Supplementary Material for: Co-occurrence of two rare diseases: a child with phenylketonuria and WNT1 osteoporosis

Introduction: Phenylketonuria (PKU), an inborn error of metabolism, when inadequately treated, may lead to nutritional deficits, which could affect bone health. This remains a controversial issue, given that in the majority of PKU cases, bone mineral density is within normal limits. On the other hand, WNT1 mutations are detrimental for bone, as they lead to primary osteoporosis. Case presentation: We present an eleven year-old girl under a very strict diet for phenylketonuria (i.e. with low phenylalanine levels) and severe osteoporosis, signified by the presence of multiple vertebral fractures, which could not be attributed to her inborn error of metabolism. Family screening, including bone densitometry revealed unexplained osteoporosis in her father and brother. Further genetic work up revealed a new WNT1, disease-causing mutation. The patient’s dietary plan was modified, in order to achieve better metabolic control and she was given vitamin D and calcium supplements. These measures led to great clinical and radiological improvement, without the use of bisphosphonates. Conclusion: In a patient with a chronic disorder known to affect the skeleton, the presence of disproportionally severe osteoporosis should prompt further diagnostic work up, in order to explain the severe bone phenotype, thus enabling more efficient and targeted therapeutic interventions.