demonstrated in 2018: on trio exome sequencing, the variant was under-represented in the mother, and study of buccal DNA confirmed the mosaicism; the authors emphasise that the recurrence risk is low but not zero [67]. The 2023 registry added two families with a mosaic parent, including a pair of affected siblings [58]. In BRPS, two sisters aged 15 and 16 years shared the p.(Arg1036Ter) variant, not detected in the parents [57]; two other families with affected siblings showed no parental mosaicism on trio exome sequencing, and a third patient with the full phenotype had the variant in mosaic form in 30–35% of blood and saliva cells [84]. In 2025, ultra-deep sequencing revealed a father with an allele fraction of 8.17% in blood and 15.03% in semen [86], and in 2026 two half-siblings inherited a variant from a clinically unaffected mother with an allele fraction of about 15% in blood [101]. In the two siblings with apraxia of speech or autism described in 2025, germline mosaicism was also suspected [60]. These data show that sibling recurrence, although rare, is real, and that a negative parental result in blood does not exclude gonadal mosaicism, which leucocyte analysis does not detect [1, 3].

8.2 Cascade testing and carriers

Cascade testing is, as a rule, limited to the parents. In BRPS, the existence of inherited variants with variable expression justifies testing other relatives when a parent is a carrier [3, 18]. High-depth sequencing, including, where possible, semen testing, allows better risk stratification in couples with mosaicism [86].

8.3 Prenatal and preimplantation diagnosis

Once the variant has been identified, prenatal diagnosis by amniocentesis or chorionic villus sampling and preimplantation genetic testing are possible; the ideal time to discuss them is before pregnancy, and decisions vary between families and professionals [1–3]. In a couple with paternal ASXL3 mosaicism, prenatal diagnosis at 18 weeks excluded the variant [86].

8.4 Counselling

Counselling should explain the nature of the syndromes, the variability in severity (greater in SHAPNS and BRPS than in BOS), the absence of specific treatment, the importance of tumour surveillance in BOS and of blood glucose in SHAPNS, and the low but non-zero recurrence risk [1–3]. The difference between a germline ASXL1 variant and a somatic clonal haematopoiesis variant discovered in an adult relative should be explained to avoid misinterpretation of risk [39]. Testing of healthy minors is justified only for clinical decisions; as the carriers of ASXL1 and ASXL2 variants with the classic phenotype are the affected probands, this question arises mainly in families with inherited ASXL3 variants [3].

8.5 Counselling in PERCHING syndrome

PERCHING syndrome is autosomal recessive: when both parents are heterozygous, each pregnancy has a 25% chance of an affected child, 50% of an asymptomatic carrier and 25% of a non-carrier [22]. Consanguinity is frequent in the published families, and affected siblings confirm recurrence [23, 41, 70]. Carrier testing can be offered to the parents' adult siblings and their partners, especially in consanguineous unions, once the phase of the variants in the parents has been confirmed [73]. Regarding carriers' retinal risk, RP42 results from dominant-negative missense variants in the BACK domain, and heterozygous parents with truncating alleles examined up to 60 years of age had no retinopathy; ophthalmological assessment of carriers is decided by variant type and symptoms [23, 43, 68]. With both variants known, prenatal diagnosis on chorionic villi or amniotic fluid and preimplantation genetic testing are possible [82].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

There are no population-based prevalence studies for any of the syndromes. Orphanet places BOS, SHAPNS and BRPS in the <1/1 000 000 class, an upper limit and not an estimate [5–7]. The available figures are counts of described patients: 43 patients with BOS published up to 2015, more than 70 with molecular confirmation in the 2026 GeneReviews and fewer than 300 according to the 2024 AACR guideline [1, 15, 75]; about 23 patients with SHAPNS [2]; and 89 patients with BRPS in the 2020 GeneReviews, 64 in the 2025 natural history study and 204 in the 2026 literature review [3, 18, 37]. ASXL3 is among the ten genes most frequently implicated in large exome studies of intellectual disability, such as the British Deciphering Developmental Disorders study, which suggests that BRPS is the most frequent of the three [3]. Adults with BOS are probably underdiagnosed, because many adults with intellectual disability have never had genomic testing [1].

9.2 Geographical distribution

The syndromes occur in all populations, with no known founder effect, and the distribution of described cases reflects access to genomic sequencing [3]. Patients with BOS have been described on several continents, including North American and European series and a report from Libya, with no population having a documented increased frequency [1, 58]. The Spanish cohort of 22 patients with BRPS is the first European national series, and the international cohorts of 2021 and 2025 brought together patients from the United Kingdom, France, the Netherlands, Italy, Ireland, Greece, Russia, the United States, Canada, Saudi Arabia and Brazil [36, 37, 59]. No epidemiological data from Portugal were found in the sources consulted; the participation of a São Paulo centre in the 2021 international cohort documents patients diagnosed in Brazil, without a frequency estimate [36].

9.3 Special populations

The truncating ASXL1 variants present in population databases reflect age-related clonal haematopoiesis, more frequent in older people, smokers, people with obesity and people with autoimmune diseases or HIV infection, and not carriers of BOS [39, 40]. Adults with mild BRPS and carriers of inherited variants constitute a recently recognised population, with their own counselling needs [18, 36].

9.4 Reference networks and patient organisations

In Europe, the syndromes fall within the European Reference Network ITHACA, dedicated to rare congenital malformations and intellectual disability [104]; the hyperinsulinism of SHAPNS is managed in paediatric endocrinology centres. Patient organisations and registries include the ASXL Rare Research Endowment (ARRE) Foundation (arrefoundation.org), the Bohring-Opitz Syndrome Foundation (bos-foundation.org), the bohring-opitz.org portal, the ASXL Patient-Driven Registry, the ASXL disorders natural history study and biobank and the REACH Biobank (reach-biobank.org), the asxl3.com website, the British association Unique (rarechromo.org) and the Simons Searchlight registry [1–3, 58, 100].

9.5 Epidemiology of PERCHING syndrome

Prevalence is unknown. The published patients come from Turkey, with seven families, almost all consanguineous, India, Iran, Guatemala, the Democratic Republic of the Congo and European centres, including the United Kingdom [23, 24, 41, 42, 68, 70, 72, 73]. In the European CS/CISS1 reference cohort, KLHL7 explained about 6.7% of the 60 families referred with clinical suspicion, a value that measures the fraction in a selected population and not the population frequency [23]. The sources consulted include no patients from Portugal or Brazil. In Europe, the syndrome falls within ERN ITHACA, and the retinopathy within the European Reference Network for rare eye diseases (ERN-EYE) [104, 105]. The Associazione Sindrome di Crisponi e Malattie Rare, in Italy, supported the research that identified the gene [23].

10. Illustrative Clinical Case

10.1 Newborn with Shashi-Pena syndrome and hyperinsulinism

Yuan and colleagues described in 2023 a male newborn, the first child of a 29-year-old mother, born by vaginal delivery at 40 weeks and 2 days, with a weight of 3 030 g and length of 48 cm (10th–50th centiles), head circumference of 36 cm (90th centile) and Apgar scores of 8, 10 and 10, with no relevant family history [55]. On the second day he was transferred to the neonatal unit of the Children's Hospital of Fudan University because of three episodes of hypoglycaemia (1.6–1.8 mmol/L) and two of cyanosis during oral feeding [55]. Examination showed a large V-shaped glabellar nevus flammeus, proptosis, hypertelorism, a broad nasal tip, a broad forehead, low-set, posteriorly rotated ears with thick lobes, arched eyebrows, retrognathia, deep palmar creases, overlapping second and fourth toes, small nails and dorsal hirsutism (figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9926125/figure/f1/) [55].

He was kept nil by mouth on parenteral nutrition and required a maximum glucose infusion rate of 9 mg/kg/min. Echocardiography showed a 3.7 mm patent ductus arteriosus and a 6.2 mm atrial septal defect, both with left-to-right shunt; an upper gastrointestinal contrast study documented gastro-oesophageal reflux and laryngoscopy laryngomalacia; MRI at 6 days showed a small cerebellum (diameter 45.7 mm), and fundoscopy bilateral white "cobblestone" lesions in the retina, unchanged at 6 weeks (figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC9926125/figure/f2/) [55]. Fasting and glucagon tests demonstrated inappropriate insulin: with glucose of 2.1 mmol/L, insulin was 2.1 µU/mL, free fatty acids 0.34 mmol/L and beta-hydroxybutyrate 0.06 mmol/L, and glucose rose only to 2.3 mmol/L 30 minutes after glucagon [55].

He tolerated full enteral feeding at 10 days, but at 19 days recurrent hypoglycaemia required a dextrose infusion at 9 mg/kg/min and glucagon at 12 µg/kg/h; at 35 days, glucagon was replaced by subcutaneous octreotide, started at 0.006 mg every 8 hours, with blood glucose of 3.0–5.8 mmol/L and discontinuation of intravenous dextrose at 41 days [55]. He was discharged at 45 days on full enteral feeding fortified with 2.5 g of enzymatic rice flour per 70 mL of breast milk every 3 hours and subcutaneous octreotide 0.004 mg/kg every 8 hours (timeline in figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC9926125/figure/f3/) [55]. Trio exome sequencing, as part of a neonatal genomic sequencing programme, identified at 21 days the de novo ASXL2 variant NM_018263.6:c.1792C>T p.(Gln598Ter), absent from population databases and confirmed by Sanger sequencing [14, 55]. At 4 months he had no developmental delay [55].

10.2 Clinical reading of the case

The case brings together the neonatal signs that should lead to suspicion of SHAPNS (V-shaped glabellar nevus, hypertelorism, proptosis, deep palmar creases, head circumference on the 90th centile, septal heart disease and hypoglycaemia) and shows the value of early molecular diagnosis [2, 55]. The therapeutic sequence (intravenous glucose, glucagon infusion and somatostatin analogue) corresponds to the options of the international hyperinsulinism guideline, but the guideline recommends diazoxide as first line and octreotide as second, and the discharge dose (0.004 mg/kg every 8 hours, 12 µg/kg/day) lies within the range of 5–20 µg/kg/day; the report does not describe a prior trial of diazoxide, and the management should not be taken as a routine regimen [16, 55]. The small cerebellum and retinal lesions were described for the first time in this syndrome and require confirmation in other patients [55]. The 4-month follow-up does not allow conclusions about neurological prognosis.

10.3 Complementary case: PERCHING syndrome with Crisponi and Bohring-Opitz overlap

A 3-year-old Indian boy, the first child of consanguineous parents, was born at term by caesarean section weighing 3.1 kg; he had a delayed cry, spent one month in intensive care and required nasogastric tube feeding for 8 weeks [42]. From birth he had recurrent fevers and regurgitation, later choking on solids, progressive body stiffness and cold-induced sweating, and at 3 years he had no head control or social smile; he measured 74 cm (−5 standard deviations), with head circumference of 43 cm (−7) and weight of 5.4 kg (−6) [42]. He had a triangular face, sparse hypopigmented hair, a prominent forehead, frontal nevus simplex, hirsutism, arched eyebrows, dysplastic ears, downturned corners of the mouth, gingival hypertrophy and a narrow palate, spasticity, elbow contractures, camptodactyly and absent tendon reflexes [42]. Magnetic resonance imaging showed periventricular nodular heterotopia adjacent to the frontal horn of the right lateral ventricle, symmetrical loss of supratentorial white matter with atrophy of the corpus callosum and delayed myelination, and fundoscopy showed pigmentary changes and retinal mottling; full blood count and liver function were normal [42]. Microarray showed no copy-number variants, but revealed a 13.6 Mb block of homozygosity on chromosome 7 containing KLHL7; trio exome sequencing identified the homozygous in-frame deletion NM_001031710.3:c.181_183del, p.(Val61del), in the BTB domain, with heterozygous parents [14, 42]. The legend of figure 1 of the article describes the pedigree, the chromatograms, the facial phenotype with elbow contractures and camptodactyly and the MRI sections with the heterotopia and corpus callosum hypoplasia [42]. The case brings together the signs that should suggest KLHL7 when BOS or CS/CISS is suspected: consanguinity, fever without a focus, oropharyngeal dysfunction, pigmentary retinopathy and cortical malformation.

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

In BOS, mortality in the early series was 40% (17/43), with 26% of deaths in the first year, mainly due to respiratory infections and to apnoea, bradycardia or cardiovascular causes [75]. Active medical treatment has increased survival, and there are patients alive at the end of their fourth decade; the disease is not progressive, but immobility worsens skeletal and respiratory dysfunction, and complex medical needs worsen the prognosis with age [1, 29]. Feeding difficulties and infections decrease with age, the posture becomes less evident and myopia tends to progress [1, 29]. In SHAPNS, hypotonia and feeding difficulties improve, hypoglycaemia frequently resolves, macrocephaly may progress, and seizures and behavioural problems persist; one patient died of heart disease at 16 months and two developed afebrile seizures in adolescence and adulthood [2, 55]. In BRPS, feeding, hypotonia, verbalisation and motor skills improve over time, obesity may appear later, and most adults live with support [3, 37]. Life expectancy in SHAPNS and BRPS has not been studied.

11.2 Surveillance

AFP, alpha-fetoprotein; DXA, dual-energy X-ray absorptiometry bone densitometry; ASD, autism spectrum disorder; MRI, magnetic resonance imaging.

11.3 PERCHING syndrome: prognosis and surveillance

In the published series, three of five children died between 7 and 24 months and two of six patients died in the first year, but there are survivors alive at 19 and 22 years, with severe intellectual disability, feeding dependence and progressive retinopathy that evolves into maculopathy in adulthood [22–24, 68]. There are no published surveillance intervals for this syndrome; the assessments below derive from the manifestations described and, for neonatal care, from the recommendations for CS/CISS.

12. Summary and Final Considerations

Bohring-Opitz, Shashi-Pena and Bainbridge-Ropers syndromes result from germline variants, almost always truncating and de novo, in the three ASXL genes, which encode components of the Polycomb repressive deubiquitinase complex PR-DUB and chromatin regulators during development. They share hypotonia, early feeding difficulties and developmental delay, but are distinguished by growth and head circumference: growth restriction, microcephaly or trigonocephaly and flexed upper-limb posture in BOS; macrosomia, macrocephaly and hypoglycaemia in SHAPNS; intellectual disability with absent speech, autism and marfanoid habitus in BRPS. Diagnosis depends on genomic sequencing, and interpretation of ASXL1 requires distinguishing a constitutional variant from a somatic clonal haematopoiesis variant, present in population databases. Treatment is supportive and multidisciplinary, with two components supported by guidelines for other conditions: quarterly ultrasound surveillance for Wilms tumour until 7 years and for hepatoblastoma with alpha-fetoprotein until 3 years in BOS, which GeneReviews extends to 4 years, and treatment of hyperinsulinism with glucose, diazoxide and somatostatin analogues in SHAPNS. Cyclic vomiting, aspiration, apnoea and infections determine the early morbidity and mortality of BOS, whose prognosis has improved with active care. Data from 2025 and 2026 suggest that the truncated proteins act through gain of function or a dominant-negative effect, providing a rationale for allele reduction with antisense oligonucleotides, already being studied in a single patient with BRPS. Sibling recurrence due to parental mosaicism, demonstrated in BOS and BRPS, justifies counselling with a low but non-zero risk and the offer of prenatal diagnosis.

PERCHING syndrome, autosomal recessive and caused by biallelic KLHL7 variants, is the main genetic differential of BOS without an ASXL1 variant and overlaps with Crisponi syndrome in the neonatal period; hyperthermia, oropharyngeal contractions, early-onset pigmentary retinopathy and recurrence in siblings born to consanguineous parents point to the diagnosis, which requires exome or genome sequencing with copy-number and splicing analysis. Treatment is supportive, with neonatal care extrapolated from CS/CISS, and recessive counselling should distinguish carriers of truncating alleles, without documented retinopathy, from the dominant-negative variants that cause RP42.

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