Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition

Ocular Manifestations of Systemic Disease



Alex V. Levin

Thomas W. Wilson

Elise Héon

The eye is the second most commonly involved organ in systemic syndromes after the central nervous system. Most syndromes are genetic in origin with the expression of abnormal genes in various tissues throughout the body. Multisystem involvement may occur because the same gene plays a vital role in each affected tissue or because more than one gene is involved, as in a contiguous gene deletion syndrome. Patients may present with ocular abnormalities that lead to the diagnosis of an underlying syndrome. Knowing the ocular manifestations of syndromes also allows for appropriate ophthalmic screening.

The number of known syndromes is in the thousands and is far beyond the scope of this chapter and the knowledge base of any one ophthalmic practitioner. Perhaps the most comprehensive source of information can be found in the online version of Mendelian Inheritance in Man ( Syndromes with a major manifestation in a particular organ system may be found elsewhere in this atlas. For example, Apert syndrome is discussed in Chapter 14: Craniofacial; WAGR syndrome in Chapter 6: Iris and Pupils; and Alagille syndrome in Chapter 17: Gastrointestinal.



Figure 29.1 Cockayne Syndrome

Cockayne syndrome is an autosomal recessive disorder characterized by rapid premature aging, deafness, miosis, cataract, and pigmentary retinopathy similar to retinitis pigmentosa (Chapter 8: Retina and Vitreous). Microphthalmia may also occur. Facial features include microcephaly with loss of facial adipose tissue and dermatitis secondary to sun exposure, which can also be seen in combination with xeroderma pigmentosa (Chapter 15: Dermatology, Fig. 15.6). Patients typically have some degree of developmental delay and growth retardation. Fibroblast cultures from patients with Cockayne syndrome have an increased sensitivity to ultraviolet light, and the underlying mechanism is most likely secondary to an inability to repair the skin following exposure to the sun. Patients with Cockayne syndrome can have pigmentary degeneration of the retina.


Figure 29.2 Cornelia de Lange Syndrome (Brachmann-de Lange Syndrome)

Cornelia de Lange syndrome is a genetic abnormality due to mutations in the NIPBL gene at 5p13.1 in 50% of patients, with a characteristic facies, variable mental and growth retardation, skeletal abnormalities ranging from small hands to severe limb reduction, and gastroesophageal reflux. Other findings may include deafness, cardiac abnormalities, Raynaud phenomena (Chapter 27: Rheumatology Fig. 27.18), and cleft palate. The most common facial features include hypertrichosis of the eyebrows with a “V shaped” synophrys and long arcuate eyelashes. Other ocular manifestations include unilateral or bilateral congenital ptosis, myopia, peripapillary hyperpigmentation, and blepharitis. Nasolacrimal anomalies and nystagmus may also be seen.




Figure 29.3 Hallermann-Streiff Syndrome (Oculomandibulodyscephaly with Hypotrichosis Syndrome)

Hallermann-Streiff syndrome is characterized by a triangular facies with hypoplastic mandible, beaked nose, hypoplastic nasal alae, proportionate short stature, and hypotrichosis. Ocular manifestations include bilateral microphthalmia (80%) and cataracts (94%). Nystagmus and strabismus are likely secondary manifestations. The cataract may spontaneously resorb, leaving the patient spontaneously aphakic. The involved gene and inheritance pattern are unknown. The majority of patients have normal development; however, mental retardation has been reported.


Figure 29.4 Johanson-Blizzard Syndrome

Johanson-Blizzard syndrome is an autosomal recessive disorder that is characterized by pancreatic agenesis, hypothyroidism, ectodermal dysplasia, deafness, and developmental abnormalities. The pancreatic insufficiency leads to malabsorption and nutritional challenges. Craniofacial findings include midline scalp defects and hypoplastic or absent alae nasi. Dental abnormalities are common and include absence or hypoplasia of the permanent teeth. The major ocular difficulties are due to the disrupted nasolacrimal system. This syndrome is caused by mutations in the E3 ubiquitin ligase gene (UBR1) at 15q14-21.1.


Figure 29.5 Joubert Syndrome

Joubert syndrome is characterized by developmental delay, a variable breathing pattern, cerebellar vermal hypoplasia, and a retinal dystrophy. Some children will have renal disease. Patients often have tremor, ataxia, and a variety of unusual, sometimes dysconjugate, abnormal eye movements. Other ocular manifestations include optic atrophy and strabismus. The fundus is often abnormal in infancy. In a patient suspected of having Leber congenital amaurosis (Chapter 8: Retina and Vitreous, Fig. 8.33), a careful history should be obtained regarding irregular breathing patterns and eye movements to evaluate the possibility of Joubert syndrome.




Figure 29.6 Kabuki Syndrome (Kabuki Make-up Syndrome, Niikawa-Kuroki Syndrome)

Kabuki syndrome is a systemic disorder characterized by mild developmental delay, characteristic facies, cardiac abnormalities, large ears with preauricular pits, and skeletal anomalies. The facial features include very unique elongated palpebral fissures in the horizontal direction with euryblepharon (turning out and laxity of the lateral portion of the lower eyelid). This is asymptomatic and requires no intervention unless there is a desire to normalize the appearance. Patients may also have high arching eyebrows, deficient lateral third of the eyebrows, and ptosis. The fingertip pads can be more prominent than normal (fetal pads).


Figure 29.7 Microphthalmia Linear Skin Defect Syndrome (MIDAS)

This syndrome is also known as MIDAS for its microphthalmia, dermal aplasia, and sclerocornea (Chapter 5: Cornea, Figure 5.2). There is localized dermal hypoplasia involving the head, face, or neck. These cutaneous lesions are typically linear and irregular with an erythematous appearance. There is an absence of fat herniation in the base of these defects. This genetic defect has been mapped to Xp22.3. The inheritance pattern is X-linked dominant (lethal in males).


Figure 29.8 Nager Syndrome (Acrofacial Dysostosis)

Nager syndrome is a combination of malar hyperplasia and auricular abnormalities, similar to Treacher-Collins syndrome (Chapter 14: Craniofacial, Figs. 14.14, 14.15 and 14.16), and radial limb anomalies, in particular short forearms and absent thumbs. Ocular abnormalities include a downward-slanting palpebral fissure and hypoplasia of the lower eyelashes with or without the typical lower lid coloboma seen in Treacher-Collins.




Figure 29.9 Nail-Patella Syndrome

In patients with Nail-Patella syndrome one finds absent or dysplastic nails and hypoplasia of the patellae. Other clinical manifestations include iliac horns, renal failure, and limited pronation and supination of the arms secondary to abnormal elbows. This autosomal dominant disorder is secondary to mutations in LIM-homeodomain transcription factor protein (LMX1B) at 9q34.1. There is an increased risk of glaucoma. The central portion of the iris has a flower-shaped area of pigmentation (Lester sign). Lester sign does not correlate with the incidence of glaucoma and can also be observed in the normal population.


Figure 29.10 Parry-Romberg Syndrome

Parry-Romberg syndrome is a disorder characterized by slowly progressive atrophy and distortion of one side of the face. The bone, cartilage, muscle, subcutaneous tissue, and skin slowly lose volume and structure over several years. Typical onset is within the first decade of life. Differential diagnosis includes linear scleroderma (Chapter 27: Rheumatology, Fig. 27.16). Ophthalmic findings include atrophy of the periocular tissues including the orbital bones and orbital fat. This loss of orbital volume leads to enophthalmos and possible strabismus. Atrophy of the lids also is common and can lead to corneal exposure and vision loss. Heterochromia and pigmentary retinopathy have also been observed.




Figure 29.11 Rubinstein-Taybi Syndrome

Rubinstein-Taybi syndrome is characterized by broad thumbs (right image) and great toes, mental retardation, and a characteristic facies. This autosomal dominant disorder is due to mutations in the CREB binding protein at 16p13.3. Ocular manifestations include heavy-arched eyebrows with long eyelashes and possible ptosis. Patients with Rubinstein-Taybi also have an increased risk of glaucoma and cataracts. Iris coloboma has also been reported.


Figure 29.12 Williams Syndrome

Williams syndrome is an autosomal dominant disorder due to mutation or deletion of the elastin gene at 7q11.2 consisting of structural cardiac abnormalities, mild mental retardation, an outgoing gregarious personality, characteristic facies, and dental abnormalities. The two most common cardiac abnormalities include supravalvular aortic and pulmonary artery stenosis. Patients have an elfin face that includes full cheeks, a broad forehead, a short nose with upturned nares, and a prominent upper lip (left image). Patients may have increased levels of serum calcium. The classic ophthalmic finding includes a stellate pattern to the iris (right image), which is present in approximately 50% of patients. Other reported findings include hyperopia, strabismus, and retinal vascular tortuosity.


Figure 29.13 Jeune Syndrome (Asphyxiating Thoracodystrophy)

This autosomal recessive, potentially lethal syndrome is characterized by a bell-shaped and constricted thorax, as seen in this radiograph. The gene locus has been mapped to 15q13. Other skeletal changes, particularly of the pelvis and limbs, may be seen. Polydactyly is not uncommon, and the kidneys, liver, and gastrointestinal tract may also be involved. Juvenile retinal dystrophy can be documented by electroretinogram in early infancy, and patients may have a relatively normal-appearing retina or pigmentary stippling at the level of the retinal pigmented epithelium with or without changes in the overlying internal limiting membrane.