Strabismus in Genetic Syndromes

Abstract

Strabismus is a feature of many genetic syndromes, with highly variable penetrance. The congenital cranial dysinnervation disorders (CCDDs) result in paralytic strabismus, with limited eye movements. CCDDs result from either deficits in differentiation of the cranial motor neuron precursors or from abnormal axon guidance of the cranial nerves. Although most individuals with comitant strabismus are otherwise healthy, strabismus is a variable feature of many genetic syndromes, most commonly those associated with intellectual disability. We review 255 genetic syndromes in which strabismus has been described and discuss the variable penetrance. The association with intellectual disability and neurological disorders underscores the likely neurological basis of strabismus, but the variable penetrance emphasizes the complexity of strabismus pathophysiology. The syndromes described here mostly result from loss of function or change in function of the responsible genes, one hypothesis is that nonsyndromic strabismus may result from altered expression or regulation of the same genes.

Introduction

Strabismus, misalignment of the eyes, is the most common ocular disorder of childhood and can be classified into esotropia (inward deviation of the eyes), exotropia (outward deviation of the eyes), and vertical misalignment. Strabismus can be comitant (same degree of deviation in all positions of gaze) or incomitant (deviation differs based on gaze position).

The prevalence of strabismus varies globally, ranging from 0.7–5% (1). Risk factors for strabismus include: family history, premature birth, prenatal smoke exposure, advanced maternal age, and other eye disorders. A genetic contribution to strabismus has long been recognized, but the genetics are complicated. For some rare forms of incomitant strabismus, the congenital cranial dysinnervation disorders (CCDDs), single causative genes have been identified. For the common forms of comitant strabismus, no single causative genes have been identified, but genetic risk factors have been identified, including single nucleotide variants (2,3) and copy number variants (4,5).

In the majority of strabismus patients, it is an isolated ocular disorder in otherwise healthy individuals. There is a higher prevalence of strabismus, however, in patients with a variety of neurologic and psychiatric conditions (6,7). This review aims to detail genetic syndromes associated with strabismus. We first discuss the genes that cause CCDDs. We then catalog genetic syndromes in which strabismus has been identified as a feature and discuss the variable penetrance of strabismus in these disorders. We show the variety of genetic variants that can lead to strabismus, but highlight that only in the CCDDs is strabismus 100% penetrant, evidence of the complexity of strabismus pathophysiology. We also discuss how milder variants or differences in gene expression of the genes associated with these genetic syndromes are candidates for genetic causes of isolated strabismus.

CONGENITAL CRANIAL DYSINNERVATION DISORDERS (PARALYTIC STRABISMUS SYNDROMES)

Congenital Cranial Dysinnervation Disorders (CCDDs) are a group of paralytic strabismus syndromes in which patients cannot fully move one or both eyes. These disorders result from abnormal innervation of the extraocular muscles (8,9). Genetic and functional studies of the CCDDs have provided insight into neuronal development and axon guidance within the ocular motor system. There are two main mechanisms that lead to CCDDs: 1) loss of transcription factors necessary for maturation of neural progenitors into motor neurons in the brainstem, and 2) abnormalities of axon guidance of the cranial motor nerves (9). CCDDs can be classified based on which cranial nerve(s) are involved. For each cranial nerve, there are examples of each mechanism.

Cranial nerve 6 - abducens nerve

Duane retraction syndrome

Duane retraction syndrome (DRS) is the most common CCDD with a prevalence of around 1:1000. It is defined as unilateral or bilateral limitation of abduction with retraction of the globe and narrowing of the palpebral fissure on attempted adduction. The majority of individuals with DRS are isolated, simplex cases, but ~10% of affected individuals have a family history consistent with autosomal dominant inheritance (10,11). Two genes have been identified that cause isolated autosomal dominant DRS, and three have been identified to cause syndromic DRS.

Heterozygous missense variants in CHN1 cause autosomal dominant DRS (12). CHN1 encodes a2-chimaerin, a RacGAP protein. a2-chimaerin is downstream of multiple signaling molecules and is involved in cytoskeleton dynamics. Causative variants lead to loss of auto-inhibition of the protein, leading to increased RacGTPase activity (12). Expression of variant a2-chimaerin in mice causes nerve stalling and premature axon termination of the abducens nerve (13). Individuals with CHN1 variants are more likely to have bilateral DRS with up-or down-shoots on adduction, but no other associated syndromic features.

Variants in MAFB cause autosomal dominant DRS, either isolated or associated with hearing loss, depending on the variant. MAFB encodes a transcription factor that is expressed in rhombomeres 5 and 6 and is required for proper hindbrain segmentation (14,15). Haploinsufficiency of MAFB causes isolated DRS (16). DRS with hearing loss results from a heterozygous dominant-negative MAFB allele, which results in less than 50% function compared to wild-type protein (16). In mice, loss of Mafb leads to absence of the abducens nerve (14,17). MAFB is expressed in developing abducens neurons but not oculomotor neurons (18); orbital dissections of Mafb^−/− mouse embryos show aberrant innervation of the lateral rectus muscle by fibers from the oculomotor nerve (16). Since Mafb is not expressed in oculomotor neurons, the aberrant innervation of the lateral rectus is secondary to the absence of innervation by the abducens nerve, not a result of a primary defect in the oculomotor axons.

Two other genes are known to cause syndromic DRS: SALL4 and HOXA1. SALL4 is a transcription factor; haploinsufficiency causes Duane radial ray syndrome (DRRS). DRRS is characterized by DRS with hand and/or upper extremity anomalies that are inherited in an autosomal dominant fashion (19,20). Radial dysplasia ranges from hypoplastic thenar eminence to absent radial bone. Lower extremity, cardiac, renal, vertebral malformations and sensorineural hearing loss may also be present. Homozygous truncating variants in HOXA1, a homeodomain transcription factor involved in hindbrain development, cause a spectrum of disorders characterized by bilateral DRS type 3, sensorineural deafness, malformations of cerebral vasculature, and autism (21). Other abnormalities may include central hypoventilation, facial and bulbar weakness, conotruncal cardiac defects, and intellectual disabilities (22,23).

Variants in ROBO3, a critical determinant in axon pathfinding and brain morphogenesis, have been associated with horizontal gaze palsy with progressive scoliosis, a rare autosomal recessive disorder characterized by congenital absence of horizontal conjugate eye movements with progressive scoliosis (24).

Cranial nerve 3 - oculomotor nerve

Congenital fibrosis of the extraocular muscles (CFEOM)

Congenital Fibrosis of the Extraocular Muscles (CFEOM) results from maldevelopment of the oculomotor and trochlear nerves. Classical CFEOM is a congenital, nonprogressive disorder characterized by bilateral ptosis, restrictive external ophthalmoplegia with eye misalignment, and limited residual eye movements (8). Typically, affected individuals adopt a chin-up head position as a result of ptosis and the downward, fixed position of the eyes (25). CFEOM has been divided into three genetic forms: CFEOM1, CFEOM2, and CFEOM3, of which CFEOM1 is the most common. Both CFEOM1 and CFEOM3 are autosomal dominant disorders of axon guidance, whereas CFEOM2 is an autosomal recessive disorder of neuronal specification.

CFEOM1 is characterized by bilateral ptosis and fixed downgaze. Some children with CFEOM1 have mild hypotonia and gross motor delays, but no other neurologic abnormalities have been found with this disorder. CFEOM1 is caused by heterozygous missense variants in KIF21A, which encodes a kinesin motor protein that moves organelles along microtubules in an anterograde direction (26,27). Postmortem and MRI findings of affected individuals have shown hypoplasia of the oculomotor nerve, abnormal innervation of extraocular muscles, and atrophy of the superior rectus and levator palpebrae superioris muscles (8,28). In vitro and in vivo studies have shown that KIF21A variants cause CFEOM1 through a gain-of-function mechanism by reducing an autoinhibition of the protein, resulting in a constitutively active molecule with increased microtubule association. These studies highlight the roles of altered microtubule regulation in CFEOM1 pathogenesis (29,30).

CFEOM2 is an autosomal recessive disorder characterized by exotropic ophthalmoplegia and ptosis, and often includes subnormal vision associated with retinal dysfunction (31). CFEOM2 is caused by homozygous loss-of-function variants in PHOX2A, a homeodomain transcription factor protein required for oculomotor and trochlear nerve development in mice and zebrafish (32–34). Orbital and brain MRIs on patients with CFEOM2 demonstrated absent oculomotor and trochlear nerves, and the extraocular muscles innervated by these nerves were small or absent (35).

Compared to CFEOM1, CFEOM3 is more phenotypically variable. CFEOM3 is characterized by restricted upgaze, which can be unilateral or asymmetric, and may not include ptosis. Horizontal eye movement restrictions are variable. CFEOM3 may also be associated with neurological abnormalities. CFEOM3 is caused by specific missense variants in TUBB3, which encodes the neuron-specific beta-tubulin. It is expressed in all postmitotic neurons in the developing and mature brain, and plays a critical role in axon guidance (36). Ten distinct heterozygous missense TUBB3 variants have been shown to cause a range of CFEOM3 phenotypic severity, with exquisite genotype-phenotype correlations (36–39). Neuroimaging of patients with different TUBB3 variants in CFEOM3 showed dysgenesis or agenesis of the corpus callosum and anterior commissure, defective cortical gyration, malformations of hippocampi, thalami, basal ganglia and cerebella, and brainstem and cranial nerve hypoplasia (36–39). CFEOM3 can also be caused by heterozygous missense variants in the tubulin genes TUBA1A and TUBB2B (40,41). Like TUBB3, TUBA1A and TUBB2B are highly expressed in postmitotic neurons. However, the primary brain malformations due to TUBA1A and TUBB2B variants, such as lissencephaly and pachygyria, are a result of cortical cell migration defects, which are not present with TUBB3 variants (36). Homozygous loss of function of the atypical kinesin KIF26A can cause a phenotype similar to CFEOM (42).

Other CCDDs - variable phenotypes

Other CCDD genes include COL25A1 and ECEL1. COL25A1 is a membrane-bound collagen in the brain that is expressed in the oculomotor and abducens nerves. Variants cause autosomal recessive CCDD (variable phenotypes within families) by interfering with axon guidance and cytoskeletal microtubule dynamics (43). Variants in ECEL1, a gene likely to be involved in neuromuscular junction formation, have also been associated with strabismus phenotypes similar to CCDDs. Ophthalmic findings in cases of ECEL1-related distal arthrogryposis include exotropia, DRS, and complex strabismus (44,45). ACKR3 is associated with ptosis with oculomotor synkinesis (46). Recently, several other candidate genes for CCDDs have been reported (47).

GENETIC SYNDROMES WHICH CAN INCLUDE STRABISMUS

Strabismus is a non-specific feature of many genetic syndromes. One hypothesis is that if a severe variant in a gene causes a genetic syndrome which includes strabismus, less severe variants or altered regulation of that gene could cause isolated strabismus. Ye et al (48) proposed a list of 233 candidate genes for strabismus. We examined the evidence of association between each gene and strabismus and the prevalence of strabismus in each disorder. Additional genes were added based on those associated with Strabismus in Smith’s Recognizable Patterns of Human mutation (49), personal knowledge, and genes related to those on the original list. This led to final inclusion of 255 genetic syndromes (Table 1, Figure 1)

Table 1.

Prevalence of Strabismus by Gene

Name of Disorder	Gene	Patients with Strabismus	n	%	Range	References
Chromosomal Anomalies
Down Syndrome/ Trisomy 21		25	77	32%	23–44%	(52,53)
Turner Syndrome/ Monosomy X		25	187	13%		(54)
Trisomy 8 Syndrome	Chromosome 8	10	15	67%		(55)
Angelman Syndrome (AS)	UBE3A	23	37	62%	29–75%	(58)
Prader Willi	SNRPN & NDN on 15q11.2-q13	25	46	54%	40–54%	(59,60)
Smith-Magenis Syndrome	RAI	7	7	100%	58–100%	(56)
Willams-Beuren Syndrome	7q11.23 Deletion	215	474	45%	16–78%	(57)
Deletion 18p Syndrome	Chromosome 18	6	7	86%		(61)
Wolf-Hirschhorn Syndrome	4p16.3 Deletion	9	10	90%		(62)
Oculo-Auriculo-Vertebral Spectrum	22q11.2 Deletion	13	36	36%		(63)
1p36 Monosomy	1p36 Deletion	25	75	33%		(64–66)
Microdeletion 15q24 Syndrome	Chromosome 15	10	45	22%		(67)
Microdeletion 2q31.1 Syndrome	Chromosome 2	8	36	22%		(68)
Koolen-de Vries Syndrome	17q21.31 Deletion	21	50	42%		(69,70)
5q14.3q15 Microdeletion Syndrome	MEF2C	14	34	41%		(71,72)
Cri-du-Chat Syndrome	Chromosome 5	2	24	8%		(73,74)
Partial Trisomy 7q	Chromosome 7	3	3	100%		(75)
Ring 14 Syndrome	Chromosome 14	4	20	20%		(76)
Trisomy 10p Mosaicism	Chromosome 10	2	5	40%		(77)
Trisomy 18 Syndrome	Chromosome 18	2	2	100%		(78,79)
Wiedemann-Steiner Syndrome/ Deletion of 11q	KMT2A	2	2	100%		(80,81)
Killian/Teschler-Nicola Syndrome	Isochrome 12P	3	3	100%	75–100%	(82–85)
Klinefelter’s Syndrome	47, XXY	2	2	100%		(86,87)
	TOTAL	451	1204	37%
Intellectual Disability with Characteristic Facial Dysmorphism
Lamb-Schaffer Syndrome	SOX5	34	46	74%	73% – 83%	(88,89)
SOX3-associated syndrome	SOX3	2	3	67%		(90)
Yon-Hoover-Fong Syndrome	TELO2	17	25	68%		(91)
Juberg-Marsidi-Brooks	HUWE1	13	20	65%		(92)
Frontonasal Dysplasia	ALX4	14	22	64%		(93)
Loeys-Dietz Syndrome	TGFBR1	7	15	47%		(94)
Loeys-Dietz Syndrome	TGFBR2	8	14	57%		(94)
Loeys-Dietz Syndrome	TGFB2	2	7	29%		(94)
Loeys-Dietz Syndrome	TGFB3	1	1	100%		(94)
Shprintzen-Goldberg syndrome	SKI	1	4	25%		(94)
SATB2-associated syndrome	SATB2	68	193	35%		(95)
SOBP-associated Syndrome	SOBP	6	7	86%		(96,97)
GAND syndrome	GATAD2B	4	4	100%		(98)
Cousin syndrome	TBX15	2	2	100%		(99)
KDM1A- associated Syndrome	KDM1A	2	3	67%		(100)
Renpenning syndrome	PQBP1	7	11	64%		(101)
Oculocerebrofacial syndrome	UBE3B	6	12	50%		(102)
Armfield	FAM50A	7	12	58%		(103,104)
TMCO1- associated Syndrome	TMCO1	5	11	45%		(105)
Neurodevelopmental disorder with microcephaly and gray sclerae	PUS3	3	10	30%		(106)
		209	422	50%
Intellectual Disability and Autism Spectrum Disorder
FOXP1 Disorder	FOXP1	23	40	62%		(111)
DYRK1A-related Intellectual Disability Syndrome	DYRK1A	19	90	21%		(118)
Fragile X Syndrome	FMR1	70	381	18%		(115)(112–114)
SETD5-related Neurodevelopmental Disorder	SETD5	7	10	70%		(119)
Pitt-Hopkins-Like Syndrome 2	NRXN1	2	2	100%		(120,121)
Rett Syndrome	MECP2	3	14	21%		(116)
VAMP2- related Syndrome	VAMP2	1	12	8%		(117)
		125	549	23%
Epilepsy
Christianson Syndrome	NHE6 (SLC9A6)	26	38	68%		(122)
Developmental and Epileptic Encephalopathy 54	HNRNPU	20	57	35%		(123)
PURA Syndrome	PURA	28	134	21%		(124)
IQSEC2 related disorder	IQSEC2	9	26	35%	14.3–59%	(125,126)
Spastic paraplegia and psychomotor retardation with or without seizures	HACE1	6	8	75%		(127)
Pyridoxine-Dependent Epilepsy (PDE)	ALDH7A1	8	12	67%		(128)
PIGH Deficiency	PIGH	2	7	29%		(129)
Kohlschutter-Tonz Syndrome	ROGD1	2	3	67%		(130)
Kohlschutter-Tonz Syndrome	SLC13A5	1	9	11%		(131)
TRIT1-related Disorders	TRIT1	4	11	36%		(132)
		106	305	35%
Intellectual Disability with Other Neurological Features
Cornelia de Lange Syndrome	RAD21	1	2	50%		(133–135)
Cornelia de Lange Syndrome	NIPBL	9	26	35%		(134,135)
Cornelia de Lange Syndrome	SMC1A	2	4	50%		(133)
Cornelia de Lange Syndrome	SMC3	2	5	40%		(133)
Intellectual Development	TAF1	7	11	64%		(136)
Ataxia-Telangiectasia	ATM	25	65	38%		(137)
X-linked sideroblastic anemia with ataxia (XLSA/A)	ABCB7	5	8	63%		(138)
Spinocerebellar Ataxia/Ataxia with Oculomotor Apraxia Type 2	SETX	11	90	12%		(140)
Machado-Joseph Disease	SCA3	11	13	85%		(144),(142,143)
Spastic Paraplegia 54	DDHD2	9	12	75%		(141)
Joubert Syndrome	TMEM237	85	260	33%		(145,367)
Joubert Syndrome	NPHP1	14	679	2%		(146)
Joubert Syndrome	CPLANE1	17	26	65%		(147,148)
Joubert Syndrome	KIF7	14	28	50%		(149–151)
Joubert Sydrome	TMEM67	19	22	86%		(145)_(157)
Joubert Syndrome	C5orf42	13	15	87%		(145)
Joubert Syndrome	CC2D2A	4	10	40%		(145)
Leber Congenital Amarosis	CEP290	5	7	71%		(145)
Joubert Syndrome	AHI1	6	6	100%		(145)(157)
Joubert Syndrome	KIAA0586	3	6	50%		(145)
Joubert Sydndrome	MKS1	3	5	60%		(145)
Joubert Syndrome	INPP5E	2	4	40%		(145)
Joubert Syndrome	TMEM231	1	1	100%		(145)
Joubert Syndrome	OFD1	1	1	100%		(145)
Joubert Syndrome	CEP164	1	1	100%		(145)
Joubert Syndrome	KIAA0753	1	1	100%		(145)
Joubert Syndrome	CELSR2	1	1	100%		(145)
Joubert Syndrome	RPGRIP1L	6	27	22%		(145,152,153)(157)
Joubert Syndrome	CSPP1	6	34	18%		(145,155,156)
Joubert Syndrome	HYLS1	2	2	100%		(158)
Joubert Syndrome	TMEM216	7	15	47%		(145,154)(157)
Joubert Syndrome Overall	Joubert Syndrome Overall	154	1122	14%		(145)
Leigh Syndrome	SURF1	4	21	19%		(160,161)
Infantile Hypotonia Syndrome	POLR2A	11	15	73%		(162)
KIF1A- associated Neurological disease (KAND)	KIF1A	9	24	38%		(163)
VLDLR Cerebellar Hypoplasia	VLDLR	4	5	80%		(164)
Poretti-Boltshauser Syndrome (PBS)	LAMA1	9	10	90%		(165,166)
		484	2584	19%
Intellectual Disability with Muscular Dystrophy or Myopathy
Congenital contractures of the limbs and face, hypotonia, and developmental delay	NALCN	27	35	77%		(167)(168)
UNC80- associated Syndrome	UNC80	24	25	96%		(168)
Marinesco-Sjogren syndrome	SIL1	14	27	52%		(170–172)
Wieacker-Wolff Syndrome	ZC4H2	11	26	42%		(169)
Muscular dystrophy, congenital, with cataracts and intellectual disability	INPP5K	3	5	60%		(173)
CCDC174- associated Syndrome	CCDC174	2	2	100%		(174)
Freeman-Sheldon Syndrome (Whistling Face Syndrome, Distal Arthrogryposis Type 2A)	MYH3	4	11	35%		(175)
		85	131	65%
Other Intellectual Disability Disorders
CAMTA1-related disorder	CAMTA1	11	26	42%		(176,177)]
TET3- associated Syndrome	TET3	9	22	41%		(176,177)
OPHN1- associated Syndrome	OPHN1	15	38	39%		(178–180)
NEXMIF Syndrome	NEXMIF	14	44	32%		(181,182)
Autism Susceptibility Candidate 2	AUTS2	8	27	30%		(184)
CHD3- associated Syndrome	CHD3	10	33	30%		(183)
NSUN2- associated Syndrome	NSUN2	7	31	23%		(185–187),
CASK- associated Syndrome	CASK	7	35	20%		(188)
ANKRF17- associated Syndrome	ANKRD17	7	34	21%		(189)
Cerebellar atrophy, visual impairment, and psychomotor retardation	EMC1	4	21	19%		(190,191)
Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type	KDM5C	3	21	14%		(192)
FG syndrome (Opitz-Kaveggia Syndrome)	MED12	3	15	20%		(193)
ADAT3- associated Syndrome	ADAT3	6	6	100%		(194)
C12ORF65- associated Syndrome	C12ORF65	2	2	100%		(195)
CLIP1- associated Syndrome	CLIP1	5	5	100%		(196)
Microcephaly and chorioretinopathy, autosomal recessive, 2	PLK4	2	2	100%		(197)
Intellectual Disability with Cerebellar Atrophy and Hypotonia	SLC39A8	7	8	88%		(198)
POGZ- associated Syndrome	POGZ	5	6	83%		(199)
AP4M1- associated Syndrome	AP4M1	6	8	75%		(200,201)
EBF3- associated Syndrome	EBF3	8	12	69%		(202,203)
Menkes Kinky Hair Syndrome (Menkes Disease)	ATP7A	11	18	61%		(204)
MID2- associated Syndrome	MID2	4	6	67%		(206)
TRPM3-related Neurodevelopmental Disorder	TRPM3	5	10	50%		(207)
HIVEP2-related ID	HIVEP2	6	12	50%		(209)
XLID	NONO	5	11	45%		(210)
Congenital Disorder of Glycosylation	SSR4	1	2	50%		(211)
HECW2- associated Syndrome	HECW2	3	7	43%		(212)
X-linked congenital hydrocephalus or ID	L1CAM	2	4	50%		(213,214)
DLG4-related Synaptopathy	DLG4	2	3	67%		(205)
TCEAL1 X-Linked Dominant Neurodevelopmental Syndrome	TCEAL1	4	8	50%		(208)
		184	482	38%
Multiple Congenital Abnormalities
Mowat-Wilson Syndrome	SMADIP1/ZEB2	18	23	78%		(215)
Rubinstein-Taybi syndrome	EP300	3	8	38%		(216)[191]
Rubinstein-Taybi syndrome	CREBBP	29	127	23%		(218)
Schimke XLID	BCAP31	13	15	87%		(219–223)
Malan syndrome	NFIX	13	20	65%		(224)
Weaver Syndrome (EZH2 Related Overgrowth)	EZH2	5	56	9%		(227)
Sotos syndrome	NSD1	3	9	33%		(224–226)
Wolfram Syndrome	WFS1/WFS2	7	18	39%		(239)
Kabuki syndrome	KMT2D	17	39	44%		(241,242)
Wiedemann-Steiner Syndrome	KMT2A	39	104	38%		(240)(241,242)
Kabuki syndrome	KDM6A	22	63	35%		(243)
Coffin-Siris syndrome	ARID2	12	33	36%		(244,245).
Bohring-Opitz syndrome	ASXL1	15	56	27%		(234–236)
C syndrome	CD96	2	2	100%		(237)
Cohen Syndrome	VPS13B	30	104	29%		(238)
Floating-Harbor (similar to Rubinstein-Taybi)	SRCAP	15	57	26%		(228,229)
KBG Syndrome	ANKRD11				5% – 22.2%	(230–233)
CHILD syndrome; CK syndrome	NSDHL	1	1	100%		(246)
Waardenburg Syndrome	PAX3	5	26	19%		(247)
Congenital Cataracts - Facial Dysmorphism - Neuropathy	CTDP1	16	16	100%		(248)
Lowe syndrome	OCRL	48	137	35%		(249)
Nance-Horan syndrome	NHS	5	16	31%		(250)
Zellweger Syndome	PEX1	2	2	100%		(251–254)
Zellweger Syndome	PEX6	1	1	100%		(251–254)
Peroxisome biogenesis disorder 14B	PEX11B	5	11	45%		(251–254)
CHARGE Syndrome	CHD7	33	49	67%		(255,256)
Myhre syndrome	SMAD4	10	32	31%		(258)
Branchio-oculo-facial syndrome	TFAP2A	3	23	13%		(259)
Alagille Syndrome (Arteriohepatic Dysplasia)	JAG1	41	361	11.3%		(260–262)
Noonan Syndrome	PTPN11	17	50	34%		(265)
Noonan Syndrome	RAF1	3	7	43%		(265)
Noonan Syndrome	SHOC2	4	5	80%		(265)
Noonan Syndrome	KRAS	4	4	100%		(265)
Noonan Syndrome	MAP2K2	1	1	100%		(265)
Noonan Syndrome	BRAF	13	34	38%		(266)
Costello Syndrome	HRAS	33	56	59%		(267)
Cardio-facio-cutaneous (CFC) Syndrome 3	MAP2K1	1	5	20%		(269)
Congenital Central Hypoventilation Syndrome (CCHS)	PHOX2B	6	22	27%		(270)
Pitt-Hopkins syndrome	TCF4	13	14	93%		(272)
Smith-Lemli-Opitz Syndrome	DHCR7	1	13	8%		(273,274)
Desmosterolosis	DHCR24	9	14	64%		(273,274)
Pituitary Stalk Interruption Syndrome	ROBO1	4	5	80%		(275)
RNF135- associated Syndrome	RNF135	1	6	17%		(278)
Aarskog-Scott syndrome	FGD1	6	116	5%		(279)
Char syndrome	TFAP2B	7	10	70%		(277)
SOX2- associated Syndrome	SOX2	3	58	5%		(280,281)
CDH2- associated Syndrome	CDH2	5	9	56%		(257)
X-linked colobomatous microphthalmia syndrome	HMGB3	2	2	100%		(282)
Mohr-Tranebjærg Syndrome	TIMM8A	2	4	50%		(283)
DDX3X-related Neurodevelopmental Disorder	DDX3X	2	5	40%		(284)
Proteus Syndrome	AKT1	6	17	35%		(276)
Microcephalic Primordial Dwarfing Syndromes (Majewski Osteodysplastic Primordial Dwarfism [MOPD II], Seckel Syndrome, MOPD I)	PCNT	1	1	100%		(285)
Melnick-Needles Syndrome	FLNA	1	1	100%		(286)
		550	1849	30%
Metabolic Disorders
Congenital disorder of glycosylation	PMM2				73–84%	(287,288)
DPAGT1 - Congenital Disorder of Glycosylation	DPAGT1	9	26	35%		(289)
disorder of glycosylation	NGLY1	15	48	31%		(290,291)
congenital disorder of N-glycosylation	ALG1	7	7	100%		(292)
ALG11-CDG syndrome	ALG11	10	11	91%		(293)
ALG6- CDG	ALG6	8	8	100%		(294)
glycosylation disorder	COG7	2	3	67%		(295)
DDOST-CDG	DDOST	5	5	100%		(296–298)
Sengers Syndrome	AGK	4	32	13%		(302,303)
Mucolipidosis Type IV	MCOLN1	54	93	58%		(299,300)
FA2H- associated Syndrome	FA2H	5	5	100%		(304)
Adenylosuccinate lyase ADSL deficiency	ADSL	23	88	26%		(301)
ACOX1- associated Syndrome	ACOX1	1	1	100%		(305)
		143	327	44%
Muscular Dystrophy (without Intellectual Disability)
Myotonic Dystrophy	DMPK	18	32	56%		(306)
Muscular Dystrophy	GMPPB	7	30	23%		(307,308)
Muscular Dystrophy	FKTN	12	166	7%		(309)
Muscular Dystrophy	POMGNT1	2	8	25%		(310)
Walker-Warburg Syndrome	POMT2	3	15	20%		(310,311)
Muscular Dystrophy	FKRP	3	8	38%		(312)
Muscular Dystrophy	COL6A2	1	3	33%		(313)
		46	262	18%
Craniosynostosis
Crouzon, Apert, Pfeiffer Syndromes	FGFR2				44–67%	(314)
Achondroplasia	FGFR3	6	11	55%		(315)
Saethre-Chotzen	TWIST1	15	21	71%		(314)(317)
Craniofrontonasal Dysplasia	EFNB1	26	45	58%		(318–320)
Craniosynostosis	TCF12	1	4	25%		(316).
		48	81	59%
Hematologic/Lymphatics
Fanconi Anemia	FANCG	11	78	14%		(321–323)
Fanconi Anemia	FANCA	3	15	20%		(321–323)
Fanconi Anemia	BRCA2	1	1	100%		(321–323)
Lymphedema-Distichiasis	FOXC2	4	75	5%		(324,325)
	TOTAL	19	169	11%
Skin Conditions
Wrinkly Skin Syndrome	ATP6V0A2	13	16	81%		(326)
Xeroderma Pigmentosum (XP)	overall XP	7	89	8%		(330)
Xeroderma Pigmentosum (XP)	XPA	1	18	6%		(330)
Xeroderma Pigmentosum (XP)	XPC	1	28	4%		(330)
Xeroderma Pigmentosum (XP)	ERCC2	3	14	21%		(330)
Xeroderma Pigmentosum (XP)	ERCC5	1	8	13%		(330)
Xeroderma Pigmentosum (XP)	POLH	1	12	8%		(330)
Gorlin Syndrome (Nevoid Basal Cell Carcinoma Syndrome)	PCTH1	7	11	64%		(331)
Focal Dermal Hypoplasia	PORCN	7	21	33%		(327,328)
Incontinentia Pigmenti	IKBKG	83	160	52%		(329)
	TOTAL	117	366	32%
Aniridia/Coloboma/Eyelid/Cornea Abnormalities
Aniridia	PAX6	155	403	38%		(337)
BPES- Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome	FOXL2	13	31	42%		(338)
BAMD and COFG	MAB21L1	12	18	67%		(339)
Corneal Dystrophy	DCN	4	11	36%		(340)
Axenfeld-Rieger Syndrome	PITX2	3	24	13%		(342)
Axenfeld-Rieger Syndrome	FOXC1	2	4	50%		(343)
Optic Atrophy	OPA1	3	7	43%		(344)
	TOTAL	192	498	39%
Retinal Dystrophies
CSNB overall	CSNB overall			26–59%		(346–348)
CSNB	NYX	20	47	43%		(346,347,349)
CSNB	CACNA1F	17	73	23%		(347,349)
CSNB	TRPM1	13	28	46%		(347,350),
CSNB	GRM6	3	16	19%		(347,348)
CSNB	GPR179	3	4	75%		(347,348)
Achromatopsia	CNGB3	7	12	58%		(351)
Achromatopsia	CNGA3	16	33	48%		(351)
Achromatopsia	GNAT2	1	19	5%		(352)
Leber congenital amaurosis	RGRIP1	9	9	100%		(354)
Bardet-Biedl Syndrome	BBS1	3	15	20%	Overall 40%	(358)
	BBS2	2	3	67%		(358)
	BBS3	1	3	33%		(358)
	BBS4	2	3	67%		(358)
	BBS5	1	3	33%		(358)
	BBS7	1	3	33%		(358)
	BBS8	1	1			(358)
	BBS9	4	5	80%		(358)
	BBS10	7	20	35%		(358)
	BBS12	1	3	33%		(358)
Retinitis Pigmentosa	RPGR	4	86	5%		(355)
Retinoschisis	RS1	2	8	25%		(356,357)
	TOTAL	118	394	30%
Retinal Disorders/High Myopia Syndromes
Stickler syndrome	COL11A1	4	8	50%		(359,360)
Stickler syndrome type 1	COL2A1	1	2	50%		(359)
Marfan Syndrome	FBN1	110	573	19%		(364)
Knobloch syndrome	COL18A1	6	8	75%		(165,361–363)
Familial executive vitreoretinopathy (FEVR)	FZD4	3	3	100%		(366)
Familial executive vitreoretinopathy (FEVR)	NDP	3	4	75%		(366)
Familial executive vitreoretinopathy (FEVR)	KIF11	3	3	100%		(366)
Familial executive vitreoretinopathy (FEVR)	ATOH7	2	2	100%		(366)
	TOTAL	132	603	22%

Figure 1.

Strabismus prevalence by type of syndrome weighted mean prevalence of strabismus for each category of disorder. Specific disorders in each category are listed in Table 1. Error bars represent SEM.

The reported prevalences are likely underestimates, because many descriptions of genetic syndromes do not report strabismus. When strabismus is included, it is often reported in an “other” category, and it is not clear if all individuals were assessed for strabismus. When possible, we have focused on reports of ophthalmologic characteristics of reported disorders. We divided the disorders into classifications based on their most prominent features, but many syndromes, particularly neurological and intellectual disability syndromes, have overlapping phenotypes, so some of the classifications may seem arbitrary. Interestingly, strabismus is not fully penetrant in almost all of these disorders, which highlights the complex pathophysiology of strabismus.

INTELLECTUAL DISABILITY

The relationship between intellectual disability (ID), developmental delays, and strabismus is well-documented. The odds ratio of developing strabismus is 5.46 in individuals with ID (7). Strabismus is a feature in 15 X-linked intellectual disability syndromes (XLIDs) (50), and was observed in 39.8% of pediatric patients with developmental delay (51).

Chromosomal Anomalies

Strabismus is prevalent in many syndromes resulting from chromosomal anomalies and structural variants. Down syndrome (Trisomy 21) has a 23–44% prevalence of strabismus, most commonly esotropia (52,53). Prevalence of strabimus is 13% in Turner syndrome (monosomy X) (54). And 675 in Trisomy 8 (55).

Several deletion syndromes commonly present with strabismus. Smith-Magenis syndrome (deletion 17p11.2) is a complex neurodevelopmental disorder including ID and autism; strabismus prevalence is 58% (56). Williams-Beuren syndrome (deletion 7q11.23) is a multi-system disorder with cardiovascular, neurological, and endocrine abnormalities; strabismus prevalence is 16–78% (57). Angelman syndrome and Prader-Willi syndrome, which result from deletion or uniparental disomy of the maternal or paternal copy of chromosome 15q11.2-q13, respectively, both have relatively high rates of strabismus: 29–75% in Angelman syndrome (58) and 40–54% in Prader-Willi (59,60). Deletion of 18p and 4p16.3 both have high prevalence of strabismus (61,62). Deletion of 22q11.2 presents with strabismus in 36% of cases (63), similar to deletion of 1p36 (64–66), 15q24 (67), 2q31.1 (68), and 17q21 (69,70). 5q14.3q15 microdeletion syndrome, which involves the gene MEF2C, results in a severe neurodevelopmental disorder with epilepsy and ID, with strabismus in 41% (71,72). Cri-du-chat Syndrome, resulting from deletions of 5p, is associated with strabismus in 8% of patients (73,74).

Several chromosomal abnormalities have been linked to strabismus in small case series, including partial trisomy of 7q, (75) ring 14 syndrome, (76) trisomy 10p mosaicism, (77), trisomy 18 syndrome (78,79), Wiedermann-Steiner syndrome (80,81), Killian/Teschler-Nicola Syndrome (82–85) and Klinefelter syndrome (47XXY) (86,87).

Intellectual Disability with Characteristic Facial Dysmorphism

Many ID syndromes present with distinctive facial dysmorphisms and high rates of strabismus. Lamb-Schaffer syndrome (SOX5) has the highest prevalence of strabismus in this category; 74% present with intermittent exotropia (88,89). Variants in a related gene, SOX3, cause strabismus in 2/3 reported individuals (90). More than half of patients have strabismus in You-Hoover-Fong syndrome (TELO2) (91) and XLID with facial dysmorphism, caused by variants in HUWE1, (92) or ALX4 (93). Loeys Dietz and Shprintzen-Goldberg syndromes are related disorders with elevated TGF-beta signaling, cardiac defects and craniofacial abnormalities, with relatively high rates of strabismus (25–57%) (94). Loeys Dietz is caused by TGFBR1, TGFBR2, TGFB2, and TGFB3; Shprintzen-Goldberg syndrome is associated with SKI. SATB2-associated syndrome involves ID and characteristic facial dysmorphisms including cleft palate; 35% of patients have strabismus (95).

Several genes within this category have only small case series in which strabismus is reported. Homozygous truncating variants in SOBP cause ID, anterior maxillary protrusion, and strabismus. 6/7 patients have strabismus (96,97). Strabismus is reported in all individuals with variants in GATAD2B (98) and TBX15 (99) and a majority of individuals with variants in KDM1A (100), PQBP1 (101), UBE3B (102), and FAM50A (103,104). Lower prevalence of strabismus is found with variants in TMCO1 (105), and PUS3 (106).

Intellectual Disability and Autism Spectrum Disorder

Autism spectrum disorder (ASD) involves difficulties in social interactions and may include other neurologic and psychiatric features, including ID, epilepsy, depression and anxiety (107). Autistic individuals have a high prevalence of strabismus, with reported odds ratios of 2–5, highest in individuals with both autism and ID (108,109). Strabismus is reported in 16% of children with ASD (110).

Many genetic syndromes causing both ID and ASD are associated with strabismus. Prevalence of strabismus in FOXP1 disorder is 62% (111). Fragile X syndrome, a common cause of ID and ASD, results from trinucleotide expansion in FMR1. The prevalence of strabismus is 16–22% (112–115). Rett Syndrome is an X-linked dominant disorder associated with developmental regression and autistic features in girls associated with variants in MECP2. Both Rett syndrome and a similar disorder caused by variants in VAMP2 are associated with strabismus (116,117). Strabismus has also been reported in ID and ASD syndromes caused by DYRK1A, (118) SETD5, (119) and NRXN1 (120,121).

Epilepsy

Many epileptic encephalopathy syndromes have a high prevalence of strabismus. We have included in this section only syndromes where epilepsy is the primary feature; seizures can be present in many neurodevelopmental disorders included in other sections. Among these disorders, the highest rate of strabismus (68%) is seen in Christianson syndrome (CS), caused by variants in NHE6 (SLC9A6) (122). Strabismus has also been reported in association with variants in HNRNPU, (123) PURA, (124) and IQSEC2 (125,126).

Small case series report strabismus in affected individuals with HACE1 deficiency, (127) ALDH7A1 variants, (128) PIGH deficiency, (129) ROGD variants, (130) SLC13A5 variants (131), and TRIT1 variants (132).

Intellectual Disability with Other Neurological Features

Cornelia de Lange Syndrome (CdLS) is a rare disorder with a wide range of symptoms, including ID, developmental delay, and microcephaly, associated with RAD21, NIPBL, SMC1A, and SMC3 (133). Strabismus is reported in 16–26% of CdLS patients (133–135); with a higher prevalence in NIPBL patients (35%) than others (134,135). TAF1 causes a Cornelia de Lange - like syndrome, with strabismus reported in 7/11 individuals (136).

Ataxia-telangiectasia, a recessive neurodegenerative disorder caused by variants in ATM, has a high prevalence of eye movement disorders, including hypometric saccades, pursuit abnormalities, and nystagmus. Strabismus prevalence is 38%, with esotropia most common (137). Several other ataxia syndromes are associated with strabismus, including X-linked sideroblastic anemia with ataxia (XLSA/A), associated with ABCB7, (138) and hereditary spinocerebellar ataxias caused by SPTBN2 or ITPR1 (139). SETX is associated with ataxia with oculomotor apraxia type 2; strabismus is reported in 12% of patients and is correlated with progression rate (140). High rates of strabismus are seen in spastic paraplegia 54, associated with DDHD2 (141) and spinocerebellar ataxia 3, caused by variants in SCA3 (142–144).

Joubert syndrome is a group of rare disorders that result from dysfunction of sensory cilia and lead to abnormal development of the midbrain-hindbrain junction. Clinical features include hypotonia, developmental delay, abnormal eye movements and a characteristic “molar tooth” sign on MRI. Over forty genes have been associated with Joubert syndrome. The prevalence of strabismus varies widely based on the genetic cause, from 87% with TMEM67 or C5orf42 variants (145) to only 2.1% with NPHP1 variants (146). Collectively, of all studies examined, we identified strabismus in 13.8% of patients with genetic variants associated with Joubert syndrome (145–157). For specific prevalences, see Table 1. Two patients have been reported with strabismus and Joubert syndrome with HYLS1 variants (which usually result in hydrolethalus syndrome) (158). NPHP1 variants cause three overlapping ciliopathies: juvenile nephronophthisis-1, Joubert syndrome, and Senior-Loken Syndrome-1. Strabismus is reported in 2% of those with NPHP1-associated nephronophthisis, but not those with NPHP1-associated Joubert or Senior-Loken syndrome (146). Leigh syndrome is an early onset neurodegenerative disease, which can be caused by several mitochondrial and nuclear genes. The overall prevalence of strabismus in Leigh syndrome is 26–41% (159). SURF1 mutations are seen in ~15% of Leigh syndrome, and 19% of those individuals have strabismus (160,161).

POLR2A variants lead to a syndrome of infantile hypotonia and developmental delay, with strabismus in 73% (162). Variants in KIF1A lead to a distinct progressive neurological syndrome with optic atrophy in almost all patients and strabismus in 38% (163). Variants in VLDLR cause cerebellar ataxia with intellectual disability (disequilibrium syndrome); strabismus is reported in 4/5 families with the disorder (164). LAMA1 variants cause Poretti-Boltshauser syndrome, characterized by cerebellar dysplasia and cerebellar cysts. Strabismus is highly penetrant, present in 9/10 reported patients (165,166).

Intellectual Disability with Muscular Dystrophy or Myopathy

Several ID syndromes associated with muscular dystrophy or myopathy have high prevalence of strabismus. NALCN variants can cause either an autosomal dominant syndrome of congenital contractures, hypotonia and developmental delay or autosomal recessive infantile hypotonia. Among patients with monoallelic NALCN variants, 7/11 have strabismus (167); with biallelic NALCN variants, 20/24 have strabismus (168). Biallelic variants in UNC80 cause a related syndrome; strabismus is reported in 24/25 patients (168). ZC4H2 causes Wieacker-Wolff syndrome, a severe neurodevelopmental disorder with onset of muscle weakness in utero. Strabismus is present in 42% (169). The prevalence of strabismus is high in patients with SIL1 variants (170–172) INPP5K variants, (173) CCDC174 variants (174), and MYH3 variants (175).

Other Intellectual Disability Disorders

There is large variation in prevalence of strabismus in other ID disorders. Strabismus is present in 30–42% of patients with variants in CAMTA1 (176), TET3 (177) OPHN1 (178–180), NEXMIF (181,182), CHD3 (183), and AUTS2 (184). Lower incidences of strabismus (14–23%) were observed in cases involving variants in NSUN2 (185–187), CASK (188), ANKRD17 (189), EMC1 (190,191), KDM5C (192), and MED12 (193).

Small case series report strabismus in all affected individuals with variants in ADAT3 (194), C12ORF65 (195), CLIP1 (196), and PLK4 (197) and the majority of individuals with variants in SLC39A8 (198), POGZ (199), AP4M1 (200,201), EBF3 (202,203), ATP7A (204), DLG4 (205) and MID2 (206). TRPM3 gain of function variants cause a neurodevelopmental disorder with a spectrum of severity; 5/10 have strabismus (207). Heterozygous variants in TCEAL1 lead to an X-linked dominant neurodevelopmental syndrome; 4/8 have strabismus (208). Strabismus is present in 40–50% of patients with variants in HIVEP2 (209), NONO (210), SSR4 (211), HECW2 (212), and L1CAM (213,214).

Multiple Congenital Anomalies

Many disorders characterized by multiple congenital abnormalities, with or without intellectual disability, have a high prevalence of strabismus. Mowat-Wilson syndrome (ZEB2) involves Hirschsprung disease, ID, epilepsy, and multiple other anomalies. The prevalence of strabismus is 78% (215). Rubinstein-Taybi syndrome is characterized by ID along with broad phalanges and facial anomalies. Early reports indicated a high (72%) prevalence of strabismus (216), but in patients with confirmed genetic testing, strabismus is reported in 37.5% with EP300 variants (217), and 23% with CREBBP variants (218). Schimke XLID syndrome, caused by BCAP31 variants, is characterized by microcephaly, short stature, hearing loss, involuntary limb movements, and early lethality. Strabismus has been identified in 13/15 patients (219–223).

Several of these disorders involve abnormal growth. Variants in NFIX cause Malan syndrome, an overgrowth syndrome with developmental delay; prevalence of strabismus is 65% (224). The prevalence of strabismus is much lower in the related syndrome, Sotos syndrome, featuring macrocephaly, overgrowth, and variable ID, caused by loss-of-function variants and microdeletions in NSD1 (224–226). Weaver syndrome, caused by variants in EZH2, also involves overgrowth and macrocephaly, but has a lower prevalence of strabismus (5%) (227). Variants in SRCAP cause Floating-Harbor syndrome, notable for facial dysmorphism, short stature, speech delay, and other neurodevelopmental abnormalities; strabismus prevalence is 26% (228,229). Loss-of-function ANKRD11 variants cause KBG syndrome, characterized by macrodontia, epicanthal folds, ptosis, short stature, developmental delay, ID and other anomalies. Strabismus is reported in 5–22.2% of patients (230–233). De-novo truncating variants in ASXL1 cause Bohring-Opitz syndrome, characterized by microcephaly, feeding difficulties, intrauterine growth restriction, developmental delay, and craniofacial abnormalities; strabismus prevalence is 27% (234–236). In the related disorder, C syndrome (Optiz trigonocephaly), associated with CD96, strabismus is reported only in case reports (237). Cohen syndrome, characterized by developmental delay, microcephaly, characteristic facies, hypotonia, myopia, and retinal dystrophy, is caused by VPS13B variants; strabismus prevalence is 29% (238).

Wolfram syndrome consists of diabetes insipidus, diabetes mellitus, optic atrophy, and sensorineural deafness, caused by autosomal recessive variants in WFS1 or WFS2. Strabismus is reported in 39% of Wolfram patients, not divided by genetic cause (239).

Heterozygous variants in KMT2A cause Wiedemann-Steiner syndrome, characterized by hypertrichosis cubiti, developmental delay, and facial dysmorphisms; strabismus prevalence is 37.5% (240). KMT2D and KDM6A variants cause Kabuki syndrome, a well-known multiple anomalies/ID syndrome. Prevalence of strabismus is 44% in KMT2D-Kabuki (241,242) and 35% in KDM6A-Kabuki (243). Deletion variants in ARID2 are associated with a mild form of Coffin-Siris Syndrome, characterized by coarse facial features, feeding difficulties, and fifth digit hypo- or aplasia and strabismus in 36% of patients (244,245).

Strabismus is common in both syndromes caused by NSDHL variants: CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects), an X-linked disorder which affects females and is lethal in males, and CK syndrome, an X-linked neurodevelopmental disorder that affects males (246).

PAX3 variants are one cause of Waardenburg syndrome, a group of genetic conditions that cause hearing loss and changes in pigmentation, skin, and eyes. Convergent strabismus is reported in 5/26 patients with Waardenburg syndrome (247).

Several multiple anomalies syndromes include congenital cataract and strabismus. CTDP1 variants cause congenital cataracts, facial dysmorphism and neuropathy syndrome. Strabismus is reported in 16/16 patients (248). Variants in OCRL cause Lowe syndrome, a rare X-linked disease characterized by congenital cataracts, glaucoma, developmental delays, and renal dysfunction. Strabismus is present in 35% of patients (249). Nance-Horan syndrome, associated with NHS, presents with strabismus in 5/16 patients (250).

Case reports describe strabismus in disorders of peroxisomal biogenesis caused by PEX1, PEX6, and PEX11B with dysmorphic facial features and neurological, hepatic, and gastrointestinal dysfunction (251–254).

Several genetic syndromes involving congenital heart defects also present with strabismus. CHARGE syndrome is an autosomal dominant disorder characterized by heart defects, coloboma, choanal atresia, and growth delay, caused by variants in CHD7. Ophthalmic studies of CHARGE syndrome report strabismus in 67% of patients (255,256). CDH2 variants cause a syndrome with ID, corpus callosum agenesis, craniofacial dysmorphisms, and ocular, cardiac, and genital anomalies; 5/9 reported individuals have strabismus (257). Gain-of-function variants in SMAD4 cause dysregulation of the TGF-beta signaling pathway and Myhre syndrome, a multi-system connective tissue disorder with congenital heart defects. Strabismus is reported in 31% of patients (258). Char syndrome (TFAP2B) is characterized by distinctive facial features, hand anomalies, and patent ductus arteriosus; strabismus is reported in 7/10 families (259). Alagille syndrome, caused by variants in JAG1, presents with cardiac defects, cholestasis, skeletal defects, and eye abnormalities; strabismus is relatively low penetrance (11%) (260–263).

Noonan syndrome presents with characteristic facial features, short stature, cardiovascular problems, ocular abnormalities, and other physical anomalies. The prevalence of strabismus in Noonan syndrome is 38–48% (264,265). Several genes result in Noonan syndrome, for specific prevalences of strabismus, see Table 1 (265,266). Costello syndrome, associated with heterozygous variants in HRAS, overlaps phenotypically with Noonan syndrome. In a study examining patients with HRAS variants, strabismus was reported in 72% examined in person, 44% based on retrospective chart review, and 30% reported in the literature (267). Cardio-facio-cutaneous (CFC) syndrome, characterized by craniofacial dysmorphia, ectodermal abnormalities, congenital heart defects and developmental and growth delays, overlaps phenotypically and genetically with Noonan and Costello syndromes. CFC is caused by variants in KRAS, BRAF, MAP2K1, and MAP2K2. Strabismus has been reported in 62% of affected individuals (268,269).

Strabismus is also present in congenital central hypoventilation syndrome (CCHS), associated with variants in PHOX2B and RET. PHOX2B-related CCHS presents with Hirschsprung disease, heart disease, behavioral disorders, and autonomic dysfunction, with strabismus in 6/22 patients (270). A case report described strabismus in RET-associated CCHS (271). Strabismus is present in over half of cases with Pitt-Hopkins syndrome, which involves intellectual disability, wide mouth, and intermittent overbreathing, and is associated with haploinsufficiency of TCF4 (272).

Defects in 2 enzymes involved in cholesterol biosynthesis, DHCR7 and DHCR24, have been associated with autosomal recessive disorders with occasional strabismus presentation (273,274). DHCR7, which catalyzes the final step in cholesterol biosynthesis, causes Smith-Lemli-Opitz syndrome, and DHCR24, which converts desmosterol to cholesterol, causes desmosterolosis.

ROBO1 variants cause pituitary stalk interruption syndrome, characterized by thin or absent pituitary stalk; there is a high (80%) prevalence of strabismus (275). Proteus syndrome, caused by variants in AKT1, is associated with strabismus in 35% of patients (276). Branchio-oculo-facial syndrome, linked to TFAP2A, has a 13% prevalence of strabismus (277). Variants in RNF135, in the NF1 microdeletion region, cause an overgrowth syndrome. 1/6 reported patients have strabismus (278). FGD1, which causes Aarskog-Scott syndrome, is associated with strabismus in 5% of patients (279). SOX2 variants and deletions are associated with anophthalmia/microphthalmia, ID, seizures, and growth issues; strabismus is reported in 5% (280,281). X-linked colobomatous microphthalmia syndrome, which also includes obesity and ID, is caused by variants in HMGB3; 2/2 patients have been reported with strabismus (282). Deafness-dystonia-optic neuropathy syndrome is caused by TIMM8A loss-of-function; strabismus is reported in 2/4 patients (283). DDX3X syndrome is associated with ID, ASD, gastrointestinal, and ophthalmic abnormalities. One study reports strabismus in 2/5 patients (284). Case series report strabismus with variants in PCNT, or Microcephalic Primordial Dwarfing Syndromes (285), and FLNA, Melnick-Needles Syndrome (286).

Metabolic Disorders

Several metabolic syndromes include strabismus. Congenital disorders of glycosylation (CDG) result from variants in several genes, including PMM2, NGLY1, ALG11, ALG6, COG7, and DDOST. Patients with the most frequent form, PMM2-CDG, have a high prevalence of strabismus: 73–84% (287,288). The prevalence of strabismus is 35% in DPAGT1-CDG (289) and 31% in NGLY1-CDG (290,291). Strabismus is reported in all or almost all patients with variants in ALG1 (292), ALG11 (293), ALG6 (294), and COG7 (295). Cases of DDOST-CDG have been rarely reported but all presented with strabismus (296–298).

MCOLN1 variants cause mucolipidosis type IV, characterized by abnormal endocytosis. Strabismus prevalence is 58% (299,300). Deficiency of ADSL results in a defect of purine metabolism; strabismus is present in 26% (301). Variants in AGK result in Sengers syndrome, characterized by mitochondrial myopathy, congenital cataract, hypertrophic cardiomyopathy, and lactic acidosis. Strabismus is present in 4/32 patients (302,303). Homozygous variants in FA2H cause neurodegeneration with brain iron accumulation. Divergent strabismus is reported in 5/5 affected patients (304). Deficiency of ACOX1 is associated with strabismus in one case report (305).

Muscular Dystrophy (without intellectual disability)

Congenital muscular dystrophies have been associated with strabismus, with variable penetrance. Variants in DMPK cause myotonic dystrophy type 1; strabismus is present in 56% of affected children (306). Studies of GMPPB-related congenital muscular dystrophy identified strabismus in 7/30 affected patients (307,308). FKTN variants cause Fukuyama congenital muscular dystrophy; a retrospective analysis found strabismus in 7% of patients (309). Strabismus is reported in 2/8 patients with POMGNT1 variants (310), 3/15 with POMT2 (310,311), 3/8 with FKRP (312), and 1/3 with COL6A2 variants (313).

Craniosynostosis

Craniosynostosis occurs when calvarial sutures fuse prematurely, leading to abnormal growth of the skull. It can be non-syndromic, involving one suture, or part of a syndrome with other clinical features. A recent systematic metaanalysis reported 19% prevalence of strabismus in non-syndromic craniosynostosis, and 58% in syndromic craniosynostosis (314). Distinct variants in FGFR2 result in Crouzon, Apert or Pfeiffer syndromes, which have overlapping clinical features. Prevalence of strabismus is 60% in Crouzon syndrome, 44% in Apert syndrome, and 67% in Pfeiffer syndrome (314). A specific variant in FGFR3 causes Muenke syndrome; strabismus prevalence is 55% (315). One patient with TCF12-related craniosynostosis was reported to have divergent strabismus (316). Variants in TWIST1 cause Saethre-Chotzen syndrome, with a 60% prevalence of strabismus (314). Strabismus in craniosynostosis has been believed to result from abnormalities of the shape of the orbit and position of the eyes within the orbit, however, TWIST1 has recently been shown to be important in development and differentiation of the extraocular muscles (317). Amongst patients with Craniofrontonasal Dysplasia, caused by variants in EFNB1, strabismus was reported in 58% (318–320).

Hematologic/Lymphatic Disorders

Several hematologic and lymphatic disorders are associated with strabismus. Fanconi Anemia is characterized by early onset bone marrow failure, various congenital anomalies, and high rates of cancer. Strabismus is reported in 16% of Fanconi anemia patients (321), specifically 11/78 patients with FANCG variants, 3/15 patients with FANCA variants, and 1 patient with a BRCA2 variant (321–323). Variants in FOXC2 are associated with lymphedema-distichiasis, a rare multisystem disorder characterized by lymphedema and extra eyelashes. Strabismus has been reported in 4/75 patients, in addition to other eye abnormalities such as early cataracts and corneal dystrophy (324,325). The reason these disorders have high prevalence of strabismus is not clear.

Skin Conditions

Several disorders with prominent skin involvement are associated with strabismus. Wrinkly skin syndrome is caused by variants in ATP6V0A2; 81% exhibit strabismus (326). Focal dermal hypoplasia, associated with PORCN, has patchy hypoplastic skin and ocular, digital and dental malformations. Strabismus prevalence is 33% (327,328). Incontinentia pigmenti, an X-linked dominant disorder linked to IKBKG has a strabismus prevalence of 18% (329). Xeroderma pigmentosum (XP) is a DNA repair disorder characterized by extreme sensitivity to ultraviolet light and a high predisposition to skin cancer. The overall prevalence of strabismus in XP is 8% (330). There are 8 genetic causes of XP; strabismus is reported in 5, with varying rates based on genetic cause: XPA (1/18), XPC (1/28), ERCC2 (3/14), ERCC5 (1/8), and POLH (1/12) (330). Gorlin syndrome, caused by variants in PCTH1, has a strabismus prevalence of 63% (331). The association of skin disorders with strabismus may be because of the differentiation of both skin and nervous system from the ectodermal layer.

OPHTHALMOLOGIC DISORDERS

Albinism

Oculocutaneous albinism (OCA) results from impaired melanin synthesis in the skin, hair, and eyes and presents with decreased pigmentation (332). OCA can be divided into seven subcategories, OCA1 to OCA7, each with specific genetic causes. Ocular albinism (OA) predominantly affects the eyes without impacting skin or hair. OCA and OA are characterized by visual abnormalities including strabismus, nystagmus, and decreased visual acuity (333). Reported prevalence of strabismus ranges from 53–71% in albinism, with esotropia as the most common type (334,335). Only one study looked specifically by genetic cause, and reported a strabismus prevalence of 100% for patients with OCA1, caused by variants in TYR (336). This notably contrasts with FRMD7, a gene linked to isolated infantile nystagmus, where strabismus is reported in only 7.8% of patients (334).

Aniridia/Coloboma/Eyelid/Cornea Abnormalities

Structural malformations of the eye, including aniridia, coloboma, and eyelid or corneal anomalies are often associated with strabismus. PAX6 haploinsufficiency classically causes aniridia, but can cause a variety of anterior and posterior segment dysgenesis; missense variants in PAX6 have been thought to cause a milder phenotype such as partial aniridia. Strabismus is present in 38% of patients with PAX6 variants (337). Variants in FOXL2 cause blepharophimosis, ptosis, and epicanthus inversus syndrome, characterized by horizontal palpebral aperture, epicanthus inversus, and ptosis. Strabismus is present in 13/31 patients (338). Heterozygous MAB21L1 variants cause BAMD syndrome (blepharophimosis plus anterior segment and macular dysgenesis) and homozygous variants cause COFG (cerebellar, ocular, craniofacial, and genital syndrome). Strabismus is reported in 6/7 with BAMD and 6/11 with COFG (339). Variants in DCN are associated with congenital stromal corneal dystrophy; strabismus is present in 4/11 patients (340). FOXC1 and PITX2 are associated with Axenfeld-Rieger syndrome, which causes anterior segment dysgenesis and often congenital glaucoma. Although treatment guidelines stress the importance of treating strabismus in Axenfeld-Rieger syndrome (341), relatively few studies report specific prevalence of strabismus. One case series reports strabismus in 3/24 individuals with PITX2 variants (342), and one series reports strabismus in 2/4 individuals with FOXC1 variants (343). OPA1 causes autosomal dominant optic atrophy. In one reported family, strabismus was present in 3/7 affected individuals (344).

Retinal Dystrophies

Retinal dystrophy refers to a large group of disorders that cause congenital or progressive loss of retinal function (345). Patients with retinal dystrophy, particularly the early-onset forms, often have strabismus.

Congenital stationary night blindness (CSNB) is a non-progressive disorder of rod function that leads to difficulty with night vision. There are currently 17 genes associated with CSNB (346). Overall, 26–59% of CSNB patients also have strabismus (346–348). NYX, an X-linked cause of CSNB, has a 43% prevalence of strabismus (346,347,349). The other common X-linked cause of CSNB, CACNA1F, has a prevalence of strabismus of 23% (347,349). In autosomal recessive forms of CSNB, TRPM1 shows a strabismus prevalence of 46% (347,350), and GRM6 a prevalence of only 19% (347,348). Presence or absence of strabismus has only been reported for 4 patients with GPR179, but 3/4 had strabismus (347,348). For the other genes associated with CSNB, specific prevalence of strabismus has not been reported. The differences in prevalence of strabismus for different genetic causes of the same retinal disorder suggests that strabismus may not be solely secondary to poor vision, but that function of these genes may be important in oculomotor development or control.

In achromatopsia, a congenital loss of cone function, CNGA3 and CNGB3 variants were associated with strabismus in about half of patients (351). Achromatopsia associated with GNAT2 had a lower prevalence of strabismus: 1/19 total individuals (352).

Leber congenital amaurosis (LCA) is an early onset loss of photoreceptor function with multiple genetic causes. Overall, strabismus occurs in 28% of LCA patients (353). Relatively few studies examine prevalence of strabismus specifically by genetic cause. RGRIP1 can present with LCA in children, one case series reports strabismus in 9/9 affected children (354).

RPGR variants cause X-linked retinitis pigmentosa; strabismus prevalence is only 5% (355). X-linked congenital retinoschisis is caused by RS1 variants, strabismus is present in 2/8 patients (356,357). Bardet Biedl Syndrome, a syndromic form of retinitis pigmentosa, is caused by mutations in multiple genes and has an overall prevalence of strabismus of 40%, with variability based on specific genetic cause (358).

Retinal Disorders/High Myopia Syndromes

Connective tissue disorders involving collagen variants can present with a variety of ocular phenotypes. Despite the prevalence of these conditions, only small cases reports discuss strabismus. Marshall and Stickler syndromes are connective tissue disorders with overlapping phenotypes involving skeletal, auditory, and ocular abnormalities, particularly high myopia, vitreoretinal degeneration, and retinal detachment. COL11A1 variants cause Marshall syndrome or Stickler syndrome type 2; strabismus is reported in 4/8 individuals (359,360). COL2A1 variants cause Stickler syndrome type 1; strabismus is reported in 1/2 patients (359). Knobloch syndrome, caused by variants in COL18A1, is associated with high myopia, vitreoretinal degeneration and retinal detachment. Strabismus is present in 6/8 patients in small cases reports (165,361–363). Similarly, FBN1 variants cause Marfan syndrome, which can cause ectopia lentis and high myopia. Prevalence of strabismus is 19% (364).

Familial executive vitreoretinopathy (FEVR) is a rare disorder associated with incomplete retinal vascularization. Strabismus is present at first visit in 20% of patients (365). FEVR is associated with variants in FZD4, LRP5, NDP, TSPAN12, ZNF408, CTNNB1, KIF11, and ATOH7. Strabismus is associated with mutations in FZD4, NDP, KIF11, and ATOH7 (366).

Conclusion

Many genetic syndromes present with strabismus, with highly variable penetrance. Strabismus is fully penetrant only in the CCDDs, which result from either deficits in differentiation of the cranial motor neuron precursors, or from abnormal axon guidance of the cranial nerves. Strabismus is a variable feature in hundreds of genetic syndromes, most commonly those associated with intellectual disability. Thus it is likely that strabismus results from abnormal neurological development or function, but the broad range of syndromes that include strabismus suggests that strabismus can arise from many different pathways. The variable penetrance underscores the complexity of strabismus genetics and pathophysiology. Strabismus in otherwise healthy children may result from altered expression or regulation of some of these genes, and we propose that each of these genes be considered a candidate gene for isolated strabismus. Furthermore, the high and variable penetrance of strabismus in genetic disorders underscores the importance of all children with genetic syndromes being assessed by an ophthalmologist.