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Synonyms: de Morsier's syndrome, pituitary hormone deficiency combined HESX1-related, septo-optic dysplasia, SOD
Septo-optic dysplasia (SOD) is a rare, heterogeneous condition characterised by a combination of:
- Optic nerve hypoplasia.
- Midline brain abnormalities (including absence of the corpus callosum and septum pellucidum).
- Hypothalamic-pituitary endocrine deficiencies.
The SOD phenotype is highly heterogeneous and diagnosis is made in the presence of at least two of these three features. Only about a third of patients have all three features but patients with any component of the syndrome should be screened for the other features too. The cause of SOD is unknown but viral infections, gestational diabetes, environmental teratogens, vascular or degenerative injury and genetic mutations have all been considered as possible predisposing factors. Management can be complicated and can entail lifelong multidisciplinary input.
This is a rare condition, in the order of 1 per 100,000 of the population. A study from Greater Manchester and Lancashire has identified cases being more common where there is high unemployment, low income and in teenage pregnancies. The association with young mothers has been previously reported in Glasgow but there is still a debate as to whether maternal age is significant.
Genetics of SOD
The condition is caused by mutation of the gene locus 3p21.2-p21.1 that controls HESX1, an important regulator of development - particularly of the pituitary. Although it appears to be genetic in origin, it rarely runs in families, suggesting that mutation is more often spontaneous than inherited. It has been claimed that there is no Mendelian basis for the condition but a rare report of its occurrence in a brother and sister raises the possibility of an autosomal recessive trait. It has also been reported in 2 siblings from a highly consanguineous marriage.
- Suspicions can be raised at midtrimester ultrasound scanning and the condition be diagnosed but it can also easily be missed.
- The child may appear normal at birth or there may be problems such as poor development of male genitalia.
- Unexplained hypoglycaemia may suggest pituitary inadequacy.
- Vision testing and screening in young children may reveal the first sign of abnormality.
- Susceptibility to infection may suggest a problem and merits investigation.
- Seizures (particularly in patients with developmental delay) and/or sleep disturbances can occur.
A study of 228 patients from Australia found that there is a broad spectrum of pituitary problems ranging from isolated growth hormone deficiency to panhypopituitarism. About two-thirds of these patients have isolated hypopituitarism and 30% had all 3 manifestations with pituitary hypoplasia, optic nerve hypoplasia and agenesis of midline structures.
- There are hypoplastic optic discs with a classical double margin.
- There may be blindness in one or both eyes; 80% of these patients are considered legally blind.
- Nystagmus and astigmatism are other common features.
- The septum pellucidum ± corpus callosum is absent in about half of patients.
- Other midline abnormalities may affect the fornix, the septum pellucidum, the corpus callosum, and cerebellum.
- Developmental delay can occur.
- A majority of patients have some psychomotor impairment.
- Associations with autism have been described.
- The most consistent clinical feature is short stature associated with poor or absent growth hormone. Weight and head circumference are normal for size.
- Lack of growth hormone and other pituitary hormones can make individuals susceptible to neonatal hypoglycaemia. There may also be hypernatraemia.
- Other pituitary hormones are often deficient and there may be diabetes insipidus, although the posterior pituitary or neurohypophysis has a different embryological origin from the anterior pituitary of adenohypophysis.
- Hormonal imbalance can lead to a precocious puberty.
- If there is illness, the lack of adrenocorticotrophic hormone (ACTH) can precipitate an adrenal crisis and sudden death.
- Thermoregulation may be deficient.
Classification according to MRI findings
A series of 55 patients was divided into 4 groups based on septum pellucidum and hypothalamic-pituitary axis appearance on MRI scan:
- In group 1 both were normal.
- In group 2 there was abnormal septum pellucidum and normal hypothalamic-pituitary axis.
- In group 3 there was normal septum pellucidum and abnormal hypothalamic-pituitary axis.
- In group 4 both were abnormal.
None of the patients in group 1 had endocrine dysfunction compared with 22% in group 2, 35% in group 3 and 56% in group 4. Group 2 was the most common to experience precocious puberty.
- Brain imaging with MRI is an important investigation and an MRI to measure the size of the optic nerves can confirm the diagnosis. MRI will indicate the degree of structural abnormality and this indicates the likely endocrine abnormality.
- Tests of pituitary function may show hypopituitarism.
- Developmental assessment is likely to show retardation.
- Growth hormone may be administered.
- If ACTH is deficient, the correct dose of cortisone to permit health and growth is a delicate balance.
- Management of puberty requires judgement. It may involve induction of puberty or delaying it if premature.
- Psychomotor retardation complicated by poor vision requires specialist help.
- A lifelong multidisciplinary approach is important to optimise growth and development.
Appearance of the septum pellucidum and hypothalamic-pituitary axis on MRI predict the likely spectrum of endocrine disorder and prognosis is also dependent upon the degree of abnormality. Early diagnosis improves outcome.
Further reading & references
- Septo-optic Dysplasia, Online Mendelian Inheritance in Man (OMIM)
- Septo-Optic Dysplasia, National Institute of Neurological Disorders and Stroke
- Fard MA, Wu-Chen WY, Man BL, et al; Septo-optic dysplasia. Pediatr Endocrinol Rev. 2010 Sep;8(1):18-24.
- de Ferran K, Paiva IA, Gilban DL, et al; Septo-optic dysplasia. Arq Neuropsiquiatr. 2010 Jun;68(3):400-5.
- Patel L, McNally RJ, Harrison E et al.; Geographical distribution of optic nerve hypoplasia and septo-optic dysplasia in Northwest England. J Pediatr. 2006 Jan;148(1):85-8. [abstract]
- Murray PG, Paterson WF, Donaldson MD.; Maternal age in patients with septo-optic dysplasia. J Pediatr Endocrinol Metab. 2005 May;18(5):471-6. [abstract]
- Dattani MT, Martinez-Barbera JP, Thomas PQ, et al; Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet. 1998 Jun;19(2):125-33.
- Benner JD, Preslan MW, Gratz E, et al; Septo-optic dysplasia in two siblings. Am J Ophthalmol. 1990 Jun 15;109(6):632-7.
- Wales JK, Quarrell OW; Evidence for possible Mendelian inheritance of septo-optic dysplasia. Acta Paediatr. 1996 Mar;85(3):391-2.
- Lepinard C, Coutant R, Boussion F, et al; Prenatal diagnosis of absence of the septum pellucidum associated with septo-optic dysplasia. Ultrasound Obstet Gynecol. 2005 Jan;25(1):73-5.
- Thomas PQ, Dattani MT, Brickman JM, et al; Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet. 2001 Jan 1;10(1):39-45.
- Birkebaek NH, Patel L, Wright NB, et al; Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. J Clin Endocrinol Metab. 2003 Nov;88(11):5281-6.
- Birkebaek NH, Patel L, Wright NB, et al; Optic nerve size evaluated by magnetic resonance imaging in children with optic nerve hypoplasia, multiple pituitary hormone deficiency, isolated growth hormone deficiency, and idiopathic short stature. J Pediatr. 2004 Oct;145(4):536-41.
- Stanhope R, De Luca F, Delemarre-Van de Waal HA, et al; Multiple pituitary hormone deficiency: management of puberty for optimal auxological results. J Pediatr Endocrinol Metab. 2001 Jul;14 Suppl 2:1009-14.
- Hellstrom A, Aronsson M, Axelson C, et al; Children with septo-optic dysplasia - how to improve and sharpen the diagnosis. Horm Res. 2000;53 Suppl 1:19-25.
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|Original Author: Dr Olivia Scott||Current Version: Dr Olivia Scott|
|Last Checked: 20/12/2010||Document ID: 2766 Version: 22||© EMIS|