miosis

Familial Acorea, Microphthalmia and Cataract Syndrome

Clinical Characteristics
Ocular Features: 

The pupil is obscured or absent secondary to fibrous overgrowth.  Microcornea and microphthalmia are present.  Iridocorneal adhesions are commonly seen on ultrasonic examination and anterior chamber angles may be narrow.  The corneas are clear but thickened centrally.  Nystagmus and esotropia have been reported.

The iris is rudimentary with a poorly developed stromal pattern and sometimes eccentrically located holes.  The ultrasound may reveal remnants of degenerative lens capsules.  Axial length in infants has been measured at about 14.7 mm but increases to 17 mm in children.  In adults the axial length is about 20 mm.  Refractive errors of +20-21 diopters have been measured.  Visual acuity is poor from birth but can be improved to some extent following pupiloplasty and lens extraction.  Intraocular pressure can be normal but one patient developed an increase in the 4th decade of life.  OCT and direct visualization of the fundus in several cases revealed normal retinal architecture and anatomy.

Systemic Features: 

None reported.  Specialty examinations failed to find any hearing loss or neurological deficits.

Genetics

The single 4 generation family tree reported is consistent with autosomal dominant inheritance.  Several likely loci on chromosomes 1, 5, 8, 11, and 17 have been reported but no candidate gene has been identified. 

Other conditions in which small pupils are found are Pierson syndrome (609049) and Warburg micro syndrome (600118) but these are associated with significant systemic abnormalities.  

Congenital microcoria (156600) is an autosomal dominant disorder with mild axial myopia and goniodysgenesis resulting from an unidentified mutation on chromosome 13.  Glaucoma is a common finding as is some iris hypoplasia.  Despite some clinical similarities, this is likely a unique disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Some improvement in visual acuity has been reported following lensectomy and reconstruction of the pupil.

References
Article Title: 

Microcoria, Congenital

Clinical Characteristics
Ocular Features: 

This disorder is a type of anterior chamber dysgenesis since the pupil and iris anomalies are associated with goniodysgenesis (prominent iris processes and high iris root insertion) and glaucoma.  The dilator muscle of the iris is hypoplastic and even topical mydriatics have little impact on pupil size. The pupil has a mean diameter of 0.8 mm and only dilates to a mean size of 1.4 mm.  The iris stroma is also hypoplastic and often lacks crypts and collarettes.  Transillumination defects of the iris are consistently present.  Axial myopia is a feature in some families (83% of affected individuals have refractive errors in the range of -10D) and seems to be progressive .  Juvenile glaucoma is frequently present (at least 30% require treatment) and is usually detected in the second (20%) through fourth decades of life.  All patients with glaucoma have evidence of 'trabeculodysgenesis' but the same features may also be seen in some patients without glaucoma.  The intraocular pressure is difficult to control pharmacologically.  Visual acuity varies widely but no retinal changes have been described.

Ultrastructural studies show lack of myofilaments and desmin in the stromal cytoplasmic processes of the anterior pigmented cells of the iris suggesting failure of full development of the pupil dilator muscle cells.

Systemic Features: 

There are no systemic abnormalities in this condition.

Genetics

This is an autosomal dominant disorder secondary to a mutation located at 13q13-q32.  The specific mutation responsible has not been identified but a large deletion at 13q32.1 in one patient has been reported. 

Congenital microcoria is also a feature of autosomal recessive Pierson syndrome (609049) caused by homozygous mutations in the LAMB2 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Glaucoma often requires surgery for control of intraocular pressure.

References
Article Title: 

Submicroscopic deletions at 13q32.1 cause congenital microcoria

Fares-Taie L, Gerber S, Tawara A, Ramirez-Miranda A, Douet JY, Verdin H, Guilloux A, Zenteno JC, Kondo H, Moisset H, Passet B, Yamamoto K, Iwai M, Tanaka T, Nakamura Y, Kimura W, Bole-Feysot C, Vilotte M, Odent S, Vilotte JL, Munnich A, Regnier A, Chassaing N, De Baere E, Raymond-Letron I, Kaplan J, Calvas P, Roche O, Rozet JM. Submicroscopic deletions at 13q32.1 cause congenital microcoria. Am J Hum Genet. 2015 Apr 2;96(4):631-9.

PubMed ID: 
25772937

RAB18 Deficiency

Clinical Characteristics
Ocular Features: 

Microphthalmia with microcornea, lens opacities, small and unresponsive pupils, and optic atrophy are the outstanding ocular features of this syndrome.  The eyes appear deeply set.  Some but not all have ERG evidence of rod and cone dysfunction.  The VEP is usually abnormal.  Short palpebral fissures have been described. 

Systemic Features: 

Patients with the micro syndrome have many somatic and neurologic abnormalities.  Infants usually have feeding problems that is sometimes accompanied by gastroesophageal reflux.  Some degree of psychomotor retardation and developmental delays is common.  Both spasticity and hypotonia have been described.  Some patients have seizures.  Facial hypertrichosis, anteverted ears, and a broad nasal bridge are often noted.   There may be absence of the corpus callosum while diffuse cortical and subcortical atrophy, microgyria, and pachygyria may be evident on MRI imaging.  Hypogenitalism may be a feature in both sexes.  Males may also have cryptorchidism and a micropenis while females can have hypoplasia of the labia minora and clitoris and a small introitus.  Microcephaly is inconsistently present. 

Genetics

This is a clinically and genetically heterogeneous disorder caused by homozygous mutations in at least 4 genes: RAB3GAP1 (WARBM1), RAB3GAP2 (WARBM2), RAB18 (WARBM3), and TBC1D20 (WARBM4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.  Vision remains subnormal even after cataracts are removed.  Nutrition may be improved with placement of a gastrostomy tube.

References
Article Title: 

New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish

Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, M?oller L,Zeschnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F. New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010 Oct;18(10):1100-6.

PubMed ID: 
20512159

Pierson Syndrome

Clinical Characteristics
Ocular Features: 

Microcoria is the most consistent ocular feature but is not present in some families.  It is congenital and sometimes seen with iris hypoplasia.  Glaucoma and lens opacities (including posterior lenticonus sometimes) are present in one-fourth of patients.  Corneal size varies with some patients having apparent macrocornea which can lead to the mistaken diagnosis of buphthalmos.  Pigment mottling and clumping is common in the retina and the ERG can show changes characteristic of cone-rod dystrophy.  Retinal thinning is often present as well.  Non-rhegmatogenous retinal detachments occur in 24% of patients and optic atrophy is seen in some individuals.  There is considerable interocular, intrafamilial, and interfamilial variability in these signs. 

Systemic Features: 

The primary and most consistent systemic problem is progressive renal disease. Congenital nephrotic syndrome with proteinuria, hypoalbuminemia and hypertension is characteristic.  Renal failure eventually occurs although the rate of progression varies. Most patients require a renal transplant for end-stage kidney disease in the first decade of life.  Kidney histology shows glomerulosclerosis, peritubular scarring, and diffuse mesangial sclerosis.  Hypotonia and muscle weakness are sometimes present and congenital myasthenia has been reported.  Severe global psychomotor retardation is common and many infants never achieve normal milestones. 

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the LAMB2 gene located at 3p21.  The normal gene encodes laminin beta-2 that is strongly expressed in intraocular muscles which may explain the hypoplasia of ciliary and pupillary muscles in Pierson syndrome.  Mutations in this gene are often associated with nephronophthisis but ocular abnormalities are not always present. 

Microcoria is also a feature of the autosomal dominant ocular condition known as congenital microcoria (156600).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Kidney replacement can restore renal function.  Glaucoma, cataracts, and retinal detachments require the usual treatment but patient selection is important due to the neurological deficits.  Lifelong monitoring is essential. 

References
Article Title: 

Ocular findings in a case of Pierson syndrome with a novel mutation in laminin ß2 gene

Arima M, Tsukamoto S, Akiyama R, Nishiyama K, Kohno RI, Tachibana T, Hayashida A, Murayama M, Hisatomi T, Nozu K, Iijima K, Ohga S, Sonoda KH. Ocular findings in a case of Pierson syndrome with a novel mutation in laminin ss2 gene. J AAPOS. 2018 Aug 16. pii: S1091-8531(18)30497-X. doi: 10.1016/j.jaapos.2018.03.016. [Epub ahead of print].

PubMed ID: 
30120985

Ophthalmological aspects of Pierson syndrome

Bredrup C, Matejas V, Barrow M, Bl?deghov?deg K, Bockenhauer D, Fowler DJ, Gregson RM, Maruniak-Chudek I, Medeira A, Mendon?ssa EL, Kagan M, Koenig J, Krastel H, Kroes HY, Saggar A, Sawyer T, Schittkowski M, Swietli?Nski J, Thompson D, VanDeVoorde RG, Wittebol-Post D, Woodruff G, Zurowska A, Hennekam RC, Zenker M, Russell-Eggitt I. Ophthalmological aspects of Pierson syndrome. Am J Ophthalmol. 2008 Oct;146(4):602-611.

PubMed ID: 
18672223

Lowe Oculocerebrorenal Syndrome

Clinical Characteristics
Ocular Features: 

Lens development is abnormal from the beginning secondary to abnormal migration of lens epithelium which has been described in fetuses by 20-24 weeks of gestation.  This leads to some degree of opacification in 100% of affected males.  The lens opacities may be polar or nuclear in location but complete opacification also occurs.   Leukocoria, miosis, microphthalmos and a shallow anterior chamber has been noted in neonates.  The cataractous lenses may be small and abnormally formed.  Glaucoma is present in more than half of affected males with onset by the age of 6 years and may be difficult to control.  Conjunctival and corneal keloids are found in about one-fourth of patients.

Adult female carriers characteristically have peripheral cortical opacities, appearing in a radial configuration.  These 'snowflake' opacities seldom cause visual symptoms.   It has been proposed that slit lamp examinations for such opacities can accurately determine the carrier status of females.

Systemic Features: 

Mental retardation, hypotonia, short stature, and developmental delays are common.  Seizures and behavior problems are seen in older children.  The renal defect secondary to defective phosphatidylinositol 4, 5-biphosphate 5- phosphatase results in a Fanconi-type aminoaciduria beginning late in the first year of life.  The phosphaturia leads to hypophosphatemia and eventually renal rickets.  Proteinuria, polyuria, as well as bicarbonate, sodium and potassium wasting with tubular acidosis are all part of the urinary profile.  Some patients have dental cysts and/or defective dentin.

Genetics

The mutation causing this X-linked disorder is in the OCRL gene located at Xq26.1.  New mutations have been found among nearly one-third of affected males.  

Another X-linked disorder with similar but less severe kidney disease, Dent disease 2 (300555), has been found to have mutations in the same gene.  However, none of the ocular features are present.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts need to be removed before sensory nystagmus and amblyopia develop.  Fluid and electrolyte balance must be maintained.  Growth hormone can be used in selected patients.  Supportive systemic care is necessary in most cases.  Lifelong kidney and ocular monitoring is recommended.

References
Article Title: 

Spastic Ataxia 7, with Miosis

Clinical Characteristics
Ocular Features: 

Several large pedigrees have been reported in which both males and females had congenital miosis and decreased pupillary light responses.  The pupils are about 2 mm in size and have been described as 'fixed' since they do not dilate in low light or constrict in bright light.  They also do not respond well to mydriatics.  Several individuals also had nystagmus and dysconjugate eye movements.

Optic atrophy is not a consistent feature although several in the original reported family were reported to have this feature which is often found in other spastic ataxia disorders, such as Friedreich's ataxia (229300).

Systemic Features: 

Ataxia in gait and limb motion with pyramidal signs is part of this disorder.  Deep tendon reflexes are increased and plantar responses are often extensor in direction.  Both pyramidal signs and the ataxia progress little.  Affected individuals begin walking late and often have slurred speech.  The IQ's in one family were measured to be less than 90.  CT scans have not revealed cerebellar atrophy.

Genetics

This condition is likely inherited in an autosomal dominant pattern based on one pedigree with 21 members in 4 generations and another with an affected mother and 3 of 5 affected children.  Nothing is known about the locus responsible.

Optic atrophy is also found in autosomal recessive SPAX4 (613672) and in an ill-defined autosomal recessive form of spastic ataxia with mental retardation (270500).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for this disorder.

References
Article Title: 
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