Hypoparathyroidism is an endocrine disorder characterized by insufficient secretion of parathyroid hormone resulting from structural or functional disorders of the parathyroid glands. Various etiological causes of hypoparathyroidism exist. The most common causes include surgical removal of the parathyroid glands, autoimmune parathyroid diseases, and developmental anomalies of the parathyroid glands [1, 2]. This paper is a comprehensive single-center study that examines all etiological causes in children.
Acquired causes of hypoparathyroidism, such as surgical removal of the parathyroid glands and autoimmune parathyroid diseases, typically present in adolescence and adulthood, whereas genetically caused hypoparathyroidism is more commonly seen in early childhood [7]. In our study, the median age at diagnosis for all cases was 5.5 [0.04-17] years. The age of acquired cases was 12.5 [4.1–17] years, while in genetically caused cases, it was 1 [0.04–2.75] years. As expected, the age at diagnosis was significantly lower in genetically caused patients. In the literature, in a study by Choe et al. evaluating surgical cases in children, the average age at diagnosis was found to be 14.9 years [7]. On the other hand, in a study evaluating genetic and acquired cases, the median age at diagnosis was three years [8] [Song et al.].
Hypoparathyroidism is diagnosed in the laboratory with persistent hypocalcemia, low or inappropriately normal parathyroid hormone [PTH] levels, and hyperphosphatemia. Hypocalcemia occurs when PTH secretion is insufficient. Hypocalcemia due to hypoparathyroidism can be associated with a spectrum of clinical manifestations, ranging from a few mild symptoms when hypocalcemia is mild to life-threatening seizures, refractory heart failure, or laryngospasm when it is severe. In addition to the severity of hypocalcemia, the rate of development and chronicity also determine the clinical findings. In acute hypoparathyroidism that may develop post-surgery, the distinguishing feature of acute hypocalcemia is tetany, characterized by neuromuscular irritability [9]. Symptoms of tetany can be mild [perioral numbness, paresthesias of the hands and feet, muscle cramps] or severe [carpopedal spasm, laryngospasm, and focal or generalized seizures]. Our study observed mild and severe signs of neuromuscular irritability, such as paresthesia, seizures, and carpopedal spasms. Specific to chronic hypoparathyroidism, basal ganglion calcifications, cataracts, dental abnormalities, and ectodermal signs may be observed [10]. Basal ganglia calcifications, cataracts, and onychomycosis were detected in one patient each.
A decrease in serum calcium levels is considered the most prominent laboratory finding in hypoparathyroidism. This finding is explained by the reduced reabsorption of calcium from the kidneys and decreased mobilization of calcium from the bones due to insufficient PTH secretion from the parathyroid glands [1]. In primary hypoparathyroidism, the elevated serum phosphorus level is explained by decreased phosphate excretion from the kidneys due to PTH deficiency. The calcium level in our patients was 6.7 [3.8–8.5] mg/dl, and hypocalcemia was detected in all patients. Additionally, hyperphosphatemia was present in all patients. The reduced secretion of PTH explains the low PTH levels due to diseases occurring in the parathyroid glands themselves [11]. In our study, all patients had low and normal PTH levels. It has been shown that serum magnesium levels are generally high in primary hypoparathyroidism. This condition is explained by the decreased excretion of magnesium from the kidneys due to PTH deficiency.
Moreover, cases of hypomagnesemia have been reported in hypoparathyroidism. Hypomagnesemia occurs due to impaired PTH synthesis and secretion in the parathyroid glands [1, 12]. In our study, hypoparathyroidism due to hypomagnesemia was detected in four patients. The hypomagnesemia was primary, and a genetic etiology was determined. Scientific studies have shown that serum ALP activity is significantly lower in cases of hypoparathyroidism, as ALP synthesis is suppressed due to PTH deficiency [13, 14]. In our study, the median ALP value was found to be 193 (70–1185) IU. When comparing patients in genetic and acquired groups, the ALP values were significantly lower in the acquired group.
It has been reported that patients with hypoparathyroidism have lower levels of 25 (OH)D and 1,25(OH)D. It has been suggested that vitamin D deficiency may contribute to the clinical presentation of hypoparathyroidism [5, 15]. In our study, the median level of 25-hydroxy vitamin D was found to be 24 (6–68), and vitamin D replacement therapy was administered to patients with diagnosed vitamin D deficiency.
The patient's family history is significant for clinical evaluation. However, access to such information is often limited due to the patient's lack of awareness of their relative's medical history. A history of consanguinity increases the likelihood of autosomal recessive diseases. Additionally, specific ethnic or geographical origins may increase the probability of known 'founder' mutations, such as AIRE mutations associated with APS1 [16]. In our study, family history was present in four patients. Isolated hypoparathyroidism was detected in three siblings in one family and two siblings in another family; however, responsible genes could not be identified in genetic analyses. In one family, after a cousin was diagnosed with hypoparathyroidism, a CASR mutation was detected in one patient. In the last family, a TRMP6 mutation responsible for Mg2 + reabsorption was present in two siblings.
Genetic forms of hypoparathyroidism include isolated hypoparathyroidism and syndromes in which hypoparathyroidism is present. Genetic defects can lead to issues with parathyroid gland formation, impaired secretion of parathyroid hormone, and damage to the parathyroid glands [17]. In our study, 39 patients were classified etiologically as having genetic causes.
Autosomal dominant, recessive, and X-linked inheritance have been reported. The autosomal form of isolated HP occurs due to mutations in genes coding for PTH, GCMB [glial cells missing homolog B], or CaSR; however, many cases are idiopathic, and the genetic mechanisms are unknown [18]. In our study, all patients considered to have isolated HP underwent additional analyses for CASR and PTH genes. In two patients, analyses were performed for CASR, PTH, and CGM2 genes, while whole clinical exome sequencing was conducted in three siblings. A male patient presenting with paresthesia also had a family history, and a mutation was detected in the CaSR gene. CaSR is a G-protein-coupled receptor that plays a crucial role in calcium homeostasis. The most common autosomal dominant activating mutation in CaSR alters the serum calcium concentrations that typically trigger PTH release, leading to hypocalcemia with accompanying urinary calcium excretion [19]. Our patient also presented with hypocalcemia accompanied by hypercalciuria. In our study, no genetic mechanism was found in 17 patients, and it was observed that they were idiopathic at a rate consistent with the literature.
Among syndromic causes, hypoparathyroidism due to parathyroid aplasia or hypoplasia is commonly found in DiGeorge syndrome. DiGeorge syndrome results from abnormal development of the third and fourth branchial pouches. Other features include thymic aplasia or hypoplasia, cardiac defects affecting the outflow tract, developmental delays, and a characteristic facial appearance [e.g., prominent nose, square nasal root] [20]. The most common cardiac anomaly seen in DiGeorge syndrome is tetralogy of Fallot. Additionally, vascular anomalies are an essential component of the syndromic disease and can be life-threatening [21]. In our study, consistent with the literature, the most frequently encountered cardiac defects were tetralogy of Fallot and ventricular septal defects [VSD]. Atrial septal defects [ASD] and aortic arch anomalies were also observed. Most cases are sporadic, but familial cases with autosomal dominant inheritance have also been reported. In most patients, there is a deletion of the 22q11.2 chromosome region [21]. Hypoparathyroidism can present with hypocalcemia in the neonatal period or later in life with decreased parathyroid reserve [22]. The frequency of hypocalcemia in these cases varies between 17% and 60% [23]. Due to our hospital being a tertiary care center, patients diagnosed with DiGeorge syndrome are referred to our outpatient clinic from the cardiology and immunology departments. Fourteen of our patients had been diagnosed with hypoparathyroidism associated with DiGeorge syndrome. Eight patients were diagnosed during routine examinations while asymptomatic, while three presented with cramps, two with hypocalcemic seizures, and one with paresthesia. In the two patients diagnosed with seizures, hypoparathyroidism was identified, and considering the typical facial features along with clinical and laboratory findings, DiGeorge syndrome was suspected, leading to the detection of a 22q11.2 deletion for confirmation. In patients with DiGeorge syndrome, intermittent hypoparathyroidism can be observed, and in our study, three patients required intermittent treatment [24].
HRD syndrome, a rare form of hypoparathyroidism with an autosomal recessive inheritance pattern, encompasses Sanjad-Sakati and Kenny-Caffey syndromes, both of which are linked to the TBCE gene. Sanjad-Sakati syndrome displays features such as parathyroid dysgenesis, short stature, intellectual disability, small stature, microcephaly, diminutive extremities, and atypical tooth development. In contrast, Kenny-Caffey syndrome is characterized by hypoparathyroidism, dwarfism, narrowing of the midsection of long bones, and ocular abnormalities [25, 26]. Our research involved a 1.5-year-old patient exhibiting hypocalcemic seizures, along with neuromotor retardation and profound developmental delay, demonstrating classic manifestations consistent with Sanjad-Sakati Syndrome. The patient manifested a homozygous c155_156del (p.ser53Sr52_Gly55del) mutation in the TBCE gene.
Another syndromic cause of hypoparathyroidism is HDR syndrome, which is characterized by hypoparathyroidism, sensorineural hearing loss, and renal dysplasia. Also known as Sanjad-Sakati syndrome, it results from heterozygous pathogenic variants in the GATA3 gene [27]. In our study, a patient diagnosed with hypoparathyroidism at 2 years and 9 months was screened for syndromic features and found to have bilateral sensorineural hearing loss and renal cysts, leading to a suspicion of HDR syndrome. A deletion involving the GATA3 gene was identified on the p arm of chromosome 10 [46,XX,10p-.arr[GRCh37]15.3p14[920970_11858056]x1]
Hypomagnesemia is a rare cause of hypoparathyroidism. It can present as secondary hypocalcemia and is associated with a familial condition that responds to magnesium administration in the neonatal period [28]. The autosomal recessive form is usually caused by mutations in the TRPM6 gene [29]. In our study, a newborn presented with seizures at 26 days of age, and hypomagnesemia was detected. A 2-year-old sibling, who later reported paresthesia, also had hypomagnesemia, leading to genetic analysis of the two siblings, which revealed a mutation in the TRPM6 gene. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis [FHHNC] is associated with primary renal magnesium wasting and high calcium excretion in the urine, and it is inherited in an autosomal recessive manner [30]. In our study, mutations in the Claudin-16 gene were identified in two patients aged 4 and 12 years with hypomagnesemia, hypercalciuria, and hypocalcemia. Mutations in the Claudin-16 gene are the main cause of FHHNC [28]. Magnesium administration improved the condition in all four patients.
Acquired causes of hypoparathyroidism include parathyroidectomy, post-thyroid surgery, autoimmune causes, iron and copper accumulation after parathyroid gland damage, sepsis, and HIV infection [31]. In our study, hypoparathyroidism due to post-thyroid surgery, autoimmune factors, and iron accumulation was identified among acquired causes.
Hypoparathyroidism is the most common complication after thyroid surgery. The risk of developing hypoparathyroidism after thyroid surgery has been reported to be between 9.6% and 60%, while the rate of permanent hypoparathyroidism is reported to be between 0% and 12% [32–35]. Risk factors for permanent hypoparathyroidism include younger age, extensive neck dissection, and repeated surgical procedures [36, 37]. In our study, between 2021 and 2023, 15 cases underwent thyroid surgery for treatment, and hypoparathyroidism developed in 9 patients within the adolescent age group. In 7 patients, the condition improved within six months, while 2 patients [13.3%] with extensive neck dissection due to metastatic papillary thyroid carcinoma experienced permanent hypoparathyroidism. García and colleagues studied 39 patients who underwent thyroid surgery, 25 of whom had prophylactic and 14 therapeutic procedures. Among 3 [7.7%] cases with metastatic thyroid carcinoma, permanent hypoparathyroidism developed [37].
Autoimmune hypoparathyroidism can manifest as an acquired disease or as a component of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome [APECED] [38]. Known as Autoimmune Polyendocrine Syndrome Type 1, APECED is primarily a monogenic disorder caused by biallelic inactivating variants in the AIRE [autoimmune regulator] gene. Additionally, APECED can develop due to lymphocytic infiltration related to anti-NALP5 antibodies, anti-calcium-sensing receptor antibodies, and other autoimmune diseases [39]. In most patients, hypoparathyroidism [in 73–90% of cases], Addison's disease, and chronic mucocutaneous candidiasis can be observed, although other autoimmune disorders and non-autoimmune symptoms may also occur [40].
In our study, APECED was considered in three patients who exhibited findings such as alopecia areata, adrenal insufficiency, Hashimoto's thyroiditis, autoimmune hepatitis, and celiac disease. A homozygous c.464-3c > g mutation was identified in two of these patients, while a homozygous p.Arg257*[c.769C > T] mutation was found in one patient. Idiopathic hypoparathyroidism may have an autoimmune etiology in some cases. Most autoimmune diseases are associated with specific human leukocyte antigen [HLA] specificities and other gene polymorphisms that regulate various aspects of immune function. The strong association of HLA-A26:01 with idiopathic autoimmune hypoparathyroidism suggests that the presentation of autoantigenic peptides to CD8 + cytotoxic T cells via major histocompatibility complex [MHC] class I plays a key role in its pathogenesis [41]. In our study, a 17-year-old male patient presenting with paresthesia was evaluated in detail, and idiopathic autoimmune hypoparathyroidism was considered, with plans to test for HLA-A26:01.
Another acquired cause is iron overload due to frequent blood transfusions, as seen in patients diagnosed with thalassemia major. Hypoparathyroidism can develop particularly in patients who are non-compliant with iron chelation therapy and have received long-term blood transfusions. In a study by Tangngam et al. on thalassemia-related hypoparathyroidism, hypoparathyroidism was detected in 25 [38%] of 66 transfusion-dependent patients aged between 5 and 23 years. These patients were asymptomatic and were identified during routine screening [42]. Our study detected hypoparathyroidism in 3 [2.9%] cases due to iron accumulation. These patients, whose follow-ups were irregular and who had received transfusions for at least 15 years, were identified during routine screening. Therefore, the risk of developing hypoparathyroidism in thalassemia patients should be monitored with frequent check-ups during chronic follow-up.
The optimal management of hypoparathyroidism is a lifelong challenge. The main difficulties in treatment involve regulating serum calcium levels and preventing complications. The primary treatment approach is the replacement of calcium and active vitamin D [calcitriol]. However, long-term calcium and vitamin D therapy can lead to complications such as kidney stones, nephrocalcinosis, and hypercalciuria [1, 43]. In our study, calcium and active vitamin D [calcitriol] were initiated in all cases except those with hypoparathyroidism due to hypomagnesemia. Treatment was planned for life, except for 7 patients with transient hypoparathyroidism following thyroid surgery. Among these patients, 7 developed hypercalciuria and nephrocalcinosis during follow-up. The development time for nephrocalcinosis has been reported in studies as 3–5 years [44]. In our study, the median time for the development of nephrocalcinosis was found to be 40 months.
Among other current treatment options, recombinant PTH [1–34 or 1–84] replacement therapy is included. PTH replacement may be more effective in maintaining normal calcium-phosphorus balance, reducing symptoms, decreasing medication requirements, and lowering the risk of complications. However, long-term reliability and efficacy data are still limited [45].
