Biological Pathways Leading to Septo-Optic Dysplasia: A Review

Major Points and Findings:

This 2025 review, by a child neurology and genetics group in Pavia, Italy, does not deal with stem cells or any other treatment. It covers what is known about why septo-optic dysplasia (SOD) happens. The authors discuss the genes that have been linked to it, the developmental signalling pathways those genes belong to, and how the older “blood supply” theory fits with the genetic findings. We include it because parents are often told that the cause is unknown. The paper sets out how much and how little is understood, and when genetic testing should be considered.

The paper is a narrative review. The authors state that it represents their own perspective based on selected literature, and they did not formally grade the quality of the case reports they collected. Much of the pathway evidence comes from work in mice and was not obtained in children with SOD.

Aim:

To collect published cases of SOD with a confirmed genetic diagnosis in genes other than the four classic ones (HESX1, SOX2, SOX3 and OTX2), and to describe the biological pathways that may lead to SOD.

Methods:

The authors searched PubMed and Google Scholar, last updated in November 2023, for primary research articles and case reports with full text available, using the terms “case reports”, “humans”, “septo-optic dysplasia” and “optic nerve hypoplasia”. There was no limit on publication year. Only peer-reviewed papers in English were used. A case was included if it met current clinical and radiological criteria for SOD (at least two of: optic nerve hypoplasia, midline brain defect, hypothalamic-pituitary dysfunction) and had a confirmed genetic finding outside the four known genes. Papers on biological pathways implicated in SOD were reviewed alongside.

Results:

Definitions used in the review:

• SOD is diagnosed when two of the three features are present. Only about 30 to 47% of patients have all three. If only one is present, the authors say it should be treated as a separate entity.
• “SOD-plus” means SOD with a malformation of the brain’s cortex, such as schizencephaly, polymicrogyria, focal cortical dysplasia or nodular heterotopia. A table gathers 14 publications describing 35 such patients. SOD-plus generally carries a more severe outlook, and drug-resistant focal epilepsy is frequent.
• Reported frequencies of hormone problems in SOD: central hypothyroidism about 70%, growth hormone deficiency 55%, adrenal insufficiency 50%, central diabetes insipidus 30%. About 30% of patients have epilepsy. Early signs are often low blood sugar and jaundice in a newborn, then abnormal eye movements within three months.

The vascular theory: One long-standing explanation is that SOD follows an interruption of blood flow in the fetus affecting the proximal trunk of the anterior cerebral artery. The evidence cited in support includes a strong and repeatedly confirmed link with young maternal age and first pregnancy, a link with low maternal body mass index, and co-occurrence with gastroschisis and amniotic band syndrome (both also thought to be vascular). There are also associations with drugs that affect blood vessels in pregnancy (valproic acid and cocaine among those named). An updated version of the theory proposes that the disruption first causes optic nerve hypoplasia or a septum pellucidum defect and can then extend to the pituitary or to the cortex.

The genetic findings:

• Fewer than 1% of cases are explained by mutations in HESX1, SOX2, SOX3 or OTX2. Most SOD is sporadic and familial cases are rare.
• The authors identified published cases with other genetic findings. The text gives twelve articles. The table lists thirteen. Exome sequencing was the method in nine. The genes or chromosome changes were: TUBB, TUBA1A, NR2F1, FLNA, ENG, SMCHD1, SON, TAX1BP3, ARID1A and VAX1, plus a chromosome 14 deletion, an unbalanced 5;12 translocation and an 8q deletion with 3p trisomy.
• Seven of these patients had features beyond the SOD triad, for example facial differences, heart defects, cleft palate, extra or fused digits, microcephaly or cardiomyopathy. According to the authors, SOD-plus patients in this set carried complex chromosome rearrangements detectable by array CGH.
• Where a formal classification was given, variants were rated pathogenic or likely pathogenic in six cases and of uncertain significance in three. Some of these links are therefore provisional.
• Several of the genes are already known for other syndromes (for example ARID1A for Coffin-Siris syndrome and ENG for hereditary haemorrhagic telangiectasia).

The pathways: The review describes six signalling systems through which these genes act during the first weeks of brain development. They are Ras-RAF-MEK-ERK/MAPK (BRAF gain-of-function mutations can cause hypopituitarism by disturbing pituitary stem cells), Wnt/beta-catenin (the pathway most represented, involving SOX2, SOX3, OTX2, TAX1BP3, TCF7L1, VAX1 and PAX6), FGF8 and FGFR1 (shared with Kallmann syndrome), PI3K-AKT, PROK2/PROKR2 (probably a modifier and not a cause, since the same variant was found in healthy relatives and in 1 of 250 controls), and Sonic hedgehog (deleting Shh in the mouse hypothalamus reproduces SOD, and SOX2 and SOX3 directly switch Shh on). Sonic hedgehog signalling is also a known target of prenatal alcohol exposure, which offers one route by which genes and environment could interact.

Conclusions:

SOD has a low rate of genetic diagnosis. The authors argue that it cannot be explained by a single event, vascular or otherwise, because the affected structures form at different times (pituitary and optic nerves at about weeks 4 to 7 of gestation, corpus callosum and septum pellucidum from about week 10 to 15). They recommend genetic investigation for children who meet at least two diagnostic criteria, particularly when there are additional syndromic features, and also for children born to older mothers who have had previous pregnancies, since these do not fit the usual vascular risk profile. In non-genetic cases, brain findings tend to be milder.

The paper does not list its own limitations in a separate section. From the methods, the main ones are that the search relied on two databases and case reports only, no quality appraisal was done, several variant classifications are uncertain, and the count of included articles is inconsistent between text and table.

Background Information:

The review gives a prevalence of about 1 in 10,000 live births and notes that the reported frequency of SOD has been rising, which may reflect changing environmental exposures.

The timing of these events bears on any discussion of treatment. Everything described here happens in the first trimester. SOD is a difference in how the forebrain, optic nerves and pituitary were built. The condition does not go on damaging these structures after birth. The review discusses no restorative therapy, and we found no clinical study of cell therapy in SOD. The consequences can be treated well, since hormone deficiencies, seizures, sleep disturbance and visual impairment each have established management. A genetic diagnosis, where one can be made, helps a family understand recurrence risk and alerts doctors to problems in other organs.