骨密度增加是骨质硬化症及相关骨吸收紊乱的遗传性疾病的特征，而这些疾病形式复杂多样。本研究的目的是探索这些疾病的临床和放射学特征的分子谱和自然史。共有28名患者和20个家庭参与了该研究，其中20名患者进行了1-16年的随访。我们进行了有针对性的基因分析和全外显子测序（WES）。在骨质硬化症组中，我们在3个家庭中检测到了CLCN7或TCIRG1的双等位基因突变，2个家庭中检测到了TNFRSF11A或CA2的双等位基因突变，1个家庭中检测到了SNX10的基因突变，其中，CLCN7的杂合变异体也在一个家庭中发现。在骨质硬化症和相关骨吸收紊乱组中，我们检测到了五个患有崩塌性骨发育不全症的家庭中的三个CTS​​K的不同突变体，以及一个家庭中的导致骨发育不全症的SLC29A3基因突变体。在随访期间，4名患有婴儿恶性型自体隐性遗传骨质硬化症（ARO）的患者中有4人死亡，其中2人接受了造血干细胞移植手术。有趣的是，所有患者在婴儿期都有长骨干骨作指征、典型的酒瓶样变形和骨内骨等骨骼特征，在早期儿童末期发展形成。有双等位错义突变体的CLCN7的两个兄弟和具有复合杂合内含子TCIRG1突变体的一名患者分别对应于中间型ARO。有一个CA2大片段缺失的患有中间型ARO和远端小管性酸中毒的两名兄弟中的一人。在一个家庭中，携带CLCN7杂合突变的两个兄弟受到影响，而具有相同突变的父亲则无症状。在没有骨质硬化症基因突变的一个家族中，通过对三个兄弟进行的WES分析，我们发现了一个与高骨密度相关的CCDC120新基因的半合子错义突变。本研究拓展了骨质硬化症不同类型的自然史，并首次提出了一个潜在导致骨质硬化症的候选基因。版权所有© 2023 Elsevier Inc. 保留所有权利。

Osteopetrosis and related osteoclastic disorders are a heterogeneous group of inherited diseases characterized by increased bone density. The aim of this study is to investigate the molecular spectrum and natural history of the clinical and radiological features of these disorders.28 patients and 20 families were enrolled in the study; 20 of them were followed for a period of 1-16 years. Targeted gene analysis and whole-exome sequencing (WES) were performed.Biallelic mutations in CLCN7 or TCIRG1 were detected in three families, in TNFRSF11A or CA2 in two families, and in SNX10 in one family in the osteopetrosis group. A heterozygous variant of CLCN7 was also found in one family. In the osteopetrosis and related osteoclast disorders group, three different variants of CTSK were detected in five families with pycnodysostosis and the SLC29A3 variant causing dysosteosclerosis was detected in one family. In autosomal recessive osteopetrosis (ARO), a malignant infantile form, four patients died during follow-up, two of whom had undergone hematopoietic stem cell transplantation. Interestingly, all patients had osteopetrorachia of the long bone metaphyses in infancy, typical skeletal features such as Erlenmeyer flask deformity and bone-in-bone appearance that developed toward the end of early childhood. Two siblings with a biallelic missense mutation in CLCN7 and one patient with the compound heterozygous intronic TCIRG1 variant corresponded to the intermediate form of ARO (IARO); there was intrafamilial clinical heterogeneity in the family with the CLCN7 variant. One of two patients with IARO and distal tubular acidosis was found to have a large deletion in CA2. In one family, two siblings with a heterozygous mutation in CLCN7 were affected, whereas the father with the same mutation was asymptomatic. In WES analysis of three brothers from a family without mutations in osteopetrosis genes, a hemizygous missense variant in CCDC120, a novel gene, was found to be associated with high bone mass.This study extended the natural history of the different types of osteopetrosis and also introduced a candidate gene potentially causing osteopetrosis.Copyright © 2023 Elsevier Inc. All rights reserved.