SEPTO-OPTIC DYSPLASIA

SOD: Definition

• Variable combination of midline forebrain abnormalities, eye abnormalities and pituitary abnormalities

• Rare: reported incidence 1/50000; probably commoner

• 2/3 features to make the diagnosis

• Commoner in younger mothers

Forebrain abnormalities

• In 75-80% of patients

• Absence of septum pellucidum

• Absence of corpus callosum

• Cerebellar hypoplasia

• Schizencephaly

Consequences of forebrain anomalies

• Fits

• Behavioural difficulties

• Learning difficulties

• Developmental delay

• Hemiplegia

Optic nerve hypoplasia

• Unilateral/bilateral

• Bilateral commoner

• Associated with anopthalmia/micropthalmia

• Visual impairment variable - complete to compensated

Pituitary gland

• Develops from the oral cavity in the embryo and the brain (hypothalamus)

• 5 different cell types in anterior pituitary producing 6 different hormones

• Secretion of hormones regulated by hypothalamus

Anterior pituitary gland

• Growth hormone: growth and helps maintain normal blood sugar levels in children; increases bone strength, muscle mass and decreases fat mass and heart disease in adults

• ACTH: regulates production of cortisol and androgens from adrenal glands; cortisol essential for normal well-being and to fight stress and infection

Anterior pituitary gland

• Prolactin: important for lactation, ?immune system

• FSH, LH: important for puberty and fertility; LH important for normal development of males and for descent of testes into scrotum

• TSH: important for regulation of thyroid gland and thyroxine production

Posterior pituitary gland

• Vasopressin: important for normal fluid balance - retains water by controlling reabsorption of water in kidney tubules

• Oxytocin: important for parturition (birth) and ejection of milk

Pituitary Hormone Deficiency

• GH: poor growth with eventual short stature, possibly increased incidence of myocardial infarction

• Prolactin: no lactation• ACTH: low cortisol leading to low blood sugar,

lethargy, inability to fight stress and infection, low blood pressure, low sodium level in blood, collapse

Pituitary Hormone Deficiency

• FSH, LH: inadequate sexual development in males, lack of puberty, lack of fertility

• TSH: lack of thyroxine with slowness, cold intolerance, constipation, growth failure, mental retardation if not picked up early

• Vasopressin: diabetes insipidus with excessive urinary output

Complexity of hypothalamo-pituitary development

• Early puberty: can be explained on basis of hypothalamic involvement

• Occasionally mixed involvement of hypothalamus and pituitary

Clinical features of SOD

• Conjugated jaundice• Neurological features• Variable visual loss• Impaired sense of smell• Endocrine features• Behavioural disturbances eg. autism• Sleep disturbance

MRI SCANS OF SOD PATIENTS

CONTROL SIBLING 2 SIBLING 1

Management of SOD

• Support from Neurologists and Opthalmologists: treatment of convulsions

• Mainstay of treatment: endocrine

Endocrine replacement

• Growth hormone: daily subcutaneous injections

• Hydrocortisone: X3 doses daily; adjustment with illness/stress

• DDAVP: nasal/oral

• Thyroxine

• Ethinyloestradiol/testosterone

Investigations

• MRI scan of brain• Visual evoked responses/electroretinogram• Routine electrolyte measurement• Thyroid function tests• Pituitary function tests:

glucagon/insulin/LHRH/TRH - in tertiary centres ideally

• Fluid balance

Monitoring

• Evolving - new endocrine features may develop

• Monitoring of growth rate at regular intervals

• Monitoring through puberty

• Regular checks of thyroid function, watch fluid balance

Long-term outlook

• Short stature

• Developmental/intellectual impairment

• Fits, hemiparesis etc

• Impaired fertility

• Visual impairment

• Sleep/behavioural difficulties

• Obesity

Why do you get SOD?

• Development of pituitary gland, forebrain, olfactory bulbs and eyes all from the same part of the early embryo. Problems occur at 3-6 weeks of gestation

• Environment and teratogens

• Familial cases: dominant or recessive

Genetics of SOD

• Mutations in HESX1: Dominant or recessive

• Occasionally, one abnormal copy of gene carried with no phenotype in parent but child affected

• Number of other developmental genes may also be involved: all extrapolated from animal studies

Research

• New genes involved in SOD: what is their function

• Why the variability in severity

• Sleep/wake cycles in children with SOD and hypothalamic involvement and the use of melatonin (10-18 year olds)