Congenital Cataracts – Facial Dysmorphism – Neuropathy syndrome

A Gypsy girl with bilateral cataracts manifesting in the first year of life, psychomotor retardation, facial dysmorphism and motor delay, had experienced three episodes of parainfectious rhabdomyolysis until the age of 9. Sural nerve biopsy revealed a demyelinating peripheral neuropathy. All these features suggested the diagnosis of Marinescu-Sjogren syndrome or a related syndrome recently described in the Gypsy communities as Congenital Cataracts-Facial Dysmorphism-Neuropathy syndrome. Sequencing of the CTDP1 gene revealed homozygosity for the mutation IVS6+389 C>T in intron 6, confirming the diagnosis of CCFDN syndrome.

The latter is an autosomal recessive disease as well, characterized by cataracts, ataxia, small stature, mental retardation, chronic myopathy, and, occasionally, peripheral neuropathy and acute rhabdomyolysis.The main symptoms of the CCFDN syndrome are already represented in the name of this disease.The diagnosis is confirmed by molecular genetic testing, based on homozygosity for a mutation in the CTDP1 gene.
Management consists in surgical treatment of the cataracts, rehabilitation, and corrective orthopedic surgery for the peripheral neuropathy allowing an acceptable quality of life and survival into adulthood.

OBJECTIVE
T o describe a little girl's case who presented with congenital cataracts, mild ataxia, hypotonia, acute rhabdomyolysis, somatic and mental retardation initially considered as a possible case of MSS.

CASE PRESENTATION
A 9-year-old girl, S.G, of gypsy origin, from Bucharest, with numerous admissions in our hospital starting 2004, presented two remarkable aspects: bilateral congenital cataract and psychomotor retardation.The child, under her grandmother's guardianship, walked with many difficulties and started speaking late, around the age of 2 years.She was a "floppy infant" and the diagnosis of cerebral palsy was considered.No distinctive facial appearance was noted.She underwent three ocular interventions (replacement by an intraocular lens implant) at 3 years (12/2001), at 6 years (06/2004) and 9 years (06/2007) without any remarkable improvement (amblyopia).The child remained hypotonic, with evident difficulties to sit, despite the affirmative acquisition of sitting (she "never can stay alone on her toilet", grandmother said) and did not learn to run.Her gait was always uncertain, hesitant, staggered (frequent falls!), and wide-based (ataxia).Her grandmother's impression was "it seems like she hasn't force enough in her lower legs".Gower's maneuver was positive.She climbed stairs with difficulty and fatigue appeared after ~ 200 meters walking distance.
Platelet counts were within normal limits.Bacterial infections (urine, blood, CSF cultures were negative), peritonitis (normal ultrasound exam) and malignancy were ruled out.CT (cranium) was normal.Steroid therapy for 5 months induced remission of all signs and symptoms described above.The patient did not develop arthritis within the next 4 years.Unfortunately, CK values have not been measured during the first and second episodes.
A second febrile episode with myalgias and vomiting (September 2006, ~7 days duration) and, the last (the 3 rd ), 11 days duration (23.01-02.01.2007) with high fever, myalgias (thighs), arthralgias (knees, hip), cervical and dorsal spine pain, lumbar pain, abdominal pain and vomiting, were investigated and treated in our hospital.
The history is relatively normal.She was delivered at term by a 17-year-old G1/P1 woman on December 8, 1998.Birth parameters were within normal ranges (weight 3400g, length 50cm, head circumference unknown).Apgar scores were not available.The neonatal period was also uneventful.She has been breastfed for the first 3 months and later fed with infant formula.Solid baby food was started at the age of 7 months.
The neurological development was delayed: she could hold the head up not until the age of 6 months, sitting without support was achieved at the age of 8 months, and walking with support started at the of 2 years.She spoke first words at the age of 2 ½ years.At the age of 9, the diagnosis of mild to moderate mental retardation was established.Her personality is very active, curious, and disobedient with affective instability and behavioral abnormalities.
According to the grandmother's information, immunization for BCG, DTP, OPV, and MMR had been administered.The tuberculin skin test was negative.
The family history is not complete as the father is unknown.The family is of Gypsy origin.All members of her family were healthy and denied any hereditary condition and consanguinity in the family.

Other investigations
CT with contrast (cranium)/27.12.2004) showed normal ventricular system, no pathologic findings in pericerebral spaces, normal density and contrast enhancement of the supra-and infratentorial parenchyma (including cerebellum).There were no focal lesions.
CSF/27.12.2004 was Pandy negative 27 elements/mmc with normal biochemical exam.
Left Sural nerve biopsy: Sensory nerve showing signs of a moderate predominantly demyelinating type neuropathy: 20% of teased fibers were regenerated and presented segmental remyelination lesions, and 3% had segmental demyelination lesions.Discrete signs of axonal degeneration could be observed too: 2% of the teased fibers presented myelinic ovoids and bullae, the myelinic fiber histogram was unimodal with maximum fiber diameter being 8-9 µm in less than 1% of fibers, indicating the predominent involvement of the large myelinic fibers.Myelinic fiber density was practically at a lower normal limit-6790 fb/mm 2 (transverse sections), due to a very intense regenerative activity-33% of teased fibers (13% regenerated fibers + 20% regenerated fibers with remyelinating lesions).
Molecular genetic testing: A DNA sample was tested for mutations in the coding region of the SIL1 gene (MSS, 5q31).The patient's DNA was found to be wild type for the nine coding exons of the SIL1 gene.In addition, a partial sequence of intron 6 of the CTDP1 gene (CCFDN, 18qter) was amplified by PCR and subjected to automated fluorescent sequencing.A homozygous mutation IVS6+389C>T was detected by comparing the patient's sequencing electropherogram with the wild type sequence.This mutation has been previously shown to result in aberrant splicing and an Alu insertion in the processed mRNA (3).The nucleotide change was confirmed in two independent PCR reactions and sequencing runs (2).All the other members of her family were unaffected and no genotyping was performed.

RESULTS
T wo reasons justify our interest in this case.
One is that the first descriptor of MSS was a famous Romanian neurologist (1,4,5).The second reason is that CCFDN was described in the Gypsy population, and despite the fact that the Gypsies represent an important ethnic group in Romania, we do not know about previous cases published in our country, except the two case-reports described as MSS with neuropathy in 1983 and 1995 (6,7).It seems that Marinesco's patients were of gypsy origin as well (5).Initially the diagnosis of MSS seemed more appropriate for our patient (bilateral cataracts, ataxia, mental retardation, short stature, pronounced hypotonia, and myopathic (although very minor) changes on muscle biopsy).The presence of others features -facial dysmorphism, peripheral neuropathy, acute parainfectious rhabdomyolysis and Gypsy originsuggested the differential diagnosis of an MSS variant, such as the CCFDN syndrome recently described in a specific gypsy group from Bulgaria (8)(9)(10).CCFDN was also described in many other countries in gypsy population (11,12).This was the reason to solicit molecular genetic testing confirming the diagnosis.

DISCUSSIONS
T o date, CCFDN has been found to occur exclusively in patients of gypsy ethnicity (carrier rate: ~ 6-7%); over 100 patients have been diagnosed (8).CCFDN and MSS have some clinical manifestations in common (bilateral cataracts, ataxia, mental retardation, short stature, hypotonia).Major features of MSS that distinguish it from CCFDN are the occurrence of more severe mental retardation marked cerebellar atrophy, and chronic myopathy with specific ultrastructural features on muscle biopsy.On the other hand, CCFDN patients present with demyelinating peripheral neuropathy, facial dysmorphism, microcornea, and episodes of myoglobinuria and rhabdomyolysis (11,13,14).
The diagnostic criteria for CCFDN include congenital cataracts and microcorneae, primary hypomyelination of the peripheral nervous system, impaired physical growth, delayed early motor and intellectual development, mild facial dysmorphism (prominent midface with a well-developed nose, thickening of the perioral tissues, forwardly anterior directed dentition and hypogonadism (8,10).Except for hypogonadism (the patient is a prepubescent girl!) and facial dysmorphism, all these abnormalities are present in our case.Facial dysmorphism develops in late childhood and is more evident in male patients.
As in our case, the most striking neurological manifestation in CCFDN patients is a symmetric, distally accentuated, predominantly motor peripheral neuropathy.Loss or depression of tendon reflexes, initially in lower limbs, is observed.Nerve conduction velocities are usually reduced in affected children after 18 months.Sensory action potentials values are of normal amplitude, suggesting a relatively uniform degree of slowing of conduction across nerve fibers, consistent with congenital hypomyelination, also provided by nerve biopsy (8,14).Other neurological abnormalities in our patient include choreiform movements and upper limb postural tremor, considered as less consistent in CCFDN).Para-infectious rhabdomyolisis, also present in our patient (severe myalgia, weakness and massive increased CK and LDH) following a unspecified viral infection, is a serious complication reported in an increasing number of patients (8) and may represent a common environmentally-triggered feature of CCFDN syndrome (8,15).Prenatal eye development is constantly affected and the congenital cataracts are the first CCFDN manifestation, recognizable in early infancy (8).Other ocular abnormalities are microcornea, microphtalmos, micropupils, floppy eyelids, long and dense eyelashes, nystagmus and strabism.Other clinical manifestations include small stature, low weight, mild facial dysmorphism, cerebral and spinal cord atrophy on neuroimaging, and osteoporosis (8,16).
Concerning the peripheral nerve involvement in Marinesco CCFDN is a genetically homogenous condition, where all patients are homozygous for the same ancestral mutation in the CTDP1 gene on chromosome 18qter (3).The CTDP1 gene encodes a protein phosphatase whose only known substrate is the phosphorylated serine residues of the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II (2).RNA polymerase II is responsible for the transcription of protein-encoding genes in eukaryotic cells, and the level of CTD phosphorylation is considered to be a key mechanism for the regulation of gene expression (15).Thus, CCFDN belongs to the small group of "transcription syndromes"and, at present, is the only known defect directly involving RNA polymerase II-mediated gene expression (8).
In early infancy, a differential diagnosis to be considered is galactokinase deficiency, common among the Gypsy ethnics, leading to cataracts in the first weeks of life.Thus, infantile cataracts should prompt molecular genetic analysis of the GALK1 gene.
Management includes the treatment of cataracts, and rehabilitation for the peripheral neuropathy.CCFDN patients may develop severe and potentially life-threatening complications during anaesthesia (pulmonary edema, inspiratory obstruction, malignant hyperthermia and epileptic seizures).During episodes of rhabdomyolysis may appear potential need for intensive care.
Prognosis.The ophtalmological and neurological abnormalities are not curable but these patients are manageable, allowing an acceptable quality of life and daily activities.
Genetic counselling and prenatal predictive testing for the disease mutation on DNA extracted from chorionic villus samples can be offered to the family.

Conclusion
The case described above is a typically one for CCFDN.This occurrence, usually exceptional, is not so rare in genetically isolated populations like Gypsies.
The mutation in the CTDP1 gene was demonstrated.The distinction between MSS and CCFDN, suggested by some authors, remains unclear but is quite evident that MSS is clinically and genetically heterogeneous.
-Sjogren syndrome, we have to mention the electrophysiological observations of Skre et al (1976, cited by 6) who