Primary congenital glaucoma (PCG) is a potentially blinding disease characterized by elevated intraocular pressure (IOP) due to dysgenesis of the trabecular meshwork. If left untreated, it leads to optic neuropathy with irreversible visual loss. It can be subdivided into neonatal or newborn onset (0–1 month), infantile onset (1–24 months), and late onset or late recognized (>2 years; ▶ Fig. 9.1). PCG occurs in 1 of 4,000 to 10,000 live births and is bilateral in more than two-thirds of patients. Incidence is higher in certain ethnic groups including gypsies and some countries of the Middle East. Due to the increased elasticity of the cornea and sclera in children, elevated IOP results in buphthalmos and corneal enlargement with rupture of Descemet’s membrane (Haab’s striae; ▶ Fig. 9.2). Although traditionally thought to be confined to children younger than 2 years, this may occur rarely even up to the age of 7 years. Other findings may include anterior iris stromal atrophy, heterochromia, and axial myopia (or loss of normal-for-age hyperopia) as well as corneal epithelial and/or stromal edema. Anterior segment dysgenesis is absent. Gonioscopy typically reveals patchy high iris insertion. The classic clinical presentation includes a triad of photophobia, blepharospasm, and epiphora due to corneal edema. The older the age of onset, the fewer the signs and symptoms. Fig. 9.1 The Childhood Glaucoma Research Network (CGRN) algorithm for categorizing childhood glaucoma. Fig. 9.2 Horizontal rupture of Descemet’s membrane (Haab’s striae) in a patient with congenital glaucoma. PCG, known as GLC3 in the genetic nomenclature, is usually an autosomal recessive (AR) disorder, although autosomal dominant (AD) patterns have also been observed. Variable expression and nonpenetrance are also known. The GLC3A locus contains the cytochrome P450 subfamily I, polypeptide 1 (CYP1B1, 2p22-p21) gene which is currently the primary known etiology for primary congenital glaucoma. Mutations in this gene are responsible for 80% of PCG in Saudi Arabia but only up to 20% of PCG in North America. Neonatal onset PCG is more likely to be due to CYP1B1 mutations. The genes for GLC3B (1p36) and GLC3C (14q24.3) have not yet been identified. All three loci are characterized by an AR pattern. Although many disorders can mimic the epiphora, photophobia, and corneal clouding that characterize PCG, buphthalmos is the key distinguishing factor and a requisite for the diagnosis. The differential diagnosis here is restricted to conditions that cause true glaucoma with buphthalmos and/or macrocornea. Axial myopia, exorbitism (shallow orbits) due to craniofacial disorders, and upper lid retraction can give the illusion of an enlarged globe. Although Haab’s striae are considered pathognomic for PCG, there are other causes of Descemet’s breaks including trauma, in particular forceps-induced breaks. Congenital rubella endothelialitis, Descemet’s folds, and syphilis may have corneal endothelial changes that mimic Haab’s striae. Corneal enlargement is only seen with true Haab’s striae due to PCG. Megalocornea (OMIM 309300) is characterized by bilateral enlarged corneal diameter (>13 mm) without increased IOP. Some authors refer to megalocornea as “anterior megalophthalmos,” since the anterior segment may appear as larger than normal. Other findings include astigmatism, atrophy of the iris stroma sometimes with radial iris transillumination, miosis, iridodonesis, and lens subluxation. Affected individuals may exhibit cataract and secondary glaucoma due to lenticular dislocation. It is usually X-linked recessive, but there is an AR form, associated with developmental delay, known as Neuhauser syndrome (OMIM 249310). X-linked recessive carrier mothers may also have mildly enlarged corneas. This condition is caused by pathogenic mutations in latent transforming growth factor β binding protein 2 (LTBP2; GLC3D; 14q24.3). LTBP2 mutations may present with primary enlarged corneas with or without increased IOP and ectopia lentis with subsequent risk of lens dislocation and acute angle closure glaucoma (▶ Fig. 9.3). Some of these patients have marfanoid habitus. It is usually an AR condition. Fig. 9.3 Glaucoma associated with LTBP2 mutation. Note ectopia lentis associated with megalocornea. Iris atrophy is often seen with a cryptless iris. (The oblique vertical line through the pupil is an artifact.) Both Sturge–Weber syndrome and neurofibromatosis may have a globe that looks bigger in the absence of glaucoma. This is usually associated with orbital involvement of the systemic disease. Some cases may present with normal IOP and optic discs but typical signs of PCG including buphthalmos and Haab’s striae that are not progressive and do not show corneal edema. These cases may be classified as spontaneously arrested PCG. Advanced buphthalmos may result in ectopia lentis. Glaucoma management is beyond the scope of this chapter. Identification of the glaucoma etiology (▶ Fig. 9.1) is a key aspect of selecting the management plan. Identification of biallelic pathogenic variants in CYP1B1 confirms the diagnosis of PCG. Deletion/duplication analysis is recommended if only one or no pathogenic variant is found, given that other genes are yet to be discovered. A negative CYP1B1 gene test does not rule out the diagnosis of PCG. Key Points Juvenile open angle glaucoma (JOAG) is an AD disorder usually affecting individuals between the age of 4 and 40 years. Intrafamilial variation in age of onset is common. Early detection is difficult. Genetic testing of at-risk individuals may allow for appropriate screening. MYOC gene mutations are the only known cause at this time.
9.1.2 Molecular Genetics
9.1.3 Differential Diagnosis
Megalocornea (OMIM 309300)
Microspherophakia and/or Megalocornea, with Ectopia Lentis and with or without Secondary Glaucoma (OMIM 251750)
Overgrowth Syndrome
9.1.4 Uncommon Manifestations
9.1.5 Clinical Testing
9.1.6 Genetic Testing
9.2 Juvenile Open Angle Glaucoma
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