Third Department of Pediatrics, National & Kapodistrian University of Athens, University General Hospital "Attikon", Medical School, Athens, Greece; Department of Clinical Biochemistry, National & Kapodistrian University of Athens, University General Hospital "Attikon", Medical School, Athens, Greece.
Third Department of Pediatrics, National & Kapodistrian University of Athens, University General Hospital "Attikon", Medical School, Athens, Greece.
Bone. 2021 May;146:115904. doi: 10.1016/j.bone.2021.115904. Epub 2021 Feb 27.
Cleidocranial dysplasia is a dominantly inherited skeletal dysplasia resulting from inherited or spontaneous mutations of Runt-related transcription factor 2 gene (RUNX2). It represents a clinical continuum typically characterized by wide calvarial sutures, clavicular hypoplasia and dental abnormalities. CDD has been rarely associated with skeletal and biochemical features that mimic hypophosphatasia. We report clinical, biochemical and molecular profile of a 3-year-old female with CCD, presented in utero with large cranial defects. She displayed severe parietal dysplasia, wide cranial sutures, clavicular abnormalities and biochemical features of hypophospatasia (HHP). She was preliminary diagnosed with benign perinatal HHP, harboring a likely pathogenic heterozygous TNSALP variant (p.Ser181Leu) inherited by the mother, who also displayed low levels of ALP. Asfotase alfa was introduced for a six-month-period with rather positive impact on cranial ossification. Nevertheless, focal skeletal disease (cranium and clavicles) and absence of clinical symptoms in the mother, carrier of the same genetic variant, posed diagnosis into question and further genetic analysis detected the novel spontaneous frameshift mutation c.1191delC (p.Phe398Leufs86) in RUNX2 gene, establishing the CCD diagnosis. Although genotype-phenotype correlations are difficult, p.Phe398Leufs86 appears to be associated with a severe cranial phenotype and absence of parietal bones, similarly to other adjacent frameshift/splicing mutations. The TNSALP variant (p.Ser181Leu) may contributed to patient's final phenotype, as well as to maternal low ALP levels. However, since low ALP levels have been also reported in few CCD patients with no alterations in TNSALP gene, studies to elucidate RUNX2 and TNSALP interactions could shed more light on differential diagnosis between CCD and HHP, CCD appropriate therapy and genetic counselling. ACCESSION NUMBER: (SUB8185506).
颅锁骨发育不全是一种常染色体显性遗传性骨骼发育不良，由 runt 相关转录因子 2 基因（RUNX2）的遗传或自发突变引起。它代表了一种临床连续体，通常表现为广泛的颅骨缝线、锁骨发育不全和牙齿异常。CDD 很少与模仿低磷酸酶血症的骨骼和生化特征相关。我们报告了一名 3 岁女性 CCD 的临床、生化和分子特征，该患者在宫内表现为大的颅缺损。她表现出严重的顶骨发育不良、宽的颅骨缝线、锁骨异常和低磷酸酶血症的生化特征（HHP）。她初步诊断为良性围产期 HHP，携带可能致病的杂合 TNSALP 变体（p.Ser181Leu），由母亲遗传，母亲也显示出 ALP 水平低。阿法特酶阿尔法被引入六个月，对颅骨骨化有相当积极的影响。然而，母亲（同一遗传变异的携带者）的局灶性骨骼疾病（颅骨和锁骨）和缺乏临床症状引起了诊断的质疑，进一步的遗传分析检测到 RUNX2 基因中 novel 自发框移突变 c.1191delC（p.Phe398Leufs86），确立了 CCD 的诊断。尽管基因型-表型相关性很困难，但 p.Phe398Leufs86 似乎与严重的颅骨表型和顶骨缺失有关，类似于其他相邻的框移/剪接突变。TNSALP 变体（p.Ser181Leu）可能导致患者的最终表型，以及母亲的低 ALP 水平。然而，由于在没有 TNSALP 基因改变的少数 CCD 患者中也报道了低 ALP 水平，因此研究 RUNX2 和 TNSALP 相互作用可以更清楚地阐明 CCD 和 HHP 之间的鉴别诊断、CCD 的适当治疗和遗传咨询。注册号：（SUB8185506）。
