Introduction

Peroxisomal D-bifunctional protein (DBP) deficiency is an autosomal recessive disorder historically described as a Zellweger-like syndrome comprising neonatal seizures, retinopathy, hearing loss, dysmorphic features, and other complications. The HSD17B4 gene encodes DBP which is essential for oxidation of peroxisomal substrates. We describe 4 patients - 2 unrelated female girls and 2 monozygotic twin sisters - with DBP deficiency and phenotypic diversity.

Patient reports

Patient 1 presented neonatally with hypotonia and seizures, and later on developed global developmental delay and regression, sensorineural hearing loss, nystagmus and cortical blindness. The brain MRI demonstrated bilateral peri-sylvian polymicrogyria. Whole exome sequencing revealed 2 mutations in the HSD17B4 gene (c.752G>A, p.(Arg251Gln); c.868 + 1delG).

Patient 2 presented with hypotonia, motor delay, and sensorineural hearing loss in infancy, considerable developmental regression during her fourth year, nystagmus, and peripheral neuropathy. Brain MRI demonstrated cerebellar atrophy and abnormal basal ganglia and white matter signal, which appeared after the age of two years. Whole exome sequencing revealed 2 mutations in the HSD17B4 gene (c.14 T>G, p.(Leu5Arg); c.752G>A, p.(Arg251Gln)).

Patients 3 and 4, two female monozygotic twins, presented with hypotonia, developmental delay, and macrocephaly from birth, and later on also sensorineural hearing loss, infantile spasms and hypsarrhythmia, and adrenal insufficiency. Brain MRI demonstrated delayed myelination, and an assay of peroxisomal beta oxidation suggested DBP deficiency. Sequencing of the HSD17B4 gene revealed the same 2 mutations as in patient 1.

Discussion

We describe 4 patients with variable and diverse clinical picture of DBP deficiency and particularly emphasize the clinical, biochemical, and neuroimaging characteristics. Interestingly, the clinical phenotype varied even between patients with the exact two mutations in the HSD17B4 gene. In addition, in two of the three patients in whom levels of VLCFA including phytanic acid were measured, the levels were within normal limits. This is expanding further the clinical spectrum of this disorder, which should be considered in the differential diagnosis of every patient with hypotonia and developmental delay especially if accompanied by polymicrogyria, seizures, sensorineural hearing loss, or adrenal insufficiency regardless of their VLCFA profile.

中文翻译：

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四名患有 D-双功能蛋白 (DBP) 缺乏症的患者：扩大高度可变疾病的表型谱。

介绍

过氧化物酶体 D-双功能蛋白 (DBP) 缺乏症是一种常染色体隐性遗传疾病，历史上被描述为齐薇格样综合征，包括新生儿癫痫发作、视网膜病变、听力丧失、畸形特征和其他并发症。HSD17B4基因编码对过氧化物酶体底物氧化至关重要的 DBP 。我们描述了 4 名患者 - 2 名无关的女性女孩和 2 名同卵双胞胎姐妹 - 患有 DBP 缺乏和表型多样性。

患者报告

患者 1 出现新生儿肌张力减退和癫痫发作，后来出现整体发育迟缓和退化、感觉神经性听力损失、眼球震颤和皮质盲。脑部 MRI 显示双侧外侧裂周多小脑回。全外显子组测序揭示了HSD17B4基因中的 2 个突变（c.752G>A，p.（Arg251Gln）；c.868 + 1delG）。

患者 2 在婴儿期出现肌张力减退、运动迟缓和感觉神经性听力损失，在她的第四年出现相当大的发育退化、眼球震颤和周围神经病变。脑部 MRI 显示小脑萎缩，基底节和白质信号异常，出现在 2 岁以后。全外显子组测序揭示了HSD17B4基因中的 2 个突变（c.14 T>G，p.（Leu5Arg）；c.752G>A，p.（Arg251Gln））。

患者 3 和 4，两个女性同卵双胞胎，从出生就出现肌张力减退、发育迟缓和大头畸形，后来还出现感觉神经性听力损失、婴儿痉挛和心律失常以及肾上腺功能不全。脑 MRI 显示髓鞘形成延迟，过氧化物酶体 β 氧化分析表明 DBP 缺乏。HSD17B4基因的测序揭示了与患者 1 相同的 2 个突变。

讨论

我们描述了 4 名患者，其 DBP 缺乏症的临床表现各不相同，并特别强调了临床、生化和神经影像学特征。有趣的是，即使在HSD17B4基因中有两个完全突变的患者之间，临床表型也有所不同。此外，在测量了包括植烷酸在内的 VLCFA 水平的三名患者中，有两名患者的水平在正常范围内。这进一步扩大了这种疾病的临床范围，在对每个患有肌张力减退和发育迟缓的患者进行鉴别诊断时应考虑到这一点，特别是如果伴有多小脑回、癫痫、感觉神经性听力损失或肾上腺功能不全，无论其 VLCFA 谱如何。