Supplementary Material for: Two Siblings with Kaufman Oculocerebrofacial Syndrome Resembling Oculoauriculovertebral Spectrum

Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder which represents a phenotype mainly involving craniofacial and neurodevelopmental manifestations due to UBE3B gene mutations. The vast majority of the affected individuals exhibit microcephaly, eye abnormalities, and typical facial gestalt including blepharophimosis, ptosis, telecanthus, upslanting palpebral fissures, dysplastic ears, and micrognathia. We encountered 2 siblings in whom severe psychomotor delay, distinctive facial features, hearing loss, and respiratory distress were observed. Some clinical manifestations of the patients, including epibulbar dermoid, microtia, and multiple preauricular tags, were reminiscent of the oculoauriculovertebral spectrum. However, 2 affected siblings exhibited a similar clinical picture consisting of microcephaly, severe developmental and cognitive disabilities, failure to thrive, and dysmorphic features, which were not fully consistent with oculoauriculovertebral spectrum. Also, hypoplastic nails, considered as a core manifestation of Coffin-Siris syndrome, were present in our patients. Therefore, whole-exome sequencing was carried out in order to identify the underlying genetic alterations, contributing to the complex phenotype shared by the 2 siblings. A homozygous pathogenic mutation was found in both affected siblings in the UBE3B gene which caused Kaufman oculocerebrofacial syndrome. Kaufman oculocerebrofacial syndrome should be considered among the autosomal recessive causes of blepharophimosis-mental retardation syndromes, particularly in populations with a high rate of consanguineous marriages, even if there are dysmorphic facial features that are not typically associated with the phenotype.考夫曼眼脑面综合征（Kaufman oculocerebrofacial syndrome）是一种罕见的常染色体隐性遗传病，其核心表型主要为因UBE3B基因突变所致的颅面及神经发育异常。绝大多数受累个体表现为小头畸形、眼部异常，以及典型面部整体特征，包括睑裂狭小、上睑下垂、内眦间距增宽、睑裂上斜、耳廓发育异常及小下颌。我们接诊了2例同胞患者，均表现为重度精神运动发育迟缓、特征性面容、听力损失及呼吸窘迫。患者的部分临床表现，包括球结膜皮样瘤、小耳畸形及多发耳前附耳，曾让人联想到眼-耳-脊椎谱系（oculoauriculovertebral spectrum）。然而，这2例受累同胞的临床表现高度相似，均表现为小头畸形、重度发育及认知障碍、生长发育迟缓及畸形面容，但与眼-耳-脊椎谱系的典型表现并不完全吻合。此外，本次收治的患者还出现了被认为是科芬-西里斯综合征（Coffin-Siris syndrome）核心表现的指甲发育不全。因此，我们对患者开展了全外显子组测序（whole-exome sequencing），以明确导致这2例同胞共有的复杂表型的潜在遗传学改变。最终在UBE3B基因中检测到纯合致病性突变，该突变可引发考夫曼眼脑面综合征。综上，在因常染色体隐性遗传导致的睑裂狭小-智力障碍综合征的鉴别诊断中，应考虑考夫曼眼脑面综合征，尤其在近亲婚配率较高的人群中，即便存在与该综合征典型表型不相符的畸形面容特征。