De Morsier syndrome

De Morsier syndrome in short

• A rare and clinically diverse disorder marked by the classic triad of optic nerve underdevelopment, pituitary hormone deficiencies, and midline brain abnormalities.

Synonyms

• Septo optic dysplasia spectrum
• SOD
• Septo-optic dysplasia

Prevalence: Unknown

Inheritance: Autosomal dominant, Autosomal recessive, Multigenic/multifactorial, Not applicable

Age of onset: Antenatal, Infancy, Neonatal

How common is De Morsier syndrome?

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

What are the symptoms of De Morsier syndrome?

Very frequent symptoms

• Optic nerve hypoplasia
• Septo-optic dysplasia
• Visual impairment

Frequent symptoms

• Abnormality of the hypothalamus-pituitary axis
• Absent septum pellucidum
• Agenesis of corpus callosum
• Anterior pituitary hypoplasia
• Cleft palate
• Cryptorchidism
• Hemiplegia/hemiparesis
• Hypoplasia of penis
• Nystagmus
• Seizure
• Short stature
• Strabismus

Occasional symptoms

• Abnormal cardiovascular system morphology
• Anosmia
• Aplasia/Hypoplasia of the cerebellum
• Autism
• Constipation
• Diabetes insipidus
• Dry skin
• Esophageal atresia
• Fatigue
• Global developmental delay
• Hypohidrosis
• Intellectual disability
• Maternal diabetes
• Obesity
• Polydipsia
• Sensorineural hearing impairment
• Sleep abnormality
• Tracheoesophageal fistula
• Incidence is estimated at 1/10,000 live births.

Clinical description

Severity of the condition varies widely, with only about 30% of individuals exhibiting the full clinical triad. Many patients also present with additional associated features. Some are diagnosed at birth with septo-optic dysplasia (SOD) alongside multiple congenital anomalies, while others may not present until childhood, typically due to growth delays or visual disturbances—most commonly strabismus or nystagmus.

Optic nerve hypoplasia may affect one eye (in 57% of cases) or both (32%), and significant visual impairment occurs in approximately 23% of patients. Hypopituitarism is observed in 62–80% of cases, with growth hormone deficiency—resulting in short stature—being the most frequent endocrine abnormality. Other hormonal deficiencies may include those affecting thyroid-stimulating hormone, adrenocorticotropic hormone, and gonadotropins.

Midline brain abnormalities, such as agenesis of the septum pellucidum (seen in 60% of cases) and/or the corpus callosum, are common. Additional cortical malformations may occur and are sometimes classified under the broader term “SOD-plus syndrome.” Neurological and cognitive issues, including intellectual disability, developmental delays, seizures, and cerebral palsy, may also be present.

Other associated findings can include diabetes insipidus, sleep disturbances, autism spectrum disorder, precocious puberty, obesity, problems with temperature regulation, anosmia, sensorineural hearing loss, and various cardiac and limb abnormalities.

What causes De Morsier syndrome?

Most cases of septo-optic dysplasia (SOD) occur sporadically, though familial cases have been documented. In such familial instances, both homozygous (autosomal recessive) and heterozygous (autosomal dominant) mutations in the HESX1 gene (located at 3p21.2–p21.1) have been identified.

Additionally, three other genes have been linked to phenotypes overlapping with the SOD spectrum:

• SOX2 mutations (3q26.3–q27): Associated with anophthalmia or microphthalmia, along with features consistent with SOD.
• SOX3 mutations or duplications (Xq26.3): Linked to midline brain abnormalities and hypopituitarism; however, no associated eye anomalies have been reported to date.
• OTX2 mutations (14q21–q22): Connected with hypopituitarism and anterior pituitary hypoplasia, sometimes with accompanying eye defects.

Mutations in these genes are rare, identified in fewer than 1% of patients. Environmental influences, such as maternal drug or alcohol use and younger maternal age, are also believed to contribute to the development of SOD.

How is this condition diagnosed?

• A clinical diagnosis of septo-optic dysplasia (SOD) is made when at least two components of the classic triad are present. Confirmation involves ophthalmologic evaluation, magnetic resonance imaging (MRI), and dynamic testing of pituitary function.
• SOD should be considered in newborns presenting with hypoglycemia, prolonged jaundice, microphallus (with or without undescended testes), and nystagmus, particularly when accompanied by midline abnormalities such as a cleft palate.

Differential diagnosis

• Differential diagnoses include congenital hypopituitarism and holoprosencephaly.

Antenatal diagnosis

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

Genetic counseling

• Genetic counseling and prenatal diagnosis can be offered to families in which a disease-causing mutation has been identified. However, in cases of autosomal dominant inheritance, caution is advised due to the potential for highly variable phenotypic expression and incomplete penetrance.

How is De Morsier syndrome treated?

• Treatment for septo-optic dysplasia (SOD) is supportive and requires a multidisciplinary approach with ongoing follow-up.
• Hormonal deficiencies are managed through replacement therapy, but careful monitoring is essential, as these deficiencies may change over time.
• Children can benefit from developmental programs tailored for visual impairment, along with physical and occupational therapy to support their overall development.

What is the prognosis?

• Prognosis varies based on the severity of the condition. Early diagnosis is linked to improved outcomes, as it enables prompt identification and treatment of hormone deficiencies.