Pseudo-TORCH Syndromes due to Neurovascular Barrier Defects (OCLN, JAM3 and RNASET2)

Genetic phenocopies of congenital infection: band-like calcification with simplified gyration and polymicrogyria (pseudo-TORCH type 1, OCLN), haemorrhagic destruction of the brain with subependymal calcification and congenital cataracts (JAM3) and cystic leukoencephalopathy without megalencephaly (RNASET2); related endothelial junction disorders: neurodevelopmental disorder with intracranial haemorrhage, seizures and spasticity (ESAM) and diencephalic-mesencephalic junction dysplasia 1 (PCDH12).

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

Pseudo-TORCH type 2 (USP18, OMIM 617397, ORPHA:481665) and type 3 (STAT2, OMIM 618886, ORPHA:714429) are type I interferonopathies, related to Aicardi-Goutières syndrome, and are included here only as differential diagnoses [31–34].

The two related endothelial junction disorders, covered in dedicated subsections throughout the article, are identified in Table 0.2.

Table 0.2. Related endothelial junction disorders: ESAM and PCDH12

1. Introduction

1.1. The concept of pseudo-TORCH

The acronym TORCH groups the infections transmitted from mother to fetus (toxoplasmosis, others, rubella, cytomegalovirus and herpes simplex) that leave a recognisable signature in the newborn: microcephaly, intracranial calcifications, white matter injury and sometimes hepatosplenomegaly, thrombocytopenia and chorioretinitis. The designation «pseudo-TORCH» arose when it was recognised that some children had this signature without any evidence of infection and that the same combination recurred in siblings, which pointed to a Mendelian cause [1, 50]. The Orphanet definition summarises the historical criterion: microcephaly and intracranial calcifications at birth, neurological delay, seizures and a course similar to that of intrauterine infection, despite repeated tests that identify no infectious agent [2].

The concept has practical importance that goes beyond nosology. Intracranial calcification in a child with neurological disease leads first to the hypothesis of congenital infection, especially cytomegalovirus (CMV), and a mistaken diagnosis of infection closes the investigation and deprives the family of counselling on the 25% recurrence risk proper to an autosomal recessive disease [12, 51, 52]. The Oxford Desk Reference recommends considering the autosomal recessive pseudo-TORCH condition whenever a newborn has signs of congenital infection without serological support or an identified virus [53, 54].

1.2. Historical milestones

Baraitser, Brett and Piesowicz described in 1983 two siblings with severe congenital microcephaly, spasticity, seizures and extensive intracranial calcification, without evidence of infection [55]. In 1986, Burn and colleagues reported two siblings of consanguineous Turkish Cypriot parents with microcephaly, jaundice, hepatomegaly, corneal opacity, thrombocytopenia, petechiae and periventricular calcification, who died at 30 and 50 days; autopsy showed lissencephaly, polymicrogyria and massive calcification [1, 56]. Reardon and colleagues brought together in 1994 ten patients from five families and proposed an «autosomal recessive congenital intrauterine infection-like syndrome» characterised by microcephaly from birth, seizures, periventricular calcification and sometimes hepatosplenomegaly, platelet dysfunction and purpura, requiring repeatedly negative TORCH investigations as a prerequisite [57]. Hence the eponym Baraitser-Reardon syndrome; Vivarelli and colleagues published diagnostic criteria for this syndrome in 2001, cited in the Oxford Desk Reference [3].

This clinical designation brought together different entities. Crow and colleagues drew attention, between 2000 and 2003, to the overlap between pseudo-TORCH syndrome and Aicardi-Goutières syndrome (AGS), and the AGS GeneReviews considers it likely that most old cases of «microcephaly-intracranial calcification syndrome» were in fact AGS, because cells and interferon-α in the cerebrospinal fluid (CSF) had rarely been studied [1, 12]. The separation of a distinct form began in 2008, when Briggs and colleagues described five patients with a band of intracranial calcification associated with simplified gyration and polymicrogyria, and Abdel-Salam and colleagues described five Egyptian siblings with band-like cortical calcification, polymicrogyria and hypogenesis of the corpus callosum and cerebellum [58–60]. Briggs and colleagues argued that the generic term «pseudo-TORCH» remained useful for cases that were not AGS [1].

1.3. Gene discovery

In 2010, O'Driscoll and colleagues used autozygosity mapping and copy-number analysis to identify intragenic deletions and point variants of OCLN in nine patients from six families with band-like calcification, simplified gyration and polymicrogyria (BLC-PMG), establishing the first molecular cause of a pseudo-TORCH phenotype unrelated to interferon [16]. In the same year, Mochida and colleagues identified a homozygous loss-of-function variant of JAM3 in a highly consanguineous Saudi family with haemorrhagic destruction of the brain, subependymal calcification and congenital cataracts (HDBSCC), and noted the similarity to pseudo-TORCH syndrome [10, 61]. Akawi and colleagues confirmed the association in three families of Turkish, Afghan and Moroccan origin in 2013 [62].

Cystic leukoencephalopathy without megalencephaly followed a parallel path. Olivier and colleagues described in 1998 three Turkish children with anterior temporal cysts and white matter disease; Gomes, Vieira and Saldanha, of Hospital de Santa Maria in Lisbon, reported in 2001 two patients with non-progressive leukoencephalopathy, bilateral temporal cysts, microcephaly and sensorineural deafness, in one of whom congenital CMV was considered; Henneke and colleagues delineated the entity in 15 children in 2005 [5, 63, 64]. In 2009, the same group identified biallelic RNASET2 variants and showed that the clinical and radiological phenotype was indistinguishable from that of congenital cerebral CMV infection asymptomatic at birth, which gave the founding paper its title [18].

1.4. Current nomenclature and classification

OMIM now designates entity 251290 as «pseudo-TORCH syndrome 1» and keeps as alternative titles «band-like calcification with simplified gyration and polymicrogyria» and the acronym BLCPMG; types 2 (USP18) and 3 (STAT2) form a phenotypic series with type 1 [1, 31, 32]. Orphanet adopted the same numbering (ORPHA:1229, 481665 and 714429) [2, 33, 34]. HDBSCC has the descriptive OMIM name (613730) and, in Orphanet, the designation «porencephaly-microcephaly-bilateral congenital cataract» [4, 10]. RNASET2-related disease is OMIM's «cystic leukoencephalopathy without megalencephaly» (612951), distinct from megalencephalic leukoencephalopathy with subcortical cysts (604004) [5].

Two readings of the class coexist. One, clinical, groups all genetic phenocopies of congenital infection, including the interferonopathies. The other, mechanistic, separates the interferonopathies (AGS, USP18, STAT2), whose injury results from inappropriate activation of the type I interferon pathway, from the diseases of the neurovascular unit. Lecca and colleagues proposed in 2023 the term «tight-junctionopathies» for the emerging group of diseases caused by genes for endothelial tight junction proteins (OCLN, JAM3, ESAM and others), which share intracranial haemorrhage, calcification and neurodevelopmental injury [35]. RNASET2-related disease occupies an intermediate position: it is a lysosomal disorder of RNA catabolism whose neuroinflammation depends on type I interferon, and it overlaps clinically and radiologically with both CMV and AGS [65, 66]. In this mechanistic framework, ESAM-related NEDIHSS is a tight-junctionopathy in the strict sense, and PCDH12-related DMJDS1 results from the loss of a non-clustered protocadherin expressed in the endothelium and neurons, which adds a defect of axonal tracts to the vascular component; OMIM and Orphanet classify DMJD as a brain malformation and group the PCDH12 and GSX2 forms under the same Orphanet code [35, 37, 42].

1.5. Definition of the entities

BLC-PMG is defined by the combination of severe progressive microcephaly, early-onset epilepsy, developmental arrest, a symmetrical band of calcification of the deep cortical grey matter, calcification of the thalami, basal ganglia, pons and cerebellum and bilateral symmetrical polymicrogyria with simplified gyration, associated with biallelic OCLN variants [16, 20]. HDBSCC is defined by the triad of haemorrhagic destruction of the brain parenchyma, subependymal calcification and congenital cataracts, with fetal or neonatal onset, caused by biallelic JAM3 variants [10, 15]. Cystic leukoencephalopathy without megalencephaly is defined by encephalopathy with onset in the first year, static or very slowly progressive, with bilateral anterior temporal cysts, multifocal white matter lesions sparing the central structures, normocephaly or microcephaly and frequently sensorineural hearing loss and calcifications, caused by biallelic RNASET2 variants [18, 64].

NEDIHSS was delineated in 2023 by Lecca and colleagues, who brought together 13 individuals from 8 families, including 4 fetuses, with biallelic loss-of-function ESAM variants; it is defined by the association of severe global developmental delay with absent or very delayed speech, epilepsy, spasticity of variable degree, ventriculomegaly and intracranial haemorrhage or brain calcifications, with prenatal or neonatal onset, and OMIM assigned it the number 620371 [35, 36]. DMJD was described in 2012 by Zaki and colleagues, in six patients from three consanguineous Egyptian families, as a malformation of the junction between the diencephalon and the mesencephalon with a «butterfly» contour of the midbrain on axial sections [67]. In 2016, Aran and colleagues identified a founder nonsense variant of PCDH12 in ten Palestinian patients with congenital microcephaly mimicking intrauterine infection, and in 2018 Guemez-Gamboa and colleagues found biallelic PCDH12 variants in two of the original DMJD families and in six new families [37, 45]. DMJDS1 is now defined as the disease due to biallelic PCDH12 variants, with a continuous spectrum ranging from congenital microcephaly with neonatal epilepsy and brainstem malformation to forms with ataxia, dystonia, exudative vitreoretinopathy and mild intellectual disability [38].

2. Molecular Genetics and Pathophysiology

2.1. The neurovascular unit and tight junctions

Tight junctions are multiprotein adhesion complexes between epithelial and endothelial cells that form a barrier to free paracellular transport; in cerebral vessels, together with pericytes and astrocytes, they constitute the blood–brain barrier. They are composed of claudins, occludin and proteins of the junctional adhesion molecule (JAM) family [15, 16]. These proteins are expressed at neurovascular junctions during angiogenesis, from early fetal life, and maintain the barrier in postnatal life [16, 25]. Neuropathology distinguishes two mechanisms of calcification in the developing brain: dystrophic calcification, through uncontrolled calcium entry into necrotic cells in ischaemia and infection, and vascular calcification, initiated in protein globules outside the endothelium of small vessels; in a study of 28 brains, from 22 weeks of gestation to 14 years, the case with OCLN variants had the vascular pattern, the same as in Sturge-Weber syndrome, and the authors suggest that pericytes initiate non-dystrophic calcification [68].

2.2. OCLN and occludin

The OCLN gene lies at 5q13.2 (GRCh38 5:69 492 547–69 558 104), has nine exons and an alternative non-coding first exon (1A) and encodes occludin, a protein of about 65 kDa with four transmembrane domains, two extracellular loops and a long C-terminal cytoplasmic tail [7, 16]. The transmembrane region corresponds to the MARVEL domain, conserved in proteins involved in membrane apposition; the tail contains the OCEL (occludin/ELL) domain, required for protein trafficking and barrier regulation [7]. Isoforms lacking the MARVEL domain, encoded by exons 3 and 4, remain in the cytoplasm and are not incorporated into tight junctions [16]. Occludin is not indispensable for junction formation, which depends mainly on claudins; it regulates the paracellular permeability of macromolecules and intracellular signalling [7, 16]. In the adult mouse, expression is prominent in layers 2 and 3 of the cerebral cortex and in Purkinje cells, a distribution that reproduces the calcification pattern of patients [16].

The structure of the locus has diagnostic consequences. There is a pseudogene (LOC647859) about 1.5 Mb downstream, with a copy of exons 6 to 9 within an inverted duplication of 500 kb, in a region devoid of probes on polymorphism microarrays [7, 16]. LeBlanc and colleagues described a rearrangement in which the pseudogene was translocated into exon 9, an exon present in all known isoforms; identification required multiplex ligation-dependent probe amplification (MLPA), targeted PCR and Sanger sequencing, because the exome only suggested the change through genotyping and read depth [21].

The mechanism is loss of function. Five of the six families in the founding study had deletions or variants affecting the MARVEL domain, which predicts a protein unable to reach the membrane [16]. The neuropathology of one patient showed diffuse gliosis, white matter loss and perisylvian polymicrogyria, with mineral deposits in the deep cerebral and cerebellar cortex around small vessels, in cells juxtaposed to the endothelium that may be pericytes or astrocytes; the endothelium, labelled by CD31, was adjacent to but not included in the calcifications, and there was no neuronal overmigration through the pia, unlike TUBB2B-associated polymicrogyria [16]. The proposed hypothesis is that a blood–brain barrier without functional occludin makes the brain vulnerable to immune cell-mediated injury in a critical developmental interval, around the fifth month of gestation, which is the window of formation of polymicrogyria of vascular or ischaemic cause; disordered signalling between cells of the neurovascular unit may contribute [14, 16]. The occludin-null mouse has postnatal growth retardation, chronic gastritis, thinning of compact bone, testicular atrophy and progressive calcification of the cerebellum and basal ganglia along the walls of capillaries and venules, but does not have the severe human neurodevelopmental picture, whereas the patients in the founding study did not have the extracerebral changes of the mouse, which suggests functional redundancy of occludin in other tissues [7, 16].

2.3. JAM3 and junctional adhesion molecule C

JAM3 lies at 11q25, has nine exons and more than 88 kb, and encodes JAM-C, a 310-amino-acid transmembrane glycoprotein of the immunoglobulin superfamily, with two Ig domains (V-type and C2-type), a transmembrane domain and a 46-amino-acid intracellular tail with a PDZ domain-binding motif [8]. The transcript is expressed mainly in the placenta, brain and kidney, and the protein is present in endothelial cells, platelets, activated T lymphocytes and NK cells; it binds strongly to JAM2 and to the leucocyte integrin MAC1 (ITGAM) [8, 69]. JAM-C participates in tight junction assembly, angiogenesis, transendothelial leucocyte migration, peripheral myelin integrity (Schwann cells), spermatid differentiation and lens development [8, 15]. Jam3-null mice have high postnatal mortality, megaoesophagus, growth retardation, tremor, pneumonia, cerebral haemorrhages, hydrocephalus, male infertility and nuclear cataracts with defective degradation of nuclei and organelles of lens fibres and activation of the unfolded protein response [8, 15].

The disease results from loss of function. The variants described include splicing, nonsense, frameshift, missense and start-codon loss changes [15]. The cellular studies of Akawi and colleagues showed three mechanisms: loss of the start codon prevents synthesis; p.(Cys219Tyr) disrupts a disulphide bridge that stabilises the Ig folds and retains the protein in the endoplasmic reticulum; p.(Glu116Lys) reaches the plasma membrane, but its position in the V-type Ig domain suggests loss of dimerisation or of interaction with partners [8, 62]. The high expression in platelets does not explain the haemorrhages: patients have no systemic bleeding diathesis and thrombocytopenia was recorded only in one patient with bacterial meningitis, so the injury is attributed to the cerebrovascular endothelium [17]. The conclusions of Mochida and colleagues point to JAM-C as necessary for the integrity of the cerebrovascular endothelium and for normal lens development [10]. The partner JAM2 reinforces the model: biallelic JAM2 variants cause early-onset autosomal recessive primary familial brain calcification (idiopathic basal ganglia calcification 8, OMIM 618824), and a 2026 study showed that these variants disturb the structure of the JAM2–JAM3 pair and the integrity of the blood–brain barrier (experimental data) [40, 70, 71].

2.4. RNASET2 and ribonuclease T2

RNASET2 lies at 6q27, is a single-copy gene with nine exons and about 27 kb, and encodes ribonuclease T2, the only human member of the Rh/T2/S family of acid ribonucleases, a 256-amino-acid glycoprotein with a signal peptide and three N-glycosylation sites, secreted and present in the endoplasmic reticulum and lysosomes [9]. The enzyme has optimal activity at pH 5 and cleaves single-stranded RNA, with a preference for polyuridine and polyadenine [9, 52]. It degrades microbial RNA into fragments recognised by the TLR8 receptor, generates TLR7 ligands and eliminates ribosomal RNA, including mitochondrial RNA; cerebral expression is strong in the temporal lobe and in the fetal brain [9, 52].

Loss of function leaves undegraded RNA in lysosomes, which activates nucleic acid sensors and produces neuroinflammation driven by type I interferon, with no measurable metabolite in blood or urine [52, 72]. In the Rnaset2−/− mouse, the cerebral phenotype is accompanied by an interferon-stimulated gene signature and depends on the IFNAR1 receptor; a 2025 study described microglial pyroptosis in this model [65, 73]. In zebrafish, microglia cannot digest developmental apoptotic cells, and it is this defect that drives the neuropathology [26, 74]. Henneke and colleagues suggested that congenital CMV and RNASET2 deficiency may disturb brain development and myelination through convergent mechanisms, linked to angiogenesis or RNA metabolism, which helps to understand the radiological similarity [18].

2.5. Inheritance

All three diseases are autosomal recessive, with transmission demonstrated in consanguineous families and in compound heterozygotes, and with asymptomatic heterozygous parents [1, 5, 10]. No manifestations have been described in heterozygous JAM3 carriers [15]. None of the sources consulted describes a second inheritance pattern for these genes.

2.6. Variant spectrum and nomenclature

The notation of variants in these genes requires care, because the literature uses different transcripts and some original descriptions do not match the reference sequence. Table 2.1 presents the most cited published variants, normalised in VariantValidator to the MANE Select transcripts (OCLN NM_002538.4; JAM3 NM_032801.5; RNASET2 NM_003730.6), with the historical nomenclature alongside [39, 75].

Table 2.1. Representative normalised variants

The JAM3 variant described by De Rose and colleagues as «c.690T>G p.C230W» on NM_001205329.1 corresponds, in that transcript, to p.(Ser230Arg) in VariantValidator; the published notation is internally inconsistent and should be re-read in the original report before any clinical use [15, 39]. No pseudodeficiency alleles, somatic mosaicism or risk variants have been described for these genes in the sources consulted. The OCLN variant c.173_194del may represent a founder effect or a mutational hotspot in Turkey, a hypothesis the authors left untested [76].

2.7. Genotype–phenotype correlations and modifiers

In OCLN, the classic variants lie in exons 3 to 6 or in the intron 5 donor, exons used by tissue-expressed isoforms; the exon 9 rearrangement, common to all isoforms, was associated with severe chronic kidney disease, and LeBlanc and colleagues proposed that loss of peripheral occludin explains the renal involvement [1, 21]. Renal dysfunction was later observed in other families, including the Turkish families with the c.173_194del deletion, and in 3 of 34 patients with variants demonstrated up to 2020 [14, 76, 77]. Cerebellar calcification, present in 8 of 13 Egyptian patients (61.5%), broadens the radiological phenotype [19].

In JAM3, missense variants are not associated with a milder phenotype than truncating ones, and the same variant produces different expressions within the same consanguineous family, so there is no useful genotype–phenotype correlation [15]. In RNASET2, age at onset ranged from 1 to 12 months and motor course from absent head control to independent walking, with no clear correspondence with variant type in the few patients described [9, 18].

2.8. Allelic disorders and genes of the same pathway

No Mendelian allelic disorders have been described for OCLN, JAM3 or RNASET2 in the sources consulted. Among the genes for endothelial adhesion proteins that produce overlapping phenotypes, ESAM and PCDH12 have their own subsections (2.9, 2.10, 3.6 and 3.7), and JAM2 and COL4A1/COL4A2 are covered in the differential diagnosis (section 6) [35, 45, 79].

2.9. ESAM and endothelial cell-selective adhesion molecule

ESAM (MIM 614281) encodes a transmembrane protein of the immunoglobulin superfamily, related to the junctional adhesion molecules, which localises to endothelial tight junctions and cooperates with claudins, mainly claudin 5, and with occludin in the formation and maintenance of the blood–brain barrier [36]. Expression is very high in the endothelium of retinal vessels, which relates to the frequency of retinal vascular anomalies in the disease, and complete loss of Esam in the mouse impairs angiogenesis [36]. With the c.115del variant, Lecca and colleagues showed that patients' endothelial colony-forming cells have much reduced in vitro tubulogenesis and that the capillary endothelium of the injured brain of a fetus does not express ESAM, which reproduces the data from the murine model [35].

The mechanism is loss of function. Most variants are truncating or splicing variants subject to nonsense-mediated messenger RNA decay; the c.731-2A>G variant causes skipping of exon 6, demonstrated in the patient's RNA, with a truncated protein predicted to escape this decay [44]. The first missense variant, c.561G>C p.(Trp187Cys), affects a conserved tryptophan and was classified as of uncertain significance by the authors themselves, despite compatible segregation and predicted protein destabilisation [36, 44]. Abdel-Salam and colleagues observed that haemorrhage is, on average, less destructive than in HDBSCC (subdural, germinal matrix, intraventricular and periventricular haemorrhages, rather than extensive multifocal haemorrhage with white matter liquefaction) and attribute this to redundancy of other endothelial adhesion molecules [44]. Inheritance is autosomal recessive with complete penetrance in the families described, almost all consanguineous, and intrafamilial variability is marked: in the same sibship, one sibling had progressive hydrocephalus and another only porencephaly with haemosiderin deposits [44]. There is no correlation between variant type and severity [44]. ESAM lies in the terminal region of the long arm of chromosome 11 included in several deletions and duplications recorded in ClinVar as pathogenic for other reasons, which justifies copy-number analysis when only one point variant is found [80].

2.10. PCDH12 and protocadherin 12

PCDH12 (MIM 605622) encodes a non-clustered protocadherin of 1184 amino acids, with six extracellular cadherin domains, a transmembrane domain and an intracellular domain, identified in endothelial cells, where it concentrates at intercellular junctions and promotes adhesion [37]. It is also expressed in neural precursor cells derived from induced pluripotent stem cells, and patients' cells, lacking the protein, have shorter neurites [37]. In cortical organoids, loss of PCDH12 reduces the proliferative zones, disorganises lamination, brings forward cell-cycle exit and progenitor differentiation and impairs neuronal migration, possibly through cleavage of the ectodomain by ADAM10 (experimental data) [81]. Tractography shows corticospinal tracts that originate in the cortex but terminate early or follow a lateral course, and the thin corpus callosum does not worsen with age, which indicates a developmental defect of the tracts rather than atrophy [37, 67]. Calcification has a subcortical and perithalamic pattern, different from primary familial brain calcification and close to that of intrauterine infections; prenatal perithalamic hyperechogenicity suggestive of tortuous vessels and the arterial changes of the Pcdh12-null mouse point to a vascular component [38, 41].

All variants published up to 2022 were biallelic loss-of-function variants, distributed along the protein; the three variants tested in cells produced no protein [37, 38]. In 2026, a preprint described three children from two families with compound heterozygous missense variants, each with one allele in the extracellular domain and the other in the intracellular domain, with phenotypes similar to those of truncating variants and visual impairment in all (data not peer reviewed) [82]. There is no genotype–phenotype correlation: the neighbouring variants p.(Trp808Ter) and p.(Gln813Ter), in the cytoplasmic domain, caused respectively the most severe form, with refractory neonatal epilepsy, and the mild adult form with ataxia and retinal detachment; within each family the phenotype is similar, which suggests genetic modifiers [38]. Penetrance is complete in the homozygotes described [37]. In a screen of 53 patients with primary familial brain calcification and 26 with calcification of unknown cause, there were no truncating variants and only three rare heterozygous missense variants, without segregation data, so PCDH12 heterozygosity is not an established cause of calcification in adults [41]. The GSX2 form of DMJD (DMJDS2), with agenesis or hypoplasia of the basal ganglia, is a distinct disease of the same malformative group [83].

Table 2.2 presents the published ESAM and PCDH12 variants, normalised in VariantValidator to the MANE Select transcripts (ESAM NM_138961.3; PCDH12 NM_016580.4) [39].

Table 2.2. Normalised ESAM and PCDH12 variants

The 2026 review on ESAM also lists a c.60T>G variant that does not match the reference base of NM_138961.3 in VariantValidator and which, therefore, was not normalised [36, 39].

3. Clinical Spectrum and Manifestations by System

3.1. Common syndromic description

The three entities share a clinical core: brain injury with prenatal onset or onset in the first months, microcephaly (congenital or acquired), epilepsy, spasticity and severe developmental delay, with intracranial calcification and white matter injury on imaging, in a context of negative or inconclusive serologies and congenital infection tests [51, 86]. They differ in the tissue primarily affected and in the timing of injury: BLC-PMG is a malformation of cortical development with perivascular calcification, HDBSCC is a destructive haemorrhagic disease with cataracts, and RNASET2-related disease is a static cystic leukoencephalopathy with hearing loss [15, 16, 18]. The available data come from small series and case reports, almost always of consanguineous families, and describe mainly the natural history, because there is no disease-modifying therapy.

3.2. Band-like calcification with simplified gyration and polymicrogyria (OCLN)

Presentation. The disease manifests at birth or shortly afterwards with epileptic seizures, feeding difficulties, microcephaly, tetraparesis and bulbar palsy [51]. In the founding series of 10 patients from 6 families, all had severe microcephaly, seizures beginning in the first 4 months, minimal developmental progress and spastic tetraparesis; head circumference at birth ranged from +1 to −3 standard deviations (SD) and fell early and persistently, to values between −2.5 and −8 SD at reassessment [16]. The Egyptian series of 13 patients from 10 families confirmed the classic phenotype of severe microcephaly, failure to acquire skills, growth retardation and calcification of the cortex, thalami, basal ganglia and pons [19]. Briggs and colleagues noted that their patients had no thrombocytopenia, hepatosplenomegaly or congenital microcephaly, unlike some old cases of «pseudo-TORCH», and that the microcephaly was postnatal [1, 58]. Abdel-Salam's Egyptian siblings had congenital microcephaly, growth retardation, generalised tonic-clonic seizures, nystagmus, spasticity and facial dysmorphism (sloping forehead, bitemporal grooves, anteverted nares, high-arched palate, micrognathia); two died within days, with high fever and status epilepticus, and three in the first years [1, 59].

Neuroimaging. CT shows a symmetrical, continuous or semi-continuous band of calcification of the deep cortical grey matter, distributed in the posterior frontal, perisylvian, anterior temporal and anterior parietal regions, with symmetrical calcification of the thalami, globus pallidus and basal ganglia and sometimes of the central pons [1, 51]. MRI shows severe loss of brain volume, simplified gyration, very primitive sulcation, wide Sylvian fissures and bilateral symmetrical polymicrogyria of perisylvian, temporal and predominantly frontoparietal distribution; serial examinations document progressive atrophy, for example between 2 weeks and 9 months in the same patient [16]. Cerebellar calcification was present in 8 of 13 Egyptian patients (61.5%), and there is hypoplasia of the cerebellum, brainstem and corpus callosum, with a brain appearance described as «hourglass» [19, 87]. Two siblings had occipital scalp rugae, a sign of fetal brain disruption [16].

Cerebrospinal fluid. In four of five patients studied, protein was raised (for example, 1021 mg/L at one month, 824 mg/L at 3 months and 666 mg/L at 4 months in the same patient, and 1260 mg/L at 3 days in another; reference 100–200 mg/L), with a normal white cell count; interferon-α in CSF and serum, measured in one patient, was normal [16]. This profile differs from the lymphocytosis and raised interferon-α of early AGS [12].

Extracerebral involvement. In the founding study there were no extracerebral anomalies, but renal dysfunction later emerged as a relevant manifestation: advanced chronic kidney disease in early childhood with small echogenic kidneys in the Canadian family with the exon 9 rearrangement, renal dysfunction in Indian siblings, kidney failure in Turkish families with the c.173_194del deletion and, in a Turkish boy, central diabetes insipidus responsive to desmopressin and renal dysfunction [14, 21, 76, 77]. Ekinci and colleagues counted 3 patients with renal manifestations among 34 with demonstrated variants and attributed most deaths in this subgroup to kidney disease [14]. Imperforate anus and cryptorchidism occurred in one Egyptian patient, and some patients had mild hepatomegaly [16, 19]. Cortical visual impairment was recorded in the Canadian family [1].

Course. Children do not acquire walking, hand use or language; epilepsy is frequently drug-resistant [1, 14]. Death occurred in the first days or years in several families, from status epilepticus, fever or sepsis, as in the Turkish boy who died at 4 years [14, 59].

3.3. Haemorrhagic destruction of the brain, subependymal calcification and cataracts (JAM3)

Presentation. The picture is defined by recurrent parenchymal and ventricular haemorrhages that begin in utero and continue in infancy, associated with dense central cataracts present at birth [15]. In Mochida's family, eight affected individuals had congenital cataracts and haemorrhagic destruction of the white matter and basal ganglia, with profound delay, seizures, spasticity and hyperreflexia; three died in early childhood [10, 61]. In Akawi's three families, the phenotype was homogeneous, with intracranial haemorrhage of neonatal onset, calcification and neurological deterioration, cataracts in all and death in childhood in all patients; there were stillbirths or unexplained neonatal deaths in the history of two families [10, 62]. The typical neonatal presentation includes irritability, excessive startle, hypotonia, apnoea and seizures in the first hours or days, progressing to status epilepticus [15]. The 2024 review counted about 20 patients with a probable or definite diagnosis [15].

Neuroimaging. Parenchymal haemorrhage is typically located in the periventricular zone and is almost always accompanied by intraventricular haemorrhage, in a pattern similar to that of severe germinal matrix haemorrhage of the preterm infant, but in term newborns, without infection or perinatal complication, more massive and destructive and beginning before birth [15]. Liquefaction, massive cystic degeneration, porencephaly, volume loss and ventriculomegaly follow, sometimes with communicating hydrocephalus that required ventriculoperitoneal shunting; other patients progress to microcephaly [15, 61]. Calcification is subependymal and parenchymal, also cortical and cerebellar, and is present in all patients described; CT shows it better, whereas MRI better shows haemorrhages at different stages [15, 17]. There is no primary cortical malformation, and the midbrain, pons and cerebellum may be thinned [10]. Radiological expression varies between siblings with the same variant [15].

Eye. The cataracts are central and dense, sometimes nuclear, isolated or with microphthalmia and nystagmus; in one case attenuated retinal vessels, optic atrophy and retinal haemorrhage appeared, and in another posterior capsule opacification recurred twice after lens aspiration with posterior capsulotomy and anterior vitrectomy [15, 17]. The cataracts prevent assessment of the posterior segment and may conceal other lesions [15, 88].

Other systems. Hepatomegaly, renal anomalies (ectopic kidney, cystic renal dysplasia, echogenic cortex, pelvicalyceal dilatation), myocardial hypertrophy, megaoesophagus, growth retardation, evolving dysmorphism and, in one patient, auditory neuropathy have been described [10, 15, 17].

Course. Mortality is high, in utero or in the first days to months; survivors have spastic tetraparesis, epilepsy, progressive microcephaly and severe visual impairment, like the young Pakistani woman described at 14 years or the Bedouin child alive at 30 months [15, 17].

3.4. Cystic leukoencephalopathy without megalencephaly (RNASET2)

Presentation. Newborns are usually asymptomatic; in the first year a static encephalopathy appears with normocephaly or microcephaly and psychomotor impairment, accompanied by seizures and sensorineural hearing loss [5, 18]. In the series of 15 children by Henneke and colleagues, 6 were normocephalic and 9 microcephalic; most walked with support, some only sat or crawled and most did not speak; there were seizures, spasticity, athetoid movements, dystonia, nystagmus and hearing loss, and three children had a «doll-like face»; the course was stable or very slowly progressive [5, 64]. In patients with molecular confirmation, age at onset ranged from 1 to 12 months; a Turkish girl walked without support and had intelligible speech at 4 years, whereas a Spanish boy had no head control at 2 years [9]. Orphanet describes the disease as non-progressive [11].

Neuroimaging. MRI shows bilateral subcortical cysts in the anterior part of the temporal lobe, enlarged temporal horns, multifocal lobar white matter lesions with abnormal myelination around the cysts, symmetrical frontal and occipital periventricular lesions and sparing of the central white matter structures; CT shows calcifications in some patients, periventricular, in the deep white matter and in the basal ganglia [18, 64, 87]. There are exceptions, such as the Chinese child without temporal cysts or hearing loss [24].

Overlap with AGS. Tonduti and colleagues described five patients with an AGS-like phenotype, all with biallelic RNASET2 variants, and concluded that the two diseases should be included in the same differential diagnosis [66].

Course. Five of the seven patients in the 2009 study were older than 10 years and all retained psychomotor delay with variable ability to sit or walk and poor speech [5, 18]. The Iranian girl of Kameli and colleagues had tonic spasms at 3.5 months, motor regression, microcephaly and spastic tetraparesis, partially improved head control and social interaction between 13 and 22 months, needed a nasogastric tube for bulbar dysfunction and remained at Gross Motor Function Classification System (GMFCS) level 4 of 5 at 31 months [72].

3.5. Comparative overview

Table 3.1. Comparison of manifestations

3.6. Neurodevelopmental disorder with intracranial haemorrhage, seizures and spasticity (ESAM)

2023 cohort. The 13 individuals of Lecca and colleagues, of Turkish, Algerian, Spanish and Arab Bedouin origin, came from almost entirely consanguineous families; 7 of 13 had prenatal hydrocephalus, and among the 9 liveborn individuals assessed weight was below the 10th centile in 7 of 9, height in 8 of 8 and head circumference in 4 of 9 [35, 44]. All nine had spasticity, hyperreflexia, severe global delay and epilepsy (focal, generalised tonic-clonic and myoclonic seizures, with hypsarrhythmia in 2 of 9); imaging showed intracranial haemorrhage and ventriculomegaly in 9 of 9, hydrocephalus in 7 of 9, calcifications in 8 of 9, abnormal myelination in 5 of 9 and porencephaly or leukomalacia in 3 of 9 [44]. There were two deaths in childhood (at 15 months and at 5 years), three terminations of pregnancy and one stillbirth [44]. The dysmorphic features, non-specific, included bitemporal narrowing (6 of 9), arched eyebrows and bulbous nasal tip (5 of 9) and long eyelashes (4 of 9) [44]. Other imaging findings were focal white matter lesions, thin corpus callosum and variable microcephaly [36].

2025 Egyptian series. Four patients from two families showed that the age at haemorrhage and the course vary: a girl with ventriculomegaly at 30 weeks needed a shunt at 2 weeks, had several shunt infections, subdural haemorrhage at 3–6 months and seizures at 6 months, and died at 14 months with unexplained thrombocytopenia and cerebral haemorrhage; her brother had progressive postnatal hydrocephalus, seizures from 1 year and died at 5 years in a context of fever and seizures; the third sibling, seizure-free at 3.5 years, had porencephaly, haemosiderin deposits, spastic tetraparesis, optic atrophy and retinal vascular tortuosity; and a girl from another family, with hydrocephalus at 27 weeks, had multifocal parenchymal haemorrhages, a shunt at 5 months, seizures from 1 year and subdural haemorrhage at 18 months, with normal platelets and haemostasis studies [44]. The obesity of one of the siblings was explained by a heterozygous MC4R variant inherited from the mother, a reminder that atypical findings may have a second genetic cause [44]. The authors ask whether the risk of new haemorrhages persists throughout life and from what age it can be considered low; the published data do not answer this question [44].

Eye. In the 2026 review, 10 of 22 patients (45%) had ocular manifestations, mainly retinal: in the 2023 cohort, 5 of 13, with retinal ischaemia (4 of 5), retinal haemorrhage (2 of 5), arterial tortuosity (2 of 5), fibrovascular proliferation (2 of 5) and retinal detachment (1 of 5) [36]. Later reports added optic atrophy, exotropia and a negative electroretinogram in a Saudi patient, a pale optic disc in two Egyptian patients, bilateral congenital cataracts in Turkish patients and, in an Albanian boy, optic nerve hypoplasia, total retinal detachment with phthisis of the left globe, spherophakia and an avascular peripheral retina with thin tortuous vessels resembling familial exudative vitreoretinopathy (FEVR) [36, 84]. In a newborn girl of 35 weeks, bilateral extraretinal fibrovascular proliferation with peripheral ischaemia and vitreous haemorrhage was present on the second day of life, without extreme prematurity or oxygen therapy, and her brother had lost an eye to total retinal detachment at 3 months [48]. Ophthalmological examination was not systematic in all patients, so the true frequency may be higher [36].

Other systems. Renal vascular morphology was abnormal in one of nine patients assessed (11%), and hypertrophic cardiomyopathy was diagnosed during the follow-up of one child [44, 48]. Bilateral clubfoot and auditory hypersensitivity appeared in the first year in the Albanian boy [36].

3.7. Diencephalic-mesencephalic junction dysplasia 1 (PCDH12)

Severe congenital form. In the ten Palestinian patients of Aran and colleagues, the disease manifested in utero with cerebral hyperechogenic foci, microcephaly and intrauterine growth restriction; after birth, the microcephaly worsened, neonatal seizures appeared and practically no developmental milestones were acquired, and imaging showed elongated dysplastic masses in the region of the midbrain, hypothalamus and optic tract, in a picture similar to AGS and intrauterine infection [45]. In the Guemez-Gamboa series, with 14 patients from 8 families, aged between 18 months and 6 years, all had microcephaly (−1.5 to −8.7 SD; 78% between −3 and −6 SD) and profound psychomotor delay; head circumference at birth, known in 7, was only between −0.6 and −1.5 SD, which indicates predominantly postnatal microcephaly [37]. No patient walked or acquired language; there was epilepsy in 76%, usually beginning before 3 months, with tonic, atonic, tonic-clonic and focal seizures partially controlled, recurrent fever without cause in 64%, vasomotor instability in 57%, ataxia in 42%, hyperreflexia in 64%, autistic traits in 28%, strabismus and dysphagia in 28% each and facial dysmorphism (low-set ears, broad nasal root, long smooth philtrum, broad chin, thin upper lip) in 85% [37]. In Zaki's original series, with six Egyptian patients, there were also clubfoot, non-obstructive cardiomyopathy and persistent hyperplastic primary vitreous in two families, and shunting of one patient with dilated ventricles did not change ventricular size, which indicates dysplasia rather than obstruction [67].

Neuroimaging. The twelve patients of the 2018 series with imaging had a brainstem malformation, with the «butterfly» sign (anterior midbrain cleft continuous with the third ventricle) most evident in the original families, frequent thin corpus callosum, ventriculomegaly in 57%, preserved cerebellum and pons and normal vascular flows; CT showed subtle calcifications in 6 of 7 patients [37]. In the review of 29 patients, brain malformations were present in 18 of 22, calcifications in 13 of 18, thin corpus callosum in 10 of 22 and ventriculomegaly in 11 of 22; medullary dysplasia and the Dandy-Walker spectrum were described in a Syrian sibship, and CT of two adults with the mild form was normal [38]. An Indian series of 2026, with four children, showed DMJD with the «butterfly» sign, enlarged lateral ventricles, hypoplasia of the corpus callosum and dysmorphic basal ganglia, without calcifications [43].

Broadened spectrum. The 2022 review found microcephaly in 23 of 29 patients, intellectual disability in 24 of 26, speech disorder in all, spasticity in 18 of 26, ataxia in 14 of 26, dystonia in 10 of 26, epilepsy in 18 of 25 and dysmorphism in 21 of 25, and episodes of sterile fever in 9 patients, in one case accompanied by transient loss of motor skills [38]. The published pictures include dyskinetic cerebral palsy with multifocal epilepsy and severe intellectual disability, without mesencephalic dysplasia or microcephaly, in a Japanese child with compound heterozygosity, and a picture of mild cerebral palsy in two siblings, one with partial fusion of the hypothalamus and midbrain and the other with normal MRI [83, 89]. At the other end, an Indian sibship had cerebellar ataxia, dystonia, exudative retinopathy and dysmorphism, and two adult Iranian siblings had mild intellectual disability, microcephaly, ataxia, dystonia with camptocormia and rhegmatogenous retinal detachment [38, 90]. In a patient of Afghan origin, epilepsy began at 2.5 years, the first description of onset after the first year [38].

Eye. Exudative vitreoretinopathy, resembling FEVR, is part of the phenotype: it was described with the typical DMJDS1 picture, with basal ganglia anomalies, in sibships with asynchronous presentation and in a 14-year-old boy with extensive retinal neovascularisation, exudates, dragging of the temporal vessels, avascular peripheral retina and fibrotic bands, treated with sequential laser photocoagulation [46, 49, 91]. Bilateral optic atrophy was found in three children without retinopathy, which suggests a direct effect on the visual pathways [38].

Interferon. In three children, the interferon score was markedly raised in one and slightly raised in another; the authors consider the finding insufficient to include the disease among the interferonopathies [38].

Table 3.2. NEDIHSS and DMJDS1 compared with HDBSCC

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Suspicion arises from a child with a picture of congenital infection in which infection is not confirmed. The Oxford Desk Reference advises thinking of the autosomal recessive pseudo-TORCH condition when there are signs of congenital infection without positive serology or an identified virus, and recalls that genetic conditions can mimic environmental causes of microcephaly [3, 53, 54]. In fetal ventriculomegaly, pseudo-TORCH syndrome enters the differential because of intracranial calcification, usually with a small head circumference [92]. The AGS GeneReviews stresses that excluding TORCH infections is the most important step, because the error leads to wrong recurrence counselling [12].

4.2. Clues from the history and examination

The history should look for affected siblings, unexplained fetal or neonatal deaths, stroke or cataract in the family, consanguinity, pregnancy and delivery history, weight and head circumference at birth, neonatal seizures, fever, coagulopathy, hepatosplenomegaly and visual and hearing loss [51, 62]. On examination, chorioretinopathy and deafness suggest congenital infection; cataract or microphthalmia suggest JAM3, COL4A1 or ESAM; chilblains suggest AGS; and occipital scalp rugae or a collapsed skull suggest fetal brain disruption [16, 51, 84, 93].

4.3. Signs by age and context

Table 4.1. Warning signs

4.4. Emergency signs

The situations that require immediate action are status epilepticus, acute intracranial haemorrhage with hydrocephalus (bulging fontanelle, vomiting, high-pitched cry, rapid increase in head circumference) and bulbar dysfunction with risk of aspiration [15, 17, 72]. In NEDIHSS, irritability with projectile vomiting and a bulging fontanelle heralded subdural haemorrhages and hydrocephalus up to 18 months, and shunt infection with ventriculitis required repeated revisions; in a newborn sibling of a patient with retinal detachment, ophthalmological examination in the first days made it possible to treat the retina before detachment [44, 48]. In BLC-PMG, high fever with status epilepticus preceded the death of two newborns, and sepsis was the cause of death in a patient with kidney disease [14, 59].

4.5. Newborn screening

There is no biochemical newborn screening for these diseases, because none has a metabolic marker [25, 52]. The dried blood spot collected for newborn screening nevertheless plays a decisive role in the differential diagnosis: it is the sample that allows retrospective detection of CMV DNA in a child who is already past the first three weeks of life [23, 51].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no consensus-validated diagnostic criteria for any of the three diseases, and no specific guideline was found in searches of PubMed and Europe PMC; diagnosis rests on the clinical and radiological pattern, the exclusion of congenital infection and the identification of biallelic variants in the respective gene [15, 25, 52]. The historical clinical criteria of Vivarelli and colleagues for Baraitser-Reardon syndrome predate the molecular era and do not distinguish the entities now separated [3, 12]. In practice, three combinations are almost specific: a band of cortical calcification with symmetrical polymicrogyria and progressive microcephaly and negative TORCH for OCLN; congenital cataracts with cerebral haemorrhage of fetal or neonatal onset and negative TORCH for JAM3; and anterior temporal cysts with multifocal leukoencephalopathy, without megalencephaly, with unproven CMV, for RNASET2 [15, 18, 25]. None of these combinations identifies the gene without molecular confirmation, because pseudo-TORCH type 2 and AGS produce overlapping pictures [25, 66].

5.2. Neuroimaging

CT has the highest sensitivity for calcification and remains the reference examination; MRI, usually the first examination, may not show even extensive calcification, so the Oxford Desk Reference recommends considering CT in any child with unexplained neurological disease, especially with leukoencephalopathy [51]. Gradient echo and susceptibility-weighted sequences are more sensitive than T1 and T2 for haemorrhage and mineralisation, and it may be impossible to separate haemorrhage from calcification on a single examination; follow-up shows resolution of haemorrhage [51]. In BLC-PMG, the two techniques complement each other: CT shows the cortical band and the thalamic, pontine and cerebellar calcifications, and MRI shows the simplified gyration and the polymicrogyria [25, 51]. In HDBSCC, MRI shows haemorrhages at different stages and CT the subependymal calcifications; serial transfontanellar ultrasound documents rapid destruction in the first months [15]. The Oxford Desk Reference advises seeking the opinion of a paediatric neuroradiologist before other investigations, because many patterns are recognisable and avoid unnecessary tests [51].

5.3. Initial laboratory investigation

The investigation recommended for intracranial calcification includes urea and electrolytes; calcium, phosphate and parathyroid hormone; congenital infection serology; CMV PCR on the neonatal dried blood spot; urinary organic acids and amino acids; plasma lactate and amino acids; CSF studies (cells, protein, lactate, interferon-α and pterins); and genomic analysis (microarray, panel or exome or genome sequencing), with DNA storage [51]. None of the three diseases has a biochemical biomarker [25, 52, 69]. In BLC-PMG, CSF protein is raised with normal cellularity and interferon-α [16]. In AGS, the CSF shows lymphocytosis and raised interferon-α, which tend to normalise in the first years, and the interferon signature in blood serves as a biomarker [12, 95]. In HDBSCC, xanthochromic CSF with protein of 236 mg/dL and glucose of 21.7 mg/dL was described, findings of haemorrhage and not of infection [17].

5.4. Exclusion of congenital cytomegalovirus

Exclusion of CMV is the step that converts the radiological pattern into a genetic diagnosis and, at the same time, the one most prone to error [25, 52]. The 2024 European consensus of the European congenital infection initiative (ECCI) recommends confirming congenital infection by CMV PCR on a sample collected in the first three weeks of life (grade D), because after that period detection of the virus does not distinguish congenital infection from infection acquired after birth [23]. For retrospective diagnosis, it recommends CMV PCR on the newborn screening dried blood spot (grade A), noting that the negative predictive value depends on the sensitivity of the assay; in a meta-analysis of 15 studies with 26,007 newborns, sensitivity was 84.4% (95% confidence interval [CI] 81.2–87.2) and specificity 99.9%, and the blood viral load is lower than in saliva and urine [23, 52, 96]. A negative result does not exclude congenital CMV and a positive one does not exclude a Mendelian disease: in the founding OCLN study, a child with normal serology at birth had a positive urine CMV PCR at 4 months, interpreted as postnatal infection, and Briggs's two Turkish siblings had serology suggestive of early postnatal infection [1, 16]. Retrospective maternal serology on stored first-trimester serum helps to date maternal infection [23]. Chorioretinitis favours infection [51, 52].

5.5. Targeted assessments

Ophthalmological examination with biomicroscopy and fundoscopy is indispensable: cataracts point to JAM3 (and also COL4A1 or ESAM), and chorioretinitis to infection [15, 79, 84]. Audiological assessment with otoacoustic emissions and auditory brainstem evoked potentials identifies the sensorineural hearing loss of RNASET2-related disease and of CMV and the auditory neuropathy described in HDBSCC, which otoacoustic emissions alone do not detect [17, 52]. The electroencephalogram characterises the epilepsy. Renal function (creatinine, electrolytes, urine sediment and renal ultrasound) and plasma and urine osmolality are justified in BLC-PMG by the renal involvement and central diabetes insipidus described [14, 77].

5.6. Genetic testing: choice of technique and limitations

OCLN. The locus is technically difficult: the downstream pseudogene and the frequency of copy-number variants (CNV), including the founder deletion of exons 3 and 4 and exon 9 rearrangements, mean that exome or panel sequencing may miss the causal allele; Jenkinson and colleagues proposed a comprehensive strategy combining sequencing with copy-number analysis and attention to the pseudogene, and in the Canadian case MLPA, targeted PCR and Sanger sequencing were needed [20, 21, 25]. The homozygous deletions of exons 3–4 were detected by polymorphism microarray and confirmed by PCR [16].

JAM3. Splicing variants, including the founder intron 5 variant, and a deep intronic variant (NM_032801.5:c.256+1260G>C) not detectable by standard exome have been described; genome sequencing with confirmation of the effect on RNA established the diagnosis of a 7-year-old boy with an inconclusive exome [22, 61]. When the phenotype is suggestive and the exome negative, the genome is the next step, with the limitations of the lack of consensus on splicing predictors and of access to validated RNA studies [22].

RNASET2. Intragenic deletions (2.5 kb including exon 2) and 6q27 microdeletions (430 kb, detected by exome read depth) add to the point variants, so the analysis should include CNV [9, 24]. As the differential includes RMND1 and the AGS genes, a leukodystrophy panel or the exome with CNV analysis are preferable to the study of a single gene [66, 72, 94].

General limitations. A negative result does not exclude the disease when the technique does not cover CNV, regions homologous to pseudogenes, deep introns or structural variants; the proportion of variants detectable by a technique is not equivalent to clinical sensitivity, which has not been estimated for any of these genes [20, 22]. Mosaicism has not been described.

5.7. Report content and interpretation

The report should state the gene, the reference transcript with version (MANE Select: NM_002538.4, NM_032801.5 or NM_003730.6), the variant in HGVS notation at DNA and protein level, the zygosity, the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and the method, with coverage of CNV and homologous regions [39]. Compound heterozygosity requires segregation studies in the parents to confirm phase. Variants of uncertain significance (VUS) are frequent: ClinVar recorded, for RNASET2, 62 pathogenic variants, 7 likely pathogenic and 84 VUS (submission count, not prevalence) [52]. Historical nomenclature should be converted to the MANE transcript with validated tools (see Table 2.1).

5.8. Practical algorithm

1. Child with microcephaly, seizures, intracranial calcification or leukoencephalopathy: MRI and CT; review by a paediatric neuroradiologist [51].
2. Exclude infection: CMV PCR on urine or saliva if younger than 3 weeks; neonatal dried blood spot if older; TORCH, Zika and other serologies according to the epidemiology; fundoscopy [23, 51].
3. Read the pattern: cortical band with polymicrogyria → OCLN; haemorrhage with cataracts → JAM3 (and ESAM, COL4A1/2); temporal cysts with leukoencephalopathy → RNASET2 (and RMND1, AGS); calcification with leukoencephalopathy, inflammatory CSF and interferon signature → AGS and interferonopathies [12, 15, 16, 18].
4. Genetic testing: exome or broad panel with CNV analysis; targeted study of OCLN with methods that circumvent the pseudogene if the pattern is typical; genome and RNA if the exome is negative [20, 22].
5. Confirm segregation in the parents and begin genetic counselling.

5.9. Prenatal and preimplantation diagnosis

With the familial variants known, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible for the three diseases [25, 52, 97]. Without known variants, ultrasound is limited. In HDBSCC, cataracts were visible at 23 weeks and progressive ventriculomegaly in the third trimester, but in another fetus MRI at 20 weeks was normal and the disease manifested after birth; De Rose and colleagues propose including JAM3 in the prenatal investigation of fetal congenital cataracts and in sequencing panels [17, 97]. In China, fetal intraventricular haemorrhage at 24 weeks and ventriculomegaly at 29 weeks led to the diagnosis in siblings with compound heterozygosity [78]. In BLC-PMG, fetal MRI allowed diagnosis in utero in an Egyptian sibling, but in recurrent primary microcephaly head circumference may fall only between 32 and 36 weeks, which makes ultrasound unreliable [3, 59].

5.10. Diagnosis of NEDIHSS and PCDH12-related disease

There are no formal criteria for either disease. In NEDIHSS, diagnosis rests on the combination of prenatal or early-infancy intracranial haemorrhage, ventriculomegaly, calcifications and severe delay, with congenital infection, fetal alloimmune thrombocytopenia, coagulopathies and COL4A1/COL4A2-related diseases excluded, and on the identification of biallelic ESAM variants [35, 47]. The French series of 113 fetuses with intracranial haemorrhage and negative COL4A1/COL4A2 justifies whole-exome sequencing, with analysis of biallelic and de novo variants, rather than restricted panels, because the yield was 8% spread across genes of different pathways [47]. ESAM was not included in the main retinal disease panels in 2026, and the authors of the review recommend including it, which means that a negative retinopathy panel does not exclude the disease [36]. Fundoscopy, ideally with fluorescein angiography, should be performed at diagnosis, because a finding of avascular peripheral retina or ischaemia changes ophthalmological management [36, 48]. Full blood count with platelets and haemostasis studies exclude haematological causes of haemorrhage and should be repeated when new haemorrhages occur [44].

In DMJDS1, MRI with thin axial sections of the midbrain looks for the «butterfly» sign, tractography may show the abnormal course of the corticospinal tract and CT detects subtle calcifications that MRI does not show; absence of malformation does not exclude the disease, because several children and all adults described with the mild form had imaging without dysplasia [37, 38]. The exome is the first-line test, because the phenotypes overlap with those of dyskinetic cerebral palsy, early-onset epilepsies and the interferonopathies [38, 89]. The interferon score may be raised and neither excludes PCDH12-related disease nor confirms an interferonopathy [38].

In both diseases, the report should state the MANE Select transcript (ESAM NM_138961.3; PCDH12 NM_016580.4), the zygosity and the ACMG/AMP classification. Splicing variants close to the exon, such as c.451+5G>C and c.731-2A>G in ESAM, benefit from RNA studies, which confirmed exon 6 skipping for the latter; missense variants, such as c.561G>C in ESAM and those described in PCDH12 in 2026, remain of uncertain significance without functional data or additional segregation [36, 44, 82]. The nomenclature of some PCDH12 variants published in 2018 does not match the current transcript and should be converted with validated tools (Table 2.2) [37, 39]. When only one variant is found, copy-number analysis should complement sequencing; for ESAM, the terminal region of 11q is affected by deletions and duplications recorded in ClinVar [80]. The clinical sensitivity of the tests has not been estimated for either gene.

6. Differential Diagnosis

6.1. Principles

Almost any pathological process can cause intracranial calcification; the diagnostic value lies in the pattern and distribution of the calcification and in the associated findings, such as cortical malformations, leukoencephalopathy or cysts [51]. In about half of paediatric cases calcification occurs in an injured, neoplastic or malformed brain, and congenital infection, especially CMV, accounts for a significant proportion; AGS, band-like calcification and RNASET2-related disease mimic infection, so systematic review of imaging and clinical features should precede the conclusion of an infectious cause [86]. Table 6.1 brings together the entities of the class and the main differentials.

Table 6.1. Differential diagnosis of genetic phenocopies of congenital infection

6.2. BLC-PMG and AGS

This distinction is the most frequent in practice, because several patients in the founding OCLN study were referred as possible AGS [16]. Polymicrogyria has never been described in AGS and is the finding that separates the two diseases; the CSF in BLC-PMG has raised protein without lymphocytosis or raised interferon-α, whereas AGS has lymphocytosis and raised interferon-α in the CSF in the first years and an interferon signature in blood [12, 16, 95]. Thrombocytopenia, hepatic dysfunction and hepatosplenomegaly at birth, which were attributed to classic pseudo-TORCH, also occur in neonatal AGS, especially due to TREX1 [12, 95].

6.3. HDBSCC, ESAM and COL4A1/COL4A2

The combination of cataracts with cerebral haemorrhage beginning in utero is almost pathognomonic of HDBSCC once infection has been excluded [15, 17]. Two entities, however, require the work-up to be broadened. COL4A1- and COL4A2-related disorders are autosomal dominant, with penetrance close to 100% and variable expressivity, and combine antenatal or perinatal haemorrhage, porencephaly, leukoencephalopathy and frequent congenital cataract; they are distinguished by inheritance, by the presence of findings in apparently healthy parents (silent lesions on MRI, retinal tortuosity, haematuria) and by the renal and muscular manifestations [79]. ESAM deficiency, described in 2023 in 13 individuals from 8 families and expanded in 2026, combines fetal intracranial haemorrhage, ventriculomegaly, calcifications, epilepsy and spasticity and, in some families, congenital cataracts and retinal vascular anomalies, which brings it close to HDBSCC [35, 36, 84]. In a French series of 113 fetuses with intracranial haemorrhage and negative COL4A1/COL4A2, the exome found a causal variant in 9 (8%), in genes of platelet production, haemostasis, endothelial adhesion (ESAM) and mitochondrial metabolism, which shows the heterogeneity of the group and favours whole-exome analysis [47]. Pseudo-TORCH type 2 (USP18) also begins with prenatal intracranial haemorrhage, but is accompanied by hepatic dysfunction, thrombocytopenia and respiratory failure, without cataracts [31, 87]. Between HDBSCC and NEDIHSS, extensive multifocal haemorrhage with white matter liquefaction and dense cataracts at birth favour JAM3, whereas subdural and germinal matrix haemorrhages, haemorrhages appearing after the neonatal period and vascular retinopathy favour ESAM; the overlap is sufficient for only genetic testing to distinguish them [36, 44].

6.4. RNASET2-related disease, CMV, AGS and RMND1

RNASET2-related disease is clinically and radiologically indistinguishable from congenital CMV asymptomatic at birth, sharing anterior temporal cysts, multifocal white matter lesions, calcifications and hearing loss [18, 51]. The distinction depends on the timing of CMV testing and on genetics: after three weeks of life, only the dried blood spot allows retrospective diagnosis, with imperfect sensitivity [23]. Chorioretinitis suggests infection [52]. AGS shares temporal cysts and calcification and, in five patients with RNASET2 variants, the phenotype resembled AGS [66]. RMND1 leukoencephalopathy also produces temporal cysts with hearing loss, but is accompanied by lactic acidosis and myopathy [94]. The absence of megalencephaly separates the disease from megalencephalic leukoencephalopathies with subcortical cysts [5, 52].

6.5. Fetal brain disruption

The external phenotype of the fetal brain disruption sequence (collapsed skull with occipital prominence, overlapping sutures, redundant scalp skin and arthrogryposis) is rare in severe CMV and characteristic of congenital Zika, but several autosomal recessive diseases reproduce it, including AGS, pseudo-TORCH, JAM3, NDE1 and ANKLE2 [93]. Abdel-Salam and colleagues described five patients from three consanguineous families with severe congenital microcephaly and underdeveloped hemispheres, without variants in NDE1, MKL2, OCLN or JAM3, and proposed the term «fetal brain arrest» for familial cases, considering the generic designation of disruption of little use [98]. The occipital scalp rugae described in two siblings with OCLN variants illustrate this overlap [16].

6.6. NEDIHSS, PCDH12-related disease and their own differentials

A neonatal vascular retinopathy with fibrovascular proliferation, peripheral ischaemia and delayed arteriovenous transit in a newborn without extreme prematurity or oxygen therapy is not compatible with retinopathy of prematurity and requires consideration of FEVR (NDP, LRP5, FZD4, TSPAN12), Norrie disease, incontinentia pigmenti (IKBKG) and the tight-junctionopathies; hydrocephalus, periventricular calcifications, thin corpus callosum and family history point to ESAM [48]. Exudative vitreoretinopathy also occurs in PCDH12-related disease, in COL4A1/COL4A2-related disorders and in HDBSCC, and the 2025 authors propose testing PCDH12 in patients with FEVR without a genetic diagnosis [36, 49]. De novo variants of CLDN5, which encodes claudin 5 of the blood–brain barrier, produce seizures, microcephaly, calcifications and neurodevelopmental delay overlapping with the recessive tight-junctionopathies [36].

DMJDS1 is distinguished from the other phenocopies of congenital infection by the absence of haemorrhage and vascular changes on imaging, by the brainstem malformation and by the axonal tract defect, which tractography did not show in OCLN-related disease [37]. It shares with AGS recurrent sterile fever, calcifications, dystonia and, in some patients, a raised interferon score, but chilblains and inflammatory CSF have not been described [12, 38]. GSX2-related DMJDS2 shares the hypothalamic-mesencephalic fusion and is distinguished by agenesis or hypoplasia of the basal ganglia [83]. The mild forms of PCDH12-related disease enter the differential diagnosis of dyskinetic cerebral palsy without perinatal cause and of ataxias with retinopathy, and subtle thalamic calcification sets them apart from primary familial brain calcification, which has a different distribution and age at onset [41, 89, 90].

7. Treatments and Risk Management Strategies

7.1. Principles and absence of specific therapy

There is no specific or disease-modifying treatment for BLC-PMG, HDBSCC or RNASET2-related disease; management is symptomatic and palliative, directed at seizures, nutrition, systemic complications and rehabilitation [15, 25, 26]. No specific guidelines or clinical trials registered in ClinicalTrials.gov were found for these genes (search of 1 November 2026), so the following recommendations derive from case series and general practices applied to the manifestations described [52]. Guidance from the European Reference Networks and multidisciplinary teams (paediatric neurology, genetics, ophthalmology, otorhinolaryngology, nephrology, nutrition, physical and rehabilitation medicine and paediatric palliative care) is the way to organise this care [27–30].

7.2. Epilepsy

Epilepsy begins in the first weeks or months in BLC-PMG and HDBSCC and may progress to status epilepticus and drug resistance [14–16]. The reports describe the use of phenobarbital and levetiracetam, with seizure control in a child with RNASET2-related disease and discontinuation of diazepam because of sialorrhoea [72]. The choice and dosage of antiseizure medications follow the general rules for early-onset epilepsy and the respective summaries of product characteristics, because there are no comparative efficacy data in these diseases; treatment of status epilepticus follows the usual paediatric protocols.

7.3. Nutrition, swallowing and growth

Bulbar palsy and feeding difficulties lead to aspiration and growth retardation; nasogastric tubes and percutaneous endoscopic gastrostomy have been used [15, 51, 72]. In HDBSCC, growth retardation may be marked (weight and height −2.7 SD at 30 months in one patient), and the megaoesophagus of the murine model and of one patient justifies the gastroenterological assessment that Abdallah Moady and colleagues recommend for all living patients [15, 17].

7.4. Renal and endocrine complications of BLC-PMG

Renal dysfunction, responsible for most deaths in the subgroup with renal involvement, should be monitored from diagnosis and referred to paediatric nephrology [14, 77]. In a Turkish boy with central diabetes insipidus, desmopressin corrected the polyuria, without preventing renal progression; the dose and route follow the summary of product characteristics for paediatric central diabetes insipidus, because the report does not specify it [14]. The authors recommend early diagnosis, renal follow-up and infection prevention measures, after the child died of sepsis at 4 years [14].

7.5. Haemorrhage and hydrocephalus in HDBSCC

Post-haemorrhagic hydrocephalus with aqueductal stenosis required urgent ventriculoperitoneal shunting at 25 days in one patient, and there were other cases with shunts [15, 17]. There are no data on pharmacological prevention of haemorrhages. The recommendations for COL4A1-related disease, another haemorrhagic microangiopathy, include avoiding anticoagulants, head trauma, smoking and hypertension, and considering the mode of delivery to avoid prolonged pressure on the fetal head; applying these measures to HDBSCC is an extrapolation from an analogous condition, without evidence of its own [79]. Thrombocytopenia is not part of HDBSCC, and the haemorrhages are attributed to the endothelium [17].

7.6. Congenital cataract in HDBSCC

Cataract surgery (lens aspiration with posterior capsulotomy and anterior vitrectomy) was performed at 6 weeks and one month later in the fellow eye in one patient; the central posterior opacification, resembling Elschnig pearls, recurred twice and required membrane excision, until the visual axis was clear [17]. This reopacification is rare after posterior capsulotomy with vitrectomy, and the murine model suggests an intrinsic change in the lens fibres [15]. In another patient vitrectomy was performed at 2 months [15]. Visual rehabilitation after clearing the axis is limited by retinal and cerebral pathology [15].

7.7. Hearing

In RNASET2-related disease, sensorineural hearing loss should be assessed with auditory evoked potentials and treated with hearing aids or cochlear implantation, according to the general indications [52]. In HDBSCC, the auditory neuropathy described in one patient, with normal otoacoustic emissions and absent evoked potentials, shows that newborn hearing screening by otoacoustic emissions is not sufficient [17].

7.8. Rehabilitation and palliative care

Spastic tetraparesis, dystonia and contractures require physiotherapy, positioning, orthoses and treatment of spasticity; the Gross Motor Function Classification System (GMFCS) was used to follow a child with RNASET2-related disease [72]. Given the severity and mortality of HDBSCC and of many children with BLC-PMG, early integration of paediatric palliative care and advance care planning with the family are part of management [15, 59].

7.9. Agents and circumstances to avoid

For HDBSCC, by analogy with COL4A1, avoid anticoagulants and head trauma whenever possible [79]. The sources consulted do not describe other contraindicated agents.

7.10. Regulatory status

Table 7.1. Regulatory status (1 November 2026)

7.11. Research and level of evidence

Table 7.2. Studies with therapeutic or mechanistic potential

None of these data allow treatment to be recommended: the results in zebrafish and mice have not been tested in patients, haematopoietic stem cell transplantation is an established therapy in other leukodystrophies but has not been studied in RNASET2-related disease, and the ruxolitinib report concerns a different interferonopathy [26, 31]. The evidence for interferon blockade in RNASET2-related disease is limited to IFNAR1 dependence in the mouse [65].

7.12. Developments in the last twelve months

Between November 2025 and November 2026, the relevant publications were descriptive or preclinical: confirmation of two Turkish families with ESAM loss of function and congenital cataracts, which reinforces ESAM deficiency as a tight-junctionopathy with congenital intracranial haemorrhage (case reports) [84]; phenotypic refinement of the same disease, with ocular findings, in an Albanian boy (case report with review) [36]; experimental demonstration that JAM2 variants linked to brain calcification disturb the JAM2–JAM3 structure and the blood–brain barrier (preclinical) [71]; microglial pyroptosis in the Rnaset2−/− mouse (preclinical) [73]; and a case of pseudo-TORCH type 2 with a review of pseudo-TORCH syndromes (case report) [50]. For PCDH12, the same period brought a case of severe exudative vitreoretinopathy treated with laser (case report) [49], a preprint with the first pathogenic missense variants and visual impairment (human study not peer reviewed) [82], two Chinese children with compound heterozygosity (case reports with review) [85] and four Indian children with DMJD without calcifications (case series) [43]. There were no applications for marketing authorisation, opinions or authorisations for these diseases. The absence of results in a search does not demonstrate the non-existence of unregistered ongoing studies.

7.13. Pregnancy, perioperative care and transition

There are no data on pregnancy in affected patients, because none of the patients described reached reproductive age with autonomy. In the perioperative period (gastrostomy, ventriculoperitoneal shunting, cataract surgery), the sources do not describe specific anaesthetic risks; the general care of the child with epilepsy, bulbar dysfunction and, in BLC-PMG, renal dysfunction applies [14, 17]. The few patients who survive into adolescence, such as the young Pakistani woman with HDBSCC at 14 years and the patients with RNASET2 variants older than 10 years, need planned transition to adult care for severe neurological disability [15, 18].

7.14. Infectious branch of the differential

When congenital CMV is confirmed, the ECCI consensus recommends valganciclovir in newborns with central nervous system symptoms or isolated hearing loss, started before 1 month of age (between 1 and 3 months there may still be benefit), and stresses that valganciclovir and ganciclovir are not licensed for this indication and that cases should be discussed with a paediatric infectious diseases specialist [23]. This treatment has no place in the genetic phenocopies, which reinforces the need for a correct diagnosis before starting it.

7.15. Specific management of NEDIHSS and PCDH12-related disease

There is no specific treatment for either disease, nor any registered clinical trials (ClinicalTrials.gov search of 1 November 2026); management is that of the manifestations [36, 38].

Hydrocephalus and haemorrhage in NEDIHSS. Ventriculoperitoneal shunting was needed in the first weeks or months in several patients, and shunt infections with ventriculitis led to repeated revisions, so neurosurgical surveillance should continue beyond the neonatal period [44]. As haemorrhages may occur up to 18 months and one child died with thrombocytopenia and cerebral haemorrhage, the platelet count and haemostasis should be checked at each haemorrhage and before surgery [44]. The measures recommended in COL4A1-related disease (avoiding anticoagulants and antiplatelet agents when not indispensable, head trauma and hypertension) apply to NEDIHSS by extrapolation from an analogous haemorrhagic microangiopathy, without evidence of their own [79].

Epilepsy. In NEDIHSS, tonic-clonic and focal seizures responded partially to levetiracetam, valproate and clonazepam, and there was status epilepticus in one patient [44]. In PCDH12-related disease, neonatal-onset epilepsy was often refractory (levetiracetam, topiramate and valproic acid in one child, with one to three focal seizures per day), and in a patient with tonic seizures, absences and drop attacks levetiracetam and lamotrigine had a moderate effect and cannabidiol reduced the frequency and intensity of seizures [38]. Cannabidiol (Epidyolex®) is authorised in the EU and the USA for Lennox-Gastaut and Dravet syndromes and for tuberous sclerosis complex, so its use in PCDH12-related disease is off-label; the choice and dosage of antiseizure medications follow the practice for early-onset epilepsy and the respective summaries of product characteristics, because there are no comparative efficacy studies in these diseases [38, 99].

Retina. In NEDIHSS, the avascular peripheral retina was treated with circumferential laser photocoagulation to prevent detachment, and in a newborn girl with bilateral extraretinal fibrovascular proliferation and vitreous haemorrhage, diode laser and intravitreal bevacizumab 0.3125 mg in each eye were used on the third day, with complete regression and no reactivation over 4 years, although with nystagmus and severe visual impairment [36, 48]. In PCDH12-related disease, exudative vitreoretinopathy was treated with sequential bilateral laser [49]. There is no guideline for these retinopathies; the authors applied by analogy the approach used for retinopathy of prematurity and FEVR, in which photocoagulation of the avascular retina is the reference treatment and combination with anti-VEGF has been described [48]. Bevacizumab (Avastin®) is not authorised for intravitreal use; the anti-VEGF agent with a European indication in retinopathy of prematurity is ranibizumab (Lucentis®), by intravitreal injection of 0.2 mg (0.02 ml) per eye, and its use in genetic retinopathies of term newborns is an extrapolation to be decided by paediatric ophthalmology [48, 100]. Newborn siblings of patients with severe retinopathy should be examined by an ophthalmologist soon after birth, even without a genetic diagnosis, because early treatment prevented the detachment that the untreated sibling suffered [48].

Abnormal movements, nutrition and rehabilitation. The dystonia, ataxia and spasticity of PCDH12-related disease and the spastic tetraparesis of NEDIHSS require physiotherapy, orthoses and symptomatic treatment according to cerebral palsy practice; dysphagia (28% in the 2018 series) and camptocormia in adults justify swallowing and orthopaedic assessment [37, 38]. The recurrent sterile fever of PCDH12-related disease requires infection to be excluded at each episode before attributing it to the disease, and the transient motor regression that accompanied it in one patient recovered within weeks [38].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

All three diseases are autosomal recessive: when both parents are heterozygous, each pregnancy has a 25% probability of an affected child, 50% of an asymptomatic carrier and 25% of a child without the variant [10, 25, 52]. The Oxford Desk Reference advises, in the presence of consanguinity, assuming autosomal recessive inheritance and a 25% recurrence risk in undiagnosed microcephaly, and recommends attention to genetic conditions that mimic environmental causes [3]. The families described show the reality of this risk: affected siblings, stillbirths with hydrocephalus and cerebral necrosis, and unexplained neonatal deaths before the diagnosis of the index case [10, 62]. Compound heterozygosity in a British family and homozygosity in a Mexican family without known consanguinity show that the disease also occurs outside consanguineous families [16]. A mistaken diagnosis of congenital infection leads to underestimation of the risk, because maternal infection rarely recurs with identical fetal consequences [12, 52].

8.2. Carrier testing and cascade testing

Once the variants of the index case have been identified, testing of the parents confirms phase and testing of healthy siblings and relatives of reproductive age identifies carriers [3]. In consanguineous families, testing spouses who are also relatives makes it possible to estimate each couple's risk. Heterozygous JAM3 carriers have no described manifestations; for OCLN and RNASET2 the sources consulted also describe no manifestations in carriers [15]. Carrier testing in minors without direct benefit should be deferred until they are old enough to decide.

8.3. Prenatal and preimplantation diagnosis

With the familial variants known, invasive prenatal diagnosis (chorionic villus sampling or amniocentesis) and preimplantation genetic testing are available [25, 52]. In the absence of a molecular diagnosis, ultrasound surveillance of a new pregnancy has limitations: in HDBSCC the cataracts were visible at 23 weeks and the haemorrhages and ventriculomegaly in the second and third trimesters, but a fetal MRI at 20 weeks was normal in an affected newborn; in primary microcephaly, head circumference may fall only between 32 and 36 weeks [3, 17, 97]. The family of the illustrative case declined prenatal molecular diagnosis, a decision that should be respected in non-directive counselling [17].

8.4. Content of counselling

Counselling should explain the genetic cause and the non-infectious nature of the disease, the 25% risk in each pregnancy, the reproductive options, the uncertain but usually severe prognosis, the absence of specific treatment, the limitations of the tests (pseudogene and CNV in OCLN, deep introns in JAM3, CNV in RNASET2) and the right to decline tests [20, 22, 24]. When the child dies without a diagnosis, DNA storage and, if possible, autopsy preserve the possibility of a future diagnosis [51].

8.5. Counselling in NEDIHSS and PCDH12-related disease

Both diseases are autosomal recessive, with a 25% risk in each pregnancy of a carrier couple, and the families described confirm this: in NEDIHSS there were three terminations of pregnancy, one stillbirth and unexplained neonatal deaths before diagnosis, and in PCDH12-related disease there were sibships with two to four affected individuals [37, 44, 45]. Heterozygous carriers have no described manifestations for either gene; for PCDH12, the heterozygous missense variants found in adults with brain calcification do not justify carrier surveillance [41]. The recurrent variants (ESAM c.115del in south-eastern Anatolia; PCDH12 c.2515C>T in Palestinian families and c.2765_2766del in four families with no known relationship) make it possible, in these communities, to offer targeted testing to spouses who are also relatives [35, 37, 45]. PCDH12-related disease has also occurred in non-consanguineous families (Moroccan Jewish, Afghan) and in compound heterozygosity, so the absence of consanguinity does not reduce the probability of the diagnosis [37, 38, 85].

With the familial variants known, invasive prenatal diagnosis and preimplantation genetic testing are possible. Without a molecular diagnosis, ultrasound has limits: in NEDIHSS, ventriculomegaly or hydrocephalus were detected at 27 and 30 weeks in two fetuses, but in other cases hydrocephalus was only postnatal; in PCDH12-related disease, hyperechogenic foci and fetal microcephaly were described in the Palestinian form, whereas in other families head circumference at birth was only slightly reduced [37, 44, 45]. Counselling should address intrafamilial variability, greater in NEDIHSS, and the broad spectrum of PCDH12-related disease, in which the same family tends to have similar severity [38, 44].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each number measures

None of the diseases has a population estimate of prevalence or incidence. Orphanet assigns all three to the prevalence class below 1/1 000 000, without a numerical value, and the Orphadata count for HDBSCC is 8 cases or families, taken from the founding paper [2, 4, 11, 69]. The published counts are of described patients and not of frequency: 17 patients from 9 families with BLC-PMG up to 2017, before the Egyptian series of 13 patients, and 34 patients with OCLN variants in 2020; about 20 patients with HDBSCC in 2024; 12 patients with molecularly confirmed RNASET2-related disease in 2019 and fewer than 50 described according to Orphanet [11, 14, 15, 19, 72]. These numbers are probable underestimates, because the similarity to CMV leads to children being classified as infected without genetic testing [52].

9.2. Geography and founder effect

Table 9.1. Origin of the families described

The diseases are concentrated in consanguineous families from the Middle East, North Africa and South Asia, but there are European and American cases [15, 16]. For Portugal, the sources consulted include the description of two patients with non-progressive leukoencephalopathy with temporal cysts, microcephaly and deafness at Hospital de Santa Maria in 2001, without published molecular confirmation, and the participation of geneticists from Porto and Braga in the 2018 series on OCLN, whose abstract does not indicate the origin of the patients [20, 63]. For Brazil, the sources consulted contain only a commentary by researchers from Recife on the Egyptian series [102]. The absence of data does not demonstrate the absence of patients.

The counts for NEDIHSS and PCDH12-related disease also measure published patients and not frequency: 22 patients with ESAM variants in five studies up to 2026, and 29 patients with PCDH12 variants in the 2022 review, to which at least 12 were added in later reports [36, 38, 43, 49, 82, 83, 85]. The sources consulted contain no patients from Portugal or Brazil for either gene; a brain calcification study with the participation of researchers from Recife found no truncating PCDH12 variants in adults with primary familial calcification [41]. The absence of published cases does not demonstrate the absence of patients.

9.3. Special populations

In regions where congenital Zika is endemic, such as Brazil since 2015 [53], imperfect laboratory diagnosis makes it necessary to recognise congenital Zika syndrome on clinical grounds, and the band-like pericortical calcifications of Zika approach the pattern of BLC-PMG; genetic diseases such as AGS, pseudo-TORCH and JAM3-related disease reproduce the fetal brain disruption phenotype [93]. In populations with frequent consanguinity, familial recurrence should be actively sought [3].

9.4. European Reference Networks and patient associations

ERN ITHACA covers malformations and neurodevelopmental disorders, ERN-RND rare neurological diseases, including the leukodystrophies, EpiCARE rare and complex epilepsies, and ERN-EYE rare eye diseases [27–30]. For the infectious branch of the differential, the European consensus recommends proposing enrolment in the international CCMVNET registry [23, 103]. The sources consulted do not identify patient associations specific to these diseases; leukodystrophy and microcephaly associations offer support to families.

10. Illustrative Clinical Case

Abdallah Moady and colleagues described in 2023 the first child of a consanguineous Bedouin couple from Israel [17]. Nuchal translucency and first-trimester biochemical screening were normal; at 14 weeks only a single umbilical artery was noted. At 23 weeks, ultrasound showed bilateral central cataracts and echogenicity in the lateral ventricles; later, the lateral ventricles dilated to about 13 mm, with irregular walls and apparently underdeveloped sulci. TORCH and parvovirus serologies were negative, and the family declined prenatal molecular diagnosis.

The child was born at 37 weeks, with an Apgar score of 9/10, weight of 2.4 kg (10th centile) and head circumference of 32 cm (6th centile); examination was normal except for dense bilateral nuclear cataracts and retrognathia. Transfontanellar ultrasound on the fourth day showed a thin corpus callosum, dilated lateral ventricles, left thalamic haemorrhage and mega cisterna magna, with normal visceral and cardiac ultrasound, biochemistry, haematology and metabolic studies. On day 18 new foci of parenchymal and ventricular haemorrhage appeared with periventricular leukomalacia; the CSF was xanthochromic, with glucose of 21.7 mg/dL, protein of 236 mg/dL and 10 white cells. MRI at 24 days showed extensive parenchymal injury with cystic malacia, haemorrhagic cavities, enlarged lateral and third ventricles, aqueductal stenosis and a non-visible corpus callosum, and an urgent ventriculoperitoneal shunt was placed on day 25. MRI at 5 months confirmed absence of the corpus callosum due to destruction, and CT at 12 months showed extensive cortical and subcortical calcifications, less in the basal ganglia, with atrophy (Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC10534027/figure/F1/).

Otoacoustic emissions were normal on the second day and at 3 months, but auditory brainstem evoked potentials recorded no recognisable waves, a picture of auditory neuropathy; a 300-gene deafness panel was negative. The cataract was operated on at 6 weeks in the left eye and one month later in the right, with lens aspiration, posterior capsulotomy and anterior vitrectomy; posterior opacification recurred twice and was finally excised, leaving the visual axis clear. Sanger sequencing of JAM3 identified the homozygous variant c.745dup, p.(Val249Glyfs*28), pathogenic according to the ACMG criteria, with both parents heterozygous; on the MANE transcript it corresponds to NM_032801.5:c.745dup [17, 39].

At 30 months, weight and height were 2.7 SD below the mean and head circumference −4.1 SD; the child had tremor, episodes of severe restlessness, intractable seizures with an abnormal EEG, absent social interaction, generalised hypertonia with opisthotonus, hyperreflexia and a Babinski sign, and dysmorphic features that became more pronounced over time [17]. The case shows four clinical points: cataracts may be the first prenatal sign; negative serologies are not enough to reassure when there is fetal haemorrhage; auditory neuropathy escapes screening by otoacoustic emissions; and capsular reopacification may require repeated surgery. The management described (shunting, repeated eye surgery) consisted of individual decisions and does not constitute a validated protocol.

Second case: neonatal retinopathy due to ESAM. Bayramoğlu and colleagues described in 2023 a newborn girl of 35 weeks and 2500 g referred on the second day of life because of a family history of bilateral retinal detachment [48]. She had bilateral iris neovascularisation and pupillary rigidity, venous dilatation and arterial tortuosity, severe extraretinal fibrovascular proliferation in both eyes, peripheral ischaemia in all four quadrants and vitreous haemorrhage on the left; fluorescein angiography showed very delayed arteriovenous transit (more than 90 seconds), incomplete venous filling and avascular peripheral retina (figures 1 and 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC10750092/). On the third day, both eyes received diode laser photocoagulation of the ischaemic retina and intravitreal bevacizumab, with additional laser on the left after the haemorrhage had resorbed; the disease regressed and did not reactivate over 4 years, but the child was left with nystagmus and severe visual impairment [48]. Examination showed a triangular face, smooth philtrum and prominent chin, and MRI revealed a thin corpus callosum, diffuse calcification of the periventricular white matter, hydrocephalus, ventricular dilatation and cerebral atrophy (figure 3 of the article); the child had severe delay, absent language, hypotonia and severe epilepsy, and developed hypertrophic cardiomyopathy during follow-up. Her brother, with the same neurological picture, had bilateral iris coloboma and total retinal detachment at 3 months, already beyond treatment. The exome identified in both children the homozygous ESAM variant NM_138961.3:c.115del p.(Arg39GlyfsTer33), with heterozygous parents, and the siblings were later included in the cohort that delineated NEDIHSS [35, 48]. The case shows that retinopathy may be the first sign recognised, that the picture is confused with retinopathy of prematurity and with FEVR, and that immediate ophthalmological examination of newborn siblings can preserve the eye; the combination of laser with anti-VEGF was an individual decision and not a validated protocol [48].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

BLC-PMG has a very severe neurological prognosis: patients do not acquire motor skills or language, microcephaly progresses to −8 SD and there are deaths within days, months or years from status epilepticus, fever, sepsis or kidney disease [14, 16, 59]. HDBSCC has high fetal and neonatal mortality; all patients in Akawi's three families died in childhood, and the survivors described, such as the 14-year-old young woman and the 30-month-old child, have spastic tetraparesis, epilepsy and severe visual impairment [15, 17, 62]. RNASET2-related disease is static or very slowly progressive; patients older than 10 years retain psychomotor delay, with variable ability to sit or walk and poor speech, and some walk without support [9, 11, 18]. In NEDIHSS, all liveborn individuals described have severe global delay, without language, and spasticity; there were deaths at 14–15 months and at 5 years, terminations of pregnancy and stillbirths, and haemorrhages may occur up to 18 months [35, 44]. Visual loss due to retinal detachment is the main avoidable complication [36, 48]. In DMJDS1, patients with the congenital form do not walk or speak, microcephaly progresses and epilepsy is often refractory, whereas patients with the mild form reach adulthood with mild intellectual disability, independent walking with ataxia and dystonia without clear progression in the last years of follow-up, but with a risk of retinal detachment [37, 38]. There are no survival curves for any of the diseases.

11.2. Surveillance

There are no published surveillance protocols. Table 11.1 proposes clinical intervals derived from the complications described; the intervals reflect practical consensus and not studies.

Table 11.1. Suggested surveillance

12. Summary and Final Considerations

The non-interferonopathic pseudo-TORCH syndromes bring together three autosomal recessive diseases that reproduce the picture of congenital infection without infection: band-like calcification with simplified gyration and polymicrogyria due to OCLN variants, haemorrhagic destruction of the brain with subependymal calcification and cataracts due to JAM3 variants, and cystic leukoencephalopathy without megalencephaly due to RNASET2 variants. The first two result from defects of the tight junctions of the neurovascular unit and belong to the emerging group of tight-junctionopathies, which also includes ESAM deficiency; the third is a lysosomal disorder of RNA catabolism with type I interferon-dependent neuroinflammation.

Diagnosis rests on reading the imaging pattern, which requires CT in addition to MRI, on rigorous exclusion of congenital CMV by PCR in the first three weeks or on the neonatal dried blood spot, on ophthalmological and auditory assessment and on a genetic study capable of detecting CNV, regions homologous to pseudogenes and deep intronic variants. A negative CMV test does not exclude infection and a late positive test does not exclude a Mendelian disease. There is no specific treatment; care centres on epilepsy, nutrition, renal function in BLC-PMG, hydrocephalus and cataract in HDBSCC, hearing in RNASET2-related disease, rehabilitation and palliative care. Studies of microglial replacement in zebrafish are, for now, the only therapeutic lead, at preclinical level.

The greatest benefit for families comes from the correct diagnosis: it identifies a 25% recurrence risk that the hypothesis of infection would conceal and opens access to carrier testing, prenatal diagnosis and preimplantation genetic testing.

Two related diseases complete the class. NEDIHSS, due to loss of function of ESAM, is a tight-junctionopathy with intracranial haemorrhage of fetal to postnatal onset, hydrocephalus, calcifications, epilepsy and spasticity, and with vascular retinopathy in almost half of patients, which makes early fundoscopy and examination of newborn siblings measures with an impact on vision. DMJDS1, due to loss of function of PCDH12, adds to calcification of infectious pattern a malformation of the brainstem and axonal tracts, without haemorrhage, in a spectrum ranging from congenital microcephaly with neonatal epilepsy to adult ataxia with dystonia and exudative vitreoretinopathy. Both are autosomal recessive, without specific treatment, and are diagnosed by exome with copy-number analysis.

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