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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.
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.
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.
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.
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.
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.
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.
No treatment is available for this disease.
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.
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.
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.
There is no known treatment for this disorder.
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 albinism disorders. The same is true of excessive decussation of retinal neuron axons at the chiasm. Many patients have significant refractive errors.
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 in 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, including actinic keratosis, nevi, lentigines and basal cell carcinoma.
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 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.
This is an autosomal recessive genetically heterogeneous condition resulting from mutations in at least 11 loci: HPS1 (203300) at 10q23.1-q23.2, AP3B1 causing HPS2 (608233) at 5q14.1, 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.
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.
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 patients. There is considerable interocular, intrafamilial, and interfamilial variability in these signs.
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.
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.
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.
Oculocutaneous albinism is a genetically and clinically heterogeneous condition. It is congenital in origin and the combination of foveal hypoplasia and anomalous decussation of neuronal axons in the chiasm results in a permanent reduction of vision in the range of 20/50-20/200. Most individuals have nystagmus, photophobia, and strabismus. The iris usually is light blue and transmits light. The retina lacks pigmentation as well. The ocular features are similar in types IA and IB. The iris may darken with age in type IB (606952 ).
There are generally no systemic abnormalities in these pigmentation disorders with the exception of sensorineural hearing loss in some, and, of course, complete absence of pigment in skin and hair. Anomalous decussation of axons in the auditory system has been demonstrated in such cases and otic pigment is lacking in albinos. The skin contains amelanic melanocytes but these cells contain granules similar to those of normal cells. Some patients with residual tyrosinase activity (type 1B, 606952 ) develop some pigmentation of hair and skin, especially in cooler areas of the body such as the extremities.
This type of oculocutaneous albinism is caused by mutations in the TYR gene (11q14-q21) and inherited in an autosomal recessive pattern.
Type IA (OCA1A) has no demonstrable tyrosinase activity while type IB (OCA1B, 606952) has a reduction in enzyme activity. Yet other patients with mutations in TYR have a variant called 'yellow albinism' in which tyrosinase activity resembles that found in type IB. To explain the difference in skin color, it has been suggested that an individual's background ethnicity may impact the pigmentation phenotype.
There is no treatment for the basic disease but low vision aids may be helpful for some patients. Dark glasses provide comfort for photophobic individuals. The skin should be protected against sunburn.
Cone-rod dystrophies (CRD) are a group of pigmentary retinopathies that have early and important changes in the macula. Cone dysfunction occurs first and is often followed by rod photoreceptor degeneration.
Common initial symptoms are decreased visual acuity, dyschromatopsia, and photophobia which are often noted in the first decade of life. Night blindness occurs later as the disease progresses. A fine nystagmus is also common. Visual field defects include an initial central scotoma with patchy peripheral defects followed by larger defects in later stages. The fundus exam can be normal initially, but is followed by pigmentary bone spicule changes, attenuation of retinal vessels, waxy pallor of the optic disc and retinal atrophy. A ring maculopathy surrounding the fovea is usually evident. The ERG first reveals photopic defects and later scotopic changes. Fluorescein angiography and fundus autofluorescence generally reveal atrophic retinopathy. Many patients eventually become legally blind as the disease progresses and some end up with no light perception.
Cone-rod dystrophies are a group of disorders separate from rod-cone dystrophies where the primary defect is in the rod photoreceptors with typical pigmentary changes in the peripheral retina. The progression of vision loss is generally slower in rod-cone dystrophies. Cone dystrophies comprise another group of disorders with exclusive cone involvement in which the macula often has a normal appearance in association with loss of central acuity.
No systemic disease is associated with simple cone-rod dystrophies. See below for syndromal disorders with cone-rod dystrophy.
Non-syndromic cone-rod dystrophies can be either autosomal dominant, autosomal recessive or X-linked and are caused by defects in at least 17 different genes. This database entry discusses only the autosomal disorders. See X-linked cone-rod dystrophies in a separate entry.
Cone-rod dystrophies inherited in an autosomal dominant pattern include:
CORD2 (120970) is caused by mutations in CRX at 19q13.3, a homeobox gene responsible for the development of photoreceptor cells. These are responsible for 5-10% of autosomal dominant cone-rod dystrophy cases (602225) and can also cause one type (LCA7) of Leber congenital amaurosis (602225) and a late-onset retinitis pigmentosa phenotype.
CORD5 (600977) is caused by mutations in the PITPNM3 gene at 17p13.1.
CORD6 (601777) is caused by a mutation in GUCY2D in a similar location on chromosome 17.
CORD7 (603649) is caused by mutations in RIMS1 at 6q12-q13.
Mutations in AIPL1 (604392), located in the same region, usually causes a form of Leber congenital amaurosis (LCA4) as well as retinitis pigmentosa (604393) but has also been reported in a cone-rod pigmentary retinopathy.
CORD11 (610381) is caused by mutations in RAXL1 (19p13.3).
CORD12 (612657) results from mutations in the PROM1 gene (4p15.3).
Mutations in the gene GUCA1A on chromosome 6p21.1 causes CORD14 (602093).
An as yet unclassified autosomal dominant type of cone-rod dystrophy has recently been localized to 10q26.
Cone-rod dystrophies inherited in an autosomal recessive pattern include:
CORD8 (605549) has been found in a single consanguineous family and the mutation localized to 1q12-q24.
ADAM9 (602713) at 8p11 and 8p11.23 contains mutations that have been shown to cause autosomal recessive CORD9 in several consanguineous families.
Mutations in RPGRIP1 (14q11) are responsible for CORD13 (608194).
The CDHR1 gene (10q23.1) contains mutations that cause CORD15 (613660).
Syndromal cone-rod dystrophies:
Cone-rod dystrophy may also be associated with other syndromes, such as Bardet-Biedl syndrome (209900), or spinocerebellar ataxia Type 7 (164500), autosomal recessive amelogenesis imperfecta with cone-rod dystrophy or Jalili syndrome (217080), neurofibromatosis type I (162200), and hypotrichosis with juvenile macular dystrophy and alopecia (601553). Metabolic disorders associated with cone-rod dystrophy include Refsum disease with phytanic acid abnormality (266500) and Alport syndrome (301050).
There is no treatment for these dystrophies but red-tinted lenses provide comfort and may sometimes improve acuity to some extent. Low vision aids can be helpful.
The term retinitis pigmentosa is applied to a large group of disorders with great clinical and genetic heterogeneity. The ocular disease is characterized by night blindness, field constriction, and pigmentary changes in the retina. The latter is sometimes described as having a ‘bone corpuscle’ appearance with a perivascular distribution. A ring scotoma is usually evident. Age of onset and rate of progression is highly variable, even within families. The rods are impacted early but cone deterioration with loss of central vision usually follows. Some patients complain of dyschromatopsia and photophobia. The ERG generally documents this progression but the mfERG shows wide variations in central cone functioning. Legal blindness is common by the 5thdecade of life or later. The course of clinical and ERG changes is more aggressive in the X-linked form than in the autosomal dominant disease. The final common denominator for all types is first rod and then cone photoreceptor loss through apoptosis.
As many as 50% of patients develop posterior subcapsular cataracts. The vitreous often contains cells and particulate debris. Retinal arterioles are often attenuated and the optic nerve may have a waxy pallor, especially late in the disease. Occasional patients have cysts in the macula. Some patients experience continuous photopsia.
The ‘simple’ or nonsyndromal type of RP described here has no systemic features. However, the retinopathy is seen in a number of syndromes and, of course, in some infectious diseases as well. It is more accurate to label the fundus finding as 'pigmentary retinopathy' in such cases.
A significant proportion of RP cases occur sporadically, i.e., without a family history. Mutations in more than 30 genes cause autosomal recessive RP disorders and these account for more than half of all cases of retinitis pigmentosa. More than 100 mutations have been identified in the RHO gene (3q21-q24) alone. Mutations in some genes cause RP in both autosomal recessive and autosomal dominant inheritance patterns. Compound heterozygosity is relatively common in autosomal recessive disease. See OMIM 268000 for a complete listing of mutations.
Many genes associated with retinitis pigmentosa have also been implicated in other pigmentary retinopathies. In addition, numerous phenocopies occur, caused by a variety of drugs, trauma, infections and numerous neurological disorders. To make diagnosis even more difficult, the fundus findings and ERG responses in nonsyndromic RP in most patients are too nonspecific to be useful for classification. Extensive systemic and ocular evaluations are important and should be combined with genotyping in both familial and nonfamilial cases to determine the diagnosis and prognosis.
Photoreceptor transplantation has been tried in without improvement in central vision or interruption in the rate of vision loss. Longer term results are needed. Resensitizing photoreceptors with halorhodopsin using archaebacterial vectors shows promise in mice. High doses of vitamin A palmitate slow the rate of vision loss but plasma levels and liver function need to be checked at least annually. Oral acetazolamide can be helpful in reducing macular edema.
Low vision aids and mobility training can be facilitating for many patients. Cataract surgery may restore several lines of vision, at least temporarily.
Several pharmaceuticals should be avoided, including isotretinoin, sildenafil, and vitamin E.
Based on clinical manifestations, three types have been described: type I or infantile form, type II or late-infantile/juvenile form, and type III or adult/chronic form but all are due to mutations in the same gene. Only the infantile form has the typical cherry red spot in the macula but is present in only about 50% of infants. The corneal clouding is due to intracellular accumulations of mucopolysaccharides in corneal epithelium and keratan sulfate in keratocytes. Retinal ganglion cells also have accumulations of gangliosides. Decreased acuity, nystagmus, strabismus and retinal hemorrhages have been described.
Infants with type I disease are usually hypotonic from birth but develop spasticity, psychomotor retardation, and hyperreflexia within 6 months. Early death from cardiopulmonary disease or infection is common. Hepatomegaly, coarse facial features, brachydactyly, and cardiomyopathy with valvular dysfunction are common. Dermal melanocytosis has also been described in infants in a pattern some have called Mongolian spots. Skeletal dysplasia is a feature and often leads to vertebral deformities and scoliosis. The ears are often large and low-set, the nasal bridge is depressed, the tongue is enlarged and frontal bossing is often striking. Hirsutism, coarse skin, short digits, and inguinal hernias are common.
The juvenile form, type II, has a later onset with psychomotor deterioration, seizures and skeletal changes apparent between 7 and 36 months and death in childhood. Visceral involvement and cherry-red spots are usually not present.
Type III, or adult form, is manifest later in the first decade or even sometime by the 4th decade. Symptoms and signs are more localized. Neurological signs are evident as dystonia or speech and gait difficulties. Dementia, parkinsonian signs, and extrapyramidal disease are late features. No hepatosplenomegaly, facial dysmorphism, or cherry red spots are present in most individuals. Lifespan may be normal in this type.
This is an autosomal recessive lysosomal storage disease secondary to a mutations in GLB1 (3p21.33). It is allelic to Morquio B disease (MPS IVB) (253010). The mutations in the beta-galactosidase-1 gene result in intracellular accumulation of GM1 ganglioside, keratan sulfate, and oligosaccharides. The production of the enzyme varies among different mutations likely accounting for the clinical heterogeneity.
There is no treatment that effectively alters the disease course.
Stargardt disease or fundus flavimaculatus is a progressive form of juvenile macular degeneration with considerable clinical and genetic heterogeneity. It may be considered a syndromal cone-rod dystrophy because of overlapping clinical features such as loss of color vision and photophobia in some patients. Adding to the confusion is the fact that mutations in at least 4 genes are responsible for similar clinical characteristics. Due to the lack of diagnostic distinctions and the wide range of nonspecific clinical manifestations, Stargardt disease and fundus flavimaculatus are discussed here as a single entity.
Onset of vision loss is often noted late in the first decade of life usually with rapid progression. However, some patients are asymptomatic until much later, even into the fifth decade. There is evidence that patients with an early onset have a worse prognosis compared to those with a later onset. Nevertheless, large series of patients contain at least 23% with 20/40 or better acuity, about 20% with 20/50 -20/100, and 55% have 20/200-20/400 and a small number have vision less than 20/400.
Some color discrimination is lost and photophobia may be a complaint. Dark adaptation is prolonged but nightblindness does not usually occur and peripheral visual fields are normal. The posterior pole characteristically has yellowish pisciform, round, and linear subretinal lipofuscin deposits which often extend to the equator. These may be present before clinical symptoms are present. Histopathology reveals accumulations of this material in RPE cells. Atrophy of the RPE in the same region is often visible as well but these changes may be subtle initially. Some patients have peripheral pigment clumping which may resemble the bone spicule configuration seen in retinitis pigmentosa. However, retinal vessel caliber is normal in Stargardt disease. Extensive macular disease can be associated with temporal pallor of the optic nerve. The ERG shows reduced photopic responses with normal or near normal scotopic tracings. Fluorescein angiography often reveals more extensive disease than seen on fundoscopy. Window defects are common in the macula where the RPE is atrophied. The flecks may be hypo- or hyperfluorescent. Over 50% of patients have patches of angiographically dark choroid in the posterior pole which is thought to be secondary to transmission blockage by lipofuscin accumulations in the RPE.
This group of disorders may be caused by mutations in at least 4 genes. These are: STGD1 (248200) caused by mutations in the ABCA4 gene located at 1p22.1, or in CNGB3 (262300) (8q21-q22) which also is mutant in achromatopsia 3 (ACHM3), STGD3 (605512) caused by mutations in the ELOVL4 gene at 6q14, and STGD4 (603786) caused by a mutation in PROM1 on chromosome 4p. STGD4 and STGD3 disease have been found in pedigrees consistent with autosomal dominant inheritance but STGD1 disease seems to be inherited in an autosomal recessive pattern.
There is considerable diagnostic confusion regarding the clinical phenotypes and classification of many patients no doubt due to the considerable genetic heterogeneity. The ABCA4 gene is huge and and contains 50 exons among which 700 mutations have been identified. Not surprisingly, the impact of specific mutations on the ABCA4 gene product is variable and those expected to have the most severe functional impact through truncation or misfolding usually result in the most severe clinical disease. Complicating matters further, intrafamilial variations in phenotypes suggest that epigenetic factors play a role as well.
Genomics should help clarify the nosology especially among individuals reported to have areolar macular dystrophy, retinitis pigmentosa, juvenile macular degeneration, and cone dystrophies in association with several of these mutations. Reports have also associated Stargardt disease with mutations in RDS.
There is no treatment for this disorder but low vision aids can be helpful especially in the early stages of the disease.
Isotretinoin has been shown to slow the accumulation of lipofuscin pigments in mice but its role in human Stargardt disease has not been reported. Trials using stem cells are underway with encouraging early results.