autosomal recessive

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). 

Pedigree: 
Autosomal recessive
Treatment
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
Article Title: 

Vision in albinism

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

PubMed ID: 
8981720

Oculocutaneous albinism

Gronskov 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. 

Pedigree: 
Autosomal recessive
Treatment
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
Article Title: 

Mutation update, eleven novel mutations and description of five independent subjects with a novel founder mutation

Pena-Quintana L, Scherer G, Curbelo-Estevez ML, Jimenez-Acosta F, Hartmann B, Roche F, Meavilla-Olivas S, Perez-Cerda C, Garcia Segarra N, Giguere Y, Huppke P, Mitchell GA, Monch E, Trump D, Vianey-Saban C, Trimble ER, Vitoria-Minana I, Reyes-Suarez D, Ramirez-Lorenzo T, Tugores A. TYROSINEMIA TYPE II: Mutation update, eleven novel mutations and description of five independent subjects with a novel founder mutation. Clin Genet. 2017 Mar 3. doi: 10.1111/cge.13003. [Epub ahead of print].

PubMed ID: 
28255985

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 ). 

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the basic malformation. 

References
Article Title: 

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 autosomal recessive condition seems to result from homozygous mutations in the PLG gene (6q26) that codes for plasminogen.  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. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Four weeks of treatment with IV human Glu-plasminogen in a small group of children and adults with congenital plasminogen deficiency produced marked clinical improvement in ocular as well as disseminated symptoms according to a recent report. 

Surgical excision of the pseudomembrane is possible but multiple recurrences are common. Spontaneous resolution has been reported.

References
Article Title: 

Treatment of plasminogen deficiency patients with fresh frozen plasma

Kizilocak H, Ozdemir N, Dikme G, Koc B, Atabek AA, Cokugras H, Iskeleli G, Donmez-Demir B, Christiansen NM, Ziegler M, Ozdag H, Schuster V, Celkan T. Treatment of plasminogen deficiency patients with fresh frozen plasma. Pediatr Blood Cancer. 2017 Sep 6. doi: 10.1002/pbc.26779. [Epub ahead of print].

PubMed ID: 
28876531

Ligneous conjunctivitis

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

PubMed ID: 
12850227

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 shows 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. 

Pedigree: 
Autosomal recessive
Treatment
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
Article Title: 

Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta

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

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.

Pedigree: 
Autosomal recessive
Treatment
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
Article Title: 

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

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

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.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disease. 

References
Article Title: 

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 in addition has digital and dental anomalies.  Partial regrowth may occur during puberty.  Light and electron microscopy of hair shafts may reveal 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. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no known treatment for this disorder. 

References
Article Title: 

Hermansky-Pudlak Syndrome

Clinical Characteristics
Ocular Features: 

Oculocutaneous hypopigmentation is common to all types of HPS.  The ocular manifestations are similar to that of other types of albinism.  Iris transillumination defects, nystagmus, and strabismus are common features.   Visual acuity is usually stable in the range of 20/40-20/300 and often accompanied by photophobia.  Foveal hypoplasia and fundus hypopigmentation are present similar to that found in other hypopigmentation disorders.  The same is true of excessive decussation of retinal neuron axons at the chiasm.  Many patients have significant refractive errors. 

Systemic Features: 

In addition to decreased hair, ocular, and skin pigmentation, HPS patients suffer from bleeding diathesis, platelet deficiencies, and accumulation of ceroid material in lysosomes.  Pigment can be found in large amounts in reticuloendothelial cells and in the walls of small blood vessels.  Some of the same features are found in Chediak-Higashi  syndrome (214500) which, however, has additional qualitative changes in leukocytes.   HPS2 differs from other forms of HPS in having immunodeficiency and congenital neutropenia.  Some patients, especially those with HPS1 and HPS4 mutations, have restrictive lung disease secondary to pulmonary fibrosis often causing symptoms in the third and fourth decades of life.  Others have granulomatous colitis, kidney failure, and cardiomyopathy.  Solar skin damage is a risk with actinic keratosis, nevi, lentigines and basal cell carcinoma seen in many patients.

Bleeding time is prolonged secondary to an impairment of the normal aggregation response of platelets.  Easy bruising, epistaxis, prolonged bleeding during menstruation, after tooth extraction, and after minor surgical procedures are often reported.  Platelets lack the normal number of 'dense bodies'.  Coagulation factor activity and platelet counts are normal.

The amount of hair and skin pigmentation is highly variable.  Some patients are so lightly pigmented that they are misdiagnosed as having tyrosinase-negative albinism while others have yellow to brown hair with irides blue to hazel.  Some darkening of hair is common. 

Genetics

This is an autosomal recessive genetically heterogeneous condition resulting from mutations in at least 12 loci: HPS1 (203300) at 10q23.1-q23.2, AP3B1 causing HPS2 (608233) at 5q14.1, and AP3D1 (617050) at 19p13.3 causing HPS 10, whereas in types HPS3 (606118) at 3q24, HPS4 (606682) at 22q11.2-q12.2, HPS5 (607521) at 11p15-p13, HPS6 (607522) at 10q24.32 the mutations themselves have not been characterized.  HPS7 is caused by mutations in the DTNBP1 gene (607145) located at locus 6p22.3 and HPS8 by mutations in the BLOC1S3 gene (609762) at 19q13.  The nature of the mutations is variable and often unique to the population in which they are found. 

Chediak-Higashi  syndrome (214500) is a somewhat similar disorder but with leukocyte abnormalities and results from a different gene mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

It has been suggested that any patients with pigmentation disorders should be asked about bleeding problems to rule out HPS.  A hematologic consultation should be obtained if necessary, especially before elective surgery, to avoid bleeding complications through the use of appropriate preoperative measures.   Low vision aids can be helpful.  The skin should be protected from sunburn.  Lifelong surveillance is required for ocular and systemic problems.  The use of aspirin and indomethacin should be avoided. 

References
Article Title: 

Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome

Ammann S, Schulz A, Krageloh-Mann I, Dieckmann NM, Niethammer K, Fuchs S, Eckl KM, Plank R, Werner R, Altmuller J, Thiele H, Nurnberg P, Bank J, Strauss A, von Bernuth H, Zur Stadt U, Grieve S, Griffiths GM, Lehmberg K, Hennies HC, Ehl S. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood. 2016 Feb 25;127(8):997-1006.

PubMed ID: 
26744459

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

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