Briggs Michael D, Wright Michael J
Professor of Skeletal Genetics, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne, United Kingdom
Consultant in Clinical Genetics, Northern Genetics Service, Newcastle upon Tyne Hospitals, Newcastle upon Tyne, United Kingdom
-related pseudoachondroplasia (-PSACH) is characterized by normal length at birth and normal facies. Often the presenting feature is a waddling gait, recognized at the onset of walking. Typically, the growth rate falls below the standard growth curve by approximately age two years, leading to a moderately severe form of disproportionate short-limb short stature. Joint pain during childhood, particularly in the large joints of the lower extremities, is common. Degenerative joint disease is progressive; approximately 50% of individuals with -PSACH eventually require hip replacement surgery.
DIAGNOSIS/TESTING: The diagnosis of -PSACH can be made on the basis of clinical findings and radiographic features. Identification of a heterozygous pathogenic variant in on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.
Analgesics for joint pain; encourage physical activities that do not cause excessive wear and/or damage to the joints; osteotomy for lower limb malalignment; rarely, surgery for scoliosis; C1-C2 fixation for symptoms and radiographic evidence of cervical spine instability; attention to and social support for psychosocial issues related to short stature for affected individuals and their families. Assess growth at each visit throughout childhood. Regular examinations for evidence of symptomatic joint hypermobility and/or lower limb malalignment, kyphoscoliosis, degenerative joint disease, and neurologic manifestations, particularly spinal cord compression secondary to odontoid hypoplasia. Assess for psychosocial issues annually or at each visit. In those with odontoid hypoplasia, extreme neck flexion and extension should be avoided.
-PSACH is inherited in an autosomal dominant manner. Some individuals diagnosed with -PSACH have an affected parent. A proband diagnosed with -PSACH may have the disorder as the result of a pathogenic variant. Each child of an individual with -PSACH and a reproductive partner with normal bone growth has a 50% chance of inheriting the pathogenic variant and having -PSACH. Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with -PSACH may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
相关假性软骨发育不全（-PSACH）的特点是出生时身长正常且面容正常。常见的首发症状是蹒跚步态，在开始行走时即可被发现。通常在大约两岁时生长速度低于标准生长曲线，导致中度严重的不成比例的短肢矮小身材。儿童期关节疼痛很常见，尤其是下肢的大关节。退行性关节病呈进行性发展；约50%的-PSACH患者最终需要进行髋关节置换手术。
诊断/检测：-PSACH的诊断可基于临床发现和影像学特征。如果临床特征不明确，分子基因检测中鉴定出相关杂合致病变异可确立诊断。
使用镇痛药缓解关节疼痛；鼓励进行不会对关节造成过度磨损和/或损伤的体育活动；对下肢畸形进行截骨术；很少对脊柱侧弯进行手术；对有颈椎不稳定症状和影像学证据的患者进行C1-C2固定；关注并为受影响个体及其家庭提供与身材矮小相关的心理社会问题的社会支持。在整个儿童期每次就诊时评估生长情况。定期检查是否有症状性关节活动过度和/或下肢畸形、脊柱侧弯、退行性关节病及神经学表现的证据，特别是齿状突发育不全继发的脊髓压迫。每年或每次就诊时评估心理社会问题。对于有齿状突发育不全的患者，应避免过度的颈部屈伸。
-PSACH以常染色体显性方式遗传。一些被诊断为-PSACH的个体有患病的父母。一名被诊断为-PSACH的先证者可能因相关致病变异而患病。一名患有-PSACH的个体与一名骨生长正常的生殖伴侣所生的每个孩子都有50%的机会继承相关致病变异并患有-PSACH。由于许多身材矮小的个体选择身材矮小的生殖伴侣，-PSACH患者的后代可能有患两种显性遗传骨生长障碍双重杂合性的风险。一旦在受影响的家庭成员中鉴定出相关致病变异，产前和植入前基因检测是可行的。
