ONH may be found in isolation or in conjunction with myriad functional and anatomic abnormalities of the central nervous system.

The majority of children affected experience improvement in vision during the first few years of life, though the reason for this occurrence is unknown.

Abnormalities evident via neuroradiography can include agenesis (absence) or hypoplasia of the corpus callosum, absence or incomplete development of the septum pellucidum, malformations of the pituitary gland, schizencephaly, cortical heterotopia, white matter hypoplasia, pachygyria, and holoprosencephaly.

Hypoplasia of the corpus callosum, often in conjunction with other major malformations, is significantly associated with poor and delayed developmental outcome.

The most common pituitary endocrinopathies are growth hormone (GH) deficiency (70%), hypothyroidism (43%), adrenal insufficiency (27%), and diabetes insipidus (5%).

A poorly functioning pituitary gland may also cause a lack of thyroid hormone, leading to central hypothyroidism.

Approximately one-quarter of patients with ONH have adrenal insufficiency, meaning they do not produce enough cortisol on a daily basis or in stressful situations.

[3][7] The posterior pituitary gland produces anti-diuretic hormone (ADH), which controls outflow of water from the body by urine.

ADH deficiency, also known as diabetes insipidus (DI), results in dehydration and high sodium levels in the body from excessive urination.

Feeding behaviors in children with ONH often include hyperphagia (overeating), resulting in obesity; or hypophagia (reduced food intake) with or without weight loss.

Disturbance of circadian sleep rhythm, resulting in abnormal sleep-wake cycles, is noted in one-third of children with ONH.

[3] Mutations of genes involved in transcription regulation, chromatin remodelling, α-dystroglycan glycosylation, cytoskeleton and scaffolding protein, RNA splicing, and the MAP kinase signalling pathway are currently known to cause ONH.

[2] ONH impacts all ethnic groups, although in the United States, occurrence is lower in persons of Asian descent.

Occasionally, optic nerve hypoplasia may be compatible with near-normal vision; in other cases, one or both eyes may be functionally, or legally blind.

Although most patients with only optic nerve involvement lead normally productive lives, those with accompanying endocrine dysfunction or other midline cerebral abnormalities are more at risk for on-going intellectual and other disabilities.

Besides having small optic nerves, persons with ONH can have agenesis of the corpus callosum, absence of the septum pellucidum, maldevelopment of the anterior and posterior pituitary gland, and anomalies of the hypothalamus.

ONH is the single leading cause of permanent legal blindness in children in the western world.