Congenital cataracts-facial dysmorphism-neuropathy syndrome (ORPHA:48431)
A rare autosomal recessive multiple congenital anomalies/dysmorphic syndrome characterized by abnormalities of the eye; mildly dysmorphic facial features; and a hypo/demyelinating, symmetric, distal peripheral neuropathy.
Epidemiology
To date, congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome has been found to occur exclusively in patients of Roma ethnicity; over 190 patients have been diagnosed.
Clinical description
Developmental abnormalities include congenital cataracts, microcornea, microphthalmia and micropupils, primary hypomyelinating polyneuropathy, impaired physical growth, delayed early motor and intellectual development, mild facial dysmorphism and hypogonadism. Para-infectious rhabdomyolysis is a serious complication reported in an increasing number of patients. During general anesthesia, patients with CCFDN require careful monitoring as they have an elevated risk of complications.
Etiology
CCFDN is a genetically homogeneous condition in which all patients are homozygous for the same ancestral mutation in the CTDP1 gene. CTDP1 maps to 18qter and encodes a protein phosphatase whose only known substrate is the phosphorylated serine residues of the carboxy-terminal domain of the largest subunit of RNA polymerase II, indicating that CCFDN affects basic cellular processes of gene expression and developmental regulation. All of the affected are homozygous for the CTDP1 Romani founder variant c.863+389C>T.
Diagnostic methods
Diagnosis is clinical and is supported by electrophysiological and brain imaging studies. The definitive diagnosis is molecular, based on homozygosity for the CTDP1 mutation.
Differential diagnosis
The major differential diagnosis is Marinesco-Sjogren syndrome. Some other disorders should be considered as well: Galactokinase (GALK) deficiency, autosomal recessive cerebellar ataxia with late-onset spasticity, INTS1-related neurodevelopmental disorder.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. Once the CTDP1 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for CTDP1-CCFDN are possible.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management includes surgical treatment of the cataracts, and rehabilitation and corrective orthopedic surgery for the peripheral neuropathy.
Prognosis
The most disabling manifestations, though not curable, are manageable, and allow for an acceptable quality of life. Current data indicate that patients survive well into adulthood.

                            Last update: 
                            October 2023


                            - Expert reviewer(s): 
                            Pr Teodora CHAMOVA | EURO-NMD* - Pr Ivailo TOURNEV | EURO-NMD*


                                * European Reference Network