Programa de Pós-graduação em Medicina e Saúde Humana, Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil.
Hospital University Hospital Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Bahia, Brazil.
JAMA Netw Open. 2021 May 3;4(5):e219878. doi: 10.1001/jamanetworkopen.2021.9878.
The Zika virus infects progenitor neuron cells, disrupts cerebral development, and, in mice, drives hypothalamic defects. Patients with microcephaly caused by congenital Zika infection present with midline cerebral defects, which may result in hypopituitarism.
To analyze postnatal growth and the presence of clinical and biochemical features associated with hypopituitarism in children with congenital Zika infections.
DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study at 2 public referral hospitals in Bahia, Brazil, specializing in the treatment of congenital Zika infection, clinical data and growth parameters of 65 patients with the infection were evaluated. Data were analyzed from April 2017 through July 2018.
Congenital Zika infection.
Length, weight, and head circumference were measured at birth and during follow up (ie, at 27 months of life) for each patient. Basal levels of free thyroxine, thyrotropin, cortisol, corticotropin, prolactin, insulin-like growth factor 1, insulin-like growth factor binding protein 3, urine and plasma osmolality, electrolytes, glucose, and insulin were evaluated at the age of 26 months to 28 months. All patients underwent central nervous system computed tomography scans and ophthalmic and otoacoustic evaluations at the time of this investigation or had done so previously.
Among 65 patients (38 [58.4%] male; median [interquartile range] age at enrollment, 27 [26-28] months), 61 patients presented with severe brain defects (93.8%), including corpus callosum agenesis or hypoplasia (ie, midline brain defects; 25 patients [38.5%]) and optic nerve atrophy (38 patients [58.5%]). Most patients presented with severe neurodevelopmental delay (62 of 64 patients [96.9%]). Past or present clinical signs of hypopituitarism were rare, occurring in 3 patients (4.6%). Severe microcephaly, compared with mild or moderate microcephaly, was associated with a shorter length by median (interquartile range) z score at birth (-1.9 [-2.5 to -1.0] vs -0.3 [-1.0 to 0]; P < .001), but this difference did not persist at 27 months (-1.6 [-2.3 to -0.3] vs -2.9 [-4.0 to -1.2]; P = .06). Growth hormone deficiency or hypothyroidism were not observed in any patients, and glucose and insulin levels were within reference ranges for all patients. Low cortisol levels (ie, below 3.9 µg/dL) were observed in 4 patients (6.2%). These 4 patients presented with low (ie, below 7.2 pg/mL) or inappropriately low (ie, below 30 pg/mL) corticotropin levels. Low corticotropin levels (ie, below 7.2 pg/mL) were observed in 6 patients (9.2%). Diabetes insipidus was evaluated in 21 patients; it was confirmed in 1 patient (4.8%) and suggested in 3 patients (14.3%).
This study found that congenital Zika infection with microcephaly was associated with midline brain defects and optic nerve atrophy. Children with congenital Zika infections presented with prenatal growth impairments with a lack of postnatal catch-up, as shown by persistent short length from birth until 27 months; these impairments were not associated with growth hormone deficiency. Patients also presented with severe developmental delay that was not associated with hypothyroidism, while central adrenal insufficiency and diabetes insipidus occurred in some patients.
寨卡病毒感染祖细胞，扰乱大脑发育，并在小鼠中导致下丘脑缺陷。先天性寨卡病毒感染引起的小头畸形患者存在中线脑缺陷，这可能导致垂体功能减退。
分析先天性寨卡病毒感染患儿的出生后生长情况，以及与垂体功能减退相关的临床和生化特征。
设计、地点和参与者：在巴西巴伊亚州 2 家专门治疗先天性寨卡病毒感染的公立转诊医院进行的这项前瞻性队列研究中，评估了 65 名感染患者的临床数据和生长参数。数据分析于 2017 年 4 月至 2018 年 7 月进行。
先天性寨卡病毒感染。
对每位患者在出生时和随访期间（即 27 个月龄）测量身长、体重和头围。在 26 至 28 个月龄时评估基础游离甲状腺素、促甲状腺素、皮质醇、促肾上腺皮质激素、催乳素、胰岛素样生长因子 1、胰岛素样生长因子结合蛋白 3、尿液和血浆渗透压、电解质、血糖和胰岛素水平。所有患者在本次检查时或之前均接受了中枢神经系统计算机断层扫描和眼科及耳声发射评估。
在 65 名患者（38 名[58.4%]为男性；中位[四分位间距]年龄为 27 [26-28] 个月）中，61 名患者存在严重的脑缺陷（93.8%），包括胼胝体发育不全或发育不良（即中线脑缺陷；25 名患者[38.5%]）和视神经萎缩（38 名患者[58.5%]）。大多数患者存在严重的神经发育迟缓（64 名患者中的 62 名[96.9%]）。过去或现在的垂体功能减退的临床症状罕见，仅见于 3 名患者（4.6%）。与轻度或中度小头畸形相比，严重小头畸形患者的出生时长度中位数（四分位间距）z 评分更短（-1.9 [-2.5 至-1.0]比-0.3 [-1.0 至 0]；P<0.001），但在 27 个月龄时这种差异并不持续（-1.6 [-2.3 至-0.3]比-2.9 [-4.0 至-1.2]；P=0.06）。所有患者均未观察到生长激素缺乏或甲状腺功能减退，血糖和胰岛素水平均在参考范围内。4 名患者（6.2%）皮质醇水平较低（即<3.9μg/dL）。这 4 名患者的促肾上腺皮质激素水平较低（即<7.2pg/mL）或不适当低（即<30pg/mL）。6 名患者（9.2%）的促肾上腺皮质激素水平较低（即<7.2pg/mL）。对 21 名患者进行了尿崩症评估；1 名患者（4.8%）确诊，3 名患者（14.3%）疑似。
本研究发现，伴有中线脑缺陷和视神经萎缩的先天性寨卡病毒感染与小头畸形相关。先天性寨卡病毒感染患儿存在产前生长受损，且缺乏出生后追赶生长，出生至 27 个月的身长一直较短；这些受损与生长激素缺乏无关。患儿还存在严重的发育迟缓，与甲状腺功能减退无关，而一些患者出现中枢性肾上腺功能不全和尿崩症。
