Microphthalmia (Microphthalmia) - Genes BCOR, BMP4, GDF3, GDF6, MFRP, OTX2, PAX6, PRSS56, RAX, SHH, SIX6, SOX2, and VSX2 STRA6

Microphthalmia is an eye abnormality in which one or both eyeballs, have a very small size. In some affected the eyeball seems nonexistent, but even in these cases, there is some eye tissue. Cases of severe microphthalmia should be distinguished from anophthalmia, in which there is no eyeball. Microphthalmia may cause or not cause the loss of vision, according to the degree of damage of the eyeball.

People with microphthalmia may also have a coloboma. Colobomas are absences of ocular tissues of the eye parts. There may be absences in the colored part of the eye (iris); retinal; vascular layer under the retina (choroid), or optic nerve. Colobomas may be present in one or both eyes and, depending on their size and location, can affect people's vision. Also, people may have microphthalmia other optical defects, including ocular opacification (cataracts) and / or reduced eye opening (palpebral opening narrowed). In addition, affected individuals may have a microcornea, in which it is small and its curvature is pronounced. Between a third and half of affected individuals have it microphthalmia as part of a syndrome that affects other organs and tissues. When microphthalmia is isolated is said to be isolated or non-syndromic.

Microphthalmia may be due to variations in many genes involved in eye development in its infancy, most of which have not been identified. Genetic changes associated with microphthalmia have been identified only in a very small number of people affected. Furthermore, microphthalmia may also be due to environmental factors affecting the early development, such as deficiencies of certain vitamins during pregnancy, radiation, infections such as German measles, or exposure to substances that cause birth defects (teratogens) .

Described microphthalmia related genes in the following mutations:

      • BCOR gene (chromosome Xp11.4) - BCL6 co - repressor (BLC6 corepressor).
      • BMP4 gene (chromosome 14q22-q23) - bone morphogenic protein 4 (bone morphogenetic protein 4).
      • GDF3 gene (chromosome 12p13.1) - Growth differentiation factor 3) (Growth differentiation factor 3).
      • GDF6 gene (chromosome 8q22.1) - growth differentiation factor 6 (Growth differentiation factor 6)
      • MFRP gene (11q23) - membrane protein related to frizz (Membrane frizzled-related protein).
      • OTX2 gene (chromosome 14q22.3) - (orthodenticle homeobox 2).
      • Gene PAX6 (11p13) - (Pairex box 6).
      • PRSS56 gene (chromosome 2q37.1) - serine protease 56 (Protease serine 56).
      • RAX gene (chromosome 18q21.32) - (Retina and anterior neural fold homeobox).
      • SHH gene (chromosome 7q36) - (Sonic hedgehog).
      • SIX6 gene (chromosome 14q23.1) - (Six homeobox 6).
      • SOX2 gene (chromosome 3q26.3-q27) - (SRY sex Determining region Y-box 2).
      • STRA6 gene (chromosome 15q24.1) - (Stimulated by retinoic acid homolog gene 6-mouse).
      • VSX2 gene (chromosome 14q24.3) - (Visual system homeobox 2).

Each of these genes encodes a protein of one form or another may interfere with the development of some body tissues, including the eye development. Sometimes mutations are accompanied by an isolated microphthalmia, ie without any other manifestation, while at other times, it manifests as a microphthalmia with other organic disorders. Therefore, to avoid having to perform genetic study of several genes is useful to know what other organic changes in the patient, so we can advise what are the genes most likely to be involved are.

Mutations located in these genes have been associated with the following genetic alterations:


  • Microphthalmia.
  • Lenz microphthalmia syndrome (Lenz microphthalmia syndrome). In this syndrome the initial development of the eye and other tissues before birth is affected. This gene is on the X chromosome, and this process is recessive, so it has been found only in men who have a single chromosome X.
  • Oculofaciocardiodental syndrome (OFCD) (oculofaciocardiodental syndrome). In this syndrome the development of the eye and other organs and tissues affected before birth. This syndrome occurs only in women, being of X - linked dominant inheritance in males who have only one X chromosome, the absence of BCL6 co - repressor protein early development is fatal.

BMP4 gene:

  • Syndromic microphthalmia type 6 (MCOPS6) (Microphthalmia, syndromic, type 6), known as microphthalmia and pituitary abnormalities or abnormalities macroftalmia with cerebral and digital, facial, genital, skeletal, neurological and endocrine development.
  • Orofacial cleft nonsyndromic type 11 (OFC11) (Non-syndromic orofacial cleft type 11), a congenital defect characterized by cleft lip with or without cleft palate.

Gen GDF3:

  • Coloboma.
  • Microphthalmia.
  • Klippel-Feil syndrome (KFS) (Klippel-Feil syndrome). A process characterized by the fusion of two or more cervical vertebrae and a variety of other features that affect many parts of the body.

Gen GDF6:

  • Klippel-Feil syndrome (KFS) (Klippel-Feil syndrome).
  • Microphthalmia isolated type 4 (MCOP4).


  • Late - onset retinal degeneration (LORD).
  • Nanophthalmos type 2 (NNO2) (Nanophthalmos type 2), impaired development characterized by extreme hyperopia and small functional eyes eye.
  • Isolated microphthalmia type 5 (MCOP5) (Microphthalmia, isolated, type 5), a process characterized by further microphthalmia, retinitis pigmentosa, and drusen foveosquisis optical disc.

Gen OTX2:

  • Microphthalmia.
  • Coloboma.
  • Combined pituitary hormone deficiency (Combined pituitary hormone deficiency).
  • Septo-optic (sept-optic dysplasia). Eye development, optic nerve, pituitary and other brain structures it affected.

Gen PAX6:

  • Aniridia.
  • Gillespie syndrome (Gillespie syndrome), a process characterized by ocular abnormalities including partial aniridia, ataxia and mild to moderate mental retardation.
  • Peters anomaly (Peters anomaly), characterized by abnormal development of certain structures in the front of the eye and corneal opacity.
  • WAGR syndrome (WAGR syndrome). Wilms tumor syndrome, aniridia, genital abnormalities and mental retardation.
  • Effect on the development of the optic nerve, ectopia papillae.

Gen PRSS56:

  • Isolated microphthalmia type 6 (MCOP6) (Microphthalmia, isolated, type 6), a process whose clinical manifestations include extreme hyperopia, corneal sharp curvatures, shallow anterior chamber, thick lenses, and thick scleral wall.

Gen RAX:

  • Microphthalmia isolated type 3 (MCOP3) (Microphthalmia, isolated, type 3).

SHH gene:

  • Coloboma.
  • Microphthalmia.
  • Holoprosencephaly non - syndromic (nonsyndromic holoprosencephaly). In these patients, as well as affected eye development, not the two cerebral hemispheres are divided.

Gen SIX6:

  • Cataracts, microphthalmia and nystagmus (Cataract, microphthalmia and nystagmus).
  • Syndromic microphthalmia type 3 (Microphthalmia syndromic type 3).
  • Optical disc abnormalities with retinal dystrophy and / or macular (retinal With Optic disk anomalies and / or macular dystrophy (ODRMD)).

SOX2 gene:

  • Combined pituitary hormone deficiency (Combined pituitary hormone deficiency).
  • Septo-optic (sept-optic dysplasia).
  • SOX2 anophthalmia syndrome (SOX2 anophthalmia syndrome).

Gen STRA6:

  • Microftamia syndromic type 9 (MCOPS9) (Microphthalmia, syndromic, type 9), or Matthew-Wood syndrome or Spear. In this syndrome microphthalmia or anophthalmia intense there, and hypoplasia or aplasia lung.

Gen VSX2:

  • Microphthalmia isolated type 2 (MCOP2) or clinical anophtalmia isolated (Microphthalmia, isolated, type 2).
  • Microphthalmia with cataracts and abnormalities of the iris (MCOPCTI) (Microphthalmia With Cataracts and iris abnormalities).
  • Microphthalmia isolated type 3 with coloboma (MCOPCB3) (Microphthalmia, isolated, with coloboma, type 3).

Sometimes microphthalmia has an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. In some cases, parents of affected individuals have less severe ocular abnormalities. When microphthalmia occurs as a sign of a genetic syndrome or chromosomal abnormality can be grouped into families according to the inheritance pattern for that process. Often, microphthalmia not inherited, so there is only one affected person in a family.

Tests performed in IVAMI: in IVAMI perform the detection of mutations in any of the genes where they have described mutations causing microphthalmia [BCOR gene (14 exons), BMP4 gene (2 exons), GDF3 gene (2 exons), GDF6 gene (2 exons), MFRP (13 exons) gene, OTX2 gene (3 exons), PAX6 (11 exons), PRSS56 gene (13 exons), RAX gene (3 exons), SHH gene (3 exons), gene SIX6 (2 exons), SOX2 (exon 1) gene, STRA6 gene (18 exons), VSX2 gene (5 exons)], by PCR amplification of complete each of the gene exons and subsequent sequencing.

To target tests to be performed, it is important to know whether there are other conditions that may exist with the manifestation of microphthalmia.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).