Microphthalmia

Template:Short description Template:Infobox medical condition (new) Microphthalmia (Greek: Template:Langx, Template:Langx), also referred as microphthalmos, is a developmental disorder of the eye in which one (unilateral microphthalmia) or both (bilateral microphthalmia) eyes are abnormally small and have anatomic malformations. Microphthalmia is a distinct condition from anophthalmia and nanophthalmia. Although sometimes referred to as 'simple microphthalmia', nanophthalmia is a condition in which the size of the eye is small but no anatomical alterations are present.<ref name="definition">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid18039390">Template:Cite journal</ref>

Presentation

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Bilateral microphthalmia

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Bilateral microphthalmia in an intellectually disabled 22-year-old

Microphthalmia is a congenital disorder in which the globe of the eye is unusually small and structurally disorganized.<ref name="definition" /><ref>Template:Cite journal</ref> While the axis of an adult human eye has an average length of about Template:Cvt, a diagnosis of microphthalmia generally corresponds to an axial length below Template:Cvt in adults.<ref name="pmid18039390" /><ref name="pmid32100474">Template:Cite journal</ref> Additionally, the diameter of the cornea is about Template:Cvt in affected newborns and Template:Cvt in adults with the condition.<ref name="pmid18039390" /> The presence of a small eye within the orbit can be a normal incidental finding but in many cases it is atypical and results in visual impairment. The prevalence of this condition is around 1 in 10,000 births, and it affects roughly 3–11% of blind children.<ref name="pmid18039390" /><ref name=medline/><ref name="pmid27601422">Template:Cite journal</ref>

Causes

It has been postulated that microphthalmia arises as a result of interference with postnatal eye growth, in contrast to anophthalmia which originates much earlier during fetal development. Genetic causes of microphthalmia include chromosomal abnormalities (e.g. Patau syndrome, mosaic trisomy 9, 13q deletion syndrome, Wolf–Hirschhorn syndrome) or monogenetic Mendelian disorders (e.g. CHARGE syndrome, Fraser syndrome, oculofaciocardiodental syndrome, Lenz microphthalmia syndrome).<ref name="pmid18039390" /><ref>Template:Cite journal</ref> Microphthalmia in newborns is sometimes associated with fetal alcohol spectrum disorder<ref name="definition" /> or infections during pregnancy, particularly herpes simplex virus, rubella and cytomegalovirus (CMV), but the evidence is inconclusive.<ref name="pmid18039390" />

The following genes, many of which are transcription and regulatory factors, have been implicated in microphthalmia, anophthalmia, and coloboma:<ref name="oculome">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid25772934"/><ref name="pmid12471201"/>

SOX2 has been implicated in a substantial number (10–15%) of cases and in many other cases failure to develop the ocular lens often results in microphthalmia.<ref name="pmid18039390" />

Microphthalmia-associated transcription factor (MITF), located on chromosome 14q32, is associated with one form of isolated microphthalmia (MCOP1). In mammals, the failure of expression of MITF in the retinal pigment epithelium prevents this structure from fully differentiating, causing a malformation of the choroid fissure of the eye and drainage of vitreous body fluid. Without this fluid, the eye fails to enlarge, resulting in microphthalmia. Waardenburg syndrome type 2 in humans may also be caused by mutations in MITF<ref name=":4">Template:Cite journal</ref> The human MITF gene is homologous to the mouse microphthalmia gene (gene symbol mi); mouse with mutations in this gene are hypopigmented in their fur. The identification of the genetics of WS type 2 owes a lot to observations of phenotypes of MITF-mutant mice.<ref name=":4" />

Diagnosis

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Microphthalmia is often diagnosed soon after birth. An initial diagnosis usually occurs after the eyes are inspected through the lids.<ref name="pmid18039390" /> In addition to visual examinations, measurements of the cornea are used in the diagnosis of this condition.<ref name="pmid18039390" /> An ultrasound may also be conducted to confirm whether the axial length of the eye is clinically below average (i.e. at least 2 standard deviations below the age-adjusted mean).<ref name="pmid18039390" /><ref name="pmid32100474" />

When a case of microphthalmia is detected, the patient should visit an eye specialist as soon as possible. It is important for an ophthalmologist to conduct a thorough examination within 2 weeks after birth.<ref name=":3">Template:Cite journal</ref> The ophthalmologist will confirm the preliminary diagnosis and look for signs of other anomalies in both eyes. These abnormalities may include coloboma, optic nerve hypoplasia, retinal dystrophy, and cataract.<ref name=":3" /> Ultrasound may also be used to determine the presence of any internal eye issues, which may not otherwise be visible.<ref name=":3" /> It is possible for individuals with microphthalmia to have some vision in the affected eye(s). For this reason, the vision of infants with microphthalmia should be evaluated early on, even in severe cases.<ref name=":3" /> Pediatric vision tests along with electrodiagnostics are typically used to assess visual acuity.<ref name=":3" />

If no related symptoms are present, microphthalmia is defined as non-syndromic or isolated microphthalmia (MCOP). When occurring in conjunction with other developmental defects, it may be diagnosed as syndromic microphthalmia (MCOPS). Approximately 60 to 80% of microphthalmia cases are syndromic.<ref name="pmid31896778">Template:Cite journal</ref> Several types of MCOPS have been recognized based on their genetic causes:

MCOPS classification

Type	Causative gene/locus	Inheritance Template:Efn	Synonyms
MCOPS1	NAA10<ref name="pmid32032630">Template:Cite journal</ref>	XL	Lenz microphthalmia syndrome
MCOPS2	BCOR<ref name="pmid15004558">Template:Cite journal</ref>	XLR
		XLD	oculofaciocardiodental syndrome
MCOPS3	SOX2<ref name="pmid31896778"/>	AD	SOX2 anophthalmia syndrome, anophthalmia/microphthalmia-esophageal atresia (AEG) syndrome
MCOPS4	Xq27-q28<ref name="pmid31896778"/>	XLR	microphthalmia-ankyloblepharon-intellectual disability syndrome
MCOPS5	OTX2<ref name="pmid31896778"/>	AD	OTX2-related eye disorders
MCOPS6	BMP4<ref name="pmid31053785">Template:Cite journal</ref>	AD	Bakrania-Ragge syndrome, microphthalmia with brain and digit anomalies
MCOPS7	HCCS, COX7B, NDUFB11<ref name="pmid31896778"/><ref name="pmid25772934">Template:Cite journal</ref>	XLD	MIDAS syndrome, microphthalmia with linear skin defects (MLS) syndrome
MCOPS8	SNX3<ref name="pmid12471201">Template:Cite journal</ref>	AD	microcephaly-microphthalmia ectrodactyly of lower limbs and prognathism (MMEP) syndrome, Viljoen–Smart syndrome
MCOPS9	STRA6<ref name="pmid21901792">Template:Cite journal</ref>	AR	anophthalmia/microphthalmia and pulmonary hypoplasia, Spear syndrome, Matthew–Wood syndrome
MCOPS10	unknown<ref name="pmid31896778"/>		microphthalmia and brain atrophy (MOBA) syndrome
MCOPS11	VAX1<ref name="pmid31896778"/>	AR	N/A
MCOPS12	RARB<ref name="pmid31896778"/>	AD, AR	microphthalmia with or without pulmonary hypoplasia, diaphragmatic hernia, and/or cardiac defects
MCOPS13	HMGB3<ref name="pmid31896778"/>	XL	colobomatous microphthalmia with microcephaly, short stature, and psychomotor retardation, Maine microphthalmos
MCOPS14	MAB21L2<ref name="pmid31896778"/>	AD, AR	colobomatous microphthalmia-rhizomelic dysplasia syndrome, microphthalmia-coloboma-rhizomelic skeletal dysplasia

Treatment

Microphthalmia cannot be cured. However, there are treatments options to manage the condition and its associated symptoms. When the affected eye(s) display some visual function, a patient's eyesight can be improved (sometimes up to good state) by plus lenses, as a small eye is usually far-sighted.<ref name=":3" /> When one of the eyes is unaffected, caution should be taken to guard this 'good' eye and preserve its vision. In these unilateral cases, eye glasses may be worn to offer a measure of physical protection.<ref name="pmid18039390" /><ref name=":3" />

A key aspect of managing this condition is accounting for the small volume of the eye. The small orbit size characteristic of microphthalmia can impact the growth and structural development of the face after birth. As a result, microphthalmia can cause hemifacial asymmetry.<ref name="pmid18039390" /><ref name=":3" /> This possibility is a particular concern for individuals with unilateral cases of microphthalmia. With one eye of average size, the asymmetry often becomes much more severe as the child ages.<ref name=":3" /> An axial length of less than Template:Cvt indicates that a microphthalmic eye's growth will not be sufficient, and intervention will be necessary to reduce the degree of facial asymmetry.<ref name=":3" />

Minimizing facial asymmetry is important for cosmetic and structural reasons.<ref name="pmid18039390" /><ref name="pmid32100474" /><ref name=":3" /> In order to address the size discrepancy of the affected eye(s), it is important to begin eye socket expansion early in life. The face reaches 70% of its adult size by roughly 2 years of age, and 90% of its adult size by about 5.5 years of age.<ref name=":3" /> Additionally, the symmetry fostered by early socket expansion allows for a better prosthetic fit later in life.<ref name="pmid32100474" /><ref name=":3" /> Typically, an infant begins wearing a conformer, or an unpainted ocular prosthesis, in the first weeks of life.<ref name="pmid18039390" /><ref name="pmid32100474" /><ref name=":3" /> The conformer is repeatedly replaced with a prothesis of a slightly larger size. This process, which takes place during the first 5 years of life, gradually enlarges the eye socket.<ref name="pmid18039390" /><ref name="pmid32100474" /><ref name=":3" /> Socket expansion through the use of implants of increasing size is another effective strategy.<ref name="pmid18039390" /><ref name=":3" />

After socket expansion is complete, a painted prosthetic eye can be worn for cosmetic reasons.<ref name=":3" /> If the microphthalmic eye has functional vision, an affected individual may opt against wearing a painted prothesis. Lenses are also sometimes used for cosmetic purposes, such as a plus lens to enlarge the microphthalmic eye.<ref name=":3" />

Epidemiology

Microphthalmia and anophthalmia combined are estimated to occur in about 1 in 10,000 births,<ref name="pmid30153864">Template:Cite journal</ref> though estimates have varied from 2 and 23 in 100,000 births. Approximately 3–11% of all blind children born globally have microphthalmia.<ref name="pmid31896778"/>

Incidence per 10,000 live births of microphthalmia (MO) and anophthalmia (AO)

Study region	Category	Incidence (95% CI)	Time period
Denmark<ref name="pmid27552085">Template:Cite journal</ref>	AO+MO	1.2	1995–2012
UK<ref name="pmid27601422" />	AO	0.24 (0.13–0.40)	1999
		0.04 (0–0.13)	2011
	MO	1.08 (0.82–1.35)	1999
		1.00 (0.76–1.24)	2011
US<ref name="pmid31580536">Template:Cite journal</ref>	AO+MO	2.08 (1.90–2.26)	1999–2001
		1.87 (1.73–2.01)	2004–2006
		1.91 (1.79–2.03)	2010–2014

Further reading

• GeneReviews/NCBI/NIH/UW entry on Anophthalmia / Microphthalmia Overview
• GeneReviews/NCBI/NIH/UW entry on Microphthalmia with Linear Skin Defects Syndrome
• OMIM-Online Mendelian Inheritance in Man