32 Syndromic Blepharoptoses

10.1055/b-0039-172780

32 Syndromic Blepharoptoses

Christine Greer, Michael A. Burnstine, Diana K. Lee, Jonathan W. Kim

Abstract

Syndromic blepharoptosis refers to patients who present with ptosis and other ocular and systemic findings. This differs from static maldevelopment ptosis which is present from birth (i.e., classic congenital ptosis). The syndromic forms of ptosis covered in this chapter are aberrant innervation syndromes, static myopathic ptoses involving other extraocular muscles, and myopathic ptoses that affect the levator muscle in children and adulthood.

32.1 Introduction

Syndromic blepharoptoses refers to a category of eyelid ptoses associated with other ocular and systemic findings. This is distinct from the classic congenital ptosis described in Chapter 28. Frequently, in patients with syndromes there is an underlying genetic basis for the phenotypic presentation. In some cases, the associated phenotypic manifestations may be fatal.

To date, syndromic ptosis has never been categorized and presented in a comprehensive, effective manner. For clarity, the syndromic forms of ptoses covered in this chapter have been subdivided into sections: aberrant innervation syndromes, static myopathic ptoses involving the extraocular muscles, myopathic ptoses that affect the levator muscle and other muscle groups presenting in childhood, and progressive myopathic ptoses seen in adulthood (Table 32.1).

**Table 32.1** Summary of syndromic progressive myopathic ptoses
Disease	Age of onset	Symptoms	Progressive/nonprogressive	Inheritance	Gene	Treatment
Aberrant innervation syndromes
Duane’s syndrome ¹	Birth	Patients have deficiency of abduction and/or adduction with associated co-contraction of the medial and lateral recti causing globe retraction and narrowing of the palpebral aperture on lateral gaze. Symptoms occur secondary to a cranial nerve III-VI synkinesis. Blepharoptosis can occur secondarily.	Nonprogressive	Majority sporadic 5–10% inherited AD Rarely AR	Sporadic mutations involve CHN1 gene (chimerin 1, GTP-ase-activating protein)	Surgical correction of strabismus and blepharoptosis where indicated
Marcus Gunn jaw-winking syndrome ² ID#b282a672_3 ^– ID#b282a672_4 ⁵ ^, ⁶	Birth	Patients typically present with congenital blepharoptosis with an upper eyelid that elevates with opening of the mouth or moving the jaw. Symptoms are secondary to cranial nerve III-V synkinesis.	Nonprogressive	Nonhereditary	N/A	For patients with mild blepharoptosis, observation. For patients with severe ptosis, levator aponeurosis disinsertion, and frontalis suspension
Marin-Amat syndrome, “Inverted Marcus Gunn phenomenon” ⁷	Typically acquired after facial nerve palsy, rarely congenital	Synkinesis of cranial nerves V and VII, whereby jaw opening leads to eyelid closure	Nonprogressive	Can be acquired or inherited (rare); unknown genetics	Unknown	Facial neuromuscular retraining and in select cases, botulinum toxin
Static myopathic ptoses involving the extraocular muscles
Blepharophimosis-ptosis-epicanthus inversus syndrome ⁸ ^, ⁹	Birth	Classically, patients have severe bilateral blepharoptosis, blepharophimosis, epicanthus inversus, and telecanthus. Other periorbital findings include lower lid ectropion, hypertelorism, superior orbital rim hypoplasia, and lacrimal system abnormalities, present in varying degrees. Type I is associated with ovarian insufficiency	Nonprogressive, possible improvement of telecanthus with growth	AD	FOXL2 (forehead box protein 2) is responsible for types I and II	Surgical correction of blepharoptosis and phimosis
Congenital fibrosis of the extraocular muscles syndrome (CFEOM) ¹⁰ ^, ¹¹	Birth	Bilateral blepharoptosis and external ophthalmoplegia involving vertical gaze, and to a variable degree horizontal gaze. Patients have hypotropia in the affected eye with chin up head posture.	Nonprogressive	CFEOM1 AD CFEOM2 AR CFEOM3 AD Tukel AR	1: K1F21A(kinesin family member 7)/TUBB3 (tubulin beta 3 class III) 2: PHOX2A (paired like homeobox 2a) 3: K1F21A/TUBB3 Tukel: Unknown	Surgical correction of strabismus and blepharoptosis where indicated
Monocular elevation deficiency, formerly “double elevator palsy” ¹² ID#b282a672_13 ^– ¹⁴	Present at birth, or acquired	Unilateral syndrome, in which the eye is not able to supraduct in all fields of gaze. Hypotropia is present in primary position. Can be associated with blepharoptosis	Nonprogressive	Sporadic	N/A	Surgical correction of strabismus, followed by surgical correction of blepharoptosis
Progressive myopathic ptoses affecting the levator muscle and other muscle groups that present in childhood
Autosomal dominant optic atrophy plus syndrome (Treft Sanborn Carey syndrome) ¹⁵	Childhood	Bilateral optic atrophy, sensorineural hearing loss, myopathy leading to ophthalmoplegia, blepharoptosis, ataxia, and peripheral neuropathy	Progressive	AD	OPA1 (OPA1 protein, a mitochondrial dynamin like GTPase)	Supportive measures Surgical correction of strabismus and blepharoptosis where indicated
Central core myopathy (Shy-Magee Syndrome), muscle core disease, central fibrillary myopathy ¹⁶ ^, ¹⁷	Birth	Hypotonia, limb weakness, blepharoptosis	Nonprogressive or progressive	AD	RYR1 gene (skeletal muscle ryanodine receptor, calcium channel in the sarcoplasmic reticulum)	Supportive care Salbutamol may help with weakness Surgical correction of blepharoptosis
Centronuclear myopathy, X-linked myotubular myopathy (XLMM)^a, ¹⁸ ^, ¹⁹	Infancy, early childhood	Facial and neck muscle weakness, including ocular (blepharoptosis, ophthalmoparesis), limb weakness, diaphragmatic weakness	Often progressive	XLR, AD, or AR	More common: DNM2 gene (dynamin 2), BIN1(bridging integrator 1), TTN (Titin) Less common: CCDC78 gene (coiled-coil domain containing 78), SPEG (A member of the myosin light chain kinase family, required for myocyte cytoskeletal development), RYR1 (skeletal muscle ryanodine receptor, calcium channel in the sarcoplasmic reticulum) XLMM: MTM1 (myotubularin)	Supportive care Surgical correction of strabismus and ptosis where indicated
Chromosome 3p- syndrome ²⁰ ^, ²¹	Birth	Poor growth, developmental delay, intellectual disability, microcephaly, autism spectrum disorder, hypotonia, blepharoptosis	Nonprogressive	Nonhereditary	Chromosomal: Secondary to a deletion of a segment of the short arm of chromosome 3	Supportive care Surgical correction of blepharoptosis in indicated cases
Congenital fiber-type disproportion^a ²² ID#b282a672_23 ^– ID#b282a672_24 ²⁵	Birth	Floppiness, limb and facial weakness; ptosis, ophthalmoplegia, bulbar weakness and diaphragmatic weakness	Usually non-progressive or may show improvement over time	AD, AR, or XLR	ACTA1 (skeletal muscle actin), SEPN1 (Selenoprotein N), TPM3 (Tropomyosin 3)	Supportive care Surgical correction of strabismus and blepharoptosis where indicated
Gillum-Anderson syndrome ²⁶	Congenital	Ectopia lentis, myopia, blepharoptosis with reduction in strength of the levator aponeurosis, findings likely secondary to connective tissue abnormalities	Non-progressive	AD	Unknown	Definitive treatment for ectopia lentis and blepharoptosis is surgical
Kugelberg-Welander syndrome^a, ²⁷	After 1 year	Hypotonia and weakness proximal >distal. 50% have scoliosis and restrictive lung disease. Diaphragmatic weakness may occur late in the disease. May have blepharoptosis.	Progressive	AR	SMN (survival motor neuron protein), NAIP (neuronal apoptosis inhibitory protein)	Supportive care Surgical correction of blepharoptosis
Limb girdle muscular dystrophy^b ^, ²⁸ ^, ²⁹ ^, ³⁰	Early childhood	Progressive weakness the shoulder and hip girdle muscles with sparing of the facial muscles (type I and type II based on inheritance). Subtype LGMD1C presents with proximal muscle weakness, ophthalmoplegia, exophthalmos, and blepharoptosis. GMPPB subtype with mental retardation, microcephaly, epilepsy, cataract, strabismus, nystagmus, and blepharoptosis.	Progressive	AR (type 2 90%), AD (type 1)	1B: LMNA (Lamins A and C are intermediate filaments which are components of the nuclear envelope) 1C: Caveolin 3 gene (caveolin 3, plays a role in the formation of muscle fibers) 2A: CAPN3(calpain-3) 2B: DYSF (dysferlin) 2C-2F: SGCA (sarcoglycan protein complex) 2J: TTN(Titin) 2L: ANO5 (anoctamin-5) 2I, 2K, 2M-N: GMPPB gene/protein POMGNT1 gene/protein	Supportive care Surgical correction of strabismus and blepharoptosis in indicated cases
Lymphedema-distichiasis-syndrome ³¹ ID#b282a672_32 ^– ³³	Variable	Lymphedema, distichiasis, blepharoptosis in 30% of patients. Possible systemic associations include cardiac defects, cleft palate, spinal cord cysts, and scoliosis	Lymphedema develops by age 40, distichiasis occurs in 94%, presentation of blepharoptosis is variable	AD; 25% sporadic	FOXC3 gene (forkhead box C2, a transcription factor)	Treatment of lymphedema and distichiasis by conventional methods. Surgical correction of blepharoptosis
Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) ³⁴	Variable (infancy to adulthood)	Gastrointestinal dysmotility, cachexia, peripheral neuropathy, leukoencephalopathy, blepharoptosis	Progressive	AR	TYMP ( thymidine phosphorylase)	Supportive care Surgical correction of blepharoptosis in indicated cases
Multiminicore myopathy^a, ¹⁷ ^, ³⁵ ^, ³⁶	Birth, infancy	Hypotonia, generalized muscle weakness (predominately axial), facial weakness, blepharoptosis, ophthalmoplegia	Static or progressive	AR	RYR1 gene in atypical cases (skeletal muscle ryanodine receptor, Calcium channel in the sarcoplasmic reticulum), SELENON gene in classic cases (Selenoprotein N)	Supportive care Surgical correction of strabismus and blepharoptosis
Myotonia congenita ³⁷	Variable	Intermittent episodes of myotonia, may include ocular muscles, relieved with repeated contractions; Thomsen disease is more mild, Becker disease more common. Symptoms may improve later in life	Nonprogressive	AD (Thomsen), AR (Becker)	CLCN1 gene, (chloride voltage gated channel 1)	Treatment of muscle stiffness.
Myotubular myopathy^a, ¹⁷	Birth to childhood	Severe weakness, hypotonia, facial weakness, bulbar weakness, diaphragmatic weakness	Frequently fatal in childhood	XLR (most severe form), AD (least severe and does not affect eyes), AR	MTM1 gene (myotubularin)	Supportive care Surgical correction of blepharoptosis where indicated
Nemaline myopathy ¹⁷ ^, ³⁸ ^, ³⁹	Childhood	Generalized hypotonia and diaphragmatic weakness. Distal weakness of lower extremities, severe facial and bulbar weakness.	Nonprogressive	AD, AR, or sporadic	ACTA1, TPM2, TPM3, NEB, TNNT1, KBTBD, CFL2 Genes encode protein components of the muscle thin filament, most commonly nebulin protein (NEB) or alpha actin.	Supportive care Surgical correction of blepharoptosis
Noonan syndrome ⁴⁰	Birth	Distinct facies notable for hypertelorism, epicanthal folds, blepharoptosis, micrognathia, webbed neck, low posterior hairline, pectus carinatum, short stature, kyphosis/scoliosis, cardiac anomalies, platelet deficiency, cryptorchidism	Nonprogressive	AD	PTPN11 (50%) SOS 1(10–13%) RAF1(5%) RIT1 (these genes encode proteins important in the RAS/MAPK cell signaling pathway important for cell division, growth, differentiation and migraine) KRAS (<5%) Less frequent: NRAS BRAF MEK2 RRAS RASA2 A2ML1 SOS2 LZTR1	Surgical correction of blepharoptosis in indicated cases
Parry Romberg syndrome ⁴¹	Late childhood/early adulthood	Hemifacial atrophy initially affecting the maxilla and between the nasolabial folds. The tongue and soft palate may be involved. Ocular manifestations include enophthalmos, blepharoptosis, uveitis	Progressive	Nonhereditary	N/A	Reconstructive or microvascular surgery where indicated
Sensory ataxic neuropathy, dysarthria and ophthalmoplegia (SANDO) ⁴² ^, ⁴³	Variable (5–17 years of age)	Sensory ataxic neuropathy, dysarthria, ophthalmoparesis. Hearing loss, seizures, myopathy may occur and lead to blepharoptosis.	Progressive	AR (nuclear coded mitrochondrial DNA)	POLG (DNA polymerase gamma gene)	Supportive care Surgical correction of strabismus and blepharoptosis in indicated cases
Saethre-Chotezen syndrome (acrocephalosyndactyly) ⁴⁴	Birth	Craniosynostosis with midface hypoplasia, hypoplastic maxilla, blepharoptosis, hypertelorism	Nonprogressive	AD	TWIST1 (encodes TWIST 1 protein, a transcription factor)	Patients may require craniofacial reconstruction, including blepharoptosis repair
Vertebral fusion posterior lumbosacral blepharoptosis ⁴⁵	Birth	Congenital blepharoptosis, posterior fusion of lumbosacral vertebrae	Nonprogressive	AD	Unknown	Treatment of lumbosacral vertebral fusion by conventional methods; surgical correction of blepharoptosis
Progressive myopathic ptoses seen in adulthood
Chronic progressive external ophthalmoplegia ¹⁷ ^, ⁴⁶	Early adulthood	Generalized weakness, blepharoptosis, ophthalmoplegia, facial weakness including orbicularis; Plus syndrome includes sensorineural hearing loss, ataxia, parkinsonism	Progressive	AR, AD, MM	Nuclear DNA (AD): POLG TWNK SLC25A4 Nuclear DNA (AR): POLG RRM2B Mutation in these genes leads to large deletions of mtDNA in muscle cells; mechanism unclear Mitochondrial DNA: MT-TL1 (disrupt tRNA function, thus interrupting production of proteins involved in oxidative phosphorylation)	Surgical correction of strabismus, followed by surgical correction of blepharoptosis where indicated
Desmin (myofibrillary) myopathy ⁴⁷ ^, ⁴⁸	Infancy to adulthood (more common)	Muscle weakness distally, progresses to proximal muscles, peripheral neuropathy, cardiomyopathy, blepharoptosis without ophthalmoparesis	Progressive	AD, AR, XLR, or sporadic	AD: DES (Desmin) TTN (Titin) DNAJB6(DnaJ heat shock protein family (Hsp40) member B6) MYOT (Myotilin) LDB3 (LIM domain binding 3) FLNC (filamin C) BAG3 (BCL2 associated athanogene 3) XLR: FHL1 (four and a half LIM domains 1) AR: CRYAB (Crystallin alpha B)	Supportive care Treatment of blepharoptosis where indicated.
Myotonic dystrophy type I and II (DMI, DMII)^b, ²⁸ ^, ⁴⁹	Congenital, juvenile, and adult forms	Hypotonia, blepharoptosis, diaphragmatic weakness, atrophy, myotonia, cardiac conduction abnormalities. DMII is less severe.	Progressive	AD	DMI: DMPK DMII: CNBP Leads to expanded microsatellite sequences and intranuclear accumulation of mutated transcripts	Supportive care; surgical correction of blepharoptosis where indicated
Oculopharyngeal muscular dystrophy^b ^, ¹⁷	Adulthood (40–60 years of age)	Ophthalmoplegia and blepharoptosis, dysphagia, proximal weakness	Progressive	AD, AR	PABPN1 (polyadenylate binding protein nuclear 1)	Supportive care, surgical correction of strabismus and blepharoptosis in indicated cases
Oculopharyngodistal myopathy ²⁸ ^, ⁵⁰ ^, ⁵¹	Adulthood	Blepharoptosis, external ophthalmoplegia, dysphagia, and distal weakness.	Progressive	AD, AR	Unknown	Supportive care Surgical correction of strabismus and blepharoptosis in indicated cases
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; MM, maternal mitochondrial; N/A, not applicable; XLR, X-linked recessive, ^aDenotes fatal genetic mutation over time due to respiratory failure and pneumonia. ^bDenotes muscular dystrophy.

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Tags: Ophthalmic Plastic Surgery of the Upper Face, Ophthalmology, Optometry, Plastic, Reconstructive and Cosmetic Surgery, Section IV Myogenic Ptosis

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32 Syndromic Blepharoptoses