Optic nerve hypoplasia (ONH) is the most frequent optic nerve head anomaly. It is a unilateral or bilateral congenital, nonprogressive developmental abnormality. The clinical presentation is extremely variable. A “double-ring sign,” which is the outline of the circle formed by the lamina cribrosa unfilled by optic nerve fibers around the small optic nerve, is not always present (▶ Fig. 30.1). Retinal vascular tortuosity and a failure of the normal arcade pattern to develop are also important but inconsistent signs. Patients usually present with reduced vision with or without nystagmus or strabismus. Visual acuity in affected individuals does not necessarily correlate with the size of the optic nerve head. In mild cases, increased disc-to-macula distance/disc diameter ratio can be used to determine if ONH is present. Other visual functions such as color vision may remain unaffected. An afferent pupillary defect can be seen. ONH may be associated with other ocular disorders such as microphthalmia, aniridia, and albinism.
Fig. 30.1 Severe optic nerve hypoplasia. The white arrow indicates the optic nerve. The black arrow indicates the double-ring sign.
ONH accounts for up to one-quarter of children with significant congenital visual loss. Depending on the population, 5 to 15% of blind children have ONH. The estimated prevalence is 1.5:10,000. It is thought that fetal exposure to teratogenic agents such as alcohol or illicit drugs has increased the incidence of ONH. Carbamazepine, isotretinoin, phenytoin, quinine, and valproic acid have also been suggested as predisposing factors. Segmental inferior hemi-ONH has been associated with maternal gestational insulin-dependent diabetes.
Individuals with ONH should be evaluated for systemic associations such as neurologic and endocrine anomalies. Many syndromes have been reported with ONH (see text box below). Approximately half of patients with ONH have hypopituitarism, while neuroimaging anomalies are detected in 60% of bilaterally affected individuals, and approximately one-third of those with unilateral ONH, and include hypoplastic optic nerves with a hypoplastic chiasm, cortical heterotopia, other neuronal migration anomalies, hydrocephalus, and absent or hypoplastic corpus callosum and/or absent septum pellucidum. Less common findings include cerebral atrophy, encephalocele, cerebellar vermis hypoplasia, and other posterior fossa anomalies. The pituitary may be absent (empty sella) or, more commonly, the posterior pituitary bright spot seen on magnetic resonance imaging (MRI) is found ectopically in the pituitary stalk (▶ Fig. 30.2). The stalk itself may be hypoplastic. When pituitary abnormalities are found along with other midline brain anomalies, the term septo-optic dysplasia (SOD) is sometimes used. Although sometimes labelled de Morsier’s syndrome, historically it is notable that de Morsier never actually described this disorder. Patients with SOD may also show facial dysmorphism, macrocrania, and a large anterior fontanelle. Patients may have developmental delay, seizures, or cerebral palsy. Hormonal alterations include thyroid, growth, adrenal (corticosteroid), and antidiuretic hormone deficiencies. The risk of developing such hormonal abnormalities is increased in bilateral cases or if there are midline brain defects, although milder hormonal alterations may occur in unilateral cases. Testing for thyroid and corticosteroid axis abnormalities is essential even if neonatal testing was normal. Sudden death may occur if these abnormalities are not identified and promptly treated (see text box ▶ below).
Fig. 30.2 Brain magnetic resonance imaging in a patient with septo-optic dysplasia, revealing ectopic pituitary “bright spot” (arrow).
Systemic Syndromes Associated with Optic Nerve Hypoplasia (ONH) (OMIM)*
Aarskog syndrome (305400).
Aicardi syndrome (304050).
Blepharophimosis syndrome (110100).
CHARGE (Coloboma of the eye, Heart defects, Atresia of the nasal choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities with or without deafness) syndrome (214800).
Duane syndrome (126800).
Goltz syndrome (109400).
Goldenhar syndrome (164210).
Neonatal central diabetes insipidus.
Nevus sebaceous of Jadassohn (163200).
Noonan syndrome (163950).
Proteus syndrome (176920).
Smith–Lemli–Optiz syndrome (270400).
STAR syndrome (300707; toe syndactyly, telecanthus, anogenital, and renal malformations).
SUNCT (Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing) syndrome.
Vici syndrome (242840).
Walker-Warburg syndrome (236670).
*Most relevant syndromes included
30.2 Molecular Genetics
Most patients with ONH will not have an identifiable molecular cause. Rarely, homozygous or heterozygous pathogenic variations in HESX1 have been seen in patients with SOD. SOX2, SOX3, PAX6, and OTX2 have also been implicated in ONH. Compound heterozygosity for two pathogenic variants in SLC25A1, which encodes the mitochondrial citrate transporter, has also been reported. FGFR1, FGF8, and PROKR2 mutations have been associated with ONH. Although ATOH7 polymorphisms have been associated with ONH, sequencing in these patients has not shown pathogenic variants.
30.3 Differential Diagnosis
30.3.1 Optic Nerve Atrophy
Pallor of the optic nerve is the hallmark sign of optic nerve atrophy. Optic atrophy can result in abnormal visual acuity, visual fields, and color vision. Causes include tumor, trauma, ischemia, papilledema, toxins, dietary deficiencies, inflammation, infiltration, primary genetic etiologies, and infection. It is distinguished from ONH in that the size of the optic nerve is normal in optic atrophy.
30.3.2 Tilted Disc Syndrome
This congenital anomaly occurs in up to 2% of the general population. Although it is mostly sporadic, there are reports of AD inheritance. It is defined by tilting of the optic disc, but can also have inferonasal crescent (peripapillary atrophy), situs inversus, and/or inferior staphyloma. It is usually bilateral. It can be associated with high myopia. Visual field can show bitemporal superior visual field defects.
A small optic nerve and double ring can be confused with the cup and the rim, respectively.
30.3.4 Optic Nerve Coloboma
Optic nerve coloboma may be rarely confused with ONH (▶ Fig. 30.3).
Fig. 30.3 Coloboma involving the optic nerve.