X Linked Dominant Congenital Isolated Bilateral Ptosis 71

70 Br J Ophthalmol 2001;85:70–73

X linked dominant congenital isolated bilateral Br J Ophthalmol: first published as 10.1136/bjo.85.1.70 on 1 January 2001. Downloaded from ptosis: the deﬁnition and characterisation of a new condition

T F W McMullan, A G Tyers

Abstract the pedigree had blepharophimosis so this may Aims—To characterise the inheritance of be a BPES pedigree. Stuckey described a fam- ptosis in one particular pedigree. ily with autosomally inherited ptosis but the Methods—The pedigree was analysed clinical details are sketchy.11 However, the pho- clinically and genetically to assess the tograph that accompanies his paper clearly mode of inheritance and to ascribe a gene depicts blepharophimosis and the individuals locus for the condition. also look as though they have epicanthus inver- Results—AVected members of the pedi- sus. gree have bilateral symmetrical congeni- Ptosis and purpura simplex were co- tal isolated ptosis, a condition which is inherited in members of a pedigree reported by linked to genetic markers on the X Fisher et al.12 However, ptosis and purpura chromosome in this family. simplex segregated independently in two indi- Conclusion—A pedigree with dominantly viduals, perhaps denoting linkage rather than a inherited congenital bilateral ptosis is common genetic defect. There was male to presented. The pedigree exhibits X linked male inheritance of ptosis in this family, dominant inheritance. A new ophthalmic excluding X linkage and mitochondrial inherit- condition was thereby characterised— ance. namely, X linked dominant congenital iso- Other hereditary conditions that incorporate lated bilateral ptosis. congenital ptosis are congenital fibrosis of the (Br J Ophthalmol 2001;85:70–73) extraocular muscles (CFEOM) types I, II, and III. These similar conditions have been linked to loci on chromosomes 12, 11, and 16 Congenital isolated ptosis can be unilateral or respectively.13–15 They are characterised by con- bilateral, although it is possible that much unilateral ptosis is in fact markedly asymmetric genital ptosis and external ophthalmoplegia. There is phenotypic heterogeneity within fami- bilateral ptosis. Controversy exists as to the 16 underlying cause of congenital ptosis. While lies and there is also evidence of locus heterogeneity outside the loci on chromosomes there is little doubt that there is abnormal http://bjo.bmj.com/ 11 and 12 which may be explained by the muscle present in the vestigial levator palpe- 15 17 brae superioris, (LPS), implying a myogenic recent description of CFEOM III. component,1 the term congenital levator dys- Engle et al have also described a family with trophy is a misnomer because (i) there is no dominantly inherited congenital isolated ptosis 418 progression in the condition, and (ii) there is which was first reported by Cohen in 1972. little histological evidence of a dystrophic They demonstrated linkage to markers that process.2 There is a growing body of evidence were defined cytogenetically to the region to suggest that the ptosis is due to a failure of 1p32-p34.1. This family is diVerent from the on September 30, 2021 by guest. Protected copyright. neuronal migration or development with mus- one we describe in three important ways. (i) cular sequelae.34 The phenotype is asymmetrical, with the ptosis There have been many reports of hereditary being either unilateral or bilateral, (ii) there are ptosis in the literature. It is not always easy to skipped generations denoting reduced pen- dissect out the precise phenotype but many etrance or variable expression, (iii) the inherit- undoubtedly relate to blepharophimosis ptosis ance is autosomal and not sex linked. The epicanthus inversus syndrome (BPES). Von autosomal recessively inherited muscle-eye- Ammon first described this condition in 1831.5 brain disease (MEB) has recently been linked Vignes described hereditary epicanthus in to the same area. MEB patients are severely 1889.6 Small et al demonstrated linkage for mentally retarded with characteristic ocular BPES to 3q22–23.7 This was later refined to abnormalities, congenital muscular dystrophy, Department of 3q23 by Messiaen et al.8 Piemontese et al have and a polymicrogyria-pachygyria type neuronal Ophthalmology, migration abnormalities.19 Ptosis is not a Salisbury District demonstrated that both BPES type I (BPES in Hospital, Salisbury, association with decreased female fertility) and feature of MEB, but it is interesting to note Wiltshire, SP2 8BJ, UK BPES type II (normal fertility) map to this that there may be genes involved in neuronal T F W McMullan region.9 migration in this area of chromosome 1. AGTyers Briggs described an extensive pedigree in There are numerous hereditary causes of 1919 with autosomally dominant ptosis in six acquired ptosis such as progressive external Correspondence to: 10 T F W McMullan or A G generations. The ptosis was remarkably sym- ophthalmoplegia (PEO), oculopharyngeal Tyers metrical and there was only one skipped muscular dystrophy (OPMD), Kearns-Sayre [email protected] generation, although this case was not evalu- syndrome (KSS), and myotonic dystrophy; Accepted for publication ated and therefore could have had decreased however, the subject of this paper is congenital 28 June 2000 expressivity. The author comments that one of ptosis.

www.bjophthalmol.com X linked dominant congenital isolated bilateral ptosis 71

funduscopy was also performed to assess the Br J Ophthalmol: first published as 10.1136/bjo.85.1.70 on 1 January 2001. Downloaded from macula and optic disc.

Results CLINICAL DESCRIPTION The pedigree has 21 aVected members and 73 unaVected members; there are six aVected males and 15 aVected females. There are 37 unaVected males and 36 unaVected females. There is no evidence of male to male transmis- sion and all daughters of aVected males are aVected. The pedigree studied exhibits dominantly inherited congenital isolated bilateral ptosis and is represented in Figure 1. An aVected male and female member of the pedigree are depicted in Figure 2. Both have bilateral symmetrical ptosis, in particular there is no evidence of blepharophimosis or epicanthus inversus. The patients have bilateral ptosis that results in an abnormally low lid position that almost impinges on the visual axis in the primary position of gaze (superior margin reﬂex distance of ≈ 0 mm). Patients have mini- mal levator function bilaterally, <5 mm, associ- Figure 2 (A) Male member of the pedigree showing ated with an absent upper lid skin crease. They bilateral symmetrical congenital ptosis. (B) Female member have pronounced frontalis overaction and a of the pedigree showing bilateral symmetrical congenital characteristic chin-up head posture. Ocular ptosis. motility is normal in most cases but there is some reduced upgaze in some aVected family Patients and methods members (Table 1). Pupillary reactions are PATIENTS normal. Corrected visual acuity is normal with The pedigree was noted by one of us (AGT) as no evidence of prevalent amblyopia in either part of his oculoplastic practice. Detailed aVected or unaVected members. The patients assessment of their phenotype was made and have a good Bell’s response and have been blood taken for DNA extraction and cyto- treated with bilateral brow suspension with genetic analysis. These procedures were under- autologous fascia lata using the Crawford taken with informed consent and the relevant method.

ethical approval. http://bjo.bmj.com/ Family members were approached and assessed. A full ocular history, medical history, Discussion and family history were obtained. The patients We subjected the pedigree to linkage studies. were then examined for corrected visual acuity, Microsatellite analysis of markers in the region ocular motility, and lid function. Undilated Xq24-Xq27.1 gives a LOD score of 2.88, con-

?? on September 30, 2021 by guest. Protected copyright.

I ??

+ II

++++++++++++++ III

+ + ++ +++++++ +++ + IV ? NND NND

+ V Figure 1 Ptosis pedigree. + = Denotes sample taken for analysis. NND = neonatal death. Table 1 Summary of the clinical ﬁndings on examination of aVected family members

Patient II:11 III:19 III:21 III:25 III:30 III:35 III:38 IV:2 IV:8 IV:9 IV:15 IV:25 IV:26 IV:28 Ocular motility RU N N RU N N RU N N RU NNNN Strabismus NNNNNNNNNNNNNRET30PD RHypoT 2 PD Levator function (mm) <5 <5 <5 <5 <5 <5 <5 <5 <5 <5 <5 <5 <5 <5 Amblyopia No No No No No No No No No No No No No RE only

RU = reduced upgaze; N = normal; RET = right esotropia; RHypoT = right hypotropia; PD = prism dioptres.

www.bjophthalmol.com 72 McMullan, Tyers

20 firming X linked inheritance. As can be seen palsy). The reduced upgaze in four of the 14 Br J Ophthalmol: first published as 10.1136/bjo.85.1.70 on 1 January 2001. Downloaded from from Figure 2, the phenotype is identical in aVected family members that were examined both males and females. Because the expressiv- may be a manifestation of SR involvement. If ity is the same in males and females this is one there was a defect in one half of the midbrain, of very few truly X linked dominant conditions aVecting the subnucleus subserving the SR and and therefore defines a new condition— half of the subnucleus supplying the LPS, then namely, X linked dominant congenital isolated there would be contralateral eVects on the SR bilateral ptosis. There are no reports of X but bilateral eVects on the LPS. If there was a linked isolated ptosis in the literature. There is defect in the central subnucleus which supplies often a vague family history of ptosis in both LPS via both oculomotor nerves then patients with congenital ptosis which might there would be bilateral sequelae, bilateral pto- implicate recessive inheritance or reduced pen- sis as opposed to unilateral ptosis. etrance. One might speculate that there are Bilateral ptosis could, therefore, be ex- other pedigrees with X linked dominant ptosis plained by a fault in the central third nerve that have not been fully assessed, or that an X subnucleus that supplies both LPS. Unilateral linked recessive form of mutation in the same ptosis, which is far more common in the wider gene might be easily missed in routine clinical population, can be explained by an asymmetri- practice. Both recessive and dominant inheritance due to diVerent mutations in the same cal outflow from the central, single midline gene have been reported, as in OPMD.21 nucleus that supplies the LPS, giving rise to The underlying defect in congenital ptosis asymmetric phenotypic sequelae—namely, may be intrinsic to the levator palpebrae supe- unilateral ptosis. Alternatively, the fault could rioris (LPS) or there may be failure to reside in the branch of the superior division of innervate the developing LPS with a secondary the oculomotor nerve that supplies the LPS; eVect on its development/maturation. This this could be defective unilaterally or bilater- defect could be at the origin of the motor- ally, giving unilateral or bilateral ptosis. We neurons in the single midline central caudal have disregarded Muller’s muscle or its (sym- subnucleus in the rostral third nerve nucleus, pathetic) innervation as the site of the primary or there may be failure of migration involving pathology because the degree of ptosis seen the branch of the superior division of the ocu- when this muscle’s function is defective is lomotor nerve that supplies the LPS. much less, as in Horner’s syndrome. The extraocular muscles constitute a sepa- There is evidence of neuronal misdirection rate allotype of muscle with distinctive proper- from a variety of other conditions. Work on ties. They have been shown in rats to express a CFEOM type I by Engle et al3 has suggested diVerent myosin heavy chain and in rabbits to that this condition is caused by an absence of express diVerent proportions of troponin the central caudal third nerve subnucleus and isoforms.22–24 They are immune from some an associated absence of the superior division muscle disorders such as Duchenne muscular of the oculomotor nerve which fails to develop

dystrophy whereas they are among the ﬁrst to and innervate the structures that it normally http://bjo.bmj.com/ be aVected in others such as OPMD, mito- supplies—the LPS and the SR. Postmortem chondrial myopathies, and myasthaenia gravis. studies on one patient with CFEOM type I The LPS is defective in isolated ptosis. Of the failed to ﬁnd either the central caudal subnu- extraocular muscles, the LPS is supplied by a cleus (which would ordinarily supply the LPS), branch of the superior division of the oculomo- or the superior division of the oculomotor tor nerve. The superior division also supplies nerve or the SR or the LPS. Other cranial another extraocular muscle, the superior rectus

nerves that supply extraocular muscles were on September 30, 2021 by guest. Protected copyright. (SR) whose primary function is to elevate the noted to have fewer fibres than matched globe. The origins of the superior division of controls. the oculomotor nerve are in two separate sub- There is also misdirection of nerve fibres in nuclei of the third nerve nucleus. Both LPS Duane syndrome,25 26 inherited levator-medial muscles receive their supply from a single mid- rectus synkinesis27 and Marcus Gunn jaw line central caudal subnucleus in the rostral winking patients, a condition that may be third nerve nucleus. In contradistinction, each 28 SR muscle is supplied from a contralateral familial. Brodsky et al report a case of subnucleus. Each superior division of the ocu- “congenital ocular fibrosis syndrome” in as- lomotor nerve, therefore, has components from sociation with Marcus Gunn jaw winking and (i) a single midline subnucleus which sends synergistic divergence—the simultaneous ab- duction of both eyes on attempted lateral fibres to the LPS, and (ii) the contralateral 29 subnucleus that sends fibres to the SR. The gaze. This provides at least two concurrent fact that the superior division of the oculomo- examples of neuronal misdirection. Similarly, tor nerve has dual origins and supplies two Wang et al postulate that in CFEOM II there is separate muscles with diVerent functions can failure of development of the motor divisions give anatomical clues as to the site of any puta- of the entire third nerve giving ptosis and an tive pathophysiological defect. If the embryo- exotropic ophthalmoplegia.14 genesis, migration, or function of the superior In conclusion, we have characterised a new division of the oculomotor nerve was aVected ophthalmic condition—namely, X linked as a whole then one would postulate that there dominant congenital isolated bilateral ptosis. would be abnormality of SR function as well as The recruitment of further families with this a defect in LPS function; this is not seen in iso- condition might help to isolate the gene lated ptosis (but may be seen in double elevator responsible and this may provide an insight

www.bjophthalmol.com X linked dominant congenital isolated bilateral ptosis 73

into the development and pathology of ex- 14 Wang SM, Zwaan J, Mullaney PB, et al. Congenital fibrosis Br J Ophthalmol: first published as 10.1136/bjo.85.1.70 on 1 January 2001. Downloaded from of the extraocular muscles type 2, an inherited exotropic traocular muscles and the genes that aVect strabismus fixus, maps to distal 11q13. Am J Hum Genet them. 1998;63:515–25. 15 Doherty EJ, Macy ME, Wang SM, et al. CFEOM3: a new extraocular congenital fibrosis syndrome that maps to We are very grateful to the patients whose cooperation made 16q24.2-q24.3. Invest Ophthalmol Vis Sci 1999;40:1687– this study possible. We also thank Professor PA Jacobs for the 94. provision of facilities for genetic analysis and for her support 16 Reck AC, Manners R, Hatchwell E. Phenotypic heterogen- and Dr DO Robinson for his supervision of the genetic aspects eity may occur in congenital fibrosis of the extraocular of the study. The work was supported by grants from the British Council for Prevention of Blindness, Salisbury Hospitals Foun- muscles. Br J Ophthalmol 1998;82:676–9. dation, Salisbury Medical Society, the Wessex Medical Trust, 17 Black GCM, Perveen R, Hatchwell E, et al. Locus and the TFC Frost Charitable Trust. heterogeneity in autosomal dominant congenital external ophthalmolplegia (CFEOM). J Med Genet 1998;35:985–8. 18 Cohen MA. Congenital ptosis: a new pedigree and classifi- 1 Clark BJ, Kemp EG, Behan WMH, et al. Abnormal cation. Arch Ophthalmol 1972;87:161–3. extracellular material in the levator palpebrae superioris 19 Cormand B, Avela K, Pihko H, et al. Assignment of the complex in congenital ptosis. Arch Ophthalmol muscle-eye-brain disease gene to 1p32-p34 by linkage 1995;113:1414–19. analysis and homozygosity mapping. Am J Hum Genet 2 Edmunds B, Manners RM, Weller RO, et al. Levator palpebrae superioris fibre size in normals and patients with con- 1999;64:126–35. genital ptosis. Eye 1998;12:47–50. 20 McMullan TFW, Collins AR, Tyers AG, et al.Anovel 3 Engle EC, Goumernov B, McKeown CA, et al. Oculomotor X-linked dominant condition: X-linked congenital isolated nerve and muscle abnormalities in congenital fibrosis of the ptosis. Am J Hum Genet 2000;66:1455–60. extraocular muscles. Ann Neurol 1997;41:314–25. 21 Brais B, Bouchard JP, Xie YG, et al. Short expansions in the 4 Engle EC, Castro AE, Macy ME, et al. A gene for isolated PABP2 gene cause oculopharyngeal muscular dystrophy. congenital ptosis maps to a 3 cM region within 1p32- Nat Genet 1998;18:164–7. p34.1. Am J Hum Genet 1997;60:1150–7. 22 Wieczorek DF, Periasamy M, Butler-Browne GS, et al. 5 Usher CH. A pedigree of epicanthus and ptosis. Ann Eugen Co-expression of multiple myosin heavy chain genes, in 1925;1:128–38. addition to a tissue-specific one, in extraocular muscle. J 6 Vignes. Epicanthus hereditaire. Rev Gen Ophthal 1889;8: Cell Biol 1985;101:618–29. 438. 23 Briggs MH, Jacoby J, Davidowitz J, . Expression of a 7 Small KW, Stalvey M, Fisher L, Blepharophimosis et al et al. novel combination of fast and slow troponin T isoforms in syndrome is linked to 3q. Hum Mol Genet 1995;4:443–8. 8 Messiaen L, Leroy BP, De Bie S, et al. Refined genetic and rabbit extraocular muscles. J Muscle Res Cell Motil 1988;9: physical mapping of BPES type II. Eur J Hum Genet 1996; 241–7. 4:34–8. 24 Porter J, Baker R. Muscles of a diVerent ‘color’: the unusual 9 Piemontese MR, Memeo E, Massimo C, et al. A yac contig properties of the extraocular muscles may predispose or spanning the blepharophimosis ptosis epicanthus inversus protect them in neurogenic and myogenic disease. syndrome and propionic acidemia loci. Eur J Hum Genet Neurology 1996;46:30–7. 1997;5:171–4. 25 Hotchkiss MG, Miller NR, Clark AW, et al. Bilateral 10 Briggs HH. Hereditary congenital ptosis with report of 64 Duane’s retraction syndrome: a clinical-pathological case cases conforming to the Mendelian rule of dominance. Am report. Arch Ophthalmol 1980;98:870–4. J Ophthalmol 1919;2:408–17. 26 Miller NR, Kiel SM, Green WR, et al. Unilateral Duane’s 11 Stuckey HP. The slit-eyed people. Constricted eyelids found retraction syndrome (type 1). Arch Ophthalmol 1982;100: in four generations of a Georgia family—vision is 1468–72. normal-defect is not sex-linked and might be a Mendelian 27 Pang MP, Zweifach PH, Goodwin J. Inherited levator— recessive. J Hered 1916;7:146–7. 12 Fisher B, Zuckerman GH, Douglass RC. Combined inher- medial rectus synkinesis. Arch Ophthalmol 1986;104:1489– itance of purpura simplex and ptosis in four generations of 91. one family. Blood 1954;9:1199–204. 28 Kirkham TH. Familial Marcus Gunn phenomenon. Br J 13 Engle EC, Marondel I, Houtman WA, et al. Congenital Ophthalmol 1969;53:282–3. fibrosis of the extraocular muscles (autosomal dominant 29 Brodsky MC, Pollock SC, Buckley EG. Neuronal misdirec- congenital external ophthalmoplegia): genetic homogene- tion in congenital ocular fibrosis syndrome: implications ity, linkage refinement, and physical mapping on chromo- and pathogenesis. J Pediatr Ophthalmol Strabismus 1989;26: some 12. Am J Hum Genet 1995;57:1086–94. 159–61. http://bjo.bmj.com/ on September 30, 2021 by guest. Protected copyright.