autosomal dominant

The primary ocular features result from pattern-specific, premature synostoses of cranial sutures.  The orbits are often shallow resulting in proptosis, sometimes to such an extent that exposure keratitis or even spontaneous subluxation of the globe results.  This is exacerbated by the midface hypoplasia that is often present.  As many as 22% of patients have optic atrophy, most likely secondary to chronic papilledema from elevated intracranial pressure.  Strabismus is common, often with a V-pattern exotropia.  Overaction of the inferior obliques and underaction of the superior obliques have been described.  One patient with narrow angle glaucoma has been reported.

In 10% of patients, keratitis and corneal scarring occur from the sometimes marked proptosis and corneal exposure.  Optic atrophy is present in over 20% of patients.  Strabismus, primarily exotropia, is found in more than 70% and various extraocular muscle anomalies may be detectable.  Usually the exotropia has a V-pattern with overaction of the inferior oblique muscles while the superior oblique is weak.  Amblyopia occurs in nearly 20%.  The lid fissures often slant downward and the eyebrows may be interrupted.

As in RIEG1 and RIEG3, glaucoma is the most serious ocular problem.  In a large family with 11 affected members, 9 had glaucoma.  All had the classic ocular signs of anterior segment dysgenesis, primarily posterior embryotoxon and iris adhesions (for a full description of the ocular features see Axenfeld-Rieger syndrome, RIEG1 [180500]).

This is a genetically and clinically heterogeneous type of corneal dystrophy.  Endothelial metaplasia seems to play a role as these cells acquire some characteristics of epithelial cells.  The posterior cornea has guttae and lesions of various sizes surrounded by a grayish halo.  These may become confluent and lead to stromal edema extending into the epithelium.  The thickness of the Descemet membrane is highly variable and a retrocorneal membrane may be present.  Onset is variable as some infants will have corneal edema whereas many, if not most, adults are asymptomatic.  The condition in severely affected children may resemble congenital hereditary corneal dystrophy.

This is primarily a disease of the posterior cornea although the secondary edema may extend to the epithelium.  The disease may be apparent at birth or shortly thereafter by the presence of excrescences or nodules in the endothelial layer with stromal edema.  Descemet membrane can be highly irregular in thickness.  The endothelial cells in PPCD may acquire some characteristics of epithelial cells.

This form of corneal dystrophy is often asymptomatic but some patients experience endothelial decompensation and corneal edema, which may even be seen soon after birth. The edema may extend into the epithelium.  The basic mechanism entails metaplasia of endothelial cells which seem to acquire some characteristics of epithelial cells.  Posterior corneal lesions of variable morphology appear in various patterns and are often surrounded by grayish halos.  When these become confluent the corneal edema is more severe and may resemble a congenital endothelial dystrophy.  The endothelial cell count is often low.  The Descemet layer also becomes abnormal.  The posterior border of the cornea appears nodular and grayish in color, often in a geographic pattern.  Surprisingly, endothelial function often is maintained and patients may remain asymptomatic for many years.

Some patients have features of anterior chamber dysgenesis with iris anomalies, anterior synechiae, and glaucoma.  It is also sometimes confused with EDICT syndrome (614303).

The skin and ocular pigmentary changes and the sensorineural hearing loss in type 4 Waardenburg syndrome resembles that of other types.  Patients, however, usually lack synophrys and dystopia canthorum.

There is little to support the designation of a corneal dystrophy as 'Avellino type' but it is included in this database because it is entrenched in the literature.  It has features of both lattice dystrophy, type I, and granular dystrophy type I, which might be expected since all of these result from mutations in the same gene, TGFBI on chromosome 5.  Not surprisingly, reported cases have clinical and histological features of both lattice and granular dystrophy and hence are labeled as having combined granular-lattice corneal dystrophy.  There is considerable variation of the nature and quantity of the stromal deposits both within and among families, a common characteristic of autosomal dominant disorders.  Even though clinical evidence may suggest primarily lattice or granular dystrophy, histological studies can reveal changes characteristic of both.

Early cases could be traced to the Avellino region of Italy from which the title was derived but more recent reports have described families from around the world.