Clinical 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 childhood

• Hypo/demyelinating peripheral neuropathy

• Mild non-progressive intellectual deficit

• Small stature

Testing

Molecular Genetic Testing

Gene. CTDP1 is the only gene known to be associated with congenital cataracts, facial dysmorphism, and neuropathy.

Clinical testing

• Targeted mutation analysis. Targeted mutation analysis for the CTDP1 founder mutation in the Roma/Gypsy population, IVS6+389C>T in intron 6, is available on a clinical basis. To date all affected individuals and carriers identified have been from this population.
  
  The ancestral CCFDN-causing mutation is a C>T substitution 389 bp downstream of the exon 6/intron 6 junction of CTDP1 (c.863+389C>T; also known as IVS6 + 389C>T) located within an intronic Alu element. The mutation results in aberrant splicing, insertion of a short intronic sequence in the mature transcript, and generation of a premature stop codon [Varon et al 2003]. All affected individuals are homozygous for this mutation.

Table 1. Summary of Molecular Genetic Testing Used in Congenital Cataracts, Facial Dysmorphism, and Neuropathy

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
CTDP1	Targeted mutation analysis	c.863+389C>T in intron 6 2	100%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Founder mutation in the Roma/Gypsy population

Testing Strategy

To confirm/establish the diagnosis in a proband

• The 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.

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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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].

Eye. Congenital 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 features. Dysmorphic 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 [Merlini et al 2002].

Nervous system

Hypomyelinating peripheral neuropathy is symmetric, 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 [Merlini et al 2002].

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 starts declining until it stabilizes 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 different from the patients’ 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 [Merlini et al 2002, Müllner-Eidenböck et al 2004].

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.

Other

Growth. Individuals with CCFDN are of small stature and most are also of subnormal weight:

• Adult males. 149.2±5 cm and 47±7.2 kg for (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 for (reference values: 160.3±6.4 cm and 63±10.7 kg) [Tournev et al 1999a]

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.

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 patients 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.

Penetrance

Penetrance of the mutation in the homozygous form is complete, i.e., individuals who have two copies of the mutant gene develop the disease phenotype.

Nomenclature

CCFDN was also referred to as ‘Marinesco-Sjögren syndrome with rhabdomyolysis’ [Müller-Felber et al 1998] until it was demonstrated that the individuals described in that study had CCFDN [Merlini et al 2002].

Prevalence

Proper figures on the prevalence of CCFDN are not available. The total number of affected individuals diagnosed to date is approximately 150, all of Roma/Gypsy ethnicity.

The carrier rate for the c.863+389C>T mutation is approximately 7% among the Rudari (the Gypsy group most affected by the disorder) and approximately 1.4% in the general Roma/Gypsy population [Morar et al 2004].

No affected individuals or carriers have been identified to date among other ethnic groups.

Evaluations 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 Manifestations

The 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 intra-ocular lenses (with a generally better tolerance to intra-ocular 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 Complications

Individuals 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.

Patients 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.

Surveillance

Annual examinations to monitor for possible ophthalmologic, neurologic, and endocrine complications are warranted.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

• The offspring of an individual with congenital cataracts, facial dysmorphism, and neuropathy are obligate heterozygotes (carriers) for a disease-causing mutation in CTDP1.

• An exception to this general rule is the birth of an affected child, as a result of the other parent being a carrier, which is more likely in closely knit endogamous communities with a high carrier rate (see Related Genetic Counseling Issues, Family planning).

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the presence of the CCFDN-causing mutation has been identified in the family.

Related Genetic Counseling Issues

Family planning

• Carrier testing and counseling should be offered to relatives, especially in view of the endogamous nature of many Roma/Gypsy communities. Even though CCFDN is a very rare disorder in the general population, the high carrier rates in specific communities translate to an increased probability of high-risk marriages.

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

The founder CCFDN-causing mutation, c.863+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.

Normal 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 and isoform b (11 exons) is 3612 nt long.

Pathologic allelic variants

Normal 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].

Literature Cited

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20. Tournev I, King RH, Workman J, Nourallah M, Muddle JR, Kalaydjieva L, Romanski K, Thomas PK. Peripheral nerve abnormalities in the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome. Acta Neuropathol. 1999b;98:165–70. [PubMed: 10442556]
21. Tournev I, Thomas P, Gooding R, Angelicheva D, King R, Youl B, Guerueltcheva V, Ishpekova B, Blechsmidt K, Swoboda K, Petkov R, Molnar M, Kamenov Z, Siska E, Taneva N, Borisova P, Lupu C, Raycheva M, Trifonova N, Popova A, Corches A, Litvinenko I, Merlini L, Katzarova M, Tzankov B, Popa G, Akkari A, Rosenthal A, Donzelli O, Kalaydjieva L. Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome – Clinical, neuropathological and genetic investigation. Acta Myologica. 2001;20:210–19.
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Revision History

• 2 March 2010 (me) Review posted live

• 29 October 2009 (lk) Original submission