Septo-optic Dysplasia (SOD) &/Or Optic Nerve Hypoplasia (ONH)

1. Septo-optic Dysplasia (SOD) &/Or Optic Nerve Hypoplasia (ONH) Geoff Bowen, Psychologist Statewide Vision Resource Centre

3. Born blind and probably autistic, Thomas Green Wiggins was known as Blind Tom. He sustained a career that spanned 50 years and performed for all manner of distinguished critics and fans, including Mark Twain, and he was the first African-American to perform at the White House. Did he have SOD/ONH? Biography of Blind Tom by Australian writer Deirdre O'Connell

4. Reference of Note Texas School for the Blind Texas Focus: Learning From Near to Far Septo-Optic Dysplasia/Optic Nerve Hypoplasia & Autism Spectrum Disorders June 10, 2010Terese Pawletko, Licensed Psychologist/Certified School Psychologist Portsmouth, NH

5. SOD: Definition • SOD previously termed de Morsier syndrome, was first described by Reeves in 1941 as an absence of the septum pellucidum in association with optic nerve abnormalities. • Variable combination of midline forebrain abnormalities, eye abnormalities and pituitary abnormalities.

6. 2/3 features to make the diagnosis: − Optic nerve hypoplasia − Absence of the septum pellucidum − Thinning of the corpus callosum − Pituitary hormone deficiency (added by Hoyt WF, Kaplan SL, Grumbach MM, et al. Septo-optic dysplasia and pituitary dwarfism. Lancet. 1970;1:893–894.)

7. “SOD can present at birth in association with multiple congenital abnormalities or much later on when growth failure occurs in a child also noted to have visual abnormalities (although not necessarily as may just have growth failure with mild undetected visual abnormalities). The child may present with strabismus, nystagmus, or other visual abnormalities. In the majority of cases, the earlier the diagnosis is made the better the outcome, as untreated hormonal abnormalities place an additional neurodevelopmental burden on a child already compromised by visual impairment, and also place the patient at risk of hypoglycaemia, adrenal crises and consequently death.” Septo-optic dysplasia Emma A Webb1 and Mehul T Dattani see reference below)

8. On The Increase!? • ONH was very rare with only 35 cases noted in the English language medical literature before 1970. • ONH is on the increase - today considered the most common single cause of congenital blindness in the industrialized world. • Swedish study (1997) an incidence of 6.7 out of 100,000 births or about 1 in 15,000 births.

9. On The Increase!? • ONH = leading cause of childhood visual impairment in the US and Europe – 12% of children with VI (Blohme et al, 200, Hatton et al, 2007) or 1/10000 chn < 16 years of age (Patel et al 2006; Garcia-Filion et al 2008). • Sixfold increase from 1977 estimate of 1.8/100,000 (Jan et al 1977)

10. On The Increase!? • ONH blindness is more common today than blindness due to retinopathy of prematurity (ROP). • Now the most common cause of blindness in children in the USA • Outdistancing many other birth defects which are currently more familiar, including congenital muscular dystrophy and Williams Syndrome.

11. On The Increase!? • On our books 14 SOD/ONH and 24 ONH in 2009 • 11 and 32 in 2012. • NB: To date, there is no pre-natal screening to detect ONH blindness.

12. SOD or ONH • The term Septo-Optic Dysplasia is slowly losing favour with physicians and researchers because the presence or absence of the septum pellucidum does not seem to be a defining aspect of the diagnosis. ONH is now the preferred term. • Some individuals can have an absent septum with no negative consequences.

13. Absence of SP in Garcia-Filion et al 2008 unrelated to development (was associated with CCH) • Absence of SP (with no pituitary or cerebral abnormalities) was associated with “normal neurodevelopmental parameters” in language, IQ, behavioral functioning - “neurodevelopmentally and endocrinologically inconsequential unless accompanied by posterior pituitary ectopia or cerebral hemispheric abnormalities” (p. 70, Brodsky & Glazier 1993)

14. Optic nerve hypoplasia (ONH) has been described as an increasingly prevalent cause of congenital blindness. Its association with hypopituitarism and absent septum pellucidum has been recognized for more than 40 years as "septo-optic dysplasia" or "de Morsier syndrome." More recent studies have suggested that these associations are independent of one another (Borchert, 2012).

15. Forebrain Abnormalities • In 75-80% of patients • Absence of septum pellucidum • Absence of corpus callosum • Cerebellar hypoplasia • Schizencephaly

16. Consequences Of Forebrain Anomalies • Fits • Behavioural difficulties • Learning difficulties • Developmental delay • Hemiplegia

17. Optic Nerve Hypoplasia • Unilateral/bilateral • Bilateral commoner • Associated with anopthalmia/micropthalmia • Visual impairment variable - complete to compensated

18. Visual Features • Optic nerve and chiasm hypoplasia (decreased # of fibers). Clinical signs: small optic disc, double ring sign and abnormal retinal vasculature. • Can affect one or both (80% of ONH, impact can be asymmetrical) eyes. • Visual acuity (may be near normal to NLP); high refractive errors (80% of bilateral in legally bl. range.)

19. Visual Features • Note: degree of visual impairment correlated with presence of severe pituitary anomaly (Riedl et al 2008) • May have field restrictions • May have color blindness • Nystagmus (may be ‘wandering’ if NLP)\

20. Visual Features • Strabismus • May lack of depth perception if amblyopic • May have mild photophobia (and squint, lower their head, avoid light by turning away, resist participating in outdoor activities) • Microphthalmia, colobomas of the iris/choroids/retina

21. 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

22. Pituitary Hormones • Adrenocorticotrophic Hormone (ACTH) • Thyroid Stimulating Hormone (TSH) • Lutenising Hormone (LH) • Arginine vasopressin (ADH) • Oxytocin • Follical Stimulating Hormone (FSH) • Growth Hormone Deficiency (GHD) • Gonadotrophic Releasing Hormone (GnRH) • Multi Pituitary Hormone Deficiency (MPHD)

23. 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.

24. 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

25. 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

26. 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

27. 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.

28. Complexity Of Hypothalamo-pituitary Development • Early puberty: can be explained on basis of hypothalamic involvement • Occasionally mixed involvement of hypothalamus and pituitary

29. Clinical Features Of SOD • Conjugated jaundice • Neurological features • Variable visual loss • Impaired sense of smell

30. Endocrine features • Behavioural disturbances e.g.. Autism • Sleep disturbance Table Next from: Septo-optic dysplasia Emma A Webb1 and Mehul T Dattani1 European Journal of Human Genetics (2010) 18, 393–397; doi:10.1038/ejhg.2009.125; published online 22 July 2009.

32. Management Of SOD • Support from Neurologists and Ophthalmologists: treatment of convulsions • Mainstay of treatment: endocrine

33. Endocrine Replacement • Growth hormone: daily subcutaneous injections. • Hydrocortisone: X3 doses daily; adjustment with illness/stress. • Desmopressin DDAVP: nasal/oral (Minirin) • Thyroxine • Ethinyloestradiol/testosterone

34. Investigations • MRI scan of brain • Visual evoked responses/electro-retinogram • Routine electrolyte measurement • Thyroid function tests

35. Investigations • Pituitary function tests: glucagon/insulin/LHRH/TRH • Fluid balance

36. 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.

37. Long-term Outlook • Short stature • Developmental/intellectual impairment • Fits, hemiparesis etc • Impaired fertility • Visual impairment • Sleep/behavioural difficulties • Obesity

38. Why Do You Get SOD? • Largely unclear • Commoner in young mothers • 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

39. Why Do You Get SOD? • “It is likely that although other genetic abnormalities are likely to be identified in the future, environmental factors such as drugs, alcohol and anterior cerebral artery supply during the neonatal period may also play a significant role in the aetiology of SOD.” Septo-optic dysplasia Emma A Webb1 and Mehul T Dattani see reference above)

40. 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.

41. Genetics Of SOD • Research is ongoing into the genetic aetiology of SOD. To date, the overall frequency of pathological genetic mutations identified in the SOD population is low, with no mutations identified in many familial cases, suggesting that mutations in other known or unknown genes may have a role in this complex disorder.

42. 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)

43. The following statement are NOT TRUE according to current research: • ONH occurs in clusters due to use of pesticides in the environment. • The associated midline brain anomalies have a profound effect on the visual outcome and/or spatial orientation of these patients. • All mothers of children with ONH were drug users during pregnancy. Optic Nerve Hypoplasia Pediatric Visual Diagnosis Fact Sheet http://www.tsbvi.edu/seehear/spring99/opticnerve.htm

44. Top 10 Things to Know About Stem Cell Treatments • There are different types of stem cells—each with their own purpose. • A single stem cell treatment will not work on a multitude of unrelated diseases or conditions. • Currently, there are very few widely accepted stem cell therapies.

45. Just because people say stem cells helped them doesn’t mean they did. • A large part of why it takes time to develop new therapies is that science itself is a long and difficult process • To be used in treatments, stem cells will have to be instructed to behave in specific ways. • Just because stem cells came from your body doesn’t mean they are safe.

46. There is something to lose by trying an unproven treatment • An experimental treatment offered for sale is not the same as a clinical trial. • Stem cell science is constantly moving forward. International Society for Stem Cell Research http://www.closerlookatstemcells.org/Top_10_Stem_Cell_Treatment_Facts.htm

47. Behaviours Seen In Children With SOD/ONH? A comprehensive behavioural survey is yet to be conducted. However, it seems clear that many commonalities exist within the ONH family: • Often have very low (or high) muscle tone. They may go limp without warning and have to be carried. • Show a very high degree of obsessive behaviour, including flapping, rocking, tapping, screaming, or chewing on a finger.

48. Like to follow strict household routines and become agitated when the routines are not followed precisely or carried out in a particular order. • Language and conversation is often very delayed and scripted, and they may repeat back what words or phrases that they hear (‘echolalia’). • Ask the same questions over and over again, paying attention to subtle variations in responses.

49. May memorize a dialogue and attempt to engage every new person they meet with it. • Often extremely sensitive to sound - may cover their ears and cry not only when sounds are loud, but because they find it difficult to adjust to overlapping sounds or to sounds which shift in register. • Often show tactile defensiveness and oral defensiveness. Many of these traits diminish over time.

50. Some children have extraordinary memories, and can quickly memorize songs and stories. They may recall these stories, word for word, months or years after they have first heard them (and with accurate intonation and inflection). • Some children have a very high interest and ability with music (savant?) • Though not all respond to music, many parents of ONH children notice the value of music as a way of stimulating conversation with their children, or in smoothing over difficult social or environmental transitions.