Rare case of nephrocalcinosis in a 14-year-old girl: Answers

This clinical quiz highlights the importance of careful evaluation of all multiorgan symptoms occurring in the described patient to prevent further complications.

In 1980, Neufeld and Blizzard proposed the first classification of autoimmune polyendocrine syndromes on the basis of clinical criteria and defined four types of APS [9]. Of these four types, polyglandular autoimmune syndrome type 1, also known as APS1, autoimmune polyendocrinopathy–candiasis–ectodermal dystrophy or Whitaker syndrome, is a rare genetic disease which is autosomal recessive, inherited in a monogenic pattern and caused by a mutation in the gene of autoimmune regulation (AIRE) localized on the long arm of chromosome 21 (21q22.3) [OMIM 240300] [10, 11]. It was described for the first time in 1946 by Leonard [12]. The prevalence of this syndrome in the Polish population was set at 1:129 000 people. APS1 occurs in both sexes. The suggested role for AIRE is to induce expression of peripheral antigens in the thymus, thereby mediating negative selection of autoreactive T cells and cause toleration [13]. The main components of APS1 are hypoparathyroidism, adrenal insufficiency and candidiasis of mucous membranes (oral, anal area, external genitals) and/or of the skin and nails. A necessary condition for the diagnosis of APS1 is the simultaneous occurrence of two of the three above-mentioned diseases. APS1 is accompanied by other diseases with an autoimmune origin [14, 15, 16]. The first symptom is usually candidiasis of the oral mucosa, which occurs before the age of 5 years. Autoimmunity in APS1 is also the responsible factor for the CYSTATIN salivary antigen1 deficiency, which causes impaired protection against Candida albicans infections [17]. The first endocrinopathy is an autoimmune hypoparathyroidism, which occurs before the age of 10 years, and the second is adrenal insufficiency, which usually develops before the age of 15 years [9, 18].

Additional disorders include other endocrinopathies (autoimmune hypothyroidism, type 1 diabetes, hypergonadotropic hypogonadism, hormonal disorders of pituitary origin), ectodermal dystrophy, including tooth enamel hypoplasia, abnormal development of nails, gastrointestinal diseases (chronic atrophic gastritis, malabsorption symptoms, cholelithiasis), autoimmune hepatitis, alopecia areata, vitiligo, sclerositis and conjunctivitis, humoral and cellular immunity deficiency, asplenia and anemia associated with B12 deficiency [8, 19, 20, 21].

In patients with APS1 it is necessary to perform periodical screening for 21-hydroxylase antibodies, anti-islet cell antibodies, antiparietal cell antibodies, transglutaminase antibodies and vitamin B12 deficiency. Autoantibodies to the T helper 17 cells and anti-cytokines interleukin (IL)-17A, IL-17 F and IL-22 appear in APS1 patients and may explain their increased susceptibility to candidal infections [22, 23].

The occurrence of several additional symptoms may be promoted by the overlap between the initial disorders and some effects of the therapeutic interventions. Among these secondary symptoms, basal ganglia calcification and the already discussed nephrocalcinosis should be mentioned. Chronic hyperphosphatemia as a primary disturbance in combination with excessive calcium and supplementation of active vitamin D analogues contributes to the ectopic calcifications in the central nervous system, most commonly in the globus pallidus [24]. These calcifications are believed to be primarily the direct consequence of chronically elevated phosphate levels and high calcium × phosphate product. Nonetheless, additional factors explaining, among others the brain tropism, are taken into consideration. For example, the high serum phosphate levels may activate the inorganic phosphate transporter (PiT1; SLC20A1), which results in the expression of osteogenic molecules in the caudate nucleus and gray matter of the brain [25, 26]. It is estimated that cerebral calcifications may be present in >50 % of patients with hypoparathyroidism. These calcifications can remain asymptomatic or lead to progressive clinical symptoms, including cognitive impairment, extrapyramidal symptoms and psychosis [27].

Consequently, because basal ganglia concretions may result from “overtreatment” of hypoparathyroidism, it is important to set the therapeutic goal so as to avoid symptomatic hypocalcemia, without constant striving for full biochemical normalization of calcemia.

Urinary calcium excretion in APS1 may vary widely between individuals and is highly dependent on treatment, medication compliance and diet. As in nephrocalcinosis of other origins, thiazide diuretics have also been successfully applied in APS1. Thiazide diuretics have been shown to reduce urinary calcium excretion and thus reduce the formation of calcium deposits. Thiazides diminish renal calcium excretion by increasing calcium reabsorption in the distal tubules and by stimulating proximal tubular reabsorption by way of volume control. Thiazides also reduce gastrointestinal absorption of calcium and phosphorus. The final result of these is to promote a positive calcium balance in the body [28]. Hypokalemia is an unwanted side effect that can lead to hypocitraturia and an unplanned increase of the urinary saturation (e.g. for calcium oxalate). In addition, thiazide medication may also lead to lowering of the blood pressure [29, 30]. Auron and Alon reported the resolution of medullary nephrocalcinosis in three children with metabolic bone disorders following treatment with thiazides [29]. Tubulointerstitial nephritis has also been mentioned as a symptom of APS1. Kluger et al. propose regular kidney monitoring for APS1 patients as they may present with kidney injury due to the presence of circulating antibodies against the distal part of the nephron [31].