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Septo-Optic Dysplasia

Septo-optic dysplasia (SOD), (de Morsier syndrome) is a rare congenital disorder in which there are abnormalities in the development of midline brain structures, the optic nerve(s), and anterior pituitary gland. Serious manifestations and complications arise with each of these features. Patient presentation varies from one child to another. 


Presentation

SOD is a congenital disorder and may display numerous abnormalities. The disease can be easy to miss [14]. At least 2 of the following must be present to diagnose SOD: Abnormalities of the midline brain, hypoplasia of the optic nerve, and abnormalities of the pituitary gland. A third of patients will exhibit all 3 features [15]. Typical newborn features are hypoglycemia, jaundice, microphallus (testes may be undescended), nystagmus, and possible cleft palate. They may be suscepetible to infections as well. 

Midline brain abnormalities

Brain anatomy morphogenesis includes absent septum pellucidum and/or corpus callosum in approximately 50% of patients. Some will have cerebellar involvement. Developmental and motor disabilities and delays are common especially in the context of coordination. There may be an association with autism. Seizures in children with or without developmental delay [4] and sleep abnormalities are other manifestations [5].

Optic nerve hypoplasia

An abnormal vision exam may be the first sign to raise suspicion. Further evaluation and search for accurate diagnosis is prudent. Nystagmus, strabismus, and astigmatism are common. Of those with visual impairment, 80% are classified as legally impaired [9]. Findings on optic exam include hypoplastic disc with a double ring sign, which is characteristic. Another abnormality is a small and/or pale optic disc

Pituitary hypoplasia

The clinical features vary from one individual to another. Some patients show a deficiency of one hormone and other may have panhypopituitarism. Most children with SOD will exhibit pituitary dysfunction and the subsequent insufficiency of hormones. Pituitary deficiency results in hormone shortages that may lead to neonatal hypoglycemia and hypernatremia. Other lacking pituitary hormones is also seen. Lack of GH causes short stature but patients exhibit normal weight.

Adrenal crisis results in neonatal fatalities. This is attributed to ACTH deficiencyPrecocious puberty can occur secondary to hormonal dysfunction and imbalance [10]. One observation is abnormal development of male genitalia. Furthermore, posterior pituitary hormones may also be deficient despite the varying embryological origins of the anterior and posterior glands. Diabetes insipidus may occur. Patients also struggle to maintain thermoregulation. 

Earlier diagnosis is pertinent for long term outcomes with regards to hormonal deficiencies, intellectual and motor development, visual impairment, etc.

Poor Feeding
  • A female infant presented with poor feeding, hypotonia, prolonged jaundice, seizure and wandering nystagmus.[ncbi.nlm.nih.gov]
Inflammation
  • Macrophage activation in hemophagocytic lymphohistiocytosis (HLH) leads to severe inflammation resulting in cytopenias and multi-organ dysfunction.[ncbi.nlm.nih.gov]
Failure to Thrive
  • Marshall-Smith syndrome is characterized by advanced bone age, failure to thrive, respiratory problems, dysmorphic facial features, and variable mental retardation.[ncbi.nlm.nih.gov]
  • Other developmental abnormalities include underdeveloped midfacial structures, hypoglycemia, hyperbilirubinemia, disturbance in temperature regulation, muscular hypotonia, microgenitalism, low Apgar scores and failure to thrive. 2 Optic Nerve Hypoplasia[aao.org]
  • Signs and symptoms, including failure to thrive, prolonged jaundice (yellow color to the skin caused by extra amounts of bile in the blood), difficulty controlling body temperature, decreased blood sugar, small genitalia, or low muscle tone, can herald[encyclopedia.com]
  • Usually, death results from failure to thrive, chronic infections, and respiratory problems. Patients with closed-lip schizencephaly may not present clinically until later in infancy or early childhood and may live to early adulthood.[slideshare.net]
Hepatosplenomegaly
  • She manifested nystagmus and severe hepatosplenomegaly. Brain magnetic resonance imaging revealed agenesis of the septum pellucidum, optic nerve hypoplasia, pituitary gland stalk hypoplasia, and absence of the posterior pituitary gland.[ncbi.nlm.nih.gov]
Epicanthal Folds
  • The patient presented with features typical of valproic acid embryopathy, including bitemporal narrowing, hypertelorism, short palpebral fissures, epicanthal folds, microphthalmia, a flat broad nasal bridge, small mouth, hypoplastic nails, mild clinodactyly[ncbi.nlm.nih.gov]
Hypoplastic Nails
  • The patient presented with features typical of valproic acid embryopathy, including bitemporal narrowing, hypertelorism, short palpebral fissures, epicanthal folds, microphthalmia, a flat broad nasal bridge, small mouth, hypoplastic nails, mild clinodactyly[ncbi.nlm.nih.gov]
Skin Lesion
  • In this case report a patient with bilateral optic nerve hypoplasia, schizencephaly and a pigmented skin lesion is described.[ncbi.nlm.nih.gov]
Broad Nasal Bridge
  • The patient presented with features typical of valproic acid embryopathy, including bitemporal narrowing, hypertelorism, short palpebral fissures, epicanthal folds, microphthalmia, a flat broad nasal bridge, small mouth, hypoplastic nails, mild clinodactyly[ncbi.nlm.nih.gov]
Primary Amenorrhea
  • In the present report, the authors described two SOD cases that presented with primary amenorrhea and abnormal pubertal development. Clinical features. Possible etiology of this condition was reviewed[ncbi.nlm.nih.gov]
Seizure
  • A 7-year-old boy was admitted for a general tonic-clonic seizure with severe hypoglycaemia (1.39 mmol/l).[ncbi.nlm.nih.gov]

Workup

A complete and thorough history, family history and exam should be performed. Infants with findings suspicious for this disorder should warrant a full workup including:

Imaging

MRI of brain is crucial for the confirmation of diagnosis [16]. This assesses the size of the anterior pituitary, location of posterior pituitary, presence of infundibulum and presence of septum pellucidum. Also evaluation of corpus callosum and optic nerves is done. Other brain abnormalities may include cerebellar hypoplasia. The findings are abnormalities of corpus callosum, absent septum pellucidum, abnormal hypothalamic pituitary axis, and hypoplasia of the optic nerve(s) and chiasm. These findings are variable from one patient to another.

Pituitary functions tests 

  • Thyroid
  • Growth hormone, if is hypoglycemia present, measure IGF-1 and IGFBP-3. In cases of inadequate growth, GH labs are warranted. 
  • Cortisol (8 am levels for children older 1 year of age). Abnormal result warrants further testing with 24 hour cortisol and glucose studies. 
  • Screen for precocious puberty
  • Screen for fluid intake and diabetes insipidus, if fluid intake is excessive, obtain fasting plasma and urine osmolalities. Water deprivation test may be indicated. 

All affected patients should be referred to opthalmology as part diagnosis process. Of note, SOD may be diagnosed on prenatal ultrasound. 

Cytopenia
  • Macrophage activation in hemophagocytic lymphohistiocytosis (HLH) leads to severe inflammation resulting in cytopenias and multi-organ dysfunction.[ncbi.nlm.nih.gov]

Treatment

Treatment includes:

  • Deficient hormones should be replaced and treated appropriately.
  • Referral to tertiary center with multidisciplinary medical team to manage the patient comprehensively especially since the patient may have numerous manifestations. 

The team should consist of endocrinologists, ophthalmologists, and neurologists, and other professionals for child and family support services. Neurodevelopmental experts can help the child progress and experience a better quality of life. In cases where SOD is diagnosed during prenatal ultrasonography, patients can opt for genetic counseling and seek social support services to prepare for medical management of the neonate. 

Prognosis

The earlier the diagnosis and treatment, the better the outcome and reduction in morbidity. In fact, early identification improves survival [13].

Etiology

Research investigations have discovered that some familial cases of SOD are likely secondary to genetic mutations. The implicated genes are HESX1, SOX2, SOX3 and OTX2 [2]. These are transcription factors that play key roles in early forebrain development. Most cases, however, are idiopathic and sporadic [3]. The disorder does not typically recur in future offspring.

A few factors have been linked to SOD. For example, it is more common in younger maternal ages. Also, environmental factors may contribute. Further research is needed to elucidate the complex multifactorial component of SOD.

Epidemiology

SOD is rare and is found in 1 per 100,000 population [4].  It occurs in 1 in 10,000 live births. There is no gender preference. An investigation in England linked cases to pregnancies in younger mothers, and backgrounds of low income and unemployment [5]. The former is corroborated by another study as well [6]. While these studies suggest that maternal age is a factor, this is not well established [4]. 

Sex distribution
Age distribution

Pathophysiology

Genetics

SOD can manifest in multiple abnormalities mainly involving early brain development, which takes place at gestational age of 4 to 6 weeks. This period represents the formation of the anterior neural plate. Mutations in genes have been identified in SOD including HESX1, SOX2, SOX3 and OTX2. 

The homeobox gene HESX1, serves as a repressor of transcription. It is significant in pituitary development. Murine studies have enabled the isolation of 5 homozygous and 8 heterozygous mutations. The homozygous mutations are associated with autosomal recessive inheritance while the latter are correlated to autosomal dominance inheritance [7] [8]. The homozygous mutations exhibit complete penetrance unlike the heterozygous, which is partially penetrant and therefore milder [9] [10]. 

The SOX2 mutation results in severe bilateral optic defects such as microphthalmia and anophthalmia. This mutation is also associated with abnormalities of the corpus callosum and under development of the anterior pituitary [11]. The SOX 2 mutation further reflects short stature, esophageal atresia, hearing loss, developmental delays, and male genital defects [12].

Complications with pituitary insufficiency

The anterior pituitary synthesizes numerous hormones: GH, adrenocorticotropic hormone (ACTH), follicle stimulating hormone (FSH), luteinizing hormone (LH), thyroid stimulating hormone (TSH), and prolactin. One or more may be affected. The pathophysiological effects of pituitary hormone deficiency can result in life threatening complications and death.

Growth hormone deficiency is frequently found in SOD patients. If GH and cortisol are deficient, a potentially life threatening complication is hypoglycemiaLow cortisol can be fatal due to adrenal crisis. While most cases result in late puberty, precocious puberty may occur due to low FSH and LH. Also hypogonadism is found in males. Insufficient thyroid hormone affects metabolism and many other physiological processes as well. Diabetes insipidus may be observed even though antidiuretic hormone (ADH) is secreted by the posterior pituitary. 

Prevention

There are no preventative measures since SOD is either genetically inherited or sporadic. Long term outcomes of children affected with SOD could be improved the earlier the condition is discovered and the sooner intervention is implemented.

Summary

Septo-optic dysplasia (SOD) is a rare congenital disorder that requires 2 of 3 features to be present to confirm diagnosis [1]. These are brain midline abnormality, optic nerve hypoplasia, and pituitary gland abnormality. While genetic mutations have been discovered, most cases are idiopathic and sporadic and likely the disease is multifactorial. 

It is important to recognize and diagnose the condition early so that intervention can reduce mortality. The deficiency of pituitary hormones can be detrimental. Main complications include hypoglycemia and hypernatremia. Low growth hormone (GH) and low cortisol level are associated with the former. Newborn fatality can occur with low cortisol levels and the subsequent adrenal crisisVisual symptoms are common and include nystagmus and astigmatism. Impairment is often severe. An optic exam is indicated in all patients. Since key brain structures may be affected, there are significant developmental and motor delays. Seizure may also be present. 

A diagnosis is confirmed with MRI, which would depict abnormal or absent midline structures such as corpus callosum, septum pellucidum, pituitary gland, and hypolasia of one or both optic nerves and chiasm. Laboratory studies testing for hormone levels are also crucial.

Treatment consists of a multidisciplinary approach comprised of specialists in neurology, endocrine, and ophthalmology. These experts in addition to neurodevelopmental professionals work as a cohesive team to provide the best management for the patient. 

Patient Information

Septo-optic dysplasia is the condition in which babies and children are diagnosed with abnormal development of the middle structures of the brain, the optic (eye) nerve, and the pituitary gland. The parts of the brain that are affected play a role in many functions and activities such as development of intelligence and motor skills. The optic nerve allows us to see and have eye coordination. The pituitary gland releases very important hormones such as growth hormone, thyroid, and sex hormones. In fact, this gland is involved in producing cortisol, the stress hormone that plays a role in may functions especially during emergencies. 

This disorder is seen in boys and girls. While there is a genetic mutation responsible, it is not usually inherited. It is not likely to recur in other children in the family. It may be more common in younger mothers but this is not clear. 

Some of the signs and symptoms in the newborn are low blood sugars, high sodium, jaundice (yellow skin), small penis in boys, and maybe cleft palate. Not all babies and children will the same signs and symptoms. As soon as you or your child's doctor notices developmental delay, visual problems or other signs, an MRI in addition with blood tests are done on the child. The MRI will show the abnormalities normally associated with septo-optic dysplasia. The lab tests will determine if there are low levels of the main hormones discussed above. Any abnormal lab may lead to further tests. 

Treatment includes replacing deficient hormones. Also it is important to establish care at a tertiary center with a team of doctors and specialists managing the child. The sooner the treatments begin, the better for the child. Neurodevelopmental experts will help the child progress and get the most from school and social activities. 

References

Article

  1. G. de Morsier. Études sur les dysraphies, crânioencéphaliques. III. Agénésie du septum palludicum avec malformation du tractus optique. La dysplasie septo-optique. Schweizer Archiv für Neurologie, Zurich, 1956, 77(1-2): 267-292.
  2. McCabe MJ, Alatzoglou KS, Dattani MT. Septo-optic dysplasia and other midline defects: the role of transcription factors: HESX1 and beyond. Best Practice and Research Clinical Endocrinology Metabolism. 2011; 25(1):115-24.
  3. Fard MA, Wu-Chen WY, Man BL, et al. Septo-optic dysplasia. Pediatric Endocrinology Review. 2010;8(1):18-24.
  4. de Ferran K, Paiva IA, Gilban DL, et al. Septo-optic dysplasia. Arquivos de Neuro-Psiquiatria. 2010;68(3):400-5.
  5. Patel L, McNally RJ, Harrison E et al. Geographical distribution of optic nerve hypoplasia and septo-optic dysplasia in Northwest England. Journal of Pediatrics. 2006;148(1):85-8. 
  6. Murray PG, Paterson WF, Donaldson MD. Maternal age in patients with septo-optic dysplasia. Journal of Pediatric Endocrinology and Metabolism. 2005;18(5):471-6. 
  7. 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. Nature Genetics. 1998;19(2):125–133. 
  8. Kelberman D, Rizzoti K, Avilion A, et al. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. Journal of Clinical Investigation.2006;116(9):2442–2455.
  9. Thomas PQ, Dattani MT, Brickman JM, et al. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Human Molecular Genetics. 2001;10(1):39–45.
  10. Cohen RN, Cohen LE, Botero D, et al. Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia. Journal of Clinical Endocrinology and Metabolism. 2003;88(10):4832–4839. 
  11. Alatzoglou KS, Kelberman D, Dattani MT. The role of SOX proteins in normal pituitary development. Journal of Endocrinology. 2009;200(3):245–258. 
  12. Hagstrom SA, Pauer GJT, Reid J, et al. SOX2 mutation causes anophthalmia, hearing loss, and brain anomalies. Am Journal of Medical Genetics Part A. 2005;138A(2):95–98.
  13. Al-Senawi R, Al-Jabri B, Al-Zuhaibi S, et al. Septo-optic dysplasia complex: Clinical and radiological manifestations in Omani children. Oman Journal of Ophthalmology. 2013;6(3):193-8. 
  14. Lepinard C, Coutant R, Boussion F, et al. Prenatal diagnosis of absence of the septum pellucidum associated with septo-optic dysplasia. Ultrasound in Obstetrics and Gynecology. 2005;25(1):73-5. 
  15. Gleason CA, Devascar, S. Congenital malformations of the Central Nervous System. Avery's Diseases of the Newborn (9 ed.). Saunders. p. 857. 2011
  16. 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. Journal of Pediatrics. 2004;145(4):536-41.

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Last updated: 2019-07-11 20:59