Optic Nerve Hypoplasia (ONH)

Key Points at a Glance

Key Points of This Disease

• Optic nerve hypoplasia (ONH) is the most common congenital optic nerve abnormality, characterized by a reduced number of optic nerve axons.
• It can be unilateral or bilateral and is frequently associated with structural central nervous system abnormalities (approximately 90%) and neurodevelopmental disorders (approximately 70%).
• Septo-optic dysplasia (SOD, de Morsier syndrome) is diagnosed when two or more of the following three features are present: ONH, pituitary hormone deficiency, and absence of the septum pellucidum.
• The double ring sign on ophthalmoscopy is a diagnostic clue, and MRI evaluation of brain structures along with endocrine screening are essential.
• Visual acuity ranges from normal to no light perception, depending on the density of the papillomacular bundle.
• Endocrine abnormalities may become apparent later in life, requiring long-term replacement therapy with growth hormone, thyroid hormone, adrenal corticosteroids, etc.
• The optic nerve hypoplasia itself is non-progressive unless glaucoma develops, but long-term follow-up with multidisciplinary collaboration is important.

1. What is Optic Nerve Hypoplasia?

Optic nerve hypoplasia (ONH) is the most common congenital optic nerve abnormality, characterized by a reduced number of optic nerve axons. It can occur unilaterally or bilaterally and may be associated with midline brain structural defects.

Briere first described it histologically in 1877, and Reeves provided a clinical description in 1941. In 1956, de Morsier reported its association with absence of the septum pellucidum, leading to the term de Morsier syndrome (septo-optic dysplasia, SOD). In 1970, Hoyt et al. reported detailed clinical features, increasing awareness of this condition.

SOD is diagnosed when two or more of the following three features are present³⁾⁶⁾:

• ONH (unilateral or bilateral)
• Pituitary hormone deficiency
• Midline brain structural abnormalities (absence of septum pellucidum, agenesis of corpus callosum, etc.)

The prevalence of SOD is estimated at approximately 1 in 10,000 births²⁾⁶⁾. Epidemiologically, it is the third most common cause of visual impairment in children under 3 years of age. Reported rates are 10.9 per 100,000 population in England and 17.3 in Sweden.

In a study of 16 cases at Niigata University in Japan, the median age at first visit was 2.4 years, 12/16 (75%) were female, and 11/16 (69%) were bilateral ¹⁾.

A severe form is optic nerve aplasia. The optic disc and retinal vessels are completely absent, and there is no light perception.

Superior segmental optic hypoplasia (SSOH) is a special type in which only the superior optic nerve fibers are hypoplastic, and an association with maternal diabetes has been noted. The prevalence in Japan is reported to be about 0.3%. There is no sex difference.

Q What is the difference between ONH and SOD?

A

ONH refers to a morphological abnormality of the optic nerve alone. SOD is a syndrome that meets two or more of the triad of ONH, pituitary dysfunction, and midline brain structural abnormalities; ONH is one component of SOD. It has been reported that approximately 37.5% of ONH patients meet the diagnostic criteria for SOD ¹⁾.

2. Main Symptoms and Clinical Findings

Fundus photograph of optic nerve hypoplasia. The left eye shows a small optic disc and a peripapillary double-ring-like halo.

Mujahid M, et al. Superior Segmental Optic Nerve Hypoplasia: A Case Report and Literature Review. Cureus. 2026. Figure 1. PMCID: PMC12906824. License: CC BY.

Comparison fundus photographs: the left panel shows a small optic disc with a peripapillary double-ring-like halo. This depicts disc hypoplasia and the double-ring sign, especially seen in the segmental type.

Subjective Symptoms

Visual acuity in ONH ranges from normal to no light perception. Many cases have acuity of 0.1 or less, and visual acuity depends on the density of the papillomacular bundle. Optic nerve hypoplasia differs from other congenital disc anomalies in this respect: even if the macula is formed, the degree of development of the papillomacular nerve fiber bundle varies, so visual acuity ranges from 1.0 to extremely low.

• Decreased visual acuity: The degree varies; some cases maintain normal visual acuity.
• Visual field defects: Localized defects in the nasal or inferior field may occur. In relatively good visual acuity cases, whether unilateral or bilateral, a tendency toward bitemporal hemianopia may be detected.
• RAPD (relative afferent pupillary defect): Present in unilateral or asymmetric cases.
• Nystagmus: In bilateral cases, onset occurs at 1–3 months of age. Often accompanied by pendular nystagmus or seesaw nystagmus.
• Strabismus: In bilateral cases, often appears by 1 year of age.

In Japanese data, poor vision was found in 11/16 cases (69%), strabismus in 8/16 cases (50%), and nystagmus in 5/16 cases (31%)¹⁾.

Clinical Findings (Findings Confirmed by Physician Examination)

Characteristic findings are observed on ophthalmoscopy.

• Optic disc: Pale or gray, about half the normal size.
• Double ring sign: A double ring appearance around the small disc, with a pale inner ring (lamina cribrosa) and an outer ring (choroidal pigment layer). This is specific to this disease. It results from the disc becoming smaller due to a decrease in nerve fiber bundles, causing the area that should have been the disc to appear as a ring.
• DM/DD ratio: Ratio of disc-macula distance (DM) to disc diameter (DD). A ratio of 3 or more is suspicious, and 4 or more is highly suggestive. A ratio of 3.2 or more indicates a small disc. For DD/DM ratio, less than 0.35 is a guideline.
• Retinal venous tortuosity: If present, suggests an associated endocrine abnormality.
• OCT findings: Thinning of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL).
• Retinal vessels: The course is almost normal, but some cases have narrowed vessel diameter.

The frequencies of major ocular findings and systemic complications are shown below.

Finding	Frequency
Structural CNS abnormalities	Approximately 90%
Neurodevelopmental disorders	Approximately 70%
Hypothalamic dysfunction (bilateral)	81%
Hypothalamic dysfunction (unilateral)	69%
Developmental delay (bilateral)	78%

Q Is systemic evaluation necessary even for unilateral ONH?

A

Even in unilateral cases, hypothalamic dysfunction is found in 69%, and brain abnormalities exist in 18.2% of asymptomatic patients¹⁾. MRI and endocrine screening are essential even for unilateral cases.

3. Causes and Risk Factors

The pathology of ONH is a developmental failure of retinal ganglion cells (RGC) and nerve fibers. There are two hypotheses: a developmental anomaly theory and a retrograde degeneration theory. A hypothesis that ischemia of the optic chiasm and optic nerve due to vascular disorders of the anterior cerebral artery is the cause has also been proposed.

Most cases are sporadic²⁾³⁾.

Genetic Factors

The following gene mutations may be involved.

• HESX1: Involved in forebrain and pituitary development. Mutation carriers account for less than 1% of all SOD cases⁷⁾.
• PAX6, SOX2, OTX2: Transcription factors involved in eye and brain development.

Environmental Factors

• Young maternal age at childbirth (especially first birth at a young age)
• Maternal diabetes: particularly strongly associated with SSOH
• Preterm birth
• Drug exposure: phenytoin, quinine, LSD, alcohol

Note on Congenital Disorders

The cause of ONH is often unknown, and only a few cases have confirmed genetic factors. Although environmental risk factors have been reported, there is no established method to completely prevent the development of ONH. Proper blood glucose control and avoidance of drugs during pregnancy are recommended.

4. Diagnosis and Examination Methods

The diagnosis of ONH is based on ophthalmoscopic findings, combined with imaging and endocrine screening.

Ophthalmoscopy

Confirmation of the double ring sign is the first step in diagnosis. A DM/DD ratio of 3 or more (3.2 or more indicates a small optic disc) is used as a guideline.

Imaging

• MRI: Recommended for all ONH patients. It evaluates absence of the septum pellucidum, morphology of the corpus callosum, and size and shape of the pituitary gland.
  • Pointing down sign: A finding where the optic chiasm is displaced downward. It is characteristic of SOD ³⁾.
  • The normal width of the optic chiasm is 11.13–16.92 mm, and an optic nerve cross-sectional area ≤4.0 mm² is considered atrophy ³⁾.
• OCT: Measurement of cpRNFL thickness (circumpapillary retinal nerve fiber layer thickness). Objective quantification of thinning is possible.

In a study of Japanese patients, brain abnormalities were found in 43.8% and SOD in 37.5%. Notably, brain abnormalities were present in 18.2% of asymptomatic patients ¹⁾. Furthermore, in 2 of 3 patients with pituitary dysfunction, MRI showed normal pituitary morphology ¹⁾.

Endocrine Screening

The following tests are recommended for all ONH patients:

• Cortisol
• TSH (thyroid-stimulating hormone), FT4 (free thyroxine)
• IGF-1 (insulin-like growth factor-1), IGFBP-3
• LH (luteinizing hormone), FSH (follicle-stimulating hormone)

Differential Diagnosis

Differentiation from the following diseases is necessary:

• Optic atrophy: Acquired axonal degeneration. Presents with optic disc pallor but no double ring sign.
• Optic nerve coloboma: Optic disc excavation due to incomplete closure of the embryonic fissure.
• Morning glory syndrome: Enlarged optic disc with a petal-like appearance.
• Tilted disc syndrome: Asymmetric tilting of the optic disc.
• Glaucomatous optic neuropathy: Characterized by enlargement of the optic cup. Key differentiating points: in ONH, visual field changes do not occur over time, and the pattern of RNFL defects differs. If possible, measure RNFL thickness regularly with OCT to check for changes.

Q Can endocrine abnormalities occur even if MRI is normal?

A

Yes. In a study of Japanese patients, 2 out of 3 patients with hypopituitarism had normal MRI findings¹⁾. Endocrine screening should be performed in all patients regardless of MRI results.

5. Standard Treatment

There is no curative treatment for ONH itself. Management focuses on optimizing visual function and addressing systemic complications (especially endocrine abnormalities). Collaboration among a multidisciplinary team (ophthalmology, endocrinology, pediatrics, neurology, rehabilitation) is essential. Growth should be evaluated every six months, and visual function annually.

Visual Function Management

• Refractive correction: Early correction of refractive errors is important in children. If nystagmus is present, try refractive correction with glasses or contact lenses.
• Strabismus surgery: If strabismus is present, perform strabismus surgery, mainly recession. Extraocular muscle surgery for nystagmus may also be considered.

Endocrine Replacement Therapy

Growth Hormone

Frequency: Required in about 70% of ONH patients.

Indication: Initiate when growth hormone deficiency is confirmed.

Thyroid Hormone

Frequency: Required in about 43%.

Indication: Initiate replacement when TSH/FT4 are abnormal.

Adrenal Corticosteroids

Frequency: Required in approximately 27% of cases.

Caution: Adrenal insufficiency can be fatal during stress. Instruction on stress dosing (increasing dose during fever or surgery) is essential⁵⁾.

Antidiuretic Hormone

Frequency: Diabetes insipidus occurs in about 5% of cases.

Caution: Rapid correction of sodium can cause seizures. The correction rate should be less than 0.5 mEq/L/hour⁴⁾.

In adult management cases, replacement regimens such as levothyroxine 137 μg, desmopressin, and hydrocortisone 10 mg (morning)/7.5 mg (evening) have been reported²⁾.

Points to Note in Endocrine Management

• Endocrine abnormalities may be asymptomatic in infancy but can become apparent later with growth. Long-term periodic evaluation is essential¹⁾.
• In cases with adrenal insufficiency, increasing hydrocortisone dose (stress dosing) during stress such as infection, trauma, or surgery can be life-saving⁵⁾.
• In managing diabetes insipidus, strictly adhere to the correction rate for hypernatremia. Rapid correction can cause seizures and cerebral edema⁴⁾.

Prognosis

Optic nerve hypoplasia itself is non-progressive unless glaucoma develops. In cases without glaucoma, unnecessary eye drops or surgical treatment to lower intraocular pressure should be avoided. However, endocrine abnormalities may appear or worsen over time, making long-term follow-up essential¹⁾. Early diagnosis and initiation of hormone replacement therapy by age 3 in necessary cases can prevent sequelae, so it is important to keep this disease in mind even in unilateral cases and not miss it.

Q Will vision worsen in the future?

A

Optic nerve hypoplasia itself is non-progressive, and vision is often stable unless glaucoma develops. However, endocrine abnormalities may appear later in life, so continued periodic systemic evaluation is important.

6. Pathophysiology and Detailed Mechanism

The essence of ONH is a reduction in the retinal nerve fiber layer (RNFL) and ganglion cells, with little effect on the outer retinal layers. There are two main hypotheses for the mechanism of development.

• Developmental anomaly hypothesis: Insufficient formation of optic nerve axons due to impaired differentiation and migration of retinal ganglion cells during the embryonic period.
• Retrograde degeneration hypothesis: Retrograde axonal degeneration associated with structural abnormalities of the central nervous system (e.g., absence of the septum pellucidum, agenesis of the corpus callosum).

There is also a hypothesis that ischemia in the optic chiasm and optic nerve region due to vascular disorders of the anterior cerebral artery may be involved.

Mechanisms of Systemic Complications

Hypothalamic dysfunction is observed in 69% of unilateral ONH and 81% of bilateral ONH. The pituitary gland and optic nerve are developmentally close, and the same developmental disorder is thought to affect both.

Developmental delay is observed in 75% of all cases, with a higher rate in bilateral (78%) than unilateral (39%) cases.

SOD plus and Its Significance

SOD plus is a condition that includes cortical malformations (e.g., polymicrogyria, schizencephaly) in addition to classic SOD, and has been reported to occur more frequently than classic SOD ⁷⁾. Neurodevelopmental prognosis is poorer, and the risk of epilepsy is higher.

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7. Latest Research and Future Perspectives (Research-stage Reports)

For patients: Please read this

The following content is currently at the research stage or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Setmelanotide Clinical Trial

A clinical trial (NCT06760546) of setmelanotide, a melanocortin 4 receptor (MC4R) agonist, is ongoing as a drug therapy for obesity associated with SOD ²⁾. Hypothalamic obesity significantly reduces the QOL of SOD patients, so this is attracting attention as a new treatment option.

New Approaches to Endocrine Intervention

In SOD neonates diagnosed with normoglycemia, testosterone therapy (25 mg intramuscular injection, once monthly for 3 months) for management of micropenis and cryptorchidism, as well as trials of recombinant FSH therapy, have been reported ⁵⁾. These indicate the potential for early endocrine intervention, but long-term efficacy and safety have not yet been established.

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8. References

1. Kiyokawa M, Ueki S, Hatase T, Hanyu T, Fukuchi T. The Prevalence of Brain Abnormalities in Japanese Patients with Optic Nerve Hypoplasia. Neuro-Ophthalmology. 2021;45(4):265-270.
2. Swami A, Sharma M, VanDyke L. Hypopituitarism and Other Endocrinopathies as a Consequence of Septo-Optic Dysplasia. Cureus. 2025;17(4):e82329.
3. Suwal S, Khatiwada A, Lamichhane S, Ghimire P, KC S. Exploring the diverse imaging spectrum of Septo-optic dysplasia: A case series. Radiol Case Rep. 2025;20:384-390.
4. Oyadiran OO, Gonzalez N, Khiami A. Hypernatremia in an Infant: A Case of Septo-Optic Dysplasia. Cureus. 2021;13(1):e12450.
5. Palorath A, Kharode I. Septo-Optic Dysplasia Diagnosed in a Newborn Infant with Normoglycemia. Case Rep Pediatr. 2021;2021:4836030.
6. Aliu E, Musa J, Parisapogu A, et al. Septo-optic dysplasia in an infant. Radiol Case Rep. 2022;17:3147-3150.
7. Reyes A, Galvis J, Estupinan Y. Septo-optic dysplasia plus: A case report. Biomedica. 2024;44:451-459.