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

A 6-month old exclusively breastfed, African boy presented to the emergency department (ED) with an out-of-hospital cardiac arrest. In the weeks prior to presentation, he had 3 brief episodes of peri-oral cyanosis and pallor and presented twice to ED with increased work of breathing. On initial assessment by paramedics he showed no signs of life and was in asystole. He was resuscitated until spontaneous circulation was restored at 36 min. Investigations revealed low ionised calcium (0.72 mmol/L), warranting repeated intravenous calcium boluses followed by continuous infusion. Cefotaxime was commenced for presumed sepsis, and oseltamivir was added after isolating influenza A on a nasal swab. Intravenous fluids and inotropes were administered. In the intensive care unit, an echocardiogram showed severe dilated cardiomyopathy with poor left ventricular ejection fraction (LVEF) of 25–30% [normal 55–70%]), fractional shortening (FS) of 7% [normal 29–40%], dyskinetic septal motion, global hypokinesia, and moderate to severe mitral regurgitation with a structurally normal heart. Rickets was confirmed radiographically (Fig. 1b), with elevated serum ALP and PTH concentrations, and low 25OHD < 15 nmol/L (Table 1). Cholecalciferol (6000 IU daily) was commenced, and intravenous calcium was continued until serum calcium normalised (72 h). Cardiac failure was managed with diuretics and vasodilators. Brain Magnetic resonance imaging (MRI) revealed severe hypoxic-ischaemic encephalopathy, correlating with the clinical finding of unresponsiveness to external stimuli. The care team and family elected to withdraw life support, and the infant died 6 days after presentation.

Post-mortem examination confirmed severe nutritional rickets with rachitic rosary (enlarged rib growth plates) (Fig. 2a), craniotabes, soft ribs, dilated cardiomyopathy (heart weight 71 g [>95th centile], with multifocal myocardial necrosis) and massive ischaemic brain injury. Histological analysis of a 7th rib growth plate showed extreme disarray, widening and lengthening, with islands of hypertrophic chondrocytes reaching far into the primary spongiosa and mature bone, typical of rickets (Fig. 2b). Histomorphometric analysis of a transiliac bone sample identified severe osteomalacia with increased osteoid thickness (23.2 μm [normal 6.4 +/− 1.4]), osteoid surface/bone surface (76.3% [normal 24.9 +/− 10]) and osteoid volume/bone volume (40.5% [normal 2.4 +/− 1.22]). Specifically, osteoid thickness was + 262% and osteoid volume/bone volume + 1573% of normal reference values [9]. Since Goldner’s Trichrome staining does not discriminate well between non-mineralized and poorly mineralized matrix, we also performed quantitative backscattered electron imaging, which confirmed the extremely low bone mineralization density (Fig. 3).

The mother had received antenatal multivitamin supplementation and attended all post-natal child surveillance and vaccination appointments. She was not informed of the need for infant vitamin D supplementation. Mother (Table 1) and a 9-year old sibling had suboptimal 25OHD concentrations.

A 6-month old, partially breastfed and previously well Somali boy presented to the ED following respiratory arrest and seizure. He was found pale, floppy and not breathing while held by his sibling. Following emergency telephone advice, his mother, a nurse, commenced Cardio-pulmonary resuscitation (CPR) at home. Two minutes later he had a 2-min tonic-clonic seizure. With continued CPR, spontaneous breathing was established at 4 min. Paramedics found him drowsy with normal blood glucose. In the ED, he responded to pain, respiratory rate was 40/min, heart rate was 112/min with normal capillary refill. A grade 2/6 systolic ejection murmur was present. A venous blood gas was normal except for low ionised calcium (0.66 mmol/L). A chest radiograph showed cardiomegaly (Fig. 1c), and echocardiogram demonstrated a structurally normal heart with severely dilated left ventricle with reduced LVEF of 29%, FS of 7%, global hypokinesia and moderate mitral regurgitation, confirming hypocalcemic dilated cardiomyopathy. Diuretic and ACE (Angiotensin converting enzyme) inhibitor therapy was commenced. Nutritional rickets due to vitamin D deficiency was confirmed with knee radiographs (Fig. 1d), elevated serum ALP and PTH, and low 25OHD of < 5.2 nmol/L (Table 1). He received intravenous calcium and oral cholecalciferol (6000 IU daily). Alfacalcidol (1-hydroxycholecalciferol) was temporarily administered to improve calcium absorption. On day 3, following a switch from intravenous to oral calcium, he had another seizure with respiratory arrest in hospital, requiring mechanical ventilation and intensive care. Intravenous calcium was recommenced, and a head computed tomography was normal. He was extubated 24 h later and continued intravenous calcium for 5 more days. He was discharged home on day 17 and 3 months later showed slow recovery (LVEF 35%; FS 16%; Left ventricle diameter 42 mm [Z-score + 4.7], marked reduction in mitral regurgitation).

The mother had been provided with one bottle of vitamin D for the baby at birth but was not informed to continue supplementation, and adherence was not assessed. She (Table 1) and three of the infant’s four siblings (aged 3, 6, 7, 9 years) were vitamin D deficient, with elevated ALP and PTH.

A five-month old British Pakistani girl presented to ED with cough, difficulty in breathing and poor feeding. She was born at 35 weeks with a birth weight of 1.75 Kg (9th centile) and required admission to the neonatal unit for 6 days to establish oral feeding. At presentation, she was found to be pale, irritable, tachypnoeic and tachycardic. She had faltering growth (fall across ≥2 weight centiles) with a weight of 4.5 kg (< 0.4th centile) and length 58 cm (on 0.4th centile). She was diagnosed with bronchiolitis. Only the faltering growth triggered further investigations which identified hypocalcemia (1.96 mmol/L). Further evaluation of hypocalcemia revealed raised ALP and PTH, and low 25OHD of 12.5 nmol/L (Table 1) and rickets on knee radiograph (Fig. 1f). An echocardiogram performed in view of persistent tachycardia, systolic murmur and cardiomegaly on chest radiograph (Fig. 1e) revealed a structurally normal heart with a severely dilated left ventricle (LVEF of 25%, FS of 15%, global hypokinesia and severe mitral regurgitation), confirming hypocalcemic dilated cardiomyopathy. She was commenced on oral calcium supplements (500 mg/day in divided doses) and cholecalciferol (initially 3000 IU daily, later increased to 6000 IU daily) and transferred to our tertiary center for specialist cardiology care. She was commenced on diuretics and ACE inhibitors.

Nobody had informed mother of the need for vitamin D supplementation during pregnancy and infancy. Her 3 year old sibling had normal 25OHD levels, however mum was deficient with a raised PTH (Table 1).