Ptosis, Hereditary Congenital 1

Description

Hereditary congenital ptosis occurs in 3 main forms: simple; with external ophthalmoplegia; and with blepharophimosis.

See PTOS2 (300245) for description of an X-linked form of congenital bilateral isolated ptosis.

Mapping

Cohen (1972) described a large family with hereditary congenital ptosis. In this family, which provided a sample of 37 meioses, Engle et al. (1997) found that 9 informative markers on chromosome 1 did not recombine with the disease. With the marker D1S2677, they found a maximum 2-point lod score of 8.8 on the assumption of 90% penetrance. By fluorescence in situ hybridization of YACs containing flanking recombinant markers, Engle et al. (1997) localized the gene to 1p34.1-p32. Thus this disorder is distinct from the blepharophimosis syndrome (110100), which maps to 3q, and from congenital fibrosis of the extraocular muscles (135700), which maps to chromosome 12.

McMullan et al. (2002) analyzed the chromosome breakpoints in a male patient with congenital bilateral isolated ptosis and a de novo balanced translocation t(1;8)(p34.3;q21.12). Both breakpoints were localized by fluorescence in situ hybridization with yeast artificial chromosomes, bacterial artificial chromosomes, and P1 artificial chromosomes. The derived chromosomes were isolated by flow sorting, amplified by degenerate oligonucleotide-primed polymerase chain reaction, and analyzed by sequence tagged sites amplification to map the breakpoints at a resolution that enabled molecular characterization by DNA sequencing. The 1p breakpoint lay approximately 13 Mb distal to the previously reported linkage locus at 1p34.1-p32 and did not disrupt the coding sequence, whereas the chromosome 8 breakpoint disrupted a gene homologous to the mouse Zfh4 gene. Murine Zfh4 codes for a zinc finger homeodomain protein that is a transcription factor expressed in both muscle and nerve tissue. McMullan et al. (2002) suggested that the ZFH4 (ZFHX4; 606940) gene is a candidate gene for congenital bilateral isolated ptosis.

Nakashima et al. (2008) performed linkage analysis in 5 affected and 12 unaffected members of a 5-generation Japanese family segregating autosomal dominant congenital ptosis and excluded all but 3 loci, on chromosomes 8q21.1, 12q24.3, and 14q22.3, with 2-point maximum lod scores of 1.16, 0.47, and 0.72, respectively. Noting that 8q21.1 was one of the translocation breakpoints previously found by McMullan et al. (2002) in a patient with congenital ptosis, Nakashima et al. (2008) analyzed the candidate gene ZFHX4 by direct sequencing and Southern blot and methylation analysis but found no disease-specific change in this family.

History

Rodin and Barkan (1935) recognized 4 types: (1) hereditary congenital ptosis, (2) hereditary ptosis with external ophthalmoplegia, (3) hereditary noncongenital ptosis, and (4) hereditary ptosis with epicanthus (see Rank and Thomson, 1959). The second type is said to be the most frequent. On the other hand, Duke-Elder (1963) stated that at least 8 types of congenital ptosis are recognizable, of which 7 show a genetic basis: (1) simple ptosis, due to failure of peripheral differentiation of muscles, transmitted as a dominant. The rectus superior muscle may also be involved; (2) ptosis with blepharophimosis, also due to faulty peripheral differentiation and transmitted as a dominant; (3) ptosis due to ophthalmoplegia (e.g., 165000) usually of central origin; (4) ptosis associated with myasthenia gravis and myotonia, both rare as congenital disorders; (5) ptosis due to congenital sympathetic palsy; (6) synkinetic ptosis (see Marcus Gunn phenomenon, 154600); and (7) intermittent pseudo-ptosis associated with the retraction syndrome. The extensive Metcalf kindred in Lafayette, Tennessee, has hereditary congenital ptosis (Briggs, 1919). The Georgia mountain family reported by Stuckey (1916) may have been related. Families with late-onset ptosis such as that of Faulkner (1939) may have represented oculopharyngeal muscular dystrophy (164300). Congenital ptosis may be only unilateral.