DiagnosisClinical Diagnosis Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) is a clinical diagnosis based on the following:Bilateral congenital cataracts, microcornea, and micropupils Mildly dysmorphic facial features apparent from late childhoodHypo/demyelinating peripheral neuropathy Mild non-progressive intellectual deficit Intrauterine growth retardation with subsequent small stature and subnormal weight in adulthood Molecular Genetic Testing Gene. CTDP1 is the only gene in which mutations are known to cause congenital cataracts, facial dysmorphism, and neuropathy.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Congenital Cataracts, Facial Dysmorphism, and Neuropathy View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityCTDP1Targeted mutation analysisc.863+389C>T (also known as IVS6+389C>T) in intron 6 2100%3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Founder mutation in the Roma/Gypsy population (also known as IVS6+389C>T) that results in aberrant splicing and premature stop codon (see Molecular Genetics) 3. To date, all affected individuals and carriers identified have been from the Roma/Gypsy population. Testing Strategy To confirm/establish the diagnosis in a probandThe diagnosis CCFDN is based on clinical findings. In the Roma/Gypsy population it is confirmed by identification of homozygosity for the founder mutation, c.863+389C>T (also known as IVS6+389C>T). Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in CTDP1.}

Natural History Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) is a complex disorder whose major manifestations involve the anterior segment of the eye, the skull and face, the nervous system, and the endocrine system [Tournev et al 1999a, Tournev et al 1999b, Tournev et al 2001, Merlini et al 2002]. EyeCongenital cataracts are the invariable first manifestation of the disease [Tournev et al 1999a, Tournev et al 2001]. The cataracts are bilateral and can appear as anterior or posterior subcapsular opacities with clouding of the adjacent part of the lens nucleus or as total cataracts involving the entire lens [Müllner-Eidenböck et al 2004]. Other ocular manifestations include microcornea, microphthalmia (documented by axial length measurements), and micropupils with fibrotic margins, showing sluggish constriction to light and dilation to mydriatics [Müllner-Eidenböck et al 2004]. Horizontal pendular nystagmus is very common [Tournev et al 1999a, Tournev et al 2001, Müllner-Eidenböck et al 2004] and unrelated to the visual defect caused by the cataracts.No fundus abnormalities are present.Facial FeaturesDysmorphic facial features become apparent in late childhood and are particularly evident in adult males. They include a prominent midface with a well-developed nose, thickening of the perioral tissues, forwardly directed anterior dentition, and hypognathism [Tournev et al 1999a]. Nervous SystemHypomyelinating peripheral neuropathy is symmetric and distally accentuated, with predominantly motor involvement progressing to severe disability by the third decade of life. In a study of 28 affected children ages four months to 16 years, Kalaydjieva et al [2005] observed an invariable delay in early motor development, with all starting to walk between ages two and three years, often with an unsteady gait. Clinical signs of lower-limb motor peripheral neuropathy (diminished or absent tendon reflexes, distal lower-limb weakness, and foot deformities) become apparent after age four years, and are soon followed by involvement of the upper limbs [Tournev et al 1999a, Merlini et al 2002, Kalaydjieva et al 2005].As muscle weakness progresses, spine deformities may also develop and lead to reduction in respiratory capacity [Merlini et al 2002].Sensory abnormalities in the lower limbs develop in persons older than ten years.Nerve conduction velocity is normal in infancy at the onset of myelination and subsequently begins to decline, stabilizing at approximately 20 m/s at around age four years [Kalaydjieva et al 2005]. Distal motor latencies are increased.Sensory nerve action potentials are of normal amplitude, suggesting a relatively uniform degree of slowing of nerve conduction across nerve fibers, consistent with congenital hypomyelination. Neuropathologic studies of sural nerve biopsies provide evidence of primary hypomyelination in the absence of morphologic abnormalities in the Schwann cell or axon [Tournev et al 1999b, Tournev et al 2001].Central nervous system manifestations vary in localization and severity and occur in different combinations. In addition to the delayed motor milestones (attributed partly to the peripheral neuropathy), early intellectual development is slow, with most affected children starting to talk around age three years. Formal assessment of cognitive ability reveals variable results, the interpretation of which should take into account the visual impairment, poor educational status, and language barriers (i.e., cognitive testing performed in a language other than the patient’s mother tongue). According to the available test results, around 20% of affected individuals have normal or borderline cognitive performance, and the rest have mild non-progressive intellectual deficit.Cerebellar involvement of variable severity with ataxia, nystagmus, intention tremor, and dysmetria is common [Tournev et al 1999a, Merlini et al 2002, Müllner-Eidenböck et al 2004]. Pyramidal signs without spasticity and extrapyramidal hyperkinesis can be observed as well [Tournev et al 2001].Magnetic resonance imaging (MRI) studies of the brain and spinal cord have given variable results. The original study identified abnormalities in 16 out of 17 persons [Tournev et al 2001]. Diffuse cerebral and spinal cord atrophy and periventricular white matter changes, the most common findings, are more pronounced in older individuals. Brain MRI in four affected children age five months to 15 years revealed abnormalities in three, including myelin immaturity and cerebral, cerebellar, and cervical hypotrophy. In another study [Kalaydjieva et al 2005], standard MRI failed to detect any abnormalities; however, diffusion tensor MRI results suggested axonal loss in the vermis and medulla oblongata. A follow-up study of an affected boy over a seven-year period found multifocal white matter hyperintensity on T₂-weighted imaging, suggesting a progressive mild demyelinating brain process [Cordelli et al 2010].OtherGrowth. Intrauterine growth retardation is suggested by a study of 22 individuals with CCFDN, born at term with significantly lower weight and length than in the general population [Chamova 2012]: Males. Birth weight 3.22±0.48 kg (reference value 3.9±0.5 kg); length 47.88±3.91cm (reference 53.1±2.1 cm)Females. Birth weight 3.06±0.53 kg (reference 3.8±0.6 kg); length 46.75±4.19 cm (reference 52.5±2.1 cm)Affected aduIts are of small stature and most are also of subnormal weight [Tournev et al 1999a]:Adult males. 149.2±5 cm and 47±7.2 kg (reference values: 173±6.8 cm and 73.9±10.4 kg)Adult females. 142.4±8.2 cm and 45.8±7.6 kg (reference values: 160.3±6.4 cm and 63±10.7 kg) Skeletal deformities, especially of the feet and hands, develop in the course of the disease as a result of the peripheral neuropathy, and are present in all affected adults.Endocrine system. Growth hormone levels in CCFDN are in the low-normal range, with a pronounced rise after insulin-induced hypoglycemia suggesting mild regulatory deficiency [Tournev et al 1999a]. Sexual development appears unimpaired, with normal secondary characteristics after puberty and normal menarche. However, most adult females report irregular menstrual cycles and early secondary amenorrhea at ages 25-35 years. Adults of both sexes show evidence of hypogonadotropic hypogonadism, with low testosterone and subnormal FSH levels in males and low estradiol and subnormal LH levels in females [Tournev et al 1999a, Tournev et al 2001]. The effect of these deficits on fertility is difficult to assess, as very few persons with CCFDN enter sexual relationships. Bone mineral density is decreased, possibly as the compound result of the endocrine involvement and the low physical activity due to the peripheral neuropathy [Tournev et al 1999a, Tournev et al 2001].Parainfectious rhabdomyolysis, a potentially life-threatening complication that leads to acute kidney failure, may in fact be an integral part of the phenotype. Rhabdomyolysis refers to disintegration of striated muscles and the release of intracellular content into the extracellular compartment, presenting clinically as profound muscle weakness, myoglobinuria, and excessively elevated serum concentration of creatine kinase. Rhabdomyolysis in CCFDN usually develops after febrile illness, mostly viral infections. The episodes are usually recurrent, acute, and dramatic but resolve spontaneously, with none of the affected individuals progressing to acute renal failure [Merlini et al 2002, Mastroyianni et al 2007]. Recovery of muscle function may take up to one year and such episodes can lead to deterioration in the clinical course of the peripheral neuropathy. Muscle biopsies have shown mild myopathic features with scattered necrotic fibers, normal histochemical reactions for myophosphorylase and phosphofructokinase, and no evidence of mitochondrial pathology [Merlini et al 2002].

Genotype-Phenotype Correlations The CCFDN phenotype is consistent, with little variation observed among affected individuals, all homozygous for the ancestral mutation c.863+389C>T in CTDP1.

Differential DiagnosisIn early infancy, when bilateral congenital cataracts are the only manifestation, the diagnosis of congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) is made highly probable by the detection of accompanying ophthalmologic abnormalities, such as microcornea and microphthalmia. In infants of Roma/Gypsy ancestry, the main differential diagnosis is galactokinase deficiency, an inborn error of galactose metabolism which, in this ethnic group, is caused by the p.Pro28Thr founder mutation in GK1 (GALK1) [Kalaydjieva et al 1999].The main differential diagnosis outlined by Marinesco et al [1931] and Sjögren [1950] is the Marinesco-Sjögren syndrome (MSS) an autosomal recessive disorder characterized by cerebellar ataxia with cerebellar atrophy, early-onset (not necessarily congenital) cataracts, mild to severe intellectual disability, hypotonia, and muscle weakness. Additional features include short stature and various skeletal abnormalities including scoliosis. Children with MSS usually present with muscular hypotonia in early infancy; distal and proximal muscular weakness is noticed during the first decade of life. Later, cerebellar findings of truncal ataxia, dysdiadochokinesis, and dysarthria become apparent. Motor function worsens progressively for some years, then stabilizes at an unpredictable age and degree of severity. Cataracts can develop rapidly and typically require lens extraction in the first decade of life. So far, only one gene, SIL1, has been found to be mutated in MSS [Anttonen et al 2005, Senderek et al 2005]. The clinical investigations providing the best distinction between CCFDN and MSS are ophthalmologic (cataracts in both but extensive involvement of the anterior eye segment in CCFDN), neurophysiologic (reduced nerve conduction velocity in CCFDN), and neuroimaging (cerebellar atrophy in MSS). It should be noted that MSS is a heterogeneous diagnostic category, which includes a substantial proportion of “atypical” cases that display a variety of additional phenotypic features (e.g., peripheral neuropathy) and may closely resemble CCFDN. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with congenital cataracts, facial dysmorphism, and neuropathy (CCFDN), evaluations are recommended to address the most disabling manifestations, namely:Visual impairment (ophthalmologic examination) Peripheral neuropathy and ensuing physical handicap (neurologic and orthopedic examinations, measurements of nerve conduction velocity) Treatment of ManifestationsThe treatment of cataracts is surgical. The surgical removal of cataracts may be complicated by the micropupils and fibrotic pupillary margins necessitating alternative mechanical methods of dilatation [Müllner-Eidenböck et al 2004]. Patients need close follow up because of unusually exaggerated postoperative inflammatory reactions and strong unspecific foreign-body reaction to contact lenses and intraocular lenses (with a generally better tolerance to intraocular lenses) [Müllner-Eidenböck et al 2004].The management of the peripheral neuropathy includes rehabilitation and corrective surgery for the secondary bone deformities. Hormone replacement therapy may be considered in young females with secondary amenorrhea and increased risk of osteoporosis. Prevention of Secondary ComplicationsIndividuals with CCFDN are prone to develop severe and potentially life-threatening complications related to anesthesia, such as pulmonary edema, inspiratory stridor, malignant hyperthermia, and epileptic seizures [Müllner-Eidenböck et al 2004] and thus need close monitoring and possibly intensive postoperative care.Affected individuals and care providers need to be aware of rhabdomyolysis as a potential complication following viral infections, and seek medical attention with the first recognizable symptoms. SurveillanceAnnual examinations to monitor for possible ophthalmologic, neurologic, and endocrine complications are warranted.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Congenital Cataracts, Facial Dysmorphism, and Neuropathy: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCTDP118q23RNA polymerase II subunit A C-terminal domain phosphataseIPN Mutations, CTDP1
CTDP1 homepage - Leiden Muscular Dystrophy pagesCTDP1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Congenital Cataracts, Facial Dysmorphism, and Neuropathy (View All in OMIM) View in own window 604168CONGENITAL CATARACTS, FACIAL DYSMORPHISM, AND NEUROPATHY 604927C-TERMINAL DOMAIN OF RNA POLYMERASE II SUBUNIT A, PHOSPHATASE OF, SUBUNIT 1; CTDP1Normal allelic variants. CTDP1 spans approximately 75 kb of genomic DNA. Alternative splicing generates two isoforms: isoform a (12 exons) is a 3,775-nt long transcript; isoform b (11 exons) is 3612 nt long. Pathologic allelic variants. The founder CCFDN-causing mutation, c.863+389C>T (IVS6 + 389C>T), triggers an unusual mechanism of aberrant splicing [Varon et al 2003]. It creates a canonical donor splice site, which activates an upstream cryptic acceptor site and triggers a rare mechanism of aberrant splicing. The cryptic acceptor site is utilized together with the regular intron 6 donor site to splice out an upstream part of the intron, while the newly created donor site together with the regular intron 6 acceptor site serve for the splicing of a downstream part of the intron. An intermediate Alu sequence of 95 nucleotides is inserted into the processed CTDP1 mRNA, resulting in a premature termination signal 17 codons downstream of exon 6. Table 2. Selected CTDP1 Pathologic Allelic Variants View in own windowDNA Nucleotide Change
(Alias ¹) Protein Amino Acid Change Reference Sequencesc.863+389C>T
(IVS6 + 389C>T) --NM_004715​.3
NP_004706​.3 See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. The carboxy-terminal domain phosphatase 1 (CTDP1), also known in the biochemical literature as transcription factor IIF-associating CTD phosphatase 1 (FCP1), is a widely expressed nuclear protein of 961 amino acids, with a catalytic N-terminal part, a phospho-protein-binding BRCT domain common to cell cycle check-point proteins and involved in protein-protein interactions, and a C-terminal nuclear localization signal [Archambault et al 1997, Cho et al 1999, Kobor et al 1999]. CTDP1 is involved in the regulation of eukaryotic transcription, its main function being the regulation of the phosphorylation level of the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII). The CTD serves as the platform for the recruitment, assembly, and interaction of multimeric protein complexes involved in the different stages of transcription and in the post-transcriptional modifications of the nascent mRNA [Maniatis & Reed 2002]. The coupling and coordination of these processes is controlled by the changing level and pattern of phosphorylation of the serine 2 and 5 residues in the CTD, a ‘CTD code’ that specifies the position of RNAPII in a transcription cycle [Maniatis & Reed 2002]. In vitro experiments have implicated CTDP1 in virtually all stages of the transcription cycle and multiple other processes regulating gene expression, in addition to the RNAPII recycling during transcription, such as mobilization of stored RNAPII sequestered in depots in the phosphorylated form [Palancade et al 2001], the recruitment of the splicing machinery [Licciardo et al 2003], and chromatin remodeling through histone methylation [Amente et al 2005]. Abnormal gene product. The molecular pathogenesis of CCFDN is most likely related to the reduced level/function of the CTDP1 protein. The CCFDN-causing mutation leads to the production of abnormal mRNA, which contains a premature termination signal and is thus likely to be subject to nonsense-mediated decay. A protein product, if present, will be truncated and will not contain the nuclear-localization domain. Since normal splicing occurs in CCFDN cells, albeit at a reduced efficiency of 15%-35% of the levels observed in control cells, the disorder is caused by partial deficiency of the carboxy-terminal domain phosphatase 1 [Varon et al 2003].