autosomal recessive

Albinism, Oculocutaneous, Type IV

Clinical Characteristics

Ocular Features

The ocular manifestations in type IV oculocutaneous albinism are similar to those of other types.  Nystagmus, strabismus, misrouting of neuronal axons, and foveal hypoplasia are prominent features although there is some clinical heterogeneity among patients.  Nystagmus may not be present at birth but is almost always evident by 3-4 months of age.  The iris may be pale blue or tan and does not generally darken with age.  Poor stereopsis is common.  Vision is stable after childhood and usually in the range of 20/100-20/400. 

Systemic Features

Hair color is generally intermediate between white and brown but many patients have only white hair and in others the hair is brown.  Little darkening occurs as patients become older.  The skin is often white or creamy yellow. 

Genetics

This type of oculocutaneous albinism is one of the more common types found among Japanese and maybe Chinese individuals although it has been reported in German and Turkish individuals.  This is an extremely rare autosomal recessive form of albinism caused by mutations in the MATP (SLC45A2) gene located at 5p13.3. 

Other types include OCA1 (203100, 606952 ), OCA2 (203200 ), OAC3 (203290), OAC5 (615179), and OCA6 (113750)..

Treatment Options

There is no treatment for the hypopigmentation.  Low vision aids and tinted lenses may help some patients.  Exposure to the sun should be limited. 

References

Gr√∏nskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis. 2007 Nov 2;2:43. Review.

PubMed ID: 
17980020

Inagaki K, Suzuki T, Shimizu H, Ishii N, Umezawa Y, Tada J, Kikuchi N, Takata M, Takamori K, Kishibe M, Tanaka M, Miyamura Y, Ito S, Tomita Y. Oculocutaneous albinism type 4 is one of the most common types of albinism in Japan. Am J Hum Genet. 2004 Mar;74(3):466-71.

PubMed ID: 
14961451

Rundshagen U, Zühlke C, Opitz S, Schwinger E, Käsmann-Kellner B. Mutations in the MATP gene in five German patients affected by oculocutaneous albinism type 4. Hum Mutat. 2004 Feb;23(2):106-10.

PubMed ID: 
14722913

Albinism, Oculocutaneous, Type II

Clinical Characteristics

Ocular Features

The iris and retina lack normal pigmentation and translucency of the iris can be demonstrated.  Anomalous decussation of neuronal axons in the chiasm and foveal hypoplasia result in decreased visual acuity.  Vision loss into the range of 20/100-20/200 does not progress after early childhood but is sometimes as good as 20/30.   Nystagmus is often present from about 3-4 months of age although it is less severe than in type I oculocutaneous albinism (203100, 606952).  The iris may darken to some extent with age.  Strabismus has been reported.  Significant refractive errors are often present and stereopsis is reduced.  The VEP responses are altered and can be used to document abnormal chiasmal decussation. 

Systemic Features

Melanin pigment is reduced in the skin and hair as well as the eyes.  Individuals at birth may be misdiagnosed as OCA type I but it is common for pigmentation to increase in older individuals resulting in yellow or reddish-blond hair and the appearance of freckles and nevi.  The skin may be creamy-white but this is often not as striking as in OCAI.  It is possible for tanning to take place in some patients.  This condition in Africans or African Americans is sometimes called brown oculocutaneous albinism (BOCA).  There is an increased risk of skin cancer of all types. 

Genetics

Type II is the most common type of oculocutaneous albinism and is especially prevalent among individuals of African heritage and in several Native American populations.  It is an autosomal recessive condition caused by homozygous 2.7 kb deletions in the OCA2 gene (15q24.3-q12).  Heterozygotes have normal pigmentation. 

Oculocutaneous albinism type I (203100, 606952) is a separate disorder with many similar features caused by mutations in the TYR gene.  Other types of autosomal recessive albinism are OCA3 (203290 ), and OCA4 (606574). 

Treatment Options

No treatment is available for the hypopigmentation.  Low vision aids can be helpful. Significant refractive errors should, of course, be corrected and dark lenses may be helpful during outdoor activities. The skin should be protected from excessive sun exposure. 

References

Oetting WS, King RA. Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Hum Mutat. 1999;13(2):99-115. Review.

PubMed ID: 
10094567

Summers CG. Vision in albinism. Trans Am Ophthalmol Soc. 1996;94:1095-155.

PubMed ID: 
8981720

Durham-Pierre D, Gardner JM, Nakatsu Y, King RA, Francke U, Ching A, Aquaron R, del Marmol V, Brilliant MH. African origin of an intragenic deletion of the human P gene in tyrosinase positive oculocutaneous albinism. Nat Genet. 1994 Jun;7(2):176-9.

PubMed ID: 
7920637

Gr√∏nskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis. 2007 Nov 2;2:43. Review.

PubMed ID: 
17980020

Tyrosinemia, Type II

Clinical Characteristics

Ocular Features

Keratitis is the outstanding ocular manifestation but not all patients have corneal involvement.  Symptoms include photophobia, pain, tearing, and redness which may occur as early as one year of age.  Corneal neovascularization, ulceration and scarring may lead to decreased visual acuity.  Linear and star-like corneal opacities in the epithelium resembling dendrites (pseudodendritic keratitis) have been described together with thickening of the conjunctiva.  The corneal lesions do not stain.  The conjunctival epithelium, fibrocytes, and blood vessel endothelial cells contain an accumulation of large inclusion bodies and tyrosine crystal-like structures. 

Systemic Features

Hydroxyphenylpyruvic acid is elevated in the urine and serum tyrosine levels are increased as the result of a defect in tyrosine aminotransferase.  Some patients have severe mental and somatic retardation.  The palms and soles can have painful punctate keratosis which may extend to the digits.  Developmental milestones such as walking are often delayed.  The keratotic lesions may be up to 2 cm in size. 

Genetics

Tyrosinemia type II is an autosomal recessive disorder caused by mutations in the tyrosine aminotransferase (TAT) gene at 16q22.1-q22.3. 

Treatment Options

The hyperkeratosis and corneal opacities may improve with a diet low in phenylalanine and tyrosine but can recur after liberalization of the diet.  Benefits, if any, on CNS symptoms are unknown. 

References

Rabinowitz LG, Williams LR, Anderson CE, Mazur A, Kaplan P. Painful keratoderma and photophobia: hallmarks of tyrosinemia type II. J Pediatr. 1995 Feb;126(2):266-9. Review.

PubMed ID: 
7844676

Reh√°k A, Selim MM, Yadav G. Richner-Hanhart syndrome (tyrosinaemia-II) (report of four cases without ocular involvement). Br J Dermatol. 1981 Apr;104(4):469-75.

PubMed ID: 
6453606

Bienfang DC, Kuwabara T, Pueschel SM. The Richner-Hanhart syndrome: report of a case with associated tyrosinemia. Arch Ophthalmol. 1976 Jul;94(7):1133-7.

PubMed ID: 
180943

Microphthalmia with Coloboma, AD

Clinical Characteristics

Ocular Features

Isolated colobomatous microphthalmia is uncommon compared with the syndromal conditions of which there are more than 100.  The clinical findings are confined to the eye in this condition.  The globe is abnormally small (defined by some as less than 20 mm in length in at least one eye).   Incomplete penetrance and variable expression are typical but often the cornea is small and may be cloudy with anterior synechiae suggesting that anterior chamber dysgenesis may also be a feature in some cases.  One or both eyes may be involved.  Visual acuity depends on the structures involved.

It is not uncommon for other ocular abnormalities to occur in association with the malformed globes, such as cataracts, microcornea, sclerocornea and optic nerve dysplasia. 

Systemic Features

None.

Genetics

The majority of isolated microphthalmos with coloboma are inherited in an autosomal dominant pattern [see also microphthalmia with coloboma, X-linked (MCOPCB1; 300345)].  Reports are mostly of single kinships.  At least 5 additional genes are involved: MCOPCB2 (605738) results from mutations in a locus at 15q12-q15, MCOPCB3 (610092) is caused by mutations in the CHX10 (VSX2) gene (14q24), MCOPCB4 (251505) frequently has a cystic malformation as well and is likely an autosomal recessive condition but the mutation and its location remain unknown, MCOPCB5 (611638) is caused by a mutation in SHH (7q36), and MCOPCB6 (613703) results from mutations in the GDF3 gene (12p13.1).

For an X-linked form of non-syndromic microphthalmia with coloboma, see Microphthalmia with Coloboma (300345 ).  For a syndromal form of X-linked microphthalmia, see Microphthalmia, Syndromic 1 (309800 ). 

Treatment Options

No treatment is available for the basic malformation. 

References

Michon L, Morlé L, Bozon M, Duret L, Zech JC, Godet J, Plauchu H, Edery P. Physical and transcript map of the autosomal dominant colobomatous microphthalmia locus on chromosome 15q12-q15 and refinement to a 4.4 Mb region. Eur J Hum Genet. 2004 Jul;12(7):574-8.

PubMed ID: 
15083168

Schimmenti LA, de la Cruz J, Lewis RA, Karkera JD, Manligas GS, Roessler E, Muenke M. Novel mutation in sonic hedgehog in non-syndromic colobomatous microphthalmia. Am J Med Genet A. 2003 Jan 30;116A(3):215-21.

PubMed ID: 
12503095

Hornby SJ, Adolph S, Gilbert CE, Dandona L, Foster A. Visual acuity in children with coloboma: clinical features and a new phenotypic classification system. Ophthalmology. 2000 Mar;107(3):511-20.

PubMed ID: 
10711890

Choroidal Dystrophy, Central Areolar

Clinical Characteristics

Ocular Features

The primary feature of this form of macular dystrophy is atrophy of the RPE and choriocapillaris in the central macula.  In early stages among young patients in the second decade of life, some pigment changes are seen in the parafoveal area.  Later, the central macula develops hypopigmentation followed by atrophy of the choriocapillaris.  The area is usually sharply defined but fluorescein angiography often shows multiple window defects beyond the edges.  The same region often has speckled autofluorescence.  Secondary dysfunction of the photoreceptors in this area leads to some mild degree of vision loss in adults between the ages of 30 and 60 years but this progressive disease may eventually result in legal blindness.  The ERG demonstrates a cone dystrophy. The rate of disease progression is highly variable.  Visual acuity varies considerably as does the appearance of the macula.  Older individuals may be misdiagnosed as having age-related macular degeneration. 

Systemic Features

There is no associated systemic disease. 

Genetics

This is a genetically heterogeneous disorder with mutations in several genes responsible.  The majority of patients have one of several mutations in the PRPH2 gene (6p21.1-cen) and the inheritance pattern seems to be autosomal recessive (CACD2).  Other family trees in which mutations in PRPH2 were excluded suggest autosomal dominant inheritance (CACD3; 613144).  CACD1 is caused by an unknown mutation localized to 17p13. 

Treatment Options

There is no treatment of the macular disease.  However, some patients can benefit from low vision aids. 

References

Ouechtati F, Belhadj Tahar O, Mhenni A, Chakroun S, Chouchene I, Oueslati S, Rebai A, Abdelhak S, Jeddi-Blouza A. Central areolar choroidal dystrophy associated with inherited drusen in a multigeneration Tunisian family: exclusion of the PRPH2 gene and the 17p13 locus. J Hum Genet. 2009 Oct;54(10):589-94.

PubMed ID: 
19696794

Boon CJ, Klevering BJ, Cremers FP, Zonneveld-Vrieling MN, Theelen T, Den Hollander AI, Hoyng CB. Central areolar choroidal dystrophy. Ophthalmology. 2009 Apr;116(4):771-82, 782.e1.

PubMed ID: 
19243827

Lotery AJ, Ennis KT, Silvestri G, Nicholl S, McGibbon D, Collins AD, Hughes AE. Localisation of a gene for central areolar choroidal dystrophy to chromosome 17p. Hum Mol Genet. 1996 May;5(5):705-8.

PubMed ID: 
8733141

Conjunctivitis, Ligneous

Clinical Characteristics

Ocular Features

The most common clinical feature of this disorder is conjunctivitis often precipitated by an injury or infection of the conjunctiva with typical inflammatory features.   A thick, ligneous (wood-like) pseudomembrane containing clotted fibrin subsequently forms that appears white, yellow-white, or finally red.  These can be surgically removed but tend to recur, often on an accelerated timescale.  This process is most pronounced on the upper tarsal conjunctiva but often involves the bulbar conjunctiva and the cornea as well.  Corneal involvement (in nearly a third of cases) can lead to vascularization, scarring, keratomalacia, and perforation.  The disease may be intermittent. 

Systemic Features

While the conjunctiva is most commonly involved, other mucosal surfaces such as oral, laryngeal, tracheal, and vaginal mucosas may have similar disease often concomitantly with the ocular lesions.  Ligneous gingivitis consists of nodular lesions with ulceration and peridodontal tissue destruction.  The ear may also be involved in the disease.   Life-threatening airway obstruction is a threat, especially in children during acute recurrences.  Occlusive hydrocephalus requiring shunting occurs in a significant number of affected children. 

Genetics

This condition seems to result from homozygous mutations in the PLG gene (6q26) that codes for plasminogen and therefore is inherited in an autosomal recessive pattern.  Tears contain plasminogen activators that convert plasminogen into the fibrinolytic enzyme plasmin which normally clears conjunctival and corneal fibrin deposits.  The lack of normal plasminogen allows fibrin to accumulate on all mucosal surfaces. 

Treatment Options

A variety of topical treatments have been tried with plasminogen being the most promising. This treatment if given systemically may also be beneficial in disseminated disease.  Surgical excision of the pseudomembrane is possible but multiple recurrences are common.  Spontaneous resolution has been reported. 

References

Sivolella S, De Biagi M, Sartori MT, Berengo M, Bressan E. Destructive Membranous Periodontal Disease (Ligneous Gingivitis): A Literature Review. J Periodontol. 2011 Aug 22. [Epub ahead of print)

PubMed ID: 
21859319

Schuster V, Seregard S. Ligneous conjunctivitis. Surv Ophthalmol. 2003 Jul-Aug;48(4):369-88. Review.

PubMed ID: 
12850227

Schott D, Dempfle CE, Beck P, Liermann A, Mohr-Pennert A, Goldner M, Mehlem P, Azuma H, Schuster V, Mingers AM, Schwarz HP, Kramer MD. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. N Engl J Med. 1998 Dec 3;339(23):1679-86.

PubMed ID: 
9834305

Jalili Syndrome

Clinical Characteristics

Ocular Features

Symptoms of photophobia and reduced vision are present in the first years of life.  Pendular nystagmus is common.  Color vision is defective and is characterized by some as a form of achromatopsia, perhaps better described as dyschromatopsia.  Reduced night vision is noted by the end of the first decade of life.  OCT reveals reduced foveal and retinal thickness.  The macula appears atrophic with pigment mottling and the peripheral retina can resemble retinitis pigmentosa with bone spicule pigment changes.  Retinal vessels may be narrow.  The ERG show reduced responses in both photopic and scotopic recordings.  This form of rod-cone dystrophy is progressive with central acuity decreasing with age. 

Systemic Features

The teeth are abnormally shaped and discolored from birth.  The amelogenesis imperfecta consists of hypoplasia and hypomineralization that is present in both deciduous and permanent teeth.  Tooth enamel is mineralized only to 50% of normal and is similar to that of dentine. 

Genetics

This is an autosomal recessive condition caused by mutations in the CNNM4 gene at 2q11.2. 

Treatment Options

No treatment is available for the ocular condition but red-tinted lenses and low vision aids may be helpful.  The teeth require dental repair. 

References

Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, Bloch-Zupan A, Carlos R, Carr IM, Downey LM, Blain KM, Mansfield DC, Shahrabi M, Heidari M, Aref P, Abbasi M, Michaelides M, Moore AT, Kirkham J, Inglehearn CF. Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta. Am J Hum Genet. 2009 Feb;84(2):266-73.

PubMed ID: 
19200525

Jalili IK, Smith NJ. A progressive cone-rod dystrophy and amelogenesis imperfecta: a new syndrome. J Med Genet. 1988 Nov;25(11):738-40.

PubMed ID: 
3236352

Septooptic Dysplasia

Clinical Characteristics

Ocular Features

Optic nerve hypoplasia is most characteristic ocular feature of this syndrome.  It may be bilateral but often is unilateral.  The hypoplastic nerve head can have a ‘double margin’.  The outer ring consists of the junction of the sclera with the lamina cribrosa while the inner margin is darker and represents the junction of the RPE with the abnormally small nerve containing less than the normal number of axons.  Visual acuity depends upon the degree of nerve hypoplasia.  Nystagmus and strabismus may be present. 

Systemic Features

Midline brain defects are common.  This usually consists of an absent septum pellucidum but sometimes absence or thinning of the corpus callosum as well.  An ‘empty sella’ with a dysplastic pituitary gland and deficiencies in hormone output can be present.  Hypoglycemia, hypogonadism, short stature and corticotrophin deficiency may result.  There is considerable clinical heterogeneity and few patients have all of these features.  Only 29% of patients have the full spectrum of brain, optic nerve, and pituitary abnormalities.  It has been proposed that the severity of the brain midline defects can be correlated with the degree of endocrinopathy.  Mental retardation and features of autism spectrum disorders may be present.

A few patients have been reported with skeletal deformities such as syndactyly and hypoplastic digits.  Rare males have underdeveloped genitalia. 

Genetics

The majority of cases occur sporadically.  Among rare cases with a family history, homozygosity of a mutation in the HESX1 gene (3p21.2-p21.1) has been found suggesting an autosomal recessive etiology.  It seems likely that there remains considerable genetic heterogeneity and it is doubtful that septooptic dysplasia is a unique disorder.  

Bilateral optic nerve hypoplasia (165550) also occurs without the CNS malformations but it results from a different mutation.

Treatment Options

All patients with optic nerve hypoplasia should be evaluated for midline brain anomalies and endocrinopathy.  There is no treatment for the optic nerve hypoplasia but low vision aids could be helpful in selected cases with bilateral nerve dysplasia.  The hormonal deficiencies, of course, need to be corrected with appropriate replacements. 

References

Garcia-Filion P, Borchert M. Optic Nerve Hypoplasia Syndrome: A Review of the Epidemiology and Clinical Associations. Curr Treat Options Neurol. 2012 Dec 13. [Epub ahead of print].

PubMed ID: 
23233151

McNay DE, Turton JP, Kelberman D, Woods KS, Brauner R, Papadimitriou A, Keller E, Keller A, Haufs N, Krude H, Shalet SM, Dattani MT. HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. J Clin Endocrinol Metab. 2007 Feb;92(2):691-7.

PubMed ID: 
17148560

Birkebaek NH, Patel L, Wright NB, Grigg JR, Sinha S, Hall CM, Price DA, Lloyd IC, Clayton PE. Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab. 2003 Nov;88(11):5281-6.

PubMed ID: 
14602752

Carvalho LR, Woods KS, Mendonca BB, Marcal N, Zamparini AL, Stifani S, Brickman JM, Arnhold IJ, Dattani MT. A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. J Clin Invest. 2003 Oct;112(8):1192-201.

PubMed ID: 
14561704

EEM Syndrome

Clinical Characteristics

Ocular Features

Granular pigmentation and a grayish coloration of the retina may be present.  The peripheral retina usually appears normal but the posterior pole and macula have pigmentary changes consisting of clumping and geographic atrophy.  Fluorescein angiography shows patchy areas of hyperfluorescence.  Patients in their 30s have been reported to have normal ERGs in one study.  Reduced acuity can be noted in the first decade but progression is slow.  Acuity levels in the 20/200 range may be seen in the fourth decade of life. 

Systemic Features

Ectodermal dysplasia with ectrodactyly and syndactyly are prominent features of this syndrome.  Hypotrichosis of the scalp, eyebrows and eyelashes is often seen.  Partial anodontia and diastema are also features.  Syndactyly of the toes is present more frequently than found among the fingers. 

Genetics

This is an autosomal recessive disorder resulting from mutations in the CDH3 gene (16q22.1).

EEM syndrome is allelic to the Hypotrichosis with Macular Dystrophy syndrome (601553).  However, the latter lacks the dental, limb, and digital anomalies as well as the hypotrichosis of eyebrows and eyelashes.  

Treatment Options

No treatment is available for this disease. 

References

Kjaer KW, Hansen L, Schwabe GC, Marques-de-Faria AP, Eiberg H, Mundlos S, Tommerup N, Rosenberg T. Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome). J Med Genet. 2005 Apr;42(4):292-8.

PubMed ID: 
15805154

Balarin Silva V, Simões AM, Marques-de-Faria AP. EEM syndrome: report of a family and results of a ten-year follow-up. Ophthalmic Genet. 1999 Jun;20(2):95-9.

PubMed ID: 
10420194

Hypotrichosis with Juvenile Macular Degeneration

Clinical Characteristics

Ocular Features

Macular dystrophy usually becomes symptomatic before the second decade of life but retinal evidence of macular degeneration can be seen in the first decade.   EOG is usually normal while the ERG responses are decreased early and with time decrease further in amplitude.  Pattern reversal VEPs are significantly subnormal even while vision is relatively good.  Visual acuity decreases slowly in spite of significant deterioration of cone- and rod-mediated retinal function.  Retinal pigmentary changes consisting of irregular clumping and areas of hypopigmentation are evident in the macular and perimacular areas and sometimes beyond.  Most patients eventually become blind. 

Systemic Features

Scalp hair loss occurs during the first months of life but the alopecia does not affect eyebrows or eyelashes unlike that seen in the EEM disorder (225280)  which also has digital and dental anomalies.  Partial regrowth may occur during puberty.  Light and electron microscopy of hair shafts reveals pili torti, longitudinal ridging with scaling, and fusiform beading but these are not present in all patients. 

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the CDH3 gene located at 16q22.1.

EEM syndrome (225280) is an allelic disorder with similar hair and retinal features plus dental, digital and limb anomalies.  The hypotrichosis also involves the eyebrows and eyelashes in this disorder, however. 

Treatment Options

There is no known treatment for this disorder. 

References

Leibu R, Jermans A, Hatim G, Miller B, Sprecher E, Perlman I. Hypotrichosis with juvenile macular dystrophy: clinical and electrophysiological assessment of visual function. Ophthalmology. 2006 May;113(5):841-7.e3.

PubMed ID: 
16650681

Indelman M, Bergman R, Lurie R, Richard G, Miller B, Petronius D, Ciubutaro D, Leibu R, Sprecher E. A missense mutation in CDH3, encoding P-cadherin, causes hypotrichosis with juvenile macular dystrophy. J Invest Dermatol. 2002 Nov;119(5):1210-3.

PubMed ID: 
12445216