autosomal recessive

Spherophakia, Isolated

Clinical Characteristics

Ocular Features

Small, spherical lenses are characteristic of this entity.  Lenticular myopia is usually present but no increased axial length.  Glaucoma has been reported in several individuals and speculated to be due to pupillary block.  No buphthalmos or angle anomalies were present.  The lens may sublux into the vitreous cavity.

Systemic Features

No skeletal, cardiovascular or metabolic disease is present.

Genetics

Isolated spherophakia is an autosomal recessive disorder resulting from homozygous mutations in LTBP2 (13q24.1-q32.12).  Parental consanguinity was present in reported families. 

Spherophakia is a clinically and genetically heterogeneous disorder and usually found in association with systemic findings.  It is commonly seen in the Weill-Marchesani syndrome 1 (277600), in Weill Marchesani syndrome 2 (608328), in the Weill-Marchesani-Like syndrome (613195), in a condition known as ‘megalocornea, ectopia lentis, and spherophakia’ (?), another one called 'spherophakia and hernia' (157150), sulfite oxidase deficiency (272300), primary congenital glaucoma D (613086) and in a syndrome known as ‘spherophakia and metaphyseal dysplasia’ (157151).

Treatment Options

The lenses may require extraction for secondary glaucoma and/or visual rehabilitation.

References

Kumar A, Duvvari MR, Prabhakaran VC, Shetty JS, Murthy GJ, Blanton SH. A homozygous mutation in LTBP2 causes isolated microspherophakia. Hum Genet. 2010 Oct;128(4):365-71.

PubMed ID: 
20617341

Ben Yahia S, Ouechtati F, Jelliti B, Nouira S, Chakroun S, Abdelhak S, Khairallah M. Clinical and genetic investigation of isolated microspherophakia in a consanguineous Tunisian family. J Hum Genet. 2009 Sep;54(9):550-3.

PubMed ID: 
19696795

Weill-Marchesani-Like Syndrome

Clinical Characteristics

Ocular Features

Several families have been reported in which the ocular features were similar to Weill-Marchesani syndromes WMS1 and WMS2 but lacked most of the skeletal features.  The ocular abnormalities included: myopia, ectopia lentis, spherophakia, and glaucoma.  Shallow anterior chambers and peripheral iris synechiae are often present. Axial length ranges from 21 to 23 mm.

Systemic Features

Short stature is a feature of this syndrome but brachydactyly and decreased joint mobility are not present.  Height is usually below the 25th percentile and often at the third or 5th percentile.

 

Genetics

This is an autosomal recessive disorder resulting from mutations in ADAMTS17 (15q26.3).  See also Weill-Marchesani Syndrome 1 (277600), and Weill-Marchesani Syndrome 2 (608328) for other conditions with clinical similarities but caused by different mutations.

Homozygous mutations in LTBP2 (14q24.3) have also been found in this disorder and in WMS1 (277600).

Treatment Options

Glaucoma requires the usual treatments.  The lens may need to be removed for visual rehabilitation and/or lens induced glaucoma.

References

Haji-Seyed-Javadi R, Jelodari-Mamaghani S, Paylakhi SH, Yazdani S, Nilforushan N, Fan JB, Klotzle B, Mahmoudi MJ, Ebrahimian MJ, Chelich N, Taghiabadi E, Kamyab K, Boileau C, Paisan-Ruiz C, Ronaghi M, Elahi E. LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum Mutat. 2012 Apr 26. doi: 10.1002/humu.22105. [Epub ahead of print] PubMed PMID: 22539340.

PubMed ID: 
22539340

Morales J, Al-Sharif L, Khalil DS, Shinwari JM, Bavi P, Al-Mahrouqi RA, Al-Rajhi A, Alkuraya FS, Meyer BF, Al Tassan N. Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Am J Hum Genet. 2009 Nov;85(5):558-68.

PubMed ID: 
19836009

Ataxia with Oculomotor Apraxia 1

Clinical Characteristics

Ocular Features

Patients with this disorder have difficulty initiating voluntary ocular movements upon command or when following targets (oculomotor apraxia).  Gaze changes are often initiated first by head thrusting, followed by saccadic eye movements.  One may test for this by holding the head whereupon the patient is unable to move the eyes.  Ocular apraxia is often evident a few years after symptoms of ataxia are noted and may progress to external ophthalmoplegia.  Most patients have exaggerated blinking.

Systemic Features

The ataxia is cerebellar in origin with onset usually in the first decade of life (mean age of onset 4.3 years. It is associated with peripheral axonal neuropathy and hypoalbuminemia. Gait imbalance is usually the first symptom followed by upper limb dysmetria.  Other variable signs include dysarthria, choreiform or athetoid movements, facial grimacing, tongue and limb fasciculations, areflexia, and distal sensory deficits.   All symptoms are progressive and ambulation is lost within a decade of onset.  Cerebellar atrophy may be seen on MRI and the EMG shows evidence of axonal neuropathy.  Mental function is normal in most patients but some have cognitive impairments.

Genetics

Mutations in the APTX gene (9p21.1) encoding aprataxin are responsible for this autosomal recessive condition. 

There is evidence of clinical and genetic heterogeneity.  At least two loci are involved, with the mutation at 9p13 causing an earlier onset of disease (first decade), and hypoalbuminemia, while the second one, ataxia with oculomotor apraxia 2  [606002]) at 9q34 causes a disorder of later onset (2nd or third decade) in which oculomotor apraxia is an inconsistent finding.  Oculomotor apraxia is more consistently found in the disorder described here.  Cogan-type oculomotor apraxia (257550) lacks other neurologic signs.

Oculomotor apraxia may be the presenting sign in Gaucher disease (230800, 230900, 231000). 

The ocular phenotype is similar to that seen in ataxia-telangiectasia (208900).

Treatment Options

No specific treatment is available although physical therapy can be helpful.

References

Amouri R, Moreira MC, Zouari M, El Euch G, Barhoumi C, Kefi M, Belal S, Koenig M, Hentati F. Aprataxin gene mutations in Tunisian families. Neurology. 2004 Sep 14;63(5):928-9.

PubMed ID: 
15365154

Barbot C, Coutinho P, Chor?PSo R, Ferreira C, Barros J, Fineza I, Dias K, Monteiro J, Guimar?PSes A, Mendon?ssa P, do C?(c)u Moreira M, Sequeiros J. Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. Arch Neurol. 2001 Feb;58(2):201-5.

PubMed ID: 
11176957

Retinitis Pigmentosa with Ataxia

Clinical Characteristics

Ocular Features

Pigmentary retinopathy has been noted by 6 months of age. Typical symptoms of retinitis pigmentosa are reported by early childhood.  The visual fields are progressively constricted and a ring scotoma can be plotted.  Night blindness and visual acuity loss are evident in the first decade of life and progressively worsen leading to severe handicaps by the third.  Fundus pigmentation in the midperiphery becomes more prominent and in at least some patients the pattern consists of typical bone spicules.  Cellophane maculopathy has been described.

Systemic Features

Proprioceptive deficits and areflexia appear in early childhood and ataxia worsens as individuals mature.  Scoliosis and general weakness and wasting become prominent manifestations.  Sensory neuropathy with loss of vibratory and position sense, astereognosia, and agraphesthesia can become apparent in the first decade of life.  Walking is delayed and gait abnormalities are clearly evident by the second decade leading to orthopedic deformities such as scoliosis.  Unassisted walking becomes impossible.  The intrinsic hand and foot muscles also have mild weakness.  Sural nerve biopsy may reveal loss of large myelinated fibers.  Hyperintense signals in the posterior spinal columns can be seen on MRI.  No anatomic changes have been described in the cerebrum or cerebellum.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in FLVCR1 (1q32.2-q41).  This disorder has some clinical similarities to Biemond 1 syndrome but differs in the inheritance pattern and the molecular basis.

Treatment Options

No specific treatment is available but physical therapy and low vision aids may improve the quality of life.

References

Rajadhyaksha AM, Elemento O, Puffenberger EG, Schierberl KC, Xiang JZ, Putorti ML, Berciano J, Poulin C, Brais B, Michaelides M, Weleber RG, Higgins JJ. Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa. Am J Hum Genet. 2010 Nov 12;87(5):643-54.

PubMed ID: 
21070897

Higgins JJ, Morton DH, Patronas N, Nee LE. An autosomal recessive disorder with posterior column ataxia and retinitis pigmentosa. Neurology. 1997 Dec;49(6):1717-20.

PubMed ID: 
9409377

Megalocornea, Ectopia Lentis, and Spherophakia

Clinical Characteristics

Ocular Features

Patients have megalocornea and mobile lenses.  Corneal diameters are at least 13 mm in diameter.  Some lenses are spherophakic (refractive errors may be in the +11-12 diopter range) and sometimes displace into the anterior chamber or cause pupillary block glaucoma.  The clinical picture often resembles congenital glaucoma in young children but the elevated pressure is usually secondary to hypermobility of the lens and/or its spherical shape.  Haab striae are not present but cloudy corneas have been reported in a few patients.

Many patients develop phthisis or have severe reductions in vision.

Systemic Features

Some but not all patients have several physical features of the Marfan syndrome (154700) such as high arched palate, tall stature, and narrow face but those tested do not have mutations in the FBN1 gene.

Genetics

This is an autosomal recessive disorder.  Parental consanguinity is common.  Homozygous mutations in the LTBP2 gene (14q24.3) are found in affected individuals.

LTBP2 competes with LTBP1 (ADAMTSL2) for binding to the gene product of FBN1 in which mutations are associated with the Marfan syndrome (154700) and may account for the variable skeletal signs sometimes found in patients with this megalocornea syndrome.  Both gene products are important to the structure of the extracellular matrix proteins of the ciliary processes, lens capsule, and lens epithelial layer.  The different modes of inheritance and the unique mutations, of course, argue for separateness of the two disorders.

Mutations in LTBP2 have also been found in a family with microspherophakia and ectopia lentis but corneal diameters were described as normal suggesting clinical heterogeneity.

This is a unique disorder which previously has been classified as Glaucoma, Congenital Primary D (613086).  The usual occurrence of ectopia lentis,  the sometimes spherophakic nature of the lenses, the congenital presence of megalocornea without corneal edema in the absence of elevated intraocular pressure, and the lack of breaks in the Descemet membrane strongly suggest that this is not a primary congenital glaucoma.

Treatment Options

Urgent lensectomy is necessary for lenses that migrate into the anterior chamber.  Patients have to be monitored as lens dislocations can occur at any age.

References

Khan AO, Aldahmesh MA, Alkuraya FS. Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma - a distinct phenotype caused by recessive LTBP2 mutations. Mol Vis. 2011;17:2570-9.

PubMed ID: 
22025892

D?(c)sir J, Sznajer Y, Depasse F, Roulez F, Schrooyen M, Meire F, Abramowicz M. LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea,spherophakia, and secondary glaucoma. Eur J Hum Genet. 2010 Jul;18(7):761-7.

PubMed ID: 
20179738

Kumar A, Duvvari MR, Prabhakaran VC, Shetty JS, Murthy GJ, Blanton SH. A homozygous mutation in LTBP2 causes isolated microspherophakia. Hum Genet. 2010 Oct;128(4):365-71.

PubMed ID: 
20617341

Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy AL, Azmanov D, Tournev I, Cherninkova S, Jafri H, Raashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, Inglehearn CF. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet. 2009 May;84(5):664-71.

PubMed ID: 
19361779

Microphthalmia, AR

Clinical Characteristics

Ocular Features

The most consistent feature associated with mutations in the VSX2 gene is, of course, microphthalmia/anophthalmia.  Other anomalies include dysplasia of the retina, cataracts and/or dislocated lenses, and iris anomalies ranging from hypoplasia to colobomas and absence of the pupils. Colobomas may also involve the posterior uveal tract as well as the optic nerve. The majority of patients are blind.   

Systemic Features

No systemic features are associated.

Genetics

This is an autosomal recessive disorder resulting from mutations in the VSX2 (formerly CHX10) gene located at 14q24.3.  The gene is expressed in progenitor cells of the developing neuroretina and in inner nuclear cells of the adult retina.   Most parents are consanguineous.

Treatment Options

None other than rehabilitation.

References

Reis LM, Khan A, Kariminejad A, Ebadi F, Tyler RC, Semina EV. VSX2 mutations in autosomal recessive microphthalmia. Mol Vis. 2011;17:2527-32.

PubMed ID: 
2197693

Bar-Yosef U, Abuelaish I, Harel T, Hendler N, Ofir R, Birk OS. CHX10 mutations cause non-syndromic microphthalmia/ anophthalmia in Arab and Jewish kindreds. Hum Genet. 2004 Sep;115(4):302-9.

PubMed ID: 
15257456

Zlotogora J, Legum C, Raz J, Merin S, BenEzra D. Autosomal recessive colobomatous microphthalmia. Am J Med Genet. 1994 Feb 1;49(3):261-2.

PubMed ID: 
8209881

Brittle Cornea Syndrome 2

Clinical Characteristics

Ocular Features

Corneal thinning and extreme fragility are characteristic of BCS2.  Ruptures of the cornea may occur with minimal trauma and repair is often unsatisfactory due to the lack of healthy tissue.  Keratoconus, acute hydrops, keratoglobus, and high myopia are frequently present as well.  Some patients have sclerocornea that obscures the normal limbal landmarks.  The sclera is also thin and the underlying uveal tissue imparts a bluish discoloration to the globe which is especially evident in the area overlying the ciliary body creating what some call a blue halo.

Systemic Features

Skin laxity with easy bruisability, pectus excavatum, scoliosis, congenital hip dislocation, a high arched palate, mitral valve prolapse and recurrent shoulder dislocations are often present.  Hearing impairment with mixed sensorineural/conductive defects is common.

Genetics

This autosomal recessive disorder results from homozygous mutations in PRDM5 (4q27).  Heterozygous carriers may have blue sclerae, small joint hypermobility, and mild thinning of the central cornea. 

BCS2 has many clinical similarities to brittle cornea syndrome 1 (229200) which results from homozygous mutations in ZNF469.

Treatment Options

Treatment for specific defects such as joint dislocations and mitral valve malfunction may be helpful.

References

Burkitt Wright EM, Porter LF, Spencer HL, Clayton-Smith J, Au L, Munier FL, Smithson S, Suri M, Rohrbach M, Manson FD, Black GC. Brittle cornea syndrome: recognition, molecular diagnosis and management. Orphanet J Rare Dis. 2013 May 4;8(1):68. [Epub ahead of print]

PubMed ID: 
23642083

Burkitt Wright EM, Spencer HL, Daly SB, Manson FD, Zeef LA, Urquhart J, Zoppi N, Bonshek R, Tosounidis I, Mohan M, Madden C, Dodds A, Chandler KE, Banka S, Au L, Clayton-Smith J, Khan N, Biesecker LG, Wilson M, Rohrbach M, Colombi M, Giunta C, Black GC. Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. Am J Hum Genet. 2011 Jun 10;88(6):767-77. Erratum in: Am J Hum Genet. 2011 Aug 12;89(2):346.

PubMed ID: 
21664999

Aldahmesh MA, Mohamed JY, Alkuraya FS. A novel mutation in PRDM5 in brittle cornea syndrome. Clin Genet. 2011 Nov 29. doi: 10.1111/j.1399-0004.2011.01808.x. [Epub ahead of print]

PubMed ID: 
22122778

Chorioretinopathy with Microcephaly 1

Clinical Characteristics

Ocular Features

The ocular features have not been well described.  Small corneas, hyperopia, pale optic nerves and a variety of pigmentary changes in the retina have been reported.  The latter may consist of diffuse, fine or granular pigmentary changes.  Areas of pigmentary atrophy are often associated with patchy areas of pigmentary clumping.  These changes are usually located posterior to the equator.  Choroidal vessels may be sparse where the RPE is absent.  It has been suggested that the patchy pattern of retinal pigmentation resembles ocular toxoplasmosis.  Strabismus is common.  One report suggests microphthalmos in a patient.  Vision has been reported as subnormal from the first year of life but no quantitative data are available.

Systemic Features

Microcephaly is a consistent feature.  The forehead is steeply sloped but facial size appears normal.  The palate is highly arched.  Patients often have hyperactive deep tendon reflexes and walk with a shuffling gait.  Children are often hyperactive and highly social.  Intelligence quotients are usually subnormal. No lymphedema has been reported.  At least some patients have cutis marmorata.

On MRI diffuse pachygryria is seen.  The vermis is hypoplastic and the surface area of the corpus callosum is reduced to half of normal. 

Genetics

Parental consanguinity was present in two reported families and pedigrees suggest autosomal recessive inheritance with homozygosity of TUBGCP6 (22p22) responsible.

This presumed recessive disorder appears to be different than the autosomal dominant disorder of lymphedema, microcephaly, and chorioretinal dysplasia  (MCLMR(152950) although molecular confirmation is lacking.

For somewhat similar disorder see Chorioretinopathy with Microcephaly 2 (616171) and Chorioretinopathy with Microcephaly 1.

Treatment Options

Treatment is supportive.

References

Puffenberger EG, Jinks RN, Sougnez C, Cibulskis K, Willert RA, Achilly NP, Cassidy RP, Fiorentini CJ, Heiken KF, Lawrence JJ, Mahoney MH, Miller CJ, Nair DT, Politi KA, Worcester KN, Setton RA, Dipiazza R, Sherman EA, Eastman JT, Francklyn C, Robey-Bond S, Rider NL, Gabriel S, Morton DH, Strauss KA. Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS One. 2012;7(1):e28936. Epub 2012 Jan 17. PubMed PMID: 22279524.

PubMed ID: 
22279524

Puffenberger EG, Jinks RN, Sougnez C, Cibulskis K, Willert RA, Achilly NP, Cassidy RP, Fiorentini CJ, Heiken KF, Lawrence JJ, Mahoney MH, Miller CJ, Nair DT, Politi KA, Worcester KN, Setton RA, Dipiazza R, Sherman EA, Eastman JT, Francklyn C, Robey-Bond S, Rider NL, Gabriel S, Morton DH, Strauss KA. Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS One. 2012;7(1):e28936. Epub 2012 Jan 17. PubMed PMID: 22279524.

PubMed ID: 
22279524

Cant?? JM, Rojas JA, Garc??a-Cruz D, Hern?degndez A, Pag?degn P, Fragoso R, Manzano C. Autosomal recessive microcephaly associated with chorioretinopathy. Hum Genet. 1977 Apr 15;36(2):243-7.

PubMed ID: 
870417

McKusick VA, Stauffer M, Knox DL, Clark DB. Chorioretinopathy with hereditary microcephaly. Arch Ophthalmol. 1966 May;75(5):597-600.

PubMed ID: 
5936364

Ectopia lentis, Isolated AR

Clinical Characteristics

Ocular Features

Most dislocated lenses of non-traumatic origin are associated with syndromes, particularly those with defective connective tissue.  However, a few families with dislocated lenses have been reported in which no evidence of defective collagen is present.  The lens is most commonly displaced temporally, often creating myopic astigmatism.  The mean age of discovery of the dislocated lenses is about 2 years of age.  The eye is otherwise normally formed, intraocular pressure is normal, and the axial length is in the normal range.  The cornea, pupil, and iris are normal unlike that found in many patients with ectopia lentis et pupillae (225200).

Systemic Features

None by definition.

Genetics

Homozygous nonsense mutations in ADAMTSL4 (1q21.3) are responsible for this autosomal recessive condition.  The same gene is mutated in ectopia lentis et pupillae (225200).  A patient has been reported with craniosynostosis and ectopia lentis in which there was a homozygous 20 bp deletion in this gene.

An autosomal dominant condition of isolated dislocated lenses (129600) secondary to a mutation in FBN1 has also been reported.

Treatment Options

Lens removal may be indicated when vision cannot otherwise be corrected.

References

Chandra A, Aragon-Martin JA, Sharif S, Parulekar M, Child A, Arno G. Craniosynostosis with Ectopia Lentis and a Homozygous 20-base Deletion in ADAMTSL4. Ophthalmic Genet. 2012 Aug 7. [Epub ahead of print].

PubMed ID: 
22871183

Ahram D, Sato TS, Kohilan A, Tayeh M, Chen S, Leal S, Al-Salem M, El-Shanti H. A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet. 2009 Feb;84(2):274-8.

PubMed ID: 
19200529

al-Salem M. Autosomal recessive ectopia lentis in two Arab family pedigrees. Ophthalmic Paediatr Genet. 1990 Jun;11(2):123-7.

PubMed ID: 
2377351

Microphthalmia with Limb Anomalies

Clinical Characteristics

Ocular Features

Patients have either microphthalmia or anophthalmia which may be present unilaterally or bilaterally.  The MRI in several patients has revealed complete absence of the globes, optic nerves, chiasm, and optic tracts.  The eyelashes are often sparse with shortened palpebral fissures and broad lateral eyebrows.

Systemic Features

Global developmental delays, failure to thrive, and mild to moderate mental retardation are common.   Syndactyly, polydactyly, and oligodactyly with hypoplasia of the long bones are present to a variable degree.  Synostosis in the digits, ankles, and wrist is often seen.  A split hand (lobster-claw deformity) is variably present.  Other anomalies such as the kidneys (horseshoe kidney), undescended testes, anomalous venous circulation and deformed vertebrae have been reported.  The midface is often flattened.  A high palate, cleft lip, and mild scoliosis may be seen.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the SMOC1 gene (14q24.2) but there is some evidence of genetic heterogeneity as the disorder has been mapped to 10p11.23 in several families.  However, no causative mutations were found in this region.  Consanguinity among parents is common.

Treatment Options

There is no treatment in most cases for the ocular malformations.  Some of the limb anomalies may be surgically correctable.

References

Abouzeid H, Boisset G, Favez T, Youssef M, Marzouk I, Shakankiry N, Bayoumi N, Descombes P, Agosti C, Munier FL, Schorderet DF. Mutations in the SPARC-related modular calcium-binding protein 1 gene, SMOC1, cause waardenburg anophthalmia syndrome. Am J Hum Genet. 2011 Jan 7;88(1):92-8.

PubMed ID: 
21194680

Okada I, Hamanoue H, Terada K, Tohma T, Megarbane A, Chouery E, Abou-Ghoch J, Jalkh N, Cogulu O, Ozkinay F, Horie K, Takeda J, Furuichi T, Ikegawa S, Nishiyama K, Miyatake S, Nishimura A, Mizuguchi T, Niikawa N, Hirahara F, Kaname T, Yoshiura K, Tsurusaki Y, Doi H, Miyake N, Furukawa T, Matsumoto N, Saitsu H. SMOC1 is essential for ocular and limb development in humans and mice. Am J Hum Genet. 2011 Jan 7;88(1):30-41.

PubMed ID: 
21194678

Hamanoue H, Megarbane A, Tohma T, Nishimura A, Mizuguchi T, Saitsu H, Sakai H, Miura S, Toda T, Miyake N, Niikawa N, Yoshiura K, Hirahara F, Matsumoto N. A locus for ophthalmo-acromelic syndrome mapped to 10p11.23. Am J Med Genet A. 2009 Mar;149A(3):336-42.

PubMed ID: 
19208380