**1. Introduction**

In pediatric age group the Grave's-Basedow disease (GD) is by far the most common cause of hyperthyroidism, accounting for greater than 95% of cases. The underlying process is an autoimmune reaction with cell proliferation and excess function (overproduction of thyroid hormone) caused by anti-thyrotropin receptor antibody (TRAb). When using term thyrotoxicosis, it depicts the clinical and biochemical manifestations of excess thyroid hormones. The annual incidence of thyrotoxicosis was less than 1 per 100,000 children <15 years of age in the last

century and rised slowly above 1.5 per 100,000 by 2012 with the pubertal dominance up to 80%. In spite of the GD is a rare disorder in children, physicians should consider Graves' Disease in any child with clinical manifestations of hyperthyroidism, regardless of the age.

All but a few GD children present with some degree of thyroid gland enlargement and most have two or more signs of excessive thyroid activity. The clinical manifestations of hyperthyroidism during fetal life are tachycardia, cardiac arrhythmia, intrauterine growth retardation and may be associated with nonimmune fetal hydrops, craniosynostosis. Features of this condition in the neonate include irritability, tachycardia, hypertension, cardiac failure and arrhythmias, diarrhea, poor weight gain, vomiting, jaundice, hepatosplenomegaly, ophthalmopathy, craniosynostosis and thyroid enlargement. In childhood hyperkinesis, tachycardia, tremor, frequent stools, nervousness are the signs of hyperthyroidism but in young children these are less characteristic, often unrecognized. In schoolage hyperthyroidism neuropsychiatric symptoms such as hyperactivity and poor school performance are common features. Adolescents usually present with classic signs including weight loss despite of good appetite, diarrhea, nervousness, and heat intolerance. Fully developed clinical picture is easy to recognize while often the onset is insidious. Thyroid hormones affect many body systems, so signs and symptoms of Graves' Disease can be wide ranging.

This chapter is aimed to draw attention to less common or less distinctive signs and symptoms which can be in relation to GD at the time of diagnosis. A survey was conducted on PubMed literature to gather all published pediatric Graves-Basedow's cases with unusual presentation at the time of diagnosis. We found all together 70 publications with relevant information from 1978 to 2020 but mainly adult cases. Half of them (36) were found to meet the criteria we focused on and were included in this paper, though in some situation the unusual findings do not consist part of hyperthyroidism, the rare manifestation is only a coexistence, or the serious disease even precedes the GD. Awareness about the relation of these rare manifestations or disorders to GD is essential to avoid wrong diagnosis, unnecessary investigations, or fatal outcome due to delay of diagnosis.

#### **2. Unusual signs and symptoms**

#### **2.1 Dermopathy and acropachy**

Thyroid dermopathy (TD), also called pretibial myxedema and thyroid acropachy (TA) together with Graves' orbitopathy (GO) are extrathyroidal manifestations of GD. Graves' ophthalmopathy in children not as common as in adults and less severe than in later age. Dermatological symptoms are rare and in general develop sequentially: Dermopathy is usually present if the patient is also affected with GO. The very rare acropachy occurs only in patients who also have dermopathy [1]. Or in other words, acropachy is an indicator of severity of ophthalmopathy and dermopathy. All have an autoimmune origin, the immune reaction is targeted to TSH receptor and, likely, the IGF-I receptor. Typical presentation of dermopathy is nonpitting edema or plaque-like lesions on the pretibial region, while thyroid acropachy presents as digital clubbing, swelling of digits and toes, and periosteal reaction of extremity bones. Awareness about the relation of TA to GD is important as clubbing usually is not a patient complaint and is noted only by clinical observers. Recently Kraus CN and al. reported a case of acropachy in a child as well as reviewed the literature of pediatric thyroid dermopathy [2].

*Unusual Presentation and Rare Comorbidity of Graves-Basedow's Disease in Children DOI: http://dx.doi.org/10.5772/intechopen.97577*

#### **2.2 Cholestasis**

Hepatic dysfunction is commonly observed in patients with thyroid disease, it can be categorized mainly into group with either hepatocellular damage (transaminases elevations), or intrahepatic cholestasis (bilirubin elevation). In newborn, the hypothyroidism is the most typical thyroid disorder associated with cholestasis. Jaundice due to intrahepatic cholestasis may be a salient symptom in GD patients, and very occasionally, it is the presenting manifestation of thyrotoxicosis. The mechanism of liver injury in pure hyperthyroid states is not well understood, and no correlation was documented between abnormal liver biochemical tests and thyroid hormone levels. A contributing factor appears to be relative hypoxia in the perivenular regions, due to an increase in hepatic oxygen demand without an appropriate increase in hepatic blood flow [3], the other might be the thyroid hormones themselves with a direct toxic effect on hepatic tissue in hypermetabolic state [4]. If other possible causes of cholestasis are excluded, recovery occurs parallelly with restoration of euthyroidism. In the absence of another evidence of liver disease, and when jaundice is purely due to the hyperthyroidism, thionamide drugs may be used with monitoring of serum bilirubin and liver function tests [5]. Newborns and adolescent patient were reported with jaundice/hyperbilirubinemia as manifestation of GD hyperthyroidism [6–8].

#### **2.3 Polydipsia, nocturnal enuresis**

Disturbance of water homeostasis can lead to polyuria-polydipsia syndrome, which is a diagnostic challenge. Polydipsia is a nonspecific symptom in various diseases, often accompanied by polyuria. Increased thirst and/or nocturnal enuresis can be the main complains, and a careful case history usually reveals the primary reason (disturbed input or output). Polydipsia has been described as a presenting symptom of hyperthyroidism in adults. A few years back a serendipitous identification of GD in identical twin girls with polydipsia was published [9]. Though etiology of nocturnal enuresis is not fully understood, evidence is growing that enuresis may have a central origin: bedwetting children have lower brainstem reflex control (impaired prepulse inhibition) than normal controls [10]. A case of a 9-year-old boy has been reported by the same team who suffered from hyperthyroidism and a new appearance of enuresis. Bedwetting ceased and prepulse inhibition – measured as a parameter of central control – increased during on course of anti-thyroid therapy [11]. In our praxis we experienced two GD cases where nighttime incontinence was the presenting feature of recurrent hyperthyroidism.
