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The iris stroma is hypoplastic resulting in a usually dark chocolate color which can suggest the diagnosis at birth. It may, however, appear slate gray in lightly pigmented individuals. The pupil is usually normal in morphology and location. Glaucoma may detectable in the newborn period but it may also not be diagnosed until the 4th decade or later. It is widely accepted that the anterior chamber angle is anomalous but the architectural and cellular details are lacking.
No systemic abnormalities have been described.
This is an autosomal dominant disorder resulting from heterozygous mutations in the PITX2 gene (4q25).
Glaucoma is the most frequent result of the anterior chamber dysgenesis in IRID2. It is often difficult to control. Early detection is of the utmost importance and all members of at-risk families require lifelong surveillance.
Glaucoma often develops in the latter part of the first decade of life but has been diagnosed in the neonatal period. It affects at least half of patients with IRID1. The disorder may be suspected in at-risk families by the hypoplasia of the iris stroma which leads to a dark chocolate color with prominent vessels. Further, the anterior iris surface appears smooth without the usual crypts. There are no defects in the pigment layer of the iris, and sphincter is intact and the pupil is in the normal position. Blue irides have a dark slate gray color. In many patients the iris is inserted anteriorly with numerous iris processes spanning the angle and inserting into the Schwalbe line. In yet other patients tissue seems to fill the angle obscuring other anatomical structures.
Systemic signs and symptoms are usually absent although CNS imaging has revealed cerebellar vermis hypoplasia in one family.
This type of iridogoniodysgenesis results from alterations in the forkhead transcription factor (FOXC1) gene (6p25.3). It is inherited in an autosomal dominant pattern. Rare individuals may have deletions in the 6p area while duplications in FOXC1 are more common than point mutations.
Another iridogoniodysgenesis disorder (IRID2) (137600) is caused by mutations in the PITX2 gene (4q25-q26), while iridogoniodysgenesis and skeletal anomalies (609515) is an autosomal recessive disorder due to as yet unknown mutations.
All members of families in which this disorder segregates should have close surveillance for the presence of glaucoma which obviously requires treatment when present.
The most important ocular feature is glaucoma, found in greater than 50% of patients. It is frequently difficult to control and blindness is far too common. The ocular phenotype has many similar features found in type 1 (RIEG1) but is discussed separately in this database since it is caused by a different mutation (see Axenfeld-Rieger syndrome, type 1 for a full description of the phenotype). It has the typical findings of anterior segment dysgenesis including anterior displacement of Schwalbe’s line, iris stromal hypoplasia, correctopia, and, of course, glaucoma.
Patients with this type of Axenfeld-Rieger disorder are less likely to have the systemic anomalies such as craniofacial and dental defects often seen in RIEG1. However, they often have a sensorineural hearing impairment and many have cardiac valvular and septal defects not usually seen in RIEG1.
This is an autosomal dominant disorder resulting from a mutation in the FOXC1 gene located at 6p25. Mutations in the same gene also cause iris hypoplasia/iridogoniodysgenesis (IGDA) (IRID1) 601631) which is sometimes reported as a unique disorder but is either allelic or the same disorder as the type of Axenfeld-Rieger syndrome discussed here.
The mutation responsible for type 2 Axenfeld-Rieger syndrome (601499) has as yet not been identified. Diagnosis is best made by ruling out mutations in PITX1 and FOXC1 although it is claimed that maxillary hypoplasia and umbilical defects are less common in type 2.
All patients with Axenfeld-Rieger syndromes must be monitored and treated for glaucoma throughout their lives.
Axenfeld-Rieger syndrome consists of a heterogeneous group of disorders with overlapping features. Type 1 is described here. Common to all three types are the presence of ocular, dental, facial, skeletal abnormalities and autosomal dominant inheritance. Anterior chamber dysgenesis of some form is universally present and severe glaucoma occurs in 50% of patients. This may have its onset in childhood with typical symptoms of congenital glaucoma such as photophobia, excessive tearing and corneal clouding. Hypoplasia of the iris is common and when progressive may result in an ectopic pupil and/or pseudopolycoria. Iris insertion and Schwalbe’s line are often anteriorly displaced with iridocorneal adhesions, a pattern that leads to the inclusion of this disorder among those with iridogoniodysgenesis or anterior chamber dysgenesis. Pupillary ectropion of the posterior pigmented layer of the iris may be seen.
There is considerable clinical overlap among conditions with iris dysgenesis. Some patients with typical systemic features of Axenfeld-Rieger syndrome may even have typical anterior chamber features of Axenfeld-Rieger anomaly in one eye and severe iris hypoplasia resembling aniridia in the other.
Dental anomalies and mid-facial hypoplasia secondary to underdeveloped maxillary sinuses are among the most common systemic features in type 1. The nasal root often appears abnormally broad and the lower lip appears to protrude. The teeth are frequently small and conical in shape with wide spaces between them (diastema). Some teeth may be missing. The umbilicus may fail to involute normally and retains excessive, redundant skin that sometimes leads to the erroneous diagnosis of an umbilical hernia for which unnecessary surgery may be performed. Hypospadius is frequently present while cardiac defects, sensorineural deafness, and anal stenosis are less common.
There is clinical and genetic heterogeneity in this syndrome and precise classification of many families remains elusive without knowing the genotype. Mutations in at least three genes are responsible and all are are responsible for phenotypes transmitted in autosomal dominant patterns. Type 1 discussed here is caused by a mutation in the homeobox transcription factor gene, PITX2, located at 4q25-q26. A type of iris hypoplasia (IH)/iridogoniodysgenesis (IGDS) (IRID2; 137600) disorder has been classified separately but is caused by a mutation in PITX2 as well and many cases have the same systemic features. Mutations in the same gene have also been found in ring dermoid of the cornea (180550) and in some cases of Peters anomaly (604229).
RIEG2 (601499) is rare but a deletion of 13q14 has been reported in several cases. Mapping in a large family with 11 affected individuals yielded a locus in the same region. Clinical signs overlap types 1 and 3 with dental, craniofacial, and ocular features, but with hearing impairment and rare umbilical anomalies.
Mutations in the FOXC1 gene (6p25) may be responsible for RIEG3 (602482). However, a family has been reported with a severe 'Axenfeld-Rieger phenotype' in which a digenic etiology may have been responsible: patients had mutations in both FOXC1 and PITX2.
The presence of glaucoma requires prompt and vigorous treatment but control is difficult with blindness too often the result. Oral surgery may be beneficial for dental problems. Low vision aids can be useful.