Etiology of hypocalcemia in infants and children

INTRODUCTION — A narrow range of extracellular calcium concentrations provides for cell stability and survival and is maintained by an intricate homeostatic system. The etiology of hypocalcemia can be related to failure of a component of this system, such as deficiency of or resistance to parathyroid hormone (PTH) or vitamin D, or a defect of the calcium-sensing receptor (CaSR).

The etiology and pathogenesis of hypocalcemia in the infant and child and a brief summary of calcium homeostasis will be presented here. An approach to determining the cause of hypocalcemia is presented separately. (See "Diagnostic approach to hypocalcemia".)

Treatment of hypocalcemia is covered in the following topic reviews:

●Hypocalcemia due to hypoparathyroidism (see "Hypoparathyroidism")

●Hypocalcemia in neonates (see "Neonatal hypocalcemia")

●Hypocalcemia due to vitamin D deficiency (see "Vitamin D insufficiency and deficiency in children and adolescents" and "Etiology and treatment of calcipenic rickets in children")

●Severe acute and/or symptomatic hypocalcemia (carpopedal spasm, tetany, seizures) (see "Treatment of hypocalcemia", section on 'Severe symptomatic and/or acute hypocalcemia' and "Primary drugs in pediatric resuscitation", section on 'Calcium')

DEFINITION — Physiologic hypocalcemia refers to a reduction in the concentration of ionized calcium in serum or whole blood. Measurements of ionized calcium and total calcium are closely related, but the relationship may vary in settings of abnormal albumin concentrations, pH extremes, and during blood transfusions. As an example, each 1 g/dL reduction in the serum albumin concentration will lower the total calcium concentration by approximately 0.8 mg/dL (0.2 mmol/L), without affecting the ionized calcium concentration. (See "Diagnostic approach to hypocalcemia", section on 'Confirm hypocalcemia'.)

Although both measures are relatively constant over the lifespan, the upper limit of the normal range may be greater in infants, particularly during the first three months of life. In one study of healthy infants during the first year of life, serum ionized calcium concentrations were [1]:

●1 month of age – Mean 5.6 mg/dL (1.4 mmol/L); observed range 5.2 to 6.1 mg/dL (1.29 to 1.52 mmol/L)

●3 months of age – Mean 5.5 mg/dL (1.38 mmol/L); observed range 5.2 to 6.0 mg/dL (1.30 to 1.49 mmol/L)

●12 months of age – Mean 5.3 mg/dL (1.33 mmol/L); observed range 5.0 to 5.6 mg/dL (1.24 to 1.39 mmol/L)

After 12 months of age, normal ranges typically used for clinical purposes are:

●Ionized calcium – 4.65 to 5.25 mg/dL (1.2 to 1.3 mmol/L)

●Total calcium – 8.5 to 10.5 mg/dL (2.12 to 2.62 mmol/L)

NORMAL CALCIUM HOMEOSTASIS — Two major and interrelated calciotropic hormonal systems, parathyroid hormone (PTH) and vitamin D, are central to calcium homeostasis and function, as described below.

●PTH – PTH serves as the primary protection against acute hypocalcemia. PTH is released from the parathyroid chief cells. The calcium-sensing receptor (CaSR) resides on the plasma membrane of the chief cells and serves as a "calcistat," which continuously senses ambient ionized calcium concentration. Acute changes in ionized calcium levels are immediately detected by the CaSR, which effects a rapid increase or decrease in PTH secretion based on the direction of change in ionized calcium. This classic negative endocrine feedback loop allows for an increase in PTH as ionized calcium concentration decreases, engaging mechanisms to increase the ionized calcium level. As ionized calcium levels rise, there is suppression of PTH secretion to maintain the steady-state narrow range of ionized calcium levels.

PTH acts to increase serum calcium by:

•Mobilizing calcium from the bone – Via stimulation of osteoclastic bone resorption and release of calcium from a rapidly exchangeable calcium pool

•Stimulating 1-alpha-hydroxylase in the kidney – Thereby converting 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (the active form of vitamin D), which directly increases intestinal calcium absorption

•Directly increasing calcium reabsorption in the distal renal tubule

●Vitamin D – 1,25-dihydroxyvitamin D, the active metabolite of vitamin D, promotes calcium and phosphorus absorption from the gastrointestinal tract. Lesser effects on calcium reabsorption from the renal tubules may also occur. Exposure to pharmacologic amounts of 1,25-dihydroxyvitamin D may also affect bone resorption, with net movement of calcium into the blood.

The hormone calcitonin plays a less critical role in calcium homeostasis. Calcitonin is synthesized in and released from the parafollicular cells of the thyroid gland when the circulating concentration of ionized calcium is increased. Calcitonin acts by decreasing bone resorption by osteoclasts.

A more detailed discussion of calcium homeostasis is found elsewhere. (See "Parathyroid hormone secretion and action".)

PATHOPHYSIOLOGY — The primary determinant of symptoms and signs in patients with hypocalcemia is the circulating ionized calcium concentration. A low ionized calcium concentration results from either decreased entry of calcium into the circulation (gastrointestinal malabsorption, decreased bone reabsorption, eg, due to hypoparathyroidism or hypovitaminosis D) or increased loss of ionized calcium from the circulation (deposition in tissue, loss in urine, or increased binding of calcium in serum) (table 1). (See "Clinical manifestations of hypocalcemia".)

Acute hypocalcemia is generally caused by rapid movement of calcium from the circulation to other tissue compartments or by formation of complexes of the calcium ion with phosphate, other counterions, or protein binding. For example, phosphate administration may lower serum ionized calcium concentrations by promoting formation of calcium-phosphate complexes, and precipitation of mineral in soft tissue or bone matrix. Alkalosis decreases the concentration of serum ionized calcium by increasing the binding of ionized calcium to albumin. Ingestion of ammonium bifluoride (an ingredient of glass-etching creams) can form calcium complexes and thereby acutely lower circulating ionized calcium concentrations [2].

Chronic or subacute hypocalcemia mainly results from long-term dysfunction of the primary organs mediating calcium movement (intestine, bone, and kidney) or defects in the calcium homeostatic system. In some cases, the hypocalcemia is caused by primary disturbances of these organs such as short gut (resulting in inadequate calcium absorption) or osteopetrosis (resulting in failure to mobilize calcium from bone). In the absence of such a defect, disturbances in the hormonal control of calcium homeostasis, such as hypoparathyroidism or vitamin D deficiency, may cause chronic hypocalcemia. (See 'Normal calcium homeostasis' above.)

NEONATAL HYPOCALCEMIA — Hypocalcemia is common in the newborn period and often transient, particularly in infants who are sick or have low birth weights. Persistent hypocalcemia may also present during the neonatal period and will be defined with time of follow-up such that therapy directed to the specific etiology can be provided. This disorder is discussed in more detail in a separate topic review. (See "Neonatal hypocalcemia".)

Transient — Transient neonatal hypocalcemia can be divided into early and late forms.

●Early transient – Early transient neonatal hypocalcemia is defined as occurring within 72 hours of life. It is often caused by multiple factors that interrupt parathyroid hormone (PTH) secretion or action and coincide to exaggerate the postnatal physiologic nadir of serum calcium levels. Such factors include:

•Maternal factors – These include maternal vitamin D deficiency, use of anticonvulsants, diabetes (either permanent or gestational), hyperparathyroidism, and toxemia of pregnancy.

•Neonatal factors – These include prematurity, low birth weight, intrauterine growth retardation, and birth asphyxia.

•Concurrent illness – Other illnesses commonly seen in the neonate such as sepsis, respiratory distress syndrome, hypomagnesemia, hyperbilirubinemia including phototherapy, and renal failure can contribute to hypocalcemia.

•Exogenous or iatrogenic factors – The administration of excess phosphate, lipid infusions, citrated blood, and bicarbonate can cause a decrease in circulating ionized calcium concentrations. Inadequate calcium in parenteral nutrition solutions may also contribute to this problem.

●Late transient – Late transient neonatal hypocalcemia develops after 72 hours of life and has been attributed to the relatively large phosphate load occurring with cow's milk and cow's milk formulas.

Encouraging breastfeeding or the use of a low-phosphate formula such as Similac PM 60/40 is useful. In our experience, these late-presenting cases are less likely to be transient compared with those presenting within the first 72 hours of life.

Persistent — Cases of either early- or late-presenting hypocalcemia that progress or fail to resolve should be investigated. The investigations should identify the nature of calcium supply (parenteral and enteral, dietary, and supplement use) and whether or not PTH levels are appropriately elevated in response to the hypocalcemia. Causes of persistent hypocalcemia are discussed below.

HYPOCALCEMIA WITH LOW PTH (HYPOPARATHYROIDISM) — Hypoparathyroidism can be classified by its pathogenesis (table 1):

●Impaired synthesis or secretion of parathyroid hormone (PTH) due to lack or loss of parathyroid gland (tissue) or to a defect in the synthesis or release of PTH. This can be either a primary or acquired condition.

●Defects in the calcium-sensing receptor (CaSR) or related proteins.

A similar clinical picture can be caused by end-organ resistance to PTH (pseudohypoparathyroidism [PHP]), which is distinguished by high rather than low PTH. (See 'End-organ resistance to PTH (pseudohypoparathyroidism)' below.)

Genetic mechanisms — Several genetic defects have been identified in patients with hypoparathyroidism (table 2).

●DiGeorge syndrome and related disorders – Some patients with DiGeorge syndrome (MIM #188400) have hypoparathyroidism, which is caused by parathyroid aplasia or hypoplasia. The hypoparathyroidism may present with hypocalcemia during the neonatal period or it may occur later in life, in the setting of increased demands for PTH with diminished parathyroid reserve.

DiGeorge syndrome is a result of abnormal development of the third and fourth branchial pouches. Other features include thymic aplasia or hypoplasia, cardiac defect affecting the outflow tract, developmental delay, and a characteristic facial appearance (prominent nose, squared nasal root). Most cases are sporadic, but familial cases with autosomal dominant inheritance have been reported. Most patients have deletion of the region of chromosome 22q11.2. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis" and "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'Hypocalcemia'.)

A deletion on chromosome 10p can result in DiGeorge syndrome type 2 (MIM 601362). Candidate responsible genes in the region include GATA3 (GATA-binding protein 3; see HDR syndrome below) and NEBL (nebulette), encoding an actin-binding protein associated with cardiac development; the mechanism of hypoparathyroidism is unknown [3,4]. The CHARGE syndrome (coloboma, heart anomalies, choanal atresia, retardation of growth and development, genital and ear/hearing anomalies) due to heterozygous mutations in CHD7 may also present with hypoparathyroidism. The protein encoded is a DNA-binding protein involved in chromatin remodeling [5]. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis", section on 'Defects on other chromosomes'.)

●Autosomal recessive – Several families with autosomal recessive hypoparathyroidism have been identified [6-9]. Two had a missense mutation in the signal peptide [6,8]; these mutations also affect the processing of pre-pro-parathyroid hormone (preproPTH). In one kindred with autosomal recessive hypoparathyroidism, the underlying defect was homozygous loss of function of the GCM2 gene (glial cells missing) [10]. In mice, the homologous Gcm2 gene, which is expressed exclusively in the parathyroid gland, encodes a transcription factor that is essential for parathyroid gland development [9].

●HDR syndrome – An autosomal dominant form of hypoparathyroidism associated with sensorineural deafness and renal dysplasia (HDR syndrome, MIM #146255) has been reported [11,12]. Mutations in GATA3, a gene localized to the chromosome region 10p14-15, have been detected in families affected by the syndrome [13,14]. GATA3 is a transcription factor that is involved in the embryonic development of the parathyroid glands, kidneys, inner ears, thymus, and central nervous findings. Similar clinical findings were reported in families with an apparent autosomal recessive mode of inheritance [7,15].

Barakat described two sets of brothers with hypoparathyroidism, sensorineural deafness, and steroid-resistant nephrotic syndrome [16]. This was termed Barakat syndrome, but it shares many of the same clinical manifestations as HDR syndrome. These disorders are thought to be the same entity.

●Sanjad-Sakati and Kenny-Caffey syndromes – Sanjad-Sakati syndrome (MIM #241410) and the autosomal recessive form of Kenny-Caffey syndrome (Kenny-Caffey type 1, MIM #244460) share the same clinical features including congenital hypoparathyroidism, intellectual disability, facial dysmorphism, and severe growth failure [17,18]. Patients with Kenny-Caffey type 1 also have osteosclerosis and immunodeficiency [19]. Sanjad-Sakati syndrome has been reported almost exclusively in Arab families. Both disorders map to 1q42-q43 [20] and are caused by mutations in the TBCE gene (tubulin-specific chaperone E), which encodes a protein involved in tubulin folding [21]. This finding suggests the two disorders are likely allelic or constitute different reports of the same condition. Yet another similar phenotype, Kenny-Caffey syndrome type 2 (MIM #127000), is an autosomal dominant disorder due to heterozygous mutations in the FAM111A gene (family with sequence similarity 111, member A) and differs from the type 1 syndrome in its absence of intellectual disability [22].

●Mutations in the CaSR and related proteins – Autosomal dominant hypocalcemia (ADH) is most frequently caused by an activating mutation of the CaSR; this type is known as ADH 1 (MIM #601198). The activating mutation causes hypocalcemia by shifting the set point of CaSR such that PTH is not released at serum calcium concentrations that normally trigger PTH release. Renal calcium reabsorption in these patients is also lower than anticipated because of the absence of PTH secretion. ADH 2 (MIM #615361) is caused by activating mutations in the GNA11 gene (guanine nucleotide-binding protein, alpha-11), a GTPase which mediates downstream CaSR signaling. Autosomal dominant inheritance also has been described for the inhibitor mutations of PTH and GCM2 described above.

Although patients with ADH can present in the neonatal period, it is not uncommon for subjects to be asymptomatic with mild to moderate hypocalcemia. However, during periods of stress such as a febrile illness, patients can become symptomatic with seizures and neuromuscular irritability (tetany). It is the authors' experience that some of these patients escape detection by being mislabeled as children with febrile seizures; hence the importance of screening serum calcium in any child presenting with seizures.

ADH is uncommon in the general population, but it is often confused with the diagnosis of isolated primary hypoparathyroidism. Patients with ADH caused by the CaSR mutation have hypocalcemia with an inappropriately normal PTH concentration and relative hypercalciuria. Urinary calcium excretion does not appear to be affected in patients with ADH due to GNA11 mutations.

Details of the genetic defect, diagnosis, and treatment of ADH are discussed elsewhere. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)

●X-linked – X-linked recessive hypoparathyroidism caused by a deletion-insertion rearrangement involving chromosomes Xq27.1 and 2p25.3 has been described in two related kindreds [23,24]. Affected male infants develop hypocalcemia with seizures because of an isolated defect in the development of the parathyroid gland.

●PTH gene mutation – An autosomal dominant mutation in the signal peptide sequence of preproPTH has been described, which impairs the normal processing of preproPTH to PTH [25].

●Mitochondrial disorders have been associated with hypoparathyroidism [26,27]. These include:

•Kearns-Sayre syndrome (MIM #530000), characterized by ophthalmoplegia, pigmentary degeneration of the retina, and cardiomyopathy. (See "Myopathies affecting the extraocular muscles in children", section on 'Kearns-Sayre syndrome'.)

•Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome (MIM #540000), characterized by mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS'.)

•Mitochondrial trifunctional protein deficiency (MIM #609015) is a fatty acid oxidation disorder that can present either as a severe condition with neonatal cardiomyopathy and sudden death, infantile onset of a hepatic Reye-like syndrome, or late adolescent onset of skeletal myopathy. Hypocalcemia or pigmentary retinopathy were reported in some cases. In some cases, mothers of an affected fetus have acute liver degeneration during pregnancy.

•Other mitochondrial disorders have also been associated with hypoparathyroidism, including medium-chain acyl-CoA dehydrogenase deficiency and Pearson syndrome, by unknown mechanisms [28]. (See "Specific fatty acid oxidation disorders", section on 'Medium-chain acyl-CoA dehydrogenase deficiency' and "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Pearson syndrome'.)

Autoimmune mechanisms — Hypoparathyroidism is part of the autoimmune polyglandular syndrome type 1 (MIM #240300), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome. In these patients, immunologic destruction of the parathyroid gland occurs in association with destruction of other endocrine glands. APECED results from mutations in the AIRE gene (autoimmune regulator), which is expressed in the thymus, lymph nodes, pancreas, adrenal cortex, and fetal liver. Antibodies to the CaSR also have been reported to cause hypoparathyroidism [29].

The three principal findings include hypoparathyroidism, primary adrenal insufficiency, and chronic mucocutaneous candidiasis. Hypoparathyroidism or candidiasis are typically the first manifestations to appear during childhood or adolescence. Because of these associations, a child with hypoparathyroidism should be examined frequently for other endocrinopathies. (See "Chronic mucocutaneous candidiasis", section on 'Autoimmune regulator deficiency'.)

This disorder is discussed in greater detail elsewhere. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Type 1 (monogenic)'.)

Other acquired mechanisms — Hypoparathyroidism can be acquired in the following clinical settings:

●Parathyroidectomy to remove a parathyroid adenoma or hyperplastic glands (eg, in patients with end-stage kidney failure and hyperparathyroidism). The presurgical hypercalcemia suppresses PTH from the remaining glands, resulting in transient hypoparathyroidism and hypocalcemia immediately after surgery. In addition, some patients may develop the hungry bone syndrome, which increases the severity of hypocalcemia postoperatively. (See 'Hungry bone syndrome' below and "Refractory hyperparathyroidism and indications for parathyroidectomy in adult patients on dialysis".)

●During thyroid surgery, as a result of manipulation of the blood supply to or removal of one or more parathyroid glands. In most cases, the hypoparathyroidism and hypocalcemia are transient.

●Iron deposition in the parathyroid gland in patients requiring chronic transfusions (eg, beta thalassemia major) [30]. (See "Management of thalassemia".)

●Copper deposition in patients with Wilson disease [31]. (See "Wilson disease: Epidemiology and pathogenesis".)

●Gram-negative sepsis, toxic shock syndrome, and HIV infection also may be complicated by hypocalcemia through mechanisms that include impaired PTH secretion and resistance. (See 'Sepsis or acute severe illness' below and "Bone and calcium disorders in patients with HIV", section on 'Alterations in bone and calcium metabolism'.)

HYPOCALCEMIA WITH HIGH PTH — Hypocalcemia with elevated serum concentrations of parathyroid hormone (PTH) is most often caused by vitamin D-related pathology, including:

●Insufficient dietary intake, intestinal absorption or skin production of vitamin D (hypovitaminosis D)

●Defects in vitamin D metabolism (physiologic or genetic)

●End-organ resistance to vitamin D (hereditary resistance to vitamin D [HRVD])

Vitamin D-independent causes include:

●Deficient dietary intake or intestinal absorption of calcium

●End-organ resistance to PTH (pseudohypoparathyroidism [PHP])

●Loss of calcium from the circulation, which may occur in "hungry bone syndrome," osteopetrosis, hyperphosphatemia, and pancreatitis (see 'Miscellaneous' below)

These disorders are outlined in the table (table 1) and described below.

Deficient calcium intake or intestinal absorption — Very low dietary intake or malabsorption of calcium can cause nutritional rickets. Occasionally, rickets occurs even in the setting of normal vitamin D [32]. More often, combined dietary deficiencies of both vitamin D and calcium contribute to nutritional rickets. Dietary deficiency of calcium may promote increased turnover of vitamin D stores [33]. (See "Etiology and treatment of calcipenic rickets in children", section on 'Calcium deficiency'.)

Deficient vitamin D intake, intestinal absorption and/or dermal synthesis — Clinical deficiency of vitamin D is identified by decreased concentrations of the most abundant circulating vitamin D metabolite, 25-hydroxyvitamin D. This disorder is characterized by elevated PTH and normal or low serum inorganic phosphorus levels and can cause the clinical syndrome of calcipenic rickets (algorithm 1). Plasma calcium is often low but may be normal because of the actions of compensatory PTH secretion. The circulating 1,25-dihydroxyvitamin D level is not a useful discriminant for this condition and may be low, normal, or elevated. Thus, we do not recommend its measurement as a primary investigation when vitamin D deficiency is the primary consideration for the diagnosis.

Vitamin D deficiency is usually the result of decreased intake, but limited sunlight (exposure to ultraviolet radiation) may substantially contribute. In the United States, most vitamin D is derived from foods that have a high content of the vitamin (fatty fishes) or are fortified with the vitamin (milk and related products and cereals). The remainder is synthesized in the skin from 7-dehydrocholesterol under the influence of ultraviolet light. Hence, vitamin D deficiency can occur in children whose dietary intake is low and/or who live without sun exposure. These children frequently have a low calcium intake as well, which contributes to the nutritional rickets. (See "Etiology and treatment of calcipenic rickets in children", section on 'Nutritional rickets'.)

In infants who are exclusively breastfed, vitamin D deficiency can occur if vitamin D supplementation is not provided, especially in dark-skinned infants during the winter months [34]. It is recommended that all breastfed infants be provided daily with 400 international units of vitamin D for this reason. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Pathogenesis and risk factors'.)

Decreased intestinal absorption of vitamin D may also contribute to reduced 25-hydroxyvitamin D stores. This may be caused by gastrectomy, celiac disease, malabsorption, extensive bowel surgery, inflammatory bowel disease, or pancreatic insufficiency as seen in cystic fibrosis. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Malabsorption and other medical conditions'.)

Defects in vitamin D metabolism — Vitamin D from the diet or dermal synthesis is biologically inactive and requires enzymatic conversion in the liver and kidney to the active metabolite, 1,25-dihydroxyvitamin D (figure 1). Physiologic or genetic disturbances in this process may lead to hypocalcemia, with compensatory PTH secretion. (See "Overview of vitamin D".)

Hepatic dysfunction — In the liver, vitamin D undergoes 25-hydroxylation to produce 25-hydroxyvitamin D. This conversion can be impaired in patients with severe liver disease. Drugs such as anticonvulsants (eg, phenobarbital, phenytoin, carbamazepine, isoniazid, theophylline, and rifampin) can also reduce available 25-hydroxyvitamin D. Although they increase the activity of P-450 enzymes that increase 25-hydroxylation, they also increase the catabolism of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to inactive metabolites.

Renal dysfunction — The final and rate-limiting step in vitamin D metabolism is the 1-hydroxylation of 25-hydroxyvitamin D in the kidney to produce 1,25-dihydroxyvitamin D, the most biologically active metabolite of vitamin D. This reaction is stimulated by PTH and hypophosphatemia but inhibited by calcium, phosphate, or fibroblast growth factor 23 (FGF23). In patients with renal failure, 1,25-dihydroxyvitamin D production is low because of the reduced expression of 1-hydroxylase, which occurs with rising circulating levels of FGF23, evident during progressive stages of chronic kidney disease. Thus, vitamin D plays a role in the development of the bone disease seen in chronic kidney disease. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Genetic disorders

●25-hydroxylase deficiency – 25-hydroxylase deficiency (MIM #600081) results in defective hepatic 25-hydroxylation vitamin D, and appears to be rare [35]. It is caused by mutations in CYP2R1, the gene that encodes synthesis of 25-hydroxylase, the major enzyme that catalyzes the production of 25-hydroxyvitamin D in the liver [35]. Biochemically, the disorder is difficult to distinguish from vitamin D deficiency as the serum 25-hydroxyvitamin D is low. It is often identified after poor clinical responses to documented administration of therapeutic doses of vitamin D. (See "Etiology and treatment of calcipenic rickets in children", section on '25-hydroxylase deficiency'.)

●1-alpha-hydroxylase deficiency – 1-alpha-hydroxylase deficiency (MIM #264700) is distinguished by defective renal 1-hydroxylation of 25-hydroxyvitamin D. It is caused by biallelic loss-of-function mutations in CYP27B1, which encodes the cytochrome P450 component of the 1-alpha-hydroxylase enzyme complex that catalyzes the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D [36-38]. The defective enzyme has impaired binding to either the substrate, 25-hydroxyvitamin D, or a requisite cofactor.

Clinical features include hypocalcemia, hypophosphatemia, elevated alkaline phosphatase levels, and rickets, with an autosomal recessive pattern of inheritance [39]. Serum concentrations of 25-hydroxyvitamin D levels are not low, whereas the circulating 1,25-dihydroxyvitamin D concentration may be decreased. This disorder can be treated with small doses of oral 1,25-dihydroxyvitamin D (calcitriol). Because it also responds to pharmacologic doses of vitamin D (cholecalciferol or ergocalciferol), 1-alpha-hydroxylase deficiency was previously known as vitamin D-dependent rickets type 1 or pseudovitamin D-deficient rickets. (See "Etiology and treatment of calcipenic rickets in children", section on '1-alpha-hydroxylase deficiency'.)

●Increased catabolism of vitamin D – Gain-of-function mutations in CYP3A4 (MIM #619073), the gene encoding the vitamin D catabolic enzyme, cause increase degradation of both 25-hydroxyvitamin D and the active 1,25-dihydroxyvitamin D metabolite [40]. Affected patients have low circulating levels of both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, indicating that genetic dysregulation of vitamin D catabolism, which can lead to a rachitic phenotype.

Defect in vitamin D action

Hereditary resistance to vitamin D — HRVD (MIM #277440), previously known as vitamin D-dependent rickets type 2 [41], is caused by end-organ resistance to 1,25-dihydroxyvitamin D, most often because of biallelic loss-of-function mutations in the gene encoding the vitamin D receptor, located in chromosome region 12q13-14 [42-44]. Mutations in the HNRNPC gene (heterogeneous nuclear ribonucleoprotein C), which encodes a coactivator of the vitamin D receptor, can also cause this syndrome [45].

The clinical findings of HRVD are similar to those observed in 1-alpha-hydroxylase deficiency (hypocalcemia, hypophosphatemia, and high PTH and alkaline phosphatase concentrations), except that serum 1,25-dihyroxyvitamin D concentrations are high rather than low. In addition to rickets, many of the patients have alopecia. Therapy with pharmacological doses of 1,25-dihyroxyvitamin D or 25-hydroxyvitamin D are ineffective in most but not all cases [46]. The rickets can be improved with long-term, high-dose intravenous calcium therapy [47,48]. (See "Etiology and treatment of calcipenic rickets in children", section on 'Hereditary resistance to vitamin D'.)

End-organ resistance to PTH (pseudohypoparathyroidism) — Pseudohypoparathyroidism (PHP) refers to a group of heterogeneous disorders defined by targeted organ (kidney and bone) unresponsiveness to PTH [49-51]. PTH resistance is characterized by:

●Hypocalcemia

●Hyperphosphatemia

●Elevated PTH concentrations

The types and mechanisms of PHP are outlined below. Detailed reviews of the topic are available [52,53]. Treatment of PHP is discussed in a separate topic review. (See "Treatment of hypocalcemia", section on 'Pseudohypoparathyroidism'.)

Type 1 PHP — In patients with PHP type 1, there is a diminished urinary cyclic adenosine monophosphate (cAMP) response to exogenous PTH administration. There are several subtypes of PHP type 1 caused by mutations of the GNAS1 gene, which encodes the alpha subunit of a GTP-binding protein (Gs, or G protein), which couples to the PTH receptor in a cyclical manner [54]. These gene mutations result in the G protein's inability to activate adenyl cyclase upon the binding of PTH to its receptor [55-57]. Activation of adenyl cyclase is required for signal transduction that produces the end-organ response to PTH. Failure of signal transduction results in the unresponsiveness of the end-organ.

GNAS1 is imprinted in humans so that expression of the allele for a specific tissue is dependent on whether the allele is maternally or paternally inherited; therefore, the disease manifestations also differ depending on the parent of origin [58]. As an example, renal expression of GNAS1 appears to be determined only by the maternal allele, so that a defect only in the maternal allele of GNAS1 will result in unresponsiveness of the renal tubule to PTH binding. This difference in tissue expression, based upon parental transmission and whether the underlying mutation leads to a GNAS1 structural or expression defect, appears to contribute to the differences in the various forms of PHP.

●Type 1a – PHP type 1a (MIM #103580) is an autosomal dominant disease with a loss-of-function mutation of GNAS1, leading to an inability to activate adenyl cyclase when PTH binds to its receptor [59]. Maternal transmission of the mutation is required for expression of PHP type 1a [60].

Patients with PHP type 1a have a constellation of findings known as Albright hereditary osteodystrophy (AHO), which includes round facies, short stature, short metacarpal bones (especially III-V), obesity, subcutaneous calcifications, and developmental delay [49,61,62]. Sleep apnea and metabolic syndrome are often encountered. Craniosynostosis may occur, as well as gonadal dysfunction and infertility. In addition, the PTH resistance of the renal tubule leads to hyperphosphatemia, hypocalcemia, and secondary hyperparathyroidism and hyperparathyroid bone disease (osteitis fibrosa).

In humans, GNAS1 also is predominantly expressed from the maternal allele in the thyroid, gonads, and pituitary glands. As a result, patients with PHP type 1a show resistance to various other G-protein coupled hormones including thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and gonadotropin-releasing hormone (GnRH), as well as blunted response to beta-adrenergic agonists [63,64]. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)", section on 'Gs alpha subunit gene mutations'.)

●Pseudo-pseudohypoparathyroidism – By contrast to patients with maternally transmitted mutations that result in loss of GNAS1 function, those with paternally transmitted mutations have the phenotype of AHO but with normal serum calcium concentrations and without renal tubular resistance to PTH; this pattern is termed "pseudo-pseudohypoparathyroidism" [65,66]. In these patients, the paternal transmission of a mutated GNAS1 gene results in AHO, but the normal maternal allele results in the maintenance of renal responsiveness to PTH [67,68]. As a result, these patients have normal calcium homeostasis with normal concentrations of calcium, phosphate, and PTH.

Paternally inherited inactivating GNAS1 mutations also can cause progressive osseous heteroplasia, a related autosomal dominant disorder characterized by extensive dermal ossification during childhood [69].

●Type 1b – Patients with the PHP type 1b disease (MIM #603233) have hypocalcemia but do not have the phenotypic abnormalities of AHO. PTH resistance appears to be confined to the kidney in this disorder, leading to only hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism [70]. This rare autosomal dominant disorder appears to be caused by methylation defects or mutations that affect the regulatory elements of GNAS1, such as STX16, rather than mutations in GNAS1 itself [71-73]. Type 1b may be maternally transmitted as well as sporadically occurring.

●Type 1c – PHP type 1c (MIM #612462) refers to a subgroup of cases in which coupling of the G protein to the PTH receptor is aberrant. The ability to stimulate adenyl cyclase remains intact but is no longer coupled to the binding of PTH and its receptor [74]. Patients with PHP type 1c are usually phenotypically similar to those with PHP type 1a.

Type 2 PHP and other forms of PTH resistance — Patients with PHP type 2 (MIM 203330) do not have the features of AHO. They have normal or even elevated urinary cAMP concentrations in response to exogenous PTH administration but without a concomitant increase in phosphate excretion [75,76]. One genetic mechanism by which this has been documented to occur is with mutations in the PRKAR1A gene (protein kinase, cAMP-dependent, regulatory, type 1, alpha), which encodes the catalytic subunit of adenylate cyclase and incorporates a phenotype of multiple hormone resistance with acrodysostosis [77].

In our experience and that of others, some patients with recently treated vitamin D deficiency have a biochemical profile that resembles that of type 2 PHP [78]. Therefore, it is important to clarify the vitamin D status of such patients before confirming a diagnosis of type 2 PHP.

Of note, other acrodysostosis-associated mutations may also be associated with PTH resistance, including heterozygous mutations in the PDE4D gene (cAMP-specific 3′,5′-cyclic phosphodiesterase 4D) [79] and the PDE3A gene (phosphodiesterase 3A) [80]. Documentation of overt hypocalcemia in the setting of mutations in the PTHR1 gene (PTH/PTHrP receptor) is lacking, although a spectrum of severity ranging from delayed tooth eruption to Blomstrand syndrome is described in this form of PTH resistance [81,82]. This panoply of defects has led to the consideration of a revised nomenclature for the PTH resistance syndromes [83].

MISCELLANEOUS

Hungry bone syndrome — Hungry bone syndrome refers to a phase of avid bone mineralization, with hypocalcemia due to rapid movement of calcium from the circulation into the skeletal compartment; this tends to occur during the early phases of recovery from a severe mineralization defect or after a prolonged period of calcium resorption from bone. A parallel increase in bone uptake of magnesium leading to hypomagnesemia may increase the severity of hypocalcemia. The hungry bone syndrome may be triggered by vitamin D therapy in the setting of severe rickets, parathyroidectomy, or rarely by thyroidectomy. (See "Etiology and treatment of calcipenic rickets in children", section on 'Treatment' and "Hungry bone syndrome following parathyroidectomy in patients with end-stage kidney disease".)

Patients with type 1 Gaucher disease often develop transient hypocalcemia after initiation of enzyme replacement therapy, likely due to hungry bone syndrome [84]. (See "Gaucher disease: Treatment", section on 'Enzyme replacement therapy'.)

Osteopetrosis — This disorder may result in significant loss of osteoclast function and decrease in bone resorption such that calcium mobilization from the skeleton is sufficiently impaired as to result in hypocalcemia.

Sepsis or acute severe illness — Hypocalcemia may be triggered by Gram-negative sepsis, toxic shock syndrome, or severe burns. The mechanism is unknown but may be related to macrophage-generated cytokines, which can affect parathyroid hormone (PTH) and vitamin D secretion and action. (See "Etiology of hypocalcemia in adults", section on 'Sepsis or severe illness'.)

Hyperphosphatemia — Endogenous or exogenous sources of phosphate can cause hyperphosphatemia if they exceed the renal capacity for phosphate excretion, such as when small infants have received a phosphate-containing enema. The ensuing hyperphosphatemia may result in calcium-phosphate precipitation in the tissues leading to symptomatic hypocalcemia.

Acute hyperphosphatemia is seen in the setting of massive tissue breakdown (eg, tumor lysis and rhabdomyolysis) or with excessive phosphate intake. Use of phosphate-containing enemas may cause hyperphosphatemia. This is especially a problem in children with poor intestinal motility, such as those with chronic constipation or neuromuscular dysfunction including cerebral palsy or neurodegenerative disorders, and if multiple phosphate-containing enemas are given to small children [85,86].

Intravenous products with citrate or lactate — Administration of large volumes of intravenous products that contain citrate (eg, blood products) or lactate may decrease the serum ionized calcium concentration through increased binding of calcium into calcium-citrate or calcium-lactate complexes.

Pancreatitis — Hypocalcemia may occur in patients with acute pancreatitis. It is primarily caused by precipitation of calcium soaps in the abdominal cavity; glucagon-stimulated calcitonin release and decreased PTH secretion also may play a role.

Drugs and toxic ingestions — Drugs that may cause hypocalcemia include bisphosphonates, denosumab, calcimimetics (cinacalcet), the antiviral agent foscarnet, and some chemotherapeutic drugs. Rarely, excess intake of fluoride can cause hypocalcemia; this effect is presumably mediated by inhibition of bone resorption [87]. Other substances associated with consequent hypocalcemia following ingestion have been reported, including ammonium bifluoride. We and others have witnessed transient infantile hypocalcemia in the context of excessive maternal calcium ingestion [88]. (See "Etiology of hypocalcemia in adults", section on 'Drugs'.)

Hypomagnesemia — Magnesium is required for PTH release and may be required for PTH effect on target organs. Hypomagnesemia can lead to hypocalcemia through the following mechanisms:

●End-organ unresponsiveness to PTH

●Impaired release of PTH

●Impaired formation of 1,25-dihydroxyvitamin D, likely secondary to both of the above effects

Patients with hypomagnesemia present with carpopedal spasm, tetany and/or seizures, muscle weakness, anorexia, and hypokalemia, as well as tachycardia with prolonged QT and PR intervals. Tetany can occur in the absence of hypocalcemia and is thought to be secondary to a depression in the threshold of nerve excitation. Serum concentrations of PTH are typically low or normal but may rise sharply in response to magnesium therapy. Hypomagnesemia can be a primary disorder or secondary to other diseases. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion".)

Primary — Hypomagnesemia with secondary hypocalcemia (also known as intestinal hypomagnesemia type 1, MIM #602014) is an autosomal recessive disease caused by mutations in the TRPM6 gene (transient receptor potential cation channel, subfamily M, member 6) located at chromosome 9q22 [89,90]. TRPM6 is expressed in the intestinal mucosa and the kidney. It encodes for a protein with dual functions, protein kinase, and a calcium and magnesium ion channel. In affected patients, there is an isolated defect of intestinal magnesium absorption with normal renal excretion of magnesium. Although this defect is considered the most severe form of heritable hypomagnesemia, mutations in other genes have been found to be causes of genetic hypomagnesemia (table 2) [91].

Patients present in the neonatal period with seizures, hypomagnesemia, and hypocalcemia, and may require large doses of magnesium, up to 20 times the usual daily requirement. These high doses completely correct the hypocalcemia and lead to resolution of symptoms, although they rarely lead to normalization of magnesium concentrations. Oral administration of magnesium can cause diarrhea, which can increase the intestinal loss of magnesium. Early diagnosis and treatment can help avoid sequelae of prolonged seizures caused by hypocalcemia and/or hypomagnesemia.

Secondary — Magnesium homeostasis is not hormonally regulated and depends on the balance between intestinal absorption and renal excretion. As a result, the major causes of secondary hypomagnesemia in children are either decreased intake or increased urinary and gastrointestinal losses. Gastrointestinal losses are seen in any disorder associated with acute or chronic diarrhea, steatorrhea, or malabsorption. Renal losses may be because of diuretic use, nephrotoxins (such as aminoglycosides), and renal tubular dysfunction or tubular-interstitial disease [92]. (See "Hypomagnesemia: Causes of hypomagnesemia".)

SUMMARY

●Calcium homeostasis – A tightly regulated extracellular ionized calcium concentration promotes cell function and survival and is maintained by an intricate calcium homeostatic system. (See 'Normal calcium homeostasis' above.)

●Pathophysiology – The primary determinant of symptoms and signs associated with hypocalcemia is the circulating ionized calcium concentration. (See 'Pathophysiology' above.)

●Neonatal hypocalcemia – Transient neonatal hypocalcemia is not uncommon, particularly in newborn infants admitted to the neonatal intensive care unit. Contributing factors include those associated with the mother (eg, maternal diabetes mellitus) and the infant (eg, premature), concurrent illnesses, and iatrogenic factors. (See 'Neonatal hypocalcemia' above.)

●Causes – A variety of genetic and acquired disorders can cause hypocalcemia (table 1). The different causes can be clinically distinguished by differences in serum parathyroid hormone (PTH), phosphate, and vitamin D concentrations.

•Low PTH – Hypoparathyroidism, a major cause of pediatric hypocalcemia, is distinguished clinically by hypocalcemia with low levels of PTH. Hypoparathyroidism is caused by impaired secretion or production of PTH or a defect in the calcium-sensing receptor (CaSR) that regulates PTH secretion (table 2). (See 'Hypocalcemia with low PTH (hypoparathyroidism)' above.)

•High PTH – Hypocalcemia with high levels of PTH may be caused by:

-Vitamin D deficiency (insufficient dietary vitamin D intake or impaired intestinal absorption, with limited dermal synthesis) (see 'Deficient calcium intake or intestinal absorption' above and 'Deficient vitamin D intake, intestinal absorption and/or dermal synthesis' above)

-Defects in vitamin D metabolism, including hepatic dysfunction (including drugs that increase cytochrome P450 activity), renal dysfunction, and genetic disorders of vitamin D metabolism (25-hydroxylase deficiency, 1-alpha-hydroxylase deficiency, or mutations in CYP3A4) (see 'Defects in vitamin D metabolism' above)

-Hereditary resistance to vitamin D (a defect in vitamin D action) (see 'Hereditary resistance to vitamin D' above)

-Genetic mutations causing end-organ resistance to PTH in either kidney or bone (pseudohypoparathyroidism [PHP]) (see 'End-organ resistance to PTH (pseudohypoparathyroidism)' above)

•Other – Other important causes of hypocalcemia arise during the course or treatment of medical illnesses. These include hungry bone syndrome (which may be triggered by vitamin D therapy in the setting of severe rickets or after surgical parathyroidectomy); osteopetrosis, sepsis, or acute severe illness; hyperphosphatemia; hypomagnesemia; or certain drugs. (See 'Miscellaneous' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges George S Jeha, MD, who contributed to earlier versions of this topic review.