Basalom Shuaa, Fiscaletti Mélissa, Miranda Valancy, Huber Céline, Couture Guillaume, Drouin Régen, Monceau Élise, Wavrant Sandrine, Dubé Johanne, Mäkitie Outi, Cormier-Daire Valérie, Campeau Philippe M
Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Center, Montreal, QC H4A 3J1, Canada.
Department of Pediatrics, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada.
Bone Rep. 2021 Aug 25;15:101121. doi: 10.1016/j.bonr.2021.101121. eCollection 2021 Dec.
Calvarial Doughnut Lesions with Bone Fragility (CDL) is an autosomal dominant genetic disease, characterized by low bone mineral density, multiple fractures starting in childhood, and sclerotic doughnut-shaped lesions in the cranial bones. Aubé and colleagues described in 1988 a French-Canadian family of 12 affected members who had a clinical diagnosis of doughnut lesions of the skull, with pathological fractures, osteopenia, "bone in bone" in the vertebral bodies and squaring of metatarsal and metacarpal bones. Herein we study new members of this family. Sequential genetic testing identified a nonsense variant c.148C>T, p. Arg50 in previously reported in other families. encodes Sphingomyelin Synthase 2, which produces Sphingomyelin (SM), a major lipid component of the plasma membrane that plays a role in bone mineralization. The nonsense variant is associated with milder phenotype. The proband presents with bone in bone vertebral appearance that had been defined uniquely in the first cases described in the same family. The proband's son was identified to carry the same variant, which makes him the sixth generation with the diagnosis of CDL. We also report that the same pathogenic variant was identified in another previously described family, from France. These reports further confirm the genetic basis of CDL, the recurrence of the same variant (p.Arg50*) in individuals of the same ancestry, and the variable penetrance of some of the clinical findings.
伴有骨脆性的颅骨环形病变（CDL）是一种常染色体显性遗传病，其特征为骨矿物质密度低、儿童期起病的多发性骨折以及颅骨中的硬化环形病变。奥贝及其同事在1988年描述了一个法裔加拿大家庭，该家庭中有12名受影响成员，临床诊断为颅骨环形病变，伴有病理性骨折、骨质减少、椎体“骨中骨”以及跖骨和掌骨方形化。在此我们研究这个家族的新成员。序贯基因检测在先前其他家族中报道过的基因中鉴定出一个无义变异c.148C>T，p.Arg50*。该基因编码鞘磷脂合酶2，其产生鞘磷脂（SM），鞘磷脂是质膜的主要脂质成分，在骨矿化中起作用。该无义变异与较轻的表型相关。先证者呈现出椎体骨中骨外观，这在同一家庭首次描述的病例中是独一无二的。先证者的儿子被鉴定携带相同变异，这使他成为第六代被诊断为CDL的患者。我们还报告在另一个先前描述的来自法国的家族中鉴定出相同的致病变异。这些报告进一步证实了CDL的遗传基础、同一家系个体中相同变异（p.Arg50*）的复发以及一些临床发现的可变外显率。
