Supplementary Material for: Hallermann-Streiff Syndrome: No Evidence for a Link to Laminopathies

Hallermann-Streiff syndrome (HSS) is a rare inherited disorder characterized by malformations of the cranium and facial bones, congenital cataracts, microphthalmia, skin atrophy, hypotrichosis, proportionate short stature, teeth abnormalities, and a typical facial appearance with prominent forehead, small pointed nose, and micrognathia. The genetic cause of this developmental disorder is presently unknown. Here we describe 8 new patients with a phenotype of HSS. Individuals with HSS present with clinical features overlapping with some progeroid syndromes that belong to the laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia (MAD). HGPS is caused by de novo point mutations in the <i>LMNA</i> gene, coding for the nuclear lamina proteins lamin A and C. MAD with type A and B lipodystrophy are recessive disorders resulting from mutations in <i>LMNA</i> and <i>ZMPSTE24</i>, respectively. <i>ZMPSTE24</i> in addition to <i>ICMT </i>encode proteins involved in posttranslational processing of lamin A. We hypothesized that HSS is an allelic disorder to HGPS and MAD. As the nuclear shape is often irregular in patients with <i>LMNA</i> mutations, we first analyzed the nuclear morphology in skin fibroblasts of patients with HSS, but could not identify any abnormality. Sequencing of the genes <i>LMNA, ZMPSTE24</i> and<i> ICMT</i> in the 8 patients with HSS revealed the heterozygous missense mutation c.1930C&gt;T (p.R644C) in <i>LMNA</i> in 1 female. Extreme phenotypic diversity and low penetrance have been associated with the p.R644C mutation. In <i>ZMPSTE24</i> and <i>ICMT</i>, no pathogenic sequence change was detected in patients with HSS. Together, we found no evidence that HSS is another laminopathy.

Hallermann-Streiff综合征（Hallermann-Streiff syndrome, HSS）是一种罕见的遗传性疾病，以颅骨与面部骨骼畸形、先天性白内障、小眼球症、皮肤萎缩、毛发稀少、比例性身材矮小、牙齿异常，以及典型的面部特征：前额突出、尖小鼻与小颌畸形为主要表现。目前该发育性疾病的遗传病因尚未明确。本文报道8例表现为HSS表型的新增患者。HSS患者的临床特征与部分隶属于核纤层病（laminopathies）的早衰综合征（progeroid syndromes）存在重叠，例如哈钦森-吉尔福德早衰综合征（Hutchinson-Gilford progeria syndrome, HGPS）与下颌骨-肢端发育不良综合征（mandibuloacral dysplasia, MAD）。哈钦森-吉尔福德早衰综合征由LMNA基因的新发点突变引起，该基因编码核纤层蛋白A与核纤层蛋白C。伴A型与B型脂肪营养不良的下颌骨-肢端发育不良综合征分别为LMNA与ZMPSTE24基因突变导致的隐性遗传病。ZMPSTE24与ICMT均可编码参与核纤层蛋白A翻译后修饰的蛋白质。我们推测HSS与哈钦森-吉尔福德早衰综合征、下颌骨-肢端发育不良综合征属于等位基因病。鉴于携带LMNA基因突变的患者常出现细胞核形态异常，我们首先对HSS患者皮肤成纤维细胞的细胞核形态进行了分析，但未发现任何异常。对8例HSS患者的LMNA、ZMPSTE24及ICMT基因进行测序后，在1名女性患者的LMNA基因中检出杂合错义突变c.1930C>T（p.R644C）。p.R644C突变已被证实与显著的表型多样性及低外显率相关。在ZMPSTE24与ICMT基因中，未检测到致病性序列变异。综上，我们未发现HSS属于另一类核纤层病的相关证据。