Bryant-Li-Bhoj Syndrome and PRR12- and OTUD6B-Related Neurodevelopmental Disorders

Three rare monogenic neurodevelopmental disorders described through genomic sequencing: Bryant-Li-Bhoj syndrome (histone H3.3, genes H3-3A and H3-3B), the neuro-ocular syndrome caused by PRR12 haploinsufficiency and the autosomal recessive OTUD6B-related intellectual developmental disorder.

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

0.1. Identification of the entities

0.2. Essential clinical data

1. Introduction

1.1. Scope and rationale for the grouping

The three entities brought together here share a path of discovery and a place in clinical practice. All were delineated in the last decade from exome or genome sequencing in children with developmental delay, all present with intellectual disability of variable severity, facial dysmorphism without a recognisable gestalt or with merely suggestive features and involvement of other organs, and none has a targeted treatment, its own clinical practice guideline or a registered clinical trial [3, 19, 26, 27]. The diagnosis is almost always molecular and arrives after a broad genomic evaluation, so the clinician meets them mainly in the laboratory report and needs to know how to interpret the variant, anticipate the natural history and organise surveillance. The genes act, however, in different pathways: H3-3A and H3-3B encode histone H3.3, a replacement variant incorporated into chromatin independently of replication; PRR12 encodes a nuclear protein with AT-hook motifs associated with cohesin loading; OTUD6B encodes a deubiquitinating enzyme required for proteasome assembly [2, 22, 28]. Bryant-Li-Bhoj syndrome is the main entity of this article, given the size of the published cohorts and the existence of a GeneReviews review; the other two are covered with the same structure, in their own subsections where they differ.

The historical link between the three genes deserves a note. The first association of PRR12 with human disease arose from a de novo balanced translocation t(10;19)(q22.3;q13.33) that simultaneously disrupted ZMIZ1 and PRR12 in a girl with intellectual disability [29], and one of the descriptions of the OTUD6B-related disorder involved a child with an additional variant in ZMIZ1 [20]. The ZMIZ1-related disorder serves as a differential diagnosis for both.

1.2. Historical milestones

Bryant-Li-Bhoj syndrome. The first patient was described in 2019 by Maver and colleagues in Slovenia: a girl with secondary microcephaly, severe developmental delay, growth restriction and a de novo variant c.185T>G p.(Leu62Arg) in H3F3A, then presented as a candidate gene [30]. In 2020, Bryant, Li and colleagues published in Science Advances a series of 46 unrelated patients with de novo germline variants in H3F3A (33) or H3F3B (13), with progressive neurological dysfunction and congenital anomalies, and without neoplasms, contradicting the notion that H3.3 variants were confined to cancer [17]. The following year, Okur and colleagues added 12 individuals from a cohort of about 16,000 clinical exomes, including the first stop-loss variant [31]. OMIM created the entries BRYLIB1 (#619720) and BRYLIB2 (#619721) in January 2022, the GeneReviews review by Bryant and Bhoj was published in September 2023 with 57 individuals, and an aggregated cohort of 96 individuals (58 published and 38 new) was published in 2024 [1, 3, 4, 12]. In 2026, a preprint reported 100 published individuals with 74 unique causal variants [13]. The eponym brings together the surnames of Laura Bryant, D. Li and Elizabeth Bhoj, authors of the founding series [3, 17].

Neuro-ocular syndrome due to PRR12. After the 2015 translocation [29], Leduc and colleagues described in 2018 three patients with de novo truncating variants, intellectual disability, neuropsychiatric features and a stellate iris pattern with coloboma [32]. In 2021, Reis and colleagues found loss-of-function variants in families with complex microphthalmia or Peters anomaly, sometimes without any systemic feature, and documented the first transmitted allele [16]; in the same year, Chowdhury and colleagues assembled, through case-sharing platforms (GeneMatcher and Matchmaker Exchange), a total of 24 individuals and defined the multisystem spectrum [15]. OMIM designated the entity neuroocular syndrome 1 (#619539) in September 2021 [6].

OTUD6B-related disorder. Santiago-Sim and colleagues described in 2017, in the American Journal of Human Genetics, 12 individuals from six families with biallelic variants, a subviable knockout mouse with congenital heart disease and a proteasome assembly defect in patient cells [22]. The first independent replication, in an Italian girl compound heterozygous for two splicing variants, appeared in 2018 [33], followed by cases from Spain, Mexico, Egypt, Turkey, Thailand, the United States and China [14, 20, 34–40]. ClinGen classified the relationship between OTUD6B and autosomal recessive syndromic intellectual disability as definitive in August 2024 [26].

1.3. Nomenclature and reclassifications

The H3.3 histone genes were renamed by the HGNC from H3F3A and H3F3B to H3-3A and H3-3B; the literature before 2021 uses the former symbols [3, 31]. The syndrome was presented in 2020 as a "neurodegenerative disorder" and reframed in 2024 as a neurodevelopmental disorder with a neurodegenerative component in a subgroup [12, 17]. A frequent source of error is amino acid numbering: the histone literature omits the initiator methionine, so that the variant designated p.Gln125Arg (Q125R) in functional studies corresponds, in HGVS nomenclature, to p.(Gln126Arg); the GeneReviews review draws attention to this one-residue offset [3, 17]. The designation "Bryant-Li-Bhoj syndrome type 2" was at one point associated, in a working database, with the gene HNRNPH2; the entity caused by HNRNPH2 is intellectual disability, Bain type, unrelated to histone H3.3.

The PRR12 entity has three names in use: neuroocular syndrome 1 in OMIM, "multiple congenital anomalies–neurodevelopmental delay–ocular anomalies syndrome" in Orphanet and "PRR12-related disorder" in the clinical literature [6, 8]. The number 1 distinguishes it from neuroocular syndrome 2, caused by variants in DAGLA (OMIM 168885) [6]. The OTUD6B entity is designated in OMIM by the acronym IDDFSDA (intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies) and in Orphanet by an equivalent symptom-based description [9, 11].

One point of molecular nomenclature has practical consequences in OTUD6B: the variants in the founding series and in OMIM were described on transcript NM_016023.3, whose numbering differs by 90 nucleotides (30 codons) from that of the MANE Select transcript NM_016023.5. The recurrent variant NM_016023.3:c.433C>T p.(Arg145Ter) corresponds to NM_016023.5:c.343C>T p.(Arg115Ter), a conversion confirmed in VariantValidator [10, 41]; a 2026 murine study already uses the designation R115* [42].

1.4. Definition of the entities in scope

Bryant-Li-Bhoj syndrome is the neurodevelopmental disorder caused by heterozygous pathogenic germline variants, almost all missense, in H3-3A (type 1) or H3-3B (type 2), characterised by developmental delay or intellectual disability, usually severe, non-specific craniofacial dysmorphism, tone abnormalities, oculomotor anomalies, epilepsy in about half and, in a subgroup, neurological progression [3, 12]. The two types do not differ clinically in a consistent way [3]. Somatic variants of the same genes in tumours (paediatric diffuse gliomas, chondroblastoma, giant cell tumour of bone) constitute a different entity, with no hereditary predisposition [3, 43].

Neuroocular syndrome 1 is the disorder caused by PRR12 haploinsufficiency (truncating variants, rare missense variants, deletions or rearrangements disrupting the gene), with a spectrum ranging from a multisystem neurodevelopmental disease with ocular, cardiac and renal malformations to isolated complex microphthalmia with normal cognition [15, 16, 19].

IDDFSDA is the autosomal recessive disorder caused by biallelic loss of function of OTUD6B, with intellectual disability, early-onset seizures, facial dysmorphism, distal limb anomalies and, with null alleles, microcephaly, growth restriction of prenatal onset, feeding difficulties and congenital heart disease [9, 22].

2. Molecular Genetics and Pathophysiology

2.1. Histone H3.3 and the H3-3A and H3-3B genes

Histones are the basic proteins around which DNA wraps to form the nucleosome. Histone H3 exists as canonical variants (H3.1 and H3.2), synthesised and deposited only during replication, and as a replacement variant, H3.3, expressed and incorporated into chromatin independently of S phase, in quiescent or differentiated cells [2, 17]. H3.3 has 135 amino acids after removal of the initiator methionine and differs from H3.1 and H3.2 at only five and four residues, respectively [17]. It is encoded by two distinct genes, H3-3A (1q42.12; four exons, the first non-coding, about 8.8 kb) and H3-3B (17q25.1; four exons, about 2.5 kb), whose nucleotide sequences and untranslated regions differ but which produce an identical protein [2, 5]. H3-3A is constitutively expressed and H3-3B is induced by stress and stimuli; knockout of either gene alone in the mouse produces distinct phenotypes, indicating that the two genes are not redundant [12]. As the only replication-independent H3, H3.3 is the main form of H3 in post-mitotic cells, including neurons; in the postnatal mouse and human brain it progressively replaces H3.1 and H3.2 until it displaces them almost completely in adulthood [3, 17].

H3.3 deposition is carried out by dedicated chaperones: the HIRA complex at active genes and promoters, and the ATRX–DAXX complex at pericentric heterochromatin, telomeres and endogenous retroelements [2]. The crystal structure of the DAXX–H3.3–H4 complex showed that glycine 90 of H3.3 (in histone numbering) is one of the determinants of specific recognition by DAXX [2]. H3.3-containing nucleosomes are labile and concentrate at active promoters, enhancers and insulators; H3.3 is enriched in activating marks, is required for maintenance of the repressive H3K27me3 marks at the bivalent promoters of developmental genes in embryonic stem cells and for silencing of endogenous retroelements; serine 31, unique to H3.3, is phosphorylated at stimulus-induced genes, where it recruits SETD2 and evicts ZMYND11 [2]. Deletion of both genes in the mouse causes developmental delay, mitotic defects, genomic instability and embryonic lethality, whereas deletion of a single gene has no apparent effect on phenotype or fertility [2, 5].

2.2. Mechanism of Bryant-Li-Bhoj syndrome

The causal variants are heterozygous and, in almost all cases, missense, distributed along the entire protein, both in the disordered N-terminal tail (amino acids 1–43) and in the core with four α-helices and two loops (amino acids 44–135) [12, 17]. Because there are two genes and four alleles, a variant in one allele affects about 25% of total H3.3, a proportion sufficient to cause severe disease; the effect appears to be gain of function or dominant negative, not haploinsufficiency [17, 44]. Both genes are intolerant of missense variation in the population (gnomAD v2.1.1 missense Z-scores of 3.16 for H3-3A and 2.88 for H3-3B) and, of the causal variants, only one (p.M120K, in a single read, probably an artefact) appears in gnomAD [12, 17].

Molecular modelling of the 37 variants in the founding series suggested three non-exclusive mechanisms: disruption of H3.3 binding to DNA (for example, arginine 83 penetrates the minor groove), disruption of the octamer or of interactions with other histones (for example, p.Q125R and p.L48R in histone numbering) and disruption of binding to chaperones and epigenetic regulators (for example, p.G90R and chaperone binding); residues R8, S31, K36 and H39 make extensive contacts with SETD2, ZMYND11, NSD3, MORC3, MLLT3, KDM1B and BRD4 [17]. Two of the five residues that distinguish H3.3 from canonical H3 (S31 and G90) are mutated in patients: G90 is essential for recognition by the chaperones DAXX and UBN1 and S31 for recognition by ZMYND11, whose variants cause a neurodevelopmental disorder with similar hypotonia, seizures and dysmorphism [17].

Functional studies point to local and heterogeneous effects. Histone mass spectrometry in patient lymphoblasts and fibroblasts showed local changes in post-translational modifications on the mutant histone, in cis, without the global dysregulation caused by the oncohistones K27M and K36M; gene expression showed overexpression of mitosis and cell division genes, and fibroblasts from five patients proliferated more than those from six controls at 72 and 96 hours, with equal viability [17]. In HEK293T cells, the variants p.R129H, p.M121I and p.I52N reduced the amount of protein, p.R41C accumulated above normal levels and p.R129H bound DAXX more strongly [31]. A preprint study showed that variants flanking glycine 34 alter H3K36 methyltransferases, H3K36 methylation states in cis and the binding of PWWP domain proteins such as DNMT3A and DNMT3B [45]. In an induced pluripotent stem cell model carrying the H3-3B variant p.Leu48Arg, differentiated into neural progenitors, forebrain neurons and cortical organoids, there was dysregulation of gene expression and chromatin accessibility at genes involved in neuronal fate, adhesion, neurotransmission and excitation–inhibition balance, altered proportions of radial glia and mature neurons and reduced neuronal electrical activity; the authors propose that the variant increases H3-3B expression and H3.3 deposition [21]. In zebrafish, the dominant h3f3a variant D123N causes craniofacial anomalies and loss of both alleles eliminates the neural crest-derived mandibular cartilages and reduces cranial glia [17]. A mouse carrying the recurrent variant T45I, described in a preprint in 2026, reproduces perinatal growth restriction, delayed milestones and progressive motor and gait deterioration [13].

2.3. Spectrum of H3-3A and H3-3B variants

In the aggregated cohort of 96 individuals there were 70 unique causal variants; all H3-3A variants were missense and de novo when the parents were tested, whereas in H3-3B there were also a synonymous variant in the canonical transcript that creates a stop codon in an alternative transcript, a stop-loss variant and the first inherited variant, p.N108S (histone numbering), transmitted by the mother [12, 31]. Some positions are mutated in both genes (N108, P121 and Q125 in histone numbering) and five variants occurred in more than one patient in the founding series [17]. The following table brings together the variants cited in the article, normalised to the MANE Select transcripts in VariantValidator [41]; the c. numbering in the articles (NM_002107.4 or .6 and NM_005324.4) coincides with that of the MANE transcripts for these variants; the histone nomenclature column is filled in only when the source itself provides it.

No consistent genotype–phenotype correlations have been identified. The four patients with p.(Thr46Ile) covered the full severity range, from walking at 21 months to no walking at 4.5 years, with and without seizures, hypotonia or hypertonia, and eight patients with p.(Gln126Arg) in the two genes differed in growth, head circumference and epilepsy [12, 17]. In the cohort of 96, tail variants were more often associated with short stature, microcephaly, abnormal neuroimaging, hypotonia and skin findings, and core variants with heart disease, excess weight and the combination of axial hypotonia with peripheral hypertonia, but the authors presented these differences as trends, without statistical significance, given the sample size [12]. The variability among carriers of the same variant suggests genetic or environmental modifiers [17].

2.4. Germline and somatic H3.3 variants: a necessary distinction

Somatic H3.3 variants are tumour drivers with residue and gene specificity: K27M in H3-3A (or in the H3.1 gene) in diffuse midline gliomas, present in about 78% of diffuse intrinsic pontine gliomas; G34R/V in H3-3A in diffuse hemispheric gliomas of children and young adults; G34W/L in H3-3A in 92% of giant cell tumours of bone; and K36M, mainly in H3-3B, in 95% of chondroblastomas [2, 5]. The World Health Organization classification of tumours of the central nervous system (5th edition) defines diffuse midline glioma, H3 K27-altered, and diffuse hemispheric glioma, H3 G34-mutant, by the respective substitution in H3.3 [43]. The germline variants of Bryant-Li-Bhoj syndrome are distributed throughout the protein and rarely coincide with these hotspots; there were two germline variants at G34 (G34R and G34V), both in H3-3B, and a single mutated lysine (K36E), in a 32-year-old patient without cancer [12, 17]. No neoplasm has been described in germline carriers, including adults, although malignancy was not systematically asked about in the 2024 cohort [3, 12]. The presence of a somatic variant in an isolated tumour does not imply hereditary risk [3].

2.5. PRR12: structure, function and mechanism

PRR12 has 14 exons and encodes, in the canonical transcript NM_020719.3, a proline-rich nuclear protein of 2036 amino acids with two DNA-binding AT-hook motifs (amino acids 347–359 and 381–393); a short isoform of 1215 amino acids, lacking exons 1 to 3 and most of exon 4, corresponds to the original KIAA1205 clone [7, 49]. In the rodent brain, the long isoform is nuclear and reaches peak expression at embryonic day 15, with much lower expression in the adult; a form of about 150 kDa is also located in the postsynaptic density and synaptosomes [7]. In zebrafish, the co-orthologues prr12a and prr12b are expressed in the central nervous system, in dopaminergic nuclei and in the ganglion cell and inner nuclear layers of the retina [50]. In 2025, a co-essentiality analysis identified PRR12 as a protein interacting with NIPBL/MAU2 and with the cohesin complex; its loss reduces cohesin localisation on chromatin and increases DNA double-strand breaks in mouse cells, and the protein co-localises with NIPBL at damage sites [28]. This link brings PRR12 mechanistically closer to the cohesinopathies, such as Cornelia de Lange syndrome, although the phenotype is different [19].

The disease mechanism is haploinsufficiency: loss-of-function variants are extremely rare in the population and ClinGen assigns the gene a haploinsufficiency score of 3 [15, 19]. Among the 24 individuals in the 2021 series there were 12 frameshift variants, 6 nonsense, 1 splicing, 2 missense and a 3.352 Mb deletion at 19q13.33–q13.41 encompassing 146 genes [6, 15]. All the initial variants affected the long transcript and only one also affected the short one, indicating that the long transcript is the relevant one [7]. A biobank analysis of predicted expression (PrediXcan) associated lower PRR12 expression with ocular and renal phenotypes, such as exudative macular degeneration and chronic kidney disease [15].

Two observations by Reis and colleagues have consequences for counselling: the variant c.677dup was found in 11 of 59 reads on the genome and in 4 of 18 on the exome, with low peaks on Sanger sequencing, suggesting somatic mosaicism; and the splicing variant was transmitted by a mother with unilateral microphthalmia to her daughter [16]. The nomenclature conversions of the PRR12 variants were confirmed in VariantValidator [41].

2.6. OTUD6B: structure, function and mechanism

OTUD6B (8q21.3, seven exons) encodes a deubiquitinating enzyme of the OTU (ovarian tumour) family, which removes ubiquitin chains from target proteins [10]. There are three isoforms (323, 192 and 293 amino acids) with the same C-terminal catalytic domain of 188 residues; the isoforms with N-terminal coiled-coil domains repress protein synthesis and proliferation, probably by destabilising the translation initiation complex, and the isoform without these domains does the opposite [10]. The protein acts downstream of mTORC1, influences cyclin D1 translation and MYC stability and participates in proteasome assembly and function [26]. In mononuclear cells from a patient with a truncating variant, incorporation of the 19S regulatory subunits into 26S proteasomes was reduced, chymotrypsin-like activity was decreased, ubiquitin conjugates accumulated and electron microscopy showed abnormal cytoplasmic inclusions in lymphocytes [9, 22]. These assays are research tools and are not available as clinical tests [26].

The Otud6b-/- mouse dies between embryonic day 18.5 and the neonatal period, with growth restriction and ventricular septal defects [10]. A 2026 preprint study showed that a hypomorphic mouse with about 10% of the protein is viable, whereas total loss causes ventricular hypoplasia, ventricular septal defect, cardiac dysfunction and perinatal death, reproduced by a knock-in of the variant equivalent to human p.(Arg115Ter), through cardiomyocyte cell cycle arrest in S phase with reduced cyclins D3, E1 and A2 and CDK2 [42]. Inheritance is autosomal recessive and the mechanism is loss of function; truncating alleles are associated with the more severe phenotype and the missense p.(Tyr216Cys) (NM_016023.3) with a milder phenotype, compatible with a hypomorphic allele [10]. Molecular dynamics suggested that p.(Tyr216Cys) causes only local destabilisation of the protein, whereas p.(Ile274Arg), associated with severe disease, distorts global folding [38].

The variant p.(Arg145Ter) in historical numbering (p.(Arg115Ter) in MANE) was found in the homozygous state in two non-consanguineous Hispanic families, a consanguineous Egyptian family and a Mexican patient born to unrelated parents, and has a frequency of 0.0026 in the ExAC Latino population, making it the most frequently described allele [10, 35]. A Thai child had a 0.118 Mb paternal deletion at 8q21.3 encompassing the gene and a maternal variant c.873del, which made the point variant appear hemizygous on the exome [20].

3. Clinical Spectrum and Manifestations by System

3.1. Description common to the three entities

The three disorders begin in infancy or before birth, with hypotonia, feeding difficulties, poor weight gain or malformations detected on ultrasound, and progress to global developmental delay and intellectual disability of variable severity. Facial dysmorphism is present in most but does not form a pattern that allows a clinical diagnosis, with the possible exception of the hands and face in the OTUD6B-related disorder and the stellate iris in the PRR12-related disorder [3, 15, 37]. Epilepsy is frequent in Bryant-Li-Bhoj syndrome and almost constant in the OTUD6B-related disorder; ocular malformations define the PRR12-related disorder. The available data come from series assembled through sequencing and case-sharing platforms, biased towards the more severe forms and with short follow-up; none of the cohorts describes a population treated with a specific intervention, so all figures reflect natural history under supportive care.

3.2. Bryant-Li-Bhoj syndrome: reference cohorts

The table compares the three main cohorts. The founding series (2020) included 46 patients aged 2 months to 32 years; the GeneReviews review (2023) aggregated 57 published patients; the 2024 cohort assembled 96 individuals (47 male and 49 female, aged 2 months to 39 years), with denominators varying according to available information and age (for example, walking was assessed only in those older than 20 months) [3, 12, 17].

ASD, atrial septal defect; ID, intellectual disability.

3.3. Bryant-Li-Bhoj syndrome: manifestations by system

Development and cognition. The delay is global and usually severe. In the GeneReviews review, about 78% of patients sat late (after 8 months) or did not sit, about 93% walked late (after 16 months) or did not walk and about 52% were non-verbal, with a further 40% having speech delay; the latest patient sat at 7 years and another began walking at 8 [3]. In the founding series, 73% eventually sat (between 6 months and 7 years), 61% walked (between 15 months and 8 years) and 37% said at least one word (between 12 months and 6 years) [17]. In the 2024 cohort, 51% were not sitting at 12 months, 79% were not walking at 20 months and 60% of those older than 20 months said at least one word; delayed walking was more frequent with H3-3A variants (85%) than with H3-3B variants (65%) and in boys (86%) than in girls (71%) [12]. The spectrum includes mild forms: one patient with an H3-3B variant had normal development and intelligence quotient, with an expressive language disorder and seizures from the age of 10 years [4, 12]. Regression occurs in a minority, is not continuous, does not always accompany seizures and is generally mild, although it may lead to loss of walking and speech [3].

Behaviour. Autism spectrum disorder (8% in the 2024 cohort), attention deficit hyperactivity disorder (ADHD, 3%), anxiety (3%), behavioural problems (4%) and stereotypies (7%) have been described; a quarter of individuals had some concomitant neurobehavioural diagnosis, which becomes evident only when the child reaches the necessary age or developmental level [12]. A happy demeanour and hand-flapping stereotypies were noted in some patients, which may recall Angelman syndrome [3, 31].

Tone, motor function and movement disorders. Hypotonia in infancy is the rule and may resolve (resolved in 5 of 55 individuals with information) or evolve into axial hypotonia with peripheral hypertonia; spasticity predominates in the lower limbs and appears in childhood [3, 12]. The combination of axial hypotonia and peripheral hypertonia or dystonia occurred only in carriers of histone core variants [12]. Ataxic or wide-based gait in all patients of a series of four, dystonia in four individuals and oral dyskinesias in two of 97 published individuals have been described [31, 48]. In 2026 a case of paroxysmal dyskinesia with the H3-3B variant c.109A>G p.(Lys37Glu) was published: episodes of hyperventilation followed by right-predominant dystonia and chorea of the face and arms, lasting seconds to 1 minute, more than 50 per day, mainly in the morning, triggered by emotion and sometimes by voluntary movement, with a normal electroencephalogram during the episodes [48]. In three of seven patients with a movement disorder the onset was asymmetric, and one of them had progressive unilateral reduction in putamen and caudate volume [48].

Progression in adulthood. All adults described in the GeneReviews review had, in the third decade, a subacute onset of motor problems that then stabilised, with camptocormia (forward flexion of the trunk when standing that disappears when lying down) and loss of independent walking [3]. The oldest patient in the founding series (32 years) had seizures from the age of 14 and progressive spastic paraparesis from 29 [17]. In the same series, 9 of 46 patients (20%) had clinical neurological deterioration and 26% had cortical atrophy even without intractable epilepsy [17]. The Okur series recorded no progression, which the authors attributed to age and shorter follow-up [31].

Epilepsy. About half of patients have seizures, with onset in infancy or childhood and varied types: myoclonic, tonic, focal with or without impaired awareness, and tonic-clonic [3]. Frequency ranges from a single seizure or controlled febrile seizures to progressively more frequent seizures, status epilepticus and refractory epilepsy [1, 3]. In the 2024 cohort, seizures were more frequent with H3-3B variants (59%) than with H3-3A variants (45%), and occurred in seven of the eight carriers of variants at residue P121 [12]. Neonatal myoclonus of uncertain origin (without an electroencephalographic correlate) was described in a Japanese girl [46], and an H3-3A variant was found in one of 470 patients with early infantile-onset developmental and epileptic encephalopathy, according to Hu and colleagues, cited by Hojo [46].

Growth and head. Growth is altered in about half of patients, with short stature (35%) predominating over tall stature (7%); weight may be below (20%) or above (18%) the normal centile [12]. Two patients classified in childhood as having overgrowth had, years later, normal or short stature, showing that the growth pattern changes with age [12]. Microcephaly (32%) is more frequent than macrocephaly (15%) and more common with tail variants (43%) than with core variants (25%) [12]. About a third have craniosynostosis or an abnormal skull shape, with no preferential suture (brachycephaly, dolichocephaly, sagittal synostosis) [3].

Face. The dysmorphism is non-specific: broad or prominent forehead, bitemporal narrowing, midface hypoplasia, hypertelorism, deep-set eyes, epicanthus, broad or depressed nasal bridge, thin upper lip, open mouth, low-set or posteriorly rotated ears and dental anomalies [1, 12]. All authors stress the absence of a recognisable facial gestalt [3, 31].

Eyes and hearing. Oculomotor anomalies affect about half of patients, mainly strabismus, with nystagmus in 7%, difficulty fixing or following in about 9% and cortical visual impairment in 5% [3]. Myopia, astigmatism (8%) and, in one patient, retinal degeneration with a dysplastic optic nerve have also been described [4, 12]. Ten patients in the founding series had unilateral or bilateral hearing loss; the GeneReviews review describes mild to moderate, static congenital hearing loss in a subgroup [1, 3].

Neuroimaging. In an analysis of 18 magnetic resonance scans, 72% had a small posterior fossa, 44% malformations of cortical development (dysgyria and hypoplastic temporal poles), 33% reduced caudate heads with an internally rotated appearance and enlarged, squared frontal horns, and 28% dysgenesis of the splenium of the corpus callosum [51]. The GeneReviews review adds hypomyelination or delayed myelination in about 25%, Chiari I malformation in 4 of 18 and no correlation between brain malformations and seizures or craniosynostosis [3]. In the 2024 cohort, 58% of scans had at least one abnormality, mainly dysgenesis of the corpus callosum (37%), dilated ventricles (8%) and hemispheric asymmetry (5%) [12].

Other organs. Congenital heart disease in 13–19%, mainly atrial septal defect [3, 12]; cryptorchidism or retractile testes in about a third of boys [3]; urinary anomalies reported by some clinicians (small kidney, horseshoe kidney, single kidney, nephrocalcinosis, recurrent urinary tract infections) [12]; chronic constipation in about a quarter [3]; feeding difficulties in about 25% of infants, most requiring a nasogastric tube or gastrostomy, and laryngomalacia in four patients of the founding series [1, 3]; skin findings in 52% (fetal fingertip pads in 16%, nipple anomalies in 17%, eczema, hypoplastic nails, 2–3 toe syndactyly) and musculoskeletal findings in 60% (scoliosis 21%, ligamentous laxity 22%, clubfoot, hip dysplasia, contractures) [12]. Endocrine abnormalities include hypothyroidism (two patients in the founding series and two congenital cases in the Okur series), type 1 diabetes, precocious puberty, advanced bone age and one growth hormone deficiency with delayed bone age [4, 31].

Mortality. In the founding series three patients died, at 2 months, 10 months and 2.5 years [17]; a carrier of p.(Gln126Arg) in H3-3A died at 10 months [2].

3.4. Neuro-ocular syndrome due to PRR12

Neurodevelopment. In the series of 24 individuals (11 female and 13 male, aged 5 months to 36 years), all had developmental impairment: global delay in 17, isolated motor delay in 3 and isolated speech delay in 4; all those older than 7 years with information had mild to severe intellectual disability [6, 15]. The first three patients had neuropsychiatric features (autism, anxiety, ADHD), sleep problems and abnormal gait [6, 32]. Severity extends to cognitive normality: two of five individuals in the Reis series had normal development and cognition and none had a neuropsychiatric diagnosis [16]. A Chinese boy with a de novo variant had an intelligence quotient of 70 at 6 years and 57 at 11, with ADHD [49].

Eyes. Structural defects are present in half of cases (12 of 24): anophthalmia, microphthalmia, colobomas and optic nerve and iris anomalies; visual impairment affects 77% (17 of 22) and strabismus 36% [6, 15]. The first three patients had a stellate iris pattern, two with iris coloboma, and myopia, esotropia or exotropia [6, 32]. In the ocular series of Reis, all five individuals had microphthalmia (four) or coloboma (one), three had Peters anomaly and there were cataract, foveal hypoplasia, persistent fetal vasculature, glaucoma and hypermetropia; the phenotype was asymmetric in all and unilateral, with a structurally normal fellow eye, in three [16]. This unilateral pattern is unusual for a genetic cause and has practical importance, because unilateral microphthalmia is the presentation with the lowest molecular diagnostic yield [16, 19].

Other organs. Hypotonia (61%), poor weight gain (54%), congenital heart disease (52%; atrial and ventricular septal defects, pulmonary stenosis), renal anomalies (35%; hydronephrosis, ureteral duplication, vesicoureteral reflux) and microcephaly (29%) [6, 15]. Synophrys, ptosis, pectus excavatum, brachydactyly, syndactyly, winged scapula, genu recurvatum and flat feet have also been described [6, 32], short stature in two patients of the ocular series [16] and, in the Chinese patient, short stature (−2.17 standard deviations) with low insulin-like growth factor 1 (IGF-1) and normal growth hormone, persistent left superior vena cava, mild scoliosis and delayed puberty [49]. Facial dysmorphism is variable and does not form a pattern [15]. Three of the 24 individuals had other genetic findings that could contribute to the phenotype [15], and a 30-year-old man with developmental delay and congenital secretory diarrhoea had two de novo variants, one in GUCY2C and the other in PRR12 [52].

ZMIZ1/PRR12 rearrangement. The Mexican girl with the t(10;19) translocation had seizures from the first week, hypertrichosis, abundant grey hair, synophrys, myopia, strabismus, long philtrum, persistent fingertip pads, bilateral pes varus, a mental age of 5 years at 11 and neuropsychiatric features; the authors attributed the Coffin-Siris-like phenotype mainly to ZMIZ1 [6, 29].

3.5. OTUD6B-related disorder

The table summarises the review of 28 patients published in 2025, which includes the 12 of the founding series [14].

Severity and alleles. The nine patients of the founding series with truncating alleles had global delay from infancy, absence of speech even in adolescence, early seizures in all, hypotonia and, in all but one, inability to walk; most had intrauterine growth restriction and all had severe feeding difficulties; two siblings had spastic tetraparesis and three siblings from another family had autism; two patients had deceased siblings with a similar disease [9]. Three Turkish siblings homozygous for the missense p.(Tyr216Cys) (historical numbering) had mild to moderate intellectual disability, without motor or speech delay, seizures at 18 months, 7 and 8 years, a long narrow face, arachnodactyly and a normal MRI [9].

Distinctive features and expansions. Broad distal phalanges, especially of the thumbs and halluces, with prominent interphalangeal joints and fetal pads, were present in all patients of two Egyptian families and were considered pathognomonic by the authors, who also described macrodontia, dental crowding and thick alveolar ridges [37]. Long palpebral fissures, prominent ears, fetal fingertip pads, a vertebral anomaly and seizures led to an initial suspicion of Kabuki syndrome in three siblings, who also had delayed eruption of the primary dentition, soft doughy skin with reduced sweating and mirror movements [40]. A Thai child had Williams syndrome-like features (periorbital oedema, full cheeks, long smooth philtrum) [20]. A Mexican boy had subclinical hypothyroidism, selective IgG and IgA immunodeficiency, nephrocalcinosis, recurrent respiratory infections and constipation; the authors note that recurrent respiratory infections (5 of 6) and chronic constipation (4 of 7) were frequent in carriers of the same variant [35]. The first Chinese patient presented at 6 months with nystagmus, hypothyroidism, optic disc hypoplasia and retinal changes [14]. The retinal degeneration of two Egyptian siblings was explained by a second recessive disease (homozygous RP1L1 variant), and not by the OTUD6B-related disorder [37].

Course. A compound heterozygous Turkish boy lost the few words he had at 7 years and, at 17, weighed 29 kg (−6 standard deviations), measured 140 cm (−5.15) and could not sit unsupported, with axial hypotonia, spasticity and hyperreflexia; MRI showed right thalamic encephalomalacia and partial agenesis of the corpus callosum [38]. An Italian girl compound heterozygous for splicing variants had, at 6 years, mild intellectual disability, mild motor difficulty and tonic-clonic seizures since the age of 5 [33].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

None of the three entities has a picture specific enough to guide single-gene testing; in practice, suspicion leads to a broad genomic evaluation, and recognition serves mainly to interpret the result and to avoid stopping the investigation after a first negative test [3, 18]. The GeneReviews review proposes considering Bryant-Li-Bhoj syndrome in a person with developmental delay or intellectual disability (especially severe) and any of the following: hypotonia; micro- or macrocephaly; craniosynostosis or an abnormal skull shape other than positional plagiocephaly; short stature; epilepsy; spasticity; progressive neurological features, in particular loss of skills, worsening of seizures or gait in adulthood; adult-onset camptocormia; strabismus or nystagmus; non-specific dysmorphism; minor heart disease, especially atrial septal defect; cryptorchidism or retractile testes; and, on MRI, cortical atrophy or a small posterior fossa [3]. Because the disease almost always arises de novo, the patient is usually the only affected family member [3].

The PRR12-related disorder should be considered in the presence of a stellate iris or iris coloboma in a child with delay, of complex microphthalmia or Peters anomaly, especially unilateral or asymmetric with a normal fellow eye, and of the association of developmental delay with ocular malformation, heart disease and renal anomaly [15, 16, 19]. The OTUD6B-related disorder should be considered in a child of consanguineous parents or of Hispanic, Egyptian or Middle Eastern ancestry with intellectual disability, early seizures, microcephaly, broad thumbs and halluces with fetal fingertip pads and a long face with long palpebral fissures, and in patients with suspected Kabuki or Rubinstein-Taybi syndrome without a variant in the main genes [10, 33, 37, 40].

4.2. Clues by age

In the prenatal period, the clues are intrauterine growth restriction and heart disease (OTUD6B-related disorder, with one prenatal diagnosis of tetralogy of Fallot described), ocular, cardiac and renal malformations (PRR12) and, occasionally, macrosomia or microcephaly (Bryant-Li-Bhoj) [4, 15, 39]. In the newborn and infant, hypotonia, feeding difficulties requiring tube feeding, laryngomalacia, myoclonus (one Bryant-Li-Bhoj case), early seizures (OTUD6B) and anophthalmia or microphthalmia (PRR12) appear [1, 3, 9, 46]. In the child, motor and language delay, strabismus, abnormal skull shape, epilepsy, autism or ADHD and growth delay become evident. In the adolescent and adult with Bryant-Li-Bhoj syndrome, the subacute appearance of spasticity, camptocormia, worsening gait or a movement disorder should be recognised as part of the disease and not attributed to another cause without investigation [3, 17, 48].

4.3. Warning and emergency signs

The following warrant urgent assessment: prolonged or clustered seizures and status epilepticus, described in Bryant-Li-Bhoj syndrome and in the OTUD6B-related disorder [3, 9]; signs of aspiration (coughing or choking with meals, recurrent pneumonia) in children with dysphagia [3]; heart failure or cyanosis in undiagnosed heart disease [15, 39]; rapid loss of skills, which requires exclusion of subclinical seizures, adverse drug effects and intercurrent causes before being attributed to the disease [3, 53]; and, in patients treated with valproate, signs of hepatotoxicity, pancreatitis or renal tubular dysfunction, the latter described as Fanconi syndrome in a patient with the OTUD6B-related disorder [35, 54]. In children with anophthalmia or severe microphthalmia, MRI of the orbits and brain and early follow-up by paediatric ophthalmology are priorities for orbital growth and visual stimulation [55].

4.4. Newborn screening

None of the three entities is a target of newborn screening. The congenital hypothyroidism described in patients with Bryant-Li-Bhoj syndrome and with the OTUD6B-related disorder may be detected by routine newborn screening, but later-onset hypothyroidism requires measurement of TSH and free T4 during follow-up [3, 31, 35].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no consensus clinical criteria for any of the entities [3, 19]. The diagnosis is established in a proband with a compatible picture and a pathogenic or likely pathogenic variant: heterozygous in H3-3A or H3-3B (Bryant-Li-Bhoj syndrome), a heterozygous loss-of-function variant or deletion including PRR12 (NOC1), or biallelic in OTUD6B (IDDFSDA) [3, 9, 19]. Under the ACMG/AMP recommendations, pathogenic and likely pathogenic variants have the same clinical value; a variant of uncertain significance neither confirms nor excludes the diagnosis [3].

5.2. Testing algorithm

Since 2021 the American College of Medical Genetics and Genomics (ACMG) has strongly recommended that exome or genome sequencing be considered as a first- or second-tier test in paediatric patients with congenital anomalies with onset before 1 year or with developmental delay or intellectual disability with onset before 18 years, because of the higher yield and because it may be cost-effective when requested early [18]. The GeneReviews review of Bryant-Li-Bhoj syndrome allows starting with chromosomal microarray, followed by a multigene intellectual disability panel or exome, and advises against single-gene testing [3]. The Oxford Desk Reference chapter on intellectual disability places these tests in context: a recognisable clinical diagnosis is obtained in about 25% of cases, the karyotype adds about 4% and microarray about 14% in non-specific cases, and the exome identifies a causal variant in up to 50% of patients with sporadic severe intellectual disability; the British Deciphering Developmental Disorders study found 94 genes enriched for de novo variants, more likely in females, with advanced paternal age and without consanguinity [56]. The same chapter recommends MRI in micro- or macrocephaly and in the presence of neurological signs, an electroencephalogram when seizures or regression are suspected, and FMR1 testing because of the non-specific presentation of fragile X syndrome, which the exome does not detect [56].

The following sequence, applicable to the three entities, is proposed. First, clinical assessment with a three-generation family tree, enquiry about consanguinity, serial head circumference and ophthalmological examination [55, 56]. Second, trio exome sequencing (or genome, where available), with copy number variant analysis, or microarray followed by exome [3, 18]. Third, if the exome is negative and suspicion of Bryant-Li-Bhoj syndrome persists, genome sequencing or reanalysis with verification of coverage of the last exon of H3-3A [17]. Fourth, confirmation of the variant, parental testing and, for OTUD6B, confirmation of the phase of the two alleles [3, 20].

5.3. Yield and limitations of tests

A negative result does not exclude the diagnosis: variants in the last exon of H3-3A may escape exome capture [17]; the synonymous H3-3B variant that creates a stop codon in an alternative transcript may be filtered out as benign if the analysis is restricted to the canonical transcript [12]; stop-loss and splicing variants require targeted interpretation [16, 31]; and balanced translocations are detected neither by the exome nor by microarray [29]. In the OTUD6B-related disorder, apparent homozygosity may result from deletion of the other allele, which only parental testing and copy number analysis can clarify [20]. In consanguineous families, full exome analysis may reveal a second recessive disease that explains part of the phenotype, such as RP1L1-related retinal degeneration [37]; and a patient may have two independent de novo diagnoses, such as PRR12 and GUCY2C [52].

5.4. Variant interpretation

In Bryant-Li-Bhoj syndrome, the most frequently used criteria are confirmed de novo occurrence (PS2), absence from population databases (PM2) and computational predictions (PP3); the intolerance of both genes to missense variation supports pathogenicity, but the variants are almost all private and scattered, without hotspots, so proof of de novo status carries decisive weight [12, 46, 48]. The inherited H3-3B variant p.N108S shows that a variant transmitted by an apparently healthy parent does not exclude pathogenicity, a situation that requires careful phenotyping of the parent [12]. When comparing with the literature, it is essential to check whether the numbering includes the initiator methionine (HGVS) or not (histone nomenclature) [3]. In PRR12, truncating variants in the long transcript NM_020719.3 are usually classified with the PVS1 criterion, as in the Chinese patient of 2024 (PVS1, PM6 supporting, PM2 supporting) [49]. In OTUD6B, the variant should be described on the MANE transcript NM_016023.5, indicating the correspondence with the historical NM_016023.3 numbering when citing the literature [41].

5.5. Complementary investigations after the molecular diagnosis

5.6. Content of the laboratory report

The report should state the gene, the versioned reference transcript (NM_002107.7, NM_005324.5, NM_020719.3 or NM_016023.5), the variant in HGVS (c. and p.), the zygosity, the ACMG/AMP classification with the criteria applied, the origin when the parents have been tested, the allele fraction when it suggests mosaicism and the technical limitations (coverage of the last exon of H3-3A, copy number analysis) [3, 16, 17]. In Bryant-Li-Bhoj syndrome it is useful to add the histone designation, to facilitate comparison with functional studies [3].

5.7. Prenatal and preimplantation diagnosis

Once the variant has been identified in the family, prenatal diagnosis on chorionic villi or amniotic fluid and preimplantation genetic testing are possible; in Bryant-Li-Bhoj syndrome and in the PRR12-related disorder, the usual indication is the risk of parental germline mosaicism, and in the OTUD6B-related disorder the 25% risk [3, 9]. Prenatal exome sequencing identified the OTUD6B-related disorder in a family whose first pregnancy had been terminated because of tetralogy of Fallot [39]. Ultrasound findings (growth restriction, heart disease, microphthalmia) are non-specific and do not allow diagnosis without molecular testing [39, 55].

6. Differential Diagnosis

6.1. Principles

The features of the three entities are not sufficient for a clinical diagnosis; the differential covers all intellectual disabilities without distinctive signs, in the OMIM phenotypic series of autosomal dominant, autosomal recessive and X-linked intellectual disability [3]. In practice, the exome or genome resolves the differential, and the clinician's role is to identify the entities that require tests not covered by sequencing (fragile X syndrome, imprinting disorders, balanced translocations) and those that share enough features to cause confusion before the result [56]. The following entities were chosen by these two criteria or because they were the initial diagnosis in published patients.

6.2. Differential table

AD, autosomal dominant; AR, autosomal recessive; CNV, copy number variants; ID, intellectual disability; MAC, microphthalmia, anophthalmia and coloboma.

6.3. Main differentials

Among the three entities. Bryant-Li-Bhoj syndrome is distinguished by the evolution of tone, the small posterior fossa and motor progression in adulthood; the PRR12-related disorder by the ocular malformations, mostly asymmetric, and the possibility of normal cognition; the OTUD6B-related disorder by recessive inheritance, the hands and feet and almost constant epilepsy [3, 14, 16, 51]. Inheritance is the first discriminating element in counselling, because it changes the recurrence risk from about 1% to 25% [3, 9].

Other histonopathies and chromatin disorders. Bryant-Li-Bhoj syndrome is the first known germline disease of histone H3; truncating variants of HIST1H1E (linker histone H1) cause Rahman syndrome, with overgrowth, and missense variants in histone H4 genes cause Tessadori-Bicknell-van Haaften neurodevelopmental syndrome, all restricted to the histone core [12, 17]. The ZMYND11-related disorder is mechanistically close, because ZMYND11 recognises serine 31 of H3.3, mutated in patients with Bryant-Li-Bhoj [17]. These entities cannot be reliably distinguished clinically and are all covered by the exome.

Recognisable syndromes confused with the OTUD6B-related disorder. The initial suspicion of Kabuki syndrome in three siblings arose from the long palpebral fissures, prominent ears, fetal fingertip pads and vertebral anomaly [40]; Kabuki syndrome is due to variants in KMT2D (about 60%) or KDM6A (10–20%) [57]. The Italian girl with splicing variants had been tested for Rubinstein-Taybi, Kabuki and epilepsy before the exome, and the authors recommend including OTUD6B when the main Rubinstein-Taybi syndrome genes are negative [33]. The Williams syndrome-like features in a child with a deletion of one OTUD6B allele show that a microarray may detect a deletion at 8q21.3 rather than 7q11.23, which should then be completed by sequencing of the other allele [20, 59].

Ocular differential of the PRR12-related disorder. In microphthalmia or anophthalmia, the Oxford Desk Reference chapter recommends a detailed ophthalmological report, ocular ultrasound with axial length, MRI of the orbits and brain in severe forms, renal ultrasound if there are genital anomalies and examination of parents and siblings for subtle colobomas; about 16% of children with microphthalmia or anophthalmia have a chromosomal anomaly and de novo truncating SOX2 variants account for 11% of anophthalmias, always bilateral [55]. In the Reis series, PRR12 explained 4 of 182 cases (2.2%) of microphthalmia, anophthalmia or coloboma undiagnosed after testing of the known ocular genes and 2 of 57 (3.5%) of the unilateral cases, which justifies including the gene in ocular panels [16]. CHARGE syndrome, with coloboma, heart disease and renal or genital anomalies, is the closest syndromic differential [62].

Epilepsy with developmental delay. In a child with seizures and delay, the Oxford Desk Reference recommends MRI (repeated if the first was performed before 15 months), microarray, an electroencephalogram looking for specific patterns and targeted biochemical screening (including biotinidase, the cerebrospinal fluid/blood glucose ratio for GLUT1 deficiency and POLG if lactate is raised), bearing in mind pseudoregression induced by high doses of antiepileptic drugs [53]. Exclusion of a POLG-related mitochondrial disease has direct therapeutic implications, because it contraindicates valproate [54].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no curative or mechanism-directed treatment for any of the three entities, no specific clinical practice guidelines have been published and there are no clinical trials registered on ClinicalTrials.gov (search of 1 November 2026) [3, 19, 27]. Management rests on multidisciplinary supportive care, guided by the known manifestations of each entity, with the aim of improving quality of life, maximising function and reducing complications [3]. The GeneReviews review of Bryant-Li-Bhoj syndrome is the only source with organised recommendations; for the PRR12-related disorder, recommendations derive from the frequencies of manifestations in the published series, and not from a guideline-issuing body [3, 19]. For the OTUD6B-related disorder, the same reasoning applies by extrapolation. The doses below come from official labels or from guidelines for analogous conditions treated with the same drugs; none has been studied specifically in these diseases, and this extrapolation is stated in each case.

7.2. Evaluations following diagnosis

7.3. Epilepsy

Principles. Treatment follows the usual standards for epilepsy, led by an experienced neurologist; several antiseizure medications may be effective, none has shown specific efficacy in Bryant-Li-Bhoj syndrome and some patients are refractory [3]. Educating caregivers about the ways seizures present and about the rescue plan is part of treatment [3]. The choice of drug depends on seizure type, age, sex and comorbidities. Case reports provide useful information but do not establish a routine: in the Japanese girl with Bryant-Li-Bhoj, neonatal myoclonus did not improve with phenobarbital and decreased with valproate; at 18 years lacosamide was ineffective and seizures resolved with levetiracetam [46]. In the OTUD6B-related disorder, one boy was stabilised with valproate and levetiracetam after phenobarbital failure, and another developed Fanconi syndrome with valproate and severe hyponatraemia with oxcarbazepine [35, 38].

Levetiracetam. A broad-spectrum antiseizure medication that binds the synaptic vesicle protein SV2A. Marketed as Keppra® (UCB) in the USA and the European Union, as tablets and a 100 mg/ml oral solution. At the label doses for focal seizures, the paediatric regimen differs between agencies, as the table shows; the maintenance dose is titrated to seizure control or to the limit of tolerance, with gradual tapering on withdrawal (in the EU, in children older than 6 months and weighing less than 50 kg, decrements of no more than 10 mg/kg twice daily every two weeks) [64, 65]. Extrapolation to the entities of this article is based on seizure type and age, not on the disease. Adverse effects to monitor include somnolence, irritability and behavioural changes; long-term effects on learning, growth and puberty in children are not known, according to the European SmPC [65].

Valproate. Used in generalised and myoclonic seizures. In the FDA label for divalproex sodium (Depakote®), the dose for complex partial seizures starts at 10–15 mg/kg/day, with increases of 5–10 mg/kg/day each week, and for absences at 15 mg/kg/day, up to a maximum of 60 mg/kg/day [54]. The boxed warning describes fatal hepatotoxicity, with a markedly increased risk before 2 years of age, especially with polytherapy, congenital metabolic disorders, severe epilepsy with intellectual disability and organic brain disease, in which case it should be used with extreme caution and as monotherapy; it is contraindicated in POLG-related mitochondrial disorders and in children under 2 years with suspected mitochondrial disease; and it causes congenital malformations, cognitive impairment and neurodevelopmental disorders after in utero exposure [54]. In the European Union, the measures endorsed in March 2018 prohibit use in pregnancy for epilepsy unless there is no effective alternative and require a pregnancy prevention programme for all girls and women of childbearing potential [66]. In patients with these three disorders, many with severe intellectual disability and early-onset epilepsy, the label's hepatic risk group frequently applies, and the Fanconi syndrome described in the OTUD6B-related disorder reinforces the need to monitor renal tubular function [35, 54]. The doses used in a published OTUD6B case (20 to 40 mg/kg/day, in combination with levetiracetam 15 to 35 mg/kg/day) lie within the label range [38, 54].

7.4. Tone, motor function and movement disorders

Rehabilitation. Physiotherapy is recommended to maximise mobility and reduce late orthopaedic complications (contractures, scoliosis, hip dislocation), with positioning and mobility devices; occupational therapy addresses fine motor skills affecting feeding, hygiene, dressing and writing; camptocormia is treated with physiotherapy, with neurological assessment [3]. For hypertonia or dystonia, the GeneReviews review mentions referral to specialists for baclofen, tizanidine, botulinum toxin, antiparkinsonian drugs or orthopaedic procedures, without doses [3].

Evidence and doses by analogous condition. The American Academy of Neurology and Child Neurology Society guideline for spasticity in cerebral palsy, the closest analogous condition, recommends botulinum toxin type A for localised spasticity (level A), considers short-term diazepam for generalised spasticity (level B) and tizanidine (level C), and found insufficient data for oral or intrathecal baclofen and for dantrolene (level U) [67]. The FDA label for onabotulinumtoxinA (Botox®) indicates, for paediatric spasticity, 3–6 U/kg in the upper limb (maximum 200 U) and 4–8 U/kg in the lower limb (maximum 300 U), divided among the affected muscles, without exceeding the lesser of 10 U/kg or 340 U per 3-month period [68]. Oral baclofen, in the FDA label for the oral solution (Ozobax DS®), is indicated only for spasticity due to multiple sclerosis in adults, with titration from 5 mg three times daily up to a maximum of 80 mg/day and slow withdrawal; there is no paediatric dose in that label and use in children with these disorders is off-label [69]. Applying these doses to the entities of the article is extrapolation.

Paroxysmal dyskinesia. In the only published case (Bryant-Li-Bhoj syndrome, H3-3B p.(Lys37Glu)), carbamazepine up to 400 mg/day, levodopa 75 mg/day, trihexyphenidyl 15 mg/day, acetazolamide 375 mg/day and levetiracetam 1250 mg/day were ineffective, clonazepam (up to 0.75 mg/day) gave transient benefit and topiramate at 130 mg/day reduced the episodes by more than 50%, from more than 50 to 3–4 per day, with a mean duration of 10 seconds [48]. This is an isolated observation that does not establish routine treatment.

7.5. Feeding and the digestive tract

Feeding difficulties benefit from feeding therapy (speech and language or occupational therapist); thickened or cold foods increase safety; the threshold for clinical swallowing assessment or radiological study should be low in the presence of choking, poor weight gain or recurrent respiratory infections; a nasogastric tube or gastrostomy is needed when dysfunction is severe [3]. In the OTUD6B-related disorder, feeding difficulties affect 16 of 22 patients and one patient received fluids by gastrostomy [14, 35].

Constipation is treated with stool softeners, prokinetics, osmotic agents or laxatives, according to the GeneReviews review [3]. The joint ESPGHAN and NASPGHAN guideline (2014) was written for functional constipation and expressly excludes children with underlying diseases, such as developmental delay, so its application is extrapolation; it recommends oral polyethylene glycol (macrogol) 1–1.5 g/kg/day for 3–6 days for disimpaction, or a daily enema for 3–6 days if polyethylene glycol is not available, and 0.4 g/kg/day as the initial maintenance dose, adjusted to response; lactulose is the first-line alternative and milk of magnesia, mineral oil and stimulant laxatives are adjuncts or second-line options; maintenance lasts at least 2 months, symptoms should have resolved for at least 1 month before stopping and tapering is gradual [70]. The British NICE guideline CG99 likewise recommends macrogol with electrolytes as first line, noting that not all macrogols are licensed below 12 years of age, and a reduction over months [71].

7.6. Endocrinology and growth

Hypothyroidism is treated in the usual way; the FDA label for levothyroxine (Synthroid®) gives weight-based initial paediatric doses that decrease with age: 10–15 µg/kg/day from 0 to 3 months, 8–10 from 3 to 6 months, 6–8 from 6 to 12 months, 5–6 from 1 to 5 years, 4–5 from 6 to 12 years, 2–3 above 12 years with incomplete growth and puberty and 1.6 µg/kg/day thereafter, with titration every 2 weeks according to TSH or free T4, a lower initial dose if there is a risk of heart failure in the first 3 months and starting with a quarter of the dose in children at risk of hyperactivity [72]. The dose is that for hypothyroidism in general, without studies in these diseases. Short stature has no proven treatment: a boy with the PRR12-related disorder and low IGF-1 treated with somatropin (4 IU/day) had an initial response that slowed after 9 weeks, with a gain of 3 cm in 6 months and arrest after discontinuation [49]. This is an isolated case, with no established indication.

7.7. Development, communication and behaviour

Early intervention (from 0 to 3 years), with occupational therapy, physiotherapy, speech and language and feeding therapy, special education and sensory impairment specialists, is recommended for all patients; this is followed by preschool and school education with an individual education plan and a vision and hearing consultant [3]. The GeneReviews review describes the North American system (federal early intervention programmes, individualised education plans up to 21 years of age, disability support); in Portugal and Brazil the equivalent national early intervention and inclusive education systems apply. Augmentative and alternative communication, assessed by a speech and language therapist, should be considered in patients with expressive difficulties and does not hinder speech development [3]. Children with autistic features may benefit from applied behaviour analysis; the developmental paediatrician guides behavioural strategies and the prescription of ADHD medication, and severe aggression is assessed by child psychiatry [3]. The Japanese girl with Bryant-Li-Bhoj received risperidone for impulsive behaviours [46].

7.8. Eyes, hearing, heart, kidneys and genitalia

Strabismus and refractive errors are treated by ophthalmology; visual impairments require low-vision services, in children through early intervention and school and in adults in a low-vision clinic [3]. In the PRR12-related disorder, early visual rehabilitation is a priority, given visual impairment in 77% of patients, and management of the malformations (microphthalmia, Peters anomaly, cataract, glaucoma) follows usual paediatric ophthalmology practice [16, 19]. Hearing aids are indicated for hearing loss [3]. Heart disease, undescended testes and craniosynostosis are treated according to specialty standards; an abnormal skull shape without synostosis may benefit from a cranial orthosis [3]. Renal anomalies in the PRR12-related disorder require follow-up by paediatric nephrology [19].

7.9. Infections and immunity

In the OTUD6B-related disorder, recurrent respiratory infections have been described in 5 of 6 patients with the p.(Arg145Ter) variant (historical numbering) and selective IgG and IgA immunodeficiency in one patient, treated with immunoglobulin; the authors propose screening for hypothyroidism and hypogammaglobulinaemia [35]. Measuring immunoglobulins is reasonable in patients with recurrent infections, by extrapolation from this report.

7.10. Agents to avoid and precautions

No drugs are contraindicated specifically because of these diseases. The label contraindications apply: valproate is contraindicated if there is POLG-related mitochondrial disease and requires the European pregnancy prevention programme in girls and women of childbearing potential [54, 66]. Baclofen should not be withdrawn abruptly [69]. Botulinum toxin should not exceed the paediatric 3-month cumulative dose [68]. In patients with dysphagia, liquid formulations and administration by tube should follow the label instructions (for example, levetiracetam oral solution with a dosing syringe) [64].

7.11. Special situations

Anaesthesia and surgery. The sources consulted do not describe specific anaesthetic complications; preoperative assessment should consider heart disease, aspiration risk in patients with dysphagia, epilepsy (maintenance of antiseizure medication in the perioperative period) and hypotonia [3, 15].

Pregnancy and lactation. Patients with Bryant-Li-Bhoj syndrome have no known reproduction and most of those described have not yet reached reproductive age [3]. The mother carrying H3-3B p.N108S and the mother with unilateral microphthalmia and a PRR12 variant show, however, that carriers with a mild phenotype may have children [12, 16]. In women with epilepsy planning a pregnancy, the choice of antiseizure medication should avoid valproate, in line with the 2018 European measures [66].

Transition to adulthood. The GeneReviews review recommends a transition plan in adolescence [3]. In Bryant-Li-Bhoj syndrome, the adult team should be aware of the risk of subacute motor deterioration in the third decade, camptocormia and spastic paraparesis, and repeat phenotyping throughout life [3, 12, 17].

Palliative care and family support. Regular assessment of the need for palliative care, home nursing, respite for the caregiver, care coordination and access to adapted sport is part of the plan [3].

7.12. Research and therapeutic prospects

Current status. There are no gene therapies, antisense oligonucleotides, pharmacological modulators or clinical trials directed at H3-3A, H3-3B, PRR12 or OTUD6B [27]. The advances of the last 12 months are all preclinical or descriptive: the pluripotent stem cell and organoid model with the H3-3B variant p.Leu48Arg, published in 2026, which the authors present as a step towards the development and preclinical testing of therapies [21]; the mouse with the T45I variant, described in a preprint in June 2026, with non-invasive and clinically translatable measures proposed as a testing platform [13]; the preprint study of the effects of variants near glycine 34 on H3K36 methylation and PWWP domain proteins, which seeks a common treatable mechanism [45]; and the preprint establishing the OTUD6B knock-in mouse as a model of heart disease [42]. From a clinical standpoint, a paroxysmal dyskinesia was described in 2026 and a review of 28 patients with the OTUD6B-related disorder in 2025 [14, 48].

Possible strategies and limits. Because Bryant-Li-Bhoj syndrome variants appear to act through gain of function or a dominant negative effect, and not through loss of function, the addition of a normal copy of the gene (gene replacement therapy) would not correct the defect; theoretical approaches would be selective silencing of the mutant allele or modulation of downstream pathways, and the authors of the founding series suggested H3.3 modulators as a hypothetical target [17, 44]. These proposals have no efficacy or safety data in animal models published to date. In the PRR12-related disorder (haploinsufficiency) and the OTUD6B-related disorder (biallelic loss of function), gene replacement or increased gene expression would in theory suit the mechanism, but there are no preclinical gene therapy studies for these genes [19, 22]. The authors of the Mexican OTUD6B case raised the hypothesis of modulating the mTOR pathway, based on animal models of other diseases with hyperactive mTOR, without data in this disorder [35].

7.13. Regulatory status

Brand names in Portugal and Brazil and the texts of the INFARMED SmPCs and ANVISA package inserts were not consulted; the non-proprietary names used follow the INFARMED forms (levetiracetam, sodium valproate, divalproex sodium, baclofen, botulinum toxin type A, levothyroxine sodium, macrogol).

7.14. Reference clinical and preclinical studies

There are no interventional clinical trials. The table brings together the studies that underpin the natural history and the models.

These studies are descriptive, without a comparison group, and bring together patients identified by sequencing at different centres and platforms, phenotyped by different clinicians and with short follow-up; the frequencies may be biased towards severe forms and should not be compared directly between series [12]. There are no effect estimates for any treatment, and the responses described in isolated cases (topiramate for paroxysmal dyskinesia, levetiracetam or valproate for epilepsy, somatropin for short stature) do not allow general conclusions [46, 48, 49].

7.15. Recommendations of the sources and divergences

The GeneReviews review is the only source with organised recommendations and is based on expert opinion [3]. There is an internal divergence: the summary recommends ophthalmological, audiological and thyroid function assessment "annually or as clinically indicated", whereas the surveillance table indicates only ophthalmology annually and leaves audiology and thyroid function "as clinically indicated" [3]. The 2024 cohort proposes adding genitourinary surveillance and repeating MRI to assess progression, when access and the need for sedation allow [12]. For the PRR12-related disorder, the curated source stresses that the recommendations are inferences from frequencies and not guidelines [19]. Guidelines for analogous conditions (functional constipation, spasticity in cerebral palsy) exclude or did not study these diseases, which limits the strength of the extrapolation [67, 70].

8. Reproductive Options and Family Counselling

8.1. Bryant-Li-Bhoj syndrome

Inheritance is autosomal dominant and, in almost all cases studied, the variant arose de novo [3, 12]. The GeneReviews review recommends molecular testing of the proband's parents to assess the recurrence risk [3]. If the variant is not found in the leucocyte DNA of either parent and biological paternity and maternity are confirmed, the proband has a de novo variant or inherited it from a parent with germline (or somatic and germline) mosaicism; leucocyte testing does not detect all somatic mosaicism or exclusively germline mosaicism [3]. In this situation, the empirical risk to siblings is estimated at about 1%, because of the theoretical possibility of germline mosaicism [3]. If a parent is a carrier, the risk to each sibling is 50% [3]. The description in 2024 of the first inherited variant (H3-3B p.N108S, transmitted by the mother) shows that this scenario exists and that a carrier parent may have a mild or not yet characterised phenotype; phenotyping of the mother, grandparents and siblings was under way [12]. The risk to other relatives is low when the variant is de novo [3]. There is no known reproduction in affected patients, many of whom have not yet reached reproductive age; an affected adult would theoretically have a 50% risk per pregnancy [3].

8.2. Neuro-ocular syndrome due to PRR12

Inheritance is autosomal dominant, with de novo variants in most probands studied, but the family with mother-to-daughter transmission and the proband with probable somatic mosaicism indicate that the parents should be tested rather than presuming a de novo variant [16, 19]. A parent with unilateral microphthalmia, fragile hair or mild learning difficulties may be a carrier, and ophthalmological examination of the parents is useful [16, 55]. The risk to the offspring of a carrier is 50%, with highly variable expressivity, from isolated microphthalmia to multisystem disease with intellectual disability; therefore, the molecular diagnosis should not be used to predict a child's development before clinical assessment [16, 19]. A deletion including PRR12 detected by microarray is interpreted as causal in the same way as a truncating variant, and counselling should take into account the other genes included in the deletion [15, 19]. A balanced translocation disrupting the gene requires chromosomal study of the parents [29, 56].

8.3. OTUD6B-related disorder

Inheritance is autosomal recessive. The parents of a patient are usually asymptomatic heterozygous carriers, and each pregnancy has a 25% risk of an affected child, 50% of a carrier and 25% of a non-carrier [9]. Consanguinity is frequent in the families described and several had more than one affected child or deceased siblings with a similar disease [9, 26]. Confirmation that each parent carries one allele is essential, because apparent homozygosity may correspond to a variant on one allele and a deletion on the other, as in the Thai child with a paternal 8q21.3 deletion [20]. The healthy siblings of a patient have a two-thirds probability of being carriers; carrier testing in adult relatives is useful mainly in consanguineous families and in couples with the same ethnic background, given the frequency of the p.(Arg145Ter) variant in the Latino population [10]. In consanguineous families, full exome analysis may reveal a second recessive disease with its own risk, as happened with RP1L1 [37].

8.4. Prenatal and preimplantation diagnosis and counselling of minors

Once the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible for the three entities, and the ideal time to discuss them is before pregnancy [3]. In de novo forms, the indication is the residual risk of about 1% due to germline mosaicism; in the OTUD6B-related disorder, the 25% risk [3, 9]. The family with the OTUD6B-related disorder whose previous pregnancy had been terminated because of tetralogy of Fallot illustrates the value of molecular diagnosis before a new pregnancy [39]. Views on prenatal diagnosis vary among professionals and families, and the decision is personal [3]. OTUD6B carrier testing in healthy minor siblings should, as a rule, be deferred until they can decide for themselves, because it does not alter their health in childhood; testing of symptomatic children is diagnostic and follows the usual rules.

8.5. Empirical recurrence before the molecular diagnosis

Before a molecular diagnosis, families are given empirical risks: in the Oxford Desk Reference series, recurrence in siblings of children with unexplained intellectual disability was 7.5–10% and, in mild intellectual disability, 20–25%, with familial, environmental and cultural contributions; in the presence of consanguinity, a 25% risk should be assumed until proven otherwise [56]. Identification of a de novo variant in H3-3A, H3-3B or PRR12 reduces the risk to about 1%, and that of two OTUD6B variants sets it at 25%, which shows the value of the diagnosis for reproductive planning [3, 9].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

There are no population studies of prevalence or incidence for any of the entities. Bryant-Li-Bhoj syndrome counted 57 individuals in the 2023 GeneReviews review, 96 in the 2024 aggregated cohort and about 100 published with 74 unique variants in 2026 [3, 12, 13]; the GeneReviews review did not identify populations at increased risk [3]. Orphanet records 29 cases or families with the PRR12-related disorder and 12 with the OTUD6B-related disorder, both with a worldwide point prevalence class below 1/1,000,000; this is a class, not a numerical estimate [8, 11]. The OTUD6B literature brings together 28 patients up to 2025 [14]. These figures measure published cases and do not reflect actual frequency, because identification depends on access to sequencing and because mild forms (isolated ocular phenotype due to PRR12, normal development in H3-3B carriers) tend not to be investigated [12, 16]. In a North American laboratory, 11 of the approximately 16,000 clinical exomes performed between 2011 and 2019 had de novo variants in H3-3A or H3-3B, a proportion that refers to a population referred for exome sequencing and not to the general population [31]. In the context of intellectual disability in general, prevalence is 1–2.5% for an intelligence quotient below 70 and 0.3–0.5% for below 50 [56].

9.2. Geographical distribution and populations

The Bryant-Li-Bhoj syndrome cohorts are multicentre, mainly from the United States and Europe, with isolated cases from Slovenia, Japan and China [12, 17, 30, 46, 47]. The PRR12-related disorder has been described in North American, European (including one Italian), Filipino and Chinese patients [7, 15, 49]. The OTUD6B-related disorder is concentrated in consanguineous families from the Middle East and North Africa (Egypt, Syria, Palestine) and Turkey, and in Hispanic families, with cases in Italy, Spain, Mexico, Thailand and China [9, 10, 14, 20, 33–35, 37–39]. The variant p.(Arg145Ter) (historical numbering; p.(Arg115Ter) in MANE) was found in the homozygous state in two non-consanguineous Hispanic families and in a Mexican patient born to unrelated parents, and has an allele frequency of 0.0026 in the ExAC Latino population, suggesting a relatively frequent allele in Latin American populations that is relevant to counselling couples of that origin [10, 35]. The sources consulted do not include patients from Portugal or Brazil, which does not mean that none exist.

9.3. Diversity and clinical assessment

Assessment of facial dysmorphism depends on the ancestry of the patient and the examiner, which limits comparison between series phenotyped by different geneticists [12]. The sex differences described in Bryant-Li-Bhoj syndrome (genital anomalies more frequent in boys, partly because of the need for intervention for cryptorchidism; oculomotor anomalies more frequent in girls) are trends in small samples [12]. In recessive disorders such as the OTUD6B-related disorder, consanguinity increases the probability of a second recessive disease in the same patient [37].

9.4. Reference networks and patient organisations

In Europe, the relevant European Reference Networks are ERN ITHACA, for rare malformations and neurodevelopmental disorders, ERN EpiCARE, for rare and complex epilepsies, and ERN-EYE, for the ocular malformations of the PRR12-related disorder [23–25]. The GeneReviews review lists as resources the American Association on Intellectual and Developmental Disabilities (AAIDD), MedlinePlus and, for families, parent-to-parent support programmes and Epilepsy Foundation materials [3]. No patient organisations dedicated specifically to these three entities were found, and contact with the research groups maintaining the cohorts (in the case of Bryant-Li-Bhoj syndrome, the Children's Hospital of Philadelphia group) allows inclusion in natural history studies [12].

10. Illustrative Clinical Case

10.1. Neonatal myoclonus and epilepsy in a young woman with a de novo H3-3A variant

Hojo and colleagues described in 2024 the first Japanese patient with Bryant-Li-Bhoj syndrome [46]. She was the third daughter of unrelated parents, with no relevant family history, born at 36 weeks after a normal pregnancy and delivery, weighing 1958 g (−1.9 standard deviations), with a length of 43.5 cm (−1.7) and a head circumference of 29.0 cm (−2.6). On the second day of life, myoclonic movements of all four limbs appeared, increasing in frequency despite phenobarbital. She was admitted at 21 days; at 1 month she weighed 2.66 kg (−2.8), measured 45.5 cm (−3.4) and had a head circumference of 33.0 cm (−2.2), with a normal physical examination. Metabolic screening, karyotype and brain MRI were normal, and the interictal electroencephalogram showed no discharges or changes corresponding to the myoclonus, so the epileptic origin remained unclear; the myoclonus decreased after the introduction of valproate.

At 2 years she had a generalised tonic-clonic seizure during a febrile episode and, later, focal seizures with impaired awareness at 3 years and 5 months and at 4 years and 3 months. After that there was no myoclonus or focal seizures, and valproate was withdrawn at 8 years. Developmental delay became progressively evident: the intelligence quotient was 42 at 6 years (Suzuki–Binet scale). At 18 years and 9 months she had a focal motor seizure evolving to bilateral tonic-clonic; she weighed 43.5 kg (−1.2) and measured 147.8 cm (−1.9), and had hypertelorism, strabismus, a broad, depressed nasal bridge and thick lips, normal tone and no involuntary movements. MRI was normal and the interictal electroencephalogram showed bilateral frontal and parietal spikes and spike-wave complexes during sleep. Two months later she had another generalised tonic-clonic seizure; lacosamide was ineffective and the seizures resolved with levetiracetam. At 18 years, the intelligence quotient was 20 (Tanaka–Binet scale); she walked independently and said simple words, and received risperidone for occasional impulsive behaviours. She had no musculoskeletal, skin or genital anomalies.

Trio exome sequencing, performed at 18 years, identified the de novo variant NM_002107.7:c.143C>G p.(Ala48Gly) in H3-3A (the authors state NM_002107; the description on the MANE transcript was confirmed in VariantValidator), confirmed by Sanger sequencing and classified as likely pathogenic by the PS2 and PM2 criteria; the authors did not apply the PP3 criterion because the computational predictions were discordant, despite a CADD score of 28.5 [41, 46]. Figure 1 of the article shows the face at 3 years and 6 months and at 18 years, the MRI and the electroencephalogram (https://pmc.ncbi.nlm.nih.gov/articles/PMC11614866/figure/Fig1/).

10.2. Lessons from the case

The case brings together several frequent features of the syndrome (severe intellectual disability, microcephaly at birth, strabismus, non-specific dysmorphism, epilepsy with varied seizure types) and a then unprecedented finding, neonatal myoclonus of uncertain origin [12, 46]. It also shows that MRI may be normal, although more than half of patients have abnormalities, and that epilepsy may have long periods of remission and recur in adulthood [3, 12]. The diagnosis was obtained only at 18 years, with the exome, which illustrates the benefit of requesting genomic sequencing early, as the ACMG recommends [18]. The sequence of antiseizure medications used (phenobarbital, valproate, lacosamide, levetiracetam) reflects the team's decisions and does not constitute a recommended treatment for the syndrome; no antiseizure medication has shown specific efficacy [3]. The variant lies outside the hotspots of somatic tumour variants, as do the other germline variants [12, 46].

10.3. Contrast: the first description

The first published case, in 2019, was a Slovenian girl with severe delay, secondary microcephaly, prenatal and postnatal growth restriction, a small atrial septal defect, hypoplasia of the corpus callosum and cerebellum and cortical visual impairment, who at 5 years could sit but could not walk or speak; the de novo variant NM_002107.7:c.185T>G p.(Leu62Arg) in H3-3A was identified only after negative panels of 1607, 611 and 155 genes, through analysis of novel genes in the trio exome [30, 41]. Figure 1 of that article shows the facial dysmorphism (https://pmc.ncbi.nlm.nih.gov/articles/PMC6956640/figure/j_bjmg-2019-0028_fig_001/).

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Bryant-Li-Bhoj syndrome. Life expectancy is not known; several adults have been described, the oldest aged 39 years in the 2024 cohort, and the GeneReviews review considers that the disease does not appear to be life-limiting, based on current data [3, 12]. In the founding series three of 46 patients died, at 2 months, 10 months and 2.5 years [17]. The functional prognosis is of usually severe intellectual disability: about 40% of patients older than 20 months had no words and 79% were not walking at 20 months, although many go on to acquire walking and some words later [12, 17]. About 20% have neurological progression, and all adults described in the GeneReviews review had subacute motor deterioration in the third decade, which then stabilised [3, 17]. Epilepsy may be controlled or refractory [3]. No cancer has been described in germline carriers [3, 12]. Longitudinal data are scarce, and the 2024 cohort recommends repeated phenotyping throughout life to characterise the neurodegenerative component [12].

PRR12-related disorder. The prognosis depends on the degree of intellectual disability (from normal to severe), the severity of the ocular malformations (visual impairment in 77%) and the cardiac and renal malformations; there are no survival data [15, 16].

OTUD6B-related disorder. Null alleles are associated with profound intellectual disability, absence of speech and walking, epilepsy and severe growth restriction; the missense allele p.(Tyr216Cys) (historical numbering) with mild to moderate intellectual disability without motor delay [9]. Deceased siblings with a similar disease and speech regression at 7 years in a severely affected patient have been described [9, 38]. The perinatal lethality of the knockout mouse, due to heart disease, suggests that congenital heart disease contributes to severity [10, 42].

11.2. Surveillance

In the absence of specific guidelines, the Oxford Desk Reference chapter on intellectual disability suggests, as a general rule, genetics reviews 1 year after the initial consultation and again 2 years later, to offer new tests, confirm developmental progress and review recurrence risks [56].

12. Summary and Final Considerations

Bryant-Li-Bhoj syndrome, the neuro-ocular syndrome due to PRR12 and the recessive OTUD6B-related disorder are rare monogenic neurodevelopmental disorders, all identified by genomic sequencing in the last decade and all without targeted treatment. Bryant-Li-Bhoj syndrome results from heterozygous variants, almost always missense and de novo, in one of the two histone H3.3 genes, H3-3A or H3-3B; with about 100 published patients, it is characterised by usually severe intellectual disability, non-specific dysmorphism, hypotonia that may evolve into peripheral hypertonia, oculomotor anomalies, epilepsy in about half, a small posterior fossa on MRI and, in a subgroup, motor deterioration in adulthood. The germline variants are distinct from the somatic tumour variants of the same genes and have not been associated with cancer. The PRR12-related disorder results from haploinsufficiency of a cohesin-associated nuclear protein, with a spectrum from a multisystem disease with ocular, cardiac and renal malformations to isolated unilateral microphthalmia with normal cognition. The OTUD6B-related disorder results from biallelic loss of a deubiquitinating enzyme required for the proteasome and combines intellectual disability, early seizures, characteristic hands and feet, microcephaly and heart disease.

Diagnosis rests on the exome or genome, which the ACMG guidelines recommend as a first- or second-tier test; a negative result does not exclude Bryant-Li-Bhoj syndrome, because some exome kits do not cover the last exon of H3-3A, and the OTUD6B-related disorder requires confirmation of allele phase and a search for deletions. Nomenclature requires attention: histone numbering omits the initiator methionine and the historical OTUD6B numbering differs by 30 codons from that of the MANE transcript. Management is symptomatic and multidisciplinary, guided by the GeneReviews review and by the frequencies of manifestations, with treatment of epilepsy, motor rehabilitation, feeding support, ophthalmological, hearing, cardiac, renal and thyroid surveillance and early educational intervention; doses of symptomatic medicines derive from labels and from guidelines for analogous conditions. Counselling differs between the dominant entities, with a recurrence risk of about 1% when the variant is de novo, although inherited variants and mosaicism exist, and the recessive entity, with a 25% risk. The cellular and murine models published in 2026 create the first platforms for testing therapies, but there are as yet no clinical trials.

13. References

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