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Septo-optic dysplasia

Orpha number ORPHA3157
Synonym(s) De Morsier syndrome
SOD
Septo-optic dysplasia spectrum
Prevalence Unknown
Inheritance Not applicable
Autosomal dominant
Autosomal recessive
Multigenic/multifactorial
Age of onset Infancy
Neonatal
ICD-10
  • Q04.8
ICD-O -
OMIM
UMLS
  • C0338503
MeSH
  • D025962
MedDRA
  • 10067159
SNOMED CT
  • 7611002

Summary

Septooptic dysplasia (SOD) is a clinically heterogeneous disorder characterized by the classical triad of optic nerve hypoplasia, pituitary hormone abnormalities and midline brain defects.

Incidence is estimated at 1/10,000 live births.

Severity varies and only 30% of patients manifest the complete clinical triad with many patients having associated findings. Some patients present at birth with SOD associated with multiple congenital anomalies, whereas others present during childhood with growth failure and/or visual anomalies (most frequently strabismus or nystagmus). The optic nerve hypoplasia can be uni- or bilateral (57% and 32% of cases, respectively) and significant visual impairment occurs in 23% of patients. Hypopituitarism is present in 62-80% of patients and although growth hormone deficiency (leading to short stature in childhood) is the most frequent endocrine anomaly, additional hormone insufficiencies may develop (thyroid-stimulating, adrenocorticotropic and gonadotropin-releasing hormone deficiencies). Midline brain defects include agenesis of the septum pellucidum (60% of cases) and/or corpus callosum. Associated cortical malformations have also been reported (sometimes referred to as SOD-plus syndrome). Intellectual deficit and neurological manifestations (developmental delay, seizures and cerebral palsy) may be present. Additional findings may include diabetes insipidus, sleep disorders, autism, precocious puberty, obesity, thermoregulatory disturbances, anosmia, sensorineural hearing loss and cardiac and digital anomalies.

The majority of SOD cases are sporadic but familial cases have been described. Both homozygous (autosomal recessive transmission) and heterozygous (autosomal dominant transmission) HESX1 mutations (3p21.2-p21.1) have been described in familial cases. Three additional genes have been implicated in associated phenotypes that may be considered as part of the SOD spectrum: SOX2 mutations (3q26.3-q27) associated with anophthalmia/microphthalmia and features of SOD; mutations/duplications in the SOX3 gene (Xq26.3) associated with midline brain anomalies and hypopituitarism (although no eye defects have yet been described); and OTX2 mutations (14q21-q22) associated with hypopituitarism and anterior pituitary hypoplasia, with or without eye defects. Mutations in these genes are detected in < 1% of patients and environmental factors (drug and alcohol abuse, young maternal age) may also be involved.

Clinical diagnosis requires the presence of at least two of the features of the classical triad and can be confirmed by ophthalmological studies, MRI, and dynamic pituitary function tests. SOD should be suspected in newborns with hypoglycemia, jaundice, microphallus (with or without undescended testes) and nystagmus with or without associated midline abnormalities (such as cleft palate).

Differential diagnoses include congenital hypopituitarism and holoprosencephaly (see these terms).

OD may be suspected antenatally by ultrasound and subsequent fetal MRI studies.

Genetic prenatal diagnosis and genetic counseling may be proposed to families in which the disease-causing mutation has been identified, but caution needs to be exercised in cases with autosomal dominant inheritance as the phenotype and penetrance may be highly variable.

Treatment is symptomatic and SOD patients should be managed by a multidisciplinary team with regular follow-up. Hormone insufficiencies can be treated with hormone replacement therapy but close monitoring is required as the hormone deficiencies evolve with age. Children may benefit from developmental programs for the visually impaired, as well as from physical, and occupational therapies.

Prognosis is variable, depending on the severity of the disease. Early diagnosis is associated with a better outcome as it allows timely management of hormone insufficiencies.

Expert reviewer(s)

  • Pr Mehul DATTANI
  • Dr Emma WEBB

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Detailed information

Practical genetics
  • EN (2009,pdf)
Clinical genetics review
  • EN (2014)
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