The etiology of central DI include: idiopathic, traumatic brain injury, iatrogenic, CNS neoplasm, midline brain malformations and genetic causes such as Wolfram syndrome. CNS neoplasms and infiltrative diseases associated with central DI include: Langerhans cell histiocytosis (LCH), germinomas, craniopharyngiomas, and optic pathway gliomas. Midline brain defects seen in optic nerve hypoplasia syndrome may result in panhypopituitarism and central DI. Wolfram syndrome type 1 (WS1 ) is an autosomal recessive or dominant disorder resulting in diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD ). Wolfram syndrome type 2 is associated with early onset optic atrophy, diabetes mellitus and deafness but not DI (Fig. 9.2).

Polyuria was identified by the ancient Greeks and termed diabetes meaning siphon or to pass through. It was not until the eighteenth century that it was recognized that there were differences in the taste of the urine between diabetes insipidis (lacking strong flavor) and diabetes mellitus (sweet taste). The connection between the pituitary gland and diabetes insipidus was made in the twentieth century. Posterior pituitary extracts lead to the development of vasopressin which was used starting in the 1970s to treat diabetes insipidus and other hemodynamic disorders [38].

Diabetes insipidus (all types) affect infants, children and adults with a prevalence reported as 1 in 25,000 with <10 % hereditary [39]. The most common causes for central DI in children include CNS tumors, Langerhans cell histiocytosis, and congenital abnormalities of midline brain development such as holoprosencephaly and septo-optic dysplasia/optic nerve hypoplasia syndrome [40].

Polydypsia, polyuria and hypernatremia are common sings of DI. Dehydration and hypovolemic shock may develop in severe cases. Associated problems with thermoregulation with alternating episodes of hypothermia and hyperthermia may be present. Hypopituitarism and neurodevelopmental delays are frequently associated with CNS neoplasms or congenital malformations of the brain .

Wolfram syndrome type 1 (WS1 ) presents with central DI, diabetes mellitus, optic atrophy and deafness (DIDMOAD ). Wolfram syndrome type 2 (WS2) is similar to WS1 except for the lack of DI.

Ophthalmic manifestations depend on the underlying etiology of DI. Suprasellar masses may result in chiasmal syndrome, vision loss, bitemporal hemifield peripheral vision loss, and optic atrophy. Congenital brain anomalies may present with optic nerve hypoplasia which may be unilateral or bilateral. Patients with optic nerve hypoplasia may have near normal visual acuity to no light perception. Infants with low vision may have with poor visual tracking, lack of a social smile and nystagmus. An afferent papillary defect, sluggish pupil reactivity to light and reduced color vision are common. Examination of the optic nerve via ophthalmoscopy may reveal optic nerve head pallor in optic atrophy or unilateral or bilateral small optic nerves, a ring of sclera around the optic nerve known as the “double ring sign” and tortuous retina vessels in optic nerve hypoplasia . Optic atrophy associated with DIDMOAD results in bilateral reduced vision and optic nerve pallor during early childhood .

A history of polydypsia and polyuria associated with dilute urine (urine osmolality typically <300 mOsm/kg) and plasma hyperosmolality (>295–300 mOsm/kg) suggests diabetes insipidus. Central diabetes insipidus is confirmed by the response to vasopressin/desmopressin challenge test with >50 % increase in urine osmolality [39, 41, 42]. Neuroimaging is necessary to identify CNS neoplasms and malformations. Serum glucose and hearing tests for diabetes mellitus and deafness respectively should be completed if the clinician suspects Wolfram syndrome. Genetic testing for Wolfram syndrome type 1 (WS1 ) should be considered in cases of DI associated with diabetes mellitus, optic atrophy and deafness. The causative gene for WS1 maps to chromosome 4p16.1. The causative gene for WS2 maps to maps to chromosome 4q22 [43].

Management of DI aims to correct hypovolemia and hypernatremia. Desmopressin administration is the mainstay of pharmaceutical treatment but children may also be treated with a low solute and/or a thiazide diuretic. Additionally, acute dehydration and hypernatremia may be managed with free water intake orally or administration of intravenous fluids. Endocrinology consultation is recommended since other pituitary hormone abnormalities may be associated with central DI.

Individuals with low vision due to optic atrophy or optic nerve hypoplasia should be evaluated and managed by a Vision Rehabilitation/Low Vision eye care professional. School aged children with low vision benefit from the services of a Vision Teacher to optimize their learning experience using tools including Braille, magnifiers, closed circuit TV, tablets and computers while at school.

Hyperthyroidism or thyrotoxicosis is a condition where inappropriately high thyroid hormone is produced and secreted. Graves disease is a multisystem autoimmune disorder resulting in hyperthyroidism , ophthalmopathy and diffuse goiter.

Goiter, diffuse enlargement of the thyroid gland, and it’s treatment with oral seaweed supplementation was first described by Chinese physicians nearly 3000 years BC. Leonardo Di Vinci was the first to identify and illustrate the thyroid gland in the 1500s. Dr. Robert Graves initially described a series of three female patients with exophthalmos, palpitations and goiter in the early 1800s. Shortly after Graves, C. von Basedow coined the classic triad of exophthalmos , tachycardia and goiter which became known as Basedow’s disease . Dr. Charles H. Mayo, a founding member of the Mayo Clinic, first used the term hyperthyroidism to describe patients with exophthalmic goiter, toxic adenoma, and adenomatous goiter in association with clinical signs of inappropriately high thyroid hormone activity. Today, autoimmune hyperthyroidism is most commonly referred to as Graves disease, but Basedow disease is appropriate as well. The etiology of Graves disease caused by an immunoglobulin G autoantibody was discovered in the 1950s [58]. Stimulating antibodies against the thyrotropin receptor and possibly the insulin-like growth factor 1 receptor (IGF-1R) result in hyperthyroidism and the extra-thyroid manifestations of Graves disease [59]. Today, we understand thyroid associated ophthalmopathy is primarily a T and B-cell mediated disease. Cytokines stimulate orbital fibroblasts resulting in the accumulation of orbital extracellular matrix macromolecules, orbital inflammation and fibrosis [60].

The treatment of Graves disease has made great strides during the twentieth century. Radioiodine 131, betablockers and antithyroid drugs were developed and implemented in the medical treatment of Graves disease over the past century. Most recently, biologic agents or disease-modifying antirheumatic drugs (DMARD ’s) have been used in the medical management of TAO [60]. Further study on the effectiveness and safety of DMARDS in TAO, especially in children, are necessary. Thyroidectomy for the treatment of thyrotoxicosis was pioneered by surgeons from around the world including: Thomas Dunhill, Theodor Kocher, Charles Mayo, William Halsted and George Crile [61]. Dr H.C. Naffziger was an innovator in the surgical management of Graves ophthalmopathy via orbital decompression in the 1930s [62].

Graves disease is the most common cause of hyperthyroidism in children and peaks during adolescence. Girls are more commonly affected than boys. The prevalence of Graves disease in the United States is 1 in 10,000 children [63]. Half of children and adolescents will have eye manifestations of Graves disease.

Symptoms of hyperthyroidism in Graves disease may be insidious and involve multiple organ systems. Behavior changes may include hyperactivity, declining school performance and sleep pattern changes. Patients may experience hair loss, heat intolerance, tremor, fullness or mass of the neck. Physical examination findings may include accelerated growth, goiter, tachycardia, hypertension, muscle weakness and weight loss .

Eyelid retraction and proptosis are the most common signs of pediatric Graves orbitopathy (Fig. 9.5) [64]. Eyelid retraction is secondary to increased Muller muscle tone. Dry eye and exposure keratopathy are secondary to lid retraction, reduced blink frequency and proptosis resulting in increased evaporative tear loss. Lid lag may be appreciated in downgaze. Orbital inflammation is not a predominant feature of pediatric thyroid eye disease in contrast with adult Graves orbitopathy. Diplopia secondary to restrictive strabismus and reduced visual acuity due to optic neuropathy are uncommon in children.

The lab evaluation of thyrotoxicosis should be guided by the patient’s clinical presentation. In a patient with signs of thyrotoxicosis , goiter, and exophthalmos, the presumptive diagnosis of Graves Disease can be made. Confirmatory laboratory studies reveal elevated serum free thyroxine (FT4) and/or total triiodothyronine (T3), suppressed serum thyroid stimulating hormone (TSH ), and presence of thyrotropin receptor stimulating antibody (TSHR-Ab). Radioactive iodine uptake is usually not necessary to make the diagnosis of Graves Disease but shows diffuse uptake throughout the gland if done. Euthyroid Graves disease consists of orbitopathy, positive TSHR-Ab but normal TSH and T4. Thyroid ultrasound imaging and radioiodine I-123 uptake testing are indicated if biochemical testing fails to confirm the diagnosis .

Treatment of thyrotoxicosis associated with pediatric Graves disease is somewhat controversial and should be tailored for each individual child. The three most commonly used therapeutic options include anti-thyroid drugs (ATDs), radioactive iodine and thyroidectomy. Most pediatric endocrinologists prefer ATDs as the initial treatment of pediatric Graves disease. Methimazole is the recommended ATD since propylthiouracil (PTU) has more frequent and severe side effects, including the small risk of severe liver injury. Children tend to have a higher relapse rate after discontinuation of ATDs compared to adults. Only 30 % of pediatric Graves patients achieve remission after 2 years of medical treatment with ATDs [10]. Alternative treatment with radioiodine 131 is considered when children have ATD toxicity, are non-compliant with ATDs or relapse after ATD discontinuation. Adjunct use of beta-blockers can control tachycardia, tremors, and anxiety associated with hyperthyroidism . A subtotal or total thyroidectomy may be considered in patients with Graves disease that presents prior to puberty, relapses after discontinuation of ATDs, is associated with severe orbitopathy or persistence of elevated TRAb levels. Reported complications after thyroidectomy in children with Graves disease include transient or permanent hypocalcemia, injury to the recurrent laryngeal nerve and keloid formation [65]. Avoidance of second hand smoke exposure may help prevent ophthalmopathy [66]. Graves orbitopathy tends to improve upon restoration of euthyroidism.

Graves orbitopathy (GO) in children presents predominantly with eyelid retraction and proptosis/exophthalmos. Systemic corticosteroid administration may be necessary if GO signs and symptoms progress despite ATDs or if they persist once the patient is euthyroid [67]. Somatostatin analogs have been reported to be of benefit in treating GO in adults, but limited information is available for children [68]. Newer treatments with B-lymphocyte depleting monoclonal antibody rituximab and anti-tumor necrosis factor-alpha agents etanercept and infliximab may play a role in the future treatment of pediatric GO but further studies to demonstrate safety and efficacy are necessary [69]. Orbital decompression is rarely needed in children as sight threatening complications secondary optic neuropathy and cornea exposure are rare compared to adults [64]. Orbit radiation is not recommended in children. Artificial tear drops and ointments may be used to address dry eye symptoms. Anterior blepharotomy to manage lid retraction may be offered if dry eye symptoms or cornea exposure fail to respond to conservative measures or if poor cosmesis is objectionable to the patient [70].

The four parathyroid glands located adjacent to the thyroid gland in the neck produce parathyroid hormone (PTH ) to control serum calcium. PTH increases serum calcium by stimulation of calcium release from bone, increased calcium absorption from the gut via activation of vitamin D and increased renal calcium reabsorption. PTH also increases renal phosphate excretion. Hyperparathyroidism is caused by elevated PTH production resulting in elevated serum calcium and end organ damage involving the kidney, pancreas and bone as well as hypertension, neuromuscular, neuropsychiatric and gastrointestinal disorders.

Hypoparathyroidism is much more common than hyperparathyroidism in children. Hypoparathyroidism is most frequently caused by injury to the glands during thyroid surgery or may be syndromic. Hypoparathyroidism results in low serum and bone calcium as well as elevated serum phosphate. Hyperparathyroidism may be due to a single adenoma, multiple parathyroid gland hyperplasia or parathyroid neoplasia.

The parathyroid glands were discovered by Ivar Sandström and symptoms of hypocalcemia after parathyroidectomy were described by W. G. MacCallum and Carl Voegtlin in the late nineteenth century [71]. Surgery to excise the parathyroid glands to treat bone disease was first performed in the early part of the twentieth century. Fuller Albright’s work established our current understanding of how the parathyroid glands regulate calcium and phosphate levels. He was the first to describe the etiology of primary hyperparathyroidism secondary to a solitary adenoma or hyperplasia of the parathyroid glands [72]. Albright also purified bovine parathyroid hormone for his research. Today, humanized truncated parathyroid hormone (Teriparatide, PTH ) and intact parathyroid hormone (Preotact, PTH) are used for the treatment of osteoporosis and hypoparathyroidism [73]. However, PTH has a black box warning in pediatrics due to a possible link between its use and osteosarcoma.

Hyperparathyroidism is rare in children with an incidence of 2–5 in 100,000 [74]. It is most often caused by a single adenoma but may be associated with genetic syndromes such as Multiple Endocrine Neoplasia (MEN ), McCune Albright Syndrome (MAS), Kearns Sayre syndrome and Autoimmune Polyglandular Syndrome type 1 .

Symptoms of hyperparathyroidsm are often vague and include fatigue, weight loss, abdominal pain, hypertension and polyuria. The most common presentation is asymptomatic mild hypercalcemia. A delay in diagnosis may result due to the rarity of the disease and vague symptoms [75]. Children may present with end organ damage secondary to hyperparathyroidism including renal calculi, pancreatitis and osteoporosis. Hypoparathyroidism may by asymptomatic or present with symptoms hypocalcemia including paresthesia, tetany, EKG changes and possibly seizures.

MEN syndromes are a group of inherited disorders characterized by tumors in multiple endocrine glands [76]. Systemic and ocular manifestations depend on the glands involved.

Kearns Sayre syndrome is a rare mitochondrial disease associated with chronic progressive external ophthalmoplegia , cardiac conduction abnormalities and retina degeneration within the first two decades of life [77]. The phenotypic presentation may be variable and include: myopathy, dystonia, cerebellar ataxia, dysarthria, nasal regurgitation, facial weakness, bilateral sensorineural deafness, dementia, proximal renal tubular acidosis, proximal skeletal muscle weakness and exercise intolerance [78]. Associated endocrinopathies include hypoparathyroidism, hypogonadism, diabetes mellitus, and hypopituitarism .

Autoimmune Polyglandular Syndrome type 1 is a rare autosomal recessive disease associated with hypoparathyroidism, adrenal insufficiency and chronic mucocutaneous candidiasis.

Primary hyperparathyroidism results in the following ocular manifestations: band keratopathy, conjunctival calcification and scleritis. Syndromic parathyroid diseases have variable ocular presentations. MEN 2B may present with mucosal neuromas of the eyelid margins as well as anteverted eyelids and medullated nerve fibers of the cornea. Cataracts may be associated with hypoparathyroidism and are often described as having multicolored flecks.

Children with Kearns Sayre syndrome initially present with eyelid ptosis. Eyelid ptosis may be asymmetric, unilateral or bilateral [79]. Chronic progressive external ophthalmoplegia results in severe extraocular muscle dysfunction and strabismus . Double vision is encountered less frequently than expected despite the presence of severe ocular dysmotility. Orbicularis oculi weakness and lagophthalmos have been reported to result in severe exposure keratitis [80]. Retina abnormalities appear to be progressive over time. Initially, patients may have a normal fundus appearance which progresses to “salt and pepper retinopathy”, chorioretinal atrophy and choroidal sclerosis [81]. Electroretinogram (ERG) testing may be normal initially but becomes extinguished over time. Visual acuity appears to parallel the development of retinopathy as vision loss progresses with time.

Chronic keratitis is the most common presenting ocular sign of Autoimmune Polyglandular Syndrome type 1 . Chronic dry eye, cataracts, iritis, retina detachment and optic atrophy have been reported [82].

Elevated serum and urine calcium and elevated PTH are diagnostic of hyperparathyroidism. Additional imaging modalities than can aid in the diagnosis of parathyroid disease include: ultrasonography, computed tomography, magnetic resonance imaging, and sestamibi nuclear scans [74].

A family history of genetic disorders including MEN syndrome should be elucidated as these disorders are autosomal dominant. Two or more endocrine tumors suggests the possibility of MEN . Other physical manifestations may help the clinician tailor their workup when investigating the possibility of other rare syndromes such as, Kearns Sayre, and autoimmune polyglandular syndrome type 1 . Electrophysiologic testing of the retina via an electroretinogram (ERG), electromyography, electrocardiogram and muscle biopsy examination for ragged red fibers may be useful in patients suspected of having Kearns Sayre syndrome .

Surgical resection of the parathyroid glands is the treatment of choice for hyperparathyroidism. Medical treatment involves administration of activated vitamin D (calcitriol) and calcium supplementation. A multidisciplinary approach is necessary to provide care for individuals with syndromic parathyroid disease.

Strabismus secondary to chronic progressive external ophthalmoplegia (CPEO) associated with Kearns Sayre syndrome is typically recalcitrant to treatment. Strabismus surgery with maximal resections and recessions of eye muscles augmented with botulinum toxin injection of the affected extraocular muscles typically fail to maintain ocular alignment long term [83]. Eyelid ptosis surgery for patients with Kearns Sayre syndrome should be undertaken with caution. The combination of external ophthalmoplegia and lagophthalmos make the eye vulnerable to injury, exposure keratopathy, corneal ulceration and perforation [84].