Increased blood 1,25 dihydroxyvitamin D levels in infants with Metabolic Bone Disease of Infancy in contested cases of child abuse

Abstract

Purpose: Metabolic Bone Disease of Infancy (MBDI) is a multifactorial disorder of bone fragility that presents with multiple unexplained fractures (MUF) and is often misdiagnosed as child abuse. The diagnosis of MBDI is made by the finding of radiographic features of healing rickets and risk factors for MBDI. Our anecdotal experience indicates blood 1,25-dihydroxyvitamin D (1,25-DiOHVD) is sometimes elevated. The purpose of this retrospective study was to review cases of MBDI in which child abuse was alleged and the alleged perpetrator denied wrongdoing.

Methods: We reviewed forensic cases of MBDI born between 2015 and 2021. The diagnosis was based on radiographic findings of healing rickets. Records were reviewed for blood 1,25-DiOHVD testing.

Results: 22 of the 76 infants (29 %) had a blood 1,25-DiOHVD level performed at the time of presentation with fractures. The average age of presentation with fractures was 11 weeks.3 of the 22 infants (14 %) had a normal 1,25-DiOHVD blood level, and 19 of the 22 infants (86 %) had an elevated level. None had low levels.

Conclusion: Blood 1,25-DiOHVD is often elevated in infants with MBDI. Elevated blood 1,25-DiOHVD levels cause increased bone resorption and decreased bone mineralization, and thus this finding is not unexpected since all infants had evidence of healing rickets on imaging studies. These results indicate blood 1,25-DiOHVD should be done in contested cases of child abuse in infants with MUF as an elevated level indicates bone fragility.

Keywords: 1,25 dihydroxyvitamin D; Healing rickets; Metabolic Bone Disease of Infancy; Multiple unexplained fractures; Non-accidental injury.

Fig. 1

Examples of Healing Rickets from the 19 cases with Elevated Blood 1,25-DiOHVD Levels Fig. 1a (Case 2): 3D CT scan images of the posterior calvarium with MIP image (left) and surface rendered image (right). Both show numerous spherical mineralization defects (several shown in red circles) and parasutural hypomineralization along the lambdoid and sagittal sutures (red arrows). Both are signs of healing rickets. Fig. 1b (Case 6): Lateral chest shows various degrees of cupping of the anterior ribs at the chondro-osseous junction and thickening of the normally delicate zone of provisional calcification (between red arrows), both signs of healing rickets. Fig. 1c (case 7): AP view of the proximal right femur shows 2 distinct lines of the zone of provisional calcification [original (red arrows) and new (green arrows)] at the chondro-osseous junction, separated by a radiolucent zone representing the rachitic intermediate zone. 15 days later the zone continues to expand as healing progresses. Note the content of the rachitic intermediate is less “trabeculated”, giving it a more featureless appearance than that seen in the adjacent metaphysis. This sequence of changes is consistent with healing rickets.

Fig. 2

Effect of Increased Blood 1,25-Dihydroxyvitamin D on Bone in Rickets Normal blood calcium level is critical for the normal function of the heart, central nervous system, and musculoskeletal system. The most common cause of a low blood calcium level is nutritional rickets – lack of calcium or vitamin D in the diet. An elegant system of adaptation exists in the human to restore a low blood calcium level to normal (9–11 mg%), as illustrated in the Figure. When blood calcium is reduced below a threshold value of about 9 mg%, this low value is detected by the blood calcium sensing receptor in the parathyroid glands called the calcistat. This low blood calcium level causes a release of PTH which activates the CYP27B1 enzyme activity in the kidney catalyzing the conversion of 25-OHVD to 1,25-DiOHVD, resulting in an increased blood 1,25-DiOHVD level. The elevated blood 1,25-DiOHVD level has an immediate effect on bone whereby osteoclasts are activated to promote bone resorption and osteoblasts are inhibited to reduce bone mineralization. The combination of these two bone-mediated effects is to quickly increase the blood calcium level and restore it to a normal level. Thus, the blood calcium level is restored at the expense of bone strength as the increased osteoclast activity and the decreased osteoblast activity decreases bone mass and bone mineralization. The elegant transgenic mice studies of Lieben et al. have demonstrated that increased levels of 1,25-DiOHVD increase osteoclast activity through RANKL secreted by osteoblasts, and also suppress bone mineralization by increasing the levels of several mineralization inhibitors including the Opn gene and pyrophosphates^,. Decreased levels of blood calcium are perceived by the calcistat (calcium-sensing receptor) in the parathyroid gland that causes increased secretion of PTH into the blood which increases the activity of CYP27B1 in the kidney. The increased blood levels of 1,25-DiOHVD mediated through increased PTH results in 4 physiologic changes that all increase blood calcium: 1. increased intestinal absorption of calcium 2. decreased renal excretion of calcium 3. increased bone resorption which leeches calcium form the bone, and 4. inhibition of bone formation The latter 2 consequences have an immediate effect to rapidly increase blood calcium compared to the former which requires more time. The transgenic mice studies of Lieben et al. have demonstrated that increased levels of 1,25-DiOHVD not only increase osteoclast activity through RANKL secreted by osteoblasts, but also suppress bone mineralization by increasing the levels of several mineralization inhibitors including the Opn gene and pyrophosphates^,.