Medicine:Syndromic microphthalmia

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Short description: Developmental disorder involving the eye
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
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]

Syndromes causing microphthalmia
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

  1. 1.0 1.1 AD: autosomal dominant; AR: autosomal recessive; XL: X-linked; XLD: X-linked dominant; XLR: X-linked recessive

References

  1. 1.0 1.1 1.2 1.3 "Microphthalmia" (in en). US National Library of Medicine. https://medlineplus.gov/genetics/condition/microphthalmia/. 
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 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. PMID 31896778. 
  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. PMID 32032630. 
  4. Ng D, Thakker N, Corcoran CM, Donnai D, Perveen R, Schneider A (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. 
  5. Blackburn PR, Zepeda-Mendoza CJ, Kruisselbrink TM, Schimmenti LA, García-Miñaur S, Palomares M (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. PMID 31053785. 
  6. van Rahden VA, Fernandez-Vizarra E, Alawi M, Brand K, Fellmann F, Horn D (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. PMID 25772934. 
  7. Vervoort VS, Viljoen D, Smart R, Suthers G, DuPont BR, Abbott A (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. PMID 12471201. 
  8. Casey J, Kawaguchi R, Morrissey M, Sun H, McGettigan P, Nielsen JE (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. PMID 21901792.