Syndromic microphthalmia
SymptomsAbnormally small eyeball(s)
Usual onsetBirth[1]
DurationLifelong[1]
CausesGenetic or environmental factors[1]
Frequency1 in 10,000 individuals[1]

Syndromic microphthalmia is a class of rare congenital anomalies characterized by microphthalmia with other non-ocular malformations.[2] Syndromic microphthalmia accounts for 60 to 80% of all cases of microphthalmia.[2] Syndromic microphthalmias are caused by mutations in genes related to embryonic craniofacial development, and they are typically classified by their genetic cause.

Classification

If microphthalmia is present, genetic testing can be done to inform a specific diagnosis of a named syndrome. Twenty to forty percent of anophthalmia and microphthalmia patients are diagnosed with a recognized syndrome.[2] There are 14 numbered syndromic microphthalmies (MCOPS) primarily defined by their ocular manifestations:

MCOPS classification
Type Causative gene/locus Inheritance [lower-alpha 1] Synonyms
MCOPS1NAA10[3] XL Lenz microphthalmia syndrome
MCOPS2 BCOR[4] XLR
XLDoculofaciocardiodental syndrome
MCOPS3SOX2[2]AD SOX2 anophthalmia syndrome, anophthalmia/microphthalmia-esophageal atresia (AEG) syndrome
MCOPS4Xq27-q28[2]XLR microphthalmia-ankyloblepharon-intellectual disability syndrome
MCOPS5OTX2[2]AD OTX2-related eye disorders
MCOPS6BMP4[5]AD Bakrania-Ragge syndrome, microphthalmia with brain and digit anomalies
MCOPS7HCCS, COX7B, NDUFB11[2][6]XLD MIDAS syndrome, microphthalmia with linear skin defects (MLS) syndrome
MCOPS8SNX3[7]AD microcephaly-microphthalmia ectrodactyly of lower limbs and prognathism (MMEP) syndrome, Viljoen–Smart syndrome
MCOPS9STRA6[8]AR anophthalmia/microphthalmia and pulmonary hypoplasia, Spear syndrome, Matthew–Wood syndrome
MCOPS10unknown[2] microphthalmia and brain atrophy (MOBA) syndrome
MCOPS11VAX1[2]AR N/A
MCOPS12RARB[2]AD, AR microphthalmia with or without pulmonary hypoplasia, diaphragmatic hernia, and/or cardiac defects
MCOPS13HMGB3[2]XL colobomatous microphthalmia with microcephaly, short stature, and psychomotor retardation, Maine microphthalmos
MCOPS14MAB21L2[2]AD, AR colobomatous microphthalmia-rhizomelic dysplasia syndrome, microphthalmia-coloboma-rhizomelic skeletal dysplasia

In addition to MCOPS1–14, there are many genetic syndromes of which microphthalmia is a key feature:[2]

Syndromes causing microphthalmia
Causative gene/locus Inheritance [lower-alpha 1] Name/synonyms
unknownXLDAicardi syndrome (AIC), agenesis of corpus callosum with chorioretinal abnormality
KIAA1109ARAlkuraya–Kucinskas syndrome (ALKKCUS)
MAFADAymé–Gripp syndrome (AYGRP)
ACTBADFryns-Aftimos syndrome, Baraitser–Winter syndrome 1 (BRWS1)
ACTG1ADBaraitser–Winter syndrome 2 (BRWS2)
unknown Biemond syndrome
FOXL2ADBlepharophimosis, ptosis, epicanthus inversus syndrome (BPES)
SMCHD1ADBosma arhinia microphthalmia syndrome (BAMS)
TFAP2AADBranchio-oculo-facial syndrome (BOFS), hemangiomatous branchial clefts-lip pseudocleft syndrome
ERCC6ARCockayne syndrome type B (CSB), cerebro-oculo-facio-skeletal syndrome 1 (COFS1)
CHD7ADCHARGE syndrome
HDAC6XLDChondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia
unknown Colobomatous microphthalmia-obesity-hypogenitalism-intellectual disability syndrome
YAP1ADColoboma, ocular, with or without hearing impairment, cleft lip/palate, and/or intellectual disability (COB1)
FAT1ARColobomatous microphthalmia, ptosis, nephropathy, and syndactyly
MITFADWaardenburg syndrome type 2
ARCOMMAD syndrome
SRD5A3ARCongenital disorder of glycosylation type 1q (CDG1q)
SMOunknownCurry–Jones syndrome (CJS)
SALL4ARDuane-radial ray syndrome, Okihiro syndrome
FANCA, FANCD2, FANCE, FANCI, FANCLARFanconi anemia complementation groups A, D2, E, I, L
PORCNXLDFocal dermal hypoplasia, Goltz-Gorlin syndrome
FRAS1ARFraser syndrome 1
FREM2ARFraser syndrome 2
GRIP1ARFraser syndrome 3
ALX3ARFrontonasal dysplasia 1 (FND1)
ALX1ARFrontonasal dysplasia 3 (FND3)
unknownARFryns syndrome
unknown GOMBO syndrome (growth retardation, ocular abnormalities, microcephaly, brachydactyly, and oligophrenia)
SLC25A24ADGorlin–Chaudhry–Moss syndrome
FAM111AADGracile bone dysplasia (GCLEB), Kenny-Caffey syndrome
unknown Hallermann–Streiff syndrome
SMG9ARHeart and brain malformation syndrome (HBMS)
14q32ADHemifacial microsomia
SIX3, SHH, PTCH1, GLI2 AD Holoprosencephaly types 1, 2, 3, 7, 9
IKBKGXLDIncontinentia pigmenti
PDE6DARJoubert syndrome 22
unknownARKapur–Toriello syndrome
KMT2DAD Kabuki syndrome
KDM6AXLD
GDF6AD Klippel–Feil syndrome types 1, 3
GDF3XLD
unknownXLDMacrosomia with lethal microphthalmia
FREM1ARManitoba oculotrichoanal syndrome (MOTA)
MKS1, TMEM216, TMEM67, CEP290, RPGRIP1LARMeckel–Gruber syndrome types 1-5
unknownlikely ADMOMO syndrome
ZEB2ARMowat–Wilson syndrome
POMT1AD Muscle–eye–brain disease type A 1-11
POMT2, POMGNT1, FKTN, FKRP, CRPPA, POMGNT2, DAG1, RXYLT1, B3GALNT2AR
NHSXLDNance–Horan syndrome
REREADNeurodevelopment disorder with anomalies of the brain, eye, and/or heart (NEDBEH)
NPDXLRNorrie disease
HMX1AROculoauricular syndrome
GJA1AD, AROculodentodigital dysplasia (ODD)
CPLANE1AROrofaciodigital syndrome type VI
LRP5AROsteoporosis-pseudoglioma syndrome
PAX2ADPapillorenal syndrome
ATOH7ARPersistent fetal vasculature (PFV)/persistent hyperplastic primary vitreous (PHPV)
RIPK4ARPopliteal pterygium syndrome (PPS)
PQBP1XLRRenpenning's syndrome
RBP4ARRetinal dystrophy, iris coloboma and comedogenic acne syndrome (RDCCAS)
DLX1, DLX2ADSplit-hand/foot malformation type V
C12orf57ARTemtamy syndrome
WNT3ARTetra-amelia syndrome
SALL1ADTownes–Brocks syndrome
PUF60ADVerheij syndrome
RAB3GAP1, RAB3GAP2, RAB18, TBC1D20ARWarburg Micro syndrome 1-4

Notes

  1. 1 2 AD: autosomal dominant; AR: autosomal recessive; XL: X-linked; XLD: X-linked dominant; XLR: X-linked recessive

References

  1. 1 2 3 4 "Microphthalmia". MedlinePlus. US National Library of Medicine. Retrieved 2021-11-04.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 Eintracht J, Corton M, FitzPatrick D, Moosajee M (2020). "CUGC for syndromic microphthalmia including next-generation sequencing-based approaches". Eur J Hum Genet. 28 (5): 679–690. doi:10.1038/s41431-019-0565-4. PMC 7171178. PMID 31896778.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ↑ George A, Cogliati T, Brooks BP (2020). "Genetics of syndromic ocular coloboma: CHARGE and COACH syndromes". Exp Eye Res. 193: 107940. doi:10.1016/j.exer.2020.107940. PMC 7310839. PMID 32032630.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ↑ Ng D, Thakker N, Corcoran CM, Donnai D, Perveen R, Schneider A; et al. (2004). "Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR". Nat Genet. 36 (4): 411–6. doi:10.1038/ng1321. PMID 15004558. S2CID 23628891.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ↑ Blackburn PR, Zepeda-Mendoza CJ, Kruisselbrink TM, Schimmenti LA, García-Miñaur S, Palomares M; et al. (2019). "Variable expressivity of syndromic BMP4-related eye, brain, and digital anomalies: A review of the literature and description of three new cases". Eur J Hum Genet. 27 (9): 1379–1388. doi:10.1038/s41431-019-0423-4. PMC 6777538. PMID 31053785.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ↑ van Rahden VA, Fernandez-Vizarra E, Alawi M, Brand K, Fellmann F, Horn D; et al. (2015). "Mutations in NDUFB11, encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome". Am J Hum Genet. 96 (4): 640–50. doi:10.1016/j.ajhg.2015.02.002. PMC 4385192. PMID 25772934.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ↑ Vervoort VS, Viljoen D, Smart R, Suthers G, DuPont BR, Abbott A; et al. (2002). "Sorting nexin 3 (SNX3) is disrupted in a patient with a translocation t(6;13)(q21;q12) and microcephaly, microphthalmia, ectrodactyly, prognathism (MMEP) phenotype". J Med Genet. 39 (12): 893–9. doi:10.1136/jmg.39.12.893. PMC 1757218. PMID 12471201.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ↑ Casey J, Kawaguchi R, Morrissey M, Sun H, McGettigan P, Nielsen JE; et al. (2011). "First implication of STRA6 mutations in isolated anophthalmia, microphthalmia, and coloboma: a new dimension to the STRA6 phenotype". Hum Mutat. 32 (12): 1417–26. doi:10.1002/humu.21590. PMC 3918001. PMID 21901792.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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