Most of the GD clinical features result from the direct effect of thyroid hormones on the target tissues, but others may be a further expression of the same autoimmune process or of another associated autoimmune disease. Indeed, it is quite common to observe other autoimmune diseases such as type 1 diabetes mellitus, coeliac disease, vitiligo, etc. in GD patients.

Tachycardia is a typical sign of thyroid hormone excess on heart, but other signs such as elevated blood pressure, precordial thrill, and/or an ejection murmur due to functional insufficiency of the mitral valve may be present. There is often a delay in the diagnosis since, before coming to the attention of a pediatric endocrinologist, the child has already been assessed by other specialists, mainly a cardiologist.

Bone is also extremely sensitive to the action of thyroid hormones. Clinically, an increased growth velocity can be observed alongside an enhanced bone maturation resulting in an advanced bone age. However, it takes time for these features to develop, and therefore they can be detected in few cases, due to increased medical knowledge and care. Moreover, thyroid hormones strongly influence bone metabolism, inducing a high bone turnover with an uncoupling between the resorptive and the anabolic phase, which may result in a net bone loss and thus osteoporosis over the years. However, this mostly happens in adults suffering from an unrecognized form of subclinical hyperthyroidism, as in the case of a nodular pathology lasting for many years. In children and adolescents, where the thyrotoxic phase is generally promptly diagnosed, there is only a transitory phase of bone loss which completely recovers after normalization of thyroid hormones [5].

Muscle function may be severely compromised, mostly due to TH-induced protein wasting. A decreased muscle mass, particularly of the proximal muscles, and a reduced force can be observed. It is speculated that the toxic muscle requires more energy to function than normal, presumably because of additional ATP-consuming mechanisms. However, myasthenia gravis, another autoimmune disease. may be associated [6].

Gastrointestinal symptoms are not very common and even when present are mild. They can depend both on TH excess which causes an enhanced intestinal transit, although not a frank diarrhea, and also on a concomitant coeliac disease. The latter should always be investigated when symptoms do not disappear following normalization of TH.

Eye involvement can be observed in most cases; however, it is not so marked as in adult patients. Signs and symptoms are milder, producing less long-term consequences. The most common sign is lid retraction, which gives a staring expression, and the lag of the lids behind the globes on downward rotation, as well as the failure to wrinkle the forehead on looking upward. All these signs are secondary to thyroid hormone excess which causes the contraction of orbicular muscles and which solves spontaneously following the normalization of TH levels. A real ophthalmopathy with inflammation of extraocular muscles, orbital fat, and connective tissue may be present in some cases, producing a proptosis together with periorbital edema and muscular dysfunction, due to inflammation of medial and lateral rectus muscles. There is now strong evidence that the immune reaction which leads to Graves’ ophthalmopathy is directed against TSH receptors expressed in the orbital fibroblasts and adipocytes. The most common symptoms are due to conjunctival or corneal irritation and include burning, photophobia, tearing, pain, and a gritty or sandy sensation. It is very rare to observe a decrease in visual acuity as in adult patients. Eye drops and sunglasses are mostly used to prevent conjunctival dryness, while treatment with corticosteroids may be avoided [7, 8].

Pretibial edema is very uncommon in pediatric age. Its mechanism, similarly to ophthalmopathy, is stimulation of TSH receptors, aberrantly expressed in the skin.

A symmetrical goiter may be present, but in many cases thyroid volume is not particularly increased. A firm goiter at palpation and a thrill can be heard due to increased perfusion of the gland [9, 10].

Biochemical profile: there is usually a favorable lipid profile with low serum total and HDL cholesterol and low total cholesterol/HDL cholesterol ratio with plasma triglycerides in the lower normal range. The carbohydrate profile is characterized by an increased demand of insulin due to increased hepatic glucose production and to reduced insulin sensitivity. On the other hand, type 1 diabetes mellitus may be present. Protein metabolism is globally accelerated. Nitrogen excretion is increased, and nitrogen balance may be normal or negative, depending on whether intake meets the demands of increased catabolism or not [11].

Central and peripheral nervous system are always affected by TH excess. Already from clinical inspection, a tremor is observed, which can be associated to brisk deep tendon reflexes and eventually fasciculation of the tongue. Tremor is best observed asking the child to outstretch both hands. In general, mood swings and behavioral problems can represent a common neuropsychological complaint in hyperthyroid children [12]. Therefore, they can be referred to a child neurologist with a diagnosis of attention hyperactivity disorder, as their attention span is decreased, their sleep pattern is deteriorated, and they are hyperactive in daily life [13].

Involuntary movement disorders, such as chorea, athetosis, ballism, or truncal flexion, eventually associated to ataxia are rarely described in children affected by hyperthyroidism; symptoms remit with treatment of hyperthyroidism [14].

Autoimmune neurological conditions, such as childhood-onset demyelinating disorder [15] or disorders of neuromuscular junction [16], rarely observed as the only symptom in children affected by GD, can represent a manifestation of the common altered immune state. As other endocrine dysfunctions, hyperthyroidism can be linked to benign intracranial hypertension in children, presenting with chronic headache, papilledema, and normal neuroimaging [17]. Correction of the endocrine alterations is associated with remission of symptoms. Finally, in children presenting with hyperthyroidism and focal neurological deficits, Moyamoya disease should be investigated [18]. Moyamoya disease is a cerebrovascular disorder characterized by bilateral stenosis or occlusion of the terminal portions of the internal carotid arteries. Typical presenting symptoms are cerebrovascular accidents and epilepsy.

The hyperthyroid phase is usually caused by inflammation and autonomous release of preformed, stored thyroid hormone; however, if TSHR-Abs with stimulating activity are also present, the hyperthyroid phase may be more severe, lasting several months. This situation called hashitoxicosis must be recognized since the therapeutic approach is very different. In case of simple release of preformed hormones, the treatment is just symptomatic, aimed at alleviating symptoms through the use of beta-adrenergic antagonists if tachycardia or tremulousness are present. Usually, propranolol 1–2 mg/kg divided in three to four doses is employed and titrated according to the clinical picture and the laboratory values. When, however, TSHR stimulating Abs are present, the treatment needs to be different since there is an additional source of thyroid hormones. In this case in addition to beta-adrenergic antagonists, thyreostatic drugs, as in GD, are needed.

TSHoma is a pituitary adenoma, usually benign, which secretes only TSH. More often, microadenomas are observed, though hormone production is often accompanied by an unbalanced hypersecretion of the glycoprotein hormone α-subunit (α-GSU). It is a rare situation in children as compared to adults. The hormonal profile is characterized by high levels of fT3 and fT4 together with a nonsuppressed TSH. This situation cannot be clinically differentiated from the more common RTH syndrome, and thus MRI is needed. Twenty to twenty-five percent of TSHomas are mixed adenomas, characterized by concomitant hypersecretion of growth hormone or prolactin [20, 21].

This condition has been recognized for the first time in 1967 while the first mutations in the THRB gene, which code for the TSH receptor β were identified in 1989 [22]. This mutation causes a decreased tissue responsiveness to thyroid hormone (TH). It has been always though that the cause were a mutation inactivating the THRB gene (RTH-ß), but lately also mutations in the THRA (RTH-α) have been detected which result in hypothyroidism. The commonest THRB gene mutations are heterozygous and exert a dominant negative effect on wild type receptor. Deletions on the other hand, behave as a recessive dominance since there is no negative effect on the wild type receptor. Homozygous mutations are rare and cause a very severe phenotype. Patients present with elevated fT4 and fT3 and an inappropriately normal TSH. From the clinical point of view, due to the different tissue sensitivity to TH, the patients may be perfectly normal, suffer from hypothyroidism, or be frank hyperthyroid. There may be also a discordance in sensitivity among tissues, and the patients may present with tachycardia and retarded bone age. Hyperthyroid features are predominant in those individuals being deemed to have predominant central or pituitary resistance. The diagnosis is suspected on the basis of the elevated TH together with inappropriately normal TSH; however, a TSHoma must always be excluded by imaging, and a genetic analysis should follow for confirmation. However, in a number of cases, no genetic anomalies can be detected (nonTR-RTH). Treatment is completely independent from TH serum levels and depends on the different sensitivity at tissue levels. If there are clinical signs and symptoms of hyperthyroidism, as in the pituitary form, the aim of the treatment should be lowering TH in serum. The best approach is to lower TSH secretion from the pituitary gland by the use of triiodothyroacetic acid (TRIAC), a TH analogue with low hormonal potency but high affinity to TR. Long-term experiences are promising. Another TH analogue, dextrothyroxine (d-T₄), had been employed but with poor results. A further possible solution is thyroidectomy alongside substitutive therapy. Up to now, there is no evidence that a prolonged period of pituitary stress (the pituitary gland continues to secret a large amount of TSH) may favor the onset of an adenoma [23].

Fetal and neonatal hyperthyroidism are rare with a prevalence of neonatal thyrotoxicosis of 1/4,000–1/50,000 pregnancies [25]; it may be a life-threatening event and could lead to death if left untreated.

The most frequent cause of fetal and neonatal hyperthyroidism is transplacental transfer of stimulatory TSH receptor antibody (TSHR-Abs) from a mother affected by GD [25]. The prevalence of GD in pregnancy is 0.2 % [26], and 1–12.5 % of the offspring show thyrotoxicosis at birth, and another 3 % show only biochemical signs of hyperthyroidism [25]. The prevalence of hyperthyroidism, however, increases to 22 % in the offspring of women who require treatment for GD in the third trimester of pregnancy [25]. The transplacental passage of stimulatory TSHR-Abs starts early in pregnancy, and the highest level in the fetus is reached during the third trimester, when maternal concentration of TSHR-Abs is the highest. At that time, fetal autoantibodies’ levels are similar to those observed in the mother.