Developmental regression of motor milestones is a rare but serious presentation of severe vitamin D deficiency which is reversed on supplementation. Severe nutritional deficiency manifesting as hypopituitarism is rare but prompt recovery with nutritional rehabilitation is noted.
Nutritional rickets is caused by vitamin D and/or dietary calcium deficiency. There are a handful of reports of children presenting with delayed motor development, in particular delay in walking as a result of nutritional rickets9,14,15 however, reports of developmental regression are rare. Such presentations lead to exhaustive neurometabolic investigations which are time and resource consuming in addition to the distress and anxiety caused to families.
Given the limited vitamin D in diet, the main source remains skin synthesis, through the action of UVB on 7-dehydrocholesterol to produce cholecalciferol (vitamin D2) and ergocalciferol (vitamin D3)16. It is then activated in the liver and the kidney via two enzymatic hydroxylation reactions to a final product of calcitriol, the active form of vitamin D. Calcitriol is responsible for the supply of phosphate and calcium to the bone, allowing for mineralisation. Factors contributing to vitamin D deficiency in our patient were low exposure to sunlight due to high latitude residence and dark skin, prolonged breast feeding, lack of consumption of fortified foods which are limited and lack of adherence to supplementation17. The resultant reduced production of calcitriol decreases dietary calcium absorption from the gut leading to hypocalcaemia16. Moreover, with prolonged breastfeeding the calcium content in breast milk also reduces18, predisposing the child to twin deficiencies exacerbating the pathology.
Breast milk is undoubtfully important for the infant; however, it is evident that prolonged exclusive breastfeeding is associated with malnutrition, short stature and poor weight gain19, owing to its low vitamin content. Beyond 6 months of age prolonged exclusive breastfeeding leads to vitamin D deficiency especially in the absence of maternal vitamin D sufficiency and/or adequate supplementation20, as seen in our case (maternal 25(OH)D < 7.5nmol/L). It is therefore imperative that all women of childbearing age follow national recommendations for vitamin D supplementation; in the United Kingdom this constitutes a 400 IU/day supplement in all pregnant women and a 1000 IU/day dose in high-risk women20.
Furthermore, there are existing concerns regarding the low levels of other micronutrients and vitamins, namely vitamins A and B in breastmilk21. A study of infants [n = 80] with birth weights between 2000–3000 grams reported a negative linear association between duration of exclusive breastfeeding [n = 48] and both vitamin B levels (colabamin, riboflavin, but not folate) and gross motor development21. Similar to the above findings, we identified low serum B12 levels at baseline in our patient, with normal serum folate. The same results were not reported in formula fed infants [n = 32] or those exclusively breastfed for < 1 month21. Current recommendations from WHO suggest weaning should start for most infants at 4–6 months. As infancy progresses the nutrient content of weaning foods becomes of increasing significance. Thus, feeding difficulties including failure in weaning, particularly when high-risk individuals are involved, warrant early referral to health care professionals, to allow for early recognition of nutritional deficiencies and prevention of severe disease.
Delayed walking as a presentation of nutritional rickets has been recognised. A study of children with confirmed vitamin-D deficiency rickets in Canada reported that 18% (10/56) of those aged 1–2 years had delayed walking14, whilst another study of children aged 3–36 months from western Saudi Arabia reported delayed walking in 15% (9/60)22. In a study by Agarwal et al9, 59% (25/42) of children aged 1-2.9 years presenting with non or delayed walking were diagnosed with nutritional rickets. Of those, 100% showed radiological response to vitamin D and calcium supplementation by 2 weeks, with complete resolution averaging 5 months (range 2–8 months) and 100% biochemical resolution by 6 months. They further reported that 85% (17/20) of these children started walking within 3 months of treatment as noted in our patient.
Suspected hypopituitarism in the setting of severe stunting in our patient added to the burden of further evaluation of the pituitary axis. Numerous studies have previously hypothesised an interaction between vitamin D and IGF1/GH axis23,24, although it is yet to be elucidated how the two are intertwined. There is some evidence suggesting that vitamin D stimulates hepatic secretion of IGF-1 and IGF-1 receptor expression in several tissues25. However, low IGF-1 levels are linked to nutritional deficiency such as in patients with eating disorders with levels returning to normal upon weight restoration26. IGF-1 levels are closely linked to body fat and BMI27 and recognised to be low in children with chronic illness such as cystic fibrosis, cyanotic congenital heart disease or short bowel syndrome27. It is therefore likely, that these changes were nutritional due to the child’s poor diet. Similar to IGF-1 levels, a reduction in thyroid hormones is also known to occur in states of chronic starvation, including anorexia nervosa, with reversal on refeeding25. In our patient, both IGF-1 and thyroxine levels normalised within 2 weeks of NG feeds, further supporting their link to nutritional depletion. Reduction in all anterior pituitary hormones including LH and FSH in nutritional depletion has been reported25,26, which was recorded in our patient.
The normal response of pituitary hormones (growth hormone, cortisol) on dynamic testing, normal brain imaging and the prompt normalisation following nutritional intervention supports nutritional deficiency as the main cause of presentation.