Anophthalmia and microphthalmia (isolated and syndromic)

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Anophthalmia/microphthalmia is a challenging clinical entity, as it can be caused by mutations in a big variety of genes. According to updated entries in the most important databases, mutated genes causing isolated or syndromic anophthalmia/microphthalmia are: CHX10, RAX, GDF3, GDF6, MFRP, SHH, SIX6, CRYBA4, BCOR, SOX2, OTX2, BMP4, HCCS, STRA6, SIX3, HESX1, PAX6, CHD7, IKBKG, NDP, POMT1, SMOC1, HMX1, RAB3GAP1, RAB3GAP2, RAB18, GJA1, TFAP2A, ISPD, ALX1, ERCC6, FOXE3, FREM1, FREM2, FRAS1, MFRP. Genes in which mutations can be occasionally associated with anophthalmia/microphthalmia are: PQBP1, some Fanconi anemia genes, Joubert syndrome and Meckel syndrome genes, PORCN, RIPK4, SALL4, DPYD, KIF11, SMAD4, FOXL2, GLI3, OCLN, MAF, CRYBB2, CRYGD, ESCO2, SLC6A19, SLC6A20, SLC36A2, MBTPS2, C2ORF64, FASTKD2, C12ORF62, COX6B1, KERA, VCAN, EYA1.

Microphthalmia is classified according to the appearance of the globe and the grade of axial length reduction. The word microphthalmia identifies an eye with a short total axial length, that is for the rest anatomically conserved. An eye with dysgenesis of the anterior or of the posterior segment is referred to as complex microphthalmia. Anophthalmia identifies the total absence of the globe. Anophthalmia/microphthalmia can be isolated or occur as part of a syndrome, can be unilateral or bilateral and can be caused by mutations in several different genes (genetic heterogeneity) or by chromosomal aberrations. Of note, in most published cases, the term ‘anophthalmia’ is used as a synonym for the more appropriate terms ‘extreme microphthalmia’ or ‘clinical anophthalmia’.

Isolated nonsyndromic microphthalmia and anophthalmia have been described in association with or without coloboma. Isolated anophthalmia is considered autosomal recessive in most cases, as several consanguineous families have been reported. Rarely, autosomal dominant and X-linked inheritance is described. Some of the genetic subtpyes (MCOP) so far identified are:

– isolated microphthalmia 1 (MCOP1, MIM 251600): mapped to chromosome 14q32 (no gene identified yet)

– MCOP2 (MIM 610093) and MCOPCB3 (MIM 610092): caused by mutation in the CHX10 gene (now known as VSX2) on chromosome 14q24

– MCOP3 (MIM 611038): caused by mutation in the RAX gene on chromosome 18q21.3

– MCOP4 (MIM 613094): caused by mutation in the GDF6 gene on chromosome 8q22.1

– MCOP5 (MIM 611040): caused by mutation in the MFRP gene on chromosome 11q23

– MCOP6 (MIM 613517): caused by homozygous or compound heterozygous mutation in the PRSS56

– MCOP7 (MIM 613704) and MCOPCB6 (MIM 613703): caused by mutation in the GDF3 gene on chromosome 12p13.1

and also:

– isolated colobomatous microphthalmia-1 (MCOPCB1, MIM 300345): mapped to the X chromosome (no gene identified yet)

– MCOPCB2 (MIM 605738): mapped to chromosome 15q12-q15 (no gene identified yet)

– MCOPCB4 (MIM 251505): also known as microphthalmia with cyst (no gene or map locus identified yet)

– MCOPCB5 (MIM 611638): caused by mutation in the SHH gene on chromosome 7q36

Then, we have conditions characterized by the association with cataract:

– isolated microphthalmia with cataract-1 MCOPCT1 (MIM 156850): mapped on 16p13.3 (no gene identified yet).

– MCOPCT2 (MIM 212550): caused by mutation in the SIX6 gene on chromosome 14q23

– MCOPCT3 (MIM 302300): incorporated into Cataract 40 (MIM 302200).

– MCOPCT4 (MIM 610426), incorporated into Cataract 23 (MIM 610425): caused by mutation in the CRYBA4 gene. Secondary enophthalmia (sinking of the eyes) is described in a series of affected patients.

Coming to the syndromic subtypes, there are conditions in which anophthalmia/microphthalmia is a typical, constant stigmata and some other conditions where it is just a possible finding.

Conditions in which microphthalmia/anophthalmia is a typical feature:

– Fryns microphthalmia syndrome (also known as ‘anophthalmia-plus’ syndrome, no identified gene yet): already detectable in utero, the syndrome can be characterized by anophthalmia/microphthalmia, congenital glaucoma, blepharophimosis, cleft lip/cleft palate and other lip and palatal anomalies, bifid uvula, choanal atresia, macrotia with lateral facial cleft, craniosynostosis, frontal bossing, frontal encephalocele, clinodactyly, neural tube defects, genital anomalies, CNS anomalies (hypoplasia of corpus callosum) and primary hypothyroidism. Adrenal hypoplasia and single umbilical artery have also been described. Additioanl findings recently described includes: ventriculomegaly, low-set ears, skeletal anomalies included (13 pairs of ribs) and premature ossification of the calcaneus and talipes.

– Holoprosencephaly 2: caused by SIX3 mutations.

– Septooptic dysplasia: caused by HESX1 mutations.

– Aniridia: caused by PAX6 mutations.

– CHARGE syndrome: caused by CHD7 mutations

– Incontinentia pigmenti: caused by IKBKG mutations

– Norrie disease: caused by NDP mutations

– Walker-Warburg syndrome caused by POMT1 mutations.

– Microphthalmia with limb anomalies: caused by mutation in the SMOC1 gene (autosomal recessive inheritance). Besides microphthalmia/anophthalmia, there can be syndactyly, oligo or polydactyly synostosis/absence of the metatarsals, fused toes, split hand, lobster-claw hand deformity, hypoplasia of the fibula with short femur or tibia,     In addition, internal organs anomalies, genital anomalies, cleft lip, skeletal anomalies of the spine. Mental retardation may appear, but psychomotor development may also be normal.

***See our SMOC1 mutation database!***

– Chondrodysplasia with platyspondyly, distinctive brachydactyly, hydrocephaly, and microphthalmia: mapped on the X chromosome and caused by mutation in the HDAC6 gene.

– Microphthalmia with cyst, bilateral facial cleft and limb anomalies.

– Oculoauricular syndrome: caused by HMX1 mutations. Described patients (the first case was published in 1945!) had mild microphthalmia, corneal opacities, coloboma of the iris, cataract, microphakia (abnormal smallness of the crystalline lens), congenital nystagmus, synechiae and abnormalities of the external ear.

– Warburg Micro syndrome: caused by RAB3GAP1, RAB3GAP2, or RAB18 mutation. Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism.

– Oculodentodigital dysplasia (ODDD): caused by mutation in GJA1. Oculodentodigital dysplasia is phenotypically variable syndrome that can include facial dysmorphisms (syndactyly and camptodactyly), digit malformations, small teeth and microphthalmia and microcornea. Neurological signs may be present.

– Hallermann-Streiff syndrome: no gene identified yet. It is characterized by microphthalmia, brachycephaly with frontal bossing, micrognathia and beaked nose. The syndrome is very typical, as patients present with a bird-like face. Additional findings are hypotrichosis (sparse hair), cataracts, skin atrophy, dental anomalies and short stature. In most cases intelligence is normal, but some may show mental retardation. The differential diagnosis is with ODDD.

–  Branchiooculofacial syndrome: caused by mutation in the TFAP2A gene. Characterized ocular anomalies such as microphthalmia, coloboma and lacrimal duct obstruction, it also includes branchial cleft sinus defects, cleft lip/palate, facial dysmoprhisms and hemangioma in some cases. Deafness (sensorineural of conductive) can also associate. Polydactyly has been documented. The syndrome is also characterized by premature ageing.

–  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7 (MDDGA7): caused by ISPD mutation. MDDGA7 is at the most sever end of the clinical spectrum represented by the so called dystroglycanopathies. It is an autosomal recessive disorder with typical brain and eye malformations. Congenital muscular dystrophy and several mental retardation associate with early death usually in affected patients.

– Frontonasal dysplasia 3 (FND3): caused by homozygous mutation in the ALX1 gene. It is characterized by severe facial clefting and extreme microphthalmia.  It seems that there is only one report of this genetic subtypes of the syndrome, therefore it is not possible to say if microphthalmia is a constant finding in ALX1 mutations. In the other types of frontonasal dyslasia, which is a syndrome characterized by phenotypic variability, ocular abnormalities such as coloboma, cataract and microphthalmia are only occasionally reported.

– Cerebrooculofacioskeletal syndrome 1 and 4 (COFS1, COFS4): caused by ERCC6. This is the extreme prenatal form of Cockayne syndrome and presents with congenital microphthalmia and arthrogryposis. Cockayne syndrome (that can also be caused by ERCC8 mutations) includes short stature, dysmorphic facies, premature aging, photosensitivity, mental retardation and neurological disorders. COFS4 is caused by ERCC1 mutation. In the patient described by Jaspers et al, 2007 (PMID: 17273966) there were microcephaly, bilateral microphthalmia, blepharophimosis, and several other abnormalities, including arthrogryposis and CNS anomalies.

– GOMBO syndrome: no gene identified yet, but found to associate with 46,XY,ish der(3),t(3;22)(p25;q13). Microcephaly, microphthalmia, brachydactyly with clinodactyly, severe mental retardation, conductive hearing loss, skeletal anomalie.

– Congenital primary aphakia: caused by mutation in the FOXE3 gene. Valleix et al, 2006 (PMID: 16826526) reported a consanguineous family with three sibs having bilateral aphakia, microphthalmia and complete agenesis of the ocular anterior segment.

–  Martsolf syndrome: caused, like Warburg Micro syndrome, by  RAB3GAP2 mutations.

– Manitoba oculotrichoanal syndrome: caused by FREM1 mutation. Manitoba-oculo-tricho-anal (MOTA) syndrome includes ocular anomlaies (eyelid colobomas, cryptophthalmos, anophthalmia/microphthalmia),  aberrant scalp hairline and anal stenosis. The facies may resemble the one of Fraser syndrome.

– Fraser syndrome: caused by FRAS1 or FREM2 mutations. In this syndrome, severe microphthalmia is complicated by unilateral or bilateral cryptophthalmos (present in most patients) as eyelids are totally closed (absence of palpebral fissures). Several additional findings characterize this syndrome.

– Oculopalatocerebral syndrome: no gene or map locus identified yet, but probably autosomal recessively inherited, as described in a consanguineous family. Microcephaly, short stature (although not in all cases), joint hypermobility, limbs anomalies (small hands and feet), palatal anomalies (highly arched palate, cleft palate), ear shape anomalies, mental and growth retardation, CNS MRI abnormalities, spasticity, cleft palate and persistent hypertrophic primary vitreous with unilateral or bilateral microphthalmia are described.

– Nanophthalmos: nanophthalmos is characterized by a small eye and frequently by angle-closure glaucoma. Nanophthalmos is genetically heterogenous. Two autosomal dominant forms (NNO1 and NNO3) have been mapped, while a recessive form (NNO2) can be caused by MFRP mutations.

– Split-hand/foot malformation 5: no identified gene yet.

– Sakoda complex: no identified gene or map locus.

– Wittwer syndrome, also known as Wolf-Hirschhorn syndrome (WHS), which is a contiguous gene deletion syndrome associated with a hemizygous deletion of chromosome 4p16.3.

– Teebi-Shaltout syndrome: no identified gene or map locus.

– MCOPS1: caused by mutation in the NAA10 gene.

– MCOPS2: caused by mutation in the BCOR gene. It can include: long narrow face with facial dysmorphisms, congenital cataract, blepharophimosis, dental anomalies, syndactyly, cardiopathy, cleft palate, renal and genital anomalies, micorcephaly. There may be mental retardation, but intelligence can be normal as well.

MCOPS3: caused by mutation in the SOX2 gene.  It is characterized by inconstant defects of the optic ways and by brain and neurological anomalies (seizures, psycho and/or motor delay), chorioretinal coloboma, urogenital anomalies, skeletal anomalies (especially of the vertebrae), low-set ears, sensorineural hearing loss, esophageal atresia and tracheoesophageal fistula, cardiopathy, supernumerary teeth, growth hormone deficiency and gonadotropin deficiency. Shah et al. also referred to this condition as ‘anophthalmia-esophageal-genital syndrome’ (AEG syndrome; Shah et al 1997, PMID: 9128938).

– MCOPS4: mapped on Xq27-q28 (no genes identified yet).

– MCOPS5: caused by mutation in the OTX2 gene or deletions of chromosome 14q22-q23 spanning both the BMP4 and OTX2 genes. It can be associated with coloboma, microcornea, cataract, retinal dystrophy, hypoplasia or agenesis of the optic nerve, agenesis of the corpus callosum, developmental delay, joint laxity, hypotonia, seizures, cleft palate, partial growth hormone deficiency with or without brain anomalies at MRI, developmental delay, short stature, genital anomalies, hypothyroidism, gonadotropin and cortisol deficiency and Chiari malformation. Inheritance is autosomal dominant. Several OTX2 mutations (including large deletions) have been described.

– MCOPS6: caused by BMP4 mutations or deletions of chromosome 14q22-q23 spanning both the BMP4 and OTX2 genes. MCOPS6 can include: iris and chorioretinal coloboma, retinal dystrophy, retrognathia/micrognathia and small tongue, brachycephaly, low-set ears, digit anomalies, genital anomalies, hypoplastic kidneys, hypoplastic cerebellum, cortical atrophy and other CNS abnormalities, absence of optic nerves, chiasma and tracts, geniculate bodies, and pituitary stalk and gland, psychomotor retardation, hypotonia, cleft palate, craniosynostosis, hypothyroidism, vertebral anomalies and sensorineural deafness. Inheritance is autosomal dominant.

– MCOPS7: caused by HCCS mutation, on the X-chromosome. Inheritance is X-linked dominant, which means that the syndrome affetcs females while affected male fetuses are not viable. It is characterized by unilateral or bilateral microphthalmia and linear skin defects of the face and neck.

– MCOPS8: mapped on 6q21 (no gene identified yet).

– MCOPS9 (also known as Matthew-Wood syndrome): caused by mutations in the STRA6 gene. It is characterized by the association with pulmonary hypoplasia/aplasia.

MCOPS10 (also known as microphthalmia and brain atrophy, MOBA): no gene and no map locus identified yet.

Conditions in which microphthalmia/anophthalmia may appear in some cases:

Renpenning syndrome 1 (RENS1): Renpenning syndrome is caused by mutation in the PQBP1 gene. It is an X-linked mental retardation syndrome that can include microcephaly, short stature, small testes, dysmorphic facies, ocular colobomas, cardiac malformations, cleft palate, and anal anomalies. Martinez-Garay et al. described two related patients who also showed unilateral microphthalmia (Martinez-Garay et al 2007, PMID: 17033686).

– Fanconi anemia

– GOLTZ-Gorlin syndrome (also known as focal dermal hypoplasia): caused by heterozygous mutation in the PORCN gene

– Popliteal pterygium syndrome, lethal type: RIPK4 mutations

– Papillorenal syndrome: PAX2 gene mutations

– Nance-Horan syndrome: NHS gene mutations

– Meckel syndrome*

– Joubert syndrome*

– Xeroderma pigmentosum*

  • the clinical features of these syndrome are very particular and their associated genes have benn therefore not included in the anophthalmia/microphthalmia panel.

– Duane-radial ray syndrome: caused by SALL4 mutations.

– Aicardi syndrome: no gene identified yet. Externally apparent microphthalmia was seen in 25% of patients by Sutton et al, 2005 (PMID: 16158440)

– Dihydropyrimidine dehydrogenase deficiency: caused by DPYD mutations.

– Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR): caused by KIF11 mutation. This syndrome is phenotypically variable. Not all patients have a clear ocular phenotype. When this is present, chorioretinopathy is the most common finding, but also microphthalmia and other anomalies have been described.

– Steinfeld syndrome: no gene or map locus identified yet.

– Myhre syndrome: caused by mutation in SMAD4

– Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES): caused by FOXL2 mutations

– Neu-Laxova syndrome 1: PHGDHmutation

– Pallister-Hall syndrome: GLI3 mutation

– Galloway-Mowat syndrome: WDR73 gene mutation.

– Band-like calcification with simplified gyration and polymicrogyria (BLCPMG): caused by OCLN mutation.

– Cerulean cataract: Vogt originally described this disorder in 1922 as characterized by bluish and white opacifications of the lens. Newborns may be asymptomatic until the first or second year of life. Microphthalmia is described in some cases. The disorder is genetically heterogeneous: cerulean type congenital cataract 1 (CCA1) is mapped on 17q24, CCA2 is caused by mutation in CRYBB2, CCA3 is caused by mutation in CRYGD, CCA4 is caused by mutation in the MAF gene and CCA5 has been mapped to chromosome 12q.

– SC phocomelia syndrome: caused by ESCO2 mutations

– MOMO syndrome: MOMO stays for macrosomia, obesity, macrocephaly, ocular abnormalities. No genes or map locus is identified so far. This is an overgrowth syndrome with mental retardation. Overgrowth is probably due to delayed bone maturation. Other typical ocular findings can be hypertelorism downslanting palpebral fissures, microphthalmia, nystagmus and convergent strabismus. The differential diagnosis of MOMO syndrome is of course with other overgrowth syndromes, like Sotos syndrome.

– Hyperglycinuria: caused by SLC6A19, SLC6A20 or SLC36A2 mutations.

– Kondoh syndrome

– Di George syndrome and DiGeorge syndrome/velocardiofacial syndrome complex 2: caused by a 1.5- to 3.0-Mb hemizygous deletion of chromosome 22q11.2 or point mutations in the TBX1 gene.

– IFAP syndrome with or without BRESHECK syndrome: caused by MBTPS2 mutations.

– Primrose syndrome: caused by heterozygous mutation in the ZBTB20 gene. Primrose syndrome is characterized by typical facial features, macrocephaly, mental retardation, enlarged and calcified external ears, sparse body hair, and distal muscle atrophia. Microphthlamia has been reported at least in one case.

– Apple peel syndrome with microcephaly and ocular anomalies

– Mitochondrial complex IV deficiency: caused by C2ORF64, FASTKD2 , C12ORF62 or COX6B1 mutation.

– Recessive congenital cornea plana 2 (CNA2): caused KERA gene mutation.

– Cumming type campomelia: no identified gene yet.

– Biemond syndrome II

– Autosomal dominant sclerocornea (Elliott et al, 1985, PMID: 3994576)

– Wagner syndrome 1: caused by VCAN mutation

– Michelin tire baby syndrome

– Cat eye syndrome

– Branchiootorenal syndrome 1, with or without cataracts (BOR1): caused by EYA1 mutation

Recommended panel testing at Breda Genetics for this condition:



CRYBA4, a novel human cataract gene, is also involved in microphthalmia. Billingsley G, Santhiya ST, Paterson AD, Ogata K, Wodak S, Hosseini SM, Manisastry SM, Vijayalakshmi P, Gopinath PM, Graw J, Héon E. Am J Hum Genet. 2006 Oct;79(4):702-9. PMID: 16960806

Fryns anophthalmia-plus syndrome in an 18-week-old fetus. Jayasinghe C, Gembruch U, Kuchelmeister K, Körber F, Müller AM. Pediatr Dev Pathol. 2012 Jan-Feb;15(1):58-61. PMID: 21675878

Disruption of ALX1 causes extreme microphthalmia and severe facial clefting: expanding the spectrum of autosomal-recessive ALX-related frontonasal dysplasia. Uz E, Alanay Y, Aktas D, Vargel I, Gucer S, Tuncbilek G, von Eggeling F, Yilmaz E, Deren O, Posorski N, Ozdag H, Liehr T, Balci S, Alikasifoglu M, Wollnik B, Akarsu NA. Am J Hum Genet. 2010 May 14;86(5):789-96. PMID: 20451171

First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure. Jaspers NG, Raams A, Silengo MC, Wijgers N, Niedernhofer LJ, Robinson AR, Giglia-Mari G, Hoogstraten D, Kleijer WJ, Hoeijmakers JH, Vermeulen W. Am J Hum Genet. 2007 Mar;80(3):457-66. PMID: 17273966

Hereditary sclerocornea. Elliott JH, Feman SS, O’Day DM, Garber M. Arch Ophthalmol. 1985 May;103(5):676-9. PMID: 3994576

Bilateral microphthalmia, esophageal atresia, and cryptorchidism: the anophthalmia-esophageal-genital syndrome. Shah D, Jones R, Porter H, Turnpenny P. Am J Med Genet. 1997 May 16;70(2):171-3. PMID: 9128938

Homozygous nonsense mutation in the FOXE3 gene as a cause of congenital primary aphakia in humans. Valleix S, Niel F, Nedelec B, Algros MP, Schwartz C, Delbosc B, Delpech M, Kantelip B.Am J Hum Genet. 2006 Aug;79(2):358-64. PMID: 16826526

A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly, and mental retardation. Martínez-Garay I, Tomás M, Oltra S, Ramser J, Moltó MD, Prieto F, Meindl A, Kutsche K, Martínez F.Eur J Hum Genet. 2007 Jan;15(1):29-34. PMID: 17033686

Facial and physical features of Aicardi syndrome: infants to teenagers. Sutton VR, Hopkins BJ, Eble TN, Gambhir N, Lewis RA, Van den Veyver IB. Am J Med Genet A. 2005 Oct 15;138A(3):254-8. PMID: 16158440 

OMIM: 610125, 600776

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