Our laboratory has identified one genetic locus for isolated congenital ptosis (PTOS1)1. This was done using the technique of linkage analysis. The PTOS1 locus is on the short arm of human chromosome 1 (1p32-34.1), as shown in the schematic to the left. The critical region for the PTOS1 disease gene is 3 cM, and is defined by the flanking polymorphic markers D1S447/D1S2733 and D1S1616.
Ptosis (or blepharoptosis) is the most common anomaly of the eyelid and presents as an abnormal drooping of the upper eyelid with secondary narrowing of the vertical palpebral fissure of the eye. It can be unilateral or bilateral. When present at birth (congenital), it can occur as an isolated neuromuscular disorder with no associated findings (isolated congenital ptosis) or may be part of a larger spectrum of birth defects. Individuals with congenital ptosis suffer from restricted vision in their upper quadrants and frequently require surgery to elevate their eyelids. Hereditary isolated congenital ptosis is generally inherited in an autosomal dominant fashion with incomplete penetrance and is characterized by a variable degree of unilateral or bilateral drooping of the upper eyelids.
We have identified a single family with more than 150 members affected by autosomal dominant, isolated congenital ptosis. It is this family whose disease gene maps to the PTOS1 locus. The degree of ptosis varies significantly among affected members of this family, as demonstrated by the two family members below. They are photographed both in primary gaze and upgaze.
In 2000 McMullan et al2 described a large family with a previously undescribed condition: X-linked dominant congenital bilateral isolated ptosis. In 2002 the same group based in Southampton, England identified two chromosome breakpoints in a patient with congenital bilateral isolated ptosis and a de novo balanced translocation 46,XY,t(1;8)(p34.3;q21.12)3. The chromosome 8 breakpoint disrupts a gene which bears homology (comparable physical structure) to the mouse zfh-4 gene. This gene codes for a zinc finger homeodomain protein and is a transcription factor expressed in both muscle and nerve tissue. It was therefore postulated that human ZFH-4 is a candidate gene for congenital bilateral isolated ptosis.
We do not yet know the pathologic basis of isolated congenital ptosis in this family. It is unclear if the disorder is neurogenic or myopathic. If neurogenic, however, we propose that it could result from a selective absence of the axons innervating the levator palpebrae superioris muscle that raises the eyelid. These absent axons are depicted in red below, and the malfunctioning levator muscle is in blue.
Our proposed congenital ptosis pathology as shown above is an absence of the axons of the superior division of CN III that innervate the levator muscle, absence of the corresponding central caudal nucleus in the midbrain, and marked abnormalities of the levator muscle. (Refer to eye muscle and nerve anatomy to review the normal lateral eye).
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, last edit date: 3/18/2004(entry number 178300-PTOS1; entry number 300245-PTOS2). Home page: http://www3.ncbi.nlm.nih.gov/Omim/
- Engle EC, Castro AE, Macy ME, Knoll JH, Beggs AH. A gene for isolated congenital ptosis maps to a 3-cM region within 1p32-p34.1. Am J Hum Genet. 1997 May;60(5):1150-7.
- McMullan TF, Collins AR, Tyers AG, Robinson DO. A novel X-linked dominant condition: X-linked congenital isolated ptosis. Am J Hum Genet. 2000 Apr;66(4):1455-60. Epub 2000 Mar 14.
- McMullan TW, Crolla JA, Gregory SG, Carter NP, Cooper RA, Howell GR, Robinson DO. A candidate gene for congenital bilateral isolated ptosis identified by molecular analysis of a de novo balanced translocation. Hum Genet. 2002 Mar;110(3):244-50. Epub 2002 Feb 01.