Skeletal and Connective Tissue Disorders With Anterior Segment Manifestations

The clarity and structural integrity of the cornea require a well-organized corneal extracellular matrix (ECM), which is primarily composed of various types of collagen and proteoglycans. Sclera and the anterior chamber angle contain many of the same connective tissue elements. Olsen and McCarthy have provided an excellent overview of the molecular structure of collagens and other components of the ECM of cornea, sclera, and vitreous. Table 59.1 lists the different types of collagen and proteoglycans within the corneal layers.

Another important component of ECM is the microfibrillar system. ^, Fibrillin-1 is one of a number of secreted ECM glycoproteins that form microfibrils, which guide the proper deposition of elastin. Microfibrils also play an essential role in the regulation of transforming growth factor-β and are important for integrity of the eye, especially in the suspensory zonule of the lens, which is almost entirely composed of fibrillin-1 and microfibrils ( Fig. 59.1 ). Other ocular structures rich in fibrillin include the sclera and lens capsule.

Open full size image

Immunohistochemical study of cornea for distribution of fibrillin shows staining in the epithelial basement membrane zone. (Original magnification × 50. Counterstain: Harris hematoxylin.)

From Wheatley HM, Traboulsi EI, Flowers BE, et al. Immunohistochemical localization of fibrillin in human ocular tissues. Relevance to the Marfan syndrome. Arch Ophthalmol 1995; 113 :103. Copyright © [1995] American Medical Association. All rights reserved.

It follows that diseases involving ECM components often have corneal, lenticular, or scleral manifestations. Conditions such as microcornea, megalocornea, and corneal opacification may be present at birth. Other connective tissue abnormalities of the cornea may manifest later in life in the form of progressive disorders, such as keratoconus and keratoglobus, or as manifestations of such diseases as Ehlers-Danlos syndrome (EDS) or Marfan syndrome. Similarly, scleral weakness may allow scleral thinning or axial myopia. Abnormalities of the corneoscleral limbal structures, including the anterior chamber angle, can result in glaucoma. Fetal or infantile glaucoma can lead to stretching of the globe causing megalophthalmos and a large cornea. The conjunctiva is generally normal in patients with connective tissue disease or skeletal dysplasias; an exception occurs in hypophosphatasia (HPP) or other disorders involving calcium deposition.

Classification of Skeletal Disorders

In 2015, the Nosology Group of the International Skeletal Dysplasia Society revised its classification of genetic skeletal disorders. In this revision, 436 conditions were included and placed in 42 groups defined by molecular, biochemical, and/or radiographic criteria, and were associated with mutations in one or more of 364 different genes.

Abnormalities of procollagen and collagen genes result in such skeletal dysplasias as Stickler syndrome, Kniest dysplasia, spondyloepiphyseal dysplasia, and osteogenesis imperfecta (OI). Mutations in fibrillin result in Marfan syndrome, some cases of dominant Weill-Marchesani syndrome and in congenital contractual arachnodactyly. A number of enzyme defects can cause lysosomal storage diseases such as the mucopolysaccharidoses and their skeletal abnormalities, collectively known as dysostosis multiplex in regard to their radiologic characteristics. Finally, abnormalities of the fibroblast growth factor receptors (FGFRs) lead to the phenotypes of Crouzon, Apert, Jackson-Weiss, Saethre-Chotzen syndromes, and to achondroplasia. However, a number of skeletal and craniofacial malformation syndromes remain characterized only at the clinical level, and further insight into their pathogenesis remains to be elucidated. Table 59.2 lists some of the skeletal disorders of special interest to the ophthalmologist because of their ocular manifestations.

TABLE 59.2

Skeletal Disorders of Interest to the Ophthalmologist

Online Mendelian Inheritance in Man, OMIM(R). McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), July 2016. World Wide Web URL: http://omim.org/

Name (OMIM #)	Corneal Findings	Other Ocular Findings	Inheritance/Gene/Locus/Other Information
Albright hereditary osteodystrophy (103580)	None	Zonular cataracts with multicolored flecks in 25% of patients optic disk edema	AD/ GNAS1 /20q13/Loss of function of the paternal allele
Apert syndrome (101200)	Exposure keratitis with severe proptosis Keratoconus (very rare) Megalocornea (very rare)	Strabismus (exotropia with V pattern) Absence of extraocular muscles, proptosis, ocular hypopigmentation, optic atrophy. Rare: nystagmus, ptosis, cataract, ectopia lentis, coloboma of iris	AD/ FGFR2/ 10q26
Carpenter syndrome; Acrocephalo-polysyndactyly type II (201000)	Exposure keratitis secondary to severe proptosis Microcornea (rare) Corneal leukoma (rare)	Epicanthal folds, antimongoloid slant, hyper or hypotelorism, optic atrophy, strabismus Rare: coloboma of the iris and choroid, congenital cataract, lens subluxation, nystagmus, retinal detachment	AR/ RAB23 /6p11.2
Cockayne syndrome (Type A: 216400; Type B: 133540)	Raised inferior corneal lesion, band keratopathy, recurrent erosions	Cataracts, retinal dystrophy, nystagmus, iris atrophy, hyperopia, enophthalmos, strabismus	AR Type A: ERCC8/ 5q12.1; Type B: ERCC6/ 10q11
Crouzon syndrome (123500)	Exposure keratitis with severe proptosis Keratoconus (very rare) Microcornea (very rare)	Strabismus (exotropia with V pattern) Exophthalmos, hypertelorism, optic atrophy in 30%. Rare: nystagmus, glaucoma, cataract, ectopia lentis, aniridia, anisocoria, myelinated nerve fibers	AD/ FGFR2/ 10q26
Ehlers-Danlos syndrome (EDS I: 130000) Brittle Cornea syndrome (EDS 9: 229200)	Thin cornea, progressive keratoconus/keratoglobus	Epicanthal folds, blue sclerae, retinal detachment, glaucoma, ectopia lentis, angioid streaks (rare)	AD/AR Multiple locations
Goldenhar-Gorlin syndrome; oculo-auriculo-vertebral sequence; hemifacial microsomia (164210)	Limbal dermoid	Upper > lower lid coloboma, strabismus (25%), Duane retraction syndrome, microphthalmia, anophthalmia, lacrimal system dysfunction, optic nerve hypoplasia, tortuous retinal vessels, macular hypoplasia and heterotropia, choroidal hyperpigmentation, iris and retinal colobomas	Sporadic Rarely AD and AR/14q32
Hallerman-Streiff-Francois syndrome; Oculo-mandibulo-dyscephaly (234100)	One case of sclerocornea	Congenital cataracts, spontaneous resorption of lens cortex with secondary membranous cataract formation, glaucoma, uveitis, retinal folds, optic nerve dysplasia, microphthalmia	Sporadic Rarely AD Increased anesthetic risk secondary to tracheomalacia
Hypophosphatasia (Infantile: 241500 Childhood: 241510 Adult: 146300)	Band keratopathy with conjunctival calcifications in infantile form	Blue sclerae, cataracts, optic atrophy secondary to craniostenosis, atypical retinitis pigmentosa. Ocular complications present only in infantile and childhood forms, not in adult form	Infantile:AR Childhood: AR, AD Adult: AD ALPL /1p36-p34
Marfan syndrome (154700)	Megalocornea Flat cornea Keratoconus (uncommon)	Ectopia lentis, strabismus, cataracts, myopia, retinal detachment, glaucoma, flat cornea	AD/ FBN1 /15q21.1
Nail-patella syndrome; Onycho-osteodysplasia (161200)	Microcornea	Cataracts, microphthalmia	AD /LMX1B/ 9q34.1
Oculo-dento-osseous dysplasia (AD—164200 AR—257850)	Microcornea	Hypotelorism, convergent strabismus, anterior segment dysgenesis, glaucoma, cataracts, remnants of the hyaloid system	AD/Connexin-43 ( GJA1)/ 6q21-23.2
Osteogenesis imperfecta group A (Type I: 259400 Type II: 166200 Type III: 259420 Type IV: 166220)	Decreased central corneal thickness Keratoconus Megalocornea (rare) Posterior embryotoxon (rare)	Blue sclerae Rare: congenital glaucoma, cataract, choroidal sclerosis, subhyaloid hemorrhage, hyperopia, ectopia lentis	AD COL1A1 (17q21.33) or COL1A2 (7q21.3)
Osteogenesis imperfecta group D (Sillence type V: 610967)	None reported	Rarely blue sclerae	AD IFITM5 (11p15.5)
Parry-Romberg syndrome; Progressive facial hemiatrophy (141300)	Neuroparalytic keratitis	Enophthalmos, oculomotor palsies, pupillary abnormalities, Horner syndrome, heterochromia, intraocular inflammation, optic nerve hypoplasia, choroidal atrophy	Sporadic 5% bilateral, left > right
Pierre Robin malformation (261800)	Megalocornea (rare)	Congenital glaucoma, high myopia, vitreoretinal degeneration, retinal detachment, esotropia, congenital cataracts, microphthalmia	Sporadic Stickler syndrome in 1/3 of cases Other syndromes N.B.: Increased anesthetic risk secondary to glossoptosis
Rothmund-Thomson syndrome (268400)	Degenerative lesions of cornea	Cataracts	AR/DNA helicase ( RECQL4 )/8q24.3/70% female
Treacher Collins syndrome; Mandibulo-facial dysostosis (154500) Type 2 (613717) Type 3 (248390)	Microcornea	Coloboma of lower lids, dysplasia of bony orbit, absent lower lid cilia, absent lower lid lacrimal punctae, iris coloboma, microphthalmia, strabismus, antimongoloid slant	AD/Treacle ( TCOF1 )/5q32-q33.1 AD/AR/POLR1D/13q12 AR/POLR1C/6p21
Werner syndrome (277700)	Corneal edema secondary to endothelial decompensation following cataract surgery Poor wound healing	Presenile posterior subcapsular cataracts (20s–30s), proptosis, blue sclerae Rare: nystagmus, astigmatism, telangiectasia of iris, macular degeneration, pigmentary retinopathy	AR/DNA helicase ( RECQL2 )/8p12-p11

For more information and bibliography on disorders listed in this table consult On-line Mendelian Inheritance in Man (OMIM) at http://www.ncbi.nlm.nih.gov/omim/ . The numbers given in column 1 after the disease name(s) are the OMIM entry numbers. AD , Autosomal dominant; AR , autosomal recessive; EDS , Ehlers-Danlos syndrome.

Craniofacial Dysostosis Syndromes

Although clinically distinguishable on the basis of cranial morphology and the presence or absence of hand malformations such as polydactyly (supernumerary digits) and syndactyly (fused digits), molecular genetic studies have shown that mutations of individual FGFR genes may lead to a number of clinically distinct phenotypes. Allelic mutations in the fibroblast growth factor receptor-2 (FGFR2) gene on chromosome 10 lead to Apert, Crouzon, or Jackson–Weiss syndrome. FGFR2 has two alternative gene products: keratinocyte growth factor receptor (KGFR) and bacterially expressed kinase (BEK). Mutations in FGFR1 , located on 8p11.2–p12, lead to Pfeiffer syndrome, characterized by premature fusion of several sutures of the skull, broad thumbs and great toes, short fingers and toes, and variable degrees of syndactyly. Pfeiffer syndrome can be caused by mutations in FGFR2 or FGFR1 . Mutations in FGFR3 lead to achondroplasia and to Crouzon syndrome with acanthosis nigricans (Crouzondermoskeletal syndrome). A discussion of the clinical differentiation between patients with intermediate phenotypes is beyond the scope of this text.

Crouzon Syndrome

In Crouzon syndrome there is craniosynostosis (abnormal development and premature fusion of the cranial sutures), maxillary hypoplasia, and shallowing of the orbits with proptosis. Premature closure of the cranial sutures can lead to increased intracranial pressure with secondary mental retardation and optic atrophy from papilledema. The globes may spontaneously subluxate. V-pattern exotropia secondary to overacting inferior oblique muscles is frequently present. Some patients can have absent extraocular muscles and strabismus, which also occurs in other craniosynostosis syndromes ( Fig. 59.2 ). Intraocular abnormalities such as iris coloboma, cataract, and ectopia lentis are noted infrequently. The proptosis caused by shallow orbits may lead to exposure keratitis, but it is typically not vision limiting. Crouzon syndrome is autosomal dominant with complete penetrance but variable expressivity. Approximately one-third of cases result from new mutations that are highly correlated with advanced paternal age. The gene maps to 10q26, and mutations have been identified in FGFR2 . ^,

Treatment of Crouzon syndrome consists of craniosynostectomy to relieve or prevent increased intracranial pressure. Major craniofacial surgery is often performed in infancy and early childhood. Strabismic amblyopia is the primary cause of vision loss in these patients. Strabismus surgery may be necessary after initial facial reconstruction has been completed.

Apert Syndrome

In Apert syndrome, mutations in FGFR2 cause an upregulated response in the androgen end-organ receptors and diffuse early epiphyseal fusion, which causes craniosynostosis, short stature, vertebral fusion, and symmetric syndactyly of the hands and feet involving at least digits two, three, and four, and severe acne vulgaris. Sutural involvement usually includes the coronal, but is variable and so is skull shape. Most patients are of normal intelligence but may have learning disabilities. A minority are mentally delayed. Hydrocephalus may be present. The orbits are flat and shallow with significant proptosis, which predisposes to severe exposure keratopathy and corneal scarring. Exotropia with a V-pattern is a common finding. There may be some phenotype/genotype correlation. Hyperhidrosis of the skin is a characteristic feature.

Most cases arise from new autosomal dominant mutations, with a prevalence of 1 in 65,000. Paternal age effect is well documented.Unlike Crouzon syndrome, the spectrum of mutations in Apert syndrome is quite narrow. Two mutations in FGFR2 appear to have differential phenotypic effects, with syndactyly more severe with the p.P253R mutation and cleft palate more common in p.S252W patients. ^, Although most cases of the Apert syndrome are sporadic, direct transmission has been reported, and affected females have given birth to affected children.

Saethre-Chotzen Syndrome

The Saethre-Chotzen syndrome is characterized by an asymmetric skull shape with frontal and parietal bossing. Limb abnormalities include brachydactyly, broad great toes, and cutaneous syndactyly of the second and third digits of the hands and feet. Head circumference is reduced, and the anterior hairline is low. In Saethre-Chotzen syndrome, ptosis and hypertelorism are common and optic atrophy may occur. Both esotropia and exotropia have been described. Patients may be confused with Crouzon syndrome. Saethre-Chotzen syndrome is autosomal dominant and results from mutations in the TWIST gene, which encodes a transcription factor. ^, Surgical correction of skull and digital anomalies may be indicated. Patients are carefully monitored for hydrocephalus. Strabismus surgery should be done as indicated, even before facial reconstructive surgery.

Children with any of the FGFR -related craniosynostosis syndromes usually require a series of surgical procedures. The first surgery is usually a bifrontal craniotomy with fronto-orbital advancement. It can be performed as early as 3 months of age, but should be performed before a child is ambulatory as the brain is vulnerable to trauma in the months following surgery. Complications such as hydrocephalus and exposure keratopathy may need even earlier surgical management such as ventriculo-peritoneal shunting or surgical eyelid closure. A multidisciplinary team approach is usually most beneficial in the management of these individuals.

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