PORCN-related microphthalmia with limb anomalies: case report and literature review.
PORCN-related microphthalmia with limb anomalies: case report and literature review.
复制标题
PORCN 相关的小眼畸形伴肢体异常：病例报告和文献综述。
DOI：
10.1002/ajmg.a.63048
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发表时间：
2023
期刊：
影响因子：
2
通讯作者：
Nagasaki K
中科院分区：
文献类型：
--
作者：
Fukahori K;Yamoto K;Saitsu H; Ogata T;Nagasaki K
致编辑 尽管 Xp11 上的 PORCN（豪猪 O-酰基转移酶）存在种系衍生的致病性变异。 23 种已知会导致局灶性真皮发育不全 (FDH)（别名，Goltz-Gorlin 综合征）(OMIM# 305600)，被认为是一种明显 X 连锁的显性男性致死性疾病（Bostwick 等人，2016），最近的研究表明，几种种系衍生的 PORCN 变体可导致明显的 X 连锁隐性遗传性疾病，其表型异常 半合子雄性和杂合性雌性正常表型（Arlt et al., 2022；Brady et al., 2015；Madan et al., 2017；Wawrocka et al., 2021）。迄今为止，据报道，受影响的男性经常表现出小眼症，并经常表现出肢体异常，但总是缺乏皮肤（外胚层）病变。因此，根据“临床基因组学中诊断实体描述的二元方法”，该方法建议使用“GENE相关表型描述符”风格来描述孟德尔疾病（Biesecker等，2021），这种情况将被指定为“PORCN相关的肢体异常小眼症（MLA）”，而Happle（2021）则 建议将此病症命名为“PORCN 非戈尔茨谱（PONGOS）”。在这里，我们报告了一名患有 PORCN 相关 MLA 的日本男孩，并回顾了已发表的患有这种疾病的男性表型。我们之前为 97 个家庭进行的手足畸形 (SHFM) 项目的报告中简要记录了这个男孩和他的父母，但没有详细的表型描述（Yamoto 等人，2019 年的第 35 号家庭）。先证者（图 1a 中的 II-2）在妊娠 40 周时出生，经过简单的妊娠和分娩。他的出生身长为 43.5 厘米（±3.3 标准差），出生体重为 2.11 公斤（±3.4 标准差）。出生后不久，他被发现患有双侧小眼症、肢体畸形（左手3-4并指和多指畸形，双足外指畸形）和双侧隐睾（图1b）。他表现出生长障碍、发育迟缓和肌张力低下，直到 11 个月大时才能够控制自己的头部。在2、10/12岁时，对严重身材矮小（±4.4SD）和隐睾进行内分泌研究和脑磁共振成像，表明生长激素、促甲状腺激素和促性腺激素分泌正常，以及轻度垂体发育不全。在 10 岁、10/12 岁时的最后一次检查中，他测量的身高为 109.4 厘米（±4.9 标准差），体重为 12.9 公斤（±8.5 标准差）。他可以自己站立，但没有支撑就无法行走。他只能遵循两步指示并说出两到三个单词的句子。值得注意的是，该患者没有发现皮肤病变。母亲的表型正常，没有任何眼部或肢体受累，父亲和姐姐也是如此。我们使用该患者及其父母的外周血白细胞样本进行了遗传学研究。这项研究得到了滨松大学医学院机构审查委员会的批准，并在获得书面知情同意后进行。 G 带分析显示所有 50 个淋巴细胞的核型均为 46, XY，阵列综合基因组杂交显示没有致病性拷贝数变异。因此，进行了全外显子组测序（WES），鉴定了 PORCN 外显子 4 处的母系遗传半合子变异（NM_203475.3: c. 368T> G: p.(Met123Arg)），并通过 Sanger 直接测序证实（图 1C）（Yamoto 等人，2019）。本研究中使用的数据库中完全不存在该变体，并且本研究中使用的计算机预测预测该变体是有害的或具有破坏性的
To the Editor Although germline-derived pathogenic variants in PORCN (porcupine O-acyltransferase) on Xp11. 23 are known to cause focal dermal hypoplasia (FDH)(alias, Goltz-Gorlin syndrome)(OMIM# 305600) recognized as an apparently X-linked dominant male-lethal disorder (Bostwick et al., 2016), recent studies have revealed that several germline-derived PORCN variants lead to an apparently X-linked recessive disorder, with an abnormal phenotype in hemizygous males and a normal phenotype in heterozygous females (Arlt et al., 2022; Brady et al., 2015; Madan et al., 2017; Wawrocka et al., 2021). Affected males reported to date frequently exhibit microphthalmia and often manifest limb anomalies, but invariably lack skin (ectodermal) lesions. Thus, according to “A dyadic approach to the delineation of diagnostic entities in clinical genomics” which recommends the delineation of Mendelian disorders with a “GENE-related phenotype descriptor” style (Biesecker et al., 2021), this condition would be designated as “PORCN-related microphthalmia with limb anomalies (MLA),” while Happle (2021) has suggested a distinct disease name of “PORCN non-Goltz spectrum (PONGOS)” for this condition. Here, we report a Japanese boy with PORCN-related MLA and review the published phenotype in affected males with this condition. This boy and his parents have been documented briefly in our previous report on the split-hand/foot malformation (SHFM) project performed for 97 families, without detailed phenotypic description (Family# 35 in Yamoto et al., 2019). The proband (II-2 in Figure 1a) was born at 40 weeks of gestation after an uncomplicated pregnancy and delivery. His birth length was 43.5 cm (À3. 3 SD), and his birth weight 2.11 kg (À3. 4 SD). Shortly after birth, he was found to have bilateral microphthalmia, limb malformations (3–4 syndactyly and polydactyly of the left hand, and bilateral ectrodactyly of the feet), and bilateral cryptorchidism (Figure 1b). He showed growth failure, developmental delay, and hypotonia and was unable to control his head until 11 months of age. At 2, 10/12 years of age, endocrine studies and brain magnetic resonance imaging were performed for severe short stature (À4. 4 SD) and cryptorchidism, indicating normal secretions of growth hormone, thyrotropin, and gonadotropins, and mild pituitary hypoplasia. On the last examination at 10, 10/12 years of age, he measured 109.4 cm (À4. 9 SD) and weighed 12.9 kg (À 8.5 SD). He could stand by himself but was unable to walk without support. He was just able to follow two-step directions and speak twoto-three-word sentences. Notably, no skin lesion was identified in this patient. The mother had a normal phenotype, without any ocular or limb involvement, as did the father and elder sister. We performed genetic studies using peripheral leukocyte samples of this patient and the parents. This study was approved by the Institutional Review Board Committee at Hamamatsu University School of Medicine, and was performed after obtaining written informed consent. G-banding analysis showed a 46, XY karyotype in all the 50 lymphocytes examined, and array comprehensive genomic hybridization revealed no pathogenic copy number variants. Thus, whole exome sequencing (WES) was carried out, identifying a maternally inherited hemizygous variant at exon 4 of PORCN (NM_203475. 3: c. 368T> G: p.(Met123Arg)), which was confirmed by Sanger direct sequencing (Figure 1C)(Yamoto et al., 2019). This variant was completely absent from the databases utilized in this study and was predicted to be deleterious or damaging by the in silico predictions employed in this study