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.

引言：苯丙酮尿症（PKU），一种先天性代谢障碍，若治疗不当，可能导致营养缺乏，进而影响骨骼健康。鉴于大多数PKU病例中骨骼矿物质密度均在正常范围内，此问题仍存在争议。另一方面，WNT1基因突变对骨骼具有损害作用，可导致原发性骨质疏松症。
病例报告：我们报道了一位11岁女孩的病例，她因苯丙酮尿症接受极为严格的饮食治疗（即苯丙氨酸水平低），并患有严重的骨质疏松症，表现为多发性椎体骨折，这些骨折不能归因于她的先天性代谢障碍。家族筛查，包括骨密度测定，发现其父亲和兄弟存在无法解释的骨质疏松症。进一步的遗传学研究揭示了新的WNT1致病突变。患者的饮食计划被调整，以实现更好的代谢控制，并给予其维生素D和钙补充剂。这些措施导致了临床和放射学上的显著改善，且未使用双磷酸盐。
结论：在已知影响骨骼的慢性疾病患者中，若出现不成比例的严重骨质疏松症，应促使进行进一步的诊断检查，以解释严重的骨骼表型，从而实现更有效和针对性的治疗干预。