Clinical Characteristics
Ocular Features
The corneal diameter is enlarged at birth to between 13.0 and 16.5 mm and the anterior chamber is deep. Male patients may develop early arcus, and eventually a crocodile shagreen pattern in the cornea. Presenile cataracts, iris thinning, and iridodenesis have also been reported. Glaucoma does not seem to be a part of this syndrome. The ERG has revealed mild cone system dysfunction in some patients..
Systemic Features
Isolated megalocornea is not associated with systemic disease by definition but systemic evaluation must be performed to rule out other syndromes.
Some patients have been reported to have a focal loss of white matter myelination with superior cognitive abilities.
Genetics
Inheritance
Only a few pedigrees have been reported. X-linked (male only) inheritance is most common. Carrier females do not have ocular disease. Multiple mutations in CHRDL1 (Xq23) have been found in at least 7 families. The gene encodes ventroptin, a morphogenic protein antagonist with multiple functions including specification of topographic retinotectal projections.. The gene is expressed in corneal development, anterior segment, and retina as well as brain.
Notably, megalocornea not only occurs as an isolated trait but also may be a part of systemic syndromes such as the Marfan syndrome (154700), Down syndrome andRieger syndrome (180500 ). It is also a part of an autosomal recessive mental retardation syndrome, sometimes called Neuhauser syndrome (249310).
Autosomal inheritance (usually recessive) has also been suggested but no locus has been found on autosomes.
Homozygous mutations in LTBP2 have been reported in consanguineous families in which sibs have congenital Megalocornea, Ectopia Lentis, and Spherophakia.
Pedigree
X-linked recessive, father affected
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the father, he has the disease since his only X chromosome is mutant and he has no normal X to blunt the effects of the abnormal gene. His sons only receive his Y chromosome and thus are all normal. However, all his daughters receive his one and only X chromosome and will be healthy 'carriers'. Thus such males will have no affected children but half their grandsons from those daughters will have the same disease as he does.
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the father, he has the disease since his only X chromosome is mutant and he has no normal X to blunt the effects of the abnormal gene. His sons only receive his Y chromosome and thus are all normal. However, all his daughters receive his one and only X chromosome and will be healthy 'carriers'. Thus such males will have no affected children but half their grandsons from those daughters will have the same disease as he does.
X-linked recessive, carrier mother
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the mother, she usually does not have the disease since the normal X chromosome without the mutation neutralizes the mutation in the abnormal X chromosome. However, half her sons will inherit the mutation-containing X chromosome and therefore have the X-linked disease. Half the daughters will inherit the mutation-bearing X chromosome and are usuallly healthy 'carriers'.
X-linked disorders are caused by a mutation on the X chromosome and both sexes can pass this to their children. If the mutation is in a recessive gene and carried by the mother, she usually does not have the disease since the normal X chromosome without the mutation neutralizes the mutation in the abnormal X chromosome. However, half her sons will inherit the mutation-containing X chromosome and therefore have the X-linked disease. Half the daughters will inherit the mutation-bearing X chromosome and are usuallly healthy 'carriers'.