CCFDN Syndrome (Congenital Cataracts, Facial Dysmorphism and Neuropathy)

An autosomal recessive developmental disorder, so far found exclusively in the Roma population, caused by the deep intronic founder variant NM_004715.5(CTDP1):c.863+389C>T, which reduces the RNA polymerase II C-terminal domain phosphatase; it combines congenital cataracts with microcornea, hypomyelinating neuropathy, late-onset facial dysmorphism, short stature, hypogonadotrophic hypogonadism, parainfectious rhabdomyolysis and anaesthetic risk.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition

Congenital cataracts, facial dysmorphism and neuropathy syndrome (CCFDN) is an autosomal recessive developmental disorder affecting the anterior segment of the eye, the skull and face, the peripheral and central nervous system and the endocrine system [1]. The diagnosis is established by identification of biallelic pathogenic variants in CTDP1, and all patients described are homozygous for a single founder variant, NM_004715.5:c.863+389C>T, which has only been found in people of Roma ancestry [1, 17]. The disease is therefore genetically homogeneous, and this homogeneity explains the constancy of the phenotype between patients [1, 18].

1.2. Original description

The entity was recognised in Bulgaria during a study of hereditary motor and sensory neuropathy type Lom (HMSN-Lom), when Tournev and colleagues found, mainly among Wallachian Roma (a recently founded genetic isolate), an undescribed neurological disorder. Published in 1999 in the Annals of Neurology, the series included 50 patients from 19 extended pedigrees, all examined clinically and electrophysiologically, with at least one patient from each family admitted in Sofia for full investigation [19]. The authors named it CCFDN to highlight its salient features: congenital cataracts and microcornea recognised in infancy, a predominantly motor neuropathy that begins in the lower limbs, spreads to the upper limbs and leads to severe disability in the third decade, non-progressive cognitive impairment, pyramidal signs and mild chorea in some patients, short stature, characteristic facial dysmorphism and hypogonadotrophic hypogonadism [19]. Electrophysiology suggested a hypomyelinating or demyelinating neuropathy, confirmed by nerve biopsy; in the same year, a study of four sural nerve biopsies (patients aged 4 to 32 years) showed diffuse hypomyelination, on which demyelination and axonal degeneration were superimposed in older patients [20]. OMIM notes that the disease was distinct from HMSN-Lom, also recessive and present in the same groups, and that the ages of the 50 patients in the original series ranged from 8 months to 40 years [7].

1.3. “Marinesco-Sjögren with rhabdomyolysis” and separation from Marinesco-Sjögren syndrome

A year earlier, in 1998, Müller-Felber and colleagues had described four children from two German Gypsy families with congenital cataract and ataxia, all with clinical and neurophysiological demyelinating polyneuropathy; three had acute rhabdomyolysis with marked weakness and creatine kinase (CK) up to 40,000 U/l after a viral infection, and the authors proposed a “new subtype” of Marinesco-Sjögren syndrome (MSS) with rhabdomyolysis [2]. In 2002, Merlini and colleagues studied three Italian Gypsy families with an MSS phenotype, demyelinating neuropathy and recurrent myoglobinuria in 5 of 6 affected individuals; linkage analysis at 18qter, where the CCFDN locus had been mapped, gave a lod score of 3.55, and the patients shared the conserved haplotype of CCFDN chromosomes, which showed that “MSS with myoglobinuria” and CCFDN are the same disease, caused by a single founder mutation [3, 7]. In the same year, Lagier-Tourenne and colleagues compared a Gypsy family and a Turkish family initially diagnosed with MSS: the Gypsy family had features of CCFDN and linkage to 18qter, whereas the Turkish family had typical MSS without linkage to 18qter; the features distinguishing MSS were more severe intellectual disability, marked cerebellar atrophy, a chronic myopathy with its own ultrastructure and absence of peripheral neuropathy, facial dysmorphism and microcornea [7, 21]. In 2004, at the 125th European Neuromuscular Centre (ENMC) workshop, rejection of allelism between CCFDN and MSS was presented, based on CTDP1 analysis in 19 families with MSS of various ethnicities [10]. Until the genes were identified, in 2003 for CCFDN and in 2005 for MSS, both diseases were designated MSS; Walter and colleagues consider it likely that Marinesco described Romanian Roma patients with CCFDN in 1931 and that Sjögren described MSS in 1950, although Marinesco's original family was never studied by nerve conduction studies to document a demyelinating neuropathy [11]. SIL1-related MSS enters the differential diagnosis.

1.4. Molecular milestones

Angelicheva and colleagues mapped the locus to 18q23-qter, between D18S1141 and D18S1268, and linkage disequilibrium with highly conserved haplotypes suggested genetic homogeneity and a founder effect [7]. In 2003, Varon and colleagues narrowed the critical interval to 155 kb by recombination mapping and found that the non-transmitted chromosomes of some unaffected parents carried the disease haplotype; assuming that these parents were homozygous across the whole interval except at the mutation itself, they developed the “not quite identical by descent” (NQIBD, not quite identical by descent) approach and identified the variant by sequencing the DNA of a single parent homozygous for the haplotype [22]. The substitution lies in an antisense Alu element in intron 6 of CTDP1, causes a rare mechanism of aberrant splicing with insertion of Alu sequence into the mRNA, and the authors presented CCFDN as the first “purely” transcriptional defect of RNA polymerase II-mediated gene expression, within the group of “transcription syndromes” [10, 22]. In 2004, Morar and colleagues used this and four other private Roma variants to reconstruct the demographic history of this founder population [9].

1.5. Nomenclature

The current GeneReviews title, CTDP1-Related Congenital Cataracts, Facial Dysmorphism, and Neuropathy, follows the dyadic gene–phenotype nomenclature proposed by Biesecker and colleagues (2021) [1, 23]. The Orphanet name is Congenital cataracts-facial dysmorphism-neuropathy syndrome [8]. The designation “MSS with rhabdomyolysis” is historical and should not be used [1]. The word “Gypsy” appears in the original literature; this article uses “Roma”, as in the recent literature, keeping the names of the subgroups as defined by the genetic studies (Rudari, Kalderash, Lom and others) [9, 24].

2. Molecular Genetics and Pathophysiology

2.1. The CTDP1 gene and the FCP1 protein

CTDP1 is located at 18q23 and encodes the C-terminal domain (CTD) phosphatase of RNA polymerase II subunit A, known as FCP1 (TFIIF-associating CTD phosphatase 1) [1, 5]. FCP1 was cloned in 1998 by screening for proteins interacting with RAP74, the largest subunit of the general transcription factor TFIIF; the main cDNA encodes a protein of 842 amino acids (FCP1A) and a splice variant (FCP1B) lacks the last 139 amino acids; the transcript of about 3.6 kb is detected in all tissues studied (heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas) [5]. GeneReviews describes two isoforms produced by alternative splicing: isoform a, with 12 exons and a transcript of 3775 nucleotides, and isoform b, with 11 exons and 3612 nucleotides [1]. NM_004715.5 is the MANE Select transcript [4].

The protein is nuclear and ubiquitous, with an N-terminal catalytic region, a phosphoprotein-binding BRCT (BRCA1 C-terminal) domain, typical of cell cycle control proteins, and a C-terminal nuclear localisation signal [1]. The crystal structure of truncated constructs shows a Y-shaped architecture formed by the FCP homology (FCPH) domain, of the haloacid dehalogenase superfamily, with the DxDxT catalytic motif, by an α-helical domain and by the BRCT domain, joined by a helical linker; FCP1 is the only phosphatase in the human proteome with a BRCT domain [17].

2.2. Function: the “CTD code” and the transcription cycle

The CTD of the largest subunit of RNA polymerase II (POLR2A) is the platform on which the initiation, elongation, mRNA processing and termination complexes are recruited and assembled, and the phosphorylation pattern of serines 2 and 5 of its repeats defines the phase of the transcription cycle in which the polymerase is found [1]. FCP1 binds RAP74 and processively removes phosphates from the CTD, returning the polymerase to the hypophosphorylated form capable of reinitiating transcription [5, 17]. In vitro experiments have implicated it in virtually every phase of the cycle, in mobilisation of polymerase stored in phosphorylated form, in recruitment of the splicing machinery and in chromatin remodelling through histone methylation [1]. FCP1 forms complexes with MEP50, a component of the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), and interacts with components of these snRNPs, which places it at the link between elongation and splicing [5].

Work from 2025 and 2026 has broadened this picture. The RPB7 subunit recruits FCP1 to the polymerase; there, dephosphorylation of the CTD and of the linker regions of RPB1 prevents the hyperphosphorylated polymerase from being ubiquitinated by the CUL3 ligase and degraded, linking FCP1 to polymerase stability and reinitiation [17, 25]. In 2026, the same group showed that FCP1 controls a polymerase phosphorylation intermediate enriched in CTD Tyr1, Ser5 and Ser7, is required for recruitment of the Mediator complex to chromatin and for transcriptional efficiency, and dephosphorylates splicing factors, and that its depletion causes widespread intron retention and aberrant splicing of cassette exons [26]. These results are from cell biology and have not yet been related to patient tissues. FCP1 also dephosphorylates the RNA polymerase I factor TIF-IA (ribosome biogenesis) and interacts, via the BRCT domain, with FANCA, FANCI and FANCD2 of the Fanconi anaemia pathway, with an effect on homologous recombination repair [17].

In the mouse, biallelic deletion of Ctdp1 is lethal before embryonic day 7.5, and embryonic fibroblasts lacking the protein arrest in G1 and G2/M; heterozygotes, with 40–50% of the protein in brain, lung, spleen and heart, have no CCFDN-like phenotype [17, 27]. These data are consistent with the observation that the human disease results from a partial deficiency rather than complete loss [1, 17].

2.3. The founder variant c.863+389C>T

Sources: VariantValidator, ClinVar and OMIM [4–6].

The C>T substitution lies 389 base pairs downstream of the exon 6/intron 6 junction, within an Alu element in antisense orientation [18]. It creates a canonical splice donor site (gt) that activates a cryptic acceptor 95 nucleotides upstream; the cryptic acceptor is used with the normal intron 6 donor to remove the upstream part of the intron, and the new donor is used with the normal acceptor to remove the downstream part, so that 95 nucleotides of Alu sequence are inserted into the processed mRNA and introduce a premature stop codon 17 codons downstream of exon 6 [1]. The mutant transcript is degraded by nonsense-mediated decay or gives rise to a truncated protein lacking the nuclear localisation signal [5, 17]. The exonisation is due to the donor created by the substitution and not to the Alu sequence itself; a similar mechanism had only been described in ornithine aminotransferase deficiency [17, 24].

The effect is partial. By RT-PCR with allele-specific competitive amplification, the normal (193 bp) and aberrant (288 bp) products coexist in patient fibroblasts, lymphoblasts, myoblasts and Schwann cells, and real-time quantification showed normal transcript at 15–35% of control levels, varying with cell type and culture conditions [1, 17]. About 30% of the protein is estimated to be normal and full-length, and the threshold for the phenotype lies close to this value [17]. Whether complete loss of the protein in humans would produce another phenotype or be compatible with life is unknown [1].

2.4. Tissue mechanism

The mutation is expressed in all cell types studied, but the phenotype is limited to some tissues; the most discussed explanation is the difference between tissues in compensatory mechanisms and in the contribution of other CTD phosphatases [18]. In peripheral nerve, the density of myelinated fibres is normal and the main abnormality is diffuse hypomyelination, that is, Schwann cells do not produce myelin of a thickness appropriate to the axon diameter; in older patients demyelination, remyelination and axonal degeneration are superimposed [17, 20]. There are no morphological abnormalities of Schwann cells or axons, and it has not been clarified whether the defect is an abnormal axonal signal, a failure of the Schwann cell response or a primary Schwann cell defect [1, 17]. In the eye, the anomalies mainly affect anterior segment structures derived from surface ectoderm and begin before birth [10]. For parainfectious rhabdomyolysis, Kalaydjieva proposed that the transcription machinery with partial FCP1 deficiency cannot respond to the increased demand imposed by the febrile state [18]; Makrygianni and colleagues suggested dysregulation of heat shock proteins, according to Sabau's review [17]. Both proposals are hypotheses.

2.5. Inheritance, penetrance and genotype–phenotype

Inheritance is autosomal recessive; heterozygotes are asymptomatic and do not develop the disease [1]. All patients described are homozygous for the same variant, and the phenotype is consistent, with little variation [1]. The 2025 review nevertheless describes variable clinical severity and intrafamilial variability, with isolated cases of cardiomyopathy, epilepsy or acquired microcephaly, and proposes a search for genetic and environmental modifiers [17]. There are no known CTDP1 allelic disorders [1].

2.6. Other CTDP1 variants

GeneReviews records no pathogenic variant other than c.863+389C>T, nor any deletions or duplications [1]. In ClinVar, the variant NM_004715.5:c.2062C>T p.(Arg688Ter) has been submitted for CCFDN with conflicting classifications, and the sources consulted describe no patients carrying it [28]. In 2006, Kalaydjieva predicted that non-Roma patients with a similar phenotype might have other variants in the same gene, probably intronic or regulatory and with partial deficiency, and advised storing cultured cells for RNA analysis [18]. In the Hungarian Charcot-Marie-Tooth (CMT) cohort, CTDP1 accounted for 0.8% of patients; as the gene was only tested for the founder variant in Roma patients, these cases correspond to CCFDN due to the founder variant and not to another allelic form [29]. Sabau's review includes CTDP1 among the genes of recessive demyelinating CMT, and the Walter cohort proposes classifying CCFDN as a recessive demyelinating sensorimotor neuropathy [11, 17].

2.7. Origin and age of the variant

The ancestral haplotype is shared by all affected chromosomes, indicating a single mutational event [9, 17]. In the analysis of 129 CCFDN chromosomes with 16 markers over 5.34 cM, Morar and colleagues found 54 haplotypes, with two main groups (A and B) in more than 90% of chromosomes, present in Rudari communities in several European countries, with about 10% of unique shared haplotypes and significant geographical differences [9]. The age of the mutation in the Rudari was estimated at 500 years (95% confidence interval 400 to 650), with 25-year generations, whereas the founding of the European Roma population as a whole dates back about 32–40 generations and the secondary founder events 16–25 generations [9]. Barešić and Peričić Salihović relate this age to the beginning of Roma slavery in the territory of present-day Romania [30]. The recent origin on a common haplotype, which also persists on normal chromosomes in the same population, makes diagnosis by linkage analysis problematic [18].

3. Clinical Spectrum and Manifestations by System

3.1. Cohorts underpinning the description

The clinical description rests on a few series, almost all European and from reference centres. GeneReviews counts about 190 patients identified up to 2022 [1]. The main series are the original Bulgarian one (50 patients from 19 pedigrees, 1999) [19], that of 28 Bulgarian children aged 4 months to 16 years presented in 2004 [10], the ophthalmological series of nine boys from five pedigrees in eastern Serbia (1.3–16.8 years) [31], that of ten unrelated Czech children (2014) [24], the cohort of 16 patients followed for 10 years in Munich and Vienna (2014) [11] and the cognitive and imaging cohort of 22 Bulgarian patients aged 4 to 47 years (2015) [32]. The rest are isolated cases from Greece, Romania, Hungary, Italy, the Netherlands and the Czech Republic [17]. No series is population-based, and the course described mixes natural history with the effects of eye surgery, rehabilitation and orthopaedics.

The Walter cohort is the only one with longitudinal follow-up. It included 16 traditional Roma patients with molecular confirmation, aged 1 to 30 years at first assessment, originating from the Balkans and Central Europe and living in Germany or Austria, with pedigrees consistent with recessive inheritance and endogamous but non-consanguineous parents; they were followed as outpatients in Vienna and Munich, with the same scales at the first assessment and 10 years later, but not all completed the period, because one patient was lost to follow-up and two were diagnosed later [11]. The study was registered on ClinicalTrials.gov as NCT01902940 [11, 33]. At the first assessment, all had congenital cataracts operated on in the first weeks of life, strabismus, facial dysmorphism, short stature, the pes cavus typical of Charcot-Marie-Tooth neuropathies and severe demyelinating neuropathy; none could walk on tiptoes or heels, and none had marked intellectual disability, pyramidal signs or a movement disorder [11]. The individual clinical and electrophysiological data are in the article's supplementary tables; the figures show the patients at the first assessment and 10 years later [11].

Source: GeneReviews, based on the approximately 190 published patients [1].

3.2. Eye

Congenital cataracts are the first manifestation and are invariable; they are bilateral, with cortical or anterior or posterior subcapsular opacities with clouding of the adjacent nucleus, or total [1, 18]. In the series of nine patients from eastern Serbia, the cataracts were diagnosed at a mean age of 3.4 weeks, and microcornea and microphthalmia (documented by axial length) were present in all [10]. The pupils are small, with fibrotic margins, constrict slowly to light and dilate poorly with mydriatics [1]. All the children in that series had floppy eyelid syndrome (floppy eyelid), pseudoptosis, nystagmus and congenital esotropia, and distance visual acuity showed moderate to severe impairment, with near acuity less affected (mild to moderate impairment) [31]. Horizontal pendular nystagmus is very common and does not depend on the visual deficit, and the fundus is normal [1]. Other findings described are long, dense eyelashes and strabismus [18].

In the Czech series, all patients had dense bilateral cataracts and microphthalmia, with a horizontal corneal diameter of 7.5 to 9 mm in infancy; all underwent surgery in the first year of life, by extracapsular extraction or pars plicata lensectomy, and aphakia was corrected with contact lenses; six had nystagmus; final best-corrected visual acuity ranged from 0.02 to 0.5 (mean 0.1) because of amblyopia; and there was secondary glaucoma in 8 eyes of 5 patients at last follow-up [24]. Surgery is complicated by the micropupils and by exaggerated inflammatory and foreign body reactions, which give rise to pupillary occlusion membranes and posterior capsular opacification with frequent reoperations; the floppy eyelid and the reaction to contact lenses cause chronic papillary conjunctivitis, meibomian gland dysfunction and, in adolescence, eyelid thickening and pseudoptosis [10].

3.3. Growth, face and skeleton

Growth deficiency begins in utero. In 22 term infants, birthweight was 3.22 ± 0.48 kg in boys (reference 3.9 ± 0.5 kg) and 3.06 ± 0.53 kg in girls (reference 3.8 ± 0.6 kg), and length 47.88 ± 3.91 cm and 46.75 ± 4.19 cm (references 53.1 ± 2.1 and 52.5 ± 2.1 cm) [1]. In the original series, adult men measured 149.2 ± 5 cm and weighed 47 ± 7.2 kg (reference 173 ± 6.8 cm and 73.9 ± 10.4 kg), and women 142.4 ± 8.2 cm and 45.8 ± 7.6 kg (reference 160.3 ± 6.4 cm and 63 ± 10.7 kg) [1]. Head circumference is small, but proportional to stature [18].

The facial dysmorphism appears in late childhood and is most evident in adult men: prominent midface with a well-developed nose, thickened perioral tissues, forward-protruding anterior dentition and micrognathia or hypognathism [1, 10]. In the photographs of the Czech series, the prominent philtrum is seen mainly in older children, and young children look almost normal [24]. Skeletal deformities are secondary to the neuropathy: pes cavus or equinovarus with claw toes, interphalangeal flexion contractures and claw hand are present in all adults, and kyphoscoliosis can reduce vital capacity [1, 18]. In the Czech series, the two oldest patients had severe scoliosis progressing since adolescence and two had severe distal atrophy with Achilles tendon shortening [24].

3.4. Peripheral neuropathy

The neuropathy is hypomyelinating, symmetric and predominantly distal, initially motor [1]. In the 28 Bulgarian children, motor delay was constant and all began walking between 2 and 3 years, many with an unsteady gait; signs of lower-limb motor neuropathy (reduced or absent reflexes, distal weakness, foot deformities) appeared after 4 years and were followed by upper-limb involvement; sensory changes (numbness) in the lower limbs appear after 10 years [1, 10]. In Chamova's cohort, mean age at walking was 2.76 ± 1.29 years, with only two patients walking within the normal range and one who never walked [32]. In the Czech series, no child walked before 2 years, some only after 6, and the gait was described as “paleocerebellar” in all [24].

Nerve conduction evolves in a characteristic way. Nerve conduction velocity (NCV) is normal at 4–8 months, when myelination begins, falls in all after 18 months, declines progressively until 4 years and stabilises at about 20 m/s between 4 and 10 years [1, 10]. In the Walter cohort, NCV was normal up to 18 months, fell to about 20 m/s by around 10 years and then stabilised [11]. Distal motor latencies become prolonged in the lower limbs after 4 years and in the upper limbs after 8 [10]. Sensory action potentials initially have normal amplitude, reflecting uniform slowing of all fibres, characteristic of congenital hypomyelination; with progression, sensory and motor amplitudes decrease and the sural potential may disappear after 10 years, a sign of secondary axonal loss [1, 11]. In the Czech children, motor NCVs were between 20 and 35 m/s and were lower in the older children [24]. Electromyography shows distal neurogenic changes in all patients tested [1]. In the Walter cohort, nerve conduction studies were performed in all 16 patients and electromyography in the six who had proximal weakness and episodes of rhabdomyolysis; distal neurogenic changes were present in all, and brainstem auditory evoked potentials, recorded in seven patients, were normal, suggesting that the cranial nerves are not affected [11].

The nature of the myelin lesion is debated. GeneReviews and the Bulgarian biopsy studies describe congenital hypomyelination [1, 20]. Walter and colleagues interpret the almost normal NCV in the youngest patients, followed by a fall and stabilisation, as a sign of demyelination rather than hypomyelination, and propose classifying CCFDN as a recessive demyelinating sensorimotor neuropathy; they admit two alternatives, demyelination superimposed on a primary developmental hypomyelination, or nerve conduction (and perhaps myelin) that does not mature beyond the infantile state [11].

In the Walter cohort, paresis of the small hand muscles and the foot extensors worsened in all 16 patients over 10 years, and the authors concluded that axonal loss is the main determinant of long-term disability [11]. Loss of tendon reflexes, beginning in the lower limbs, was universal, and no patient complained of sensory loss in the hands or feet; disability was greater in older children and adults, and was greatest in the patient who had no access to physiotherapy in early childhood [11]. Distal weakness did not differ between patients with and without rhabdomyolysis, and only those who had rhabdomyolysis developed proximal weakness [11]. Progression to severe disability in the third decade is the classic description [1, 19].

The functional measures of the Walter cohort quantify this disability. The Vignos scale (1, independent walking with stair climbing; 9, wheelchair dependence) ranged from 1 to 7 at the first assessment and 10 years later; the mean for the reassessed patients went from 2.9 to 2.7 according to the results (2.6 according to the discussion of the same article), without a clear correlation with age, and patients scoring above 4 at the first assessment did not improve [11]. The 10-metre walk test, the nine-hole peg test (9-Hole Peg Test, fine motor skills) and the Charcot-Marie-Tooth Neuropathy Score (CMTNS) were applied only at reassessment: walking speed was 0.4 to 1 m/s (mean 0.5 m/s), against a mean of 1.5 m/s in a healthy British population with a median age of 19 years; the nine-hole peg test took 30.5 to 106 seconds with the dominant hand (mean 57) and 30 to 214 seconds with the non-dominant hand (mean 90); and the CMTNS ranged from 8 to 27 (mean 13), unrelated to age [11]. Without baseline measurement of these three tests, the values describe the state at the end of follow-up and not its evolution.

3.5. Central nervous system

Early intellectual development is slow, and most children begin to speak at about 3 years [1]. In Chamova's cohort (22 patients, 11 men and 11 women, mean age 23.5 ± 13.66 years), mean age at onset of speech was 2.98 ± 2.15 years (1.3 to 12 years); 18 patients had mild intellectual disability and 4 borderline intelligence, none had normal intelligence or moderate or severe disability, and all domains tested (general intelligence, verbal memory, executive functions, language) were similarly affected [32]. The comparison was made with 24 matched controls from the same social and educational background, and there was no correlation between cognitive impairment and age or motor severity, suggesting a non-progressive deficit [32]. The patients were socially integrated but needed guidance in daily life [32]. GeneReviews estimates that about 10% of patients have normal or borderline performance and recommends interpreting tests taking into account the visual deficit, schooling and the language in which they are administered [1]. In the Walter cohort, psychological assessment of seven children (Kaufman battery in four and the Hamburg-Wechsler Intelligence Test for Children, HAWIK-III, in three) gave subnormal to borderline values; most patients attended mainstream school and completed secondary education with a certificate, and only some required special school or integrated education; all the children were bilingual in German and Serbo-Croatian, and some spoke a third language [11].

Cerebellar involvement (ataxia, nystagmus, intention tremor, dysmetria) is variable [1]. Among the 28 Bulgarian children, six older than 6 years had ataxia [10]; in Chamova's cohort, five had mild ataxia, with a Klockgether score between 7 and 11 out of 35 [32]; and in the Walter cohort the Klockgether ataxia score (each item from 0, best, to 5, worst) was 6 to 25 (mean 15) at the first assessment and 4 to 20 (mean 11) 10 years later, with improvement in most patients; the article also reports a mean improvement of 1.7 points over 10 years, a figure that does not match the difference between the two means [11]. In that cohort, ataxia was the predominant symptom in childhood and the cause of delayed walking (most walked at 2 years), improved with regular physiotherapy and only worsened again many years later, with progression of the neuropathy; the authors dispute the designation of “paleocerebellar” gait, because no MRI showed cerebellar abnormalities [11, 24]. Pyramidal signs without spasticity, chorea and other hyperkinesias, postural tremor of the upper limbs and extensor plantar responses occur in some patients [1, 18, 32]. In the Walter cohort, none of the 16 patients had pyramidal signs or a movement disorder [11]. The electroencephalogram is often abnormal, with diffuse slow activity [18].

Magnetic resonance imaging (MRI) shows abnormalities that increase with age and may be absent in children [18]. In Chamova's cohort, MRI was abnormal in 19 of 20 patients (95%): cerebral atrophy with dilatation of the lateral ventricles and subarachnoid spaces in 18 (mild in 7, moderate in 6, severe in 5), white matter hyperintensities in 18 (frontal periventricular in 17, parieto-occipital in 9, frontal U-fibres in 7 and parieto-occipital U-fibres in 6), periventricular rim in 13, white matter volume loss in 4, thin corpus callosum in 3 and cerebellar atrophy in a single patient [32]. Severity scores (scale adapted from metachromatic leukodystrophy, maximum 33) ranged from 0 to 18, with values above 10 in three patients aged 37 to 46 years; all adults had complete central myelination, a pattern different from the hypomyelinating leukodystrophies, and only short-term verbal memory correlated with the imaging changes [32]. In a 10-year-old Italian boy, focal supratentorial white matter lesions progressed on serial scans, other causes having been excluded, and the authors suggested a demyelinating mechanism common to nerve and brain [34]. In five patients studied by diffusion tensor MRI, increased apparent diffusion coefficient and reduced fractional anisotropy in the vermis and medulla suggested axonal loss [1, 10]. Unlike in MSS, cerebellar atrophy is not typical [32]. In the Walter cohort, brain MRI, performed in 13 patients aged 1 to 19 years and almost always before the molecular diagnosis, was normal in six and showed non-specific changes in seven, mainly ventricular dilatation, with mild diffuse atrophy in a 1-year-old infant and non-specific periventricular gliosis in an 18-year-old patient; none had cerebellar atrophy [11].

3.6. Endocrinology and bone

Growth hormone is at the lower limit of normal, with a pronounced rise after insulin-induced hypoglycaemia, suggesting a mild regulatory deficit [1]. Secondary sexual development and menarche are normal, but most adult women report irregular cycles and secondary amenorrhoea between 25 and 35 years [1]. More than half of adults of both sexes have hypogonadotrophic hypogonadism, with low testosterone and subnormal follicle-stimulating hormone (FSH) in men and low oestradiol and subnormal luteinising hormone (LH) in women [1, 19]. In 2006 Kalaydjieva considered that the classification as hypogonadotrophic was not conclusive and that the problem might lie in gonadal gene expression [18]. The effect on fertility has not been studied [1]. Bone mineral density is reduced in cortical and trabecular bone, probably through the combination of hypogonadism and low physical activity [1, 18].

The Walter cohort differs from the Bulgarian one regarding the gonadal axis: hormone levels were normal for age in all patients studied, puberty began at the usual age in all and one patient later had a healthy child, although the results table records isolated low values of oestrogen in one female patient and of testosterone in one male patient [11]. Bone density, measured by peripheral quantitative computed tomography or dual-energy X-ray absorptiometry (DXA) in 12 patients, was normal in four and showed mild osteopenia in two, moderate osteoporosis in two and marked osteoporosis in four, in one case in a wheelchair-dependent patient; osteoporosis accompanied vitamin D deficiency in some patients, not in all [11]. The authors write that osteoporosis was not frequent, unlike in the Bulgarian series, and attribute this to healthcare and regular access to physiotherapy in Germany and Austria; the article's own table, however, records osteoporosis in half of the patients assessed [11].

The same cohort found fat-soluble vitamin deficiencies, not previously described in CCFDN. In 14 patients, vitamin D was low in 8, vitamin E in 5 and vitamin A in 4, with B-complex vitamins, vitamin K and carotene normal in all; vitamins A and E were low mainly in patients with recurrent rhabdomyolysis, an association the authors acknowledge may be coincidental in such a small subgroup [11]. The lipid profile was normal in 13 of 14 patients (12 of 13 according to the discussion), with one raised cholesterol; postprandial chylomicronaemia, assessed by ultracentrifugation and electrophoresis, was absent in 4 of 6 patients according to the text (the table records seven patients tested, with absence in five), and the authors suggest a relationship with chylomicron retention disease, already described with vitamin E deficiency in patients diagnosed with MSS [11]. Parathyroid hormone was slightly elevated in 3 of the 14 patients, with low vitamin D, and serum calcium and phosphate were normal in all [11]. Marinesco had compared the disease he described to an avitaminosis [11]. A child with bilateral orchidopexy [17, 35] and congenital inguinal hernia in two siblings [17] have been described.

3.7. Muscle: parainfectious rhabdomyolysis

Parainfectious rhabdomyolysis is the most serious acute complication and may be an integral part of the phenotype [1]. It occurs after a febrile illness, mainly viral, with acute and severe proximal weakness, myalgia, myoglobinuria and very high CK; outside these episodes, proximal weakness is not typical [1]. The episodes tend to recur and are dramatic, but in the published series they resolved without progressing to acute kidney injury [1]. In the Walter cohort, 6 of the 16 patients had acute, severe proximal weakness with myalgia, rhabdomyolysis, myoglobinuria and hyperCKaemia after febrile infections, with CK of 2,000 to 40,000 U/l during episodes and normal or slightly elevated between them; four had repeated episodes [11]. Two brothers, the most severely affected, became wheelchair-dependent at 22 years, after the fourth episode, with permanent proximal weakness; the article's abstract reports permanent loss of ambulation in 3 patients, but the results text identifies only these two [11]. The numbering of the patients with rhabdomyolysis also differs between the results (patients 1–5 and 11) and the discussion (patients 1–5 and 12), which adds these cases to the 9 patients then published worldwide [11]. Electromyography during the episodes showed proximal myopathic changes that disappeared after recovery [1, 11]. In the 1998 German series, CK reached 40,000 U/l and normalised within 2 weeks in all the children, motor recovery took about a month in two, and one child with recurrences was left with severe disability [2]. Mastroyianni and colleagues described the first Greek case, a boy homozygous for the founder variant with demyelinating neuropathy (motor NCV 25 m/s and sensory 35 m/s): at 3.5 years, while convalescing from a febrile respiratory infection due to influenza A virus, he had acute weakness with muscle and abdominal pain, CK of 48,530 U/l, myoglobinuria, lactate dehydrogenase of 5,930 U/l and elevated transaminases, with normal CK-MB, urea, creatinine, electrolytes and carnitine; CK normalised in 10 days, but the child was unable to walk for 6 weeks [36]. At 5.5 years, 5 days after a febrile infection with no agent identified (influenza A and B negative), the episode recurred with peak CK of 44,174 U/l, normalised in 12 days; he was unable to sit for 3 weeks and only walked again, with an unsteady gait, in the 9th week, with partial recovery [36]. The table in that article gathers the six patients then published (one Italian, four German and the Greek boy): the first episode always arose in childhood (between 2 and 7 years in the dated cases), a few days after a febrile illness, with CK between 1,767 U/l (a value measured only 2 weeks after the onset of myalgia) and 52,072 U/l, and the interval to recovery ranged from 3 weeks to 1 year; in the same patient, subsequent episodes tended to have slower recovery (for example, 3 weeks in the first and 3 months in the second episode of a German boy) [36]. One of the German patients had only intense myalgia during febrile infections, without prolonged weakness, and myalgia after prolonged exercise; the authors point to prolonged exercise and general anaesthesia as other possible triggers [36]. In the Czech series, 3 of 10 children had rhabdomyolysis after a viral infection; one boy had four episodes, at 9, 12, 15 and 16 years, always with recovery to his previous state [24]. In his second episode, CK was 679 μkat/l on day one (about 300 times the upper limit of 2.27 μkat/l) and fell to 542, 235, 150, 51, 20.27 and 3.76 μkat/l on days 2, 4, 6, 9, 12 and 18; in the first episode, treated with forced diuresis without dialysis, there were raised antibodies against Coxsackie virus and adenovirus, without myocardial or renal involvement [24]. A girl from the same series had an initial CK of 627 μkat/l at 7 years, and it was the electromyography of that episode that revealed the demyelinating neuropathy [24]. Recovery may take between 2 and 6 months and up to a year, and recurrent episodes worsen the neuropathy [1]. The true frequency of rhabdomyolysis and its triggers have not been determined [18].

Muscle biopsy shows mild myopathic changes with scattered necrotic fibres, normal histochemistry for myophosphorylase and phosphofructokinase and no mitochondrial pathology [1]. In the most severely affected patient in the Walter cohort, muscle MRI of the proximal lower limbs showed generalised symmetric atrophy with fatty degeneration and, with gadolinium, diffuse oedema consistent with rhabdomyolysis; the biopsy, performed earlier, had normal fibre size variation, without inflammation or necrosis, histochemistry without a defect of mitochondrial, lipid or glycogen metabolism, mitochondria of normal size on electron microscopy and normal respiratory chain enzymes [11]. The authors ask for CCFDN to be included in the list of neurogenetic disorders causing recurrent rhabdomyolysis [11]. One patient had myalgia with prolonged exercise [1].

3.8. Rare findings

The 2025 review gathers findings described in isolated cases, whose causal relationship with CCFDN is not established: severe dilated cardiomyopathy triggered by a febrile illness, with fatal cardiorespiratory collapse in a Greek boy, whose sister had microcephaly, dystonia, ataxia and demyelinating neuropathy with axonal loss [17, 37]; generalised tonic-clonic epilepsy responsive to standard antiseizure medications in a Romanian girl [17]; developmental dysplasia of the hip with normal intelligence in a Roma girl of Hungarian origin studied in the Netherlands [17, 38]; and, in a Czech child, megaureter and hydronephrosis detected on prenatal screening [24]. A consanguineous Czech family had both CCFDN in an uncle and nanophthalmos due to a homozygous PRSS56 variant in his niece and her father, which shows that two ocular founder disorders can coexist in the same family [39].

3.9. Pregnancy

Only three women with CCFDN have been described as having children; the pregnancies were uneventful and reached term [1].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

In the newborn and infant, suspicion arises at the eye examination. Bilateral cataracts with microcornea, microphthalmia and micropupils in an infant of Roma ancestry make CCFDN the most likely diagnosis, and the combination of ocular findings with ethnic information allows the diagnosis at an age when the non-ophthalmological manifestations are not yet apparent [1, 18, 31]. Intrauterine growth restriction and low birthweight reinforce the suspicion [1].

Between the first and fourth years, the sign is motor delay: children sit late, walk between 2 and 3 years with an unsteady gait and speak at about 3 years; NCV, normal up to 18 months, then falls into the demyelinating range [1, 10]. Lassuthova and colleagues describe an alerting triad: bilateral congenital cataract, developmental delay and later demyelinating neuropathy [24]. After 4 years, areflexia, distal weakness and foot deformities become evident; after 10, sensory changes; in late childhood, facial dysmorphism; and in adults, short stature, hypogonadism and, in women, secondary amenorrhoea [1].

The suggestive clinical criteria in GeneReviews are: bilateral congenital cataracts, microcornea and micropupils; mild facial dysmorphism from late childhood; hypo- or demyelinating peripheral neuropathy; mild non-progressive intellectual disability; intrauterine growth restriction with short stature and low weight in adulthood; and a family history consistent with autosomal recessive inheritance, the absence of which does not exclude the diagnosis [1].

4.2. Settings that delay diagnosis

In the Czech series, the correct diagnosis was never made before 2 years; a child with rhabdomyolysis at 2 years was initially diagnosed with Guillain-Barré syndrome and only received the correct diagnosis at 4 years [24]. The child described by Masters and colleagues had the same initial error [17]. Several children were labelled as MSS before molecular testing [2, 3], and a Czech man, uncle of the proband of a family with nanophthalmos, only received the definitive diagnosis at 41 years [17, 39]. In Roma infants, galactokinase deficiency, also a founder disorder in this population, is the main alternative diagnosis for the cataracts [1].

4.3. Emergency signs

Acute muscle weakness, mainly proximal, with myalgia or dark urine in the days following a febrile illness indicates rhabdomyolysis and requires immediate assessment, with measurement of CK, urinary myoglobin, electrolytes and renal function [1, 24]. Patients and carers should be aware of this risk so that they seek care at the first symptoms and thus prevent acute kidney injury [1, 18]. In anaesthesia-associated rhabdomyolysis, sudden bradycardia with peaked T waves or cardiac arrest due to hyperkalaemia may occur [35]. In the perioperative period, seizures, pulmonary oedema and inspiratory stridor are described complications [1, 12]. New visual loss or eye pain after cataract surgery may reflect a pupillary occlusion membrane, capsular opacification or secondary glaucoma [10, 24].

4.4. Newborn screening

There is no molecular newborn screening for CCFDN. The Czech Republic introduced newborn screening for congenital cataracts in 2005, and Lassuthova and colleagues propose testing for the founder variant in all Roma children with congenital cataract detected by that screening [24]. Hudec and colleagues reiterate the recommendation to test all Roma children with congenital cataract [35].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

The diagnosis is established by identification of biallelic pathogenic or likely pathogenic variants in CTDP1 [1]. In 2006, Kalaydjieva proposed primary clinical criteria (bilateral congenital cataracts with microcornea, microphthalmia and micropupils; developmental delay; short stature and low weight; hypo- or demyelinating neuropathy; mild facial dysmorphism; mild hypogonadism) and additional criteria (mild cognitive impairment; cerebral and spinal atrophy on imaging; post-infectious rhabdomyolysis; osteoporosis), with a clinical diagnosis supported by electrophysiology and imaging and a definitive molecular diagnosis [18]. Homozygosity for c.863+389C>T confirms the diagnosis [1].

5.2. Complementary tests

5.3. Molecular tests and their limitations

The 100% refers to the proportion of known pathogenic variants that the method detects, not to clinical sensitivity in a patient with a similar phenotype; a negative targeted test does not exclude a different CTDP1 variant or another diagnosis [1, 18]. An exome limited to coding regions and exon–intron junctions does not cover a position 389 nucleotides from the exon, and the variant will not appear on a neuropathy or cataract panel that does not explicitly include it [1]. In the Czech family with nanophthalmos, exome sequencing identified the PRSS56 variant, but the uncle's CCFDN was confirmed by targeted testing, and the authors emphasise that phenotypic assessment and knowledge of founder variants remain necessary [39]. Linkage analysis is unreliable because the ancestral haplotype persists on normal chromosomes in the same population [18]. In non-Roma patients with a compatible phenotype, Kalaydjieva recommended sequencing CTDP1 and SIL1 and storing cultured cells for RNA study, because other CTDP1 variants, if they exist, would probably also have a partial effect and be intronic or regulatory [18].

5.4. Interpretation and reporting

The report should state the gene, the versioned transcript (NM_004715.5), the variant in HGVS (c.863+389C>T; p.?), the genomic coordinate, zygosity, the classification according to the standards of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and, when there are two different variants, confirmation that they are in trans by parental testing [1, 4]. The historical nomenclature IVS6+389C>T should be converted [1]. Homozygous variants of uncertain significance (VUS), or a pathogenic variant with a VUS, neither establish nor exclude the diagnosis [1]. Parental testing is recommended to confirm heterozygosity in both [1].

5.5. Algorithm

5.6. Prenatal and preimplantation diagnosis

Once the familial variants are known, prenatal diagnosis and preimplantation genetic testing are possible [1]. Kalaydjieva recommended analysis of chorionic villus DNA [18], and prenatal diagnosis has been described in a subsequent pregnancy of a Greek family [40]. The prenatal ultrasound phenotype is not described in the sources consulted.

6. Differential Diagnosis

6.1. Comparative table

AR: autosomal recessive; AD: autosomal dominant; XL: X-linked; NCV: nerve conduction velocity.

6.2. Galactokinase deficiency

In a Roma infant with cataracts, when there are not yet other signs, galactokinase deficiency is the main differential [1, 18]. It is also a Roma founder disorder: Kalaydjieva and colleagues identified the GALK1 p.(Pro28Thr) variant in six Bulgarian families in 1999, and OMIM attributes to it the cases of juvenile cataracts described by Gitzelmann in a Gypsy family in 1967 [41]. The variant, normalised as NM_000154.2:c.82C>A p.(Pro28Thr), is classified as pathogenic or likely pathogenic in ClinVar [4, 42]. In the Morar series, carrier frequency was 1.54% across 1301 Roma controls, with 6.45% among the Lom and 2.88% among the Rudari [9]. The distinction is made by specialist ophthalmological examination, looking for the other ocular manifestations of CCFDN, and by testing for the two founder variants; the practical importance is that the cataracts of galactokinase deficiency can be prevented with a lactose-free diet [18, 41].

6.3. Marinesco-Sjögren syndrome

MSS was the diagnosis given to the first families with CCFDN outside Bulgaria, and it is the differential with the most overlap: cataracts, developmental delay, short stature, ataxia and hypogonadism occur in both [3, 21]. Kalaydjieva summarised the differences in a table that remains useful [18]:

Source: Kalaydjieva 2006 [18].

GeneReviews indicates as the most useful discriminators ophthalmological examination (extensive anterior segment involvement in CCFDN), neurophysiology (reduced NCVs in CCFDN), neuroimaging (cerebellar atrophy in MSS) and muscle biopsy ultrastructure, considered specific to MSS [1]. Cognitively, CCFDN is homogeneous (borderline to mild), whereas MSS ranges from normal intelligence to severe disability [32]. OMIM describes the hypogonadism of MSS as hypergonadotrophic [43]. In the Walter cohort, ataxia was the predominant symptom in childhood, contrary to the “rare” classification in Kalaydjieva's table, but it improved with age, and none of the 13 brain MRIs showed cerebellar atrophy, which keeps imaging as a discriminator [11]. SIL1-related MSS is the main differential diagnosis.

6.4. GBA2 and INTS1

GBA2-related disease was described in a family with an MSS-like phenotype, with normal early development, progressive ataxia in early childhood, lower-limb spasticity, axonal neuropathy, mild cognitive decline and cataracts only later; in OMIM it corresponds to autosomal recessive spastic paraplegia 46, with cerebellar signs, cognitive impairment and cataracts in some patients [1, 44, 45]. The axonal neuropathy, spasticity and postnatal onset separate it from CCFDN.

The INTS1-related neurodevelopmental disorder shares cataracts, short stature and dysmorphism, but has no peripheral neuropathy [1]. The OMIM series describe cataracts between 1 and 3 years, sometimes with microphthalmia or microcornea, moderate to severe intellectual disability with absent or poor speech in many patients, and usually normal brain imaging [46]. A Polish case published in 2025, with two novel compound heterozygous missense variants, broadens the spectrum to milder forms, with preserved speech and no intellectual disability in some of the patients described [47]. INTS1 and CTDP1 take part in the same RNA polymerase II regulatory pathway, which may explain the overlap [17].

6.5. Hereditary neuropathies in the Roma and demyelinating CMT

A Roma child with demyelinating neuropathy should be tested for the founder variants known in this population. HMSN-Lom (CMT4D, due to NDRG1 p.(Arg148Ter)) is the most common form of CMT in the Roma, with 104 known cases in Bulgaria alone in 2004, and is associated with deafness in the third decade, without cataracts [10, 48]. HMSN-Russe is another severe recessive neuropathy described in the same groups [10]. Congenital myasthenic syndrome due to CHRNE 1267delG and limb-girdle muscular dystrophy 2C due to SGCG p.(Cys283Tyr) complete the group of founder neuromuscular disorders, and about one in ten European Roma carries one of the four variants (NDRG1, CHRNE, CTDP1, SGCG) [10]. In the Hungarian CMT cohort, the CTDP1 variant explained 0.8% of all patients, the same as EGR2, which justifies including it in the demyelinating neuropathy panels used in populations with Roma patients [17, 29]. The sarcoglycanopathies (LGMD R3, R4, R5 and R6) also enter the differential diagnosis.

6.6. Rhabdomyolysis and acute weakness

A child with acute weakness after an infection may be diagnosed with Guillain-Barré syndrome, as happened in at least two published cases [17, 24]. Very high CK, myoglobinuria, a history of operated cataracts and a prior chronic neuropathy point to CCFDN. Muscle biopsy in CCFDN has normal histochemistry for myophosphorylase and phosphofructokinase and shows no mitochondrial pathology, which, in this context, rules out muscle glycogenoses and mitochondrial myopathies as the explanation for the rhabdomyolysis [1]. The relationship with malignant hyperthermia is discussed in section 7.

7. Treatments and Risk Management Strategies

7.1. Principles and evidence base

There is no treatment directed at the molecular defect and no authorised drug for CCFDN, and GeneReviews records that no clinical practice guidelines have been published [1]. The available recommendations are expert opinion, based on observational cohorts: those of GeneReviews for general management and the OrphanAnesthesia anaesthetic recommendation, a project of the German Society of Anaesthesiology and Intensive Care Medicine (DGAI), drawn up by two anaesthesiologists and published in 2023 [1, 12]. There are no controlled trials of any intervention [33]. Management is multidisciplinary (paediatric ophthalmology, paediatric neurology and neurology, physical and rehabilitation medicine, orthopaedics, endocrinology, anaesthesiology and genetics), and the most disabling manifestations, although not curable, are manageable, allowing acceptable quality of life and daily activities [18].

Sources: [1, 10–12].

7.2. Initial assessment after diagnosis

GeneReviews recommends ophthalmological examination (cataracts and the other ocular manifestations); neurological examination with nerve conduction studies (neuropathy and cerebellar signs); assessment by orthopaedics, physical and rehabilitation medicine, physiotherapy and occupational therapy (gross and fine motor skills, mobility, activities of daily living, need for assistive devices); developmental assessment (motor, adaptive, cognitive, speech and language; need for early intervention or special education); endocrinological assessment (growth, fertility, osteopenia); and genetic counselling [1].

7.3. Eye

The cataracts are treated surgically, and all children in the published series underwent surgery in the first year of life [1, 24]. The micropupils with fibrotic margins make surgery difficult and may require mechanical pupil dilation methods [1]. Postoperative inflammatory reactions are exaggerated, and the foreign body reaction to contact lenses and intraocular lenses is intense and non-specific; intraocular lenses are generally better tolerated than contact lenses, and postoperative follow-up must be close [1, 18]. Pupillary occlusion membranes may require reconstructive surgery and capsular opacification leads to frequent reoperations [10]. The chronic papillary conjunctivitis and meibomian gland dysfunction associated with the floppy eyelid and contact lenses require ocular surface treatment [10]. Secondary glaucoma (8 eyes in 5 of 10 Czech children) justifies lifelong ophthalmological follow-up, and amblyopia is the main limit on final acuity [24].

7.4. Neuropathy, orthopaedics and rehabilitation

The neuropathy is treated symptomatically by physical and rehabilitation medicine, with corrective orthopaedic surgery for secondary bone deformities and positioning and mobility aids [1]. Physiotherapy aims to maximise mobility and reduce late orthopaedic complications (contractures, scoliosis, hip dislocation); occupational therapy works on fine motor skills for feeding, hygiene, dressing and writing; and assistive devices include wheelchair, walker and orthoses [1]. In the Walter cohort, early and sustained physiotherapy brought functional benefit, and ataxia scores stabilised or improved; the patient without access to physiotherapy in early childhood had the most severe disability in the cohort, and the authors add surgery for foot deformities to early cataract surgery and physiotherapy as key interventions for independence [7, 11]. Rehabilitation should target prevention and treatment of scoliosis and foot deformities, and even children who only walk after 6 years can progress [24]. Severe neuromuscular scoliosis may require surgical correction, as in the case described in section 10 [35]. Cerebellar signs are treated with physiotherapy and occupational therapy [1].

7.5. Development and education

GeneReviews recommends early intervention from 0 to 3 years (occupational therapy, physiotherapy, speech therapy, support for sensory impairment), preschool education with an individualised education plan from 3 to 5 years, follow-up by a developmental paediatrician and a transition plan in adolescence; the educational team should include a vision support specialist, and augmentative and alternative communication helps those with expressive difficulties without hindering speech [1]. These recommendations reflect the United States system and should be adapted to the organisation of each country [1]. Cognitive assessment should take into account the patient's visual deficit, schooling and language [1].

7.6. Parainfectious rhabdomyolysis

Patients and carers should know that rhabdomyolysis usually occurs after a febrile illness, and any sign (muscle weakness, dark urine) requires urgent assessment [1]. The immediate aim is to prevent acute kidney injury [18]. Supportive treatment has no CCFDN-specific protocol; a Czech boy was treated with forced diuresis, without the need for dialysis [24]. The only published description of a corticosteroid regimen is that of the Walter cohort, which GeneReviews summarises as a treatment option (oral corticosteroids for 2 to 3 weeks, without specifying the drug or dose) [1, 11]. Of the 6 patients with rhabdomyolysis, most received oral corticosteroids for 2 to 3 weeks, with complete recovery 2 to 6 months after starting treatment; in the 4 patients with repeated episodes, treatment was started in each episode shortly after symptom onset, with prednisone 2 mg/kg body weight per day, tapered to withdrawal, generally over 4 weeks, and recovery was slow, over 4 to 6 months [11]. The article does not state a maximum dose, tapering schedule, exact number of patients treated beyond these four, or adverse effects [11]. The authors' rationale is the hypothesis of an inflammatory mechanism, and the response is described as presumed: the biopsy of the most severely affected patient showed no inflammation, there was no control group, the two most severely affected brothers were left with permanent proximal weakness despite repeated treatment, and spontaneous recovery within 2 weeks to 1 month has also been described [2, 11]. None of the other sources read (Sabau, Müller-Felber, Mastroyianni, Lassuthova) specifies a corticosteroid or a dose [2, 17, 24, 36].

The reference dose is that of the Walter series. The labels of oral glucocorticoids serve only for comparison; none includes rhabdomyolysis, so the use is outside the approved indications. In Portugal, the comparator is prednisolone, and applying the Walter dose to this drug assumes the dose equivalence between prednisone and prednisolone stated in the FDA label:

Sources: [11, 50, 51].

The SmPC warns that glucocorticoids mask signs of infection and that patients with ongoing viral infections need close monitoring, which is relevant because the rhabdomyolysis of CCFDN occurs precisely after infections; it also warns that prolonged treatment can cause posterior subcapsular cataracts and glaucoma, delay growth in children and worsen osteoporosis, three problems already present in the disease [50]. A 2–4-week course entails less exposure to these effects than prolonged treatment, but the decision is individual. The Walter dose corresponds to twice the usual paediatric daily dose in the prednisolone SmPC (about 1 mg/kg); the Walter series does not define a maximum dose, and the SmPC states that there is no known maximum dose [11, 50].

Mastroyianni and colleagues argue that prevention and early diagnosis of rhabdomyolysis should be part of management, that patients and carers should receive education on prevention and treatment of episodes and, based on the information then available, that influenza vaccination be recommended for patients with CCFDN, a recommendation taken up by Sabau's review [17, 36]. The same authors point out that muscle lysis causes hyperphosphataemia, hyperkalaemia, hypo- or hypercalcaemia, hyperuricaemia and myoglobinuria, and that, if these abnormalities are not corrected in time with forced alkaline diuresis, acute kidney injury and death from arrhythmia can occur; this is the general principle of rhabdomyolysis treatment, with no CCFDN-specific protocol [36]. Walter and colleagues raised the hypothesis of benefit from fat-soluble vitamin supplementation, after finding vitamin D, E and A deficiencies in some patients; they proposed supplementing when levels were low, with follow-up measurement, but adherence was low, the article does not specify preparations or doses, and the benefit, including on rhabdomyolysis, was not assessed, so the authors call for studies to determine it [11, 17]. Prolonged exercise caused myalgia in one patient [1].

7.7. Endocrinology, growth and bone

The growth deficiency has no known treatment; growth hormone is at the lower limit of normal and GeneReviews does not expect a considerable effect from growth hormone treatment [1]. Hormone replacement therapy may be considered in young women with secondary amenorrhoea, because of the risk of osteoporosis [1]. Hormone replacement regimens are those of hypogonadotrophic hypogonadism in general. For osteoporosis, GeneReviews recommends regular rehabilitation [1]. The Walter cohort added to densitometry the measurement of vitamins A, D and E, parathyroid hormone, calcium and phosphate, and proposed supplementation of deficiencies with follow-up measurement [11].

7.8. Anaesthesia and the perioperative period

General anaesthesia has been associated with pulmonary oedema, inspiratory stridor, malignant hyperthermia and seizures; these complications are not unequivocally documented, but GeneReviews, Masters and Hudec recommend cautious use of general anaesthesia, close postoperative monitoring and, possibly, intensive care [1, 18]. The most frequent operations are cataract surgery, correction of scoliosis and limb deformities and tendon transfers; more rarely, correction of gonadal anomalies [12].

Source: OrphanAnesthesia [12].

Masters and colleagues, based on a child operated on in Birmingham, concluded that patients are at risk of rhabdomyolysis with certain anaesthetics but should not be labelled as malignant hyperthermia susceptible, and recommended avoiding depolarising relaxants, using non-depolarising ones with caution and minimising volatile agents, according to Sabau's review [17]. Walter and colleagues point out that the only case of malignant hyperthermia, reported in 1965 during cataract surgery, does not allow it to be known whether the patient had CCFDN or MSS, and that no other patient with CCFDN and rhabdomyolysis has had it; even so, they recommend careful monitoring during general anaesthesia and counselling about this risk [11]. The divergence is one of degree: all sources avoid suxamethonium and volatile agents when possible, and what differs is the classification of the risk as malignant hyperthermia or as anaesthesia-induced rhabdomyolysis [11, 12, 35]. The doses used in Hudec's case (rocuronium 0.6 mg/kg as a single bolus for intubation, propofol and remifentanil infusions guided by the bispectral index) are those of the report and do not constitute a recommendation [35].

7.9. Pregnancy, lactation and transition

Only three women with CCFDN have been described as having children, with uneventful term pregnancies [1]. Obstetric anaesthesia has not been described [12]. In pregnancy, the anaesthetic precautions in section 7.8 and the SmPC warnings on corticosteroids apply if rhabdomyolysis needs to be treated [12, 50]. Transition to adult care should include neurology (progressive neuropathy), ophthalmology (glaucoma), endocrinology (hypogonadism and bone) and reproductive counselling [1, 24].

7.10. Regulatory status, trials and developments

Sources: [11, 13, 50, 51].

ClinicalTrials.gov has a single record dedicated to CCFDN, study NCT01902940 (Natural History in CCFDN and IBM Syndromes, Ludwig-Maximilians-Universität Munich): observational, retrospective, with 350 participants including patients with inclusion body myopathies, conducted between June and October 2013, completed and without results posted on the registry [33]. The publication by Walter and colleagues declares this registration and presents the data of the 16 patients with CCFDN followed for 10 years [11]. There are no registered interventional trials.

Sources: [11, 33].

The absence of trials and designations found in these searches does not demonstrate that there are no unregistered programmes. The review by Sabau and colleagues, published in December 2025, discusses approaches that are purely conceptual, without its own experimental data: steric-blocking antisense oligonucleotides to mask the cryptic site (on the nusinersen model), small-molecule splicing modulators (on the risdiplam model), adeno-associated virus gene replacement (the cDNA of about 3.5 kb fits in the vector, but there are concerns about high systemic doses and overexpression), genome editing (limited by homologous recombination repair in post-mitotic cells) or RNA editing, and oligonucleotides targeting inhibitory elements of the 5′ untranslated region to increase translation of the normal transcript, which accounts for about 30% of the protein [17]. Delivery to peripheral nerve and lens epithelium is identified as the main obstacle [17].

Developments from November 2025 to October 2026, by level of evidence: conceptual review (Sabau, December 2025) [17]; preclinical mechanistic studies on the role of FCP1 in the polymerase phosphorylation intermediate, in Mediator recruitment and in splicing (July 2026) [26]; review of RNA polymerase II phosphorylation dynamics and human disease (July 2026) [52]; and broadening of the spectrum of the INTS1 differential [47]. There were no clinical trials, press releases, opinions or authorisations.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

Inheritance is autosomal recessive. The parents of an affected child are presumed to be heterozygous, and testing them is recommended to confirm carrier status and calculate the risk reliably [1]. At conception, each sibling of a patient has a 25% chance of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier [1]. The children of a patient are obligate carriers, unless the partner is also affected or a carrier, which is more likely in endogamous communities with a high carrier frequency; each sibling of the proband's parents has a 50% chance of being a carrier [1]. Heterozygotes do not develop the disease [1]. Neither germline mosaicism nor a de novo variant has been described; given the single founder variant, homozygosity is the expected situation [1].

8.2. Carrier testing and cascade testing

Carrier testing requires the familial variant to be identified, which in this disease is almost always c.863+389C>T [1]. Because of the endogamy of many Roma communities and the higher frequency of consanguineous marriages, GeneReviews recommends considering testing in the extended families of both parents and in the future partners of carriers [1]. Kalaydjieva adds that, given the high frequency of the variant and the endogamous tradition, discussion of consanguinity is irrelevant and may be counterproductive, and that most families accept counselling and predictive testing well [18]. In Bulgaria, community pilot programmes integrated into the National Programme for the Prevention of Genetic Diseases included education, screening for several founder variants, genetic counselling, prenatal diagnosis of at-risk pregnancies and training of health professionals and Roma mediators [10]; the Bulgarian samples in Morar's study came from that programme, with counselling before and after testing [9]. The marked differences in frequency between groups indicate that a carrier programme should be designed for the specific group: the variant is frequent in the Rudari and absent in other Vlax groups, such as the Bayash of Croatia [10, 30].

8.3. Siblings and minors

Apparently asymptomatic older and younger siblings of a patient should be tested, to start ophthalmological, neurological and endocrine treatment early [1]. This testing has direct clinical benefit and differs from carrier testing in minors, which mainly serves future reproductive decisions; counselling about risks and reproductive options should be offered to young adults who are affected, carriers or at risk of being carriers [1].

8.4. Prenatal and preimplantation diagnosis

The most appropriate time to determine risk and discuss prenatal diagnosis and preimplantation genetic testing is before pregnancy [1]. Once the variant is known, both are possible; Kalaydjieva advises analysis of chorionic villus DNA, and a Greek family underwent prenatal diagnosis in the pregnancy following the birth of an affected child [1, 18, 40]. Views on the use of prenatal diagnosis vary among professionals and families, and the decision is personal [1]. The impact of hypogonadotrophic hypogonadism on patients' fertility has not been assessed, and experience of pregnancy in affected women is limited to three uncomplicated cases [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What is known about frequency

The prevalence is unknown [1]. Orphanet places it in the <1/1,000,000 class, only as a class, and records 170 cases; GeneReviews counts about 190 patients up to 2022 and MedlinePlus about 150, all of Roma ethnicity [1, 8, 53]. These numbers measure published or referred cases, not prevalence, and Sabau and Lassuthova consider the disease underdiagnosed [17, 24]. No patient or carrier has been identified outside the Roma population [1].

9.2. Carrier frequency by group

Source: Morar et al. 2004, Table 1 [9].

The data show a variant concentrated in one subgroup: about 7% among the Rudari, a recently founded endogamous group, and much lower or zero frequencies in other groups of the same migration category [9, 18]. When the variant was discovered, screening of 887 controls found 6.9% carriers among the Rudari, 0.6% on average in other Roma groups and none among non-Roma Europeans [5]. Among the Bayash Roma of Croatia (Baranja and Međimurje), a Vlax group, none of 250 individuals tested was a carrier [30]. GeneReviews summarises this as about 7% in the Rudari and 1.4% in the Roma population in general [1]. Sabau's review states that the variant was absent in 832 non-Vlax and European controls; the original table shows that 832 is the total of Roma controls tested, with carriers in Balkan and Spanish groups, so that reading does not match the source [9, 17]. Summing the five founder variants studied by Morar, the cumulative carrier frequency was 12.9% [9].

9.3. Data by region

Bulgaria. It is the country of the original description, with more than 70 cases investigated by 2004; a door-to-door survey of 1400 residential areas, covering about 90% of the Roma population, identified 511 patients with neuromuscular diseases, among which CCFDN was one of the most prominent [10].

Central Europe. In the Czech Republic, a single laboratory diagnosed 10 children born between 1984 and 2004; with about 4000 Roma births per year, the authors estimated an incidence of 1 in 8000 Roma births, an estimate limited by the approximate denominator and probable underdiagnosis [24]. They found no carriers among 116 anonymous Roma controls from the Czech Republic and Slovakia, which places the observed frequency below 0.9% in a predominantly Romungro population [24]. In Hungary, the first case was published in 2007, in an extended Roma family, and the authors attribute the arrival of the variant to the emigration of Vlax Roma in the 18th century [54]; in the Hungarian CMT cohort, 0.8% of patients had CCFDN [29].

Other European countries. There are cases in Romania, Serbia, Greece, Italy, France and the Netherlands, and among migrants in Austria and Germany [17, 18]. In 2004, CCFDN appeared common among recent migrants from the former Yugoslavia [10]. Roma migrations from Central Europe after 1989 to the United Kingdom, Belgium, France, Spain, Germany and Canada broaden the area in which the disease may appear [24].

Iberian Peninsula and Portugal. At the 125th ENMC workshop, data from Spain (Catalonia and Valencia) and Portugal (collected by questionnaire from all Portuguese paediatric neurologists and neurologists and the molecular genetics department) showed that, among Iberian Roma, limb-girdle muscular dystrophy 2C was the most common neuromuscular disease, followed by peripheral neuropathies, and that HMSN-Lom, HMSN-Russe and CCFDN had been demonstrated in several cases, without breakdown by country; some Portuguese patients with CMT had associated cerebellar ataxia [10]. In Morar's study, 1.19% of 84 Spanish Roma were carriers of the variant [9].

The Americas. Kalaydjieva mentions cases diagnosed in the United States and Canada, without numbers [18]. The sources consulted contain no data from Brazil, which does not demonstrate the absence of patients.

9.4. Special populations and equity

European Roma (estimated at 8 to 10 million) are a founder population divided into multiple socially and linguistically distinct sub-isolates, with sustained endogamy [9]. The general health of Roma in Central and South-Eastern Europe is worse than that of the majority population, with lower life expectancy, and the genetic homogeneity of the “private” diseases simplifies diagnosis and prevention and makes them cheaper [24]. Collection of data on ethnic origin is sensitive, which limited, for example, the number of controls in the Czech study [24]. The Bulgarian programmes included Roma mediators and the promotion of equal access to health and social services [10].

9.5. European networks and resources

No source formally links CCFDN to a European Reference Network; by scope, EURO-NMD (neuromuscular diseases, including hereditary neuropathies), ERN-EYE (rare eye diseases) and ERN ITHACA (congenital anomalies and intellectual disability) are relevant [14–16]. MedlinePlus Genetics has a page dedicated to the disease, and GeneReviews also refers to the National Eye Institute for cataracts [1, 53]. The OrphanAnesthesia recommendation is freely available to anaesthesia teams [12]. The sources consulted did not identify CCFDN-specific patient organisations; Orphanet lists centres and organisations by country [8].

10. Illustrative Clinical Case

Hudec and colleagues, from Brno University Hospital, described in 2022 the anaesthesia of a 13-year-old Roma girl with CCFDN for posterior correction of neuromuscular scoliosis [35]. She had mild intellectual disability, with preserved communication; she walked about 20 metres without support and had limited upper-limb movement due to the neuropathy; the facial dysmorphism consisted of a prominent philtrum and upper incisors. The scoliosis was progressing, limited rehabilitation and reached a Cobb angle of 83°, so no brace was prescribed. A previous general anaesthetic, for cataract surgery in Prague, had been uneventful, with no record of the technique. She had a patent foramen ovale and pulmonary valve stenosis without haemodynamic repercussion, and there were no cases of rhabdomyolysis, seizures or CCFDN in the family. She weighed 45 kg and measured 136 cm, with height reduced by the curve; the Mallampati classification was 1 and the American Society of Anesthesiologists (ASA) class III. Laboratory tests were normal; pulmonary function tests showed a restrictive pattern (forced vital capacity of 54% and forced expiratory volume in the first second of 62%), and the radiograph showed the 83° curve (figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9131212/figure/F1/) [35].

The team chose total intravenous anaesthesia, to allow monitoring of motor evoked potentials and to avoid the rhabdomyolysis associated with other techniques. Induction was with propofol and a remifentanil infusion at 0.1 µg/kg/min, and a single bolus of rocuronium 0.6 mg/kg was given for intubation; direct laryngoscopy with a Macintosh 3 blade was Cormack-Lehane grade 1, and a 6.5 mm cuffed tube was placed at the first attempt, with no difficulty in mask ventilation. Anaesthetic depth was maintained with a bispectral index between 40 and 60, and evoked potential monitoring began only with a train-of-four ratio above 90%. Volatile anaesthetics were avoided. The patient was placed prone with gel pads because of the osteoporosis; blood loss was 1600 ml (36 ml/kg), with replacement of 754 ml of packed red cells, 200 ml of plasma, 4000 mg of fibrinogen, crystalloids and gelatin guided by thromboelastometry and pulse pressure variation, in addition to tranexamic acid. The evoked potentials did not change during the T2 to L2 fusion. Extubation took place 4 minutes after return to the supine position [35].

There was no rhabdomyolysis or seizure. The intensive care stay was free of cardiorespiratory complications, the wound healed by primary intention and the patient was discharged on day 11, without new neurological deficit. At 6 months, the scoliosis was compensated, with an almost unmeasurable curve and the instrumentation in the correct position (figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9131212/figure/F2/), and the patient continued regular physiotherapy [35]. The authors linked each sign of the disease to an anaesthetic risk: the ocular anomalies to iatrogenic eye injury, the micrognathia, malar prominence, prominent incisors and philtrum and cervical anomalies to a difficult airway, developmental delay to limited cooperation, the neuropathy to rhabdomyolysis, the scoliosis to restrictive lung disease and the osteoporosis to positioning injury [35].

The case illustrates three points of management. The first is that the airway, although predicted to be difficult, was easy, and the recommendation to have difficult airway equipment available stands [12, 35]. The second is that the technique without volatile agents or depolarising relaxants, with rocuronium reversible by sugammadex and neuromuscular monitoring, corresponds to the OrphanAnesthesia recommendation later written by the same authors, and not to an approach validated in a series [12]. The third is that the doses and volumes in the report are those of a specific patient and are not a routine recommendation. The dysmorphism that justified the airway preparation can be compared with the photographs of the Czech series, in which the prominent philtrum appears mainly in older children (https://pmc.ncbi.nlm.nih.gov/articles/PMC3976362/figure/F1/), and with patient 5 of that series, who had rhabdomyolysis at 2 years and was initially diagnosed with Guillain-Barré syndrome (https://pmc.ncbi.nlm.nih.gov/articles/PMC3976362/figure/F6/) [24].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

There is no prospective follow-up that allows life expectancy to be estimated; patients survive well into adulthood, with known cases over 40 years and patients up to 47 years in the Bulgarian cohort [18, 32]. The neuropathy progresses to severe disability in the third decade, and secondary axonal loss is the main determinant of long-term disability [1, 11]. In the Walter cohort, 6 of 16 patients had parainfectious rhabdomyolysis; permanent loss of ambulation is reported in 3 in the abstract and documented in the text in 2 brothers, at 22 years, after the fourth episode, and recurrences are the second determinant of the course [11]. Recovery from each episode takes 2 to 6 months and may reach 1 year [1]. The cognitive impairment is mild or borderline and does not correlate with age, suggesting non-progression, although longitudinal studies are lacking; MRI changes worsen with age [32]. Ataxia improves during childhood (mean Klockgether score from 15 to 11 over 10 years) and only worsens in adulthood, with the neuropathy; global motor function measured by the Vignos scale remained stable over 10 years, but patients with greater initial disability did not improve, and walking speed at the end of follow-up was about one third of that of healthy young people [11]. In the Czech series, mean final visual acuity was 0.1 and secondary glaucoma affected half of the patients [24]. In that group, the patients attended special schools; in the Walter cohort, most attended mainstream school and completed secondary education [7, 11, 24].

11.2. Surveillance

Asymptomatic siblings should be assessed as soon as the diagnosis is known in the family [1]. The patient should carry written information on the risk of rhabdomyolysis and the anaesthetic precautions, to be shown at any surgery or febrile episode [1, 12].

12. Summary and Final Considerations

CCFDN is an autosomal recessive developmental disorder, described so far only in Roma people, mainly of the Rudari group, in which about 7% are carriers; all known patients are homozygous for the same deep intronic CTDP1 variant, c.863+389C>T, which creates a splice donor site, inserts 95 nucleotides of Alu sequence into the mRNA and leaves about 15–35% of normal transcript. Partial deficiency of the RNA polymerase II C-terminal domain phosphatase makes it a transcription syndrome, with ubiquitous expression but a phenotype limited to the anterior segment of the eye, peripheral and central myelin, growth and the gonadal axis.

The diagnosis is simple when it is considered: a Roma infant with bilateral congenital cataracts, microcornea, microphthalmia and micropupils should undergo targeted testing for the variant, alongside testing for galactokinase deficiency. Outside this context, the variant escapes exomes and panels that do not cover deep introns. Motor delay, the fall in conduction velocity after 18 months to about 20 m/s, the dysmorphism of late childhood, short stature and hypogonadotrophic hypogonadism complete the picture, and the absence of marked cerebellar atrophy and of chronic myopathy separates it from Marinesco-Sjögren syndrome.

Management is supportive: early cataract surgery with surveillance for inflammatory reactions and glaucoma, rehabilitation and orthopaedics, developmental support and annual endocrinological assessment. The two acute risks are rhabdomyolysis after febrile infections, which can lead to permanent loss of ambulation and was treated in the Walter series with oral prednisone 2 mg/kg/day (no maximum dose defined in the source) withdrawn over about 4 weeks, without a control group, and anaesthetic complications, which the OrphanAnesthesia recommendation addresses with total intravenous anaesthesia, limitation of volatile agents and depolarising relaxants, rocuronium with sugammadex and postoperative monitoring. There are no authorised drugs, European orphan designations or interventional trials; splicing-correction therapies are, for now, conceptual proposals. Prevention rests on carrier testing directed at the groups with the highest frequency, with culturally appropriate counselling.

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