Pontocerebellar Hypoplasias and Cerebellar Hypoplasia

Class of monogenic disorders, mostly autosomal recessive and of prenatal or neonatal onset, defined by hypoplasia and/or atrophy of the cerebellum and pons (PCH1A–PCH17, PHRINL due to ATAD3A), together with the X-linked and autosomal recessive entities that reproduce the same imaging pattern (MICPCH due to CASK, CAMRQ1–4, OPHN1) and the general approach to cerebellar hypoplasia and atrophy.

Literature and regulatory information updated: 26 October 2026.

0. Initial Reference Table

0.1. Table of all types in the class

The table follows OMIM phenotypic series PS607596 consulted on 26 October 2026; the "?" prefix marks the entries that OMIM classifies as provisional. The entities outside the series (PHRINL, MICPCH, CAMRQ1–4, OPHN1) have their own phenotype numbers. The 2018 review by van Dijk and colleagues designated SLC25A46 as PCH1D; in current OMIM, PCH1D corresponds to EXOSC9, SLC25A46 has become PCH1E and PCH1F corresponds to EXOSC1 [2, 4]. Orphanet does not list PCH5 or PCH15 among the descendants of ORPHA:98523 in classification 156; PCH5 has its own code (ORPHA:166068) classified as a malformation syndrome [1, 3].

1. Introduction

1.1. Hypoplasia, atrophy and neighbouring entities

The term "cerebellar hypoplasia" denotes a congenitally small cerebellum, of normal shape and static, whereas "cerebellar atrophy" denotes progressive reduction in cerebellar volume with widening of the spaces between the folia and worsening neurological sequelae [4, 62]. The Oxford Desk Reference stresses that distinguishing primary non-development from an atrophic process is difficult without serial MRI and therefore treats the two situations together; the geneticist's role is to establish a specific diagnosis, review the images with the neuroradiologist, determine whether the anomaly is restricted to the cerebellum or involves the cerebral cortex and other tissues and, within the cerebellum, whether the hypoplasia is limited to the vermis or involves the hemispheres [62]. The same source defines pontocerebellar hypoplasias as rare genetic conditions, mostly autosomal recessive, with underdevelopment of the cerebellum and brainstem, and brings together in a glossary the neighbouring entities: Dandy-Walker malformation (triad of cystic dilatation of the fourth ventricle, complete or partial agenesis of the vermis and an enlarged posterior fossa with displacement of the tentorium), vermis aplasia (midline defect between the hemispheres without an enlarged posterior fossa), the molar tooth sign (deep interpeduncular fossa, thick and elongated superior cerebellar peduncles and hypoplastic superior vermis, characteristic of Joubert syndrome and other ciliopathies) and Chiari malformations I to IV, type IV being a form of cerebellar hypoplasia [62]. The designation "hypoplasia of the cerebral hemispheres" sometimes appears associated with this group; the sources consulted describe no genetic entity with this designation, and the corresponding clinical content is hypoplasia of the cerebellar hemispheres, central to the "dragonfly" pattern of PCH2 and PCH4, and the cerebral cortical atrophy that accompanies about 40% of patients with PCH2 [63]. Posterior fossa malformations with an enlarged fossa (Dandy-Walker, Blake's pouch, mega cisterna magna), Joubert syndrome, lissencephalies with cerebellar hypoplasia and early-onset ataxias enter the differential.

1.2. From neuropathological description to modern classification

The first report of PCH dates from 1917, under the designation "hypoplasia ponto-neocerebellaris", which reflected the relative preservation of the vermis (paleocerebellum) compared with the hemispheres [4]. In 1928 Krause described an atrophic 16-month-old child with dysphagia, spasticity and jerky movements, a picture compatible with PCH2; in 1961 the first patient with PCH and Werdnig-Hoffmann-type motor neuron degeneration, the prototype of PCH1, was published; in 1977 Peiffer and Pfeiffer reported extrapyramidal hyperkinesia; and in 1990 Barth and colleagues described seven children from five families of a Dutch genetic isolate with PCH, microcephaly, severe extrapyramidal dyskinesia and absence of voluntary movement [4]. The first classification, in 1993, separated PCH1, defined by anterior horn degeneration with weakness and hypotonia, from PCH2, defined by neonatal jitteriness, sucking-swallowing incoordination, absent voluntary motor development and almost absent cognitive development [4]. In 1995, Barth and colleagues pooled 16 patients from 10 unrelated pedigrees (six Dutch, two Swedish and two German) with the same profile of virtually absent developmental milestones, severe early-onset chorea, microcephaly and pontocerebellar hypoplasia, and a family distribution compatible with autosomal recessive inheritance, consolidating PCH2 as an entity [64].

1.3. Molecular milestones

The molecular era began in 2008, when Budde and colleagues identified variants in three of the four subunits of the tRNA splicing endonuclease complex (TSEN) in PCH2 and PCH4, showing that RNA processing is an underlying mechanism in neurological diseases [27]. In the same year, Najm and colleagues associated CASK variants with an X-linked malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum, MICPCH [5, 65]. There followed RARS2 in PCH6 (2007), VRK1 in the association of SMA with PCH (2009), SEPSECS in progressive cerebello-cerebral atrophy (2010), EXOSC3 in PCH1 (2012), CHMP1A in PCH8 (2012), AMPD2 in PCH9 (2013), CLP1 in PCH10 (2014), EXOSC8 (2014), VPS53 (2014), PCLO (2015), TSEN15 and SLC25A46 (2016), TOE1 and TBC1D23 (2017), COASY and EXOSC9 (2018), VPS51 (2019), MINPP1 (2020), PPIL1 and CDC40 (2021), EXOSC1 (2021) and PRDM13 (2022) [16, 18, 19, 21, 23, 29, 31, 33, 34, 36, 38, 40, 41, 43–46, 48, 50, 51, 54, 56, 66]. In 2005, Boycott and colleagues had associated homozygous deletion of VLDLR with an autosomal recessive cerebellar hypoplasia with simplification of the cerebral gyri in the Hutterite population, the basis of CAMRQ1 [59, 67].

1.4. Subtype counts and reclassifications

The number of subtypes has followed gene discovery. The 2011 review by Namavar and colleagues recognised seven subtypes (PCH1–7), with unknown incidence, symptomatic treatment and death in childhood for most patients [68]. The Oxford Desk Reference (2017) mentioned at least eight genes and the Saudubray textbook (2022) nine subtypes [62, 63]. The 2018 review by van Dijk and colleagues described 11 types and 17 genes in OMIM, most of them with a function in RNA processing or translation, and warned that the inclusion of non-degenerative phenotypes (PCH8, PCH11) and of phenotypes with postnatal onset (PCH2D, PCH2E, PCH10) contradicted the original definition of a degenerative disease of prenatal onset, making the classification confusing [4]. In 2023, Sakamoto and colleagues counted 16 subgroups with pathogenic variants in up to 24 genes, and the 2025 review by Škarica and colleagues refers to 17 variants (types) distinguished by clinical, radiological and biochemical features [69, 70]. At the date of this article, OMIM records PCH1A to PCH17 in 27 entries, without PCH18, four of them provisional (PCH1F, PCH2C, PCH5 and PCH15) [2]. Three reclassifications illustrate this evolution: PCH2D and PCH2E corresponded to progressive cerebello-cerebral atrophy types 1 and 2 (PCCA1 and PCCA2), and PCH3 to cerebellar atrophy with progressive microcephaly (CLAM) [4]; PCH5, defined in a single family by prenatal seizures and greater vermis involvement, has the same TSEN54 genotype as PCH4, which makes the distinction redundant [4]; and the 2026 international cohort of Killam and colleagues proposes renaming PCH2D "SEPSECS-related neurodevelopmental disorder", because pontine involvement occurs in fewer than half of patients [30].

1.5. Current classifications

Three ways of classifying these patients coexist. The numbered classification of OMIM and Orphanet (PCH1–PCH17, with lettered subtypes according to the gene) is based on the clinical and imaging phenotype and, within each phenotype, on the gene; the PCH2 subtypes were designated in the chronological order of gene identification [8, 9, 63]. The developmental and genetic classification of Barkovich, Millen and Dobyns (2009) groups midbrain and hindbrain malformations into four categories: early defects of anteroposterior and dorsoventral patterning or of germinal zone specification; malformations associated with generalised developmental disorders that affect the brainstem and cerebellum; localised malformations (proliferation, specification, migration, axonal guidance); and combined hypoplasia and atrophy of degenerative diseases of probable prenatal onset, the category in which PCH belong [71, 72]. Finally, the Canadian cohort of Zakaria and colleagues (2024) showed that, in a set of 38 children with PCH on imaging, only one had variants in a PCH gene listed in OMIM and 21% had a chromosomal cause, and proposed using "PCH" as a radiological term that does not imply a neurodegenerative disease [13]. This proposal separates PCH as an imaging finding, of heterogeneous cause, from PCH as a group of numbered monogenic diseases.

The French National Diagnosis and Care Protocol (PNDS) published by the Haute Autorité de Santé (HAS) in 2026 adopts a practical division into three groups [12]. The first brings together the PCH of the historical classification into 17 types, mostly neurodegenerative and autosomal recessive; the protocol itself notes two exceptions to the definition, PCH11 (TBC1D23), a non-degenerative developmental form, and PCH2D (SEPSECS), which corresponds to a progressive cerebello-cerebral atrophy without prior hypoplasia. The second groups the neurodevelopmental PCH, without regression and with a more stable course, which OMIM does not classify as PCH: CASK (the most frequent), SPTAN1 (much rarer), VLDLR and RELN. The third corresponds to diseases in which brainstem and cerebellar hypoplasia is inconstant and forms part of a syndromic picture, whose diagnosis rests on the overall context or on genome-wide analysis, and to genetic metabolic diseases that may be accompanied by PCH on imaging (CDG, urea cycle defects, fatty acid β-oxidation defects, diseases with hyperlactataemia) [12]. The PNDS presents PCH1F as an exception to autosomal recessive inheritance, but the two reports it cites describe biallelic EXOSC1 variants, homozygous in the second case, and OMIM records PCH1F as recessive; recessive inheritance is the one supported by the primary sources [2, 12, 23, 24].

1.6. Definition of the entities in scope

PCH1 is defined by the association of pontocerebellar hypoplasia or atrophy with degeneration of the anterior horn motor neurons of the spinal cord, weakness and hypotonia; the neuromuscular manifestations may present as amyotrophic lateral sclerosis, hereditary motor neuropathy, non-5q SMA or hereditary motor and sensory neuropathy, and isolated neuromuscular forms have a later onset and a better course [70]. PCH2 is defined by generalised clonus, impaired swallowing, dystonia, chorea and progressive microcephaly, with a "dragonfly" pattern on MRI; PCH4 is its severe form with congenital contractures and polyhydramnios [4]. PCH3 and PCH6 to PCH17 are defined by additional features (optic atrophy, lactic acidosis, DSD, "figure-of-8" midbrain, neuropathy, arthrogryposis, hypoplastic basal ganglia, brainstem dysfunction) summarised in table 0.1 [4]. MICPCH is an X-linked disorder with intellectual disability, severe postnatal microcephaly and pontine and cerebellar hypoplasia affecting the vermis and hemispheres in similar proportion; CAMRQ (dysequilibrium syndrome) groups non-progressive congenital cerebellar ataxias with intellectual disability and, sometimes, quadrupedal locomotion [5, 10, 62].

2. Molecular Genetics and Pathophysiology

2.1. Common mechanisms of the class

PCH genes participate in neuronal development and survival and in the processing of RNA molecules [62]. The 2018 review highlights the central question of the class: it is unknown why defects in ubiquitous processes, such as tRNA splicing, mRNA degradation or selenoprotein synthesis, produce a phenotype restricted to the brain [4]. One hypothesis is the vulnerability of the cerebellum during the third trimester, a period of very rapid cerebellar growth, the same window that explains cerebellar injury in extremely preterm infants [4, 73]. The mechanisms group into tRNA processing (TSEN54, TSEN2, TSEN34, TSEN15, CLP1), mitochondrial aminoacylation (RARS2), selenocysteine synthesis (SEPSECS), RNA degradation and maturation by the exosome (EXOSC3, EXOSC8, EXOSC9, EXOSC1), snRNA processing (TOE1), splicing by the major spliceosome (PPIL1, CDC40), purine metabolism and GTP synthesis (AMPD2), coenzyme A synthesis (COASY), inositol phosphate metabolism (MINPP1), vesicular and endosomal trafficking (VPS53, VPS51, CHMP1A, TBC1D23), mitochondrial dynamics (SLC25A46, ATAD3A), synaptic organisation (CASK, PCLO), neuronal migration through the reelin pathway (VLDLR) and neuronal specification (PRDM13) [4, 63].

2.2. TSEN complex and CLP1: PCH2A–2C, PCH2F, PCH4, PCH5 and PCH10

The human genome has 506 tRNA genes; only about 6% of pre-tRNAs have an intron, but for some amino acids most tRNAs are intron-containing (tRNA-Tyr GTA, tRNA-Ile TAT) [4, 8]. The intron is removed by the TSEN endonuclease, a tetramer with two catalytic subunits (TSEN2 and TSEN34) and two structural ones (TSEN15 and TSEN54); the complex also participates in 3'-end formation of mRNA, because TSEN2 knockdown impairs this process in vitro [8, 74]. CLP1 is a polynucleotide kinase that interacts with the TSEN complex and phosphorylates the 5' end of the 3' tRNA half after cleavage, allowing ligation [4, 63]. Neurons are particularly sensitive to tRNA splicing defects, which alter protein translation [63]. The mechanism of TSEN54 variants is loss or reduction of function, and patients with nonsense variants are more severely affected than patients with missense variants [8]. The functional results for p.(Ala307Ser) are ambiguous: Budde and colleagues found no unprocessed tRNA-Tyr products in fibroblasts [4]. Structural studies showed that complexes with TSEN34 p.(Arg58Trp) and mutant TSEN15 assemble, but with thermal destabilisation, defective tetramer assembly and reduced pre-tRNA cleavage [28]. The CLP1 p.(Arg140His) variant prevents interaction with the TSEN complex and reduces pre-tRNA cleavage; induced neurons from patients show depletion of mature tRNAs and accumulation of unprocessed pre-tRNAs, and tRNA fragments worsen the loss of survival under oxidative stress [43, 44]. TSEN15 p.(Tyr152Cys), p.(Trp76Gly) and p.(His116Tyr) cause almost complete loss of cleavage activity in vitro [33].

2.3. RNA exosome: PCH1B, PCH1C, PCH1D and PCH1F

The exosome is a 3'→5' exoribonuclease complex with a core of nine subunits, responsible for the maturation of rRNA, snRNA and snoRNA, for the degradation of defective mRNAs and those with AU-rich elements, and for cytoplasmic surveillance [4, 9]. EXOSC3 (RRP40) is the RNA-binding unit of the "cap" of the complex; EXOSC8 (RRP43) belongs to the central ring [4]. EXOSC3 was the first nuclear exosome component associated with human disease: Wan and colleagues identified recessive variants in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global delay, and in another 8 of 12 families with PCH1; knockdown in zebrafish reproduced the phenotype and was rescued by wild-type mRNA [66]. EXOSC8 variants increase mRNAs with AU-rich elements encoding myelin proteins, which explains the hypomyelination [18]. Exosome variants also increase p53 and ribosome biogenesis factors, with G2/M arrest and apoptosis, which has led to the proposal of exosome diseases as ribosomopathies [75]. In PCH1D, fibroblasts and muscle show reduction of the whole complex, and exosc9 zebrafish reproduce the absence of parts of the cerebellum and hindbrain and motor neuron failure [19]. In PCH1F, the EXOSC1 p.(Ser35Leu) variant reduces EXOSC1 and the EXO9 complex [23].

2.4. VRK1 and SLC25A46: PCH1A and PCH1E

VRK1 is a nuclear serine/threonine kinase that phosphorylates p53 and CREB, is essential for nuclear envelope formation and participates in cell division and Cajal bodies; murine knockdown impairs cortical neuronal migration [4, 16]. SLC25A46 is an outer mitochondrial membrane protein, homologous to yeast Ugo1, which promotes mitochondrial fission and cristae organisation; its spectrum ranges from optic atrophy with cerebellar atrophy to lethal PCH [4, 22]. Lethal variants strongly destabilise the protein, whereas those causing non-lethal optic atrophy do not, so that severity correlates inversely with the stability of the mutant protein [21, 76]. The original Dutch PCH1 family, described by Barth, had SLC25A46 variants, the first genetic basis of the most severe end of PCH1 [4, 77].

2.5. Aminoacylation, selenocysteine, purines and coenzyme A: PCH6, PCH2D, PCH9 and PCH12

RARS2 encodes mitochondrial arginyl-tRNA synthetase; the intronic variant of the original Sephardic family produced an abnormal short transcript and a marked reduction of mitochondrial tRNA(Arg) in fibroblasts, with the remaining molecules almost all charged [4, 36]. Of the 31 patients published up to 2018, none had two null alleles, suggesting that complete abolition is lethal [4]. In aminoacyl-tRNA synthetase defects there are no specific biochemical markers and aminoacylation assays are research tools [63]. SEPSECS catalyses the last step of selenocysteine synthesis, the conversion of Sep-tRNA into Sec-tRNA, on which the whole selenoproteome depends; its loss abolishes the only selenocysteine synthesis pathway [4, 29]. The 2026 cohort found increased glutathione and sulphur metabolites in plasma, a sign of oxidative stress [30]. AMPD2 converts AMP into IMP; its deficiency depletes guanine nucleotides and impairs GTP-dependent translation initiation, a defect rescuable in vitro by purine precursors; AMPD2 is the predominant paralogue in the cerebellum [4, 41]. COASY is the bifunctional coenzyme A synthase that performs the last two steps of synthesis from pantothenate; partial deficiencies cause CoPAN, a neurodegeneration with iron accumulation, and almost complete loss of function causes lethal PCH12 with arthrogryposis [48, 78].

2.6. Spliceosome, inositol phosphates, trafficking and synapse

PPIL1 is a cyclophilin of the major spliceosome that isomerises CDC40 (PRP17), a protein of the second catalytic step of splicing; biallelic variants in the two genes mainly impair splicing of short, GC-rich introns, and PPIL1 knock-in mice show specific neuronal apoptosis, which underpinned the concept of "major spliceosomopathies" [51]. MINPP1 is the only human phosphatase that hydrolyses the inositol phosphates InsP5 and InsP6 in the lumen of the endoplasmic reticulum; its loss leads to accumulation of intracellular InsP6, which chelates iron and calcium, and MINPP1-null induced pluripotent stem cells differentiate poorly into neurons [54]. VPS53 and VPS51 are subunits of the GARP (retrograde transport from the endosome to the trans-Golgi) and EARP complexes; VPS51 variants reduce both complexes [31, 50]. CHMP1A belongs to the ESCRT-III complex and regulates repression of INK4A by BMI1; its loss reduces cerebellar progenitor proliferation [40]. TBC1D23 participates in intracellular vesicular transport; a homozygous truncating variant partially escapes nonsense-mediated decay (NMD) and produces a stable, cytotoxic truncated protein [4, 79]. TOE1 is a non-conventional deadenylase of Cajal bodies that trims the 3' ends of pre-snRNAs; it is unknown why its loss affects the brain and the gonads [4, 38]. Piccolo, encoded by PCLO, is a presynaptic cytomatrix protein of the active zone; its loss leads to degradation of synaptic proteins and disassembly of the synapse [4, 34]. ATAD3A organises mitochondrial DNA and participates in cholesterol metabolism; the locus has three tandem paralogues (ATAD3C, ATAD3B, ATAD3A), which facilitates recurrent deletions and hinders short-read sequencing [4, 6]. PRDM13 is a regulator of cerebellar GABAergic fate; mutant mice have reduced PAX2+ progenitors, ectopic TLX3 expression and reduced hypothalamic kisspeptin neurons, which explains the association of cerebellar hypoplasia with hypogonadotropic hypogonadism [56, 57].

2.7. CASK, VLDLR and OPHN1

CASK is a calcium/calmodulin-dependent serine protein kinase of the MAGUK (membrane-associated guanylate kinase) family, with an N-terminal CaMK domain, two L27 domains, PDZ, SH3 and a C-terminal guanylate kinase domain, widely distributed in the brain; it controls presynaptic organisation and neurotransmitter release, dendritic spine morphology, glutamate receptor trafficking and transcription of cortical development genes [5]. Most variants in MICPCH are predicted null alleles; some heterozygous missense variants in girls with MICPCH specifically impair binding to Mint1 or neurexin [5, 80]. VLDLR is an 873-amino-acid receptor of the low-density lipoprotein receptor family that, together with ApoER2, binds reelin, phosphorylates Dab1 and activates the cascade that allows neuroblasts to complete migration in the cerebral cortex and cerebellum; without the receptor, migration is not completed, and there is no change in the lipid profile [10, 62]. Oligophrenin-1, encoded by OPHN1, causes X-linked intellectual disability with neonatal hypotonia and variable cerebellar hypoplasia [61].

2.8. Variant spectrum, transcripts and founder variants

Variants were normalised in VariantValidator with the MANE (Matched Annotation from NCBI and EMBL-EBI) Select transcript and confirmed in ClinVar; historical numbering is given when it differs [81, 82]. TSEN54 NM_207346.3:c.919G>T p.(Ala307Ser) explains about 88% of PCH2 cases according to GeneReviews, which uses version NM_207346.2, and about 90% in the German cohort [8, 15]. In CASK and TBC1D23, the MANE numbering differs from the literature, which uses NM_003688.3 and NM_018309.5, respectively [81].

The founder variants with population data are TSEN54 p.(Ala307Ser) in the Netherlands and Germany, EXOSC3 p.(Gly31Ala) in the Roma populations of Central and Eastern Europe, the SEPSECS variants in Jews of Iraqi and Moroccan origin, the VPS53 variants in Moroccan Jews, CLP1 p.(Arg140His) in Turkey, PPIL1 p.(Ala99Thr) in Egypt, the VLDLR deletion in Hutterites and the deep intronic variant NM_176096.3:c.334+243G>A of CDK5RAP3 in South Asian populations (section 9) [8, 10, 11, 29, 31, 44, 52, 91].

2.9. Genotype-phenotype correlations, penetrance and expressivity

In the TSEN54 spectrum, homozygosity for p.(Ala307Ser) gives PCH2 with survival into childhood, and compound heterozygosity for p.(Ala307Ser) with a nonsense, frameshift or splice variant gives the PCH4/PCH5 end, with more perinatal symptoms, ventilator dependence and early death [4, 8, 92]. In EXOSC3, homozygosity for p.(Asp132Ala) is associated with a prolonged course, with possible survival to puberty, some patients walking or saying single words, a normal-sized pons and mild cerebellar hypoplasia; the combinations p.(Asp132Ala)/p.(Val80Phe) and p.(Asp132Ala)/p.(Gly191Asp) are equally mild [9, 17]. p.(Asp132Ala) in trans with a nonsense allele or with p.(Tyr109Asn), and homozygosity for p.(Gly31Ala) or p.(Gly135Glu), give a rapidly progressive course, death in infancy and attenuation of the ventral pons; two siblings homozygous for p.(Gly31Ala) had severe growth restriction, fetal akinesia, microlissencephaly and malformations compatible with rhombencephalosynapsis [17, 93]. In SLC25A46, severity follows protein instability [76]. In AMPD2 the phenotype is uniformly severe, with no genotype-phenotype correlation and no hotspot [94]. In RARS2 and TOE1 the variants are distributed throughout the gene without a clear correlation [4, 39]. In CASK, girls with MICPCH have heterozygous loss-of-function variants, and hypomorphic variants (missense, splice) give X-linked intellectual disability with or without nystagmus; in boys, germline loss of function gives MICPCH with severe epileptic encephalopathy, somatic mosaics and variants with partial penetrance give MICPCH without severe epilepsy, and hypomorphic variants give intellectual disability with or without nystagmus [5, 95]. Penetrance of MICPCH is apparently complete in the girls and boys described; in mosaics, the level of mosaicism may determine the variability, and in carriers of hypomorphic variants penetrance is incomplete [5]. In the series of Burglen and colleagues there was no clear genotype-phenotype correlation: a girl with p.(Trp657Ter) walked and ran at 3 years and used words at 8, whereas another with p.(Trp656Ter) acquired neither language nor walking [58]. In VLDLR there are no clinically relevant correlations, except for a less severe phenotype with p.(Cys419Tyr) in a less essential domain [10].

2.10. Allelic disorders

Several PCH have allelic forms outside the class. VRK1 also causes autosomal recessive distal hereditary motor neuronopathy 10 (OMIM 620542), with slowly progressive distal weakness and atrophy of the lower limbs and juvenile or adult onset; Stoll and colleagues described siblings with adult distal SMA and a child with motor neuron disease without PCH, and Greenbaum and colleagues two Moroccan Jewish patients homozygous for p.(Arg387His) with length-dependent motor neuropathy beginning at 48 and 40 years [4, 87, 96]. SLC25A46 causes hereditary motor and sensory neuropathy type 6B (early optic atrophy with axonal neuropathy of the Charcot-Marie-Tooth 2 type) [22]. AMPD2 causes SPG63, described in a family homozygous for a frameshift variant [97, 98]. COASY causes CoPAN (neurodegeneration with brain iron accumulation 6), with epilepsy, deafness, language disorder, autism spectrum disorder (ASD), atrophy and microcephaly, and a riboflavin-responsive lipid storage myopathy [99–101]. TSEN2 causes TRACK syndrome (TSEN2-Related Atypical haemolytic uremic syndrome, Craniofacial malformations, Kidney failure) [26]. VPS53 has a mild end of complicated hereditary spastic paraparesis with mild to moderate intellectual disability, normal head circumference and MRI, and siblings with the same alleles were diagnosed as PEHO syndrome (progressive encephalopathy with oedema, hypsarrhythmia and optic atrophy) [32, 102]. EXOSC3 has reports of complicated hereditary spastic paraplegia and of isolated cerebellar hypoplasia with anterior horn involvement [9, 103]. PRDM13 causes, in addition to PCH17, a recessive syndrome with intellectual disability, ataxia with cerebellar hypoplasia, scoliosis and delayed puberty due to hypogonadotropic hypogonadism (OMIM 619761), and, through cis regulation, North Carolina macular dystrophy, which is autosomal dominant and not detected by exome sequencing [57, 104]. The ATAD3A spectrum ranges from neonatal lethal recessive PCH to dominant Harel-Yoon syndrome and dominant neonatal lethal cardiomyopathy [6]. CASK has as its allelic phenotype X-linked intellectual disability with or without nystagmus, which includes the former FG4 syndrome [5, 105].

2.11. Neuropathology

In PCH2, the cerebellum shows hypoplasia with reduced foliar branching, segmental degeneration of the cerebellar cortex and dentate nucleus, variable Purkinje cell degeneration and relative preservation of the flocculus and vermis; the pons has ventral neuronal death with relative preservation of the tegmentum; the medulla has hypoplasia and segmental degeneration of the inferior olivary nuclei and loss of the arcuate nuclei; myelin is not involved [8, 106]. The findings combine features of hypoplasia ("stunted foliar growth") and degeneration, and the term "hypoplasia" is historical [4]. In PCH4 there is delayed cortical maturation and growth, pericerebral fluid accumulation, extensive gliosis and neuronal loss in the thalamus and caudate, very hypoplastic cerebellar hemispheres without Purkinje cells, dentate remnants, a vermis more affected than in PCH2 and horseshoe-shaped inferior olives without folding [4]. In PCH1B there is grouped atrophy and type II fibre atrophy in muscle, loss of anterior horn motor neurons, loss of Purkinje cells, foliar atrophy, degeneration of the dentate nuclei and loss of the ventral pontine nuclei and transverse pontine fibres [9]. In PCH7, neuropathology showed cerebral atrophy with profound reduction of white matter, almost absent cerebellar hemispheres, a relatively spared vermis, a ventral pons without pontine nuclei and unidentifiable inferior olives [4, 107]. In PCH17, MRI and fetal pathology show marked hypoplasia of the inferior olives, dysplasia of the dentate nucleus and a sparse, disorganised Purkinje layer [56]. The first neuropathological description of VLDLR cerebellar hypoplasia, in a third-trimester term fetus, showed cerebellar hypoplasia with marked hypoplasia of the vermis and cortical simplification without lissencephaly [108]. According to the French PNDS (National Diagnosis and Care Protocol), in PCH2, PCH4 and PCH5 the internal granular layer is sparse, the dentate nuclei are hypoplastic and fragmented, the olives have very few cells and the anterior horn of the spinal cord is normal, whereas loss of anterior horn motor neurons characterises PCH1 [12]. In a boy with a CASK variant, neuropathology showed neuronal loss in the pons, shallow, malformed and unbranched cerebellar folia, an abnormally thick external granular layer, a virtually absent internal granular layer, a disorganised Purkinje layer and hypercellularity of the molecular layer. In two fetuses and one patient with PCH due to PRDM13, severe hypoplasia of the vermis was accompanied by abnormal foliation, dysplastic and fragmented dentate nuclei, very hypoplastic olives with preserved pyramidal tracts, a disorganised Purkinje layer with decreasing cell density over time and Purkinje cell heterotopias in the cerebellar white matter [12].

3. Clinical Spectrum and Manifestations by System

3.1. Common features of the class

The features shared by the PCH are hypoplasia and/or atrophy of the cerebellum and pons, progressive microcephaly, variable cerebral involvement, severe cognitive and motor deficits and frequent epileptic seizures; treatment is symptomatic and most patients die in childhood [1, 68]. Most neurological signs reflect dysfunction of the cortex and basal ganglia (severe intellectual disability, central motor impairment, epilepsy), and overt cerebellar signs are very rarely reported, despite severe cerebellar involvement on imaging [4]. The Oxford Desk Reference describes the phenotype as neurodegenerative, with microcephaly and severe delay, typical feeding and swallowing problems and, sometimes, weakness compatible with infantile SMA [62]. Orphanet adds the wide clinical variation between and within forms, and lists cot death, sleep apnoea, rhabdomyolysis and malignant hyperthermia as potentially fatal complications in PCH2 [1]. In the Canadian cohort of 38 children with PCH on imaging (21 boys and 17 girls, aged 8 days to 15 years, Montreal), all had hypoplasia of the pons and vermis, 63% hypoplasia of the cerebellar hemispheres and 71% supratentorial anomalies; none had regression; about one third died (median 8 months); all had global delay, 50% were non-verbal, 64% did not walk and 45% had a gastrostomy [13]. This cohort measures PCH as a radiological finding of any cause and not the natural history of the numbered monogenic PCH.

The extraneurological manifestations are mostly a consequence of multiple disability and not specific to PCH [12]. Neuro-orthopaedic changes (kyphoscoliosis due to axial hypotonia and tone abnormalities, hip dislocation) develop quickly, sometimes from the neonatal period, and bone mineralisation defects are multifactorial (lack of weight-bearing, immobilisation, malnutrition, calcium and vitamin D deficiency, corticosteroids and antiepileptic drugs), with a risk of pathological fractures, bone pain and sleep disturbance. Respiratory vulnerability (apnoeas, recurrent infections, respiratory failure) results from the combination of impaired development of the lung parenchyma, neurological disturbance of respiratory control, a narrow and rigid chest, scoliosis, ineffective cough, food or saliva aspiration and reflux. Bladder-sphincter dysfunction may present as an unstable bladder, recurrent urinary tract infections and a trabeculated bladder (thickened wall with diverticula), with possible repercussions on the upper urinary tract. Sleep disturbances have organic causes (pain, discomfort, epilepsy, apnoeas) and/or disruption of the sleep-wake rhythm, with a major impact on the person and the family. Pain is sought by interviewing those close to the patient (unusual change in behaviour), by careful observation and by examination, with scoring scales, and its causes are digestive, dental, ear-nose-throat, neurological, bone, skin or psychological. Rare visceral malformations have been described, cardiac (ventricular septal defect, tetralogy of Fallot) and renal (hydronephrosis), and, in PCH2, raised CK with occasional rhabdomyolysis during infections [12].

3.2. PCH2A (homozygous TSEN54 p.(Ala307Ser))

Pregnancy is usually uneventful; newborns have no external dysmorphic features or visceral anomalies and are born at term with normal weight and length, with a normal head circumference that is always below the 50th centile, and microcephaly progresses in the first year to values below −2 standard deviations (SD) [8]. The newborn has oropharyngeal incoordination (weak latch, sucking-swallowing incoordination) and generalised clonus ("jitteriness"); there is no voluntary motor development, and sitting without support or voluntary reaching and grasping are rarely achieved; severe chorea frequently appears in the first 6 months, usually with spasticity, and patients who never develop chorea remain spastic quadriplegic; central vision is impaired without primary optic atrophy; and there is a subclinical myopathy with raised creatine kinase (CK) that can progress to rhabdomyolysis after severe infections [8].

The most complete natural history is the German and Swiss cohort of Sánchez-Albisua and colleagues, recruited between April and November 2012 through the PCH2 support group of Germany and Switzerland, with a standardised questionnaire, a 1- to 2-hour telephone interview and medical records: 33 patients (17 boys and 16 girls) born between 1991 and 2011, with typical MRI and homozygous p.(Ala307Ser), no consanguineous couples and grandparents of German (78 of 101), Polish (10), Swiss (7) and Russian (6) origin [15]. Nine patients had died (three girls and six boys), at a mean age of 6 years and 7 months (7 months to 15 years and 6 months); considering the children with possible follow-up to 10 years, 8 of 15 (53%) had died, 3 before 6 years and 5 between 6 and 10 years [15]. The article abstract and some secondary sources state "53% at 11 years"; the full text sets the denominator at 15 children and the limit at 10 years [15]. The causes of death were sudden unexpected death at night in five, and multiorgan failure, a crisis with apnoea, pneumonia and refractory progressive hypothermia (at 15 years) in one each [15].

Table source: Sánchez-Albisua and colleagues, full text; GeneReviews reproduces the same percentages [8, 15]. The frequency of epilepsy differs between sources: 82% in this cohort followed into childhood and about 50% in the general clinical description of GeneReviews; the difference probably reflects the age of the patients observed, because none of the six patients without seizures was older than 28 months [8, 15].

Prenatal signs occurred in 10 children (microcephaly on ultrasound at 32–35 weeks in 4, polyhydramnios in 4, trembling fetal movements perceived by 6 mothers) and were not associated with survival at 1, 5 or 10 years; 20 newborns (61%) were admitted to neonatal care, with feeding difficulties in 85%, abnormal tone in 70%, "jitteriness" in 64%, excessive sleepiness in 58% and respiratory difficulty or apnoea in 27% [15]. Mean head circumference went from −1.24 SD at birth to −5.58 SD at 5 years (−2.95 to −8.84), with length of −2.14 SD and weight of −2.51 SD at 5 years [15]. Epileptic seizures were tonic-clonic, atypical absences, myoclonic, tonic, focal, atonic and associated with apnoea, with frequent febrile convulsions; 25 patients were taking antiepileptic drugs, 15 of them two or more, and only 3 were seizure-free; the electroencephalogram (EEG) showed diffuse slow activity and multifocal discharges progressing with age [15]. Dystonic crises occurred from twice a week to twice a year, began at a mean of 15 months, ceased in 5 of 11 between 2 and 8 years and, in 8 of 11, ended only with natural sleep [15]. Motor and social gains were fixing and following (76%), attempted grasping (76%), moderate head control (73%), social smile (70%), rolling from prone to supine (58%) and sitting without support (9%); 10% lost acquired skills, and language was absent in 10 and rudimentary in 19 [15]. The authors interpret the course as an early-onset degeneration that subsequently stabilises [15].

The German natural history study of Herrmann and colleagues (2026), with 65 children (33 girls and 32 boys), showed symptom onset at a median of 0 months (0 to 6), often suggesting an acute rather than congenital disease, and a median interval of 5 months between the first symptoms and genetic confirmation in those born after 2008 [109]. In the same group, specific growth charts constructed from retrospective data from December 2020 to September 2022 (mean age 8 years and 7 months), compared with the German KiGGS reference, showed normal height and weight at birth, significantly lower height from 6 months, weight from 3 months and body mass index from 4 months, with head circumference below the mean from birth and severe progressive microcephaly in all; growth failure was frequent despite a caloric intake within or above reference values [110]. Life expectancy in PCH2 is usually less than 10 years, although survival beyond 20 years has been described; improved care, especially gastrostomy feeding, has probably prolonged survival, and the typical complications are sudden death during sleep in infants and death during hyperthermic crises [8]. In the Italian series of Cassandrini and colleagues, 9 of 12 children with clinical and MRI features of PCH2/PCH4 had p.(Ala307Ser), and two siblings without a TSEN variant had a Bartter-like tubulopathy [83].

3.3. PCH4 and PCH5

PCH4, formerly called olivopontocerebellar hypoplasia, presents prenatally with polyhydramnios in many pregnancies and, at birth, with central respiratory failure due to probable brainstem failure, prolonged or permanent dependence on mechanical ventilation, microcephaly usually already present, contractures (arthrogryposis) in about 50% of newborns, hypertonia and generalised clonus triggered by handling or noise, sometimes extreme; death usually occurs in the neonatal period and survival beyond it is rare [4, 8]. PCH5 was described in three siblings with a severe form of fetal onset, seizure-like fetal activity and predominant degeneration of the vermis, with death very shortly after birth [8, 35].

3.4. Other PCH2 subtypes

PCH2B (TSEN2) is rare and reproduces the PCH2 phenotype; the patient published in 2025, a 7-year-old Japanese girl, had progressive microcephaly, epilepsy, delay, cerebellar atrophy and dystonia [25, 111]. In the same TSEN2 gene, a founder intronic variant with exon 10 skipping caused, in six patients from four consanguineous families, TRACK syndrome: microcephaly, multiple craniofacial malformations, central nervous system anomalies and variable cognitive impairment, with atypical haemolytic uraemic syndrome in all (thrombotic microangiopathy, microangiopathic haemolytic anaemia, thrombocytopenia, proteinuria, severe hypertension) and early end-stage kidney disease [26]. PCH2C (TSEN34) rests on a single family homozygous for p.(Arg58Trp) [27]. PCH2F (TSEN15) was described in three consanguineous families (Pakistani, Saudi and Syrian) with five affected individuals: progressive microcephaly (from normal or near normal at birth to −3.0 to −9.7 SD), delay, mild to severe intellectual disability, poor or absent expressive language, seizures in 2 of 4 (onset at 8 and 11 months), none with central visual failure and only one with the typical extensive motor deficit [33].

PCH2D (SEPSECS) has a severe early form, with neonatal or early-infancy irritability and opisthotonus, progressive microcephaly, profound intellectual disability, spasticity or dystonic quadriplegia, loss of motor skills, visual impairment and progressive cerebellar atrophy followed by cerebral atrophy, and a mild late form with mild delay in childhood, slowly progressive ataxia and spasticity until adolescence or adulthood, without pontine atrophy [4, 29]. The international cohort of 27 biallelic patients (13 novel variants) distinguished three courses: severe early onset with cerebellar or cerebral atrophy, milder early onset with gradual deterioration and mild late onset; only 1 of 8 patients studied had thyroid hormones suggestive of a defect in conversion of T4 to T3 [30]. Early-onset cases are concentrated in Arab countries and Finland [112]. PCH2E (VPS53), described in 10 patients from four non-consanguineous Moroccan Jewish families, has a normal pregnancy and normal head circumference at birth, delay in the first months, progressive spasticity leading to spastic quadriplegia, multiple contractures, progressive microcephaly, seizures, profound intellectual disability, osteoporosis and scoliosis; MRI is initially normal and cerebellar atrophy appears in the first year, followed by cerebral atrophy [4, 31].

3.5. PCH1

The initial reports of PCH1 described a neonatal lethal disease with polyhydramnios, congenital contractures, respiratory failure and severe hypotonia; later studies included patients with a spared pons and survival to puberty [4]. In PCH1B (EXOSC3), described in 82 individuals from 58 families, pregnancy is usually normal, with fetal akinesia, prenatal contractures and polyhydramnios in only 1–2%; birth weight and length are normal and head circumference normal or small [9]. Hypotonia is the most common initial finding, present at birth in most and evident only at 3–6 months in the rest; there follow signs of neurogenic muscular atrophy (atrophy, reduced reflexes, fasciculations and enlarged motor unit potentials on electromyography), respiratory failure and swallowing difficulties in the first year and, in survivors, spasticity, dystonia and seizures (in about 25% of long-term survivors), strabismus and nystagmus [9]. Motor milestones are delayed or absent; few crawl, sit or walk without support, and these skills are often lost; speech is usually absent, with short sentences in a few; swallowing failure requires tube feeding in most, from birth to a few years; the causes of death are infections and respiratory failure due to muscle weakness, with age at death ranging from a few weeks to adolescence [9].

In the series of Rudnik-Schöneborn and colleagues (37 patients from 27 families of mixed ethnicity), EXOSC3 explained 10 of 27 families (37%), p.(Asp132Ala) accounted for 11 of 20 alleles (55%), three patients survived beyond adolescence, and intrauterine anomalies, postnatal hypoventilation, contractures and neonatal death were rare in EXOSC3-positive patients and typical in negative ones [84]. Mean age at death was 9 months with EXOSC3 and 3 months without EXOSC3 [4]. In the series of Eggens and colleagues, of 99 patients from 90 families negative for TSEN, RARS2, VRK1 and CASK, EXOSC3 was identified in 12 families, all with PCH1 [17]. The proportion of PCH1 explained by EXOSC3 is about half according to GeneReviews and Eggens and colleagues, and 30–40% in the Rudnik-Schöneborn series; the estimates depend on cohort selection [9, 17, 84]. The review by Ivanov and colleagues of all genetically confirmed PCH1 found signs of prenatal onset in all subtypes except homozygous p.(Asp132Ala); early death (1 day to 17 months) with p.(Gly31Ala) and with SLC25A46, with a picture of SMA type 1, global delay, visual and hearing impairment, and variable microcephaly, nystagmus and optic atrophy; milder forms (homozygous p.(Asp132Ala) and VRK1) with upper motor neuron signs, dystonia or ataxia and death between 5 and 18 years; the remaining EXOSC3 and EXOSC8 intermediate, with death between 3 months and 5 years; no correlation between the age at neurological onset and lifespan; and it added cutis marmorata and congenital laryngeal stridor to the phenotype [14]. In the Iranian cohort of 10 patients with PCH subtypes, EXOSC3 c.395A>C was recurrent in 40% [113].

A renal manifestation was added in 2026: the review of 34 European children with PCH1B identified 13 cases of EXOSC3-associated thrombotic microangiopathy (TMA) (8 boys and 5 girls), with an incidence in the United Kingdom of 0.004 per million per year; three children received long-term eculizumab, one without response and two with relapse on treatment [114].

PCH1A (VRK1) was described in a consanguineous Ashkenazi Jewish family with SMA and PCH, with severe microcephaly from birth and only mildly affected cognition; subsequently, VRK1 has been associated mainly with motor neuron disease without PCH [4, 16]. PCH1C (EXOSC8) was described in 22 infants from three consanguineous lineages with hypoplasia of the cerebellum and corpus callosum, abnormal myelination, spinal motor neuron disease, growth retardation, severe weakness, spasticity, psychomotor delay and visual and hearing impairment [18]; a 16-year-old Spanish patient, a compound heterozygote, had cerebellar and spinal muscular atrophy, spasticity, nystagmus, ophthalmoparesis and epilepsy, with normal supratentorial structures and long survival [115], and a fifth family also had diaphragmatic hernia and hypoplastic temporal lobes [116]. PCH1D (EXOSC9) presents at birth or in infancy with severe generalised hypotonia, respiratory failure and cerebellar atrophy; one child had congenital long-bone fractures [19]; two Japanese families had relatively greater intellectual development and a structurally normal pons [20], and 9 patients had been described by 2022 [117]. PCH1E (SLC25A46) is lethal: siblings from two families died shortly after birth with PCH and apnoea [21]. PCH1F (EXOSC1) was described in an 8-month-old boy with delay, microcephaly, subtle dysmorphic features and hypotonia, whose brother with a similar picture died at 4 years and 6 months [23].

3.6. PCH3, PCH6 to PCH17 and PHRINL

PCH3 (PCLO) was identified in a sibship from Oman with severe global delay and seizures in the first year, progressive microcephaly, short stature, facial dysmorphism and optic atrophy in some, without extrapyramidal movement disorder; MRI showed diffuse atrophy of the cerebrum, cerebellum and brainstem [4, 34, 118]. PCH6 (RARS2) has as its canonical phenotype severe early epilepsy, progressive global atrophy including the pons and cerebellum and lactic acidosis and/or respiratory chain defects; all survivors of the neonatal period have severe delay and almost all refractory epilepsy, lactate is raised in plasma or cerebrospinal fluid (CSF) in most, and the respiratory chain deficiency is not always confirmed [4, 36]. The phenotype extends to developmental and epileptic encephalopathies with normal initial imaging, and some authors advocate the designation early-onset mitochondrial encephalopathy [37, 119, 120].

PCH7 (TOE1) associates PCH with DSD. In 46,XY individuals, undervirilisation ranges from almost completely female external genitalia to micropenis with hypoplastic scrotum, with uterine or ovarian remnants in some and atrophic testes or absent gonadal tissue in others; in 46,XX individuals, the genitalia are usually normal [4]. In the 12 families of Lardelli and colleagues, global delay occurred in 13 of 13, progressive microcephaly in 12 of 13 and pontine hypoplasia in 12 of 12 [38]. The 2026 systematic review of 28 46,XY cases found neurological involvement in all but one, abnormal external genitalia in 17 of 23, non-localised testes in 5 of 5, absent uterus in 4 of 7, raised follicle-stimulating hormone (FSH) in 7 of 7 and low testosterone in 3 of 3, with a gonadal phenotype of testicular regression syndrome or partial gonadal dysgenesis with Müllerian regression [39]. The index case was a boy with hypoplastic genitalia and impalpable testes who died at 24 weeks of life ("PCH with vanishing testes") [107], and a mild form without microcephaly or reduced cerebellar volume has been described [121].

PCH8 (CHMP1A) presents with microcephaly, severe delay (some with independent walking), dystonic posturing and/or chorea, contractures and seizures in some, without progression on serial MRI [4, 40]; compound heterozygosity and homozygosity due to segmental uniparental disomy have broadened the mutational spectrum [69, 122]. PCH9 (AMPD2) has progressive postnatal microcephaly, profound delay, cortical visual impairment, dysphagia, spasticity with neonatal clonus, axial hypotonia and, in older patients, axonal neuropathy; the course is largely non-progressive, with some deaths in the first decade; the series of Kortüm and colleagues pooled 25 patients [4, 42, 123, 124]. PCH10 (CLP1) was described in Turkish families with severe delay, typically refractory seizures, progressive spasticity, dysmorphism, microcephaly and severe motor and sensory axonal neuropathy; by 2022 there were 21 patients from 10 Turkish families homozygous for the same variant, and a Sudanese family was the first non-Turkish one [4, 86]. PCH11 (TBC1D23) is non-degenerative, with moderate to severe intellectual disability, microcephaly, hypotonia, ataxia in about half, seizures in 2 of 13 and some patients walking independently; the 2026 review of 21 cases with 12 variants added behavioural and psychiatric problems [4, 45–47].

PCH12 (COASY) has prenatal onset with PCH, microcephaly and arthrogryposis, and death in infancy; by 2026, 14 fetuses or newborns from 8 families with complete loss of function had been described, and a p.(Ala214Val)/p.(Arg339Ter) combination produced a similar perinatal lethal phenotype, suggesting a continuum between PCH12 and CoPAN [48, 125, 126]. PCH13 (VPS51) was described in a 6-year-old child with severe global delay, microcephaly, hypotonia, epilepsy, cortical visual impairment, poor weight gain, liver dysfunction, lower limb oedema and dysmorphism, and later in siblings with an intragenic deletion, in siblings with deafness and dysphagia and in a child with recurrently raised transaminases, low caeruloplasmin and steatosis with fibrosis [50, 127–129]. PCH14 (PPIL1) has progressive microcephaly, poor or absent psychomotor development, spastic quadriplegia and early seizures; in the Egyptian series of nine patients from eight families, all had early drug-resistant epilepsy, profound delay and visual impairment, three had Dandy-Walker malformation and 4 of 9 (44%) a haematopoietic disorder [51, 52]. PCH15 (CDC40) associates PCH and microcephaly with chronic anaemia and thrombocytopenia in a consanguineous multiplex family; a second patient, identified by exome reanalysis in a British cohort with suspected mitochondrial disease, had muscle and central nervous system involvement, lactic acidosis and secondary deficiency of complexes I and IV [51, 53]. PCH16 (MINPP1) has hypotonia and severe global delay from infancy, stereotyped movements, spasticity and progressive microcephaly; the 2026 Egyptian series raised the published total to about 26 patients from 17 families and described, in all, global delay, microcephaly, hypotonia, nystagmus, severe motor impairment, seizures, intellectual disability and a facial gestalt (high forehead, long smooth philtrum, thin upper lip, broad chin, low-set ears) [55, 130]. PCH17 (PRDM13) presents with neonatal hypotonia, feeding and respiratory difficulties, central apnoea and bradycardia, with death usually in infancy; patients with homozygous truncating variants are the most severe [56]. PHRINL due to ATAD3A is a lethal disease of prenatal onset with polyhydramnios, contractures, severe PCH, microcephaly, abnormal basal ganglia and gyration abnormalities when there are biallelic deletions; four compound heterozygous p.(Leu77Val)/exon 3–4 deletion patients had a less severe course and longer survival, with combined oxidative phosphorylation deficiency in one of them [4, 6].

3.7. MICPCH (CASK)

GeneReviews pools 130 individuals (45 boys and 85 girls) [5]. In the 85 girls with MICPCH (the oldest aged 25 years), head circumference at birth is normal or low-normal in about two thirds; microcephaly invariably becomes severe (−3.5 to −10 SD) in the first year, usually in the first 4 months; head control and eye contact appear between 2 and 24 months, most sit without support between 7 and 36 months and only 20–25% walk (between 18 and 72 months); language is almost absent in most; and intellectual development is severely impaired in almost all [5]. There are sleep disturbances, hand stereotypies and self-biting; axial hypotonia with limb hypertonia that may progress to spasticity, dystonia and other movement disorders; seizures of various types in about 40%, with onset between birth and 10 years; frequent short stature at 4 years and scoliosis; optic nerve hypoplasia, retinopathy, nystagmus and strabismus; sensorineural deafness in about 28%; rare congenital visceral anomalies without a recurrent pattern; and a facial phenotype with well-defined arched eyebrows, broad nasal root and tip, short nose, long philtrum or prominent maxilla, small chin and large ears [5, 131]. The severity of PCH on MRI has no prognostic value, and mortality in girls has not been described [5]. The three Japanese women aged 31, 43 and 50 years described in 2026 show the adult course: two unable to stand, with severe scoliosis and tube feeding, and one walking, with mild scoliosis and oral feeding, with a dissociation between radiological and clinical severity [132].

The 45 boys fall into three groups. MICPCH with severe epileptic encephalopathy has rapid postnatal microcephaly (−2.7 to −9 SD), absent or profoundly delayed development, early intractable seizures (Ohtahara syndrome, West syndrome, myoclonic epilepsy) with burst-suppression, MRI with severe diffuse PCH, simplified gyri, cortical atrophy and hypomyelination, multiple minor anomalies, septal defects, tetralogy of Fallot or hydronephrosis, and perinatal or early lethality (deaths at 2, 7 and 21 months) [5, 133, 134]. MICPCH without severe epilepsy, in six boys, is comparable to the female form, with one death at 2 weeks [5]. X-linked intellectual disability with or without nystagmus, the largest group (29 boys), has mild to severe intellectual disability, epilepsy, congenital nystagmus, strabismus, mild optic disc pallor and MRI without PCH in the minority studied [5, 95]. Heterozygous females with hypomorphic variants usually have normal intelligence [5].

The spectrum broadens with genomic testing: in the British BINGO project (31 children and young people, compared with 151 published individuals), the prevalence of tone abnormalities, sensorineural deafness and epilepsy was similar, but that of severe or profound intellectual disability, MICPCH, optic atrophy and nystagmus was lower; sleep disturbances and cerebral visual impairment were frequent and epilepsy was associated with the severity of intellectual disability [135]. In the Chinese series of 21 patients (18 girls), girls were more frequent and milder than boys, and seizures began earlier than in other cohorts [136]. At a Bulgarian centre, a boy with an inherited likely pathogenic missense variant had severe intellectual disability, drug-resistant epilepsy and a cerebral palsy-like picture without microcephaly or PCH [137]. The prenatal phenotypes described are microcephaly, cerebellar hypoplasia, enlarged posterior fossa and polyhydramnios [138], and the movement disorder can be complex [139].

3.8. CAMRQ, VLDLR-CH and OPHN1

VLDLR cerebellar hypoplasia (CAMRQ1) is characterised by non-progressive congenital ataxia, predominantly axial, with very late walking (often after 6 years) or walking never acquired, moderate to profound intellectual disability, dysarthria, strabismus and seizures [10]. More than 50 individuals have been identified [10].

Source: GeneReviews VLDLR Cerebellar Hypoplasia, table 2 [10]. Gait is broad-based and without tandem; patients from Turkey showed quadrupedal locomotion, a behavioural adaptation probably dependent on environmental influences [10, 140]. Most follow simple commands and some communicate in short sentences; adults do not live independently; seizures occurred in 40% of affected Hutterites and are less frequent in non-Hutterites; life expectancy has not been formally studied, but the Hutterite experience suggests that it is not significantly reduced [10, 67]. The first African family with CAMRQ1, of four siblings with variable severity, had a novel homozygous variant retained in the endoplasmic reticulum [141]. CAMRQ2 (WDR81), CAMRQ3 (CA8) and CAMRQ4 (ATP8A2) present with congenital cerebellar ataxia and intellectual disability, and CA8 is associated with a predisposition to quadrupedal gait [10, 60]. The Oxford Desk Reference spells "ATP6A2" in CAMRQ, a misprint; the correct gene is ATP8A2 [2, 142]. In X-linked intellectual disability due to OPHN1, intellectual disability is moderate to severe, with neonatal hypotonia, vermian hypoplasia and cystic dilatation of the cisterna magna [61].

3.9. Recent genes with a PCH-like phenotype

Between October 2025 and October 2026, genes with a PCH-like phenotype not yet numbered in OMIM were published. Two siblings homozygous for MED29 (Mediator complex) p.(Leu139Pro) had profound global delay, severe microcephaly, cataracts, variable seizures and marked cerebellar and pontine hypoplasia [90]. A 25-year-old woman with a de novo c.510_511delTC variant in FTH1 had delay and PCH that were stable for years and deterioration at 20 years (hypertonia, ataxia, dystonia, dysarthria, apathy), with iron accumulation in the basal ganglia, thalamus, cerebral peduncles and hippocampus, in a picture of cerebellar atrophy of prenatal onset with late neuroferritinopathy [7]. Three patients from two families homozygous for the South Asian deep intronic founder variant of CDK5RAP3 (UFMylation adaptor) had fetal growth restriction, fetal akinesia, PCH, arthrogryposis, liver pathology and a lethal course [91].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In the prenatal period, suspicion arises in the presence of polyhydramnios, contractures or fetal akinesia, microcephaly in the third trimester, trembling fetal movements reported by the mother or a small transverse cerebellar diameter [8, 15, 143]. Ultrasound frequently fails: in the PCH2A cohort of 65 children, only 4 of 21 specialist ultrasound scans between 12 and 32 weeks showed cerebellar anomalies, and these were non-specific, and detection often fails at the 20-week anomaly scan [4, 109]. In the newborn, the warning signs are generalised clonus and sucking-swallowing incoordination (PCH2), central respiratory failure with arthrogryposis and hypertonia (PCH4, PCH12, PHRINL, PCH17), hypotonia with weakness, areflexia and SMA-like respiratory failure in a patient without SMN1 deletion (PCH1), lactic acidosis with intractable seizures (PCH6) and ambiguous genitalia or impalpable testes in an infant with encephalopathy (PCH7) [4, 8, 9, 39]. In PCH2A, onset is usually at birth and often suggests an acute rather than congenital disease, which delays diagnosis [109]. In the infant, progressive microcephaly with severe delay, chorea or dystonia in the first 6 months, seizures and infantile spasms should prompt brain MRI [5, 8]. In a girl with intellectual disability, progressive postnatal microcephaly and pontocerebellar hypoplasia without choreoathetosis, especially with optic atrophy, glaucoma or deafness, the first gene to consider is CASK [5, 58]. In the older child, non-progressive congenital ataxia with very late walking, intellectual disability and strabismus suggests CAMRQ; signs of ataxia only become evident between 1 and 2 years, when the child starts walking, and infants present with hypotonia, weak suck and motor delay [10, 142]. Ataxic cerebral palsy is a diagnosis of exclusion and requires high-resolution MRI before counselling [142].

The French PNDS (National Diagnosis and Care Protocol) organises the signs by age [12]. Up to 3 months: hypotonia with absent head control at 3 months, poor visual tracking and oculomotor abnormalities, congenital or progressive microcephaly, arthrogryposis, sucking-swallowing and respiratory disturbances, epilepsy, abnormal movements and opisthotonus due to hypertonia of the posterior muscles, motor axonal neuropathy and visual (optic atrophy, retinopathy) or hearing deficits. After 3 months: severe disorder of motor and cognitive neurodevelopment, progressive microcephaly, chorea, dyskinesia or dystonia, tetrapyramidal syndrome, sleep disturbances with or without obstructive sleep apnoea syndrome (OSAS) and respiratory failure. In adulthood: moderate to profound intellectual disability, severe motor impairment, epilepsy, abnormal movements, sensory deficits and peripheral neuropathy. These signs justify a paediatric neurology consultation for aetiological investigation, and the diagnosis of PCH is radiological, by brain MRI in a department with paediatric experience [12].

4.2. Clues from the history and examination

The history includes a three-generation pedigree with consanguinity, exposures in pregnancy (retinoic acid, cytomegalovirus, excess alcohol), episodic breathing (hyperventilation alternating with hypoventilation, suggestive of Joubert), loss of skills, visual problems, swallowing difficulties and recurrent infections (suggestive of Hoyeraal-Hreidarsson syndrome) [62]. On examination, macrocephaly is rare and points to SNX14 or PIGT; microcephaly points to PCH and MICPCH; one looks for muscle weakness (alpha-dystroglycanopathies, mitochondrial diseases), nystagmus and oculomotor apraxia (ciliopathies), lingual cysts and excess oral frenula (orofaciodigital syndromes, Joubert), aniridia (Gillespie syndrome) and polydactyly [62]. Ethnic origin guides targeted testing: Roma ancestry and an SMA-like picture with normal SMN1 (EXOSC3 p.(Gly31Ala)), Dutch or German ancestry with a "dragonfly" pattern (TSEN54 p.(Ala307Ser)), Moroccan or Iraqi Jewish ancestry (SEPSECS, VPS53), Turkish (CLP1), Egyptian (PPIL1, MINPP1) or Hutterite (VLDLR) [4, 10, 14, 29, 31, 44, 52].

4.3. Warning and emergency signs

4.4. Newborn screening

There is no newborn screening targeted at PCH. Tandem mass spectrometry screening may, however, raise suspicion of COASY-associated disease: three patients with CoPAN, two of them siblings who died in infancy with PCH on MRI, had an acylcarnitine profile mimicking carnitine palmitoyltransferase 1A (CPT1A) deficiency, with a raised C0/(C16+C18) ratio [49]. The review of five cases in the CLIR (Collaborative Laboratory Integrated Reports) project found 25 metabolites or ratios outside the ranges, mainly raised free carnitine and reduced long-chain acylcarnitines, and recommends considering COASY disease when screening suggests CPT1A deficiency, especially when confirmatory biochemistry is normal [145].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal clinical criteria published by a society for PCH. The diagnosis is clinico-radiological and is confirmed by molecular genetics [1]. In the autosomal recessive forms, the diagnosis is established by identification of biallelic pathogenic or likely pathogenic variants in the gene; two variants of uncertain significance (VUS), or one pathogenic variant with one VUS, neither establish nor exclude the diagnosis, according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [8, 9]. In MICPCH, the diagnosis is established in a girl with a heterozygous variant, in a boy with a hemizygous variant or, rarely, in a boy with a mosaic variant [5]. Suspicion of TSEN54-PCH rests on a severe neurological deficit with suggestive imaging and a family history compatible with recessive inheritance; the absence of a family history does not exclude the diagnosis [8, 106, 146]. For PCH1, Ivanov and colleagues proposed guiding testing by detailed clinical assessment and ethnic origin; these are author guidelines and not those of a scientific society [14].

5.2. Neuroimaging

MRI is the reference examination: in the PCH2A cohort of 65 children, postnatal cranial ultrasound was suggestive in 26 of 54 and MRI confirmed PCH in 62 of 63 [109]. A single MRI does not reliably distinguish hypoplasia from atrophy; hypoplasia corresponds to a normally shaped but small cerebellum and atrophy to progressive loss with widening of the interfoliar spaces [4, 62]. In PCH, the vermis is relatively spared compared with the hemispheres, in contrast to Joubert syndrome and Dandy-Walker malformation, in which the vermis is the most affected; hypoplasia of the basis pontis (loss of ventral pontine neurons and transverse fibres) greatly narrows the differential [4]. A small posterior fossa suggests genetic syndromes (Dandy-Walker variant, rhombencephalosynapsis, PCH, cerebellar atrophy), whereas a large posterior fossa mainly suggests sporadic disorders (classic Dandy-Walker malformation, Blake's pouch, mega cisterna magna, arachnoid cyst) [147].

The absence of these signs does not exclude the diagnosis. In PCH1, cerebellar and pontine hypoplasia may be absent in early infancy [14]; the pons is structurally normal in some EXOSC9 families [20]; in MICPCH, two girls with progressive microcephaly and intellectual disability had a normal pons and cerebellum [5, 149]; in PCH7, a mild form had only an enlarged lateral ventricle and deepened cerebellar sulci [121]; and in PCH2E the initial MRI is normal [4]. The MRI of a 2-month-old infant with PCH2 published by Budde and colleagues and reproduced in GeneReviews shows, on the midsagittal section, a hypoplastic vermis and flat ventral pons and, on the lateral sagittal section, a hypoplastic cerebellar hemisphere with empty space in the posterior fossa [8].

The French PNDS (National Diagnosis and Care Protocol) defines the MRI protocol when PCH is suspected: sagittal, axial and coronal T2 sections, 3D T1 sequence and axial or 3D FLAIR from 1 year of age; depending on the context, susceptibility-weighted sequences (useful for distinguishing ischaemic-haemorrhagic lesions of the posterior fossa), diffusion tensor imaging and tractography [12]. T2 in the three planes analyses the morphology of the brainstem, vermis, cerebellar hemispheres and corpus callosum (sagittal for the vermis, axial for the white matter, myelination and basal ganglia), and T1 better assesses biometry and the degree of atrophy; 3D T2 is useful for CSF flow but less suited to white and grey matter signal. The midsagittal section shows the reduced volume of the pons, often flattened with loss of the pontine bulge, of the brainstem and of the vermis; coronal sections show hemispheric hypoplasia and axial sections the shape of the midbrain. Because radiological diagnosis is subjective, the paediatric biometric norms for the vermis and brainstem published by Jandeaux and colleagues in 2019, obtained in 718 children, serve as a reference. Cerebellar or brainstem involvement may predominate, and several PCH have supratentorial anomalies (gyration, myelination, corpus callosum, basal ganglia, cerebral atrophy, ventricular dilatation, arachnoid cysts). The relationship between the severity of hypoplasia and the clinical course remains debated; longitudinal studies show worsening with cerebral atrophy in the degenerative forms, whereas other PCH are stable. Follow-up MRI, which often requires sedation or general anaesthesia, is discussed when there is clinical progression or new signs and is not essential for follow-up [12].

5.3. Complementary investigations

In aminoacyl-tRNA synthetase defects and in disorders of nucleic acid processing there are no specific metabolic markers, and the diagnosis is molecular [63, 150]. Plasma InsP6 measurement in PCH16 is a research method [151].

5.4. Genetic testing strategy

In an infant with a "dragonfly" pattern, dysphagia and extrapyramidal movement disorder, testing for the TSEN54 c.919G>T variant should be performed promptly, because it is by far the most frequent [4, 8]. Outside this scenario, targeted panels quickly become outdated and some cerebellar hypoplasia panels do not include TSEN54 or EXOSC3 [4, 8, 9]. In radiological PCH, the cohort of Zakaria and colleagues identified an aetiology in 68% (chromosomal 21%, monogenic 34%, acquired 13%) and recommends chromosomal microarray combined with exome or multigene panel [13]. When MICPCH is suspected, single-gene testing is rarely useful; an intellectual disability, brain malformation or PCH panel with deletion/duplication analysis, or exome/genome sequencing, is recommended and, if nothing is detected, CNV analysis by exome array or microarray; karyotyping may be appropriate if sequencing and CNV analysis are negative and suspicion is high, because two girls had balanced Xp inversions disrupting CASK [5, 65]. In Hutterite ancestry, targeted testing for the VLDLR founder deletion is the first step [10].

These percentages describe the proportion of known variants that each method detects and not the clinical sensitivity of the test [5, 8]. In the 2011 series of Moog and colleagues, 11 of the 20 CASK alterations in the new patients were submicroscopic CNVs (deletions of about 11 kb to 4.5 Mb and two duplications) [131], and in the Burglen series three of the 13 alterations were Xp11.4 deletions detected by array comparative genomic hybridisation (array-CGH), with severity similar to that of intragenic variants even when the deletion encompassed nine genes [58].

The 2026 French PNDS (National Diagnosis and Care Protocol) proposes a sequential strategy [12]. After positive diagnosis by MRI and a genetics clinic appointment with consent, a picture highly suggestive of PCH2 justifies testing for the major TSEN54 variant by Sanger sequencing; in the others, a targeted NGS panel is prescribed that includes the genes of the 17 types, CASK, SPTAN1, VLDLR and the tubulinopathy genes, with a yield close to 60% in the cohort of 260 patients from the reference centre. With a negative panel and the differentials excluded, or immediately in a highly atypical picture, trio exome or genome sequencing with CNV analysis follows; the genome also detects large structural rearrangements and, if the genome-wide analysis has not assessed structural variants, chromosomal microarray is performed. The result is given in clinic, and a conclusive panel may require complementary studies (segregation in the parents, validation by transcript analysis) and information on prenatal diagnosis. According to the protocol, the molecular diagnosis is conclusive in more than 70% of patients in France [12]. This strategy differs from the proposal of Zakaria and colleagues, who recommend microarray combined with exome or panel from the outset, and from the CASK GeneReviews, which prefers a panel with CNV or exome/genome; the difference reflects the populations studied (radiological PCH of any cause in Canada; reference centre cohort with a predominance of CASK and TSEN54 in France) [5, 12, 13].

5.5. Limitations of tests

A negative result does not exclude the diagnosis. Short-read sequencing has difficulty at loci with paralogues, such as the ATAD3 cluster, in which the recurrent exon 3–4 deletion and point variants require targeted sequence and CNV analysis [6]. Deep intronic variants escape exome sequencing: the CDK5RAP3 founder variant, which activates a cryptic donor with pseudoexon inclusion and NMD, was detected only by genome sequencing with RNA sequencing or by exome reanalysis [91]. CNV analysis is mandatory for CASK, and large deletions may include adjacent genes whose breakpoints targeted del/dup does not detect [5]. Somatic mosaicism occurs in boys with MICPCH (three of eight new boys in the 2015 Moog series, and the boy with a nonsense variant in lymphocytes and buccal mucosa in the Burglen series), and negative parental blood does not exclude parental mosaicism [5, 58, 95]. De novo variants are rare in recessive diseases, but they do occur; testing of the parents is therefore recommended to confirm phase [8]. Exome reanalysis increases the yield, as shown by the second case of PCH15 in a cohort with suspected mitochondrial disease [53], and variants in novel genes benefit from sharing on platforms such as GeneMatcher [4].

5.6. Report content, VUS and segregation

The report should identify the gene, the transcript with version (MANE Select, with the correspondence to the historical transcript when the literature uses another, as for CASK and TBC1D23), the HGVS c. and p. nomenclature, the zygosity, the phase confirmed in the parents and the ACMG/AMP class [8, 81]. For VUS, family segregation, concordance of the phenotype with the imaging pattern of the subtype and, for some genes, research functional studies (exon skipping, reduction of the exosome complex by native electrophoresis, aminoacylation) help with reclassification [19, 63, 116]. A variant in TSEN54 or EXOSC3 without the second allele should not be interpreted as a diagnosis.

5.7. Practical algorithm

The French PNDS adds a clinical orientation tree, which helps to interpret the genetic result in the light of the clinical picture and imaging [12].

5.8. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing (PGT) are possible [1, 8, 62]. Without a known variant, diagnosis of cerebellar hypoplasia by early ultrasound is not reliable: the vermis completes its development only at 17–18 weeks, an incomplete vermis is common at 15–16 weeks and Dandy-Walker malformation should not be diagnosed before 18 weeks [62, 147]. In the cohort of 116 fetuses with posterior fossa malformations on fetal MRI (Montreal), cerebellar hypoplasia was the most frequent structural finding (33%), agreement between fetal MRI and postnatal imaging was 51% (69% excluding CSF-only lesions), four fetuses with cerebellar hypoplasia had normal postnatal imaging and genetic testing was positive in 24% of those tested [152]. In PCH2A, only one of three fetal MRIs (at 31 weeks) showed clear cerebellar hypoplasia [109]. Fetal MRI led to the prenatal diagnosis of VLDLR cerebellar hypoplasia in one published case [153], and severe cerebellar hypoplasia on ultrasound and fetal MRI in two pregnancies of a consanguineous Pakistani couple led, after fetal pathology, to the diagnosis of PCH12 [126].

The French PNDS systematises the prenatal approach [12]. Outside a family context, screening rests on measurement of the transverse cerebellar diameter, recommended by the French National Conference on Obstetric and Fetal Ultrasound (CNEOF) in the 2nd (around 22 weeks) and 3rd trimester (around 32 weeks), and on an unusual appearance of the cerebellum or of the fluid spaces of the posterior fossa; an abnormal finding leads to diagnostic ultrasound and, if necessary, fetal MRI. The signs sought are hypoplasia and/or atrophy of the cerebellum, sometimes predominant in the hemispheres with a "dragonfly" appearance on coronal sections, and a reduced anteroposterior diameter of the pons; more rarely, fetal akinesia, arthrogryposis, hydramnios and intrauterine growth restriction. Reference charts before 24 weeks are less reliable, which calls for caution and repeat scans, and even in experienced hands false positives and false negatives occur. Many PCH are not visible before birth, even on MRI, especially the neurodegenerative forms, because the cerebellum grows considerably in the last trimester: in the study by Steinlin and colleagues (2007) of 24 children with PCH2, the 22-week ultrasound scans and, in two, MRI in the second half of pregnancy showed no anomalies. With a family history and no known variant, reference ultrasound scans and fetal MRI at 32 weeks are offered if the scans are normal, or from 26 weeks if there is an ultrasound sign, bearing in mind that many aetiologies escape this surveillance [12]. After termination of pregnancy for medical reasons, neuropathological examination can characterise the malformation and lead to the diagnosis [12]. The PNDS places the prenatal diagnosis of PCH, on average, at 27 weeks, citing the series of Jaillard and colleagues; in this single-centre Paris series of 42 fetuses with confirmed PCH (27 referred for a reduced transverse cerebellar diameter at screening), neurosonography and fetal MRI were performed at a mean of 29 weeks and 4 days and 31 weeks, pregnancy was terminated in 24, neuropathology confirmed the diagnosis in 24 and genetic testing identified alterations in 29 (28 families), 14 of them chromosomal; classic PCH were associated with pontine atrophy and with measurements that decreased with advancing gestational age [12, 154].

6. Differential Diagnosis

6.1. Comparative table

6.2. Main differentials

The first clinical differential is 5q SMA, because PCH1 presents as SMA type 1. Normal cognition, normal MRI and SMN1 deletion distinguish SMA; in the Bulgarian Roma population, homozygous EXOSC3 p.(Gly31Ala) explained 14 patients, three quarters of all Roma cases of SMA without SMN1 deletion [9, 14]. Within the class, PCH1 is distinguished from PCH2 by anterior horn involvement and by a pons that may be normal, whereas in PCH2 the spinal cord is normal and the pons is attenuated; the central motor signs of a child with EXOSC3 and typical MRI may falsely suggest PCH2 [9]. The differential table of the EXOSC3 GeneReviews describes TSEN54-PCH as "severe PCH with relative sparing of the pons", in contradiction with the TSEN54 GeneReviews, which describes ventral pontine atrophy in most; the reading consistent with the other sources is relative sparing of the vermis [4, 8, 9]. The two GeneReviews also diverge on the imaging of PCH8, described as similar to PCH2 in one and to PCH1B in the other; van Dijk and colleagues describe profound PCH with a thin but complete corpus callosum and no progression [4, 8, 9].

MICPCH is the second most frequent cause of PCH at the French reference centre (13 of 40 patients, 32%, after 18 of 40 with PCH2/PCH4) and is distinguished from PCH1 by the absence of motor neuron disease and from PCH2 by the absence of chorea, by the dysmorphism (round face, small chin, broad nasal bridge), by sensorineural deafness and by ophthalmological anomalies; the imaging pattern is "butterfly", with a vermis that does not protrude between the hemispheres [4, 5, 58]. The severely affected hemizygous boy in the Burglen series resembled PEHO syndrome, but severe PCH, and not progressive cerebellar atrophy, should prompt testing for CASK [58]. The French PNDS (National Diagnosis and Care Protocol) adds, in favour of CASK in a girl, neurosensory deficits (retinopathy, optic atrophy, glaucoma, megalocornea, deafness) and a round face with well-defined eyebrows and broad nasal root and, in a boy, a very severe picture from the outset with epilepsy, optic atrophy and marked PCH; in doubtful cases, it recommends testing for the major TSEN54 variant or the PCH panel [12]. For the mild forms of PCH genes (homozygous EXOSC3 p.(Asp132Ala), TSEN54 with cerebellar ataxia, SEPSECS without multiple disability, CASK missense variants), the protocol refers to the French PNDS on congenital ataxias [12]. VLDLR-CH is distinguished from PCH1 and PCH2 by milder pontine hypoplasia, non-progressive ataxia with long survival and simplification of the gyri [10]. Because hypoplasia is difficult to distinguish from atrophy on early imaging, ataxias with childhood-onset cerebellar atrophy also enter the differential [10].

Among acquired phenocopies, PCH in the extremely preterm infant results from very rapid cerebellar growth in the third trimester, which makes the cerebellum vulnerable to ischaemic or haemorrhagic injury and to underdevelopment, also secondary to supratentorial lesions through cortico-cerebellar pathways; it is associated with motor and cognitive impairment and, with vermis involvement, with autistic features, and it is not progressive [4, 73, 160]. The Orphanet list of differentials adds progressive cerebello-cerebral atrophy, infantile cerebral and cerebellar atrophy, phosphoserine aminotransferase deficiency, congenital fibrosis of the extraocular muscles type 3 and lissencephalies with two-layered cortex, extreme microcephaly and cerebellar and pontine hypoplasia [1, 8, 169]. Isolated global cerebellar hypoplasia is a morphological anomaly without a defined gene, and OPHN1 intellectual disability should be considered in boys with vermian hypoplasia and an enlarged cisterna magna [3, 61].

7. Treatments and Risk Management Strategies

7.1. Principles and assessment after diagnosis

There is no curative or disease-modifying treatment for any PCH, MICPCH or CAMRQ; management is symptomatic, multidisciplinary and aimed at maximising function and reducing complications [4, 5, 8, 63]. There is no international scientific society guideline specific to PCH. The first dedicated national protocol is the French PNDS (National Diagnosis and Care Protocol) published by the HAS in September 2026, prepared by the reference centre for cerebellar malformations and congenital diseases according to the HAS method, based on the literature and the centre's experience; it recommends an early, multidisciplinary approach, while acknowledging that no study has formally proven its effectiveness [12]. The other recommendations come from the GeneReviews chapters, the PCH2A natural history cohort and guidelines for analogous conditions, especially cerebral palsy, whose application to PCH is an extrapolation [8, 15, 170, 171]. Orphanet summarises treatment as medication for dystonia, dyskinesia and seizures, percutaneous endoscopic gastrostomy feeding and, sometimes, respiratory support [1].

According to the PNDS, the diagnosis should be disclosed, if possible to both parents, by the referring physician (usually a paediatric neurologist or neurogeneticist) after identification of PCH on MRI, explaining the symptoms and the posterior fossa malformation and proposing genetic testing; at a second stage, the risks of nutritional, orthopaedic and respiratory complications, the need for initial assessment and close surveillance, the variability of the prognosis and the absence of curative treatment are explained [12]. The protocol favours day hospital or planned admission, to concentrate the multidisciplinary consultations and limit travel for frail patients, and a care plan with a shared medical summary addressed to the general practitioner and the medico-educational facility, describing the current status, the drugs and their monitoring and the warning points [12].

7.2. Feeding, reflux and growth

Feeding difficulties are present in all children with PCH2A, begin in the first 6 months and rarely cease; in the cohort of 33 patients, 22 underwent percutaneous endoscopic gastrostomy (mean age 3 years and 8 months), 31 had excessive vomiting, 24 had diagnosed GORD, 18 were taking a proton pump inhibitor (PPI) and 12 underwent Nissen fundoplication (mean age 4 years and 7 months) [15]. The authors recommend early recognition and treatment of GORD, and the improvement of dystonic crises in two patients with an increased PPI dose suggests a link with reflux [15]. Modification of food consistency, nasogastric tube feeding and gastrostomy reduce aspiration [8, 9]. In MICPCH, the threshold for clinical feeding assessment or radiological swallowing study should be low in the presence of choking, poor weight gain, frequent respiratory infections or food refusal, and thickened or cold foods may help [5]. In PCH2A, growth failure occurs despite a caloric intake within or above reference values, so the specific charts avoid interpreting expected growth as malnutrition and avoid overfeeding [110]. Omeprazole (Prilosec®, in the USA) is FDA-approved for symptomatic GORD from 1 to 16 years at a weight-based dose, once daily (table 7.10) [172]. Constipation is frequent and is part of gastrointestinal surveillance [8, 58].

The French PNDS recommends screening for and treating digestive disorders throughout life [12]. Swallowing disorders are detected by interviewing the family and, when useful, by nasofibroscopy or videofluoroscopy; prevention rests on speech and language therapy, adaptation of food texture and hydration and positioning at mealtimes, and daily aspiration may lead to stopping oral feeding and to enteral feeding, with regular reassessment in adults. Reflux, the more frequent the greater the hypotonia and often poorly symptomatic, justifies a therapeutic trial of PPI as first line; investigations (upper gastrointestinal contrast study, pH monitoring, endoscopy) are reserved for failure, complex situations and preparation for gastrostomy, before which reflux is investigated to decide on the need for an antireflux procedure. Nutritional status is assessed by weight, triceps skinfold thickness, mid-arm circumference and BMI, respecting each person's own balance, and correction progresses from dietitian-guided food enrichment to supplements and to supplementary or exclusive enteral feeding. Constipation, favoured by immobility, axial hypotonia, insufficient hydration, scoliosis and drugs, may progress to obstruction; it is prevented with fibre, hydration, mobilisation and standing and daily laxatives, with enemas or rectal irrigation if necessary. Gastrostomy requires specific follow-up at least once a year. A gastroenterology consultation is justified in the presence of weight stagnation for more than 6 months with severe malnutrition, severe and early sucking-swallowing disorders requiring a nasogastric tube and then gastrostomy, PPI-resistant reflux, aspiration or respiratory complications leading to discussion of gastrostomy and constipation resistant to usual treatments [12].

7.3. Breathing, apnoea and sleep

Sleep apnoea is frequent and potentially fatal in PCH2A, can lead to sudden death and is detectable by sleep monitoring [4]. In the cohort of 33 patients, 22 had apnoeas, mainly nocturnal (two to four per night), tactile stimulation was generally sufficient, 13 were monitored by oximetry and 5 underwent tracheostomy (mean age 7 years); the five sudden nocturnal deaths and one death from a crisis with apnoea make apnoea the most likely cause of death, probably underdiagnosed because only 13 of 22 were monitored [15]. In PCH4 and PCH5, respiratory support is usually time-limited and weaning is possible only for short periods [8]. Recurrent respiratory infections, including aspiration pneumonia, lead to about two admissions per year in PCH2A [15]. Sleep disturbance affects 96% of children with PCH2A (mean latency of 70 minutes and three awakenings per night) and is frequent in MICPCH [5, 15, 135]. Prolonged-release melatonin (Slenyto®) is authorised in the EU for insomnia in children and adolescents aged 2 to 18 years with ASD and/or neurogenetic disorders with aberrant daytime melatonin secretion and/or nocturnal awakenings, when sleep hygiene is insufficient; use in PCH falls within this category by extrapolation [173].

In the French PNDS, respiratory morbidity is proportional to the degree of neuromotor impairment and is the leading cause of death in multiple disability [12]. Respiratory assessment guides prevention: intermittent positive-pressure insufflation device (Alpha 300), mechanical insufflation-exsufflation device (cough assist), antibiotic and salbutamol protocols and respiratory physiotherapy; general prevention includes positioning against aspiration, monitoring of scoliosis, which worsens the restrictive syndrome, avoidance of drugs that increase secretions and vaccination, including influenza vaccination. In acute decompensation, admission follows a care plan defined in advance, and respiratory follow-up is at least annual from the time respiratory symptoms appear; consultation is required in the presence of recurrent swallowing or aspiration pneumonia, chronic respiratory failure due to thoracovertebral deformity or resistant chronic bronchial congestion, and includes investigation for swallowing disorder, reflux and OSAS [12]. Suspected sleep hypoventilation leads to a sleep clinic consultation with blood gases on waking, overnight oximetry and capnography or polysomnography [12].

7.4. Epilepsy

Seizures should be treated by a neurologist experienced in epilepsy, according to standard practice; many antiepileptic drugs may be effective, but none has shown specific efficacy in these diseases [5, 8]. In PCH2A seizures are difficult to treat, but the response was relatively favourable to phenobarbital and topiramate [4, 15].

Source: Sánchez-Albisua and colleagues, table 1, only drugs used in more than two patients [15]. The data come from parental report and records, without a control group, without a uniform definition of response and with small denominators; they do not allow the drugs to be ranked, only the initial choice to be guided. Of the 25 patients treated, 15 were receiving two or more drugs and only 3 were seizure-free [15].

Antiepileptic drugs have no specific dose for PCH; the doses in table 7.10 come from the labels of the approved indications, and use in PCH is an extrapolation. Oral phenobarbital has, in the oral suspension authorised in the United Kingdom, an indication for all forms of epilepsy except absences, in children and adults, with a daily dose by weight band [174]; in the USA, the only FDA phenobarbital label (Sezaby®, intravenous) is restricted to neonatal seizures, and oral phenobarbital is marketed without FDA approval [175]. Topiramate is approved from 2 years of age as monotherapy and adjunctive therapy [176]. Levetiracetam is approved for focal seizures from 1 month of age [177]. Vigabatrin, approved for infantile spasms from 1 month to 2 years, carries a boxed warning of permanent bilateral vision loss due to concentric visual field constriction, relevant in patients with pre-existing visual impairment (PCH1, MICPCH) [178]; West syndrome has been described in MICPCH [58]. Valproate is contraindicated in mitochondrial diseases due to POLG and in children under 2 years with suspected POLG-related disease; the risk of fatal hepatotoxicity is considerably higher below 2 years, especially with polytherapy, congenital metabolic diseases and severe epilepsy, which requires liver function tests before initiation and at frequent intervals, and calls for caution in PCH6 and the other forms with mitochondrial dysfunction [179]. Clobazam combined with opioids can cause profound sedation and respiratory depression [180].

Status epilepticus occurred in 39% of children with PCH2A, so every patient with epilepsy should have a written emergency plan [15]. Buccal midazolam (Buccolam®) is authorised in the EU for prolonged acute convulsive seizures from 3 months of age in patients with a diagnosis of epilepsy, being administered in hospital between 3 and 6 months of age; the caregiver gives one dose and calls emergency services if the seizure does not stop within 10 minutes; combination with other antiepileptic drugs may increase sedation and respiratory depression [144]. Intranasal diazepam (Valtoco®) is FDA-approved for seizure clusters from 2 years of age [181]. Caregiver education in epilepsy is part of management [5].

7.5. Movement disorder, tone and posture

Choreoathetosis is present in about 90% of children with PCH2A, and irritability, often linked to chorea, has no specific treatment [4, 8]. Opisthotonic posturing is prevented by flexion of the large joints, with an ergonomic wheelchair and physiotherapy [4]. The non-epileptic dystonic crises of PCH2A ended only with natural sleep in 8 of 11 patients; analgesics and levodopa brought no reported benefit, diazepam, phenobarbital or chloral hydrate were partially effective in only 2, and increasing the PPI dose improved 2 patients [15]. One patient with PCH2 had improvement of dystonic crises and choreoathetosis with levodopa, an isolated report that contrasts with the absence of benefit in the cohort [4, 15]. In MICPCH, GeneReviews recommends involving specialists in the management of baclofen, tizanidine, botulinum toxin, antiparkinsonian drugs or orthopaedic procedures for hypertonia and dystonia [5].

The evidence on these drugs comes from cerebral palsy. The practice parameter of the American Academy of Neurology and the Child Neurology Society (2010) recommends offering botulinum toxin type A for localised or segmental limb spasticity (level A), considering diazepam for short-term treatment of generalised spasticity with caution regarding toxicity (level B), allows tizanidine (level C) and considers the data insufficient for oral and intrathecal baclofen and for dantrolene (level U) [170]. The 2018 systematic review of the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) on dystonia considers intrathecal baclofen and deep brain stimulation possibly effective (level C), trihexyphenidyl possibly ineffective (level C) and the evidence insufficient for oral drugs and for botulinum toxin, with most management based on expert opinion [171]. The two sources diverge on botulinum toxin, recommended in spasticity and without sufficient evidence in dystonia, because they assess different outcomes [170, 171]. Oral baclofen is FDA-approved for spasticity due to multiple sclerosis and spinal cord injury in adults, and it should be discontinued by slow dose reduction, avoiding abrupt withdrawal [182]. Tizanidine is approved for spasticity in adults and requires measurement of aminotransferases at baseline and 1 month after reaching the maximum dose [183]. Botulinum toxin type A (Botox®) is approved for paediatric spasticity from 2 years of age and carries a boxed warning of distant spread of toxin effect, with potentially fatal dysphagia and breathing difficulty, a risk probably greater in children treated for spasticity — a point to weigh in patients with pre-existing dysphagia [184]. Trihexyphenidyl is labelled only for parkinsonism and drug-induced extrapyramidal symptoms in adults [185]. Tetrabenazine is approved only for chorea of Huntington disease in adults, and the sources consulted have no data on use in PCH or a paediatric dose, so its extrapolation is not recommended [186]. Physiotherapy and occupational therapy, adaptive devices, serial casting and splinting, stretching and orthoses prevent contractures, clubfoot, hip dislocation and scoliosis, and orthopaedics intervenes with orthoses or surgery [5, 8].

The French PNDS (National Diagnosis and Care Protocol) recommends systematically looking for pyramidal syndrome, which may affect all four limbs and the trunk and is quantified with the modified Ashworth scale or the Tardieu scale; antispastic drugs have inconsistent efficacy [12]. In the presence of abnormal movements (dystonia, choreoathetosis, dyskinesias, myoclonus), the first step is to confirm by EEG that they are not epileptic and then to assess their frequency, intensity and impact (nuisance, discomfort, pain); there are no studies on their treatment in PCH, and isolated reports describe efficacy of levodopa, tetrabenazine and benzodiazepines [12]. The French SmPC for tetrabenazine (Xenazine®) limits the indication to abnormal movements of Huntington disease and hemiballismus, with dosing defined for adults (weekly titration from 12.5 mg/day to a mean dose of 50–75 mg/day, maximum 200 mg/day), an electrocardiogram before starting and at the end of titration and contraindication in untreated depression, suicidal risk, hepatic impairment and parkinsonism, and advises against paediatric use for lack of data [187]. The physical medicine and rehabilitation physician and the paediatric neurologist may discuss oral or intrathecal baclofen, botulinum toxin and neurosurgery for spasticity [12].

Orthopaedic deformities require regular physical medicine and rehabilitation and orthopaedic consultations [12]. In children, the aims are to guide growth, allow pain-free sitting and lying positions and educate caregivers; in adults, to improve comfort, facilitate transfers and hygiene care and reduce respiratory, digestive and skin repercussions. Severe scoliosis compromises comfort, respiratory capacity and digestion; rehabilitation maintains spinal and thoracic flexibility, a brace (often of the Garches type) slows progression and, if this is not enough, surgery (growing rods or spinal fusion) is discussed by a multidisciplinary team, with the patient in the best possible condition, prior correction of malnutrition, treatment of osteoporosis when necessary and trained postoperative teams. The risk of hip migration and dislocation increases with growth and is monitored annually clinically and radiographically, adapting rehabilitation and positioning to avoid the dislocating position; hip and/or spine radiographs are performed annually or every six months until the end of puberty, given the potential for progression linked to the pubertal growth spurt [12].

Reduced mobility without walking increases the risk of osteopenia and osteoporosis, especially with malnutrition, and the PNDS considers prevention of bone fragility essential from very early on and throughout life: motor activity in physiotherapy, standing when possible, age-appropriate protein and calcium intake and vitamin D supplementation according to the recommendations for people with risk factors [12]. The signs of vitamin D and calcium deficiency, apart from spontaneous fractures, are not very specific (fatigue, bone pain, sleep disturbance), and a calcium-phosphate work-up, in the presence of warning signs or systematically, guides prevention; after a fracture, the specialist consultation includes densitometry and discusses bisphosphonate infusions [12]. The PNDS does not specify doses. The 2022 French paediatric consensus recommends, from 0 to 18 years without risk factors, 400 to 800 IU of vitamin D per day and, from 2 to 18 years with lower vitamin D availability (such as lack of sun exposure), 800 to 1,600 IU per day or, if adherence is lacking, 50,000 IU every 6 weeks or 80,000–100,000 IU every 3 months, avoiding single doses of 200,000 IU; it includes antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, topiramate) and glucocorticoids among the risk factors for deficiency, proposes a 25-hydroxyvitamin D target above 30 ng/ml in chronic diseases and recommends 500–1,000 mg/day of supplemental calcium when dietary intake is below 300 mg/day [188]. Application to PCH is an extrapolation. Intravenous bisphosphonates have no approved paediatric indication in secondary osteoporosis; the Ward guide (2023) describes pamidronate up to 9 mg/kg/year from 3 years of age (3 mg/kg divided over 3 days every 4 months), 2.25 mg/kg every 3 months from 2 to 3 years and 1.5 mg/kg every 2 months below 2 years, or zoledronic acid up to 0.1 mg/kg/year (0.05 mg/kg every 6 months from 2 years; 0.025 mg/kg every 3 months below 2 years), with frequent hypocalcaemia and hypophosphataemia after the infusion; use in PCH is an extrapolation from paediatric secondary osteoporosis [189].

7.6. Thermoregulation and rhabdomyolysis

Hyperthermia without infection occurred in 60% of children with PCH2A and hypothermia in 2, one of them fatal [15]. Subclinical myopathy with raised CK can progress to rhabdomyolysis after severe infections, which has been repeatedly described; monitoring especially during infections and maintaining adequate hydration during prolonged periods of high fever are recommended [4, 8].

7.7. Sialorrhoea, communication, vision and hearing

Oral glycopyrronium (Cuvposa®) is FDA-approved for chronic severe drooling from 3 to 16 years in neurological conditions such as cerebral palsy; it is an anticholinergic, and use in PCH is an extrapolation within this indication [190]. Drooling persisted in 4 of 11 girls with MICPCH in the Burglen series [58]. Augmentative and alternative communication (AAC) should be assessed by a speech and language therapist; AAC devices do not hinder verbal development and, in many cases, improve it [5, 10]. Strabismus and visual deficits follow standard ophthalmological treatment, and hearing aids may help in the sensorineural deafness of MICPCH [5, 10].

In the French PNDS, the approach to sialorrhoea begins with exclusion of an iatrogenic cause and correction of contributing factors (poor oral hygiene, reflux, swallowing disorder) [12]. Scopolamine (hyoscine) patches, placed behind the ear, reduce saliva production for 3 days, with somnolence, thickening of bronchial secretions, constipation and urinary retention as the main adverse effects; bilateral botulinum toxin injections into the parotid and submandibular glands are performed under ultrasound guidance, last 3 to 6 months and are repeated if necessary; and, since 2025, glycopyrronium bromide oral solution (Sialanar®) has been available in France, with good efficacy and tolerability provided titration is slow, requiring monitoring of bowel transit and the risk of urinary retention at high doses [12]. In the SALIVA trial, which supports this recommendation, 87 children and adolescents aged 3 to 17 years with neurological disability (43 with cerebral palsy) and severe drooling were randomised to glycopyrronium 320 µg/ml or placebo, in addition to non-pharmacological care; the median change in the total Drooling Impact Scale score at day 84 was −29.5 with glycopyrronium and −1 with placebo (p < 0.001), treatment-related constipation occurred in 20.5% and 16.3% and adverse events in 77.3% and 69.8% [191]. The European SmPC limits Sialanar® to severe sialorrhoea from 3 years of age, advises against it in mild to moderate sialorrhoea and recommends short-term, intermittent use for lack of safety data beyond 24 weeks [192]. The French SmPC for incobotulinumtoxinA (Xeomin®) authorises chronic sialorrhoea of neurological or neurodevelopmental cause from 2 to 17 years with a weight of 12 kg or more, with a weight-based dose divided in a 3:2 ratio between the parotid and submandibular glands, a minimum interval of 16 weeks and a dental consultation at the start because of the risk of caries [193]. The French SmPC for the scopolamine patch (Scopoderm®) does not include sialorrhoea among the indications (motion sickness and death rattle in palliative care) and contraindicates it below 15 years of age, so the paediatric use proposed by the PNDS is off-label; the same SmPC reports increased seizure frequency in epileptic patients in isolated cases and requires removal of the patch before MRI, because it contains aluminium [194]. Sensory assessment follows the French protocol for multiple disability; the electroretinogram and retinal imaging detect poorly symptomatic involvement, and hearing is assessed at diagnosis [12]. Oral follow-up consists of an annual dental screening consultation, with scaling and treatment of caries when necessary, also in adults, because dental complications increase with the degree of disability and may cause severe pain revealed only by behavioural changes [12].

7.8. Subtype-specific manifestations

In EXOSC3-associated TMA, eculizumab (Soliris®), a C5 inhibitor FDA-approved for atypical haemolytic uraemic syndrome in adults and children with weight-based dosing, produced no response in one of three children and the other two relapsed on treatment; the authors describe a severe, early TMA resistant to C5 inhibitors and recommend considering EXOSC3 (and EXOSC5) in eculizumab-resistant paediatric TMA with a neurodevelopmental disorder [114, 195]. In TRACK syndrome due to TSEN2, the sources consulted describe no effective treatment of the microangiopathy [26]. In PCH7 with atypical genitalia, the approach includes karyotype or microarray, multidisciplinary DSD assessment, endocrinology (gonadotropins, testosterone) and gonadal imaging [4, 39]. In the cerebellar forms of PRDM13 with hypogonadotropic hypogonadism, puberty should be induced by endocrine treatment and severe scoliosis monitored; PCH17 has largely palliative care [56, 57]. In PCH6 and the forms with mitochondrial dysfunction, the Mitochondrial Medicine Society consensus statements on diagnosis and standards of care in primary mitochondrial disease apply, which are not specific to RARS2 [166, 196]. In PCH14 and PCH15 a full blood count is justified at diagnosis and during follow-up, and in PCH13 liver function tests [50–52]. In SLC25A46, the management model includes low vision support, physiotherapy, occupational therapy and orthoses as in Charcot-Marie-Tooth neuropathies and, in the PCH form, neonatal respiratory support with palliative care [21, 22]. In boys with severe MICPCH, echocardiography and renal imaging look for the rare cardiac and renal anomalies [5]. In SEPSECS, plasma biomarkers of selenium and oxidative stress have been proposed to monitor therapeutic trials, without a validated treatment [30]. The French PNDS notes very rare cases of thrombotic microangiopathy after viral infections in patients with EXOSC3 or EXOSC5 variants; an increased risk in exosome genes has not been demonstrated, but it should be communicated to allow an appropriate response if the complication arises [12]. EXOSC5 variants, which do not cause PCH but a neurodevelopmental disorder with short stature, hypomyelination and cerebellar anomaly, are associated with cardiac conduction disturbances that may require a pacemaker; EXOSC5 patients should therefore have cardiac assessment targeted at conduction and rhythm disturbances, and the protocol allows it to be offered to patients with variants in the other exosome genes, in whom these disturbances have never been described, until studies confirm or exclude the risk [12].

7.9. Rehabilitation, education and family support

Physiotherapy maximises mobility and promotes walking in CAMRQ, with adapted equipment (wheelchairs, walkers, bath chairs, orthoses, adapted pushchairs), and occupational therapy works on fine motor skills (feeding, hygiene, dressing, writing) [10]. Early intervention and the individualised education plan are adapted to cognitive level; GeneReviews describes the North American framework (early intervention from 0 to 3 years, preschool from 3 to 5 years, individualised education plan), which in other countries corresponds to the national systems of early intervention and inclusive education [8, 9]. In MICPCH, interventions for ASD include applied behaviour analysis, and child psychiatry intervenes in aggression and destructive behaviour [5]. Social services, caregiver respite, care coordination, home nursing, adapted sport and ongoing assessment of palliative needs complete management [5]. Palliative care should be offered when the family and caregivers consider it appropriate, and in PCH4, PCH5, PCH12, PCH17 and PHRINL it is often the main aim from the neonatal period [8, 56].

In the French model, early intervention takes place in an early medico-social action centre (CAMSP) or through a coordination and orientation platform (PCO), coordinated by a paediatric neurologist or a physical medicine and rehabilitation physician, who define the technical aids (seating brace, orthoses, adapted pushchairs) and the frequency of therapies [12]. Physiotherapy strengthens the axial muscles, relaxes the peripheral ones and works on the levels of motor development and walking with or without aids, with standing in the most severe cases; psychomotor therapy works on sensorimotor experiences, coordination and balance; occupational therapy adapts the environment and technical aids; speech and language therapy treats orofacial, language and communication disorders and advises families on mealtimes; AAC is offered jointly with an occupational therapist and an educator; and a psychologist supports the child and the parents [12]. Consultations should be long, in accessible locations, with the participation of legal representatives and professional carers, who help to interpret the needs of patients who rarely express their wishes; multidisciplinary consultations, outreach consultations in medico-social facilities with telemedicine and, in some regions, consultations dedicated to the somatic health of people with multiple disability are favoured [12]. The PNDS describes French social rights: long-term illness scheme (ALD 30, severe form of neurological or muscular disease or severe epilepsy) with exemption from co-payment, means-tested complementary health cover, transport to a reference or competence centre more than 150 km away subject to prior request, daily parental presence allowance, carer's leave (up to 3 months, divisible and renewable up to 1 year), education allowance for a disabled child and its supplements, disability compensation benefit, disability card with incapacity of 80% or more, parking card and, in adults, adult disability allowance and a legal protection measure (guardianship, curatorship or family authorisation) from 18 years of age [12].

In most children with multiple disability, the approach is palliative from the outset, in the sense of active and comprehensive care oriented towards comfort and quality of life, adjusting the level of treatment at each stage [12]. The French legal framework applies (the 2005 Leonetti law, which defines unreasonable obstinacy, and the 2016 Claeys-Leonetti law, which establishes the right to deep and continuous sedation until death), and children with PCH fall within groups 3 or 4 of the 2006 Quebec classification of children in need of palliative care, or within group 5 (newborns with very limited life expectancy). The collegial decision not to start or to withdraw a life-sustaining treatment aims not to oppose the natural course of the disease unreasonably. The SAMU paediatric emergency form ("notable patient" form), written by a physician who follows the child, conveys the care plan to emergency physicians and avoids disproportionate interventions. The regional paediatric palliative care resource teams (ERRSPP) act as second line, at regional level, in training, coordination between hospital and home, support for teams, family respite and bereavement, in liaison with in-hospital mobile teams [12]. Contact with patient associations should be offered to families, who decide freely whether to make it [12].

7.10. Dosing of symptomatic drugs

No drug has a specific indication, dose or trial in PCH, MICPCH or CAMRQ. The following doses are those of the official labels for the closest approved indication; use in PCH is extrapolated from the indication or from analogous conditions (paediatric epilepsy, cerebral palsy), and use outside the approved ages is off-label. The choice between drugs follows seizure type, age, weight and comorbidities, under the guidance of a paediatric neurologist.

There is no FDA label for oral phenobarbital, and the Portuguese Summary of Product Characteristics (SmPC) for oral phenobarbital was not consulted; the paediatric oral maintenance dose comes from the British SmPC [174, 175]. The AAN/CNS guideline considers short-term oral diazepam in generalised spasticity, but the summary consulted does not give the dose [170].

7.11. Comparative regulatory status

The sources for regulatory status are the labels and SmPCs cited in table 7.10 [144, 173–175, 181, 184, 187, 190, 192–195]. The non-applicability of 5q SMA drugs to PCH1 follows from their acting on SMN1 or SMN2, whereas the diseases due to VRK1 and the exosome genes occur in patients with normal SMN1 [9, 14]. FDA or EMA orphan designations for PCH were not searched.

7.12. Clinical trials

A ClinicalTrials.gov search on 26 October 2026 ("pontocerebellar hypoplasia", CASK, TSEN54, EXOSC3, "cerebellar hypoplasia", VLDLR, MICPCH, SEPSECS, RARS2, AMPD2) identified no interventional trial targeting a PCH; a negative search does not prove that no studies exist. The only interventional trial that included a PCH among the eligible conditions was MIT-E.

The MIT-E trial was negative on the primary outcome and had no subgroup analysis for PCH6 in the registry, so it provides no information on the efficacy of vatiquinone in this disease [197]. Observational studies do not test interventions. Therapeutic evidence in PCH is limited to observational series without a control group, such as the response to antiepileptic drugs in PCH2A, which does not allow indirect comparisons between drugs [15].

7.13. Developments and research

In the last 12 months, no trial, opinion or regulatory authorisation specific to a PCH has been published. In terms of recommendations, the HAS published on 7 September 2026 the first national diagnosis and care protocol dedicated to PCH [12]. The advances belong to three levels of evidence. Observational human studies: the international SEPSECS cohort with proposed monitoring biomarkers [30], C5 inhibitor-resistant TMA in PCH1B [114], the diagnosis and growth charts of PCH2A [109, 110], newborn screening in COASY disease [49, 145] and the CASK series [132, 135–137]. Preclinical studies: in PCH9, supplementation with AICAr (a purine nucleotide precursor) rescued the phenotype in yeast and in patient neural progenitors, but inhibited axonal growth in murine neurons and no patient has been treated [4, 41]; IMPDH2 filaments protect against neurodegeneration in models of AMPD2 deficiency, suggesting induction of their polymerisation as a therapeutic hypothesis [200]; systemic AAV-PHP.B-Slc25a46 rescued premature death, nerve conduction, mobility, mitochondrial complex activity and dendritic loss of Purkinje cells in Slc25a46−/− mice [201]; splice-correcting antisense oligonucleotides restored CDK5RAP3 expression in amniocytes [91]; and single-cell transcriptomics in rars2−/− zebrafish identified alterations in the Notch and Wnt pathways and in glia [202]. For COASY, downstream or gene-targeted strategies have been proposed, without a trial [101]. Academic projects: the PCH2cure project (Tübingen and Freiburg with the PCH-Familie e.V. association), funded in December 2022 by the Chan Zuckerberg Initiative with 2 million dollars over 4 years, uses brain organoids derived from patients' skin cells; the sources consulted up to October 2026 describe no therapeutic results [203].

7.14. Agents to avoid, anaesthesia, pregnancy and transition

Despite the hyperthermic episodes documented in PCH2, GeneReviews identifies no special risk with general anaesthesia [8]. Orphanet includes malignant hyperthermia among the potentially fatal complications of PCH2 [1]. The two sources diverge; in practice, the anaesthetic team should be aware of the tendency to hyperthermia, the subclinical myopathy with raised CK and the risk of apnoea and aspiration. Valproate should be avoided in the forms with mitochondrial dysfunction and used with caution below 2 years [179]; vigabatrin requires weighing of the visual risk in patients with pre-existing visual impairment [178]; benzodiazepines and phenobarbital combined with opioids can cause severe respiratory depression in patients with apnoea [175, 180]; and botulinum toxin can worsen dysphagia [184]. Patients with MICPCH have no known reproduction, and in CAMRQ and mild VPS53 pregnancy is not described in the sources consulted; if a carrier or patient with epilepsy becomes pregnant, phenobarbital is associated with major malformations two to three times more frequently and with neurodevelopmental effects, and should be used only if the benefit outweighs the risk, at the lowest effective dose [5, 174]. Transition to adult medicine applies mainly to MICPCH, CAMRQ, PCH1B with p.(Asp132Ala), PCH11 and the late forms of SEPSECS; adult women with MICPCH need long-term multidisciplinary management of scoliosis, feeding and mobility [10, 30, 132].

The French PNDS (National Diagnosis and Care Protocol) considers that there is no excess anaesthetic risk in PCH and that the precautions are those of multiple disability, in line with GeneReviews; the only published anaesthetic protocol concerns PCH1E (SLC25A46) and was adapted to the mitochondrial function of the gene [12]. In PCH2, the protocol advises enhanced monitoring and good hydration during infections, given the possible myopathy with raised CK and rhabdomyolysis, without described excess anaesthetic risk [12]. Neurological follow-up begun in childhood continues in adulthood, and the legal protection measure from 18 years of age is part of transition [12].

7.15. Guidelines and divergences

Sources: [5, 8–10, 13, 14, 30, 166, 170, 171, 196]. The divergences between sources are botulinum toxin (recommended in spasticity, insufficient evidence in dystonia) and anaesthetic risk (no special risk in GeneReviews, malignant hyperthermia among the complications in Orphanet) [1, 8, 170, 171].

The French PNDS diverges from the other sources on several points [12]. In the genetic strategy, it starts with a targeted panel (about 60% of diagnoses) and reserves trio exome or genome sequencing for negative cases, whereas Zakaria and colleagues recommend microarray with exome or panel from the outset and the CASK GeneReviews accepts exome or genome as first line [5, 13]. On anaesthetic risk, it aligns with GeneReviews and not with Orphanet [1, 8]. For sialorrhoea, it proposes transdermal scopolamine, which the French SmPC does not indicate for sialorrhoea and contraindicates below 15 years, and describes good tolerability of glycopyrronium, whereas the European SmPC restricts use to severe sialorrhoea, for short and intermittent periods; the trial supporting the recommendation lasted 84 days [191, 192, 194]. It attributes a duration of 3 to 6 months to salivary toxin injections, and the Xeomin® SmPC sets a minimum interval of 16 weeks between sessions [193]. It refers to efficacy of tetrabenazine in isolated patients, which the French SmPC advises against in paediatrics and the FDA label restricts to Huntington disease in adults [186, 187]. It places the mean prenatal diagnosis at 27 weeks, whereas the series it cites reports neurosonography and fetal MRI at a mean of 29 weeks and 4 days and 31 weeks [154]. It presents PCH1F as an exception to recessive inheritance, contrary to OMIM and the two published reports [2, 23, 24]. Finally, it sets intervals where GeneReviews defers to clinical judgement: annual or six-monthly hip and spine radiographs until the end of puberty, physical medicine and rehabilitation consultation at least annually, annual blood tests and annual dental and gastrostomy follow-up [8, 9]. For doses, the reference is the guideline when it specifies them, and the SmPC serves for comparison; the PNDS gives no doses, and those in table 7.10 come from the SmPCs and consensus statements cited.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by mode of inheritance

In the numbered PCH, recessive PHRINL, CAMRQ and the other recessive forms, the parents of a patient are obligate heterozygotes and asymptomatic; in each pregnancy, the risk is 25% of an affected child, 50% of an asymptomatic carrier and 25% of an unaffected non-carrier [1, 8–10]. Testing of both parents is recommended to confirm phase and allow a reliable risk estimate, because de novo variants occur, albeit at a low rate, in recessive diseases [8]. Despite some intrafamilial variability, siblings affected by EXOSC3 usually have a presentation similar to that of the proband [9]. Patients with severe PCH do not reproduce, because of severe intellectual disability and death before reproductive age; those affected by VLDLR also have no known reproduction [8, 10]. The parents' siblings have a 50% probability of being carriers, and carrier detection requires prior identification of the familial variants [8, 10].

In MICPCH, most cases are simplex due to a de novo variant or, in boys, somatic mosaicism; because penetrance appears to be complete, an asymptomatic parent is unlikely to be a carrier, but parental somatic or germline mosaicism is possible (described in an asymptomatic mother with mosaicism for a CASK deletion); the recurrence risk for siblings is low but higher than that of the population, and maternal germline mosaicism puts brothers and sisters at risk, whereas paternal germline mosaicism puts only sisters at risk [5, 133]. The sources consulted do not quantify this risk, and the Burglen series recommends reassuring counselling in the presence of a de novo variant, because PCH are mostly recessive [58]. In X-linked intellectual disability with or without nystagmus, the father of an affected boy is not a carrier; the mother may be heterozygous or the variant may be de novo, and with more than one affected individual she is an obligate heterozygote; a heterozygous mother transmits the variant in 50% of pregnancies, with affected boys and girls usually asymptomatic, but with possible mild to severe intellectual disability, ocular signs, absences or tremor; if the variant is not detected in maternal leucocytes, the risk remains above that of the population; maternal aunts and cousins of a male proband may be at risk [5]. In the Burglen families with inherited missense or in-frame variants, 10 of 13 female carriers had no intellectual disability, 2 had mild and 1 severe intellectual disability [58]. For OPHN1, X-linked inheritance follows the same logic [61].

8.2. Cerebellar hypoplasia without a molecular diagnosis

After careful assessment and exclusion of syndromic and monogenic causes, the Oxford Desk Reference notes that many syndromic causes of structural cerebellar anomalies are recessive and that, in apparently isolated cerebellar hypoplasia or vermis agenesis, the recurrence risk may be as high as 25%, with no empirical data available [62]. Autosomal dominant vermis aplasia has been described, so MRI is recommended for a parent with ataxia, nystagmus or other neurological abnormalities; there is phenotypic overlap with the spinocerebellar ataxias; tubulinopathies may be dominant; and in non-Mendelian, non-chromosomal Dandy-Walker malformation the risk is 1–5% [62]. An acquired cause (prematurity, perinatal injury) changes counselling, and congenital structural cerebellar lesions help to estimate the risk [4, 142]. DNA banking is recommended when the molecular diagnosis is not confirmed, to allow future reanalysis [8].

8.3. Cascade testing and carrier screening

Cascade testing of the parents' siblings and other relatives of reproductive age is possible once the familial variants have been identified [8]. Carrier screening programmes exist in founder populations. In a genetically isolated community in the Netherlands with preconception counselling since 2012, 203 people were counselled in one year (92 couples and 19 individuals), 65 of 196 tested (33.2%) were carriers of at least one of four diseases, the PCH2 carrier frequency was 14.3% and four PCH2 carrier couples were identified [204]; since 2010, seven carrier couples have been identified in this community [4]. People of Roma ancestry can have carrier testing for EXOSC3 p.(Gly31Ala), and a Slovak centre recommends voluntary carrier testing of couples and prenatal and newborn screening in this population [9, 205]. In Hutterites, the carrier frequency of the VLDLR deletion (about 1/15) could justify population screening for reproductive purposes, by analysis targeted at the founder deletion [10, 67]. In Moroccan Jews, the VPS53 carrier frequency of about 1/37 supports targeted testing [31].

8.4. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, invasive prenatal diagnosis (chorionic villus sampling, amniocentesis) or PGT is offered [1, 4, 8]. Ultrasound does not replace molecular testing: it often fails at 20 weeks, and the detailed ultrasound offered in a subsequent pregnancy has limitations that should be discussed with the parents [4, 62, 109]. For the consanguineous Pakistani couple with two pregnancies affected by PCH12, the authors recommend PGT and cascade testing [126]. The perspectives of professionals and families on prenatal diagnosis of severe diseases may differ and should be discussed [8].

The French PNDS details the options in a new pregnancy [12]. Without a molecular diagnosis, it offers close morphological surveillance (reference ultrasound scans and fetal MRI at 32 weeks, or from 26 weeks if there is an ultrasound sign), whose limitations in progressive PCH should be explained. With an identified variant, prenatal diagnosis is performed by trophoblast biopsy early in pregnancy or by amniocentesis, and non-invasive prenatal diagnosis on maternal plasma is possible in some situations (recessive PCH with a paternal variant different from the maternal one, dominant de novo PCH), with technical limitations to be discussed with the laboratory in each case. Other options are PGT, gamete donation and adoption. In dominant PCH due to a de novo variant, the recurrence risk is low and corresponds to that of germline mosaicism [12]. After a prenatal diagnosis, termination of pregnancy for medical reasons is discussed case by case according to the type of PCH, the imaging, the genetic data and what the parents consider acceptable; in France, the multidisciplinary prenatal diagnosis centre (CPDPN) may certify eligibility after a complete assessment. Couples who continue the pregnancy can build with the perinatal team a palliative care plan at birth, centred on comfort and support, put into practice once the diagnosis and prognosis have been confirmed [12].

8.5. Counselling of minors and family planning

GeneReviews recommends genetic counselling of young adults who are affected, carriers or at risk of being carriers, and family planning before pregnancy [8, 9]. The sources consulted do not specifically address carrier testing in asymptomatic minors; because carrier status has no health consequences for the person, the information is mainly reproductive and can wait until the age at which the person decides for themselves [8].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The prevalence of PCH is unknown, and most subtypes appear to be very rare [1]. The Orphanet prevalence classes below 1/1,000,000 for the subtypes reflect counts of published cases and not population studies: about 40 families worldwide for PCH1 (all genes), about 81 families for PCH2 ("unknown" prevalence), about 10 families for PCH4, 3 families for PCH3, 6 cases for PCH8, 23 cases for PCH10, 4 cases for PCH12, 7 cases for progressive cerebello-cerebral atrophy and 51 validated cases for dysequilibrium syndrome [206]. The Orphanet count for PCH7 (4 cases) is outdated in view of the 12 families of Lardelli and the 28 46,XY cases reviewed in 2026 [38, 39]. PCH2A is the most frequent type, with an estimated incidence below 1/200,000, according to van Dijk and colleagues, who cite Sánchez-Albisua [4, 15]. By 2014, fewer than 100 families with PCH2 had been published [15]. GeneReviews counts at least 131 individuals with TSEN54-PCH, 82 with EXOSC3-PCH, more than 50 with VLDLR-CH and 130 with CASK disorders (151 published by 2025 according to the BINGO review), with unknown prevalence in all [5, 8–10, 135].

The relative distribution of genes depends on the cohort. In routine diagnostics in Amsterdam between 2012 and 2017, 42 patients had variants in PCH genes (20 homozygous for p.(Ala307Ser), 13 EXOSC3, 4 RARS2, 1 SEPSECS, 1 AMPD2), and another 9 had CASK variants [4]. At the French reference centre, PCH2/PCH4 accounted for 18 of 40 patients (45%) and MICPCH for 13 of 40 (32%) [58]. In the current cohort of the same reference centre, with 260 patients, CASK (21%) and TSEN54 (17%) were the most frequent causes, followed by EXOSC3; the distribution also included TUBA1A, VLDLR, SEPSECS, SPTAN1, DYRK1A, chromosomal anomalies and ischaemic-haemorrhagic lesions, and 34% had no diagnosis [12]. The same protocol estimates the proportion of conclusive molecular diagnoses in France at more than 70%, a figure that does not match that of the cohort and whose basis is not explained, and keeps the prevalence of PCH as unknown [12]. In the Namavar cohort (169 patients from 141 families with suspected PCH tested for TSEN54, TSEN2, TSEN34 and RARS2), 106 had variants [92]. In the Canadian cohort of radiological PCH, only 1 of 38 had variants in an OMIM PCH gene [13]. The 2017 Oxford Desk Reference states that PCH1A due to VRK1 is probably the most frequently diagnosed form; this statement diverges from all the other sources, which identify PCH2A as the most frequent type and VRK1 as a very rare cause of PCH1 [4, 8, 62, 63].

9.2. Europe, North America and founder populations

The data available come mainly from Western and Central Europe (Netherlands, Germany, Switzerland, France, Italy, Czech Republic, Slovakia, Bulgaria, United Kingdom), North America (Canadian cohorts from Montreal and Hutterite populations) and founder or consanguineous populations of the Middle East, North Africa, Turkey and South Asia. The sources consulted include no data from Portugal or Brazil; the Canadian cohort of Zakaria has a Brazilian co-author, without Brazilian patients [13]. The absence of data in the sources consulted does not demonstrate the absence of patients or publications in these countries.

9.3. Special populations

Extremely preterm newborns are a population in which PCH may be acquired rather than genetic, which calls for caution before assigning a recurrence risk [4, 73]. Fetuses with isolated cerebellar hypoplasia may have normal postnatal imaging [152]. Adults with MICPCH, CAMRQ, mild PCH1B and late forms of SEPSECS or VPS53 are an emerging population, also identified by exome sequencing at older ages [4, 30, 32, 132]. In girls with MICPCH, variability of X inactivation did not explain severity in the nine tested, all with random inactivation [58].

9.4. European networks and patient associations

The most relevant European reference network is ERN-ITHACA, for rare hindbrain malformations and MICPCH; ERN-RND covers ataxias and rare neurological diseases, ERN EpiCARE refractory epilepsies and EURO-NMD PCH1 and motor neuronopathies. The German association PCH-Familie e.V. is a German-language self-help portal for families of children with PCH, the basis of the German natural history cohorts, and participates in the PCH2cure project [203, 207]. CASK Kinder- und Lebenshilfe e. V. (Germany) supports families with CASK disorders [5], as does the CASK Gene Foundation in the USA. In the USA, the National Institute of Neurological Disorders and Stroke (NINDS) and the National Ataxia Foundation provide information on cerebellar hypoplasia and ataxias [10]. Orphanet lists specialist centres, diagnostic tests, patient organisations and registries for the group [1]. In France, patients are followed by the reference centre for cerebellar malformations and congenital diseases (2M2C), with its coordinating site at Armand-Trousseau Hospital (AP-HP, Paris), constituent sites in Lille and Lyon and competence centres in Besançon, Montpellier, Paris-Pitié-Salpêtrière, Reims and Tours, within the DéfiScience health network for rare neurodevelopmental diseases; depending on local conditions, centres for multiple disability, intellectual disability and developmental anomalies also follow these patients [12]. The French associations are the Association Enfants CASK France (AECF), for CASK disorders, and Connaître les Syndromes Cérébelleux (CSC), with a paediatric branch, for cerebellar syndromes in general [12].

10. Illustrative Clinical Case

10.1. Boy with MICPCH due to a mosaic CASK variant (Burglen and colleagues, 2012)

The case belongs to the series of the French reference centre for cerebellar malformations (Paris, Assistance Publique–Hôpitaux de Paris), which studied 14 patients with PCH on imaging without anterior horn disease or chorea; TSEN54 had been sequenced and was normal in five, and the 27 exons of CASK (NM_003688.3) were sequenced, with array-CGH in negative cases [58]. Patient 12 was born at term after a normal pregnancy, with a weight of −1.5 SD, length of −2 SD and head circumference of −3 SD [58]. He had psychomotor delay: he sat at 18 months and acquired independent walking at 4 years [58]. At 15 years he had severe intellectual disability, a vocabulary of about 12 words, supported by non-verbal communication tools, independent walking, dystonia, stereotypies and orofacial dyskinesia, with head circumference and height of −3.5 SD; ophthalmological and hearing examinations were normal, and he had neither epilepsy nor spasticity [58]. MRI showed mild cerebellar hypoplasia [58]. The nonsense variant NM_003688.3:c.316C>T p.(Arg106Ter) was identified in mosaic form, present in lymphocytes and buccal mucosa, absent in the parents (de novo variant, with confirmed paternity) [58]. He was the first mosaic boy with MICPCH described [58].

The same series describes, in contrast, patient 13, a boy hemizygous for the splice variant c.278+1G>A, with severe neonatal hypotonia, refractory epilepsy with daily spasms and tonic seizures with burst-suppression, distal contractures, diaphragmatic eventration, microcephaly that went from normal to −6 SD at 16 months, absent eye contact, spastic quadriparesis, severe dystonia with opisthotonus, severe GORD with dysphagia and gastrostomy, very hypoplastic optic discs with absent visual evoked potentials, almost absent central auditory responses and almost absent cerebellar hemispheres on MRI [58]. The pair illustrates the clinico-radiological correlation in boys described by the authors: the mosaic nonsense variant produced a picture comparable to that of heterozygous girls, and constitutional hemizygous loss of function produced severe epileptic encephalopathy [58, 95].

10.2. Figures consulted

Figure 3 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC3351739/figure/F3/) shows the facies of six patients with a CASK variant; panel D corresponds to patient 12 at 13 years, and the legend describes minor dysmorphism, with a round face, small chin and well-defined eyebrows in the younger patients and a longer face, high and broad nasal bridge, long nose and protruding maxilla in the older ones [58]. Figure 4 (https://pmc.ncbi.nlm.nih.gov/articles/PMC3351739/figure/F4/) shows, on sagittal sections, the spectrum of vermis and pontine hypoplasia, with a very small pons but relative preservation of the superior bulge and very mild vermian hypoplasia in patients 10 to 12 and severe in patient 13, and, on coronal sections, frequently asymmetric hemispheres without protrusion of the vermis, unlike the "dragonfly" of PCH2; there was no progression between successive MRIs in patient 9 (at 4 months and at 11 years) [58]. The legends of both figures were read in the source; the images were not viewed.

10.3. Clinical interpretation

The case shows that a boy with PCH, microcephaly and intellectual disability may have an X-linked disease without a family history and with a variant not detectable in all cells, that walking and some language are possible and that PCH may be mild on MRI [58]. The authors recommend testing CASK, including exonic deletions and duplications, in children with intellectual disability, microcephaly and PCH without signs of PCH2, and consider reassuring counselling appropriate in the presence of a de novo variant [58]. GeneReviews adds that negative parental blood does not exclude parental mosaicism, so the recurrence risk is low but not zero [5]. The management described in the report (non-verbal communication, developmental follow-up) is consistent with the general management recommendations for CASK disorders [5].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis by entity

The overall prognosis is poor: many children live only until infancy or childhood, although some patients have reached adulthood [1]. The data available come from observational cohorts of disease treated with supportive care, and there is no comparable untreated natural history.

In PCH2A, the presence of prenatal signs did not alter survival at 1, 5 or 10 years [15]. In PCH1, there is no correlation between the age at neurological onset and lifespan [14]. In MICPCH, the severity of PCH on MRI has no prognostic value in girls and the clinico-radiological correlation is clearer in boys [5, 58]. Improved care, especially gastrostomy feeding, has probably prolonged survival in PCH2 [8]. The French PNDS (National Diagnosis and Care Protocol) attributes the shorter lifespan of the neurodegenerative forms to respiratory involvement (respiratory failure, recurrent infections), anterior horn involvement in PCH1, epilepsy and the complications of multiple disability; in the neurodevelopmental forms, survival depends on complications and on the severity of multiple disability, and the highly variable neurocognitive prognosis justifies regular assessments to adapt medico-educational guidance [12].

11.2. Surveillance table

The GeneReviews specify intervals only for annual gastrointestinal assessment in PCH2 and PCH1, for annual neurological and rehabilitation assessments in VLDLR-CH, for annual ophthalmology and audiology and the other assessments at each visit in MICPCH and for hepatic monitoring of drugs; the other intervals depend on the clinical picture [5, 8–10]. The French PNDS adds intervals for the paediatric neurology consultation (annual), physical medicine and rehabilitation (at least annual) and respiratory medicine (at least annual after the first symptoms), for hip and spine radiographs (annual or six-monthly until the end of puberty), for blood tests (annual) and for dental and gastrostomy follow-up (annual) [12].

12. Summary and Final Considerations

The pontocerebellar hypoplasias are a class of monogenic disorders, almost all autosomal recessive, of prenatal or neonatal onset, defined by hypoplasia and/or atrophy of the cerebellum and pons and numbered PCH1 to PCH17 in OMIM, with more than 25 genes linked mainly to RNA processing (TSEN complex, CLP1, exosome, spliceosome, TOE1), translation and metabolism (RARS2, SEPSECS, AMPD2, COASY, MINPP1), vesicular trafficking (VPS53, VPS51, CHMP1A, TBC1D23), the mitochondrion (SLC25A46, ATAD3A), the synapse (PCLO) and neuronal specification (PRDM13). PCH2A, due to homozygous TSEN54 p.(Ala307Ser), is the most frequent and best characterised type, with neonatal clonus, dysphagia, choreoathetosis, epilepsy, apnoea and thermoregulation disturbances, a "dragonfly" pattern on MRI and 53% mortality by 10 years of age in the German cohort. PCH1 combines PCH with anterior horn degeneration and should be sought in children with an SMA-like picture without SMN1 deletion, especially of Roma ancestry. MICPCH due to CASK, X-linked and almost always de novo, is the second cause of PCH in reference series and is distinguished by proportionate hypoplasia of the vermis and hemispheres, the absence of chorea and of motor neuron disease and a low recurrence risk. VLDLR-CH and the other CAMRQ are non-progressive congenital ataxias with intellectual disability. Diagnosis rests on MRI, which should be interpreted by a neuroradiologist and may be normal at onset in several forms, and on genetic testing with CNV analysis, which begins with the TSEN54 c.919G>T variant in the PCH2 phenotype and with exome or genome sequencing plus microarray in the others; in radiological PCH, chromosomal and acquired causes, including extreme prematurity, are more frequent than the classic genes. There is no disease-modifying treatment and no targeted interventional trial; management rests on gastrostomy feeding and treatment of reflux, antiepileptic drugs (with the highest proportion of responses to phenobarbital and topiramate in PCH2A), a rescue plan for status epilepticus, apnoea monitoring, hydration during fever, treatment of spasticity and dystonia extrapolated from cerebral palsy, rehabilitation, augmentative communication and palliative care. Genetic counselling, cascade testing, carrier screening in founder populations and prenatal or preimplantation diagnosis depend on molecular identification, because fetal ultrasound does not detect most cases. The 2026 French national protocol organises this pathway, from MRI and the targeted genetic panel to multidisciplinary follow-up with defined intervals for rehabilitation, orthopaedics, bone health, nutrition, breathing and teeth, and to the palliative approach.

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177. Keppra (levetiracetam) tablets and oral solution, prescribing information. NDA 021035/021505. Revised 2026-01-28. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=021035
178. Sabril (vigabatrin) tablets and powder for oral solution, prescribing information. NDA 020427. Revised 2021-10-20. DailyMed set id a5d389d2-d0e1-4395-a2a2-b552808e7f98.
179. Depakote (divalproex sodium) delayed-release tablets, prescribing information. NDA 018723. Revised 2026-03-31. DailyMed set id 08a65cf4-7749-4ceb-6895-8f4805e2b01f.
180. Onfi (clobazam) tablets and oral suspension, prescribing information. NDA 202067/203993. Revised 2024-03-12. DailyMed set id de03bd69-2dca-459c-93b4-541fd3e9571c.
181. Valtoco (diazepam nasal spray), prescribing information. NDA 211635. Revised 2026-06-03. DailyMed set id 1a8bcc90-68fa-474d-832c-0df01e825f39.
182. Fleqsuvy (baclofen) oral suspension, prescribing information. NDA 215602. Revised 2025-12-16; and Ozobax DS (baclofen) oral solution, NDA 208193, revised 2026-03-13.
183. Zanaflex (tizanidine) tablets and capsules, prescribing information. NDA 020397/021447. Revised 2025-05-05. DailyMed set id 043d9e51-bfa2-4add-9058-5ece332f7e99.
184. Botox (onabotulinumtoxinA) for injection, prescribing information. BLA 103000. Revised 2023-11-18. DailyMed set id 33d066a9-34ff-4a1a-b38b-d10983df3300.
185. Trihexyphenidyl hydrochloride tablets/elixir, prescribing information. ANDA 040251. Revised 2022-06-21.
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