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Congenital Cataracts, Facial Dysmorphism, and Neuropathy

, MD, PhD and , MD.

Author Information
, MD, PhD
Laboratory for Molecular Genetics
Western Australian Institute for Medical Research and Centre for Medical Research
The University of Western Australia
Perth, Australia
, MD
Neurology Clinic
University Hospital Alexandrovska
Medical University of Sofia
Sofia, Bulgaria

Initial Posting: ; Last Update: August 16, 2012.

Summary

Disease characteristics. Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) is characterized by abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils); mildly dysmorphic facial features apparent in late childhood; and a hypo/demyelinating, symmetric, distal peripheral neuropathy. The neuropathy is predominantly motor at the onset and results in delays in early motor development, progressing to severe disability by the third decade. Secondary scoliosis and foot deformities are common. Sensory neuropathy develops after age ten years. Most affected individuals have a mild non-progressive intellectual deficit and cerebellar involvement including ataxia, nystagmus, intention tremor, and dysmetria. All have short stature and subnormal weight. Adults have hypogonadotropic hypogonadism. Parainfectious rhabdomyolysis (profound muscle weakness, myoglobinuria, and excessively elevated serum concentration of creatine kinase usually following a viral infection) is a potentially life-threatening complication. To date all affected individuals and carriers identified have been from the Roma/Gypsy population.

Diagnosis/testing. The diagnosis of CCFDN is based on clinical findings. CTDP1 is the only gene in which mutations are known to cause CCFDN. Targeted mutation analysis identifies IVS6+389C>T in intron 6, the CTDP1 founder mutation in the Roma/Gypsy population.

Management. Treatment of manifestations: Cataracts are treated surgically; exaggerated inflammatory response and foreign-body reaction to contact lenses and intraocular lenses warrant close postoperative follow up. Peripheral neuropathy is managed symptomatically in the usual manner. Secondary spine and foot deformities may require surgical intervention. Hormone replacement therapy for hypogonadotropic hypogonadism may help prevent osteoporosis.

Prevention of secondary complications: Close monitoring during and after anesthesia for potentially life-threatening complications (pulmonary edema, inspiratory stridor, malignant hyperthermia, and epileptic seizures).

Surveillance: Annual examinations for possible ophthalmologic, neurologic, and endocrine manifestations.

Genetic counseling. CCFDN is inherited in an autosomal recessive manner. 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. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

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
  • 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 testing

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

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
CTDP1Targeted mutation analysisc.863+389C>T (also known as IVS6+389C>T) in intron2100%3

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 (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 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 (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.

Clinical Description

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 [Tournev et al 1999a].

Nervous System

Hypomyelinating 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].

Other

Growth. 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.

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 160, 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.

Differential Diagnosis

In 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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 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 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.

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.

Surveillance

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

Evaluation 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. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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

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 disease-causing mutations have been identified in the family.

Because of the endogamous nature of Roma communities and the increased frequency of consanguineous marriages, carrier testing should be considered for both members of the extended family and future reproductive partners of individuals already determined to be carriers.

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.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • Neuropathy Association, Inc.
    60 East 42nd Street
    Suite 942
    New York 10165
    Phone: 212-692-0662
    Fax: 212-692-0668
    Email: info@neuropathy.org

Molecular Genetics

Information 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 Databases

Data 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)

604168CONGENITAL CATARACTS, FACIAL DYSMORPHISM, AND NEUROPATHY
604927C-TERMINAL DOMAIN OF RNA POLYMERASE II SUBUNIT A, PHOSPHATASE OF, SUBUNIT 1; CTDP1

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; 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

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequences
c.863+389C>T
(IVS6 + 389C>T)
--NM_004715​.3
NP_004706​.3

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

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].

References

Literature Cited

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Chapter Notes

Revision History

  • 16 August 2012 (me) Comprehensive update posted live
  • 2 March 2010 (me) Review posted live
  • 29 October 2009 (lk) Original submission
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