Alternative titles; symbols
SNOMEDCT: 702433001; ORPHA: 48431;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q23 | Congenital cataracts, facial dysmorphism, and neuropathy | 604168 | Autosomal recessive | 3 | CTDP1 | 604927 |
A number sign (#) is used with this entry because congenital cataracts with facial dysmorphism and neuropathy (CCFDN) is caused by homozygous mutation in the CTDP1 gene (604927) on chromosome 18q23.
Congenital cataracts, facial dysmorphism, and neuropathy is an autosomal recessive disorder that is prevalent among Bulgarian Gypsies. Additional features include delayed psychomotor development, skeletal anomalies, and hypogonadism. The predominantly motor neuropathy becomes evident during childhood and progresses to severe disability by the third decade (Tournev et al., 1999).
CCFDN is genetically distinct from Marinesco-Sjogren syndrome (MSS; 248800), although the 2 disorders share some overlapping features, including congenital cataracts, delayed psychomotor development, and ataxia (Merlini et al., 2002).
Tournev et al. (1999) identified a novel autosomal recessive demyelinating disorder among Gypsy families, which they proposed to call the 'CCFDN syndrome' for 'congenital cataracts, facial dysmorphism, and neuropathy.' The disorder was distinct from the Lom type of hereditary motor and sensory neuropathy (HMSNL; 601455), another autosomal recessive disorder associated with deafness found among Gypsy groups. CCFDN was found in 50 affected individuals who ranged in age from 8 months to 40 years. The disorder was first recognized in infancy by the presence of congenital cataracts and microcornea. Motor and intellectual development were delayed. Facial dysmorphism became evident during childhood, characterized by a prominent midface, thickening of the perioral tissues, forwardly directed anterior dentition, and hypognathism. A progressive distally accentuated, predominantly motor peripheral neuropathy affecting first the lower and then the upper limbs developed during childhood and adolescence and was associated with skeletal deformities. Motor and sensory conduction studies showed slowing into the demyelinating range. Nerve biopsy examination indicated generalized hypomyelination superimposed upon which were demyelination and axonal degeneration in older subjects. Central nervous system involvement was evidenced by a mild nonprogressive cognitive deficit, accompanied in some patients by extensor plantar responses, mild chorea, upper limb postural tremor, and mild ataxia. Magnetic resonance imaging demonstrated cerebral and spinal cord atrophy and occasional focal lesions. Associated nonneural features included short stature and hypogonadism with secondary amenorrhea in female subjects.
Tournev et al. (1999) reported observations on the peripheral nerve changes in 4 patients, ranging in age from 4 to 32 years, with this disorder. Myelinated fiber density was within normal limits. The salient abnormality was diffuse hypomyelination which, in the older patients, was associated with demyelination and then axonal degeneration. These findings could be correlated with the relative preservation of sensory action potential amplitude despite markedly reduced nerve conduction velocity. Unmyelinated axon density was preserved. The morphologic changes suggested a developmental process affecting myelination with a later superimposed degenerative disorder.
Muller-Felber et al. (1998) described 4 children from 2 German Gypsy families with congenital cataract and ataxia. All 4 had clinical and neurophysiologic signs of demyelinating polyneuropathy. Three of them developed acute rhabdomyolysis with marked weakness and CK levels up to 40,000 units/l following a viral infection. The CK levels returned to normal within 2 weeks. Symptoms were recurrent in 1 of the children and resulted in severe disability. In 2 other children, recovery of motor function took about 1 month following the first attack. Based on the findings of congenital cataract and ataxia, the authors referred to the phenotype as a 'new subtype of Marinesco-Sjogren syndrome with rhabdomyolysis.'
Merlini et al. (2002) reported 3 Italian Gypsy families who manifested clinical features of Marinesco-Sjogren syndrome, including congenital cataracts, delayed motor development, and ataxia, in addition to acute recurrent myoglobinuria, demyelinating neuropathy, facial dysmorphism, and mild mental retardation. These families originated from the same genetically isolated founder population as did patients with CCFDN. Merlini et al. (2002) noted that the phenotype was similar to that reported by Muller-Felber et al. (1998) in 2 unrelated Gypsy families from Germany.
Navarro and Teijeira (2003) provided a detailed review of neuromuscular disorders among the Romany Gypsies.
Walter et al. (2014) reported a 10-year follow-up of 16 patients with genetically confirmed CCFDN. The patients had developed worsening paresis of distal muscles of the hands and feet as well as recurrent episodes of rhabdomyolysis and myoglobinuria associated with proximal muscle weakness. Electroneurography studies showed a reduction in sensory nerve conduction velocities as well as a progressive reduction in sensory and motor nerve amplitudes. The ataxia became less severe and only worsened secondarily because of progression of neuropathy. Mental retardation was mild or borderline, and most patients were able to attend secondary schooling. The most disabling feature at 10-year follow-up was the motor and sensory neuropathy associated with secondary axonal loss, followed by recurrent parainfectious rhabdomyolysis, which was severe in a few patients. Physiotherapy resulted in clinical improvement of motor disabilities.
By linkage studies, Angelicheva et al. (1999) assigned the CCFDN locus to chromosome 18q23-qter, between D18S1141 and D18S1268. Linkage disequilibrium and highly conserved haplotypes suggested genetic homogeneity and founder effect. CCFDN colocalized with an EST that shows high homology to a conserved Drosophila gene involved in the regulation of nervous system development in vertebrates.
Using recombination mapping, Varon et al. (2003) refined the position of the CCFDN locus to a 155-kb critical interval. During haplotype analysis, they found that the nontransmitted chromosomes of some unaffected parents carried the conserved haplotype associated with the disease. Assuming such parents to be completely homozygous across the critical interval except with respect to the disease-causing mutation, they developed a new 'not quite identical by descent' (NQIBD) approach.
By multipoint linkage analysis of the German (Muller-Felber et al., 1998) and Italian Gypsy families with features of MSS, myoglobinuria, neuropathy and facial dysmorphism, Merlini et al. (2002) obtained a combined maximum lod score of 3.55 at marker 1908ca1 in the 18qter region where the CCFDN locus is located. Haplotype analysis of 6 markers in the same chromosomal region showed that the 6 patients shared several alleles with the haplotype found in CCFDN chromosomes. Merlini et al. (2002) suggested that the presumed 'subtype' of MSS with myoglobinuria and peripheral neuropathy is actually genetically identical to CCFDN and caused by a single founder mutation.
Lagier-Tourenne et al. (2002) reported clinical and linkage analyses of 1 Gypsy family and 1 Turkish family in which the patients presented with congenital or juvenile cataracts and ataxia. Both families were initially diagnosed as having MSS. The authors found that the Gypsy family had CCFDN features and was linked to 18qter, whereas the Turkish family had typical MSS features and was not linked to 18qter. Major clinical features of MSS that distinguished it from CCFDN were occurrence of more severe mental retardation, marked cerebellar atrophy, chronic myopathy with specific ultrastructural features on muscle biopsy, and the absence of peripheral neuropathy, facial dysmorphism, and microcornea. Thus, the study of Lagier-Tourenne et al. (2002) showed that classic MSS and CCFDN are clinically and genetically distinct.
The transmission pattern of CCFDN in the families reported by Varon et al. (2003) was consistent with autosomal recessive inheritance.
Varon et al. (2003) showed that CCFDN is caused by a single-nucleotide substitution in intron 6 of the CTDP1 gene (604927.0001).
Angelicheva, D., Turnev, I., Dye, D., Chandler, D., Thomas, P. K., Kalaydjieva, L. Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome: a novel developmental disorder in Gypsies maps to 18qter. Europ. J. Hum. Genet. 7: 560-566, 1999. [PubMed: 10439962] [Full Text: https://doi.org/10.1038/sj.ejhg.5200319]
Lagier-Tourenne, C., Chaigne, D., Gong, J., Flori, J., Mohr, M., Ruh, D., Christmann, D., Flament, J., Mandel, J.-L., Koenig, M., Dollfus, H. Linkage to 18qter differentiates two clinically overlapping syndromes: congenital cataracts-facial dysmorphism-neuropathy (CCFDN) syndrome and Marinesco-Sjogren syndrome. J. Med. Genet. 39: 838-843, 2002. [PubMed: 12414825] [Full Text: https://doi.org/10.1136/jmg.39.11.838]
Merlini, L., Gooding, R., Lochmuller, H., Muller-Felber, W., Walter, M. C., Angelicheva, D., Talim, B., Hallmayer, J., Kalaydjieva, L. Genetic identity of Marinesco-Sjogren/myoglobinuria and CCFDN syndromes. Neurology 58: 231-236, 2002. [PubMed: 11805249] [Full Text: https://doi.org/10.1212/wnl.58.2.231]
Muller-Felber, W., Zafiriou, D., Scheck, R., Patzke, I., Toepfer, M., Pongratz, D. E., Walther, U. Marinesco-Sjogren syndrome with rhabdomyolysis: a new subtype of the disease. Neuropediatrics 29: 97-101, 1998. [PubMed: 9638664] [Full Text: https://doi.org/10.1055/s-2007-973542]
Navarro, C., Teijeira, S. Neuromuscular disorders in the Gypsy ethnic group: a short review. Acta Myol. 22: 11-14, 2003. [PubMed: 12966699]
Tournev, I., Kalaydjieva, L., Youl, B., Ishpekova, B., Guergueltcheva, V., Kamenov, O., Katzarova, M., Kamenov, Z., Raicheva-Terzieva, M., King, R. H. M., Romanski, K., Petkov, R., Schmarov, A., and 10 others. Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations. Ann. Neurol. 45: 742-750, 1999. [PubMed: 10360766]
Tournev, I., King, R. H. M., Workman, J., Nourallah, M., Muddle, J. R., Kalaydjieva, L., Romanski, K., Thomas, P. K. Peripheral nerve abnormalities in the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome. Acta Neuropath. 98: 165-170, 1999. [PubMed: 10442556] [Full Text: https://doi.org/10.1007/s004010051065]
Varon, R., Gooding, R., Steglich, C., Marns, L., Tang, H., Angelicheva, D., Yong, K. K., Ambrugger, P., Reinhold, A., Morar, B., Baas, F., Kwa, M., and 14 others. Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome. Nature Genet. 35: 185-189, 2003. [PubMed: 14517542] [Full Text: https://doi.org/10.1038/ng1243]
Walter, M. C., Bernert, G., Zimmermann, U., Mullner-Eidenbock, A., Moser, E., Kalaydjieva, L., Lochmuller, H., Muller-Felber, W. Long-term follow-up in patients with CCFDN syndrome. Neurology 83: 1337-1344, 2014. [PubMed: 25186864] [Full Text: https://doi.org/10.1212/WNL.0000000000000874]