Jecan-Toader Diana, Trifa Adrian, Lucian Bogdan, Pop Tudor Lucian, Cainap Simona Sorana
Medical Oncology Discipline, Department of Oncology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
2nd Pediatric Clinic, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania.
Front Pediatr. 2024 Sep 25;12:1463903. doi: 10.3389/fped.2024.1463903. eCollection 2024.
Alström disease is a rare disorder caused by various variants in the ALMS1 gene. It is characterised by multiorgan involvement, namely neurosensory deficits, endocrine and metabolic disturbances, cardiomyopathy, and hepatic and renal dysfunction. The disease exhibits marked interindividual variability, both in clinical manifestations and age of onset. Several attempts have been made to establish a relationship between phenotype and genotype, with little success.
We present the case of an infant who presented with dilated cardiomyopathy, above-average weight and neurosensory deficits, raising the suspicion for Alström syndrome, later confirmed through genetic testing. Moreover, we conducted an extensive literature search to identify all reported cases having the same variant as our patient, in order to evaluate whether specific mutated alleles have a role in determining phenotype-genotype associations.
A 4-month-old female infant with a recent history of bronchiolitis was referred to our centre due to a systolic murmur. In our service, the clinical exam was significant for above-average weight, dyspnea, wheezing and a grade II systolic murmur. Echocardiography revealed dilated cardiomyopathy with severe systolic dysfunction of the left ventricle. Laboratory investigations revealed elevated NT-proBNP and troponin levels, along with positive IgM antibodies for CMV and EBV. Dilated cardiomyopathy attributed to viral myocarditis was suspected. Treatment with ACE inhibitors and diuretics was started, with a favourable response initially. However, after a few months, the patient presented with vertical nystagmus and head bobbing. The ophthalmologic exam revealed cone-rode dystrophy. Considering the constellation of symptoms, Alström syndrome was suspected. Genetic testing revealed a homozygous variant [c.4156dup (p.Thr1386Asnfs*15)] in the ALMS1 gene, confirming the diagnosis.
Our literature review revealed 8 additional cases harbouring the same variant as our patient, five in a heterozygous state, two in a homozygous state and one with only one allele identified. The identified patients presented high heterogeneity of clinical manifestations and age of onset. The heterogeneity persisted even in patients with homozygous variants, suggesting the involvement of factors beyond the specific disease-causing variant in determining disease manifestation. Therefore, genotype-phenotype correlations might not be supported by specific variants.
阿尔斯特伦综合征是一种由ALMS1基因的各种变异引起的罕见疾病。其特征是多器官受累，即神经感觉缺陷、内分泌和代谢紊乱、心肌病以及肝肾功能障碍。该疾病在临床表现和发病年龄上均表现出明显的个体差异。人们曾多次尝试建立表型与基因型之间的关系，但收效甚微。
我们报告了一例婴儿病例，该婴儿表现为扩张型心肌病、体重高于平均水平和神经感觉缺陷，引发了对阿尔斯特伦综合征的怀疑，后来通过基因检测得以证实。此外，我们进行了广泛的文献检索，以确定所有报告的与我们患者具有相同变异的病例，以便评估特定的突变等位基因是否在决定表型 - 基因型关联中起作用。
一名近期有细支气管炎病史的4个月大女婴因收缩期杂音被转诊至我们中心。在我们科室，临床检查发现体重高于平均水平、呼吸困难、喘息以及二级收缩期杂音。超声心动图显示扩张型心肌病，左心室严重收缩功能障碍。实验室检查显示NT - proBNP和肌钙蛋白水平升高，同时巨细胞病毒和EB病毒的IgM抗体呈阳性。怀疑为病毒性心肌炎所致的扩张型心肌病。开始使用血管紧张素转换酶抑制剂和利尿剂治疗，最初反应良好。然而，几个月后，患者出现垂直性眼球震颤和点头动作。眼科检查发现圆锥 - 视杆营养不良。考虑到一系列症状，怀疑为阿尔斯特伦综合征。基因检测显示ALMS1基因存在纯合变异[c.4156dup (p.Thr1386Asnfs*15)]，确诊为该病。
我们的文献综述发现另外8例与我们患者具有相同变异的病例，其中5例为杂合状态，2例为纯合状态，1例仅鉴定出一个等位基因。已确定的患者临床表现和发病年龄具有高度异质性。即使在纯合变异的患者中，这种异质性仍然存在，这表明在决定疾病表现方面，除了特定的致病变异外，还有其他因素参与其中。因此，特定变异可能无法支持基因型 - 表型的相关性。
