Introduction
As is broadly evident in multiple other ocular and orbital tissues, systemic disorders commonly exhibit ocular manifestations. Because of the multiplicity and complexity of these disorders, this chapter presents these associations largely in tabular form. Where known, the causative genetic loci and resultant metabolic defects are specified. Finally, as many disorders are genetically heterogeneous, only the more commonly associated genetic loci are listed.
Congenital Disorders
Congenital disorders are nonmetabolic disorders present at birth that have generalized systemic features as well as ocular anterior segment abnormalities. These groupings are arbitrary and may change as genetic information allows for more specific categorizations. Some craniofacial malformation syndromes with associated anterior ocular findings are given in Table 4.25.1 . Given the severity of these disorders, management is multidisciplinary and requires a team approach by ophthalmologists, facial plastic surgeons, neurosurgeons, and others.
| Syndrome | Protein Defect | Gene Locus | Ocular Manifestations | Systemic Manifestations |
|---|---|---|---|---|
| Crouzon’s, Apert’s, and Pfeiffer’s | Fibroblast growth factor receptor-2 | 10q26 | Shallow orbits, decreased motility, secondary corneal exposure | Craniofacial malformation and syndactyly (Apert’s) |
| Meyer–Schwickerath (oculodentodigital dysplasia) | Connexin43 (Cx43) or gap junction alpha 1 gene ( GJA1 ) | 6q22-q24 | Microphthalmos, microcornea, narrow palpebral fissures, blue sclera | Syndactyly, dysplastic tooth enamel and microcephaly |
| Goldenhar’s (oculoauriculovertebral dysplasia) | Limbal dermoids, microphthalmos, anophthalmos, lid notching, blepharophimosis | Facial asymmetry, vertebral anomalies, ear deformities, mandibular hypoplasia | ||
| Hallermann–Streiff | Connexin43 | 6q22-24 | Microphthalmos, spontaneously resorbing cataracts, macular pigment changes, Coats’ disease | Facial malformation, hypoplastic mandible, short stature, skin atrophy |
Chromosomal Disorders
Syndromes consequent to chromosomal disorders are defined by their abnormal genetic loci ( Table 4.25.2 ). With rapid advances in molecular genetics, more thorough understanding of relevant regulatory or other gene mechanisms involved will allow for better interpretation of their widespread, multisystemic (also see Section I: Genetics). A striking finding is that different chromosomal defects may lead to similar phenotypic abnormalities.
| Genetic Findings | Ocular Manifestations | Systemic Manifestations |
|---|---|---|
| 13q deletion | Hypertelorism, ptosis, epicanthal folds, microphthalmos, retinoblastoma | Growth retardation, microcephaly, facial malformation, absent thumbs |
| 18p deletion | Ptosis, epicanthal folds, hypertelorism, corneal opacity, keratoconus, microphthalmos, strabismus | Brachycephaly, growth retardation, mental retardation |
| 18q deletion | Hypertelorism, epicanthal folds, nystagmus, corneal opacity, microphthalmos, corneal staphyloma, microcornea | Growth retardation, mental retardation, facial malformation, microcephaly, prostate cancer, hearing loss, endocrine disorders |
| 4p deletion (Wolf–Hirschhorn syndrome) | Hypertelorism, ptosis, microphthalmos, strabismus, cataract | Growth retardation, microcephaly, micrognathia, hypotonia seizures, epilepsy |
| Turner’s syndrome (45×0) | Ptosis, epicanthal folds, strabismus, rarely microcornea, blue sclera, corneal opacity | Female, short stature, webbed neck, hearing loss |
| Trisomy 13 (Patau’s syndrome) | Microphthalmos, corneal opacity, Peters’ anomaly, cataract, retinal dysplasia ( Fig. 4.25.1 ) | Microcephaly, cleft lip and palate, low-set ears |
| Trisomy 18 (Edwards’ syndrome) | Corneal opacity, ptosis, hypertelorism, epicanthal folds, microphthalmos, colobomas, cataract, retinal dysplasia | Low birth weight; failure to thrive; brain hypoplasia; cardiac, gastrointestinal, renal, and musculoskeletal anomalies |
| Trisomy 21 (Down syndrome) | Shortened, slanted palpebral fissure, neonatal ectropion, later trichiasis and entropion, keratoconus, cataract | Cardiac defects, mental retardation, short stature, characteristic facies |
| Partial trisomy 22 (cat’s eye syndrome) | Microphthalmos, hypertelorism, colobomas | Mental retardation, microcephaly, cardiac anomalies, ear anomalies, anal atresia |
Inherited Connective Tissue Disorders
The inherited connective tissue disorders are striking in their musculoskeletal manifestations and often serious in their visceral involvements ( Table 4.25.3 ). More detailed discussions on this topic are featured elsewhere (also see Chapter 4.3, Chapter 4.19, Chapter 4.20 ).
| Disease | Biochemical Defect | Gene Locus | Ocular Manifestations | Systemic Manifestations |
|---|---|---|---|---|
| Marfan’s syndrome | Fibrillin-I gene mutations ( FBN1 ) | 15q21.1 | Megalocornea, lens subluxation, high myopia, retinal detachment, microspherophakia | Long extremities, lax joints, aortic/mitral dilatation, aortic dissection |
| Osteogenesis imperfecta | Type I procollagen COLIA1 COLIA2 | 17q21.31–q22 7q22.1 | Blue sclera, keratoconus, megalocornea, optic nerve compression | Bone deformities, recurrent fractures, otosclerosis, dental anomalies |
| Ehlers–Danlos syndrome type VIA | Lysyl hydroxylase | lp36.3–p36.2 | Blue sclera, keratoconus, keratoglobus, lens subluxation, myopia, floppy eyelids, ocular fragility to trauma | Skin stretching, scarring joint hypermobility, scoliosis, tissue fragility |
| Ehlers–Danlos syndrome type VIB | Normal lysyl hydroxylase | Unknown | Same as VIA | Same as VIA |
Metabolic Disorders
Numerous inherited metabolic disorders affect the eye. Frequently autosomal recessive, these disorders are often consequent to a defect or reduction of a single lysosomal enzyme (hence the broad term lysosomal storage diseases [LSDs]) resulting in accumulation of metabolites in multiple affected tissues. For many disorders, the specific genetic defect has been identified, and for some (notably Fabry’s disease) synthesis of the defective enzyme has facilitated enzyme replacement therapy. In contrast to most corneal dystrophies, corneas affected by metabolic disorders demonstrate abnormality in multiple cell types, affect the peripheral cornea as well as the central cornea, and may be progressive.
Protein and Amino Acid Metabolic Disorders
As specified in Table 4.25.4 , the accumulated metabolites are sometimes amenable to treatment. For cystinosis, therapy is accomplished with oral cysteamine. In tyrosinemia, dietary therapy (avoiding phenylalanine and tyrosine) keeps tyrosine levels controlled. Vitamin C and nitisinone may be effective for alkaptonuria. Chelation therapies to reduce elevated ceruloplasmin levels in Wilson’s disease utilize D-penicillamine and trientine.
| Disorder | Enzyme Deficiency | Gene Locus | Metabolite Accumulated | Mode of Inheritance | Ocular Manifestations | Systemic Manifestations |
|---|---|---|---|---|---|---|
| Cystinosis | Probable defect of lysosomal cysteine transport protein | 17p13 CTNS gene | Cystine | Autosomal recessive | All forms: conjunctival and corneal cystine crystals deposition, band keratopathy, blepharospasm, photophobia Infantile and adolescent forms: retinal abnormalities, occasional macular changes ( Fig. 4.25.2 ) | Infantile form (90%): renal failure, death Adolescent form (5%): renal failure, skeletal deformities Adult form or ocular cystinosis (5%): no renal failure, nonnephro-pathic ocular form |
| Tyrosinemia type II (tyrosinosis, Richner–Hanhart syndrome) | Tyrosine transaminase deficiency | 16q22.1–22.3 | Tyrosine | Autosomal recessive | Dendritiform corneal epithelial changes (branches or snowflake opacities), red eye, photophobia | Palmar–plantar hyperkeratosis, mental retardation, growth retardation, epilepsy |
| Alkaptonuria | Homogentisate-1, 2-dioxygenase | 3q21–q23 | Homogentisic acid | Autosomal recessive | Pigmentation (ochronosis) of sclera near insertion of horizontal rectus muscles, “oil-droplet” opacities in limbal corneal epithelium and Bowman’s layer, pigmented pingueculae | Joint pain and stiffness |
| Wilson’s disease | Defective excretion of copper from hepatic lysosomes | 13q14.3–q21.1 ( ATP7B gene) | Copper | Autosomal recessive | Kayser–Fleischer ring, “sunflower” cataract ( Fig. 4.25.3 ) | Liver dysfunction, spasticity, behavior disturbance, nephrotic syndrome |
| Lattice dystrophy type II (Meretoja’s syndrome) | Gelsolin gene defect (G654A–Finnish type) or G654T (Danish type) | 9q32-34 | Amyloid | Autosomal dominant | Lattice dystrophy, dry eye, light sensitivity, ptosis, glaucoma | Progressive cranial neuropathy, facial paralysis, cardiac disease |
Mucopolysaccharidoses
The mucopolysaccharidoses (MPSs) comprise the quintessential LSDs because their hydrolytic enzyme defects result in progressive intralysosomal (and eventual extracellular) storage of mucopolysaccharides (more properly termed glycosaminoglycans ) ( Table 4.25.5 ), often with variably profound skeletal and mental consequences. Corneal clouding in varying degrees and patterns, as well as retinal pigmentary degenerations, are the hallmarks of MPS disorders caused by accumulation of heperan, keratan, and dermatan sulfates.
| Disorder | Enzyme Deficiency | Metabolite Accumulated | Mode of Inheritance | Gene Locus | Ocular Manifestations | Systemic Manifestations |
|---|---|---|---|---|---|---|
| Mucopolysaccharidosis I-H (Hurler) | α-L-Iduronidase ( IDUA gene) | Heparan sulfate Dermatan sulfate Glycosaminoglycans (GAGs) | Autosomal recessive | 4p16.3 | Corneal clouding, pigmentary retinopathy, optic atrophy, trabecular involvement | Gargoyle facies, mental retardation, dwarfism, skeletal dysplasia, valvular heart disease, hepatosplenomegaly |
| Mucopolysaccharidosis I-S (Schieie’s, previously MPS V) | α-L-Iduronidase | Heparan sulfate Dermatan sulfate | Autosomal recessive | 4p16.3 | Corneal clouding, pigmentary retinopathy, optic atrophy, glaucoma | Coarse facies, claw-like hands, aortic valve disease |
| Mucopolysaccharidosis I-H/S (Hurler–Scheie; Fig. 4.25.4 ) | α-L-Iduronidase | Heparan sulfate Dermatan sulfate | Autosomal recessive | 4pl6.3 | Corneal clouding, pigmentary retinopathy, optic atrophy | More severe than I-S, less severe than I-H |
| MPS II (Hunter’s) | Iduronate sulfate sulfatase (iduronate sulfatase) | Heparan sulfate Dermatan sulfate | X-linked recessive | Xq28 | Rare corneal clouding, pigmentary retinopathy, optic atrophy | Similar to I-H with less bony deformity |
| MPS III (Sanfilippo’s) | Variable, depending on type | Heparan sulfate | Autosomal recessive | 17q25.3 17q21.1 12q14 Chr #14 | All forms: clinically clear cornea, occasional slit-lamp corneal opacities pigmentary retinopathy, optic atrophy | All forms: mild dysmorphism, progressive dementia, hearing loss, behavior issues |
| MPS IV (Morquio’s) | A: galactose-6-sulfatase B: β-galactosidase | Keratan sulfate, chondroitin-6 sulfate | Autosomal recessive Autosomal recessive | 16q24.3 3p21.33 | Corneal clouding, optic atrophy | Severe bony deformity, aortic valve disease, normal intelligence |
| MPS VI (Maroteaux–Lamy) | N-acetylgalactosamine-4-sulfatase | Dermatan sulfate | Autosomal recessive | 5q11–q13 | Corneal clouding, optic atrophy | Similar to I-H, but normal intellect |
| MPS VII (Sly’s) | β-glucuronidase | Dermatan sulfate Heparan sulfate | Autosomal recessive | 7q21.1 | Corneal clouding | Similar to I-H |
Sphingolipidoses
Also considered LSDs, the sphingolipidoses arise from dysfunction of catabolic enzymes, with consequent accumulation of sphingolipids ( Table 4.25.6 ). Notable among sphingolipidoses are Tay–Sachs and Niemann–Pick diseases, which are not included as they lack major anterior segment manifestations.
| Disorder | Enzyme Deficiency | Gene Locus | Metabolite Accumulated | Mode of Inheritance | Ocular Manifestations | Systemic Manifestations |
|---|---|---|---|---|---|---|
| GM 2 gangliosidosis II (Sandhoff’s disease) | Hexosaminidase B, HEX B chain | 5q13 | Ganglioside GM 2 | Autosomal recessive | Membrane-bound vacuoles within corneal keratocytes, cherry-red macula | Psychomotor retardation, hepatosplenomegaly, Mongolian spots (unusual) |
| Metachromatic leukodystrophy (Austin’s juvenile form) | Arylsulfatase A isozymes | 22q13.31-qter | Sulfatide | Autosomal recessive | Corneal clouding | Mental retardation, seizures |
| Fabry’s disease | α-Galactosidase A | Xq22 | Ceramide trihexoside | X-linked recessive | Conjunctival and retinal vascular tortuosity, anterior subcapsular lens opacities, oculomotor abnormalities, cornea verticillata ( Fig. 4.25.5 ) | Renal failure, peripheral neuropathy, hypo/hyperhidrosis, hypoacusis |
| Gaucher’s disease | Glucocerebrosidase | Iq21 | Glucocerebrosidase | Autosomal recessive | Prominent pinguiculae, white corneal epithelial deposits, vitreous opacities, paramacular gray ring | Hepatosplenomegaly, bone pain, anemia |
Dyslipoproteinemias
The dyslipoproteinemias ( Table 4.25.7 ) comprise a somewhat diverse group of disorders resulting from the multiplicity of lipid metabolic processes and pathways. In the anterior eye, they variably manifest as eyelid xanthelasmas, corneal arcus, and corneal clouding.
| Disorder | Deficiency | Gene Locus | Metabolite Accumulated | Mode of Inheritance | Ocular Manifestations | Systemic Manifestations |
|---|---|---|---|---|---|---|
| Lecithin–cholesterol acyltransferase (LCAT) deficiency | Lecithin–cholesterol acyltransferase | 16q22.1 | Free cholesterol | Autosomal recessive | Dense peripheral arcus, gray dots in central stroma, no visual changes | Atherosclerosis, xanthomas, premature coronary artery disease, hepatosplenomegaly, anemia, renal insufficiency |
| Fish eye disease (high-density lipoprotein lecithin–cholesterol acyltransferase) | α-Lecithin–cholesterol acyltransferase | 16q22.1 | Triglycerides, very low density lipoproteins (VLDL); low-density lipoproteins (LDL) | Autosomal dominant | Progressive corneal clouding, increased corneal thickness | None |
| Tangier’s disease (analphalipoproteinemia) | High-density lipoprotein | 9q22–q31 (ABCA1 gene) | Triglycerides; low levels of high-density lipoproteins (HDL), cholesterol and phospholipids | Autosomal recessive | Fine dot corneal clouding, severe visual loss, incomplete eyelid closure, ectropion, no arcus | Lymphadenopathy hepatosplenomegaly, coronary artery disease |
| Hyperlipoproteinemia I (hyperchylomicronemia) | Lipoprotein lipase | 8p22 | Triglycerides, chylomicrons | Autosomal recessive | Lipemia retinalis, palpebral eruptive xanthomata | Xanthomas |
| Hyperlipoproteinemia II, hyper-β-lipoproteinemia IIA, hyper-β-lipoproteinemia IIb | LDL receptor (type IIa); defective lipid metabolism in type IIb | 19p13 (type IIa); 1q21-23 (type IIb); others | Type IIa: LDL, cholesterol Type IIb: LDL, VLDL, cholesterol, triglycerides | Autosomal dominant | Both forms: corneal arcus, conjunctival xanthomata, xanthelasma | Coronary artery disease |
| Hyperlipoproteinemia III (dys-β-lipoproteinemia; broad β-disease) | Abnormality in apolipoprotein E | 19q13.2 | VLDL remnants, cholesterol, triglycerides | Autosomal recessive with pseudo-dominance | Arcus, xanthelasma, lipemia retinalis | Peripheral vascular disease, diabetes mellitus |
| Hyperlipoproteinemia IV (hyperpre-β-lipoproteinemia) | Lipoprotein lipase; apolipoprotein A | 15q11-13; 21q11; others | Triglycerides, VLDL | Autosomal dominant | Arcus, xanthelasma, lipemia, retinalis | Vascular disease, diabetes mellitus |
| Hyperlipoproteinemia V (hyperprelipoproteinemia and hyperchylomicronemia) | Apolipoprotein A | 11q23 | VLDL, chylomicrons | Uncertain | Lipemia retinalis, no arcus | Xanthomas, hepatosplenomegaly |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
