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

Abstract

Background: 22q11.2 deletion syndrome (22q11.2DS) is a relatively common yet under-recognized genetic syndrome that may present with endocrine features. We aimed to address the factors that contribute to the high prevalence of hypocalcaemia.

Methods: We investigated hypocalcaemia in a well-characterized sample of 138 adults with 22q11.2DS (65 m, 73 F; mean age 34.2, SD 11.8, years) using laboratory studies and lifelong medical records. Logistic regression modelling was used to identify features associated with lifetime prevalence of hypocalcaemia.

Results: Of the total sample, 111 (80.4%) had a lifetime history of hypocalcaemia. Eleven (84.6%) of 13 subjects with neonatal hypocalcaemia had documented recurrence of hypocalcaemia. Lifetime history of hypocalcaemia was associated with lifetime prevalence of hypoparathyroidism (P < 0.0001) and hypothyroidism (P = 0.04), as statistically independent factors. Hypomagnesaemia was associated with concurrent hypocalcaemic measurements, especially in the presence of concurrent hypoparathyroidism (P = 0.02).

Conclusions: The results suggest that, in addition to the major effect of hypoparathyroidism, hypothyroidism may play a role in hypocalcaemia in 22q11.2DS and that there is a high recurrence rate of neonatal hypocalcaemia. Hypomagnesaemia may contribute to hypocalcaemia by further suppressing parathyroid hormone (PTH). Although further studies are needed, the findings support regular lifelong follow-up of calcium, magnesium, PTH and TSH levels in patients with 22q11.2DS. At any age, hypocalcaemia with hypoparathyroidism and/or hypothyroidism may suggest a diagnosis of 22q11.2DS.

Figure 1

Scatterplot of 397 simultaneously obtained intact PTH and ionized calcium levels available for 116 subjects with 22q11·2DS. Most measurements (n = 364, 91·7%) were collected in adulthood. The dotted lines represent approximately normal ranges of intact PTH and ionized calcium levels. The pink shaded area E represents 145 values in the normal range for both ionized calcium and PTH from 66 subjects, of whom 32 (48·5%) subjects had previously documented episodes of hypocalcaemia and 46 (69·7%) subjects had a lifetime prevalence of hypocalcaemia. Area A (low calcium and high PTH levels) has 7 measurements from 7 subjects; area B (low calcium and normal PTH levels) 153 measurements from 77 subjects; area C (low calcium and low PTH levels) 47 measurements from 21 subjects; area D (normal calcium and high PTH levels) 4 measurements from 3 subjects; area F (normal calcium and low PTH levels) 35 measurements from 23 subjects (of whom 19 (82·6%) had previously documented episodes of hypocalcaemia). Areas H (high calcium and normal PTH levels) and I (high calcium and high PTH levels) together have 6 measurements from 6 subjects, all of whom had previously documented episodes of hypocalcaemia. Area B contains 99 measurements representing relative hypoparathyroidism.

Figure 2

Scatterplot of 31 intact PTH and ionized calcium levels from six subjects with 22q11·2DS and elevated intact PTH (areas A and D from Fig.1 after excluding those with values just above the norm for PTH). The dotted lines represent approximately normal ranges of intact PTH and ionized calcium levels. Area labels A to I correspond to those in Figure1. At the time of elevated PTH level, subjects 1 and 2 had elevated creatinine (subject 2 also had worsening of Parkinson's disease); subject 3 had ruptured sinus of Valsalva; subjects 4 and 5 were apparently healthy, and subject 6 had a history of chronic renal insufficiency. Subject 4 was the only one of these six subjects for whom calcitriol was ever prescribed.