mid-face hypoplasia

Kniest Dysplasia

Clinical Characteristics
Ocular Features: 

High myopia and vitreoretinal degeneration are characteristic ocular features in this disorder.   The myopia is in the range of -7.5 to -15.25 with most patients having about -11 diopters.  Acuity may be normal but inoperable retinal detachments can lead to blindness.  The vitreous demonstrates liquefaction and syneresis and often detaches posteriorly forming a retrolental curtain.  About half of affected eyes have perivascular lattice degeneration and the same proportion of patients at some point develop a retinal detachment.  Giant tears and retinal dialysis are commonly the cause.  The lens is often dislocated and cataracts are common.

Systemic Features: 

Short stature, cleft palate, stiff joints, and conductive hearing loss are characteristic extraocular features of Kniest dysplasia.  Some patients develop frank joint contractures and many are unable to make a tight fist due to inflexibility of the interphalangeal joints.  Lumber kyphoscoliosis is common.  Epiphyseal cartilage has a 'Swiss cheese appearance' with prominent lacunae.  The facies are round and the midface is underdeveloped with a flat nasal bridge.  Mild psychomotor retardation is sometimes seen.  

High levels of keratin sulfate are found in the urine.

Genetics

Mutations in the COL2A1 gene (12q13.11-q13.2) coding for type II collagen is responsible for this autosomal dominant disorder. This is one of a number of disorders known as type II collagenopathies (see Stickler syndrome I [609508]).  The clinical features arise from a defect in type II procollagen.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the dysplasia.  Displaced lenses can be removed but the myopia and degenerated vitreous require a cautious approach.  Rhegmatogenous detachments demand prompt attention.

References
Article Title: 

Ophthalmic and molecular genetic findings in Kniest dysplasia

Sergouniotis PI, Fincham GS, McNinch AM, Spickett C, Poulson AV, Richards AJ, Snead MP. Ophthalmic and molecular genetic findings in Kniest dysplasia. Eye (Lond). 2015 Jan 16. doi: 10.1038/eye.2014.334. [Epub ahead of print].

PubMed ID: 
25592122

The Kniest syndrome

Siggers CD, Rimoin DL, Dorst JP, Doty SB, Williams BR, Hollister DW, Silberberg R, Cranley RE, Kaufman RL, McKusick VA. The Kniest syndrome. Birth Defects Orig Artic Ser. 1974;10(9):193-208.

PubMed ID: 
4214536

Axenfeld-Rieger Syndrome, Type 1

Clinical Characteristics
Ocular Features: 

Axenfeld-Rieger syndrome consists of a heterogeneous group of disorders with overlapping features.  Common to all 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.

Systemic Features: 

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.

Genetics

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 four 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. 

Heterozygous mutations in the PRDM5 gene (4q25-q26) have been identified in 4 members of a Pakistani family with typical features of the Axenfeld-Rieger syndrome. It is labeled type 4 Axenfeld-Rieger syndrome in this database. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

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.

References
Article Title: 

Axenfeld-Rieger syndrome

Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2017 Oct 3. doi: 10.1111/cge.13148. [Epub ahead of print] Review.

PubMed ID: 
28972279

The Rieger syndrome

Jorgenson RJ, Levin LS, Cross HE, Yoder F, Kelly TE. The Rieger syndrome. Am J Med Genet. 1978;2(3):307-18.

PubMed ID: 
263445
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