PDF(Pubmed)
Abstract：
Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of osteosclerosis of the metaphyseal margins of long tubular bones. To date, only thirteen cases have been reported (eight molecularly confirmed). Five homozygous sequence variants in the leucine-rich repeat kinase 1 (LRRK1) gene have been identified to cause OSMD. We present two male siblings with OSMD with a novel LRRK1 variant.
The index case, now aged 6 years, was referred aged 9 months when diffuse sclerosis of the ribs and vertebral bodies, suggestive of osteopetrosis, was incidentally identified on a chest radiograph for suspected lower respiratory tract infection. Parents were consanguineous and of Pakistani origin. Further evaluation revealed developmental delay, nystagmus with bilateral optic nerve hypoplasia and severe visual impairment. Skeletal survey confirmed typical changes of OSMD, with widespread diffuse sclerosis and Erlenmeyer flask deformity of long bones. His older sibling, now aged 12 years, was 7 years at the time of referral and had similar clinical course and skeletal findings. Additionally, he had a chronic progressive osteonecrosis of the left mandible that required debridement, debulking and long-term antibiotics. Skeletal survey revealed findings similar to his sibling. Neither sibling had significant skeletal fractures or seizures. Unlike most previous reports suggesting sparing of the skull and lack of visual impairment, our patients had evidence of osteosclerosis of the cranium. Genetic screening for the common autosomal recessive and dominant pathogenic variants of osteopetrosis was negative. Whole Exome Sequencing (WES) followed by Sanger sequencing, identified a novel homozygous LRRK1 c.2506C>T p. (Gln836Ter) nonsense variant predicted to result in premature truncation of LRRK1 transcript.
Our cases confirm the autosomal recessive inheritance and expand the spectrum of genotype and phenotype of OSMD reported in the literature. Increasing reports of LRRK1 variants in this phenotype raise the question of whether LRRK1 should be included in targeted osteopetrosis panels. Bone histology in previous cases has shown this to be an osteoclast rich form of osteopetrosis raising the possibility that haematopoietic stem cell transplantation may be an appropriate treatment modality.
The index case, now aged 6 years, was referred aged 9 months when diffuse sclerosis of the ribs and vertebral bodies, suggestive of osteopetrosis, was incidentally identified on a chest radiograph for suspected lower respiratory tract infection. Parents were consanguineous and of Pakistani origin. Further evaluation revealed developmental delay, nystagmus with bilateral optic nerve hypoplasia and severe visual impairment. Skeletal survey confirmed typical changes of OSMD, with widespread diffuse sclerosis and Erlenmeyer flask deformity of long bones. His older sibling, now aged 12 years, was 7 years at the time of referral and had similar clinical course and skeletal findings. Additionally, he had a chronic progressive osteonecrosis of the left mandible that required debridement, debulking and long-term antibiotics. Skeletal survey revealed findings similar to his sibling. Neither sibling had significant skeletal fractures or seizures. Unlike most previous reports suggesting sparing of the skull and lack of visual impairment, our patients had evidence of osteosclerosis of the cranium. Genetic screening for the common autosomal recessive and dominant pathogenic variants of osteopetrosis was negative. Whole Exome Sequencing (WES) followed by Sanger sequencing, identified a novel homozygous LRRK1 c.2506C>T p. (Gln836Ter) nonsense variant predicted to result in premature truncation of LRRK1 transcript.
Our cases confirm the autosomal recessive inheritance and expand the spectrum of genotype and phenotype of OSMD reported in the literature. Increasing reports of LRRK1 variants in this phenotype raise the question of whether LRRK1 should be included in targeted osteopetrosis panels. Bone histology in previous cases has shown this to be an osteoclast rich form of osteopetrosis raising the possibility that haematopoietic stem cell transplantation may be an appropriate treatment modality.
摘要：
■骨硬化性干phy端发育不良（OSMD，OMIM615198）是一种极为罕见的常染色体隐性食骨症，导致长管状骨的干phy端边缘骨硬化的独特模式。迄今为止,仅报告了13例（8个分子证实）。已鉴定出富含亮氨酸的重复序列激酶1（LRRK1）基因中的五个纯合序列变体引起OSMD。我们提出了两个具有OSMD的男性兄弟姐妹，它们具有新的LRRK1变体。
■索引案例，现在6岁，在9个月时，肋骨和椎体弥漫性硬化，提示骨质疏松，在胸片上偶然发现疑似下呼吸道感染。父母是近亲，有巴基斯坦血统。进一步评估显示发育迟缓，眼球震颤伴双侧视神经发育不全，视力严重受损。骨骼调查证实了OSMD的典型变化，广泛弥漫性硬化症和锥形瓶畸形的长骨。他的哥哥姐姐,现在12岁，转诊时为7年,临床病程和骨骼检查结果相似.此外,他患有慢性进行性左下颌骨坏死，需要清创，减积和长期抗生素。骨骼调查显示发现与他的兄弟姐妹相似。兄弟姐妹都没有明显的骨骼骨折或癫痫发作。与以前的大多数报告显示保留头骨和缺乏视力障碍不同，我们的患者有颅骨硬化的证据。对石骨病常见常染色体隐性和显性致病变异的遗传筛查为阴性。全外显子组测序（WES），然后进行Sanger测序，鉴定了一种新的纯合LRRK1c.2506C>Tp。（Gln836Ter）无义变体，预测会导致LRRK1转录物的过早截短。
■我们的病例证实了常染色体隐性遗传，并扩大了文献报道的OSMD的基因型和表型谱。在这种表型中，越来越多的LRRK1变体的报道提出了一个问题，即LRRK1是否应包括在靶向的骨硬化组中。先前病例的骨组织学表明，这是一种富含破骨细胞的骨硬化症，这增加了造血干细胞移植可能是一种适当的治疗方式的可能性。
■索引案例，现在6岁，在9个月时，肋骨和椎体弥漫性硬化，提示骨质疏松，在胸片上偶然发现疑似下呼吸道感染。父母是近亲，有巴基斯坦血统。进一步评估显示发育迟缓，眼球震颤伴双侧视神经发育不全，视力严重受损。骨骼调查证实了OSMD的典型变化，广泛弥漫性硬化症和锥形瓶畸形的长骨。他的哥哥姐姐,现在12岁，转诊时为7年,临床病程和骨骼检查结果相似.此外,他患有慢性进行性左下颌骨坏死，需要清创，减积和长期抗生素。骨骼调查显示发现与他的兄弟姐妹相似。兄弟姐妹都没有明显的骨骼骨折或癫痫发作。与以前的大多数报告显示保留头骨和缺乏视力障碍不同，我们的患者有颅骨硬化的证据。对石骨病常见常染色体隐性和显性致病变异的遗传筛查为阴性。全外显子组测序（WES），然后进行Sanger测序，鉴定了一种新的纯合LRRK1c.2506C>Tp。（Gln836Ter）无义变体，预测会导致LRRK1转录物的过早截短。
■我们的病例证实了常染色体隐性遗传，并扩大了文献报道的OSMD的基因型和表型谱。在这种表型中，越来越多的LRRK1变体的报道提出了一个问题，即LRRK1是否应包括在靶向的骨硬化组中。先前病例的骨组织学表明，这是一种富含破骨细胞的骨硬化症，这增加了造血干细胞移植可能是一种适当的治疗方式的可能性。
