Parathyroid hormone reserve in 22q11.2 deletion syndrome

Abstract

Objective: We hypothesized that most patients with 22q11.2 deletion and a history of hypocalcemia have inadequate parathyroid function, manifested by intact parathyroid hormone levels below normal. We aimed to evaluate intact parathyroid hormone levels both during normocalcemia and at hypocalcemia, in this population.Study Design: Retrospective chart review of 103 patients with 22q11.2 deletion born since 1997 and cared for at the Children's Hospital of Philadelphia. Calcium and intact parathyroid hormone drawn simultaneously were recorded, along with clinical presentation at hypocalcemia. Results: Forty-seven simultaneous Ca/intact parathyroid hormone values were available. Seventy-nine percent of calcium levels and 81% of parathyroid hormone levels were within normal range. There were 19 patients with a history of symptomatic hypocalcemia, for whom any available simultaneous Ca/parathyroid hormone levels, before, during, or after hypocalcemia were analyzed. In this subgroup, 59% of calcium and 76% of parathyroid hormone levels were normal. None had an intact parathyroid hormone of Ͼ39.2 pg/mL at hypocalcemia. Seventy-three percent of hypocalcemic events had a precipitating stressor. Conclusions: Hypoparathyroidism in 22q11.2 deletion is mild, manifesting as a phenomenon of decreased parathyroid hormone reserve. Subjects are normocalcemic most of the time, but are unable to mount elevated intact parathyroid hormone levels, and therefore unable to correct hypocalcemia, in response to stressors. Genet Med 2008:10(3):224 -228.Key Words: parathyroid hormone, PTH, calcium, Digeorge, 22q11.2, hypocalcemia, hypoparathyroidism, intact PTH Microdeletion of chromosome 22q11 occurs with an incidence of approximately 1/4000 -7000 live births. [1][2][3] This deletion results in failure of development of the derivatives of the 3rd and 4th pharyngeal pouches, with anomalous migration of the cells derived from the cephalic neural crest. 4 Clinical expression varies from one patient to another. Features can include congenital cardiac defects, hypocalcemia, short stature, immunodeficiency from thymic hypoplasia, palate abnormalities, cognitive impairment, and minor facial dysmorphism. 5 Hypocalcemia due to hypoparathyroidism in this population was described originally by Digeorge. 6 The parathyroids are derivatives of the 3rd and 4th pharyngeal pouches, and therefore hypoparathyroidism in this syndrome is not unexpected. It has been documented by aplasia or hypoplasia of parathyroid glands at surgery or autopsy. 7 Our center previously reported hypocalcemia in 77 of 158 (49%) patients. 8,9 Brauner et al. 10 combined a cross-sectional study with historical review to reveal abnormal parathyroid gland function in 69% of patients. However, hypoparathyroidism in 22q11.2 deletion syndrome has been difficult to characterize. The varying degrees of parathyroid dysfunction in the 22q11.2 deletion population, and even intra-individual variation in parathyroid function, have been described by multiple authors. 1,5,10 -15 We hypothesiz...

Clinical manifestations and frequency of hypocalcemia in 22q11.2 deletion syndrome

“…Kapadia et al . concluded that hypocalcemia in 22qDS patients is caused by a decrease in the PTH reserve in response to stressors …”

“…The presence of neonatal hypocalcemia was not predictive of postnatal hypocalcemia in the present study. It has been reported that neonatal hypocalcemia is associated with the later development of permanent hypoparathyroidism . Another study has reported that 13–30% of 22qDS patients have possible hypoparathyroidism outside of the neonatal period .…”

Association of hypocalcemia with congenital heart disease in 22q11.2 deletion syndrome

“…Hypocalcemia is reported in approximately 50%–69% of patients with 22q11.2DS and is caused by agenesis or hypoplasia of the parathyroid glands, which are derivatives of the third and fourth pharyngeal pouches (Weinzimer, 2001). Hypoparathyroidism in this condition generally seems to be a result of decreased PTH reserve, with a predisposition to develop hypocalcemia during periods of stress or illness (Kapadia, Kim, McDonald-McGinn, Zackai, & Levitt Katz, 2008). Other endocrine manifestations include hypothyroidism, Graves’ disease, and growth hormone deficiency (Choi et al, 2005).…”

Prevalence of hypocalcaemia and its associated features in 22q11·2 deletion syndrome

“…As originally described by DiGeorge, hypocalcaemia was attributed to aplasia or hypoplasia of the parathyroid glands due to a developmental defect. There are however few reported supporting autopsy findings to document structural parathyroid defects in 22q11·2DS . The analysis of the PTH response to ionized calcium in individuals with 22q11·2DS in our study suggests that the parathyroid glands were not completely dysfunctional but displayed variable (often poor) efficiency of response, likely related to reduced PTH reserve, in these subjects.…”