Congenital Cataracts, Facial Dysmorphism, And Neuropathy
Summary
Clinical 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 pathogenic variants are known to cause CCFDN. Targeted analysis identifies the pathogenic variant IVS6+389C>T in intron 6, the CTDP1 founder variant 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). Awareness of rhabdomyolysis as a potential complication following viral infections in order to seek medical attention with the first recognizable symptoms and to provide oral corticosteroid treatment (for 2-3 weeks for optimal recovery).
Surveillance: Annual examinations for possible ophthalmologic, neurologic, and endocrine manifestations.
Evaluation of relatives at risk: It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from early initiation of treatment and preventive measures.
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. If the pathogenic variants in the family are known, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) should be suspected in individuals with the following clinical findings:
- 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
Establishing the Diagnosis
The diagnosis of CCFDN is established in a proband with the identification of biallelic pathogenic variants in CTDP1 on molecular genetic testing (see Table 1). Molecular genetic testing approaches can include targeted analysis of a pathogenic variant and single-gene testing:
- Targeted analysis of the pathogenic variant, c.863+389C>T (also known as IVS6+389C>T) in intron 6 (a founder variant in the Roma/Gypsy population) can be performed first in individuals of Roma/Gypsy ancestry. To date, all affected individuals and carriers identified have been from the Roma/Gypsy population.
- Single-gene testing. Although it is theoretically possible for other sequence variants in CTDP1 to cause CCFDN, no variants other than c.863+389C>T have been reported to date.
It is important to note that c.863+389C>T reduces, but does not abolish, CTDP1 expression (see Molecular Genetics). It is not known if complete loss of CTDP1 results in different clinical features or is compatible with life.
Table 1.
Molecular Genetic Testing Used in Congenital Cataracts, Facial Dysmorphism, and Neuropathy
| Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| CTDP1 | Targeted analysis | Detects c.863+389C>T, the founder variant in the Roma/Gypsy population |
| Sequence analysis 3 | The Roma/Gypsy founder variant, c.863+389C>T, is the only pathogenic variant described to date. | |
| Gene-targeted deletion/duplication analysis 4 | Unknown 5 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 5.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
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, Lassuthova et al 2014, Walter et al 2014].
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 micrognathia [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, Walter et al 2014].
As muscle weakness progresses, spine deformities may also develop and lead to reduction in respiratory capacity [Merlini et al 2002].
Sensory abnormalities (numbness) in the lower limbs develop in persons older than age ten years.
Nerve conduction velocity is normal in infancy at the onset of myelination and subsequently (age >18 months) begins to decline, stabilizing at approximately 20 m/s at around age four to ten years [Kalaydjieva et al 2005, Walter et al 2014]. 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. Sensory and motor nerves show reduction of amplitudes with disease progression, and some (n. suralis) can become unobtainable after age ten years, indicating secondary axonal loss [Walter et al 2014].
In distal muscles of the upper and lower extremities, neurogenic changes compatible with the underlying neuropathy are seen in all tested patients [Tournev et al 1999b, Tournev et al 2001, Walter et al 2014]. Electromyography, performed in six patients with proximal weakness during the rhabdomyolisis weakness episodes, showed myogenic changes in proximal muscles that were not found after recovery [Walter et al 2014].
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 [Tournev et al 1999b, Chamova et al 2015].
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 10% of affected individuals have normal or borderline cognitive performance, and the rest have mild non-progressive intellectual deficit. Verbal memory, executive functions, and language skills are similarly affected [Chamova et al 2015].
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, Lassuthova et al 2014, Walter et al 2014, Chamova et al 2015]. Ataxia scores remain stable or improve slightly during the course of the disease [Walter et al 2014].
Pyramidal signs without spasticity and extrapyramidal hyperkinesis are observed in some [Tournev et al 2001, Chamova 2012, Chamova et al 2015].
Magnetic resonance imaging (MRI) findings of the brain and spinal cord vary.
- The original study identified abnormalities in 16/17 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 spine hypotrophy [Tournev et al 2001].
- 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].
- In 19/20 affected individuals, ages four to 47 years [Chamova 2012, Chamova et al 2015] brain MRI identified abnormalities including cerebral atrophy with enlargement of the lateral ventricles, hyperintense lesions in periventricular white matter and brain stem (varying from small single to multiple diffuse), and occasionally thin corpus callosum and cerebellar atrophy. Hyperintensities were located predominantly in frontal and parietooccipital periventricular white matter.
- In 7/16 affected individuals, brain MRI showed nonspecific changes, including accentuated ventricles and white matter hyperintense periventricular lesions [Walter et al 2014].
Other
Growth. Intrauterine growth restriction is suggested by a study of 22 infants 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]. Subnormal sex hormone levels were rarely observed in a recently reported 16 patients [Walter et al 2014]. 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) and is characterized by acute severe proximal weakness and myalgia [Walter et al 2014]. Proximal muscle weakness is not otherwise typical for CCFDN [Walter et al 2014]. 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, Lassuthova et al 2014, Walter et al 2014]. 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 pathogenic variant c.863+389C>T in CTDP1.
Nomenclature
Congenital cataracts, facial dysmorphism, and neuropathy (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 170, all of Roma/Gypsy ethnicity.
The carrier rate for the c.863+389C>T pathogenic variant 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 in other ethnic groups have been identified to date.
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.
The differential diagnosis with other conditions presenting in the first year of life with congenital cataracts, microcornea, and microphthalmia will be helped by the delayed developmental milestones in children with CCFDN and subsequent signs of peripheral neuropathy.
Galactokinase deficiency (OMIM 230200), an autosomal recessive inborn error of galactose metabolism, is the main differential diagnosis of CCFDN in infants of Roma/Gypsy ancestry; in this ethnic group, it is caused by the p.Pro28Thr founder variant in GK1 (GALK1) [Kalaydjieva et al 1999].
CCFDN also shares findings with Marinesco-Sjögren syndrome (MSS) and the GBA2-related Marinesco-Sjögren syndrome-like disorder.
Marinesco-Sjögren syndrome (MSS) is an autosomal recessive disorder characterized by cerebellar ataxia with cerebellar atrophy, early-onset (not necessarily congenital) cataracts, myopathy, muscle weakness, and hypotonia. Additional features may include psychomotor delay, hypergonadotropic hypogonadism, short stature, and various skeletal abnormalities. 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. Diagnosis is based on clinical findings and/or biallelic pathogenic variants of SIL1 identified on molecular genetic testing.
The clinical investigations providing the best distinction between CCFDN and MSS are ophthalmologic (cataracts in both disorders but extensive involvement of the anterior eye segment in CCFDN), neurophysiologic (reduced nerve conduction velocity in CCFDN), and neuroimaging (cerebellar atrophy in MSS). Electron-microscopic ultrastructural changes on muscle biopsy are thought to be specific to MSS.
GBA2-related Marinesco-Sjögren syndrome-like disorder (OMIM 614409) is an autosomal recessive condition characterized by progressive cerebellar ataxia developing in early childhood accompanied by lower-limb spasticity as well as an axonal peripheral neuropathy resulting in weakness, muscle wasting, and foot deformities. Early psychomotor development is normal; however, mild progressive cognitive decline accompanies the other progressive central nervous system findings. Bilateral cataracts are observed later in the disease course [Martin et al 2013, Haugarvoll et al 2017].
See Microphthalmia, syndromic: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.
See Cataract: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.
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) and to address the most disabling manifestations, the following evaluations are recommended:
- Visual impairment (ophthalmologic examination)
- Peripheral neuropathy and ensuing physical handicap (neurologic and orthopedic examinations, measurements of nerve conduction velocity)
- Endocrinologic evaluation, related to growth delay, fertility problems, and osteopenia
- Consultation with a clinical geneticist and/or genetic counselor
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 (intraocular lenses are generally better tolerated) [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. Regular rehabilitation can prevent or postpone osteoporosis.
Growth hormone levels in CCFDN are in low normal range and somatotropin hormone substitution is not expected to have considerable effect.
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. Oral corticosteroid treatment for two to three weeks can result in a full recovery within two to six months [Walter et al 2014]. The long-term outcome depends on the recurrence of rhabdomyolysis episodes [Walter et al 2014].
Surveillance
Annual examinations to monitor for possible ophthalmologic, neurologic, and endocrine complications are warranted.
Agents/Circumstances to Avoid
General anesthesia in patients with CCFDN may cause complications such as pulmonary edema, inspiratory stridor, malignant hyperthermia, and epileptic seizures [Müllner-Eidenböck et al 2004]. Although such complications have not been unequivocally documented, Masters et al [2017] recommend cautious use of general anesthesia until more information on related risks is available.
Prolonged exercise was reported to provoke myalgia in one patient with CCFDN [Merlini et al 2002].
Evaluation of Relatives at Risk
It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.
- If the CTDP1 pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
- If the pathogenic variants in the family are not known careful monitoring of at-risk sibs for the early disease manifestations (ocular, delayed motor milestones, early signs of peripheral neuropathy) will ensure timely diagnosis of those affected.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
Experience is very limited, as only three females with CCFDN are known to have given birth [Tournev et al 2001, Walter et al 2014]. The pregnancies are reported as uneventful and were carried to term. Normal pregnancy and delivery have also been reported by mothers of children with CCFDN.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.