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 deficiency. Precocious 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.

• Precocious Puberty

  The patient also showed central precocious puberty in addition to GH and ATCH deficiency. In SOD, both gonadotropin deficiency and central precocious puberty have been reported [ 3, 6 - 8 ]. [omicsonline.org]

  The clinical manifestations include poor visual function in one or both eyes, developmental delay, seizures, sleep disturbances, and precocious puberty. [ncbi.nlm.nih.gov]

  Precocious puberty can occur secondary to hormonal dysfunction and imbalance. One observation is abnormal development of male genitalia. [symptoma.com]

  Group 2 was the most common to experience precocious puberty. [patient.info]

• 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]

• Severe Short Stature

  Compared to other children referred for evaluation of short stature, children with SOD were younger (mean age 3.7 +/- 3.6 vs 8.6 +/- 4.9 years), had less severe short stature (mean +/- SD height SDS -1.80 +/- 1.64 vs -2.17 +/- 0.95), and were more likely [ncbi.nlm.nih.gov]

  Although dynamic tests were not made for the confirmation of the GH deficiency, it probably exists, being suggested by the combination of abnormalities in the hypothalamic-pituitary axis, severe short stature and insignificant plasmatic IGF-1 levels. [scielo.br]

• Visual Impairment

  The optic nerve hypoplasia can be uni- or bilateral (57% and 32% of cases, respectively) and significant visual impairment occurs in 23% of patients. [orpha.net]

  Support for visual impairment will enable children to get the most out of school and social life as can additional help for development delay. [gosh.nhs.uk]

  Epidemiology: ONH is the third most prevalent cause of visual impairment in kids under three years of age. Most common congenital optic disc abnormality. [pedclerk.bsd.uchicago.edu]

  It also examines two cases that demonstrate the variety and severity of visual and physical impairments associated with SOD. [ncbi.nlm.nih.gov]

  Conclusions : Although SOD is a rare, heterogeneous condition, systematic ophthalmologic and neuroendocrinologic examination allow early diagnosis of both visual impairment and pituitary hormone abnormalities associated to optic nerve hypoplasia and brain [iovs.arvojournals.org]

• Visual Impairment

  The optic nerve hypoplasia can be uni- or bilateral (57% and 32% of cases, respectively) and significant visual impairment occurs in 23% of patients. [orpha.net]

  Support for visual impairment will enable children to get the most out of school and social life as can additional help for development delay. [gosh.nhs.uk]

  Epidemiology: ONH is the third most prevalent cause of visual impairment in kids under three years of age. Most common congenital optic disc abnormality. [pedclerk.bsd.uchicago.edu]

  It also examines two cases that demonstrate the variety and severity of visual and physical impairments associated with SOD. [ncbi.nlm.nih.gov]

  Conclusions : Although SOD is a rare, heterogeneous condition, systematic ophthalmologic and neuroendocrinologic examination allow early diagnosis of both visual impairment and pituitary hormone abnormalities associated to optic nerve hypoplasia and brain [iovs.arvojournals.org]

• Strabismus

  Symptoms of septo-optic dysplasia may include decreased visual acuity in one or both eyes, nystagmus, strabismus, and endocrine dysfunction (including growth hormone deficiency, hypothyroidism, adrenal insufficiency, diabetes insipidus, and hypogonadism [msdmanuals.com]

  Long-term management is focused on: Control of associated endocrine symptoms (including hormone replacement) Occupational/Physical therapy Early Intervention for patients with developmental delays Patching or surgery for strabismus in some patients Further [pedclerk.bsd.uchicago.edu]

  SOD may manifest as strabismus, nystagmus, decreased visual acuity, or visual impairment; as an endocrine dysfunction in isolation; or in addition to mental retardation, cerebral palsy, developmental delay, or delayed growth. [ncbi.nlm.nih.gov]

• Hemianopsia

  […] beeinflussen entscheidend den… (More) DOI: 10.1007/s001150050282 Topics Optic Nerve Septum Pellucidum Optic nerve hypoplasia optic nerve development Optics nerve development Wallerian Degeneration Nystagmus Septo-Optic Dysplasia Hypoplasia brain lesion Hemianopsia [semanticscholar.org]

  17,18,19] Patients may have hypopituitarism that ranges from panhypopituitarism to growth hormone deficiency, thyroid- stimulating hormone deficiency, elevated prolactin, or ACTH or ADH deficiency. [16] Visual symptoms include nystagmus, amblyopia, or hemianopsia [slideshare.net]

• Behavior Disorder

  Symptoms or conditions resulting from abnormal brain or fetal development may include: Behavioral disorders such as autism spectrum disorder or attention deficit/hyperactivity disorder (ADHD). Cerebral palsy. Cleft lip and palate. [my.clevelandclinic.org]

• Nystagmus

  This type of nystagmus is believed to result from a defect that prevents the eyes from compensating for head rotations. [journals.lww.com]

  Ophthalmologic manifestations include conditions, such as optic nerve hypoplasia, reduced visual acuity, and nystagmus. [iovs.arvojournals.org]

  A female infant presented with poor feeding, hypotonia, prolonged jaundice, seizure and wandering nystagmus. [ncbi.nlm.nih.gov]

  But in infants with nystagmus and those with significant refractive error, magnetic resonance imaging is said to be useful [8]. [ijo.in]

  The ocular features of nystagmus, strabismus, amblyopia, and visual field defects were noted in our patient. [mjdrdypu.org]

• Seizure

  Seizures may occur. Although some children have normal intelligence, many have learning disabilities, intellectual disability, cerebral palsy, or other developmental delay. MRI Diagnosis of septo-optic dysplasia is by MRI. [msdmanuals.com]

  Intractable seizures frequently are noted in schizencephaly. Several types of seizures have been reported including generalized tonic-clonic, partial motor, and sensory seizures. Infantile spasms have been seen in a few children. [slideshare.net]

  A 7-year-old boy was admitted for a general tonic-clonic seizure with severe hypoglycaemia (1.39 mmol/l). [ncbi.nlm.nih.gov]

• Encephalopathy

  Toxic and metabolic encephalopathies -- Deficiency diseases of the nervous system -- Effects of toxins and physical agents on the nervous system -- Effects of drug abuse on the nervous system -- Brain edema and disorders of cerebrospinal fluid circulation [worldcat.org]

  Optic nerve hypoplasia, encephalopathy, and neurodevelopmental handicap. Br J Ophthalmol 1991;75:236-239. [ Links ] 21. Costin G, Murphree AL. Hypothalamic-pituitary function in children with optic nerve hypoplasia. [scielo.br]

• Mydriasis

  Pupils that dilate, or widen, abnormally in response to light (mydriasis). Symptoms of pituitary dysplasia may include: A lack of hormones from your pituitary gland (panhypopituitarism). [my.clevelandclinic.org]

• Paresis

  Other symptoms that may occur are hypotonic muscles and paresis of one side of the body. Variation between the different functional impairments is great. Individuals with hormonal deficiency may need hormone supplements. [mun-h-center.se]

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. 

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. 

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

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.

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]. 

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 hypoglycemia. Low 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. 

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.

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 crisis. Visual 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. 

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. 

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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.
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