Center for Autonomic Medicine in Pediatrics, Ann and Robert H. Lurie Children's Hospital, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Am J Med Genet A. 2012 Sep;158A(9):2297-301. doi: 10.1002/ajmg.a.35499. Epub 2012 Jul 20.
Congenital central hypoventilation syndrome (CCHS), a rare disorder characterized by alveolar hypoventilation and autonomic dysregulation, is caused by mutations in the PHOX2B gene. Most mutations occur de novo, but recent evidence suggests that up to 25% are inherited from asymptomatic parents with somatic mosaicism for these mutations. However, to date, germline mosaicism has not been reported. This report describes a family with recurrence of PHOX2B mutation-confirmed CCHS due to germline mosaicism. The first occurrence was a baby girl, noted on day 2 of life to have multiple episodes of apnea, bradycardia, and cyanosis while breathing room air. PHOX2B gene testing confirmed the diagnosis of CCHS with a heterozygous polyalanine repeat expansion mutation (PARM); genotype 20/27 (normal 20/20). Both parents tested negative for this mutation using fragment analysis (limit of detection<1%). Upon subsequent pregnancy [paternity confirmed using short tandem repeat (STR) analysis], amniocentesis testing identified the PHOX2B 20/27 genotype, confirmed with repeat testing. Elective abortion was performed at 21.5 weeks gestation. Testing of abortus tissue confirmed amniocentesis testing. The PHOX2B 20/27 expansion was not observed in a paternal sperm sample. This case represents the first reported family with recurrence of PHOX2B mutation-confirmed CCHS without detection of a parental carrier state or mosaicism, confirming the previously hypothesized possibility of germline mosaicism for PHOX2B mutations. This is an important finding for genetic counseling of CCHS families, suggesting that even if somatic mosaicism is not detected in parental samples, there is still reason for careful genetic counseling and consideration of prenatal testing during subsequent pregnancies.
先天性中枢性低通气综合征（CCHS）是一种罕见的疾病，其特征为肺泡通气不足和自主神经失调，由 PHOX2B 基因突变引起。大多数突变是从头发生的，但最近的证据表明，高达 25%的突变是由无症状的父母遗传而来，这些父母存在这些突变的体细胞核镶嵌现象。然而，迄今为止，尚未报道生殖细胞镶嵌现象。本报告描述了一个家族中由于生殖细胞镶嵌现象而导致 PHOX2B 突变确认的 CCHS 复发。首次发生是一个女婴，在出生后第 2 天，在呼吸空气时出现多次呼吸暂停、心动过缓和发绀。PHOX2B 基因检测证实 CCHS 的诊断为杂合性多聚丙氨酸重复扩展突变（PARM）；基因型 20/27（正常 20/20）。使用片段分析（检测限<1%），父母双方均未检测到该突变。随后的妊娠[使用短串联重复（STR）分析确认父亲身份]中，羊膜穿刺术检测到 PHOX2B 20/27 基因型，重复检测后证实。在 21.5 周妊娠时进行选择性流产。流产组织检测证实了羊膜穿刺术检测结果。在父亲的精子样本中未观察到 PHOX2B 20/27 扩展。该病例代表了第一个报道的家族中，在未检测到父母携带状态或镶嵌现象的情况下，PHOX2B 突变确认的 CCHS 复发，证实了先前假设的 PHOX2B 突变生殖细胞镶嵌的可能性。这对于 CCHS 家族的遗传咨询是一个重要的发现，表明即使在父母样本中未检测到体细胞核镶嵌现象，仍有理由进行仔细的遗传咨询，并在随后的妊娠中考虑产前检测。
