KEY POINTS
- 1.
Disorders of mineral homeostasis in the neonatal period are often exaggerated responses to the normal physiologic transition. Parathyroid hormone (PTH) is the principal regulator of postnatal calcium metabolism, with vitamin D and its metabolites involved in the regulation of serum calcium levels.
- 2.
Neonatal hypercalcemia is uncommon and often asymptomatic; calcium concentrations need to be interpreted based on age-related norms, which are higher in neonates, and in concert with serum phosphorus and PTH levels.
- 3.
Hypocalcemia is common in the neonatal intensive care unit and is transient in most infants; congenital hypoparathyroidism should be considered in the setting of prolonged hypocalcemia.
- 4.
Metabolic bone disease of prematurity (MBD) results from interrupted maternal–fetal mineral transfer during the third trimester and is exacerbated by inadequate postnatal nutritional mineral intake and pharmacologic exposures.
- 5.
No single biochemical marker is sufficient for diagnosis of MBD, but common screening approaches include measurements of alkaline phosphatase, PTH, calcium, phosphorus, and 25-hydroxyvitamin D (25(OH)D).
- 6.
Prevention and treatment of MBD are often the same and include nutritional optimization, targeted enteral calcium and phosphorus supplementation, limiting bone active medications, and physical therapy interventions.
- 7.
MBD slowly self-resolves over time, although long-term follow-up in former preterm infants suggests negative impacts on overall growth and bone mineralization in childhood and adulthood.
Background
Neonatal calcium and phosphorus metabolism are influenced by fetal and maternal factors and are postnatally controlled by complex parathyroid-renal hormonal interactions. Homeostasis of calcium and phosphorus is critical for physiologic stability (with roles in signal transduction, neurotransmitter release, and muscle contraction) and for postnatal growth and skeletal development. Preterm infants are at particular risk for disordered mineral metabolism, resulting from interrupted maternal–fetal mineral transfer in the third trimester and exacerbated by inadequate postnatal mineral intake in the setting of rapid growth. Metabolic bone disease (MBD), or osteopenia of prematurity, primarily occurs in very low birth weight (VLBW) infants with birth weight <1500 g, although extremely low birth weight (ELBW) infants <1000 g are disproportionately affected. MBD rates were as high as 50% among ELBWs in the 1980s, although with advancements in overall neonatal care, MBD rates have declined, and 10% to 40% of ELBW infants are affected in more contemporary reports. , In this chapter, we review fetal and postnatal mineral physiology and discuss disorders of neonatal mineral metabolism, including calcium derangements and metabolic bone disease of prematurity.
Fetal Bone Development
Fetal bone mineralization primarily occurs during the third trimester and is reliant on active transport of calcium and phosphorus across the placenta. Eighty percent of total gestational calcium accretion occurs during the third trimester, during which time the fetus is supplied (approximately 120–150 mg/kg/day of calcium), with phosphorus accretion of approximately half that amount (70 mg/kg/day). It is thus unsurprising that perinatal conditions of decreased placental efficiency (preeclampsia, intrauterine growth restriction) in preterm infants are associated with MBD postnatally. Rapid fetal bone length growth in the third trimester (about 1.2 cm/week) is supported by these nutrients as well as bone remodeling via mechanical forces between the fetal skeleton and the uterine wall.
The fetus exists in a state of relative hypercalcemia, which is mediated by the calcium-sensing receptor (CaSR) and suppresses fetal parathyroid hormone (PTH). In addition to promoting fetal bone mineralization, fetal hypercalcemia may also buffer the physiologic drop in serum calcium that occurs after birth. Calcium binding to albumin is dependent on pH—as the neonate initiates breathing, the serum pH rises, albumin is increasingly able to bind calcium, and the free ionized calcium level falls. Active ATP-mediated transport of minerals from mother to fetus appears to be primarily mediated by elevations in fetal PTH-related peptide (PTHrP). Fetal calcitonin is also elevated and enhances bone mineral absorption; PTH and calcitriol are suppressed. , , PTHrP is expressed in the placenta and is instrumental in regulation of active placental calcium transport from mother to fetus as well as in modulating chondrocyte differentiation and osteoblast development. However, PTHrP is not routinely measured in clinical practice because it is transiently present in serum, technically difficult to assay, and challenging to interpret given the lack of reference ranges for age.
The role of vitamin D in placental mineral transport is unclear; 25(OH)D crosses the placenta, but calcitriol does not. Fetal calcitriol levels are less than half of maternal levels, and some authorities assert that maternal 25(OH)D levels do not significantly influence fetal bone development. However, lower maternal 25(OH)D levels at 34 weeks’ gestation were associated with greater femoral metaphyseal cross-sectional area and femoral splaying at both 19 and 34 weeks’ gestation. Maternal vitamin D status does correlate with neonatal serum vitamin D levels postnatally, and additional evidence suggests that maternal 25(OH)D status influences later bone mineralization. Higher maternal serum 25(OH)D levels in late gestation were associated with increased bone area and bone mineral content as measured by dual energy x-ray absorptiometry (DXA) in female infants at 2 weeks of life. Lower maternal 25(OH)D stores in the third trimester have been associated with lower bone mineral content in offspring at 9 years of age.
The mechanisms for placental phosphorus transfer are less understood, but they also appear to be governed by PTHrP-mediated active transport. Phosphorus is also essential for fetal bone development; it mediates apoptosis of chondrocytes and is subsequently incorporated into newly formed osteoid matrix.
Postnatal Mineral and Hormone Physiology
Upon umbilical cord clamping, previously high rates of placental-fetal mineral transfer abruptly cease. In the first 12 to 24 hours of life, both serum total and ionized calcium concentrations drop by 20% to 30% (with deeper nadirs in preterm than term infants), while serum phosphorus concentrations rise, both returning to normal values within the first few days of life. In the neonate, calcium is almost entirely (99%) located in bone matrix, where it is complexed to phosphorus. In the remaining 1% of circulating calcium, 50% is ionized and biologically active, 40% is protein-bound (mostly to albumin) and biologically inactive, and the remainder is complexed to organic and inorganic acids. , Phosphorus is primarily (85%) stored in the skeleton, with the remainder circulating in the serum either in ionized form (55%), complexed to cations (35%), or protein-bound (10%).
Postnatal control of calcium and phosphorus metabolism is governed primarily by PTH, calcitonin, and vitamin D ( Fig. 28.1 ). PTH is the primary hormone governing calcium homeostasis after birth. Suppressed in the fetus due to relative hypercalcemia, PTH is secreted by the parathyroid gland in the setting of hypocalcemia and induced two- to five-fold in both preterm and term infants after the postnatal calcium drop. Although an acute increase in PTH has anabolic effects on the neonatal skeleton and promotes bone formation, prolonged elevation in PTH promotes osteoclast proliferation and differentiation, leading to bone resorption and release of calcium and phosphorus. In the kidney, PTH promotes calcium reabsorption and phosphorus excretion at the distal convoluted tubule and stimulates production of calcitriol in the proximal tubule by activation of renal 1-hydroxylase. Calcitonin is produced by parafollicular cells of the thyroid gland and acts in opposition to PTH, decreasing serum calcium by inhibition of osteoclasts and increasing renal excretion of calcium and phosphate.
Vitamin D is either ingested or synthesized in skin after UV exposure. In the neonatal intensive care unit (NICU), vitamin D comes almost exclusively from dietary intake. It is first hydroxylated to 25(OH)D in the liver, and given its long half-life, 25(OH)D is most reflective of overall vitamin D status. PTH mediates hydroxylation of 25(OH)D in the kidney, to produce 1,25(OH) 2 D (calcitriol). Calcitriol has multiple effects via binding of the vitamin D receptor, including increased intestinal absorption of calcium and phosphorus, promotion of bone formation by mineralization of osteoid, and negative feedback over PTH via transcriptional downregulation. Calcitriol levels are low at birth but increase to adult levels in the first day of life. Postnatal mineral and hormone kinetics change rapidly in the first several postnatal days and are summarized in Fig. 28.2 .
Hypercalcemia
Hypercalcemia is far less common than hypocalcemia in the neonatal and infantile periods. Interpretation of an elevated serum total calcium level with suspected hypercalcemia requires measurement of the either the ionized calcium level or determination of the serum albumin concentration, with appropriate adjustment of the serum calcium level if the albumin level is abnormal. The effects of acid-base status must be considered as well, with acidosis resulting in decreased calcium binding to albumin and an increase in the ionized calcium, whereas alkalosis increases protein binding of calcium and a decrease in ionized calcium. In addition, the reference range for neonates is higher than at other ages, with the upper limit of normal at 11.3 mg/dL. Initial biochemical testing must also include determination of the serum phosphorus level, because hypophosphatemia can cause hypercalcemia, particularly in premature or low birth weight infants who receive inadequate dietary phosphorus.
Symptoms of hypercalcemia are highly variable and depend on the age of the patient, the degree of hypercalcemia, and the clinical disorder. For cases of mild to moderate hypercalcemia, usually up to 13 mg/dL, patients may be without symptoms or with nonspecific symptoms such as anorexia, feeding intolerance, irritability, or constipation. Chronic hypercalcemia can present as failure to thrive, but the vague nature of symptoms can lead to delayed diagnosis and increase the risk for morbidity and mortality. Hypercalcemia can also lead to shortened ST segment and heart block, polyuria secondary to renal resistance to vasopressin leading to nephrogenic diabetes insipidus with associated dehydration, and hypertension due to the direct vasoconstriction from elevated serum calcium levels. Renal complications such as hematuria, nephrocalcinosis, and nephrolithiasis can be early manifestations of hypercalcemia. Severe hypercalcemia can directly affect the nervous system, leading to lethargy and seizures, with rare progression to coma.
The differential diagnosis of neonatal hypercalcemia can be broadly divided into PTH-dependent and independent causes ( Table 28.1 ). Iatrogenic causes of hypercalcemia can be seen with hypophosphatemia, excessive administration of calcium and/or vitamin D, and the use of thiazide diuretics, which lead to decreased urinary calcium excretion.
| Category | Differential Diagnoses |
|---|---|
| Neonatal Hypercalcemia | |
| Iatrogenic | Hypophosphatemia Vitamin D excess Excessive calcium supplementation Thiazide diuretics |
| PTH-dependent | Maternal hypocalcemia/transient neonatal hyperparathyroidism Inactivating mutations of the calcium-sensing receptor Familial hypocalciuric hypercalcemia (OMIM #145980) Neonatal severe hyperparathyroidism (OMIM #239200) Jansen’s metaphyseal chondrodysplasia (OMIM #156400) |
| PTH-independent | Subcutaneous fat necrosis Williams syndrome (OMIM#194050) Idiopathic infantile hypercalcemia/ CYP24A1 mutations (OMIM #143880) Inborn errors of metabolism (e.g., lactase deficiency) Hypophosphatasia Endocrine causes (adrenal insufficiency, thyrotoxicosis) |
| Neonatal Hypocalcemia | |
| Early onset (days 1–4) | Infant of diabetic mother Perinatal asphyxia Preeclampsia Prematurity Maternal hyperparathyroidism |
| Late onset (days 5–10) | Vitamin D deficiency Dietary phosphate load (e.g., cow’s milk formula) Hypomagnesemia Transient PTH resistance Transient hypoparathyroidism Congenital hypoparathyroidism (see Table 28.2 ) |
PTH-Dependent Hypercalcemia
Neonatal hyperparathyroidism is characterized by high serum calcium levels with inappropriately elevated PTH levels, with low levels of serum phosphorus, normal or elevated alkaline phosphatase (ALP) levels, and relative hypocalciuria.
Neonatal transient primary hyperparathyroidism can occur in response to low in utero maternal calcium concentrations. This more commonly occurs in lower birth weight infants but otherwise comes without clinical signs. Thorough investigation of the infant’s mother will disclose previously known but inadequately treated hypoparathyroidism or clinically unsuspected hypocalcemia. Decreased calcium transport from the hypocalcemic mother to the fetus leads to fetal hypocalcemia, with secondary increased secretion of fetal PTH, stimulating mobilization of calcium from the fetal skeleton and causing bone demineralization and subperiosteal resorption. This hyperfunction of the developing parathyroid glands may persist after birth, resulting in postnatal hyperparathyroidism with resulting transient moderate hypercalcemia. Postnatally, the skeleton avidly takes up calcium, and the bone lesions heal spontaneously within 4 to 6 months. Careful management of the plasma calcium concentration in hypoparathyroid women during pregnancy will prevent the development of functional hyperparathyroidism in the fetus.
Neonatal Severe Hyperparathyroidism and Familial Hypocalciuric Hypercalcemia
Inactivating mutations of the CaSR result in altered calcium sensing with inappropriate PTH production with respect to the serum calcium level. Hypercalcemia results from this altered set point, with higher calcium levels required to suppress PTH release, resulting in higher serum calcium levels. Most cases of neonatal severe hyperparathyroidism (NSHPT) and familial hypocalciuric hypercalcemia (FHH) are homozygous and heterozygous manifestations, respectively, of the same genetic defect in the CASR gene at 3q13.3–21 that inactivates the CaSR. , Despite this relationship, the clinical presentations of NSHPT and FHH are distinct. NSHPT is a severe and life-threatening disorder and usually presents in the first week of life. It likely begins in the fetal period, as suggested by the finding of generalized skeletal demineralization and localized erosions at the ends of long bones and subperiosteal resorption along the shafts of tubular bones. Parathyroid glands are enlarged and biochemical findings include markedly elevated serums levels of PTH and 1,25(OH) 2 D, low-to-normal serum phosphorus, normal-to-high serum magnesium, elevated ALP, and inappropriately normal or low urinary calcium excretion. A family history of NSHPT or FHH in a sibling can provide strong confirmation of the diagnosis. Genetic testing is available for evaluation of CASR gene mutations and the less common AP2S1 and GNA11 gene mutations, which can cause NSHPT/FHH in some families. By contrast, FHH is characterized by a relatively benign course and is generally asymptomatic despite mild-to-moderate hypercalcemia. It is most commonly discovered as an incidental finding or during the evaluation of relatives of patients with hypercalcemia. The hypercalcemia may be present at birth, or the diagnosis may be made during infancy and childhood. Circulating levels of PTH are normal or high-normal, but in the presence of hypercalcemia, they are inappropriately high, reflecting the higher set point of the parathyroid calciostat.
The treatment of hypercalcemia depends on the severity of the presentation. Hypercalcemia seen in newborns exposed to maternal hypocalcemia is often mild, transient, and self-limiting and responds to conservative management. Most patients with FHH lack symptoms and treatment is not required. By contrast, cases of severe hypercalcemia such as with life-threatening hypercalcemia of NSHPT require more aggressive treatments. In NSHPT, traditional management has involved subtotal parathyroidectomy, but appropriate medical treatments can preclude the need for surgical intervention in select cases. Initial therapies include maintenance of adequate hydration and avoiding excessive vitamin D and calcium. Intravenous isotonic fluids are the primary treatment for hypercalcemia, with the goal of increasing the urinary excretion of sodium because sodium and calcium clearance are closely linked during osmotic diuresis. Loop diuretics such as furosemide have traditionally been used to enhance calciuresis once hydration has been optimized. However, such agents must be used with caution because they may induce dehydration, which can actually worsen hypercalcemia through reduction in the glomerular filtration rate. In cases of NSHPT, hypercalcemia is often life-threatening and requires urgent medical intervention. Glucocorticoids are ineffective in the treatment of NSHPT-associated hypercalcemia. Calcitonin (2-4 U/kg every 6–12 hours) can be given by subcutaneous injection and can directly reduce osteoclastic bone resorption and lower serum calcium levels. However, calcitonin typically only works for a short time because tachyphylaxis develops quite rapidly. Nitrogen-containing bisphosphonates (e.g., pamidronate 0.5–1.5 mg/kg/dose × 3 days, zoledronic acid 0.015–0.05 mg/kg/dose), are analogs of inorganic pyrophosphate that adsorb to the hydroxyapatite matrix and can provide a more sustained inhibition of bone resorption and effectively lower serum and urinary calcium in NSHPT. Calcimimetics such as cinacalcet could be potential therapeutic options in NSHPT because they increase CaSR sensitivity to calcium and can lower serum calcium levels. Although a trial of cinacalcet may be considered in infants with severe hypercalcemia related to CASR mutations, this approach must be pursued with caution because only limited information is available regarding its safety and efficacy in children with primary hyperparathyroidism.
PTH-Independent Hypercalcemia
Subcutaneous fat necrosis is common in neonates with complicated deliveries and may lead to hypercalcemia within days or weeks of birth. Affected infants often have a history of birth asphyxia and may have the added risk factor of receiving hypothermia treatments after asphyxia. Subcutaneous fat necrosis usually presents as reddish or purple subcutaneous nodules at sites of pressure such as the back, buttocks, and thighs or in areas of direct trauma that occur during a difficult birth process, such as forceps or vacuum extraction. Hypercalcemia results from excess circulating 1,25(OH) 2 D levels produced by macrophages present within the granulomatous reaction to the necrotic fat. The hypercalcemia is compounded by calcium release from fat tissues and possibly from increased prostaglandin E activity, as well the expression of ectopic 1-α-hydroxylase activity that is not regulated by PTH, calcium, phosphorus, or 1,25(OH) 2 D. Hypercalcemia may persist for several weeks, and infants should receive a low calcium, reduced vitamin D diet until serum calcium levels normalize. Traditional management has involved isotonic intravenous fluids, loop diuretics, and glucocorticoids, but other therapies may be required in refractory cases. Glucocorticoids, most commonly prednisone at a dose of 1 to 2 mg/kg/day, may be effective in lowering serum calcium levels and decreasing inflammation of the fat necrosis but come with risk of adrenal suppression. Calcitonin can be used but requires multiple daily injections, and tachyphylaxis can develop. Bisphosphonates, either pamidronate or zoledronic acid, can be used for long-term management of hypercalcemia and should be strongly considered in refractory cases.
Williams syndrome (WS) is a sporadic multisystem disorder characterized by dysmorphic facies, cardiovascular disease (most commonly supravalvular aortic stenosis), “cocktail party” personality despite intellectual disability, and hypercalcemia in 15% to 45% of cases, although hypercalciuria may be more common. WS has been associated with microdeletions of 7q11.13 and likely represents a contiguous gene deletion that typically includes the gene for elastin (ELN) , found in connective tissue of many organs. Hemizygosity of the ELN gene likely accounts for some of the features, such as cardiac defects and some of facial characteristics, but cannot explain the hypercalcemia. The majority of cases of WS are detected through a chromosomal microarray or fluorescent in situ hybridization of lymphocytes using a probe for ELN. Hypercalcemia typically occurs during infancy and usually resolves between 2 and 4 years of age. PTH is most commonly suppressed, and hypercalciuria may be seen even in children who do not have hypercalcemia. Nephrocalcinosis and soft-tissue calcifications may be seen in WS. Patients typically show exaggerated responses to pharmacologic doses of vitamin D and blunted calcitonin responses to calcium loading. , Elevated plasma concentrations of calcitriol have been reported in some patients despite low or normal circulating PTH levels. Overall, studies have failed to show any consistent abnormality in vitamin D metabolism to explain the mechanism of hypercalcemia in WS.
Of note, some children with hypercalcemia have similar disturbances in vitamin D sensitivity but lack other phenotypic features of WS and do not have a 7q11.13 deletion. Termed “idiopathic infantile hypercalcemia” (IIH), biallelic loss-of-function mutations of CYP24A1 , which encodes the key degradative enzyme in vitamin D catabolism, have been identified. These mutations likely account for the increased vitamin D sensitivity. With defective catabolic activity, elevated 25(OH)D and 1,25(OH) 2 D are accompanied by hypercalcemia and hypercalciuria. The hypercalcemia in IIH usually resolves within the first few years of life, but persistent hypercalciuria is common. Inactivating mutations of CYP24A1 have been increasingly identified in older children and adults with nephrocalcinosis and recurrent nephrolithiasis and present a long-term risk for chronic kidney disease. 24,25(OH) 2 D levels can be measured by certain commercial laboratories, with increased 25(OH)D/24,25(OH) 2 D supporting the diagnosis of reduced CYP24A1 activity. Genetic analysis of CYP24A1 can confirm the diagnosis.
Treatment of hypercalcemia in WS and IIH includes a low calcium diet with elimination of vitamin D. Bisphosphonate therapy could also be considered in cases refractory to initial therapies of severe hypercalcemia. Case reports suggest rifampin, a powerful inducer of CYP3A4, with a dose of 10 mg/kg/day, can restore vitamin D homeostasis in individuals with CYP24A1 mutations through an alternative pathway for vitamin D and can lead to inactivation of vitamin D metabolites. Other options such as CYP27B1 inhibitors fluconazole and ketoconazole have also been used but have less desirable safety profiles.
Hypocalcemia
Neonatal hypocalcemia is the most typical form of hypocalcemia encountered by the pediatrician and is particularly common in the NICU. A fall of total calcium (adjusted for albumin) below 7.5 mg/dL or of ionized calcium below 4 mg/dL (1 mmol/L) is considered hypocalcemia in newborns, whereas in infants 3 months of age or younger, it is defined as total serum calcium less than 8.8 mg/dL or ionized calcium less than 4.9 mg/dL (1.22 mmol/L).
Infants with hypocalcemia will often lack specific signs or symptoms and may only be identified by lab studies. Potential symptoms can include neuromuscular irritability, which may manifest as myoclonic jerks, twitching, exaggerated startle responses, and seizures. Apnea, cyanosis, tachypnea, vomiting, laryngospasm, or heart failure may also be seen. Marked reduction in ionized calcium levels can lead to Q-Tc prolongation on electrocardiogram. Particular attention should be paid to high-risk infants such as preterm infants and infants of diabetic mothers. Different causes of neonatal hypocalcemia can be grouped according to the time of onset.
Early Neonatal Hypocalcemia
Early neonatal hypocalcemia occurs within the first 4 days of birth and represents an exaggeration of the physiologic fall in plasma calcium that occurs during the first 24 to 48 hours of life. Early neonatal hypocalcemia is thought to result from insufficient release of PTH from immature parathyroid glands or inadequate responsiveness of the renal tubules to PTH. An exaggerated rise in calcitonin secretion in premature infants may also contribute. Perinatal stress (e.g., difficult delivery), respiratory distress, prematurity, low birth weight, hypoglycemia, and maternal diabetes mellitus are common associated findings. Hypomagnesemia has been especially noted in infants of diabetic mothers but is typically mild and transient and is unlikely to play a prominent role in pathophysiology of neonatal hypocalcemia in these infants. Transient neonatal hypoparathyroidism may occur in infants exposed to maternal hypercalcemia in utero, as intrauterine hypercalcemia suppresses fetal parathyroid activity and leads to delayed responsiveness of parathyroid glands to postnatal hypocalcemia.
Late Neonatal Hypocalcemia
Late neonatal hypocalcemia typically occurs from days 5 to 10 after birth and is considered to be a manifestation of relative resistance of the immature kidney to PTH. This leads to renal retention of phosphorus and hypocalcemia, with biochemical features that strongly resemble those of pseudohypoparathyroidism, albeit without the defects in the GNAS gene that characterize genetic forms of pseudohypoparathyroidism. The high phosphorus content of cow’s milk and many infant formulas can reduce intestinal calcium absorption. In addition, many infants are unable to excrete the high phosphate load and develop hyperphosphatemia, which in turn directly reduces serum calcium levels. PTH resistance also inhibits renal production of 1,25(OH) 2 D, further reducing intestinal calcium absorption. Because human milk (HM) is low in phosphorus, breast-fed infants rarely develop late hypocalcemia. Neonatal vitamin D deficiency can also present with late onset hypocalcemia, especially in preterm infants (<28 weeks) and infants born to mothers with poor vitamin D status. Because neonatal vitamin D stores are exclusively derived from maternal stores in utero, hypocalcemia occurs after the first few days when intestinal absorption of calcium becomes dependent on vitamin D. Hypomagnesemia is a rare cause of late onset hypocalcemia because it causes resistance to PTH and impairs PTH secretion.
In most infants, neonatal hypocalcemia is transient and calcium levels normalize within a few weeks. Genetic causes of parathyroid dysfunction (i.e., congenital hypoparathyroidism) are more likely to underlie hypocalcemia and hyperphosphatemia that persist beyond 1 month of age. Depending on the severity of the defect in parathyroid development or function, hypoparathyroidism may present in the newborn period, may be transient or permanent, or may not manifest until the child is older. Causes of congenital hypoparathyroidism can be divided into defects that impair formation of the parathyroid glands or those that interfere with normal function of the parathyroid glands. In both cases, PTH levels will be inappropriately low in the context of hypocalcemia and hyperphosphatemia, with elevated fractional excretion of urinary calcium.
Advances in molecular genetic testing have led to the identification of a growing number of genes that are associated with hypoparathyroidism ( Table 28.2 ). One of the best-known examples is the DiGeorge sequence (DGS), a common developmental field defect that includes cardiovascular malformations, hypoparathyroidism, thymic hypoplasia, and characteristic facial (e.g., low-set posteriorly rotated ears, short palpebral fissures, shortened philtrum) and palatal (submucous or overt cleft palate) dysmorphism as major clinical features. Hemizygous microdeletions within chromosome 22q11.21–23 are the most common cause of DGS and account for about 85% of cases. Hypoparathyroidism is present in up to 60% of patients with DGS but is highly variable and can range from severe, early-onset hypocalcemia with neonatal seizures to mild asymptomatic hypocalcemia that is only discovered later in childhood or even adulthood. Hypoparathyroidism is more common in DGS during the neonatal/infantile period, especially among those with congenital heart disease and receiving concomitant loop diuretics. Hypocalcemia may resolve during childhood, even in some children as young as 1 year of age, but hypoparathyroidism is often latent and can be unmasked during times of stress (e.g., surgery or severe illness), presumably due to insufficient parathyroid reserve. Hypoparathyroidism can be a component of the CHARGE (Coloboma, Heart defects, Atresia choanae, Restricted growth and development, Genital hypoplasia, and Ear anomalies/deafness) syndrome. More than 75% of CHARGE cases are due to heterozygous loss-of-function mutations in the coding region of the CHD7 gene at chromosome 8q12.2. There is significant clinical overlap with DGS because both conditions display hypoparathyroidism, cardiac anomalies, cleft palate, renal anomalies, ear abnormalities/deafness, and developmental delay. In fact, hypoparathyroidism may be more common in newborns with CHARGE syndrome compared with newborns with DGS.
| Disease | Gene | Locus | OMIM a | Associated Comorbidities |
|---|---|---|---|---|
| Disorders of Parathyroid Gland Formation | ||||
| Isolated parathyroid aplasia | GCM2 SOX3 | 6p23–24 Xq-26–27 | *603716 *307700 | |
| DiGeorge sequence Type 1 Type 2 | TBX1 NEBL | 22q11.21–q11.23 10p13 | #188400 %601362 | Thymic hypoplasia with immunodeficiency, cardiac defects, cleft palate, dysmorphic facies |
| CHARGE syndrome | CHD7 SEMA3E | 8q12.2 7q21.11 | #214800 #214800 | Cardiac defects, cleft palate, renal anomalies, ear abnormalities/deafness, developmental delay |
| Hypoparathyroidism, deafness, renal dysplasia | GATA3 | 10p14–15 | #146255 | Deafness and renal dysplasia |
| Hypoparathyroidism, retardation, dysmorphism (Sanjad-Sakati syndrome) | TBCE | 1q42–43 | #241410 | Growth retardation, developmental delay, dysmorphic facies |
| Kenny-Caffey syndrome Type 1 Type 2 | TBCE FAM111A | 1q42–43 11q12.1 | #244460 #127000 | Short stature, medullary stenosis, dysmorphic facies; type 1 with developmental delay and type 2 with normal intelligence |
| Smith-Lemli-Opitz syndrome | DHCR7 | 11q13.4 | #270400 | Microcephaly, abnormal male genital development, renal dysplasia, syndactyly, adrenal insufficiency, developmental delay |
| Disorders of Parathyroid Hormone Synthesis or Secretion | ||||
| PTH gene mutations | PTH | 11p15.3-p15.1 | *168450 | |
| Autosomal dominant hypocalcemia Type 1 Type 2 | CASR GNA11 | 3q13.3–q21.1 19p13.3 | #601198 #615361 | Milder phenotype, may not present until second decade Hypercalciuria Short stature; no hypercalciuria |
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