Metopic and sagittal synostosis in Greig cephalopolysyndactyly syndrome: five cases with intragenic mutations or complete deletions of GLI3

Greig cephalopolysyndactyly syndrome (GCPS) is a multiple congenital malformation characterised by limb and craniofacial anomalies, caused by heterozygous mutation or deletion of GLI3. We report four boys and a girl who were presented with trigonocephaly due to metopic synostosis, in association with pre- and post-axial polydactyly and cutaneous syndactyly of hands and feet. Two cases had additional sagittal synostosis. None had a family history of similar features. In all five children, the diagnosis of GCPS was confirmed by molecular analysis of GLI3 (two had intragenic mutations and three had complete gene deletions detected on array comparative genomic hybridisation), thus highlighting the importance of trigonocephaly or overt metopic or sagittal synostosis as a distinct presenting feature of GCPS. These observations confirm and extend a recently proposed association of intragenic GLI3 mutations with metopic synostosis; moreover, the three individuals with complete deletion of GLI3 were previously considered to have Carpenter syndrome, highlighting an important source of diagnostic confusion.     

GLI3‐related polydactyly: a review

GLI3 mutations are known to be associated with nine syndromes/conditions in which polydactyly is a feature. In this review, the embryology, pathogenesis, and animal models of GLI3‐related polydactyly are discussed first. This is followed by a detailed review of the genotype–phenotype correlations. Based on our review of the literature and our clinical experiences, we recommend viewing GLI3‐related syndromes/conditions as four separate entities; each characterized by a specific pattern of polydactyly. These four entities are: the preaxial polydactyly type IV‐Greig‐acrocallosal spectrum, postaxial polydactyly types A/B, Pallister–Hall syndrome (PHS), and oral‐facial‐digital overlap syndrome. We also provide illustrative clinical examples from our practice including a family with a novel GLI3 mutation causing PHS. The review also introduces the term ‘Forme Fruste’ preaxial polydactyly and gives several conclusions/recommendations including the recommendation to revise the current criteria for the clinical diagnosis of PHS.     

Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations

Greig cephalopolysyndactyly (GCPS) (OMIM 175700) is an autosomal dominant disorder characterized by a distinct combination of craniofacial, hand and foot malformations. In this report, clinical and radiological findings of 12 patients with GCPS derived from 4 independent families and 3 sporadic cases with documented GLI3 mutations are presented with particular emphasis on inter- and intrafamilial variability. In a particularly instructive family in which 9 members of 4 generations could be studied clinically and molecularly, a missense mutation (R625W) is transmitted and shows a partially penetrant pattern. In a branch of the family, the GCPS phenotype skips a generation via a normal female carrier without clinical signs providing evidence that GCPS does not always manifest full penetrance as generally supposed.     

Mosaic pathogenic variants in AKT3 cause capillary malformation and undergrowth

Capillary malformations are slow-flow vascular malformations that affect the microcirculation including capillaries and post capillary venules and can be associated with growth differences. Specifically, the association of capillary malformations with undergrowth is a vastly understudied vascular syndrome with few reports of genetic causes including PIK3CA, GNAQ, and GNA11. Recently, a somatic pathogenic variant in AKT3 was identified in one child with a cutaneous vascular syndrome similar to cutis marmorata telangiectatica congenita, undergrowth, and no neurodevelopmental features. Here, we present a male patient with a capillary malformation and undergrowth due to a somatic pathogenic variant in AKT3 to confirm this association. It is essential to consider that mosaic pathogenic variants in AKT3 can cause a wide spectrum of disease. There is a need for future studies focusing on capillary malformations with undergrowth to understand the underlying mechanism.     

GLI3基因与单纯性马蹄内翻足的关联分析及其突变筛查

目的对GLU基因与单纯性马蹄内翻足进行关联分析和突变筛查，探讨GLU基因与单纯性马蹄内翻足的相关性。方法应用限制性片段长度多态性分析技术，分析84个单纯性马蹄内翻足核心家系中GLI3基因内两个单核苷酸多态（single nucleotide polymorphisms, SNP）位点的基因型，并应用ETDT软伯统计分析各SNP位点基因型与单纯性马蹄内翻足的关联；应用变性梯度凝胶电泳技术对103例单纯性马蹄内翻足患者GLI3基因的第9至12外显子进行突变筛查。结果经ETDT分析，位于GLI3基因第4外显子的cSNP rs846266差异无统计学意义（χ^2=3．3582，P〉0．05）；第14外显子的cSNP rs929387差异有统计学意义（χ^2=7．2466，P〈0．05），在单纯性马蹄内翻足核心家系中存在传递不平衡；发现1例患者及其母亲的第9外显子有108（G→A）的同义点突变。结论GLI3基因与单纯性马蹄内翻足相关，其第9至12外显子可能并非该病的突变热点。     

A specific mutation in the distant sonic hedgehog (SHH) cis‐regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb

Werner mesomelic syndrome (WMS) is an autosomal dominant disorder with unknown molecular etiology characterized by hypo‐ or aplasia of the tibiae in addition to the preaxial polydactyly (PPD) of the hands and feet and/or five‐fingered hand with absence of thumbs. We show that point mutations of a specific nucleotide within the sonic hedgehog (SHH) regulatory region (ZRS) cause WMS. In a previously unpublished WMS family, we identified the causative G>A transition at position 404 of the ZRS, and in six affected family members of a second WMS family we found a 404G>C mutation of the ZRS. The 404G>A ZRS mutation is known as the “Cuban mutation” of PPD type II (PPD2). Interestingly, the index patient of that family had tibial hypoplasia as well. These data provide the first evidence that WMS is caused by a specific ZRS mutation, which leads to strong ectopic SHH expression. In contrast, we show that complete duplications of the ZRS region lead to type Haas polysyndactyly or triphalangeal thumb‐polysyndactyly syndrome, but do not affect lower limb development. We suggest the term “ZRS‐associated syndromes” and a clinical subclassification for the continuum of limb malformations caused by different molecular alterations of the ZRS. Hum Mutat 30:1–9, 2009. © 2009 Wiley‐Liss, Inc.     

GLI3基因在单纯性马蹄内翻足发生中的调控机制

目的 探讨在单纯性马蹄内翻足发生过程中GLI3基因的凋控机制.方法 构建荧光素酶报告基因表达载体,分析大鼠Gli3基因5′侧翼启动子区域的活性.用P-Match软件预测Gli3基因上游序列中转录因子的结合位点,并通过染色质免疫沉淀实验、凝胶迁移实验验证.用RNA干扰实验以及构建Hoxd13表达载体,观察其在L6细胞中对Gli3基因表达的影响.结果 在大鼠Gli3基因序列的启动子区域发现2个Hoxd13的结合位点,染色质免疫沉淀和凝胶迁移实验证实Hoxd13结合于结合位点2上.Hoxd13表达下调时,Gli3基因表达明显上调.Hoxd13基因表达上调时,Gli3基因则表达下调.结论 在大鼠胚胎肢体发育中,Hoxd13蛋白可能与Gli3基因启动子区的Hoxd13结合位点2结合,调控Gli3的表达.     

Wiedemann-Steiner syndrome: Novel pathogenic variant and review of literature

Wiedemann-Steiner syndrome (WDSTS) is a very rare genetic disorder characterized by short stature, intellectual disability and distinctive facial appearance. We present a five-year-old boy who was diagnosed with WDSTS based on identification of a novel de novo pathogenic variant in the KMT2A gene (OMIM: 159555) by Whole Exome Sequencing and supported by some characteristic clinical features. Genotype and phenotype of the patient is compared with the earlier reported patients in the literature, in an attempt to broaden our knowledge of this rare syndrome.     

GLI3基因在单纯性马蹄内翻足发病机制中的作用

目的 探讨GLI3基因与单纯性马蹄内翻足(idiopathic congenital talipes equinovarus,ICTEV)的相关性.方法 应用变性梯度凝胶电泳技术检测GLI3基因编码区的突变.用逆转录-PCR方法研究GLI3基因在1CTEV患者下肢的表达情况.构建ICTEV大鼠模型,应用实时定量PCR、免疫组织化学染色和蛋白质免疫印迹(Western blotting)方法研究Gli3基因在ICTEV模型鼠下肢肌肉组织中的表达.结果 在84例ICTEV患者外周静脉血中未发现GLI3基因第1～8外显子以及第13外显子存在突变.在ICTEV患者及正常人下肢拇长屈肌中均未检测到GLI3基因的表达.不论在mRNA水平还是在蛋白质水平,Gli3基因在ICTEV模型胎鼠下肢组织中的表达均明显高于正常对照胎鼠.结论 GLI3基因的编码区突变可能不是ICTEV发病的主要原因,但GLI3基因的表达异常与马蹄内翻足的发病可能有关.     

Novel phenotype of achondroplasia due to biallelic FGFR3 pathogenic variants

Pathogenic variants in the fibroblast growth factor receptor 3 (FGFR3) gene are responsible for a broad spectrum of skeletal dysplasias, including achondroplasia (ACH). The classic phenotype of ACH is caused by two highly prevalent mutations, c.1138G > A and c.1138G > C (p.Gly380Arg). In the homozygous state, these variant results in a severe skeletal dysplasia, neurologic deficits, and early demise from respiratory insufficiency. Although homozygous biallelic mutations have been reported in patients with ACH in combination with hypochondroplasia or other dominant skeletal dysplasias, thus far, no cases of heterozygous biallelic pathogenic ACH‐related variants in FGFR3 have been reported. We describe a novel phenotype of an infant with two ACH‐related mutations in FGFR3, p.Gly380Arg and p.Ser344Cys. Discordant features from classic ACH include atypical radiographic findings, severe obstructive sleep apnea, and focal, migrating seizures. We also report the long‐term clinical course of her father, who harbors the p.Ser344Cys mutation that has only been reported once previously in a Japanese patient. The phenotype of heterozygous biallelic mutations in FGFR3 associated with ACH is variable, underscoring the importance of recognition and accurate diagnosis to ensure appropriate management.