Syndromic microphthalmia
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.
| Syndromic microphthalmia | |
|---|---|
| Symptoms | Abnormally small eyeball(s) |
| Usual onset | Birth[1] |
| Duration | Lifelong[1] |
| Causes | Genetic or environmental factors[1] |
| Frequency | 1 in 10,000 individuals[1] |
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:
| Type | Causative gene/locus | Inheritance [lower-alpha 1] | Synonyms |
|---|---|---|---|
| MCOPS1 | NAA10[3] | XL | Lenz microphthalmia syndrome |
| MCOPS2 | BCOR[4] | XLR | |
| XLD | oculofaciocardiodental syndrome | ||
| MCOPS3 | SOX2[2] | AD | SOX2 anophthalmia syndrome, anophthalmia/microphthalmia-esophageal atresia (AEG) syndrome |
| MCOPS4 | Xq27-q28[2] | XLR | microphthalmia-ankyloblepharon-intellectual disability syndrome |
| MCOPS5 | OTX2[2] | AD | OTX2-related eye disorders |
| MCOPS6 | BMP4[5] | AD | Bakrania-Ragge syndrome, microphthalmia with brain and digit anomalies |
| MCOPS7 | HCCS, COX7B, NDUFB11[2][6] | XLD | MIDAS syndrome, microphthalmia with linear skin defects (MLS) syndrome |
| MCOPS8 | SNX3[7] | AD | microcephaly-microphthalmia ectrodactyly of lower limbs and prognathism (MMEP) syndrome, Viljoen–Smart syndrome |
| MCOPS9 | STRA6[8] | AR | anophthalmia/microphthalmia and pulmonary hypoplasia, Spear syndrome, Matthew–Wood syndrome |
| MCOPS10 | unknown[2] | microphthalmia and brain atrophy (MOBA) syndrome | |
| MCOPS11 | VAX1[2] | AR | N/A |
| MCOPS12 | RARB[2] | AD, AR | microphthalmia with or without pulmonary hypoplasia, diaphragmatic hernia, and/or cardiac defects |
| MCOPS13 | HMGB3[2] | XL | colobomatous microphthalmia with microcephaly, short stature, and psychomotor retardation, Maine microphthalmos |
| MCOPS14 | MAB21L2[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]
| Causative gene/locus | Inheritance [lower-alpha 1] | 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 syndrome |
| SALL1 | AD | Townes–Brocks syndrome |
| PUF60 | AD | Verheij syndrome |
| RAB3GAP1, RAB3GAP2, RAB18, TBC1D20 | AR | Warburg Micro syndrome 1-4 |
Notes
- AD: autosomal dominant; AR: autosomal recessive; XL: X-linked; XLD: X-linked dominant; XLR: X-linked recessive
References
- "Microphthalmia". MedlinePlus. US National Library of Medicine. Retrieved 2021-11-04.
- 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) - 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) - 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.
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{{cite journal}}: CS1 maint: multiple names: authors list (link) - 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) - 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.
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