Abstract：
Osteosclerotic metaphyseal dysplasia is a rare disorder which features osteosclerosis involving long bones, vertebrae, ribs, clavicles and the iliac crests. Additional features which have variably been reported include developmental delay, short stature, hypotonia and seizures. The disease is caused by pathogenic variants in the LRRK1 gene, and inherited in an autosomal recessive manner. We report three siblings (ages 14 years, 11.5 years and 0.9 years), born to consanguineous parents of Arab-Muslim descent, harboring a homozygous pathogenic variant in the LRRK1 gene (Chr15:101068759 AGGGGCT>A, c.5965_5970del TGGGGC, p.Trp1989Gly1990del). The patients displayed variable degrees of skeletal dysplasia, with the oldest sibling most severely affected, and the youngest infant with minor skeletal involvement. Two of the siblings exhibited normal neurological development, while the youngest sibling exhibited global developmental delay. None of the siblings had seizures; however, two of them exhibited nystagmus. Optic nerve involvement has not previously been reported to be part of the clinical spectrum of this disease. The degree of optic nerve involvement did not correlate with the degree of skeletal involvement. This indicates both intra-familial variable expressivity along with a broadening of the spectrum of LRRK1-associated disease. These findings warrant reconsideration of therapeutic strategies, including the possibility of hematopoietic stem cell transplantation (HSCT) as is performed in cases of malignant and intermediate forms of osteopetrosis.
摘要：
骨硬化性干phy端发育不良是一种罕见的疾病，其特征是涉及长骨的骨硬化，椎骨,肋骨,锁骨和髂峰.已报道的其他特征包括发育迟缓，身材矮小,张力减退和癫痫发作。该疾病是由LRRK1基因的致病变异引起的，以常染色体隐性方式遗传。我们报告了三个兄弟姐妹(14岁，11.5年和0.9年)，生于阿拉伯穆斯林血统的近亲，在LRRK1基因中具有纯合致病性变异(Chr15:101068759AGGGGCT>A，c.5965_5970delTGGGGC,P.Trp1989Gly1990del)。患者表现出不同程度的骨骼发育不良，最年长的兄弟姐妹受影响最严重，和骨骼轻微受累的最小婴儿。两个兄弟姐妹表现出正常的神经发育，而最年轻的兄弟姐妹表现出全球发育迟缓。兄弟姐妹都没有癫痫发作；然而，其中两个表现出眼球震颤。先前尚未报道视神经受累是该疾病临床谱的一部分。视神经受累程度与骨骼受累程度无关。这表明家族内可变表达以及LRRK1相关疾病谱的扩大。这些发现需要重新考虑治疗策略，包括造血干细胞移植（HSCT）的可能性，如在恶性和中间形式的骨硬化病例中进行的。
