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

__TOC__ 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. There are 14 numbered syndromic microphthalmies (MCOPS) primarily defined by their ocular manifestations:

+ MCOPS classification Type Causative gene/locus Inheritance Synonyms MCOPS1 NAA10 XL Lenz microphthalmia syndrome MCOPS2 BCOR XLR XLD oculofaciocardiodental syndrome MCOPS3 SOX2 AD SOX2 anophthalmia syndrome, anophthalmia/microphthalmia-esophageal atresia (AEG) syndrome MCOPS4 Xq27-q28 XLR microphthalmia-ankyloblepharon-intellectual disability syndrome MCOPS5 OTX2 AD OTX2-related eye disorders MCOPS6 BMP4 AD Bakrania-Ragge syndrome, microphthalmia with brain and digit anomalies MCOPS7 HCCS, COX7B, NDUFB11 XLD MIDAS syndrome, microphthalmia with linear skin defects (MLS) syndrome MCOPS8 SNX3 AD microcephaly-microphthalmia ectrodactyly of lower limbs and prognathism (MMEP) syndrome, Viljoen–Smart syndrome MCOPS9 STRA6 AR anophthalmia/microphthalmia and pulmonary hypoplasia, Spear syndrome, Matthew–Wood syndrome MCOPS10 unknown microphthalmia and brain atrophy (MOBA) syndrome MCOPS11 VAX1 AR N/A MCOPS12 RARB AD, AR microphthalmia with or without pulmonary hypoplasia, diaphragmatic hernia, and/or cardiac defects MCOPS13 HMGB3 XL colobomatous microphthalmia with microcephaly, short stature, and psychomotor retardation, Maine microphthalmos MCOPS14 MAB21L2 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:

+ Syndromes causing microphthalmia Causative gene/locusInheritance Name/synonyms unknown XLD Aicardi syndrome (AIC), agenesis of corpus callosum with chorioretinal abnormality KIAA1109 AR Alkuraya–Kucinskas syndrome (ALKKCUS) MAF AD Aymé–Gripp syndrome (AYGRP) ACTB AD Fryns–Aftimos syndrome, Baraitser–Winter syndrome 1 (BRWS1) ACTG1 AD Baraitser–Winter syndrome 2 (BRWS2) unknown Biemond syndrome FOXL2 AD Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) SMCHD1 AD Bosma arhinia microphthalmia syndrome (BAMS)TFAP2A AD Branchio-oculo-facial syndrome (BOFS), hemangiomatous branchial clefts-lip pseudocleft syndrome ERCC6 AR Cockayne syndrome type B (CSB), cerebro-oculo-facio-skeletal syndrome 1 (COFS1) CHD7 AD CHARGE syndrome HDAC6 XLD Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia unknown Colobomatous microphthalmia-obesity-hypogenitalism-intellectual disability syndrome YAP1 AD Coloboma, ocular, with or without hearing impairment, cleft lip/palate, and/or intellectual disability (COB1) FAT1 AR Colobomatous microphthalmia, ptosis, nephropathy, and syndactyly MITF AD Waardenburg syndrome type 2 AR COMMAD syndrome SRD5A3 AR Congenital disorder of glycosylation type 1q (CDG1q) SMO unknown Curry–Jones syndrome (CJS) SALL4 AR Duane-radial ray syndrome, Okihiro syndrome FANCA, FANCD2, FANCE, FANCI, FANCL AR Fanconi anemia complementation groups A, D2, E, I, L PORCN XLD Focal dermal hypoplasia, Goltz-Gorlin syndrome FRAS1 AR Fraser syndrome 1 FREM2 AR Fraser syndrome 2 GRIP1 AR Fraser syndrome 3 ALX3 AR Frontonasal dysplasia 1 (FND1) ALX1 AR Frontonasal dysplasia 3 (FND3) unknown AR Fryns syndrome unknown GOMBO syndrome (growth retardation, ocular abnormalities, microcephaly, brachydactyly, and oligophrenia) SLC25A24 AD Gorlin–Chaudhry–Moss syndrome FAM111A AD Gracile bone dysplasia (GCLEB), Kenny–Caffey syndrome unknown Hallermann–Streiff syndrome SMG9 AR Heart and brain malformation syndrome (HBMS) 14q32 AD Hemifacial microsomia SIX3, SHH, PTCH1, GLI2 AD Holoprosencephaly types 1, 2, 3, 7, 9 IKBKG XLD Incontinentia pigmenti PDE6D AR Joubert syndrome 22 unknown AR Kapur–Toriello syndrome KMT2D AD Kabuki syndrome KDM6A XLD GDF6 AD Klippel–Feil syndrome types 1, 3 GDF3 XLD unknown XLD Macrosomia with lethal microphthalmia FREM1 AR Manitoba oculotrichoanal syndrome (MOTA) MKS1, TMEM216, TMEM67, CEP290, RPGRIP1L AR Meckel–Gruber syndrome types 1-5 unknown likely AD MOMO syndrome ZEB2 AR Mowat–Wilson syndrome POMT1 AD Muscle–eye–brain disease type A 1-11 POMT2, POMGNT1, FKTN, FKRP, CRPPA, POMGNT2, DAG1, RXYLT1, B3GALNT2 AR NHS XLD Nance–Horan syndrome RERE AD Neurodevelopment disorder with anomalies of the brain, eye, and/or heart (NEDBEH) NPD XLR Norrie disease HMX1 AR Oculoauricular syndrome GJA1 AD, AR Oculodentodigital dysplasia (ODD) CPLANE1 AR Orofaciodigital syndrome type VI LRP5 AR Osteoporosis-pseudoglioma syndrome PAX2 AD Papillorenal syndrome ATOH7 AR Persistent fetal vasculature (PFV)/persistent hyperplastic primary vitreous (PHPV) RIPK4 AR Popliteal pterygium syndrome (PPS) PQBP1 XLR Renpenning's syndrome RBP4 AR Retinal dystrophy, iris coloboma and comedogenic acne syndrome (RDCCAS) DLX1, DLX2 AD Split-hand/foot malformation type V C12orf57 AR Temtamy syndrome WNT3 AR Tetra-amelia syndromeSALL1 AD Townes–Brocks syndrome PUF60 AD Verheij syndrome RAB3GAP1, RAB3GAP2, RAB18, TBC1D20 AR Warburg Micro syndrome 1-4

Notes

References