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Genetic diseases affecting the eyelids: what should a clinician know?

Allen, Richard C.a,b

Current Opinion in Ophthalmology: September 2013 - Volume 24 - Issue 5 - p 463–477
doi: 10.1097/ICU.0b013e3283638219
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Purpose of review The molecular basis of a number of inherited diseases that affect the eyelids has been elucidated over the last two decades. Due to the vast number of these diseases, a clinician may become overwhelmed by the volume of data, making it difficult to incorporate newer information into his or her clinical practice. This article intends to review the recent developments of inherited diseases that affect the eyelids that a typical oculoplastic surgeon will encounter.

Recent findings This review proposes categorizing genetic diseases affecting the eyelids on rarity and whether the disease manifests itself at birth or later in life. Based on this classification system the following 10 diseases (the first five manifesting at birth, the last five later in life) are considered more likely to be encountered by the typical oculoplastic surgeon and reviewed in detail: blepharophimosis–ptosis–epicanthus inversus syndrome, congenital fibrosis of the extraocular muscles, lymphedema-distichiasis syndrome, neurofibromatosis type 1, congenital myasthenic syndrome, oculopharyngeal muscular dystrophy, chronic progressive external ophthalmoplegia, myotonic dystrophy, neurofibromatosis type 2, and basal cell nevus syndrome. The remaining known genetic disorders that affect the eyelids are considered less likely to be encountered by the typical oculoplastic surgeon and are listed in tabular form.

Summary It is prudent for the oculoplastic surgeon to be knowledgeable of inherited disorders that affect the eyelids to aid in accurate diagnosis, counseling, and treatment. The development of future therapies may at some point make treatment of these diseases no longer surgical.

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aDepartment of Ophthalmology and Visual Sciences

bDepartment of Otolaryngology – Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA

Correspondence to Richard C. Allen, MD, PhD, Department of Ophthalmology and Visual Sciences, 200 Hawkins Drive, Iowa City, IA 52242, USA. Tel: +1 319 356 2590; fax: +1 319 356 0363; e-mail:

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (

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Genetic diseases that affect the eyelids cannot be avoided by the oculoplastic surgeon. Whether the disease is limited to the eyelids or associated with dysmorphology or a systemic condition, an oculoplastic surgeon may be the first physician to encounter the patient. Clinically, repositioning the tissue of the periorbital region may be relatively straightforward; however, it is the physician's responsibility to generally understand the patient's disease with its associated conditions and prognosis. Knowledge of the fundamental defect that causes disease leads to more accurate diagnosis and counseling, better understanding of the pathophysiology of the disease, and ultimately more appropriate treatment.

There are a myriad of inherited diseases that affects the eyelids. The purpose of this review is to discuss the conditions that primarily affect the eyelids; there may be overlap with lacrimal disorders and orbital disorders, but genetic diseases that mostly affect the orbit or lacrimal system is not the subject of this review. Classification schemes for genetic disorders may be based on inheritance, gene function, or whether the disease is isolated to a particular structure (i.e., eyelid only) or associated with other conditions. Classification by inheritance is useful, but may sometimes be difficult to apply to the patient due to unknown family history or the patient's harboring a new mutation. Gene function is a very useful classification to the basic scientist, but not as useful to the clinician whose knowledge of the molecular mechanisms of the disease may not be up-to-date. Classification on whether a disease is isolated to the eyelids or associated with other systemic conditions may be difficult for the clinician whose diagnostic abilities of systemic associations may be limited. Other issues that may confuse the diagnosis are penetrance and expression of the disease. Penetrance refers to whether an individual that carries a mutation has any sign of the disease. Some diseases may not have complete penetrance and therefore ‘skip’ generations. Expression refers to signs of the disease that may be variable between patients.

Box 1

Box 1

This article proposes classifying the disease depending on its rarity and whether the disease manifests itself at birth. Whether a condition is congenital or not should be relatively easy for the clinician to determine. By definition, all genetic diseases that result in an abnormality are rare. Rarity will be divided into whether a typical oculoplastic surgeon will encounter multiple patients with the disease in his or her career (rare) or not (very rare). Therefore, there will be four categories: rare/congenital, rare/noncongenital, very rare/congenital, and very rare/noncongenital. The primary purpose of this review is to discuss the rare categories of diseases that affect the eyelids and touch briefly on the very rare categories.

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There are five genetic rare diseases that affect the eyelids and manifest themselves at birth. The typical oculoplastic surgeon will likely encounter each of these diseases at least once in his or her career.

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Blepharophimosis–ptosis–epicanthus inversus syndrome

Blepharophimosis–ptosis–epicanthus inversus syndrome (BPES; OMIM 110100) is one of the classic inherited diseases of the eyelids [1,2]. This is an autosomal dominant condition; the gene was mapped to 3q22-q23 and cloned in 2001 [3–5]. The gene, FOXL2, is a winged/forkhead transcription factor. Genes containing the DNA-binding forkhead domain are crucial in several signal transduction pathways, embryogenesis, tumorigenesis, and the maintenance of differentiated cell states [6].

Clinically, there is a variability of expression of the disease. The most common characteristics are blepharophimosis, ptosis, epicanthus inversus, and lateral ectropion of the lower lids [7,8]. Two forms of the syndrome are recognized: type I shows BPES with premature ovarian failure in girls, which may present as primary or secondary amenorrhea; type II shows BPES without premature ovarian failure [9]. Type I results in female infertility; male fertility is not affected. It is important to discuss with the parents of girls with BPES the possibility of infertility, and referral to a reproductive specialist should be considered.

Type I BPES was found to be caused by mutations that produce a truncated protein either lacking or containing the forkhead domain, while type II was found to be caused by duplications within or downstream of the forkhead domain, or other mutations resulting in an extended protein [10]. However, these phenotype–genotype correlations are not perfect and there are exceptions, as well as some reports of both type I and II BPES in the same family, suggesting that other genes influence the phenotype [11,12].

Treatment of BPES centers on correcting the ptosis and canthal abnormalities. Amblyopia is as high as 56.4% in these patients and treatment should center on preserving visual development [13]. Mustarde [14] popularized a four-flap technique to address the epicanthus. Anderson and Nowinski [15] suggested a five-flap technique consisting of a double Z-plasty and Y to V flap (Fig. 1). They also advocated the removal of excessive deep muscle, adipose, and fibrous tissue between the skin and medial canthal tendon. The medial canthal tendon may be plicated or resected and advanced, with or without transnasal wiring. A skin redraping technique has been recently described by Sa et al.[16▪]. There is some debate regarding the sequence and timing of ptosis repair and canthoplasties [17]. If the ptosis is severe, then it is reasonable to address only the ptosis early; technique is usually dependent on the strength of the muscle and amount of ptosis (Fig. 2). If the ptosis is not amblyogenic, then a combination surgery could be performed, but some advocate addressing the ptosis 3–6 months after the medial canthus [18,19]. Recently, there has been evidence that the belly of the levator muscle is positioned posteriorly in the orbit [20]. The authors suggest that all BPES patients would be best served with a supramaximal levator resection, which repositions the levator anteriorly. Patients who had this surgery performed were noted to have an improvement in their levator function postoperatively [21]. Lower eyelid abnormalities include downward concavity with lateral ectropion and lateral displacement of the inferior punctum. Both medial and lateral canthoplasty procedures have been advocated for the lower lid malpositions [22].





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Congenital fibrosis of the extraocular muscles

Congenital fibrosis of the extraocular muscles (CFEOM) has been defined genetically into three different types: CFEOM1, CFEOM2, and CFEOM3 [23]. Generally, patients with this condition are born with bilateral myogenic ptosis and restrictive external ophthalmoplegia and no other neurological findings [24,25]. The condition is nonprogressive and the etiology is believed to be due to dysfunction of part or all of the oculomotor nerve thus affecting the muscles that the nerve innervates [26].

CFEOM1 (OMIM 135700) is the ‘classic form’ of congenital fibrosis. The condition is autosomal dominant. Affected individuals have bilateral ptosis and the primary vertical position of each eye is fixed below the horizontal (Fig. 3). The degree of horizontal eye movement is variable, but in general, the eye cannot be brought above the horizontal mid-line, consistent with an absence of the superior division of the oculomotor nerve with atrophy of the levator and superior rectus. The gene for CFEOM1 is a kinesis motor protein encoded by KIF21A and located at the centromeric region of chromosome 12 [27]. Kinesins are responsible for anterograde axonal transport in neurons. In the mouse, KIF21A is enriched in adult neural tissues [28].



CFEOM2 (OMIM 602078) is autosomal recessive and individuals have bilateral external ophthalmoplegia and ptosis, with virtually absent eye movements. The primary fixed position of the eye in individuals with CFEOM2 is in abduction with marked exotropia. The gene was identified in 2001 as a homeodomain transcription factor protein named PHOX2A, located at 11q13 [29]. PHOX2A has been shown to be required for the development of cranial nerves III and IV in mouse and zebrafish [30].

CFEOM3 shows phenotypic overlap with CFEOM1, but with more variability. The disease is autosomal dominant and mutations have been identified in at least two genes: TUBB3 (CFEOM3A; OMIM 600638) and rarely KIF21A (CFEOM3B; OMIM 607034) [31,32].

Currently, the term congenital cranial dysinnervation disorders (CCDDs) is favored over congenital fibrosis to describe these syndromes [33,34]. As evidence confirms CFEOM to be secondary to disturbances in brainstem and/or cranial nerve development, CCDDs more accurately reflect the underlying developmental problem in these disorders. Other disorders included in CCDDs include Duane's syndrome, Mobius syndrome, monocular elevation deficiency, and Marcus Gunn jaw winking [35].

Treatment centers on placing the eyes in primary position with elevation of the eyelids. Numerous treatment options have been proposed [36–38]. A step-wise sequence of strabismus surgery followed by ptosis correction, if needed, is usually adequate. Ptosis surgery may not be needed after strabismus surgery as the upper lid position may be affected by surgery on the extraocular muscles. Strabismus outcomes can be unpredictable secondary to the restrictive nature of the ocular motility. Ptosis surgery is likely best treated with a silicone frontalis sling as these patients have learned to use their brows well; exposure can be an issue secondary to the absent Bell's phenomenon.

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Lymphedema-distichiasis syndrome

Lymphedema-distichiasis syndrome (OMIM 153400) is an autosomal dominant condition associated with distichiasis of the upper and lower lids and lymphedema of the extremities, usually the legs [39–41]. The disease was mapped to 16q24.3, and the gene was cloned in 2000 [42,43]. The gene, FOXC2, is a member of the forkhead/winged-helix family, the same gene family as that responsible for BPES. Examination of mutations in the gene shows no clear phenotype–genotype correlation, and there is significant intrafamilial variation [44–46]. The lymphedema is due to primary failure of the venous and lymphatic valves [47]. In the mouse, the gene has a restricted and temporal expression in the developing mesodermal mesenchyme of the head, kidney, and bones; it is also expressed in the developing heart, blood vessels, and limbs [48,49]. Such wide spectrum of expression of the gene accounts for the multiple tissue/organ systems potentially involved in affected individuals.

Clinically, patients with mutations in FOXC2 can have significant variability of expression. Distichiasis is the most common clinical feature (Fig. 4), followed by lymphedema, which has an earlier onset in men compared to women [50]. The lymphedema in this condition typically has its onset at puberty and should be differentiated from congenital lymphedema (Milroy disease). There can be significant intrafamilial variation [51,52]. Congenital heart disease and cleft palate are seen in approximately 7 and 4% of affected individuals, respectively, whereas congenital ptosis is noted in 31% of affected individuals. Extradural cysts are also noted in some affected individuals.



Treatment of the distichiasis can be challenging. Many techniques have been described including electrolysis, mucosal and tarsoconjunctival grafting, cryotherapy with and without eyelid splitting, and excision, trephination, and microhyfrecation of individual follicles [53–59]. Recurrence can occur as well as loss of the normal anterior eyelashes, cicatricial entropion, and eyelid margin deformities.

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Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1; OMIM 162200) is an autosomal dominant condition with 100% penetrance by the age of 5 years and extreme variability of expression both within and among families. One-third of patients with NF1 will develop serious complications from the disease, but it is difficult to provide the patient and their families prognostic information due to the phenotypic variability in the disorder [60]. NF1 is one of the classic genetic diseases and the gene was one of the first to be mapped by positional cloning. The gene neurofibromin, located at 17q11.2, is a tumor suppressor gene that silences activated Ras, a proto-oncogene, which controls cellular proliferation [61]. NF1 is often thought of as peripheral neurofibromatosis whereas type 2 neurofibromatosis is thought of as central neurofibromatosis, both of which have a predisposition to nerve sheath tumors.

Diagnostic criteria of NF1 dictate that two of the following must be met: six or more café au lait spots; two or more neurofibromas or one plexiform neurofibroma, freckling in the axillary or inguinal regions, optic glioma, two or more Lisch nodules, distinctive osseous lesion (sphenoid wing dysplasia or cortical thinning of long bones), or first-degree relative with NF1 [62]. Due to the multiorgan involvement, a multidisciplinary team is best involved in the care of NF1 patients.

Although the eyelid findings in neurofibromatosis are not a primary issue, secondary problems arise due to plexiform neurofibromas, which may be misdiagnosed. These lesions may result in a spectrum of findings from subtle ptosis to complete ptosis with orbital and intracranial extension of the neurofibroma. The ptosis in patients with a plexiform neurofibroma classically has an S-shape to the contour of the eyelid with temporal drooping (Fig. 5). Other ocular findings include optic nerve gliomas and Lisch nodules. Systemic findings include café au lait spots and axillary freckling. We believe it is always prudent to examine the skin closely in patients with unilateral congenital ptosis to look for signs of NF1. A recent study found that 62% of NF1 patients with orbitotemporal plexiform neurofibromas developed amblyopia [63▪▪].



Lee et al.[64] proposed the following classification for periorbital deformities in patients with NF1: brow ptosis, upper lid infiltration with ptosis, lower lid infiltration, lateral canthal disinsertion, and conjunctival and lacrimal gland infiltration. The authors recommended delaying surgery, if possible, in children due to rapid expansion of the tumors with a high rate of recurrence.

Treatment of clinically significant plexiform neurofibromas involves debulking of the tumor and elevation of the eyelid. Due to the expansion of the eyelid by the tumor, often a concomitant upper lid shortening (wedge resection or upper lateral tarsal strip) is performed, which can make predication of the final height of the eyelid challenging. These cases can be frustratingly challenging in patients with large tumors [65,66,67▪]. Debulking often leads to additional debulking with additional deformation of the eyelid. Complete excision of the tumor is difficult, if not impossible without damage to normal structures. Some authors have advocated exenteration in patients with significant disease to give a more desirable cosmetic result with a prosthesis [68].

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Congenital myasthenic syndrome

Congenital myasthenic syndrome (CMS) is a heterogeneous group of inherited disorders of neuromuscular transmission. Patients often present in the neonatal period with ocular, bulbar, or respiratory symptoms. This should be differentiated from transient neonatal myasthenia gravis, which occurs after transfer of maternal acetylcholine receptor (AChR) antibodies [69]. Ptosis is the most common initial sign; however, the ptosis is usually not severe enough to warrant surgical intervention [70–72]. Gene defects may affect presynaptic, synaptic, or postsynaptic structures [73]. The disease proteins identified to date include choline acetyltransferase (ChAT), the endplate species of acetylcholinesterase (AChE), β-2-laminin, the AChR, rapsyn, plectin, Nav1.4, the muscle-specific protein kinase (MuSK), agrin, downstream of tyrosine kinase 7 (Dok-7), and glutamine-fructose-6-phosphate transaminase 1 (GFPT1) [74▪]. The majority of all cases of CMS is due to postsynaptic mutations, over one-half of which are mutations in the AChR subunits. The inheritance of CMS due to mutations in the AChR is usually autosomal recessive. There are many other structures involved in neuromuscular transmission, mutations in which may be identified in other patients with CMS.

Due to the ptosis, extraocular muscle weakness, and orbicularis weakness, it is difficult to treat patients with CMS because of the increased risks of exposure keratopathy with any elevation of the eyelids with poor orbicularis tone and usually a poor Bell's phenomenon. In addition, the risk of surgery is increased with decreasing pulmonary function with age. These patients may become ventilator dependent as they get older.

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There are five rare genetic diseases that affect the eyelids and manifest themselves later in life. The typical oculoplastic surgeon will likely encounter each of these diseases at least once in his or her career.

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Oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD; OMIM 164300) is characterized by progressive ptosis, external ophthalmoplegia, dysphagia, and proximal limb weakness [75–79]. The disease is autosomal dominant and caused by a short triplet repeat expansion in the poly(A) binding protein nuclear 1 gene (PAPBN1) [80,81]. The gene is located at 14q11.2-q13 and involved in polyadenylation of messenger RNA. Classically, patients have French Canadian ancestry; however, there is a worldwide distribution of OPMD with significant populations in the state of New Mexico in the USA and Bukhara Jews in Israel [82,83]. Studies have documented the notorious misdiagnosis and delayed diagnosis of the disease; this will improve with better education of ophthalmologists, gastroenterologists, and otolaryngologists [84▪]. Diagnosis is made with a DNA test to look at the number of triplet repeats in the affected area of the gene. There have been recent reports of OPMD being caused by a rare point mutation that mimics the effect of the common triplet repeat expansion mutation [85,86].

Clinically, the ptosis in OPMD starts as early as the fifth decade of life. Swallowing difficulties may precede or follow the ptosis by a few years. Patients also develop proximal limb weakness, facial weakness, gait abnormalities, and pain in the proximal muscles. Extraocular motility usually remains intact until late in the disease, although supraduction may be affected earlier in some patients. Saccades have been found to be reduced in speed even when eye movements are totally preserved [87]. Bell's phenomenon and orbicularis strength usually remain intact.

Many different surgical strategies have been proposed to treat the ptosis in OPMD, but there is good evidence that these patients are best treated with a primary silicone frontalis sling [88,89▪] (Fig. 6).



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Chronic progressive external ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) is a term best reserved for disorders secondary to mitochondrial dysfunction clinically characterized by slowly progressive bilateral ocular immobility associated with ptosis. The spectrum of mitochondrial-associated disease is broad, ranging from late-onset CPEO with slow progression to the severe early-onset multisystemic disorder, Kearns–Sayre syndrome (ophthalmoplegia, retinal pigmentary changes, cardiac conduction disorders, cerebellar ataxia, and high cerebrospinal fluid protein) [90,91]. Extraocular motility is affected significantly in patients with CPEO, as opposed to OPMD (Fig. 7). In addition, orbicularis function is also usually appreciably affected. This makes the ptosis associated with CPEO more difficult to treat since Bell's phenomenon is often affected and there is some difficulty with closure of the eyelids. Tissues affected by mitochondrial respiratory chain disease are those with a high energy demand such as muscle and nerve. The diagnosis is supported pathologically by the finding of ragged-red fibers and partial cytochrome C oxidase deficiency on muscle biopsy. Deltoid or vastus lateralis muscles are relatively easy to access with good specimens. Others have advocated orbicularis oculi biopsies during eyelid surgery [92,93▪].



Mitochondria are unique in that they contain their own genome and are maternally inherited. Each cell contains multiple mitochondria, and each mitochondrion has several copies of a circular strand of DNA (mtDNA), which encompasses 16 569 base pairs encoding proteins of the respiratory chain, tRNAs, and ribosomal RNAs [94]. All other enzymes required for mitochondrial function are encoded by the nuclear genome, translated in the cytoplasm, and then imported into the mitochondrion. Due to the multiple copies of mtDNA in each mitochondrion, an individual is considered to be homoplasmic if each of these copies is identical, or heteroplasmic if mutant and normal mtDNA coexist. The expression of disease due to a mutation in the mtDNA depends upon three factors: the particular mutation, the degree of homoplasmy or heteroplasmy, and the ratio of mitochondria carrying the mutation [95].

Nuclear DNA encodes additional enzymes that are required for mitochondrial function. Mutations in nuclear DNA can cause structural changes in enzymes or affect intergenomic communication between the nucleus and mitochondrion, resulting in secondary mitochondrial DNA changes, usually multiple deletions in the mtDNA [96]. These nuclear mutations are inherited in a Mendelian fashion, rather than maternally.

Therefore, CPEO can be caused by two different molecular mechanisms: mutations in the mitochondrial DNA (maternal inheritance) or mutations in nuclear DNA, which affect mitochondrial function (Mendelian inheritance). CPEO caused by mtDNA mutations reveals rearrangement of segments of mtDNA in the form of deletions and duplications and, less commonly, point mutations [97]. Patients are typically heteroplasmic, and this can lead to a wide spectrum of disease, even within families.

There are currently seven genes from the nuclear genome known, mutations in which cause CPEO [98]. Autosomal dominant CPEO is associated with six genes: adenine nucleotide translocator 1 (ANT1; 4q35.1), Twinkle (C10orf2; 10q24.31), polymerase gamma (POLG; 15q26.1), polymerase gamma 2 (POLG2; 17q23.3), RRM2B (8q22.3), and DNA2 (10q21.3) [99–101]. Other clinical manifestations noted in autosomal dominant CPEO include proximal limb weakness, severe depression, peripheral neuropathy, sensorineural hearing loss, cataracts, and endocrine dysfunction.

Autosomal recessive CPEO is associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and autosomal recessive cardiomyopathy ophthalmoplegia (ARCO). MNGIE is caused by mutations in the thymidine phosphorylase gene (TYMP; 22q13.33) [102]; the cause of ARCO has been shown to be caused by recessive mutations in the POLG gene [101,103].

Treatment of CPEO centers on elevation of the eyelids without worsening exposure keratopathy. These patients are likely best served with a primary silicone frontalis sling [104–107]. This allows a single surgery through the upper eyelid, which results in minimal compromise of an already weakened orbicularis muscle. Patients with CPEO have been shown to have relatively preserved brow motility, which also supports the use of a frontalis sling [108]. The sling can be tightened for recurrent ptosis. For those patients who fail medical treatment of dry eye and cannot tolerate lowering of the upper eyelids, elevation of the lower lids with an appropriate spacer usually improves the situation. With regard to screening for cardiac issues, all early-onset patients should be evaluated by a cardiologist and later-onset patients should be screened at 3–5 year intervals [109▪].

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Myotonic dystrophy

Myotonic dystrophy (DM1; OMIM 160900), previously known as Steinert's disease, is an autosomal dominant disorder caused by a triplet repeat expansion in the dystrophia myotonica-protein kinase (DMPK) gene [110–112]. The gene is located at 19q13.32 and contains a noncoding trinucleotide repeat (CTG) that is expanded in affected individuals. Normal individuals have 5 to 37 repeats, whereas mildly affected individuals have 50–150 repeats, classically affected individuals have 100–1000 repeats, and congenital onset is associated with greater than 2000 repeats [113]. Expanded, noncoding RNAs are thought to cause human disease through abnormal interactions with RNA-binding proteins [114]. DM1 demonstrates ‘anticipation’ – worsening of the phenotype in successive generations, which correlates with expansion of the repeat [115,116]. Extreme amplification of the trinucleotide repeat is only noted when the gene is passed maternally [117].

The classical form of DM1 usually becomes symptomatic in the second to third decade of life. In addition to muscular dystrophy, patients exhibit myotonia, a condition in which muscle relaxation is delayed after contraction. Other findings include cardiac conduction abnormalities, polychromatic cataracts, hypogonadism, and frontal balding. The diagnosis is usually confirmed through genetic testing.

Clinically, patients exhibit symptoms similar to CPEO with regard to ptosis, extraocular motility, and orbicularis weakness. The orbicularis weakness in DM1 is much more impressive compared to CPEO or OPMD. Facial nerve palsy has been found to result in meibomian gland dysfunction, and the orbicularis weakness observed in DM1 patients supports this finding [118▪,119▪▪]. Patients usually demonstrate significant meibomian gland dysfunction, which can almost be diagnostic of the disorder (personal observation).

Treatment involves elevation of the eyelids and treatment of the meibomian gland disease, with attention paid to the poor orbicularis tone and compromised Bell's phenomenon. Similar to other patients with progressive myogenic ptosis, these patients are best served with a primary silicone frontalis sling [106]. In addition, lower lid elevation may be necessary. Meibomian gland plugging should be addressed with warm compresses, possible doxycycline, and fish oil, among others.

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Neurofibromatosis type 2

Neurofibromatosis type 2 (NF2; OMIM 101000) is an autosomal dominant disorder associated with mutations in the neurofibromin-2 gene also known as merlin [120]. The gene is located at 22q12.2 and is a tumor suppressor gene, which negatively regulates Schwann cell production. Onset of the disease is usually in the second or third decade. NF2 is less common than NF1, but similar to NF1 with 100% penetrance and its gene product being a tumor suppressor gene.

Clinically, the disease is characterized by the development of bilateral vestibular schwannomas, meningiomas, ependymomas, neurofibromas, nonvestibular schwannomas, and posterior subcapsular cataracts [121]. Diagnostic criteria for NF2 from the National Institutes of Health is the following: bilateral vestibular schwannoma; or first-degree relative with NF2 and either unilateral vestibular schwannoma or two of the following: meningioma, schwannoma, glioma, neurofibroma, or juvenile posterior subcapsular cataract. Due to the multiple systems involved, these patients are best treated by a multidisciplinary team. Early age at symptom onset and the presence of intracranial meningiomas at diagnosis are markers of increased disease severity and associated with a heightened risk of early mortality [122].

Similar to NF1, NF2 does not cause primary eyelid problems but secondary problems occur due to the development of acoustic neuromas (Fig. 8). Clinically, the oculoplastic surgeon is involved in treating the facial nerve palsy secondary to the patient's acoustic neuromas. Treatment involves static or dynamic measures to help the eyelids close. This may involve loading the upper lids with gold or platinum weights and elevating the lower eyelids and midface. Other ophthalmic findings include epiretinal membranes, retinal hamartomas, and optic nerve sheath meningiomas. Due to the fact that these patients are usually hearing impaired, it becomes critical to preserve their vision.



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Basal cell nevus syndrome

Basal cell nevus syndrome (BCNS; OMIM 109400), also known as Gorlin–Goltz syndrome and nevoid basal cell carcinoma (BCC) syndrome, is an autosomal dominant disorder resulting in multiple BCCs. Although the disease does not typically result in primary eyelid malpositions, the oculoplastic surgeon is often involved early in the care of these patients due to the development of basal carcinomas in the periocular region (Fig. 9a). The gene was localized 9q22.32 and later identified as the human homolog of the Drosophila Patched gene (PTCH1) that acts as a primary inhibitor of the hedgehog signaling pathway [123–125]. Genotype–phenotype correlations are not evident and a great deal of variability in presentation has been noted [126]. In BCNS, PTCH1 acts as a classical tumor suppressor gene. Ultraviolet irradiation results in a mutation in the normal copy of the gene in cells, which in turn results in a BCC. The oculoplastic surgeon becomes involved with these patients due to the high UV exposure to the face.



Clinically, diagnosis of BCNS is made in the presence of two major, or one major and two minor criteria [127]. Major criteria include greater than two BCCs or one at less than 20 years old; histologically confirmed odontogenic keratocysts of the jaw; three or more palmar or plantar pits (Fig. 9b); bilamellar calcification of the falx cerebri; bifid, fused or markedly splayed ribs; first-degree relative with BCNS; and desmoplastic medulloblastoma. Minor criteria include macrocephaly, congenital malformations, skeletal abnormalities, radiological abnormalities, and ovarian fibroma. Due to the wide spectrum of findings, care of these patients should be multidisciplinary.

Ocular findings have been reviewed in patients with BCNS [128]. In addition to periocular BCCs, strabismus, nystagmus, cataract, glaucoma, eyelid cysts, hypertelorism, myelinated nerve fibers, iris transillumination defects, and uveal coloboma have been reported among others. In a series reported by Honavar et al.[129] three of four patients had orbital infiltration of their periocular BCC.

Treatment classically has centered on the archaic therapy of the slow ‘whittle’ of new BCCs with either Mohs microangiographic techniques or frozen section evaluation. This approach has almost uniformly resulted in less than ideal results. Fortunately, therapy with a systemic agent has shown promise [130▪]. Vismodegib is a new orally administered hedgehog-pathway inhibitor. Studies have shown that use of the drug in patients with BCNS reduces the BCC tumor burden and blocks growth of new BCCs [131▪▪]. Adverse side-effects of the drug include loss of taste, muscle cramps, hair loss, and weight loss.

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Table 1 lists the disorders included in the very rare category of genetic diseases involving the eyelids. It should be noted that other numerous diseases that affect the eyelids have been proposed to have a genetic basis with evidence of pedigrees and linkage. However, only those diseases with strong evidence of genes identified are included in Table 1. Due to their rarity, only the information noted in the table will be presented; detailed review of these diseases is not undertaken in this article. The conditions ichthyosis and xeroderma pigmentosum are not included in the table due to the large number of genes involved with each of these disorders. Ichthyosis results in desquamation of the skin, and the eyelids are affected through shortening of the anterior lamellae, which causes cicatricial ectropion. Xeroderma pigmentosum is a DNA repair defect that results in early skin cancers, and the oculoplastic surgeon is involved when the periocular skin acquires a skin cancer. The reader is directed to the referenced reviews on ichthyosis and xeroderma pigmentosum for details of the genetics of these disorders [132,133].

Table 1-a

Table 1-a

Table 1-b

Table 1-b

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All disciplines within ophthalmology have classic genetic diseases associated with them, and this includes oculoplastic surgery. Familiarity of genetic diseases that affect the eyelids is indispensable to the oculoplastic surgeon that cares for these patients. Appropriate diagnosis is the key to providing appropriate treatment. Treatment can imply a number of avenues: this may include the appropriate surgical procedure that has been shown to be successful for the particular genetic disease, the appropriate environmental or lifestyle modification that could decrease the progression or severity of the disease, the appropriate testing or screening protocols for surveillance of disease (e.g., neoplasm), the use of a medication that has been shown to be efficacious for the particular disease, or the use of gene therapy to provide a healthy copy of the gene to the target tissue to replace the mutant copy. Due to the fact that these are molecular diseases, molecular therapies will eventually be developed as witnessed in BCNS. However, until that time is realized for the other diseases noted in this review, an oculoplastic surgeon's skills will continue to be in demand.

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Conflicts of interest

Support for the work was provided by an unrestricted grant from Research to Prevent Blindness, New York, NY, USA.

The author has no conflict of interest to declare.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 517–518).

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Patients with a unilateral facial nerve palsy were analyzed with infrared meibography. The side with the facial nerve palsy was found to have significantly worse meibomian gland morphology compared to the unaffected control side.

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Patients with unilateral facial nerve palsy were found to have a significant correlation with meibomian gland dysfunction on the side of the palsy.

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The authors review targeted therapy for orbital and periocular BCC and cutaneous squamous cell carcinoma. A patient with BCNS is presented that has been successfully treated with vismodegib.

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Forty-one patients with BCNS are described that were treated with vismodegib. Vismodegib was found to reduce tumor burden and block the development of new BCCs in these patients. Half of the patients discontinued the therapy due to adverse events.

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eyelid; gene; genetic; inherited; ptosis

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