Tucci Arianna, Ronzoni Luisa, Arduino Carlo, Salmin Paola, Esposito Susanna, Milani Donatella
Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano,Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Commenda 9, 20122, Milan, Italy.
S.C.D.U. Genetica Medica, A.O. Città della Salute e della Scienza, Torino, Italy.
BMC Med Genet. 2016 Mar 11;17:22. doi: 10.1186/s12881-016-0287-1.
Smith Lemli Opitz syndrome (SLOS; OMIM #270400) is an autosomal recessive metabolic disorder caused by mutations in the DHCR7 gene. SLOS is characterized by a plethora of abnormalities involving mainly the brain and the genitalia but also the cardiac, skeletal and gastroenteric system, typical dysmorphic facial features, and variable degrees of developmental delay and intellectual disability (ID). SLOS has a broad phenotypic spectrum, ranging from multiple congenital malformation syndrome, to mild developmental delay and minor malformations. A large number of mutations have been described in the DHCR7 gene, with few common mutations accounting for the majority of mutated alleles found in patients and a large number of very rare or even private variants. Due to the wide variety of clinical presentations, diagnosis can be difficult, especially in the milder forms of the disorder. Furthermore, establishing a molecular diagnosis can be complicated by finding variants of unknown clinical significance in such cases.
We report a case of SLOS at the mild end of the clinical spectrum, presenting with bilateral pelvis ectasia, mild dysmorphic features and mild intellectual disability. The case is compound heterozygous for a known pathogenic mutation (c.724C > T, p.Arg242Cys) and a mutation that has only been reported once in a Portuguese patient (c.521 T > C, p.Phe174Ser) whose pathogenicity has not been yet assessed. We compared the two patients carrying the p.Phe174Ser variant and concluded that this variant is associated with mild forms of SLOS.
We report a patient with a mild case of SLOS, highlighting the importance of recognizing subtle anomalies of the genitourinary system, associated with mild dysmorphic features and mild intellectual disability in establishing the diagnosis of mild forms of SLOS. With this report, we confirm the pathogenicity of the p.Phe174Ser variant and we also provide evidence of its association with mild forms of SLOS. This finding further facilitates the establishment of a genotype-phenotype correlation for SLOS. This helps in counselling for this disorder and in predicting therapeutic responses.
史密斯-勒米-奥皮茨综合征（SLOS；OMIM #270400）是一种常染色体隐性代谢紊乱疾病，由DHCR7基因突变引起。SLOS的特征是出现大量异常情况，主要累及大脑和生殖器，但也涉及心脏、骨骼和胃肠系统，具有典型的畸形面部特征，以及不同程度的发育迟缓与智力残疾（ID）。SLOS具有广泛的表型谱，从多发性先天性畸形综合征到轻度发育迟缓和轻微畸形。在DHCR7基因中已描述了大量突变，少数常见突变占患者中发现的大多数突变等位基因，还有大量非常罕见甚至是私人变体。由于临床表现多种多样，诊断可能很困难，尤其是在该疾病的较轻形式中。此外，在这种情况下发现临床意义不明的变体可能会使分子诊断变得复杂。
我们报告了一例处于临床谱较轻端的SLOS病例，表现为双侧肾盂扩张、轻度畸形特征和轻度智力残疾。该病例为复合杂合子，携带一个已知致病突变（c.724C>T，p.Arg242Cys）和一个仅在一名葡萄牙患者中报道过一次的突变（c.521 T>C，p.Phe174Ser），其致病性尚未评估。我们比较了两名携带p.Phe174Ser变体的患者，并得出结论，该变体与SLOS的轻度形式相关。
我们报告了一例轻度SLOS患者，强调了在诊断轻度形式的SLOS时，认识到与轻度畸形特征和轻度智力残疾相关的泌尿生殖系统细微异常的重要性。通过本报告，我们证实了p.Phe174Ser变体的致病性，并且还提供了其与SLOS轻度形式相关的证据。这一发现进一步促进了SLOS基因型与表型相关性的建立。这有助于对该疾病进行咨询并预测治疗反应。
