Cardiac, bone and growth plate manifestations in hypocalcemic infants: revealing the hidden body of the vitamin D deficiency iceberg

Abstract

Background: Whilst hypocalcemic complications from vitamin D deficiency are considered rare in high-income countries, they are highly prevalent among Black, Asian and Minority Ethnic (BAME) group with darker skin. To date, the extent of osteomalacia in such infants and their family members is unknown. Our aim was to investigate clinical, cardiac and bone histomorphometric characteristics, bone matrix mineralization in affected infants and to test family members for biochemical evidence of osteomalacia.

Case presentation: Three infants of BAME origin (aged 5-6 months) presented acutely in early-spring with cardiac arrest, respiratory arrest following seizure or severe respiratory distress, with profound hypocalcemia (serum calcium 1.22-1.96 mmol/L). All infants had dark skin and vitamin D supplementation had not been addressed during child surveillance visits. All three had severely dilated left ventricles (z-scores + 4.6 to + 6.5) with reduced ejection fraction (25-30%; normal 55-70), fractional shortening (7 to 15%; normal 29-40) and global hypokinesia, confirming hypocalcemic dilated cardiomyopathy. They all had low serum levels of 25 hydroxyvitamin D (25OHD < 15 nmol/L), and elevated parathyroid hormone (PTH; 219-482 ng/L) and alkaline phosphatase (ALP; 802-1123 IU/L), with undiagnosed rickets on radiographs. One infant died from cardiac arrest. At post-mortem examination, his growth plate showed a widened, irregular zone of hypertrophic chondrocytes. Histomorphometry and backscattered electron microscopy of a trans-iliac bone biopsy sample revealed increased osteoid thickness (+ 262% of normal) and osteoid volume/bone volume (+ 1573%), and extremely low bone mineralization density. Five of the nine tested family members had vitamin D deficiency (25OHD < 30 nmol/L), three had insufficiency (< 50 nmol/L) and 6/9 members had elevated PTH and ALP levels.

Conclusions: The severe, hidden, cardiac and bone pathology described here exposes a failure of public health prevention programs, as complications from vitamin D deficiency are entirely preventable by routine supplementation. The family investigations demonstrate widespread deficiency and undiagnosed osteomalacia in ethnic risk groups and call for protective legislation.

Keywords: Cardiomyopathy; Hypocalcemia; Policy; Rickets; Seizures; Vitamin D.

Fig. 1

Radiographs. Chest and knee radiographs of Patient 1 (a, b), 2 (c, d) and 3 (e, f) demonstrate cardiomegaly and rickets

Fig. 2

Post-mortem Findings. At post-mortem examination, Patient 1 had a rachitic rosary (a) and the rib growth plate showed extreme disarray (b, Elastica van Gieson staining). Normal growth plate in a 6 months-old control with normal 25OHD (c)

Fig. 3

Histomorphometric and Quantitative Backscattered Electron Microscopic Analysis. Goldner’s Trichrome staining (light microscopy) of a post-mortem transiliac bone sample from Patient 1 (a, b) demonstrated broad seams of pink stained areas corresponding to non- or poorly mineralized matrix and regions with blurred pink-green transition (black arrows), next to mineralized matrix (green). Backscattered electron images of the complete bone sample surface (c, d) show low mineral content in dark grey, normal/high mineral content in bright grey and unmineralized matrix appears black (c). To demonstrate the massively increased primary mineralization, represented by areas mineralized below 17.68 wt% calcium, corresponding to the 5th percentile of the adult reference range (CaLow) [10], these areas were highlighted in red (d). The BMDD curve of patient 1 (e) was shifted towards lower mineral content, its width at half-maximum was broader (CaWidth + 55%) due to increased heterogeneity in mineralization, and the fraction of poorly mineralized matrix was markedly increased (CaLow + 640%). References from Fratzl-Zelman et al. [36]