Very little information is known pertaining to the causes of the impaired outflow in each of the primary childhood glaucomas. The secondary glaucomas can be understood related to the primary ocular disease complicated by glaucoma, e.g., neoplasm or uveitis. Some information is available, however, from studies of PCG.

PCG results from an abnormality of the trabecular meshwork that may represent a developmental arrest or relative immaturity of the trabecular tissue causing increased resistance to aqueous outflow [2, 3]. Initially, the defect was thought to be an imperforate membrane lining the anterior chamber angle based on its gonioscopic appearance suggesting a “clothed membrane with a shagreened surface.” [4, 5] Evidence of this membrane has not been found [6].

The histopathology of PCG is characterized by an anterior insertion of the iris with variable exposure of the trabecular meshwork to the anterior chamber [6]. The anterior iris insertion may cover a variable amount of ciliary body band and trabecular meshwork. The anterior portion of the ciliary body overlaps the posterior portion of the trabecular meshwork with underdevelopment of the angle recess. The longitudinal fibers of the ciliary muscle insert directly into the corneoscleral meshwork passing in front of the internal tip of an underdeveloped scleral spur. In one study (77.8 %), eyes with PCG had either an invisible or narrow ciliary body band compared to only 13.8 % of control eyes [7].

Anderson showed that the trabecular meshwork is porous and that the intertrabecular beam spaces are present, but also that the trabecular beams in between these spaces are abnormally thickened [6]. Maul et al. found an increased amount of collagen fibrils in the core of the trabecular beams [8]. The juxtacanalicular meshwork in the eyes with PCG had been found to be thicker than in normal eyes [6, 8, 9]. Unlike the corneoscleral meshwork, this external layer of the meshwork is normally compact with a lack of intertrabecular spaces [9]. The cells in the juxtacanalicular layer are normally round with short cytoplasmic processes and are surrounded by extracellular materials comprising of collagen, elastic fibers, and amorphous substances, giving it a compact appearance [8, 9].

Enucleated eyes of premature infants reveal that the trabecular sheets first appear on the anterior chamber side of the trabeculum and gradually progress with fetal age toward Schlemm’s canal [3]. The trabecular meshwork at 42 weeks of gestation shows intertrabecular spaces similar to that seen in adult eyes, with only a few layers of cells in the juxtacanalicular area. Hence, it has been postulated that the thicker-compact juxtacanalicular meshwork seen in PCG is perhaps the result of delayed differentiation [3].

The absence of Schlemm’s canal has also been described in PCG, but this is an exception and indicates more severe maldevelopment [10, 11]. Both immaturity of the juxtacanalicular meshwork and/or underdevelopment of Schlemm’s canal or collector channels could explain the failure of goniotomy [11].

Similarity of the angle histopathology in PCG, glaucoma with the Sturge–Weber syndrome, and in the maternal rubella syndrome with glaucoma [12] suggests that a common pathway for angle development is affected in these diverse conditions. The underlying mechanism of trabecular dysgenesis is still unknown even though the genetic basis for PCG has been determined in many cases [13, 14]. The most probable mechanism is offered by Anderson who reported that excessive formation of collagen in the trabecular tissue results in thickened and taut trabecular beams that prevent posterior sliding of the peripheral iris and ciliary body along the inner eye surface, resulting in the anterior location of the uveal tract and underdevelopment of the angle recess [6]. The success of goniotomy in PCG may be explained by the relief of tension on the thickened and compact trabecular meshwork, with resultant decreased resistance to the outflow of aqueous [6].

PCG, which accounts for approximately 55 % of primary pediatric glaucomas and is the most common type, is hereditary with a variable incidence in different populations, but with an overall occurrence of 1 in 10,000 births [15, 16]. The majority (about 75 %) of PCG cases are bilateral, and asymmetric expression should be suspected in clinically apparent unilateral cases [12]. More than 80 % present within the first year of life, with 25 % diagnosed in the neonatal period, and 60 % within the first 6 months of life [12].

The majority of PCG cases are sporadic, but 10–40 % are familial with frequent related consanguinity [17]. In most familial cases, transmission is autosomal recessive with variable expression and penetrance of 40–100 % [17]. Three loci for PCG have been found [17–19]. The initial locus on chromosome 2p21 (GLC3A) was described in 1995 by Sarfarazi et al. who identified significant genetic linkage to this region in 11 of 17 Turkish families [13, 17]. Although three chromosomal loci have been linked to PCG, only the gene CYP1B1 in locus GLC3A has been identified [14]. Mutations in the CYP1B1 gene were found responsible for 87 % of familial cases but present only in 27 % of sporadic cases of PCG [17]. Approximately, 45 mutations of this gene have been identified and include deletion, insertion, point mutation, missense, nonsense, frameshift, and terminator mutations [20]. Genotype–phenotype correlation was described related to the success of glaucoma management and abnormalities secondary to elevated IOP; the most severe phenotype was associated with frameshift mutations [20]. In cases of parent–child transmission, molecular analysis invariably found homozygosity or compound heterozygosity for the mutant alleles in the affected parent and gene carrier status in the normal parent [21]. These are examples of pseudodominance involving an autosomal recessive trait.

PCG is genetically distinct from conditions classified as an anterior segment dysgenesis or Axenfeld–Rieger syndrome/anomaly, which is transmitted by autosomal dominant inheritance resulting from mutations in the transcription factor genes PITX2 or FOXC1 [22, 23]. PCG is also unrelated to JOAG in which the MYOC (TIGR) gene has been identified at locus GLC1A on chromosome 1q25 [24]. Glaucoma associated with a facial nevus flammeus (Schirmer–Sturge–Weber Syndrome) is the most common nonhereditary primary glaucoma seen in infancy.

Importantly, in the evaluation of a child with primary childhood glaucoma, it is frequently informative to examine all other family members for evidence of related disease. This especially includes younger and future siblings and parents. The penetrance and expressivity of PCG is highly variable [17]. Complete examination of siblings is essential to rule out the presence of glaucoma, which could be easily missed if the clinical presentations are quite different and less severe than present in the affected sibling. When autosomal dominant inheritance is responsible for anterior segment dysgenesis, highly variable expressivity is frequent, and the examination of parents and other family members of suspected cases is frequently informative and always indicated.

The signs and symptoms of glaucoma in infancy are variable dependent on the child’s age, the severity of glaucoma, the presence of associated ocular anomalies, and the development of secondary corneal IOP-related abnormalities (Table 22.2). Very few children are asymptomatic and show minimal evidence of glaucoma.

Infants are most likely to present with subtle corneal enlargement and diffuse corneal opacification, which is often recognized promptly by physicians or parents. The classic symptoms of epiphora, photophobia, and blepharospasm are secondary to corneal edema and opacification and breaks in Descemet’s membrane. Infants may exhibit irritable behavior, which may be mistakenly attributed to colic or formula intolerance. The epiphora may be misinterpreted as evidence of a congenital nasolacrimal duct obstruction, or a “red eye” mimicking conjunctivitis, leading to further delayed diagnosis. The corneas are often diffusely thick due to stromal edema and later become thin with pathologic corneal enlargement. Alternatively, focal stromal thickening and opacification occur in association with breaks (Haab’s striae) in Descemet’s membrane. These defects are typically horizontal, curvilinear, and parallel to the limbus in the peripheral cornea. Progressive corneal enlargement secondary to the IOP ceases by 3–4 years of age. Both parents and physicians may accept corneal enlargement as a normal variation, even when more exaggerated unilaterally. The etiologic differential diagnosis of the classical signs of infantile glaucoma is tabulated for reference in Table 22.3.

In older children, astigmatism and progressive axial myopia cause symptomatic decreased uncorrected visual acuity and refractive amblyopia. These children with a late-recognized infantile glaucoma may be asymptomatic and discovered to have elevated IOP or optic nerve cupping on routine ocular examination or when examined for unrelated ocular conditions. While cupping of the optic nerve in glaucoma is generally a gradual process in older children and adults, it can occur rapidly in infants. Reversibility of the cupping with normalization of IOP in young children occurs due to suspected increased elasticity of the lamina cribrosa.

The clinical examination (Table 22.4) of a child with glaucoma requires patience, time, and skill. A detailed examination utilizing a table-mounted slit-lamp for tonometry and biomicroscopy of the anterior segment and optic nerve head is not possible in most children under 5 years of age, but an informative office evaluation can still be obtained.

An appropriate medical and family history and examination of family members are essential due to the genetic basis of some types of childhood glaucoma. A general physical examination is also indicated when evidence of a systemic and/or ocular developmental defect suggests diagnoses other than isolated glaucoma, or when general anesthesia is planned. Because children resist being held down or touched in the eye region, clinical information must be gained by careful inspection before laying hands on them. The presence of glaucoma may be obvious on inspection alone by observing the presence of hazy, enlarged or asymmetrical corneas, light sensitivity, and abnormal visual behavior.

Vision assessment includes observing the child’s behavior, interest in toys, willingness to follow objects, presence of nystagmus, and pupillary reactivity. The relative function of the two eyes should be compared when clinically appropriate.

The inspection and examination of the anterior segment is facilitated by the use of a penlight and a handheld slit-lamp, which allow maneuverability regardless of the child’s position. Magnification obtained with loupes or with the oculars present on handheld slit-lamps is useful. The corneal size and clarity should be studied. Asymmetry in cornea size is usually more obvious on inspection than by measurement. Breaks in Descemet’s membrane must be identified and differentiated from other abnormalities such as the more vertically oriented defects seen after forceps-induced birth trauma, or the irregular-scattered defects seen with posterior polymorphous dystrophy.

The iris and pupil should be carefully studied for abnormalities such as iris stromal hypoplasia, pupillary ectopia, and pupillary enlargement and irregularity as seen with newborn PCG, Axenfeld–Rieger anomaly, and aniridia. The anterior chambers are typically deep, and the lenses are clear in most PCG patients.

Tonometry is an essential component of the examination and can be the most difficult part with an uncooperative child. The best IOP measurements are taken with a sleeping or relaxed child using topical anesthesia. IOP readings are variably altered by sedation and general anesthesia and falsely elevated with a struggling patient. Time and patience are the most important requirements for success. Repeated measurements during the same or return office visits may be necessary. Parents can help by holding the child to provide reassurance and to distract the patient with a toy or a bottle. Tonometry efforts should be initially directed to the more normal eye as IOP measurements are more critical in determining if this eye has glaucoma. Various instruments have been used in the measurement of IOP in children. The Perkins applanation tonometer probably ranks highest in terms of accuracy, and the Tono-Pen (Medtronic Solan, Jacksonville, Florida, USA) highest in ease of use. The corneal thickness should be measured when possible to improve the interpretation of the eye pressure measurements. The Schiotz tonometer is still useful to give an indication of the IOP in the young or struggling child examined in the supine position, although its accuracy is most affected by corneal thickness and curvature and scleral rigidity. In older cooperative children, the familiar slit-lamp-mounted Goldmann tonometer may be used more confidently.