Rare Brainstem Malformations (Cap Tegmental Dysplasias, Brainstem Disconnection, ATOH1, Diencephalic-Mesencephalic Dysplasia, Irahara-MACF1 and EXOSC5)

Class of congenital malformations in which the anomaly of the midbrain, pons or medulla is the dominant feature, with EXOSC5-related disease in the same differential diagnosis.

Literature and regulatory information updated: 6 November 2026.

0. Reference Summary Table

The class corresponds to the Orphanet group "syndrome with brainstem malformation as a major feature" (ORPHA:729519; genetic branch ORPHA:730696), which, in the 2026 Orphadata neurological classification, brings together pontine tegmental cap dysplasia, medullary tegmental cap dysplasia, ATOH1-related sensorineural hearing loss with brainstem malformation syndrome, posterior-predominant lissencephaly with broad flat pons and medulla, horizontal gaze palsy with progressive scoliosis and brainstem disconnection syndrome [1]. The French National Diagnosis and Care Protocol (PNDS) for pontocerebellar hypoplasias, published by the Haute Autorité de Santé (HAS) in September 2026, places these entities in the differential diagnosis of pontocerebellar hypoplasias under the heading "predominant brainstem malformations (cap dysplasia, Irahara syndrome)" and adds specific recommendations for EXOSC5-related disease [2]. Orphanet prevalence classes are upper limits and not rates; the counts refer to published cases reviewed by Orphanet [3–9].

1. Introduction

1.1. The brainstem as an object of classification

The brainstem comprises the midbrain, derived from the embryonic mesencephalon, the pons, formed from the rostral portion of the rhombencephalon (metencephalon), and the medulla oblongata, formed from the caudal portion (myelencephalon); the cerebellum is a dorsal extension of the rostral rhombencephalon [44]. For decades, radiologists and pathologists examined these structures little, as they are small and difficult to remove without damage, and only improvements in MRI, neuropathology and neurogenetics made it possible to recognise malformations of the midbrain and hindbrain as relevant causes of neurodevelopmental dysfunction [44]. In 2009, Barkovich, Millen and Dobyns proposed a developmental and genetic classification of these malformations into four groups: early defects of anteroposterior or dorsoventral patterning and of specification of the germinal zones (group I); malformations associated with generalised developmental disturbances with significant involvement of the brainstem and cerebellum, such as lissencephalies with cerebellar hypoplasia and the "molar tooth" dysplasias of the ciliopathies (group II); localised malformations, of partly known pathogenesis attributed to proliferation, cell specification, migration or axonal guidance, subdivided into multilevel malformations and malformations of the midbrain, of rhombomere 1 and the cerebellum, of the pons and of the medulla (group III); and combinations of hypoplasia and atrophy in degenerative disorders of prenatal onset, such as the pontocerebellar hypoplasias (PCH) and congenital disorders of glycosylation (group IV) [45]. The classification orders the entities by genotype when this is known and by the clinical-radiological phenotype when it is not [45].

In this classification, pontine tegmental cap dysplasia belongs to the malformations of the pons (III.D), medullary tegmental cap to the malformations of the medulla (III.E), brainstem disconnection to the segment-loss defects (I.A.2.b, loss of the midbrain or rhombomere 1, and I.A.3.b, loss of the pons or medulla), and horizontal gaze palsy with progressive scoliosis due to ROBO3 to the multilevel malformations (III.A), alongside the congenital cranial dysinnervation disorders (CCDD) [45]. In 2013, Doherty, Millen and Barkovich retained the practical division into predominantly cerebellar, cerebellar and brainstem, predominantly brainstem and predominantly midbrain malformations [44]. In fetal imaging, an expert panel proposed in 2024 a simplified classification into predominantly cerebellar, brainstem and cerebellar, and predominantly brainstem malformations, as it is easier to apply when the structures are still growing [46], and a 2026 paediatric review organises prenatal infratentorial anomalies by the dominant finding: cystic anomalies, cerebellar dysgenesis and brainstem malformations [47]. Orphanet groups the entities in which the brainstem malformation is the main feature in group ORPHA:729519, independent of the cerebellar malformation categories [1].

1.2. Historical overview

Medullary tegmental cap was the first to be described: Barkovich defined it in the 2005 book Pediatric Neuroimaging as an abnormal mass protruding from the posterior surface of the medulla, observed in infants studied for multiple anomalies and associated with agenesis or severe hypogenesis of the corpus callosum, and included it in the 2009 classification [22, 45]. Pontine tegmental cap dysplasia was delineated in 2007 by Barth and colleagues, in Amsterdam, from four unrelated children with the same malformation on MRI: vermian hypoplasia, subtotal absence of the middle cerebellar peduncles, flattened ventral pons, bulging pontine tegmentum, a molar tooth appearance at the pontomesencephalic junction and absence of the inferior olivary prominence; DTI showed an ectopic transverse fibre bundle in the tegmentum and absence of transverse fibres in the ventral pons, and the authors proposed the name that refers to the most distinctive feature on routine MRI [10]. In 2009, Jissendi-Tchofo and colleagues described six patients and interpreted the malformation as a defect of axonal navigation [17]. Cases of brainstem disconnection appeared between 1994 and 2008 (Mamourian and Miller, Sarnat, Bednarek, McCann, Poretti, Barth), with seven patients brought together in the 2009 classification [45].

Diencephalic-mesencephalic junction dysplasia was described in 2012 by Zaki and colleagues in six patients from three consanguineous Egyptian families, with a "butterfly" midbrain contour on axial slices [48]; in 2016, Aran and colleagues linked a recessive microcephaly mimicking intrauterine infection in a Palestinian community to a founder variant in PCDH12 [49], and in 2018 Guemez-Gamboa and colleagues demonstrated biallelic PCDH12 variants in the original families and in six new families [37]. In 2019, De Mori and colleagues described agenesis of the putamen and globus pallidus with junction dysplasia due to recessive GSX2 variants [40]. In 2014, Irahara and colleagues, in a Japanese team with the participation of Engle, published the case of a girl with pontine malformation, undecussated pyramidal tracts and regional polymicrogyria and proposed a new syndrome [34]; in 2018, Dobyns and colleagues found an intragenic MACF1 deletion in that patient and defined posterior-predominant lissencephaly with a "W-shaped" brainstem malformation [35]. EXOSC5-related disease was described between 2019 and 2020, first in an Iranian family with autosomal recessive intellectual disability and conduction blocks requiring pacemakers [50], then in a series of five patients with functional studies in yeast and zebrafish [51]. ATOH1 entered human pathology in 2020 as a gene for autosomal dominant non-syndromic hearing loss in a five-generation Iraqi Jewish family [52], in 2022 as a candidate cause of recessive PCH in two Slovenian siblings [33] and, in January 2026, as the cause of two distinct syndromes: a dominant one, with a recognisable brainstem malformation and mild to moderate hearing loss, and a recessive one, with severe pontocerebellar hypoplasia and profound hearing loss [31].

1.3. Nomenclature, reclassifications and divergences in definition

The name "Irahara syndrome", used by the 2026 French PNDS [2], does not appear as an entry of its own in OMIM or Orphanet; it corresponds to the phenotype published by Irahara in 2014, whose molecular cause was identified in 2018 as an in-frame deletion of exons 62 to 93 of MACF1 [34, 35]. Reanalysis of the patient's imaging in the 2018 series classifies the cortical malformation as diffuse pachygyria with a posterior-to-anterior gradient and thin cortex, rather than polymicrogyria, which places the case within lissencephaly 9 (LIS9, OMIM 618325) and the Orphanet entity "posterior-predominant lissencephaly-broad flat pons and medulla-midline crossing defects" (ORPHA:572013) [8, 35]. This article uses the eponym as a historical synonym and covers LIS9 in the depth required for the differential diagnosis; the other MACF1-related disorders belong to the lissencephaly spectrum.

Medullary tegmental cap is not a single aetiological entity: the 2023 multicentre series brought together 13 patients and 27 published cases with a dorsal medullary protuberance, including 11 with Joubert syndrome and 14 with fibrodysplasia ossificans progressiva (FOP), and reclassified as medullary cap the dorsal medullary lesion described in 13 patients with FOP by Severino in 2016 [22]. There is also an anterior mesencephalic cap dysplasia, described in 2017 in three patients with Joubert syndrome, two of them siblings compound heterozygous for TMEM67 missense variants, which belongs to the Joubert spectrum [53]. Diencephalic-mesencephalic junction dysplasia has two classifications in use: the molecular one, which distinguishes DMJDS1 due to PCDH12 and DMJDS2 due to GSX2 [36, 38], and the radiological one of Severino and Lawrence, with types A (complete hypothalamic-mesencephalic fusion), B (incomplete thalamic-mesencephalic cleavage with parenchymal bands) and C (complete or near-complete thalamic-mesencephalic continuity, generally with fetal hydrocephalus); the correlation between the two has not been established [39]. In OMIM, EXOSC5-related disease is named "cerebellar ataxia, brain abnormalities, and cardiac conduction defects" (CABAC) and in Orphanet "neurodevelopmental delay-hypotonia-cerebellar ataxia-cardiac conduction defects syndrome" [9, 41]. For ATOH1, OMIM retains, in the version consulted, only DFNA89 with the symbol "?", which marks a provisional association, with no entry for the syndromic forms described in 2026, whereas Orphanet records the entity ORPHA:728662 with autosomal dominant and recessive inheritance [6, 29, 32].

1.4. Definition of the entities in scope

Pontine tegmental cap dysplasia is defined by the combination of a hypoplastic, flattened ventral pons with a dorsal bulge of the pontine tegmentum protruding into the fourth ventricle, hypoplasia or absence of the middle and inferior cerebellar peduncles, laterally positioned superior peduncles with a molar tooth appearance, absence of the olivary prominence and vermian hypoplasia, clinically associated with multiple cranial neuropathies [10, 16, 44]. Medullary tegmental cap is defined as an abnormal protuberance of the dorsal surface of the medulla, of variable shape [22]. Brainstem disconnection syndrome is defined by the near-complete absence of a brainstem segment, with the rostral and caudal portions connected only by a thin cord of tissue [27]. Dominant ATOH1-related disease is defined by sensorineural hearing loss with a specific brainstem malformation (short midbrain, small pons with a linear T1-hypointense and T2-hyperintense signal, laterally widened medulla with an anterior cleft) in carriers of C-terminal truncations, and the recessive form by severe pontocerebellar hypoplasia with profound hearing loss due to biallelic loss of function [31]. LIS9 is defined by the triad of posterior-predominant lissencephaly, midline crossing defects and a "W-shaped" brainstem [35]. Diencephalic-mesencephalic junction dysplasia is defined by abnormal cleavage between the diencephalon and mesencephalon, with a ventral midbrain cleft continuous with the third ventricle and the axial "butterfly sign" [37, 39]. EXOSC5-related disease is defined by biallelic variants in the gene in a setting of hypotonia, ataxia and cerebellar hypoplasia, often with brainstem hypoplasia and with a risk of cardiac conduction disease [41].

1.5. Table of the class

2. Molecular Genetics and Pathophysiology

2.1. Common embryological bases

After neural tube closure and segmentation into prosencephalon, mesencephalon, rhombencephalon and spinal cord, most neurons of the midbrain and hindbrain are generated in the neuroepithelium lining the fourth ventricle; in the midbrain, neurons migrate mainly radially to form the dorsal tectum and, ventrally, the substantia nigra, the red nuclei and the motor nuclei of cranial nerves III and IV [44]. The cerebellum derives from the dorsal anterior rhombencephalon (rhombomere 1): the upper rhombic lip generates the glutamatergic precursors, including the granule cells, and the adjacent ventricular zone generates the GABAergic neurons, including the Purkinje cells; ATOH1 and PTF1A define these two germinal zones [44]. The lower rhombic lip does not contribute to the cerebellum and produces the neurons that migrate to form the precerebellar nuclei (pontine, reticulotegmental, inferior olivary, external cuneate and lateral reticular nuclei), connected to the cerebellum from early stages; the genes regulating the two rhombic lips overlap, which explains the frequent coexistence of cerebellar and brainstem defects [44]. The neurons of the pontine and inferior olivary nuclei migrate circumferentially beneath the pia mater from the lateral recess of the fourth ventricle to the ventral brainstem and cross the midline; the ROBO3 receptor, which responds to Slit ligands, is essential for this decussation, and the netrin-1/DCC axis participates in attraction to the midline [10, 34]. Anteroposterior patterning depends on genes such as Pax6, Pax2, En1, En2, Otx2, Gbx2, Wnt1 and Fgf8 in the isthmic organiser, and rhombomere identity depends on HOX genes: in the mouse, loss of Hoxb1 eliminates the facial motor neurons and loss of Krox20 eliminates rhombomeres 3 and 5, the abducens and the visceromotor component of the facial nerve [45]. The malformations in this article result from failures at different points of this sequence: axonal navigation and neuronal migration (cap dysplasias, MACF1, ROBO3), rhombic lip neurogenesis (ATOH1), patterning or segmental disruption (brainstem disconnection), ventral telencephalic specification and diencephalic-mesencephalic cleavage (GSX2, PCDH12) and RNA processing in sensitive tissues (EXOSC5).

2.2. Pontine tegmental cap dysplasia

The cause of pontine tegmental cap dysplasia is not known. Barth and colleagues excluded coding variants in NTN1 and DCC, chosen by analogy with mice lacking netrin-1 or its receptor, which have similar axonal guidance defects [10]. The 2007 DTI showed an ectopic transverse bundle in the pontine tegmentum and complete absence of transverse fibres in the ventral pons, indicating an embryonic defect of axonal growth and guidance with loss of the ventral pontine neurons [10]; in 2009, DTI showed absence of decussation of the superior cerebellar peduncles and of the fibres to the pontine nuclei and an abnormal bundle crossing the midline in the dorsal pons [12]. A high-resolution analysis with high angular resolution diffusion imaging (HARDI) at 3 tesla identified bilateral ectopic peripontine arcuate fibres, a second structural anomaly [57], and neuropathological confirmation was published in 2016 [58]. A hypothesis of a neuronal migration defect has also been proposed [59]. All cases published up to 2011 were sporadic, without consanguinity and with both sexes affected, which led Briguglio and colleagues to postulate a de novo heterozygous defect with dominant action; one patient had a heterozygous deletion of about 96 kb at 2q13 including NPHP1, but a causal relationship is unlikely, because homozygous NPHP1 deletions cause juvenile nephronophthisis, heterozygous carriers are asymptomatic and no patient with cap dysplasia, including the 16-year-old carrier, had nephronophthisis [11, 16]. A high-resolution single nucleotide polymorphism array revealed no pathogenic copy-number variants in three adolescents [12]. The existence of an unaffected monozygotic twin of a patient points to a post-zygotic or non-genetic mechanism in at least some cases [12].

2.3. Medullary tegmental cap

Medullary tegmental cap results from several aetiologies. In the 2023 series, genetic investigation included karyotype (1 of 13), array (5 of 13), exome (5 of 13), genome (3 of 13) and targeted analysis (1 of 13) and identified a paternal 15q21.2 deletion covering part of GLDN, the classic ACVR1 variant p.Arg206His in a child with hallux valgus and normal development, a mosaic anomaly of the entire short arm of chromosome 11 consistent with the Beckwith-Wiedemann spectrum and a CSPP1 variant in a patient with Joubert syndrome [22]. Neuropathology showed, in a 35-week fetus, a dorsolateral mass with mature neurons consistent with a hamartoma, connected to the cerebellum, with intact olives and pyramidal tracts; in a 17-week fetus, a rotated medulla with a white matter mass and fibre continuity with the cerebellum; and, in an 11-month-old child with a progressive course, spheroids in the posterior tracts of the medulla suggestive of neuroaxonal dystrophy, with normal genome and mitochondrial DNA [22]. In an autopsy of a 75-year-old patient with FOP, the cap corresponded to glial hyperplasia [22]. The authors postulate abnormal axonal guidance in some cases and ciliary dysfunction in others, based on rotation of the medulla, callosal agenesis and polydactyly, and point out that ACVR1 is involved in cilium formation [22].

2.4. Brainstem disconnection

Two hypotheses have competed since the first descriptions. The malformation hypothesis rests on the neuropathology of two cases by Sarnat, with a thin median cord between the upper and lower segments, cerebellar hypoplasia, an abnormal basilar artery and a disorganised mixture of neurons in the tegmentum, without gliosis suggestive of hypoxia or ischaemia [45], and on the 2007 case of Poretti [60]; Barkovich acknowledges that some disconnections may be segmental dysgeneses due to misexpression of segmentation genes [45]. The disruption hypothesis rests on Barth's 2008 autopsy, which reconstructed a fragile tube of mature tissue around a cylinder of fluid from the ventral pons to the midbrain, with the basilar artery reduced to a minimal median vessel, heterotopic glial tissue, absence of the olive and a dysplastic dentate nucleus, and interpreted the lesion as a syrinx due to insufficient perfusion and obstructed venous drainage near birth [28]. In 2017, the same school described dysregulated EZH2 expression in tissue from patients with congenital disconnection [24]. In 2022, Vekemans and colleagues documented, in the prenatal and postnatal imaging of a newborn girl whose mother had three admissions for very severe dehydration from 18 weeks, the prenatal occurrence of a vascular disruption, and noted that vascular disruption had been suggested in 8 of 13 published cases and confirmed at autopsy in at least 2 [26]. In 2026, Alshehri and colleagues described an affected twin from a discordant pregnancy, with aplasia or hypoplasia of the basilar and distal vertebral arteries, negative exome and genome and heterozygous for a TMEM67 frameshift variant (c.579_580del, p.Gly195IlefsTer13), considered only a plausible ciliary modifier without proof of causality [25]. Okumura and colleagues had described periventricular nodular heterotopia and bilateral proatlantal intersegmental arteries in one case, with normal array, FLNA and EN2 [23].

2.5. ATOH1

ATOH1 (4q22.2; GRCh38 4:93,828,753–93,830,964) encodes a basic helix-loop-helix (bHLH) transcription factor homologous to the Drosophila proneural gene atonal, with 89% identity between human and mouse [29]. It is required for the genesis, survival and maturation of neuronal and non-neuronal populations involved in proprioception, interoception, balance, respiration and hearing [29]. In the mouse, absence of Atoh1 prevents formation of the cerebellar granule cells and the external germinal layer and causes neonatal death from respiratory failure; the gene is also essential for inner ear hair cells, Merkel cells and the cochlear and accessory auditory nuclei; the hypomorphic S193A allele causes coordination deficits, altered cerebellar foliation, partly defective migration of pontine nucleus progenitors and deafness [29]. Lower rhombic lip progenitors expressing Atoh1 generate the pontine nuclei and the dorsal column nuclei, the origin of the transverse pontine fibres and the medial lemniscus [31].

Human variants fall into two classes with opposite mechanisms. C-terminal truncations (c.853_856dup, c.1030dup, c.1030del, c.1053del) give rise to proteins that remain nuclear, retain transcriptional activity and have a prolonged half-life; the C-terminal region contains serines phosphorylated by casein kinase 1, which recruit the ubiquitin ligase Huwe1 and promote degradation, and their loss is the candidate mechanism for the stabilisation [31]. In zebrafish embryos with C-terminal truncations of atoh1a, rhombic lip progenitors proliferate more and differentiate early, and lateral line hair cells increase transiently, the opposite of what happens with loss of function; the authors conclude that this is a gain of function [31]. Variants that eliminate the bHLH domain (c.102dup, c.212del) or inactivate it (c.481C>G, p.Arg161Gly, with no transcriptional activity and partial cytoplasmic mislocalisation) cause loss of function and have an effect only in the homozygous state; heterozygotes are asymptomatic, because ATOH1 is not sensitive to haploinsufficiency [31, 33]. This duality requires each variant to be interpreted by its position and predicted effect on the protein: the same American College of Medical Genetics and Genomics (ACMG) class of "likely pathogenic" has opposite inheritance consequences depending on whether it is a C-terminal truncation (dominant) or an early variant (recessive).

2.6. MACF1 and Irahara syndrome

MACF1 (1p34.3) encodes a giant spectraplakin that binds actin and, through the GAR domain, microtubules, stabilises cortical microtubules, regulates focal adhesions and cell migration and is required for neuronal migration, neurite outgrowth and axonal guidance [35]. LIS9 variants are de novo heterozygous missense variants in the zinc-binding residues of the GAR domain (Cys7135, Asp7186 and Cys7188 in version ENST00000372915.7 of the Ensembl transcript MACF1-204 and Cys5177, Asp5228 and Cys5230 in NM_012090.5, the two numberings used in the article; Cys7236, Asp7293 and Cys7295 in the MANE Select transcript NM_001394062.1) or, in the Irahara case, a 39.6 kb intragenic deletion of exons 62 to 93 of MACF1-204 that removes in frame residues Ala5498 to Arg7150 (ENST00000372915.7 numbering), including the last ten spectrin repeats, the two EF-hand domains and the first two zinc-binding residues [30, 35]. Version ENST00000372915.8 of the same transcript, used in the 2025 cohort, numbers the GAR domain residues three units lower (p.Asp7186Tyr of 2018 corresponds to p.Asp7183Tyr of 2025), so that comparison between series requires the version to be stated or conversion to the MANE transcript [35, 61]. The deletion was not detected by sequence variant analysis and appeared only on inspection of read depth and with CNV-calling algorithms on the exome and structural variant callers on the genome, with breakpoints confirmed by PCR [35]. The proposed mechanism is gain of function or dominant negative, because there are heterozygous truncations in the population without the phenotype, and a 2025 cohort of 45 individuals showed that variants in the EF-hand/GAR module increase microtubule binding [35, 61]. Patient fibroblasts have a higher proportion of short cilia [35]. Biallelic variants, mainly in the plakin domain, are associated with a distinct central and peripheral neurodevelopmental picture [61].

2.7. PCDH12 and GSX2

PCDH12 (5q31.3) encodes protocadherin 12, a non-clustered cadherin concentrated at interendothelial junctions and also expressed in neural precursors [37]. DMJDS1 variants are biallelic loss-of-function variants: the Palestinian founder c.2515C>T (p.Arg839Ter) with nonsense-mediated mRNA decay [36, 49] and five homozygous truncating variants in exon 1 in the Egyptian and Turkish families, with no protein detectable in HEK293 cells [37]. Patient-derived induced pluripotent stem cells, differentiated into neural precursors and endothelial cells, do not express PCDH12 and show reduced neurite outgrowth, which links the malformation to a dual neuronal and endothelial deficit and explains the coexistence of calcifications and exudative vitreoretinopathy [37, 55]. GSX2 (4q12) encodes a homeodomain transcription factor expressed in progenitors of the lateral and medial ganglionic eminences, from which the basal ganglia and olfactory tubercles derive; the nonsense variant p.(Ser9Ter) abolishes the protein and the missense p.(Gln251Arg) reduces expression, destabilises the homeodomain, weakens DNA binding and reduces nuclear localisation, with dysregulation of ASCL1, PAX6, SOX4 and MAP2 [38, 40]. The Gsh2-null mouse dies on the first day from apnoea and lacks the area postrema, a chemosensitive cardiorespiratory centre of the hindbrain [38].

2.8. EXOSC5 and the RNA exosome

The RNA exosome is a ten-subunit complex that processes and degrades RNA in the 3'→5' direction, with a ring-shaped core (EXOSC4 to EXOSC9) and a cap of three subunits (EXOSC1 to EXOSC3); the exonucleases bind to this catalytically inactive core [42]. EXOSC5 (RRP46) is a structural subunit of the ring located on the same face as EXOSC3 and in direct contact with EXOSC8 and EXOSC9, which explains the clinical overlap with the PCHs due to EXOSC3 (PCH1B), EXOSC8 (PCH1C) and EXOSC9 (PCH1D) [51]. The known missense variants are hypomorphic: p.Thr114Ile and p.Leu206His alter interactions with other subunits, and in yeast the orthologous variant of p.Leu206His impairs growth, whereas that of p.Thr114Ile does not [41, 51]; the yeast variant modelling p.Leu206His is among those producing the largest transcriptome changes, with consequences shared in ribosome biogenesis and consequences specific to each variant [62]. All exosome subunits are essential for viability in yeast and in the mouse, and complete biallelic loss of function is probably incompatible with human life; the degree of residual function would determine severity and extraneurological involvement [42]. In zebrafish, complete knockdown of exosc5 is non-viable and partial knockdown causes a short curved tail, oedema, small eyes and head and brain anomalies [41]. The mechanism of thrombotic microangiopathy does not depend on complement dysregulation; in the conditional Exosc3 mouse model, knockdown causes cell-cycle arrest and apoptosis, with death at a median of eight days and lesions in the dividing cells of the bone marrow and intestine [43, 63].

2.9. Normalised variants

All variants in the table were validated in VariantValidator on GRCh38 with the MANE Select transcript (Matched Annotation from NCBI and EMBL-EBI) and Human Genome Variation Society (HGVS) nomenclature [30]. The notation published by Brownstein for the DFNA89 variant (p.His344Ilefs*17) corresponds, in current nomenclature, to p.(His344IlefsTer18) [30, 31].

2.10. Genotype–phenotype correlations, penetrance and allelic disorders

In ATOH1, the position of the variant predicts inheritance and phenotype: C-terminal truncations are associated with mild to moderate hearing loss, subtle motor and cerebellar signs and a specific brainstem malformation in 7 of 7 patients studied by MRI, and early or bHLH-domain variants, in the homozygous state, with severe PCH with profound hearing loss in 4 of 4 [31]. It is not known whether carriers of the DFNA89 c.1030del have the malformation, because no MRI was reported, and its classification as non-syndromic hearing loss may reflect mild neurological signs that were not looked for [31]. In EXOSC5, the six patients with cardiac conduction disease recognised up to 2021 shared p.Thr114Ile; the absence of abnormalities in the others may reflect young age (three aged 14 months or less), reduced penetrance or an allele-specific effect [42]. In PCDH12, there is intrafamilial variability and a spectrum ranging from classic DMJDS1 to cerebral palsy-like pictures with normal MRI and cerebellar ataxia with retinopathy [39, 55]. In LIS9 (ENST00000372915.7 numbering of the 2018 series, which corresponds to p.(Cys7236Phe), p.(Asp7293Tyr), p.(Cys7295Phe) and p.(Cys7295Gly) in NM_001394062.1), patients with p.Cys7135Phe have more severe hypoplasia of the anterior commissure, those with p.Asp7186Tyr more severe lissencephaly, and those with p.Cys7188Phe, p.Cys7188Gly or the Irahara deletion larger residual nodules of pontine crossing fibres; a variant in the SR4 spectrin repeat domain causes mild posterior lissencephaly with subtle brainstem dysplasia [35]. ACVR1 is the FOP gene, in which medullary cap is a frequent imaging finding; variants in TMEM67, CSPP1 and other ciliary genes are associated with medullary and mesencephalic cap in the context of Joubert syndrome [22, 53].

3. Clinical Spectrum and Manifestations by System

3.1. Pontine tegmental cap dysplasia

Cohorts and natural history. The descriptions rest on small series: four children aged 2 to 7 years in the founding series [10], six patients assessed as infants for failure to thrive or delay [17], three adolescents with neuropsychological assessment [16], 16 patients with temporal bone studies in Seattle [14], 22 responses to an ophthalmological survey of families [15], three patients with polysomnography [20] and a review of 29 sporadic cases in 2017 [13]; four Chinese patients seen between 2007 and 2024 [64] and isolated cases from India, Kuwait, Brazil and South Africa complete the picture [65–70]. In the 2007 series, peripheral hearing loss was present in 4 of 4, facial palsy in 3 of 4, dysphagia in 2 of 4, ataxia in 2 of 4, horizontal gaze palsy and bilateral trigeminal sensory involvement in 1 of 4 each, and vertebral anomalies in 3 of 4 [10]. Patients present with neonatal hypotonia, pyramidal and cerebellar signs, multiple cranial nerve deficits and extracranial cardiac, gastrointestinal, genitourinary and skeletal malformations, mainly vertebral and costal [16].

Cranial nerves and ear. Sensorineural hearing loss is almost constant and results from absence or hypoplasia of the vestibulocochlear nerve. Of 16 patients, 15 (94%) had duplication of one or both internal auditory canals; the 24 duplicated canals had stenosis or atresia of the vestibulocochlear nerve canal and ipsilateral aplasia of the nerve; of the 8 non-duplicated canals, 63% were atretic or stenotic, 38% had absence of the vestibulocochlear nerve and 38% isolated aplasia of the cochlear nerve; 15 of 16 patients had bilateral cochlear aplasia; 4 of 32 temporal bones (13%) had facial nerve aplasia, and 22 of 28 facial nerves present (79%) had an aberrant origin or course [14]. In the four Chinese patients, CT showed a narrow cochlear nerve canal in 8 ears, a duplicated internal auditory canal in 4 or a narrow one in 1, an enlarged vestibular aqueduct in 2, enlarged vestibules with dysplastic lateral semicircular canals in 3, deformed ossicles in 2 and facial canal anomalies, and MRI showed dysplastic cochlear nerves in 3 ears and aplastic ones in 5 [64]. Auditory brainstem responses (ABR) reveal bilateral profound hearing loss, and the accessory canal containing the facial nerve corresponds to the duplicated internal auditory canal [71]. Facial palsy may be unilateral or bilateral, trigeminal sensory involvement leads to corneal anaesthesia and the glossopharyngeal and hypoglossal nerves contribute to dysphagia [13, 72]. One case report showed that trigeminal anaesthesia can exist with a normal facial nerve, swallowing and voice [73].

Eye. In the survey of 22 families, neurotrophic cornea was the most frequent ocular diagnosis (82%), followed by facial palsy (59%), dry eye (59%), blepharitis (55%), cortical visual impairment (27%), strabismus (27%), amblyopia (18%) and nystagmus (18%); 64% had undergone temporary or permanent tarsorrhaphy and 23% amniotic membrane grafts, 68% of families reported ocular self-injury and 91% described the child as a mainly visual learner [15]. Bilateral corneal opacification due to trigeminal anaesthesia can compromise vision and adds to the hearing loss, depriving the child of the main channel of sensory compensation [15, 72]. Retrograde airflow through abnormal nasolacrimal ducts contributes to corneal scarring and ulcers [20].

Breathing and sleep. In three patients with polysomnography, the dominant pattern was central apnoea with periodic breathing and bradypnoea: a 41-year-old woman with severe central apnoea and an apnoea-hypopnoea index of 49.0 per hour, a 20-year-old man with an index of 27.1 per hour (central apnoea index 17.2) since the age of 7 and stable in studies at 10, 13, 15 and 19 years, and a 1.5-year-old girl with a central index of 11.6 mainly in REM sleep [20]. The authors attribute these abnormalities to dysfunction of pontine structures essential for respiratory control, such as the Kölliker-Fuse nucleus adjacent to the superior cerebellar peduncle, and to increased loop gain of the chemoreceptor feedback circuit [20]. Cyclical vomiting, scoliosis, epileptic seizures and osteopenia have been described in adults [20].

Development and cognition. Most patients have severe delay, and bilateral hearing loss contributes to absent or severely delayed language [16]. Cognitive outcome ranges from severe impairment to normal cognition, with an intelligence quotient of 94 at 7 years in the original series [12, 16]. In the three adolescents assessed with the non-verbal Leiter-R scale, the deficit was mild to moderate in the first two, with better visuospatial performance, and the global quotient was borderline in the third; two had mild behavioural problems (emotional fragility, attention deficit, low frustration tolerance) [12, 16]. Chewing and swallowing difficulties improved with age in all three, allowing a solid diet; independent walking was limited to a few steps [16]. One of the adolescents developed atypical absences and tonic-clonic seizures from the age of 8, controlled with valproate and carbamazepine, and had an atrial septal defect with a long QT interval [16].

Severe end of the spectrum. Two children described in 2009 had difficulty opening the mouth and sucking, involvement of the facial, cochlear and glossopharyngeal nerves with hearing loss and dysphagia requiring gastrostomy, bilateral corneal opacification in one case, minimal progress without speech and vertebral and rib anomalies, and died at 15 and 32 months from intercurrent infections [72]. The first extremely preterm infant described, born at 25 weeks, had severe hypotonia, persistent temperature instability, involvement of the facial, cochlear and hypoglossal nerves and paroxysmal episodes of pain with facial tics, tonic and clonic contractions, blepharospasm and hiccups [13].

Extracranial malformations. Hemivertebrae and vertebral segmentation defects [12], butterfly vertebrae and VACTERL association [67, 74], rib fusions [64], atrial and ventricular septal defects [16, 64], repaired tetralogy of Fallot [65], aortic arch hypoplasia and mirror movements [75], oesophageal atresia with tracheo-oesophageal fistula [16], oculo-auriculo-vertebral spectrum [76] and a lip deformity requiring multidisciplinary reconstruction [77] have been reported. An Indian child with corneal opacities, non-healing oral ulcers, hearing loss and absence of sweat and tears mimicked hereditary sensory and autonomic neuropathy type II or III [68].

Adults. The oldest adult patient described in detail is a 48-year-old Brazilian woman assessed before cochlear implantation, with cognitive deficits and profound hearing loss, ataxia and a brother with intellectual disability of unknown cause [66]; a 41-year-old woman was diagnosed by MRI at 29 years [20].

3.2. Medullary tegmental cap

In the multicentre series of 13 patients (3 fetuses of 17, 21 and 32 weeks, whose parents opted for termination of pregnancy, and 10 children and adolescents aged 9 months to 18 years), the clinical data available in 9 patients showed normal cognition in 4, severe global delay in 2 and low-average performance in 1; motor delay in 5 (severe in 3, mild in 1 and left hemiparesis in 1); central apnoeas in 2; normal neurological examination in 3 and abnormal in 5 (axial hypotonia; hypotonia, dysarthria, strabismus and nystagmus; hemiparesis; absent eye contact with abnormal movements, self-injury and exclusive gastrostomy feeding; absent eye contact with hyperkinetic movements and hypotonia) [22]. Two children died in early childhood, one from cardiac arrest after a respiratory infection at 9 months and the other from COVID-19 at 11 months [22]. Symptoms depend mainly on the underlying disease: patients with FOP had only skeletal anomalies, and in two the cap was an incidental finding during investigation of skin lesions of the scalp [22]. Extraneurological findings included polydactyly, hallux valgus, large ears, coarse facies, paresis of one vocal cord and haematological disease with cholestasis [22]. In 2025, a 3-year-old boy was described with global delay and hypotonia, a social maturity quotient of 82, normal vision and hearing, a left globular cap of about 6.5 × 8 mm contiguous with the inferior cerebellar peduncle and diffuse pontine atrophy [78].

3.3. Brainstem disconnection

The presentation is severe and neonatal: apnoea, absent sucking and swallowing, hypertonia or generalised weakness with absent reflexes, epileptic seizures and, sometimes, polyhydramnios and absent fetal swallowing [23, 60]. Up to 2015, most children died in the first two months without acquiring any skills, with a maximum survival of 7 weeks among the six cases of 2007 [27, 60]. Two patients described in 2015 survived without intubation or mechanical ventilation, one to 8 months and the other alive at 4.5 years, and the latter acquired some developmental milestones [27]. A Japanese girl weighing 1938 g at birth, with no spontaneous movements or breathing but with preserved facial movements, was alive at 4 years on mechanical ventilation and gastrostomy [23]; an infant girl described in Riyadh in 2026, with tonic-clonic seizures, severe cerebral palsy of all four limbs, gastrostomy and failure of oxygen weaning, was alive at 12 months [25]. The extracerebral anomalies described include bilateral anotia, micrognathia, hypertelorism, scoliosis, vertebral and rib anomalies, short trachea, middle ear anomalies and hamartoma of the tuber cinereum [25, 79], ectopic thyroid and parathyroid with a small thymus, hydronephrosis, patent foramen ovale and ventricular septal defect, and transposition of the great arteries with pulmonary atresia [25]. In a 2009 case, MRI on the first day showed absence of the pons between the midbrain and medulla with no visible cord of tissue, with ectopic pontine remnants, absence of the vermis and of the inferior and middle peduncles, a hypoplastic corpus callosum, right anophthalmia and, on second-trimester ultrasonography, ventriculomegaly, hydronephrosis, single umbilical artery, vertebral segmentation anomalies and polyhydramnios [80]. Disconnection has also been described in newborns with fetal alcohol syndrome [81, 82].

3.4. ATOH1-related disorders

Dominant form. In the 25 carriers of C-terminal truncations (7 from Bertola and 18 from Brownstein), hearing loss was bilateral sensorineural in all, mild to moderate in almost all and severe in one; it was detected by newborn screening in two (confirmation at 1 and 7 months) and between 3 and 7 years in the rest, generally because of language delay; it was congenital in at least three, stable in most and progressive in one patient after the age of 20; none had ear malformation or vestibular dysfunction [31]. On targeted examination, 4 of 5 had motor delay, 4 of 6 cerebellar signs (balance problems, tremor), 5 of 6 language delay, none absent language, one intellectual disability attributable to a second de novo variant in RNU4-2, and none regression; school difficulties were frequent and the three adults had normal occupational integration [31]. The neurological component did not appear progressive [31]. In the DFNA89 family, hearing loss was described as non-syndromic and progressive age-related, with onset at birth or in early childhood [32].

Recessive form. The patient homozygous for c.102dup had profound congenital hearing loss and, at 24 years, was normocephalic but unable to sit unaided because of truncal tremor, to walk or to communicate verbally, with severe autism spectrum disorder and profound intellectual disability [31]. The two Slovenian siblings homozygous for c.481C>G had severe global delay, intellectual disability, severe to profound bilateral sensorineural hearing loss, horizontal nystagmus, convergent strabismus, pale optic discs, severe visual impairment and, in the sister, hypertonia, hyperreflexia and opisthotonus from 6 months without ever sitting or walking [33]. The four published recessive patients had severe delay, cerebellar signs, absent language in the three old enough to assess it, severe intellectual disability and severe to profound hearing loss, without regression [31].

3.5. Irahara syndrome and MACF1-related LIS9

Irahara's patient was born at term to non-consanguineous Japanese parents; she smiled at 4 months, achieved head control at 6, sat at 12 and stood with support at 19 months; at 2 years and 6 months she had a height of 82.5 cm (−1.6 standard deviations, SD), weight of 10.0 kg (−1.6 SD) and head circumference of 47.2 cm (−0.4 SD), a developmental quotient of 19, absence of meaningful words and social gestures, stereotypies and autistic traits, ocular abduction limited to half of the normal excursion with full adduction and vertical movements, normal hearing, normal tone and reflexes and absence of pyramidal signs, weakness or ataxia, scoliosis and swallowing difficulties [34]. In the 2018 series, the tabulated data for this patient record sitting at 1 year, walking at 3 years, absent language, severe intellectual disability, limited abduction and myoclonic and tonic-clonic seizures beginning at 5 years [35]. All eight patients in the founding series had severe intellectual disability; seizures began between 3 and 7 months in most (infantile spasms, Lennox-Gastaut syndrome, status epilepticus, myoclonus); several never sat or walked, and eye movements were abnormal in some [35].

3.6. Diencephalic-mesencephalic junction dysplasia

DMJDS1 (PCDH12). In the 14 patients from 8 families (10 boys and 4 girls, aged 18 months to 6 years), all had microcephaly and profound psychomotor delay; head circumference was between −1.5 and −8.7 SD (78% between −3 and −6 SD) and, in the 7 measured at birth, between −0.6 and −1.5 SD, indicating mainly postnatal and progressive microcephaly; none stood or walked without support or developed useful fine motor skills or language; there was recurrent fever of unknown cause in 64% (onset by 2 months), epilepsy in 76% (generally before 3 months; tonic, atonic, tonic-clonic and focal, partly controlled), vasomotor instability in 57%, autistic traits in 28%, ataxia in 42%, pyramidal signs in all, strabismus and dysphagia in 28% each, dysmorphism in 85% [37]. In the Palestinian community, fetuses had hyperechogenic brain foci, microcephaly and intrauterine growth restriction, and patients had neonatal seizures and virtually no acquisitions, in a picture reminiscent of Aicardi-Goutières syndrome and intrauterine infections; a 26-year-old woman had microcephaly of −7.5 SD and severe visual impairment, and four older siblings had died of pulmonary aspiration [36, 49]. Exudative vitreoretinopathy and other ophthalmic abnormalities are part of the picture [55]. In the compilation of 35 patients published up to 2024, the frequencies were: developmental delay or intellectual disability 30 of 32 (93.8%), microcephaly 33 of 35 (94.2%), spasticity 17 of 32 (53.1%), dystonia 13 of 32 (40.6%), seizures 21 of 32 (65.6%), hypotonia 18 of 32 (56.2%), dysphagia 6 of 25 (24%) and dysmorphism 20 of 32 (62.5%) [39]. Two Turkish siblings with the p.(Arg151Ter) variant were at the mild end: a 2-year-old boy walking at 18 months, with few words and right hemiparesis, with normal MRI, and a 12-year-old sister who walked at 3 and spoke at 5 years, in special education and with borderline intellectual functioning [39]. Four children from southern India in 2026 had global delay, microcephaly, axial hypotonia, spasticity, dystonia and ataxia, seizures in three and no calcifications [83]. PCDH12-related disease enters the differential diagnosis.

DMJDS2 (GSX2). The two girls described in 2019 (5 years old, of consanguineous North African parents, and 14 years old, of unrelated Italian parents) presented in the first weeks with global delay, hypotonia and feeding difficulties and developed spastic tetraparesis with contractures, foot deformities, clenched hands and severe truncal and limb dystonia, with preserved eye contact, severe to profound intellectual disability, absent language, bulbar dystonia and dysphagia with tube feeding; one had microcephaly; neither had seizures or central apnoeas [38]. In the third family, Turkish and consanguineous, the patient had aspiration without opening of the upper oesophageal sphincter, atrial septal defect, drug-resistant dystonia with status dystonicus and apnoeas, sepsis with acute kidney injury, tracheostomy at 16 months and home ventilation, and died at 2 years from respiratory failure; a sister had died at 4 months with the same imaging [39].

3.7. EXOSC5-related disease

Neurodevelopment and growth. Patients have infantile-onset hypotonia, motor delay, feeding difficulties, short stature and ataxic gait, with dysarthria, nystagmus, esotropia, myopia and astigmatism, and variable spasticity and hyperreflexia; most have global delay and intellectual disability, but not all [41]. In the five patients of 2020, all had height below the 10th centile and none had diagnostic dysmorphism [51]. The spectrum ranges from two siblings with mild ataxia after the onset of walking, mild cerebellar hypoplasia and normal cognition [51] to an Iraqi infant with no motor acquisitions, with respiratory failure requiring gastrostomy and tracheostomy, craniosynostosis, regression and subacute axonal neuropathy resembling spinal muscular atrophy, who died at 11 months [41, 51]. In the Mexican siblings of 2021, serial MRI showed progressive loss of cerebellar volume and hypomyelination, with microcephaly (head circumference Z-score of −2.77 in the proband at 10 years) and, in the 20-year-old brother, profound intellectual disability, optic atrophy, scoliosis, spasticity, orolingual dyskinesia and refractory myoclonic epilepsy, suggesting neurodegeneration [42]. A Syrian infant girl in 2024 had PCH on MRI, an immature gyral pattern, bilateral mixed hearing loss, central and obstructive apnoeas, tube feeding, livedo reticularis, non-febrile seizures, increasing pyramidal and dystonic tone and no development at 3 months [43].

Heart. In the Iranian family, the three siblings developed, from adolescence, valvular disease, right bundle branch block and bradycardia and received pacemakers [41]. The first patient of 2020 had syncope at 2 years due to complete atrioventricular block and received a pacemaker [42, 51]. In the Mexican siblings, screening was prompted by ventricular bigeminy during anaesthetic induction for strabismus surgery; the ECG showed intraventricular conduction delay, left axis deviation, junctional rhythm and high-grade atrioventricular block, and 24-hour Holter monitoring showed a rate between 37 and 98 per minute (mean 51), first-degree block, second-degree block of types I and II and monomorphic ventricular tachycardia of 120 to 150 per minute; the brother had trifascicular block; the echocardiogram was normal in both, and during implantation of a dual-chamber ICD both had intermittent complete block and profound sinus node dysfunction [42]. Six of the ten patients published up to 2021 had recognised conduction disease [42]. In the Syrian infant, repeated cardiac assessments showed no significant abnormalities [43].

Thrombotic microangiopathy. The Syrian infant homozygous for p.(Glu77del) had rotavirus gastroenteritis and, at 4 months, a septic picture followed, five days later, by oedema, oliguria, hypertension and thrombotic microangiopathy (lactate dehydrogenase up to 2000 U/L, undetectable haptoglobin, schistocytes); Shiga toxin-producing Escherichia coli infection, pneumococcal disease, disseminated intravascular coagulation and thrombotic thrombocytopenic purpura were excluded and complement was normal; she received one dose of eculizumab, normalised within two weeks with supportive treatment and died at 6 months in palliative care from progressive neurological disease and respiratory failure [43]. Up to 2024, five patients with variants in exosome genes had thrombotic microangiopathy, all preceded by a viral trigger [43]; in 2026, 13 of 34 European children with PCH1B due to EXOSC3 had thrombotic microangiopathy, severe, early and resistant to C5 inhibitors [63]. The French PNDS considers the excess risk not yet demonstrated, but recommends that it be flagged in patients with variants in the EXOSC genes [2].

4. Clinical Recognition and Red Flags

4.1. In the prenatal period

Suspicion usually arises from a small transverse cerebellar diameter or a poorly defined posterior fossa on second-trimester ultrasonography. The four pregnancies with pontine tegmental cap dysplasia in the French series were referred between 22 and 27 weeks for a small cerebellar diameter [84], and the 2022 Indian case was studied by fetal MRI at 22 weeks for cerebellar hypoplasia, with the cap recognised only retrospectively after postnatal MRI [85]. In an extremely preterm infant, the hypoplastic and rostrally displaced cerebellum on prenatal ultrasonography was the early sign [13]. In medullary cap, the earliest identification was in an 18-week fetus, and the three fetuses of the 2023 series were diagnosed at 17, 21 and 32 weeks [22, 46]. In brainstem disconnection, polyhydramnios and absent fetal swallowing may be the only signs, and prenatal imaging sometimes showed cerebellar and pontine hypoplasia without detecting the disconnection [23, 25]. In DMJDS1 in the Palestinian community, peri-thalamic or periventricular hyperechogenic foci with microcephaly and growth restriction led to termination of pregnancy in three fetuses [49]. The vermis only completes its development at 17–18 weeks, and early ultrasonography is not reliable for diagnosing cerebellar hypoplasia [86, 87]. A transverse cerebellar diameter below the 5th centile should raise suspicion of hypoplasia, with caution before 24 weeks because biometry may normalise in the third trimester [46].

4.2. In the newborn and infant

The postnatal presentation of brainstem malformations is often non-specific, with hypotonia, motor delay, nystagmus and reduced visual attention; in severe cases there is apnoea, feeding difficulties, aspiration, spasticity, lack of progress or seizures [44]. The combination of bilateral sensorineural hearing loss detected on newborn hearing screening with facial palsy, sucking and swallowing difficulties and corneal anaesthesia should lead to MRI with attention to the pons and cranial nerves, because this is the pattern of pontine tegmental cap dysplasia [20, 44, 73]. Painless corneal abrasions or ulcers, ocular self-injury and corneal opacification in an infant with hearing loss suggest trigeminal anaesthesia [15, 72]. Vertebral or rib anomalies, congenital heart disease or oculo-auriculo-vertebral spectrum in an infant with hearing loss and bulbar dysfunction reinforce the suspicion [74, 76]. Neonatal respiratory failure with absent spontaneous movements and swallowing, but with preserved facial movements, suggests brainstem disconnection [23]. Progressive postnatal microcephaly with early seizures, unexplained fever and vasomotor instability suggests DMJDS1 [37], and spastic tetraparesis with severe dystonia and dysphagia, without seizures, suggests DMJDS2 [38]. In an infant with hypotonia, ataxia and cerebellar hypoplasia, bradycardia, syncope or block on the ECG should prompt consideration of EXOSC5 [42].

4.3. In the child, adolescent and adult

Mild to moderate sensorineural hearing loss detected because of language delay between 3 and 7 years, with mild motor delay, impaired balance or tremor, suggests the dominant ATOH1 form; MRI with a triangular pons and a central T1-hypointense area confirms the suspicion [31]. In adults with profound hearing loss assessed for cochlear implantation, CT with a duplicated internal auditory canal and MRI with absence of the vestibulocochlear nerve and a pontine cap allow a late diagnosis [66]. Central sleep apnoea, bradypnoea and cyclical vomiting have been described in adults with cap dysplasia [20].

4.4. Red flags and urgent signs

Urgent signs are: apnoeas, bradypnoea or hypoventilation during sleep (risk of hypoxaemia and hypercapnia; mask ventilation is limited when there is corneal anaesthesia) [2, 20]; aspiration and aspiration pneumonia due to dysphagia [36, 72]; corneal ulcer or perforation in a patient with trigeminal anaesthesia [15]; syncope, bradycardia, high-grade atrioventricular block or ventricular tachycardia in EXOSC5-related disease, including during anaesthesia [42]; and oliguria, oedema, hypertension, haemolytic anaemia and thrombocytopenia after a viral infection in a patient with EXOSC variants, which suggest thrombotic microangiopathy [43, 63]. There is no newborn screening directed at these entities; universal newborn hearing screening detects the hearing loss of cap dysplasia and of some of the ATOH1 forms [31, 73].

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Imaging criteria

There are no formal criteria published by societies; the diagnosis of each entity is radiological and, when a gene is known, molecular. The features that define each malformation are shown in the following table.

5.2. Imaging technique

When a pontocerebellar anomaly is suspected, the French PNDS recommends sagittal, axial and coronal T2 slices, a 3D T1 sequence and axial or 3D FLAIR after the first year, with susceptibility-weighted sequences for the differential diagnosis with ischaemic-haemorrhagic lesions of the posterior fossa and, depending on the context, DTI and tractography; paediatric biometric norms for the vermis and brainstem have existed since 2019 [2]. For assessment of the cranial nerves, heavily T2-weighted 3D steady-state sequences (such as CISS or FIESTA) allow the nerves to be seen in the basal cisterns [44]. The approach to the midsagittal plane begins by checking that the posterior border of the brainstem is almost straight from the aqueduct to the obex, that the fastigium lies just below the midpoint of the ventral pons and that the rostrocaudal length of the ventral pons is about twice that of the midbrain [44]. High-resolution CT of the temporal bones is useful in cap dysplasia, because the duplicated internal auditory canal, the stenosis of the cochlear nerve canal and the aberrant course of the facial canal are characteristic and allow the diagnosis even when MRI is limited [14, 64]. MRI under sedation or anaesthesia should be weighed against the expected benefit, especially for repeat scans [2].

5.3. Initial complementary assessment

In pontocerebellar anomalies, the PNDS recommends an initial extraneurological assessment with abdominal, renal and cardiac ultrasonography, complete ophthalmological assessment (acuity, oculomotor function, slit lamp, fundus and electroretinogram if indicated), auditory assessment, baseline blood tests, investigation for sleep hypoventilation (with sleep consultation, blood gas on waking, overnight oximetry and capnography or polysomnography in case of any doubt) and assessment of nutrition, swallowing, gastro-oesophageal reflux and bowel transit [2]. For the group of cerebellar anomalies, the Oxford Desk Reference adds a three-generation family tree with enquiry about consanguinity, prenatal exposures (retinoic acid, cytomegalovirus, alcohol), full blood count, liver function tests, creatine kinase, renal ultrasonography, array and panel, exome or genome sequencing, 7-dehydrocholesterol, transferrin isoelectric focusing, alkaline phosphatase and lactate and pyruvate, and electromyography when a spinal muscular atrophy phenotype is suspected [87]. In brainstem malformations, assessment of the cranial nerves (corneal sensation, facial expression, swallowing), ABR, CT of the petrous bones, ECG and Holter monitoring when EXOSC5 is being considered, and MR angiography in brainstem disconnection are added [14, 25, 42]. When DMJDS1 is suspected, CT or MRI with susceptibility sequences demonstrates the calcifications, and fundus examination looks for exudative vitreoretinopathy [37, 55].

5.4. Genetic strategy

The PNDS molecular strategy for pontocerebellar anomalies is a next-generation sequencing panel that includes the PCH genes and the most frequent developmental causes, followed by trio exome or genome sequencing if the panel is negative or immediately in the case of an atypical picture; in the cohort of the French reference centre (260 patients), the panel gave a diagnosis in about 60% [2]. For the entities in this article, the practical order follows from imaging: in pontine tegmental cap dysplasia there is no gene to test, and trio exome or genome sequencing serves mainly to exclude differentials (Joubert, tubulinopathies, CCDD, ATOH1) and for research [16, 25]; in medullary cap, hallux valgus justifies targeted analysis of ACVR1 and a molar tooth a ciliopathy panel [22]; when dominant ATOH1 is suspected, sequencing of the single coding exon, included in hearing loss panels, exome and genome, is sufficient, and the analysis must include the C-terminal end [31]; in LIS9, sequencing detects the GAR domain missense variants, but the Irahara intragenic deletion was found only with read-depth CNV analysis and structural variant analysis on the genome [35]; in DMJD and EXOSC5-related disease, the exome is the test of choice [37, 42].

5.5. Limitations of testing

A negative exome or genome does not exclude a genetic cause, especially in entities without a known gene; and a variant found may not be the cause: the patient with a heterozygous NPHP1 deletion and cap dysplasia illustrates a probably incidental association [16], and the finding of TMEM67 carrier status in brainstem disconnection does not establish causality [25]. Sequence variant analysis misses multi-exon intragenic deletions, such as that of MACF1 [35], and the 1023 bp deletion of exons 5 and 6 of EXOSC5 was confirmed only by array [51]. Uniparental isodisomy can render homozygous a variant inherited from a single parent, as occurred with EXOSC5 p.(Met148Thr), and can render homozygous other recessive variants on the same chromosome that contribute to the phenotype [51]. Homozygosity without known consanguinity or runs of homozygosity, such as that of ATOH1 p.(Arg161Gly), requires confirmation of segregation [33]. Interpretation of ATOH1 requires attention to position: a heterozygous C-terminal truncation is causal, whereas a heterozygous early truncation corresponds to an asymptomatic carrier [31]. For variants of uncertain significance, such as GSX2 p.(Trp249Cys) (ACMG criteria PP3 and PM2), concordant imaging and segregation support the interpretation but do not change the class without functional evidence [39]. The report should state the gene, the transcript with version (NM_005172.2, NM_020158.4, NM_016580.4, NM_133267.3), the HGVS c. and p. notation, zygosity, the ACMG/AMP class and segregation [30].

5.6. Prenatal and preimplantation diagnosis

In the absence of an identified variant, surveillance of a subsequent pregnancy relies on serial fetal ultrasonography and MRI, with known limitations [2]. The sensitivity and specificity of prenatal imaging for malformations of the midbrain and hindbrain are not known [44], most cap dysplasias are recognised only after birth [46], and fetal MRI can be imprecise in the anatomical analysis of the vermis [86]. Fetal MRI allows biometry of the pons and vermis independently of gestational age, and fetal DTI may help to identify aberrant tracts in Joubert syndrome and cap dysplasia [46]. When the familial variant is known, prenatal diagnosis is performed by chorionic villus sampling or amniocentesis; non-invasive prenatal diagnosis using cell-free fetal DNA is possible in some situations (recessive disorders with a paternal variant different from the maternal one, de novo dominant disorders) with technical limitations to be discussed with the laboratory; preimplantation genetic testing, gamete donation and adoption are alternatives [2].

5.7. Algorithm

6. Differential Diagnosis

The French PNDS groups in the differential diagnosis of pontocerebellar hypoplasias the tubulinopathies, the syndromes in which pontocerebellar hypoplasia is not cardinal but is frequent (DYRK1A, PPP2CA, cerebro-oculo-facio-skeletal syndrome), the congenital muscular dystrophies with muscle-eye-brain disease, the lissencephalies with pontocerebellar hypoplasia, the predominant brainstem malformations (cap dysplasia, Irahara syndrome), the chromosomal anomalies with frequent involvement of the posterior fossa (trisomy 18, chromosome 5 deletion, 19p13.12 deletion), the amino acid and organic acid metabolic disorders and the mitochondrial disorders; prenatal ischaemic-haemorrhagic lesions and extreme prematurity are the acquired causes to be excluded, by looking for haemosiderin on T2* or susceptibility sequences [2].

The distinction that matters most for counselling is the one that separates pontine tegmental cap dysplasia from Joubert syndrome. Both share absent decussation of the superior cerebellar peduncles and some cap dysplasias have a "molar tooth-like" appearance, but in cap dysplasia the superior peduncles are laterally positioned and less elongated and horizontal, the tegmental cap is never seen in Joubert syndrome, and the multiple cranial neuropathies and vertebral and rib anomalies of cap dysplasia do not occur in Joubert syndrome, which, for its part, has retinopathy, progressive nephronophthisis, congenital hepatic fibrosis and polydactyly [16]. The difference has direct consequences: Joubert syndrome is autosomal recessive, with a 1 in 4 risk in each pregnancy, whereas all published cases of cap dysplasia are sporadic [16]. Cap dysplasia is distinguished from the other PCHs by the cap and by severe hypoplasia of the inferior and middle peduncles [44], and a paediatric review recommends considering it whenever the pons is severely flattened [47].

Irahara syndrome was initially compared with horizontal gaze palsy with progressive scoliosis, because it shares ventral hypoplasia of the pons and medulla, the midline cleft and absent pyramidal decussation demonstrated by DTI; it differed by minimal limitation of horizontal gaze, severe psychomotor delay and bilateral cortical malformation, and ROBO3, SLIT1, SLIT2, NTN1, SEMA3A and SEMA3F were normal [34]. The 2018 series showed that the "W-shaped" brainstem of LIS9 is more severe than the "butterfly" configuration of ROBO3 and DCC, with a very narrow and very broad pons and medulla, and added to the differential biallelic ARHGEF2 variants, with severe hypoplasia of the transverse pontine fibres and an enlarged medulla [35]. Anterior mesencephalic cap dysplasia, with anterior bulging of the midbrain, belongs to the Joubert spectrum [22, 53].

Medullary cap requires the shape to be distinguished, because the shape points to the cause: in Joubert syndrome the cap is right-angled, tubular, the size of the medulla and low medullary ("step" and "caterpillar"); in FOP it is soft, smooth, flat and high, up to the mid-pons; and the "step" resembles the hypertrophy of the clava in infantile neuroaxonal dystrophy and beta-propeller protein-associated neurodegeneration (BPAN), which are distinguished by cerebellar atrophy and iron deposition in the substantia nigra [22]. Other dorsal medullary masses may result from brainstem tethering or tumours [78]. Brainstem disconnection is distinguished from PCH, with which it was confused on the initial MRI of a 2026 case, by the absence of an entire brainstem segment and by MR angiography [25]. In DMJD, the similarity to congenital infection and to Aicardi-Goutières syndrome justifies serology and investigation of genetic causes of calcification before reaching a conclusion [37, 49]. In EXOSC5-related disease, the combination of cardiac conduction disease with cerebellar hypoplasia and hypomyelination is rare; Zaki-Gleeson syndrome, described in a single consanguineous family with an unknown locus, is the only overlap found [42].

7. Treatment and Risk Management Strategies

7.1. General principles

None of the entities has a specific treatment, disease-modifying therapy or registered clinical trial; management is symptomatic, multidisciplinary and directed at the foreseeable complications of each malformation [2, 37]. The French PNDS, which is the only guideline addressing some of these entities, recommends for pontocerebellar anomalies admission to neonatology when adaptation is poor, with nasogastric tube feeding and ventilatory support if needed, disclosure of the diagnosis by the reference specialist after MRI, a genetic counselling consultation, a multidisciplinary assessment of the child's abilities and difficulties to organise rehabilitation (physiotherapy, psychomotor therapy, occupational therapy, speech and language therapy, psychology, adapted physical activity) and information for families about social benefits [2]. Follow-up should pay attention to pain, epilepsy, motor function, digestion, nutrition and growth, neuro-orthopaedic complications and bone fragility, breathing, the skin and the sense organs [2]. The recommendations specific to cap dysplasia, brainstem disconnection and the ATOH1 forms derive from series and case reports, not from guidelines, and are presented with that level of evidence.

7.2. Hearing

The hearing loss of pontine tegmental cap dysplasia results, in the great majority of cases, from cochlear nerve aplasia, which limits the benefit of hearing aids and cochlear implantation [14, 71]. In a series of three patients with bilaterally absent cochleovestibular nerves, bilateral cochlear implantation in one of them produced a minimal response, and the authors considered the prognosis of implantation poor [71]. In contrast, the first child implanted progressed, 22 months after surgery, from speech perception category 0 (no detection) to category 3 (beginning of word identification), and connected speech became intelligible to a listener with little experience of deaf people [19]; a second adolescent implanted at 13 years had a slight improvement in hearing with progress in relationships and learning [16]. In a Seattle patient implanted at 7 months, preoperative MRI had not identified the malformation [20]. The decision to implant should therefore rest on radiological demonstration of the cochlear nerve (3D T2 MRI and CT of the cochlear nerve canal) and on realistic expectations shared with the family [14, 71]. In the dominant ATOH1 form, the hearing loss is mild to moderate, without ear malformation, and responds to conventional auditory rehabilitation; audiometric surveillance is justified because worsening occurred after the age of 20 in one patient [31]. In the recessive form, the hearing loss is profound [31]. Sign language is used by some patients without oral language [16], and 91% of families of children with cap dysplasia describe them as mainly visual learners, which makes protection of vision a priority [15].

7.3. Cornea and ocular surface

Neurotrophic keratopathy due to trigeminal anaesthesia is the main threat to vision in cap dysplasia. The measures described include lubricant drops (59% of families) and ointment (50%), contact lenses (14%), punctal plugs (27%), spectacles (45%) and occlusion (18%), and the most frequent surgical interventions were temporary or permanent tarsorrhaphy (64%) and amniotic membrane grafting (23%) [15]; a 1-year-old boy with anaesthetic corneas underwent left tarsorrhaphy at 6 months [73]. The ophthalmologist should be aware of the risk of neurotrophic cornea, because timely treatment prevents scarring, perforation and blindness [15]. Corneal neurotisation is a promising intervention to restore sensation, lubrication and healing capacity, and may make non-invasive ventilation possible [20, 96]. Retrograde airflow through abnormal nasolacrimal ducts aggravates the injury when mask ventilation is used [20].

Cenegermin. Cenegermin is a recombinant human nerve growth factor in eye drops, with the trade name Oxervate® in the United States, the European Union and Portugal [97–99]. There is no published dose for cap dysplasia; the dose used in the only case described coincides with the label dose for neurotrophic keratitis, which is therefore the reference dose by extrapolation. In a 9-year-old boy with bilateral V1 and VIII palsies, moderate (stage II) neurotrophic keratopathy in the right eye and mild (stage I) in the left and more than four years of medical and surgical treatments without lasting effect, cenegermin 20 µg/mL was administered "1 drop in the conjunctival sac 6 times a day at 2-hour intervals, from 8 a.m. to 8 p.m." for 8 weeks, first in the right eye and then also in the left, with resolution of the keratopathy, improved corneal sensation and no local adverse effects [18].

7.4. Breathing and sleep

Full polysomnography should be performed in the presence of apnoeas, poor-quality sleep or suspected hypoventilation, as the PNDS recommends for pontocerebellar anomalies [2]. In cap dysplasia, non-invasive positive pressure ventilation was effective in an adult woman (apnoea-hypopnoea index from 49.0 to 1.9 per hour with bilevel pressure in spontaneous/timed mode), but mask leak, facial asymmetry and abnormal nasolacrimal ducts caused corneal irritation and injury and forced its discontinuation, as had happened in a child treated with bilevel pressure of 20/10 cmH2O [20]. Low-flow nasal cannula oxygen during sleep reduced central events in all three patients: from 28.8 to 10.0 per hour with 0.5–1.0 L/min in the adult woman (with an increase in mean carbon dioxide), from a central index of 17.2 to 4.3 with 1.0–1.5 L/min in the boy, and from 11.6 to 6.8 and 2.3 with 0.25 and 0.5 L/min in the infant [20]. The maintained doses were 0.25–0.50 L/min, 1.0 L/min and 0.5 L/min during sleep, respectively, with non-invasive ventilation considered contraindicated because of previous corneal injury [20]. The authors handled the decisions within a shared decision-making model, in which families gave priority to preserving vision, and accepted that the aim is to avoid hypoxia without normalising the ventilatory pattern, accepting the residual risk of hypoventilation, pulmonary hypertension and, theoretically, sudden death from prolonged central apnoeas [20]. Conventional treatments for central apnoea include positive pressure, acetazolamide and nocturnal oxygen; in a systematic review, nocturnal oxygen reduced the central apnoea index by 24–84% in the short term and 34–81% in the long term [20]. In brainstem disconnection, prolonged invasive ventilatory support with gastrostomy allowed survival of years in one case [23], and the decision to start or continue it should be discussed with the family in the light of the prognosis [27]. Intubation may be difficult [25].

7.5. Feeding, swallowing and sialorrhoea

The sucking, chewing and swallowing difficulties of cap dysplasia may require gastrostomy in severe cases [20, 72], but improve progressively with age in many patients [16]. The PNDS recommends looking for gastro-oesophageal reflux before gastrostomy to decide on fundoplication, reviewing the gastrostomy at least once a year and considering gastrostomy in the event of significant weight stagnation for more than 6 months with severe malnutrition, aspiration or respiratory complications [2]. According to the PNDS, sialorrhoea secondary to dysphagia is treated with scopolamine patches (3-day action, with drowsiness, thickening of bronchial secretions, constipation and urinary retention), ultrasound-guided botulinum toxin injections into the parotid and submandibular glands (effect of 3 to 6 months) or, since 2025 in France, glycopyrronium oral solution with slow titration [2]. Glycopyrronium (Sialanar® 320 µg/mL oral solution, EU) is indicated for the symptomatic treatment of severe sialorrhoea in children and adolescents aged 3 years and older with chronic neurological disorders, for intermittent short-term use; the starting dose is about 12.8 µg/kg of glycopyrronium per dose (16 µg/kg of glycopyrronium bromide) three times a day, increased every 7 days up to a maximum of 64 µg/kg or 6 mL (1.9 mg of glycopyrronium) three times a day, whichever is lower; it is stopped in the event of constipation, urinary retention or pneumonia, and is contraindicated in pregnancy, breastfeeding and glaucoma [101]. Use in brainstem malformations is an extrapolation from the general indication for chronic neurological disorders, which the PNDS applies to pontocerebellar anomalies [2].

7.6. Epilepsy, dystonia and spasticity

Epilepsy occurs in cap dysplasia (an adolescent with atypical absences and tonic-clonic seizures from 8 years, controlled with valproate and carbamazepine) [16], in LIS9 (seizures beginning between 3 and 7 months, including infantile spasms and Lennox-Gastaut syndrome) [35] and in DMJDS1 (76%, partly controlled) [37], and treatment follows the general principles of childhood epilepsy, with regular electroencephalography and antiepileptic drug level monitoring when necessary [2]. In GSX2-related DMJDS2, the dystonia was drug-resistant, with episodes of status dystonicus and apnoeas; clonazepam was stopped because it increased secretions and there was improvement with the combination of diazepam, baclofen and gabapentin, with no published doses [39]. In the absence of a dose for the condition, the reference doses for these drugs are those of the labels for the approved indications, and use in dystonia is off-label.

7.7. The heart in EXOSC5-related disease

The French PNDS recommends that all patients with EXOSC5 variants undergo cardiac assessment directed at conduction and rhythm disturbances, which may require a pacemaker; these disturbances have never been described in other EXOSC genes, but, until studies confirm or exclude the risk, the same assessment may be offered to patients with variants in the other exosome genes [2]. Calame and colleagues, in documenting sinus node dysfunction, intraventricular conduction delay, atrioventricular block and ventricular tachycardia in two siblings, advocated proactive cardiac screening because of the risk of sudden death [42]. Conduction disease may be silent and, in one of the cases, was discovered only through ventricular bigeminy during anaesthetic induction, and both siblings had intermittent complete block and profound sinus node dysfunction under anaesthesia [42]; this observation supports performing an ECG before any general anaesthesia in these patients. There is divergence regarding the device: the Iranian family and the first patient of 2020 received pacemakers [41, 51], and the Mexican siblings, with ventricular tachycardia in addition to block, received dual-chamber ICDs [42]. The choice between pacemaker and ICD depends on the presence of ventricular arrhythmia and follows general cardiology indications.

7.8. Exosome-associated thrombotic microangiopathy

The PNDS recommends that the potential excess risk of thrombotic microangiopathy after viral infection be flagged in patients with EXOSC3 or EXOSC5 variants, so that the complication is recognised and treated in time [2]. Treatment is supportive, with elimination of the infectious trigger: in the infant with EXOSC5, creatinine, haemoglobin, platelets and lactate dehydrogenase normalised within two weeks, and the improvement was attributed to supportive care and not to the single dose of eculizumab [43]. Of the 13 European children with EXOSC3-associated microangiopathy, the three who received prolonged eculizumab did not respond (one) or relapsed on treatment (two), and the disease was characterised as resistant to C5 inhibitors [63]. Exosome-associated microangiopathy should be considered in paediatric forms resistant to eculizumab, especially with neurodevelopmental disease, and eculizumab has no established role in this indication [43, 63].

7.9. Rehabilitation, orthopaedics, bone and oral health

Rehabilitation should begin early and be adapted to the sensory profile: in cap dysplasia, the combination of hearing loss and threatened vision requires physiotherapy, occupational therapy and speech and language therapy to use accessible communication channels [2, 15]. For the patient with multiple disabilities, the PNDS recommends a physical medicine and rehabilitation consultation at least annually, annual pelvic and spinal radiographs to monitor scoliosis and hip dislocation, annual blood tests for deficiencies and osteoporosis factors (calcium, phosphate, 25-hydroxyvitamin D, parathyroid hormone, urea, creatinine, C-reactive protein, albumin, prealbumin, full blood count, ferritin), densitometry in the event of a suspected fracture or high risk, and an annual oral health consultation [2]. Scoliosis has been described in cap dysplasia, brainstem disconnection and EXOSC5-related disease [20, 25, 42], and congenital vertebral anomalies may contribute to it [25, 74]. Facial reconstruction surgery in cap dysplasia requires a multidisciplinary team [77].

7.10. Anaesthesia, perioperative care, pregnancy and transition

General anaesthesia concentrates three risks: corneal protection in patients with trigeminal anaesthesia [15], the conduction disease of EXOSC5-related disease, revealed or aggravated under anaesthesia [42], and the difficult airway and bulbar dysfunction in severe brainstem malformations [25]. MRI under sedation should be indicated after weighing the expected benefit [2]. The sources consulted describe no pregnancies in women with these malformations; the 41-year-old woman with cap dysplasia was followed in a paediatric sleep clinic because of the centre's experience with the disease, which illustrates the difficulty of transition to adult services [20]. The PNDS recommends lifelong follow-up, with adult specialists when necessary [2].

7.11. Regulatory status

7.12. Registered clinical trials and studies

On 6 November 2026, ClinicalTrials.gov had no trials registered for pontine tegmental cap dysplasia, for EXOSC5 or for diencephalic-mesencephalic dysplasia; the search "pontocerebellar hypoplasia" returned a recruiting natural history study (NCT06092346), a completed observational study and a terminated trial of vatiquinone in mitochondrial disease (NCT04378075) [104]. The only study directly related to a gene of the class is that of ATOH1 gene therapy for acquired hearing loss, described in 7.13.

The therapeutic data available for the malformations in this article are case reports and retrospective series, without a control group; they do not allow effects to be estimated or interventions to be compared, and the absence of registered trials does not prove that studies are not being conducted on other platforms.

7.13. Gene therapy

There is no gene therapy for any of the brainstem malformations; the only line of clinical research involving a gene of the class is overexpression of ATOH1 to regenerate hair cells in acquired hearing loss, which is described for its mechanistic interest and because it does not apply to hearing loss due to cochlear nerve aplasia. It is an in vivo, local gene addition therapy that does not correct a pathogenic variant but uses ATOH1 as a cellular reprogramming gene: the strategy is to transduce the supporting cells of the organ of Corti with a vector expressing the transcription factor, inducing them to differentiate into hair cells [29, 105]. At the preclinical stage, cochlear infusion of an adenovirus carrying Atoh1 in young adult guinea pigs with complete hair cell loss due to ototoxic drugs increased the number of hair cells at 2 months relative to the contralateral ear (p<0.0006) and improved auditory evoked potential thresholds at all frequencies, and in utero transfer of Atoh1 in the mouse produced functional supernumerary hair cells, with stereociliary bundles, ribbon synapses and mechanoelectrical transduction [29]. At the clinical stage, CGF166, a recombinant adenovirus 5 carrying the cDNA of the human Atonal transcription factor (Hath1), administered by intralabyrinthine infusion, was studied in a phase 1/2 trial in 22 patients with unilateral or bilateral severe to profound hearing loss, with safety and pure-tone audiometry endpoints, completed in December 2019 with results deposited in the registry [105]; the sources consulted do not include the analysis of these results, so no efficacy is attributed to it. The sources consulted do not describe the adverse events observed in the trial; the experience of the C-terminal ATOH1 variants, in which excess activity of the factor alters rhombic lip neurogenesis and the number of hair cells, illustrates that the level and duration of expression are critical [31]. In pontine tegmental cap dysplasia, cochlear nerve aplasia renders any peripheral regeneration strategy useless [14].

7.14. Developments in the last 6 to 12 months

Between November 2025 and November 2026 the following were published: the delineation of the dominant and recessive ATOH1-related disorders with functional studies in cells and zebrafish (published result; human and preclinical study) [31]; the European series of EXOSC3-associated thrombotic microangiopathy, with an incidence in the United Kingdom of 0.004 per million per year and resistance to eculizumab (published result; retrospective cohort and mouse model) [63]; a case of brainstem disconnection with 12-month survival, a discordant twin and TMEM67 carrier (case report) [25]; four Indian children with biallelic PCDH12 variants without calcifications (case series) [83]; four Chinese patients with cap dysplasia and characterisation of the temporal bones (case series) [64]; a case of globular medullary cap (case report) [78]; the first South African case of cap dysplasia [67]; a case of cap dysplasia with vestibulocochlear nerve aplasia [107]; and a paediatric review of prenatal imaging of infratentorial anomalies [47]. The publication of the French PNDS on pontocerebellar hypoplasias in September 2026 is the first official recommendation to include EXOSC5-related disease and the brainstem malformations in the differential diagnosis [2]. There were no regulatory procedures, applications for authorisation or opinions relating to these entities in the sources consulted.

7.15. Recommendations and divergences between sources

The recommendations of the French PNDS derive from the pontocerebellar hypoplasias and apply to brainstem malformations by analogy, with two exceptions in which the PNDS itself refers to them: inclusion in the differential diagnosis and the recommendations for EXOSC5 [2]. Four divergences should be noted. First, regarding the cardiac device in EXOSC5-related disease, the PNDS mentions the pacemaker and the 2021 series used an ICD because of coexisting ventricular tachycardia [2, 42]. Second, regarding eculizumab, one dose was administered while the cause of the microangiopathy had not been clarified [43], but the 2026 series concludes that there is resistance to C5 inhibitors [63]. Third, in the central apnoea of cap dysplasia, non-invasive ventilation, the conventional first-line treatment for central apnoea, was considered contraindicated because of corneal injury, and low-flow oxygen was preferred by shared decision [20]. Fourth, regarding cochlear implantation, results range from minimal response with absent nerves to functional improvement with word identification, and selection depends on demonstration of the nerve [19, 71].

8. Reproductive Options and Family Counselling

8.1. Principles

The PNDS recommends that, after the diagnosis of a pontocerebellar anomaly, the couple be referred for genetic counselling by a clinical geneticist or genetic counsellor, and that counselling be refined when there is a molecular diagnosis [2]. The first task is correct classification of the malformation, because entities with similar imaging have very different recurrence risks: Joubert syndrome is autosomal recessive, with a 1 in 4 risk per pregnancy, whereas all published cases of pontine tegmental cap dysplasia are sporadic [16].

8.2. Recurrence risk by entity

The PNDS sets out the general risks: in autosomal recessive forms, 25% in each pregnancy; in dominant forms due to a de novo variant, a low risk corresponding to that of germline mosaicism [2]. For apparently isolated cerebellar hypoplasia after syndromic and monogenic causes have been excluded, the Oxford Desk Reference allows a recurrence risk that may reach 25%, without empirical data, and for non-Mendelian Dandy-Walker malformation a risk of 1 to 5% [87]. Applying these figures to primary brainstem malformations without a molecular diagnosis requires caution, because the published series are very small.

8.3. ATOH1: the same variant does not have the same meaning in all relatives

In families with recessive ATOH1-related disease, heterozygous parents and siblings are asymptomatic, because ATOH1 is not sensitive to haploinsufficiency [31, 33]. In families with C-terminal truncations, by contrast, heterozygosity is causal: the c.1053del variant was found in a mother and her son with hearing loss, and then in the granddaughter, and in the DFNA89 family transmission spanned five generations [31, 32]. Cascade testing should therefore be accompanied by audiometry and, when the family accepts it, by MRI, because the neurological signs of carriers are subtle and may go unnoticed [31].

8.4. Cascade testing, carriers and minors

In the autosomal recessive disorders (DMJDS1, DMJDS2, EXOSC5, recessive ATOH1), carrier testing can be offered to adult siblings and partners, especially in consanguineous communities or those with a known founder; in the Palestinian community of a small village, 3 of 83 healthy individuals were carriers of the PCDH12 founder variant [36]. In dominant disorders with onset in childhood (dominant ATOH1), testing of minor siblings is justified by clinical utility (audiometry and early rehabilitation) [31]. Identification of an EXOSC5 variant in an asymptomatic sibling would have consequences for cardiac surveillance [2, 42].

8.5. Prenatal and preimplantation diagnosis and surveillance of subsequent pregnancies

With a known variant, prenatal diagnosis is possible by chorionic villus sampling or amniocentesis, non-invasive diagnosis using cell-free fetal DNA in selected situations, and preimplantation genetic testing, gamete donation and adoption are alternatives [2]. Without a variant, fetal morphological surveillance with ultrasonography and MRI is the only option, with clear limits: cap dysplasia was diagnosed between 22 and 27 weeks in the French series [84], medullary cap from 18 weeks [46], brainstem disconnection is rarely recognised before birth, although it was diagnosed by fetal MRI in one case with inner ear anomalies [25, 108], and early ultrasonography is not reliable for cerebellar hypoplasia [87]. For the fetuses with medullary cap in the 2023 series, all couples opted for termination of pregnancy under national legislation [22]. Prenatal counselling should explain the variability of prognosis between entities with similar imaging, which ranges from normal cognition in medullary cap associated with FOP to profound impairment in brainstem disconnection [22, 27].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

There are no population-based estimates of prevalence or incidence for any of the entities; in Orphanet, all belong to the prevalence class below 1 per 1,000,000, which is an upper limit and not a rate [3–9]. The case counts reviewed by Orphanet are 22 for pontine tegmental cap dysplasia, 27 for medullary cap, 15 for brainstem disconnection, 7 for dominant ATOH1-related disease, 33 for diencephalic-mesencephalic dysplasia of all causes, 8 for posterior lissencephaly with flat pons and medulla and 10 for EXOSC5-related disease [3–9]. These counts have already been overtaken by the literature (29 cases of cap dysplasia in a 2017 review, 13 new medullary caps in 2023, 25 carriers of C-terminal ATOH1 truncations in 2026) [13, 22, 31]. For comparison, Dandy-Walker malformation has an estimated postnatal prevalence of between 1 in 30,000 and 1 in 5000 and a prenatal prevalence of about 1 in 10,000 in a British registry [44]. The only rate available in the extended class is the incidence of EXOSC3-associated thrombotic microangiopathy in the United Kingdom, of 0.004 per million per year [63].

9.2. Populations and regions

The cap dysplasia series come from Europe (the Netherlands, Italy, France, Germany, Switzerland), the United States, Japan, India, Kuwait, China, South Africa and Brazil, with no identified ethnic predominance [10, 14, 16, 64–67, 72, 76, 84]. DMJDS1 is concentrated in consanguineous Egyptian and Turkish families, in a Palestinian community with a founder variant (c.2515C>T, p.Arg839Ter; carrier frequency of 0.018 in one village), in a Moroccan Jewish family and in four children from southern India [36, 37, 49, 83]. DMJDS2 has been described in a consanguineous North African family, a non-consanguineous Italian family and a consanguineous Turkish family [38, 39]. EXOSC5-related disease has been described in consanguineous Iranian and Iraqi families, a family of Mexican ancestry from a village of 3000 to 4000 inhabitants, a family of mixed origin and a consanguineous Syrian family living in the Netherlands; the p.Thr114Ile variant has a maximum allele frequency of 0.06% in the Latino population of gnomAD [41–43, 51]. The families with dominant ATOH1 came from France (France Médecine Génomique plan), from other European countries through GeneMatcher and from a Jewish community of Iraqi origin in Israel [31, 52]. The HOXA1 dysgeneses are concentrated in Athabaskan Native American tribes and in Saudi and Turkish families [45]. From Brazil, the only description in the sources consulted is that of a 48-year-old woman with pontine tegmental cap dysplasia, published in the journal Radiologia Brasileira [66]; the Brazilian textbook of genetic syndromes covers Möbius sequence, a relevant differential, and associates it with prenatal exposure to misoprostol [94]. The sources consulted include no Portuguese cases.

9.3. Special populations

Patients with cap dysplasia who lose vision through keratopathy are left with a dual sensory deficit, which requires educational programmes adapted to deafblindness [15]. Extremely preterm infants may have acquired pontocerebellar hypoplasia, which must be distinguished from primary malformations, and the first 25-week preterm infant with cap dysplasia shows that the two situations can coexist [2, 13]. Adults with these malformations continue to need specialised follow-up in sleep medicine, ophthalmology and rehabilitation [20].

9.4. Reference networks and patient associations

The relevant European reference network is ERN ITHACA, for rare malformation syndromes and congenital anomalies [21]. In France, the reference centre for malformations and congenital diseases of the cerebellum, part of the DéfiScience network for rare neurodevelopmental diseases, is the author of the 2026 PNDS and of the ATOH1 series [2, 31]. The French association "Connaître les Syndromes Cérébelleux" supports families and research in this area [31]. Orphanet lists 101 patient associations, 55 specialised centres, 3 networks of centres and 22 registries linked to the group of genetic syndromes with brainstem malformation [1]. Families with cap dysplasia have organised themselves on social networks, which were the means of recruitment for the 2020 ophthalmological survey [15].

10. Illustrative Clinical Case

In 2011, Briguglio and colleagues described, in an Italian series of three adolescents with pontine tegmental cap dysplasia, a 13-year-old girl who had been the first patient with this malformation to receive a cochlear implant, at the age of 11 [16, 19]. She was hypotonic at birth and had delayed developmental milestones. The multiple cranial neuropathies included bilateral hearing loss, corneal anaesthesia, left facial palsy, strabismus, vertical nystagmus and chewing and swallowing difficulties, which resolved progressively with age. Examination showed pyramidal signs, with brisk reflexes and ankle clonus, and truncal, gait and limb ataxia, but the patient was able to take a few steps without support. The extracranial anomalies comprised oesophageal atresia with tracheo-oesophageal fistula repaired at birth, ventricular septal defect, multiple thoracic hemivertebrae and partial fusion of the right 4th and 5th ribs [16]. MRI at 1.5 tesla showed, on the sagittal T1 slice, the typical cap of the pontine tegmentum protruding into the fourth ventricle, with a flattened ventral pons and a dysplastic vermis, and, on T2 slices at the level of the isthmus, the "molar tooth-like" appearance with laterally displaced superior cerebellar peduncles; Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC3123550/figure/F1/) brings together the imaging of the three patients, and Figure 2 (https://pmc.ncbi.nlm.nih.gov/articles/PMC3123550/figure/F2/) the tractography of patients 1 and 3, in which the cap corresponds to a bundle of transversely oriented fibres, some continuing towards the expected location of the middle peduncles [16]. Cognitive assessment with the non-verbal Leiter-R scale, applied to circumvent the expressive and receptive deficits of the hearing loss, showed mild to moderate intellectual disability in the first two patients with better visuospatial performance [16]. Before implantation, with hearing aids, the patient did not detect speech and her connected speech was unintelligible; 22 months after right cochlear implantation, she reached the level of word identification and had intelligible connected speech, with gains in self-confidence and social integration [16, 19]. There was no family history or consanguinity, and a high-resolution array revealed no pathogenic copy-number variants [12, 16].

The case illustrates the elements that the clinical approach should bring together: the sagittal imaging that identifies the cap, the imaging of the isthmus that distinguishes it from Joubert syndrome, the search for vertebral, cardiac and digestive anomalies, neuropsychological assessment with non-verbal instruments and the individual decision on cochlear implantation. This patient's response to the implant is not the rule: in another series, bilateral implantation of a patient with absent cochleovestibular nerves produced a minimal response, and the indication depends on demonstration of the cochlear nerve [14, 71]. A Brazilian case, published in Radiologia Brasileira, shows the same malformation diagnosed at 48 years in a woman with cognitive impairment, ataxia and profound hearing loss assessed before implantation, with a narrow and duplicated internal auditory canal on CT, absence of cranial nerve VIII on MRI and a small posterior pontine prominence (Figure 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC5586526/figure/f1/) [66].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Prognosis varies greatly between entities and, within each, between patients. In pontine tegmental cap dysplasia, the outcome ranges from death at 15 and 32 months from intercurrent infections, in the forms with severe dysphagia and gastrostomy [72], to survival into adulthood (patients aged 20, 41 and 48 years) with cognitive impairment and hearing loss [20, 66], and cognitive performance ranges from severe impairment to a quotient of 94 [12, 16]. Severity may correlate with the brainstem dysplasia, with a rounded bulge in mild cases and "beak-like" angulation in severe ones [44]; a paediatric review describes the prognosis as poor, with severe motor and cognitive disorders and cranial nerve deficits [47]. Swallowing difficulties tend to improve with age [16], and central apnoea persists over time [96]. In medullary cap, the prognosis is that of the underlying disease: of the 9 patients with data, 4 had normal cognition, and 2 died in early childhood [22]. In brainstem disconnection, most children die in the first two months without acquiring any skills; survival beyond 2 months without ventilation has been described in two patients and prolonged survival on ventilation in others [23, 25, 27]. In the dominant ATOH1 form, the neurological picture did not appear progressive, no patient had intellectual disability attributable to ATOH1 and the three adults had a normal working life; in the recessive form, dependence is total in adulthood [31]. In LIS9, all patients had severe intellectual disability and most had early-onset epilepsy [35]. In DMJDS1, none of the 14 patients walked without support or developed language, and there were deaths from aspiration [36, 37]; in DMJDS2, one patient died at 2 years from respiratory failure and a sister at 4 months [39]. In EXOSC5-related disease, the prognosis ranges from normal cognition with mild ataxia to death in the first year, and cardiac conduction disease, with a risk of sudden death, appears in childhood or adolescence [42, 51]; two siblings with serial MRI had progressive loss of cerebellar volume [42].

11.2. Surveillance

The intervals are based on the French PNDS for pontocerebellar hypoplasias, applied by analogy to brainstem malformations, and on the recommendations of the published series where these exist.

12. Summary and Concluding Remarks

Rare brainstem malformations form a class in which the anomaly of the midbrain, pons or medulla is the dominant feature and which the 2026 French PNDS places in the differential diagnosis of pontocerebellar hypoplasias. Pontine tegmental cap dysplasia, described in 2007, is the most frequent and best characterised: the dorsal cap of the pons with a flat ventral pons, almost absent middle and inferior peduncles and ectopic transverse bundles on DTI is accompanied by cochlear nerve aplasia with a duplicated internal auditory canal, trigeminal anaesthesia with neurotrophic keratopathy, facial palsy, dysphagia, central apnoea and vertebral, rib and cardiac anomalies, with no known genetic cause and no familial cases. Medullary tegmental cap is an imaging sign with several causes, of which FOP and Joubert syndrome are the best documented, and brainstem disconnection is a severe neonatal malformation in which vascular disruption explains some cases. ATOH1-related disease shows how the same protein causes opposite syndromes: stabilising, dominant C-terminal truncations produce a recognisable brainstem malformation with mild to moderate hearing loss and subtle neurological signs, and homozygous loss-of-function variants produce a malformative pontocerebellar hypoplasia with profound hearing loss. Irahara syndrome is a MACF1-related posterior-predominant lissencephaly with a "W-shaped" brainstem, solved in 2018 by an intragenic deletion that conventional sequencing did not detect. The diencephalic-mesencephalic junction dysplasias due to PCDH12 and GSX2 combine the butterfly sign with microcephaly, epilepsy, dystonia and, in the former, calcifications and vitreoretinopathy. EXOSC5-related disease, which is not a primary brainstem malformation but enters the same differential, requires cardiac surveillance because of the risk of block and ventricular tachycardia and attention to post-viral thrombotic microangiopathy resistant to eculizumab. Treatment is symptomatic in all of them: corneal protection, with cenegermin for refractory neurotrophic keratopathy, auditory rehabilitation with careful selection for cochlear implantation, low-flow oxygen for central apnoea when mask ventilation threatens the cornea, management of swallowing and sialorrhoea, motor rehabilitation and cardiac devices in EXOSC5-related disease. Counselling depends on correct classification, because cap dysplasia is sporadic, Joubert syndrome recessive and the ATOH1 forms dominant or recessive depending on the variant; the series are small, the prevalence classes are upper limits and there are no registered clinical trials for any of the entities.

13. References

1. Orphanet. Syndrome with a brainstem malformation as a major feature (ORPHA:729519) and Genetic syndrome with a brainstem malformation as a major feature (ORPHA:730696). https://www.orpha.net/en/disease/detail/729519
2. Haute Autorité de Santé; Centre de Référence des Malformations et Maladies Congénitales du Cervelet; Filière DéfiScience. Protocole National de Diagnostic et de Soins (PNDS): Hypoplasies ponto-cérébelleuses. Saint-Denis La Plaine: HAS; juillet 2026 (publié 2026-09-07). https://www.has-sante.fr/jcms/p_4406492
3. Orphanet. Pontine tegmental cap dysplasia (ORPHA:269229). https://www.orpha.net/en/disease/detail/269229
4. Orphanet. Medullary tegmental cap dysplasia (ORPHA:727881). https://www.orpha.net/en/disease/detail/727881
5. Orphanet. Brainstem disconnection syndrome (ORPHA:727820). https://www.orpha.net/en/disease/detail/727820
6. Orphanet. Sensorineural hearing loss-brainstem malformation-motor delay-balance impairment syndrome (ORPHA:728662). https://www.orpha.net/en/disease/detail/728662
7. Orphanet. Diencephalic-mesencephalic junction dysplasia (ORPHA:319192). https://www.orpha.net/en/disease/detail/319192
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