背景:已知WDR35变异体可导致一种罕见的常染色体隐性遗传疾病-颅外胚层发育不良(CED)。CED患者通常存在面部畸形(额叶和低沉的耳朵),矢状颅骨融合,生长迟缓,dolichocephaly,骨骼畸形(短指,手指和狭窄的胸部末端发育不全),外胚层异常(稀疏的头发,和手指/脚趾指甲发育不良),肾单位,视网膜营养不良和肝纤维化。CED的诊断可能很困难,因为它具有高度的遗传异质性。然而,我们对由WDR35变异引起的CED表型的理解可能更明确,基因型与表型的相关性有待进一步提高。
方法:我们报告了首例由WDR35变异引起的CED患者,一个3岁3个月大的病人,他被送进我们医院,生长迟缓,低耳朵,dolichocephaly,稀疏的头发,和小四肢,肾功能异常,和中度贫血。除了表现出典型的CED特征外,该儿童表现出异位睾丸的新表型,并鉴定出具有新的复合杂合WDR35变体(c.2590C>T,p.Gln864*andc.2408_2416del,p.Asn803_Ala805del;NM_001006657)。他被给予琥珀酸铁和促红细胞生成素,以改善贫血,并通过酸校正抑制反复代谢性酸中毒和高钾血症,利尿剂,和降钾治疗。父母拒绝接受孩子的肾脏替代疗法,并自愿出院。
结论:这是首例报道的WDR35变种可导致CED和异位睾丸的病例,这也是首例与WDR35变异相关的中国患者。这项研究扩展了我们对WDR35变异患者基因型-表型关联的理解,并为预防和干预这种遗传性疾病提供了遗传咨询。新生儿携带者应对肾脏和CED相关疾病进行随访,以发现警告信号。
WDR35 variants are known to cause a rare autosomal recessive disorder-Cranioectodermal dysplasia (CED). The CED patients are commonly present with facial dysmorphisms (frontal bossing and low-set ears), sagittal craniosynostosis, growth retardation, dolichocephaly, skeletal deformities (brachydactyly, terminal hypoplasia of the fingers and narrow thorax), ectodermal abnormalities (sparse hair, and finger/toe nail dysplasia), nephronophthisis, retinal dystrophy and hepatic fibrosis. Diagnosis of CED can be difficult because it presents with high genetic heterogeneity. However, our understanding of the phenotype of CED caused by WDR35 variants could be more explicit, and the correlation between genotype and phenotype needs further improvement.
We report a case of the first Chinses patient of CED caused by WDR35 variants, a 3-year-and-3-month-old patient, who was admitted to our hospital with frontal bossing, growth retardation, low set ears, dolichocephaly, sparse hair, and small limbs, abnormal renal function, and moderate anemia. The child showed a novel phenotype of the ectopic testis except for presenting typical CED characteristics, and he was identified with novel compound heterozygous WDR35 variants (c.2590 C > T, p.Gln864* and c.2408_2416del, p.Asn803_Ala805del; NM_001006657). He was given iron succinate and erythropoietin to improve anemia and to inhibit repeated metabolic acidosis and hyperkalemia through acid correction, diuretic, and potassium-lowering treatments. The parents refused to accept renal replacement therapy for their child and were discharged voluntarily.
This is the first reported case of the WDR35 variants that can lead to CED and ectopic testis, which is also the first Chinese patient associated with WDR35 variants. This study expands our understanding of genotype-phenotype association in patients with WDR35 variants and provides genetic counseling for prevention and intervention in this genetic disorder. Neonatal carriers should be followed up for kidney and CED-related diseases to detect warning signs.