Genetic regulatory pathways of split‐hand/foot malformation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146859/1/cge13434-sup-0001-EditorialProcess.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146859/2/cge13434_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146859/3/cge13434.pd

Clouston syndrome with dental anomalies, micropores of hair shafts and absence of palmoplantar keratoderma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154514/1/jde15236.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154514/2/jde15236_am.pd

Clouston syndrome with pili canaliculi, pili torti, overgrown hyponychium, onycholysis, taurodontism and absence of palmoplantar keratoderma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155882/1/jde15333.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155882/2/jde15333_am.pd

TRPS1 mutation associated with trichorhinophalangeal syndrome type 1 with 15 supernumerary teeth, hypoplastic mandibular condyles with slender condylar necks and unique hair morphology

Trichorhinophalangeal syndrome type 1 (TRPS1; Online Mendelian Inheritance in Man #190350) is an autosomal dominant disorder caused by mutations in TRPS1. We report a Thai male with TRPS1 who carried a c.1842C>T (p.Arg615Ter) mutation. He had 15 supernumerary teeth, double mental foramina, hypoplastic mandibular condyles with slender condylar necks and unique ultrastructural hair findings. Body hair was absent. The hair in the area of a congenital melanocytic nevus had a greater number of hair cuticles than normal. Occipital hair had abnormal hair follicles and cuticles. The scale edges of the hair cuticles were detached and rolled up. Hypoplastic mandibular condyles with slender condylar necks, double mental foramina and the rolled up edges of hair cuticles have not been reported in patients with TRPS1.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155929/1/jde15360.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155929/2/jde15360_am.pd

Treacher Collins syndrome: A novel TCOF1 mutation and monopodial stapes

Treacher Collins syndrome (TCS: OMIM 154500) is an autosomal dominant craniofacial disorder belonging to the heterogeneous group of mandibulofacial dysostoses.ObjectiveTo investigate four Treacher Collins syndrome patients of the Sgaw Karen family living in Thailand.MethodClinical examination, hearing tests, lateral cephalometric analyses, Computed tomography, whole exome sequencing and Sanger direct sequencing were performed.ResultsAll of the patients affected with Treacher Collins syndrome carried a novel TCOF1 mutation (c.4138_4142del; p.Lys1380GlufsTer12), but clinically they did not have the typical facial gestalt of Treacher Collins syndrome, which includes downward‐slanting palpebral fissures, colobomas of the lower eyelids, absence of eyelashes medial to the colobomas, malformed pinnae, hypoplastic zygomatic bones and mandibular hypoplasia. Lateral cephalometric analyses identified short anterior and posterior cranial bases, and hypoplastic maxilla and mandible. Computed tomography showed fusion of malleus and incus, sclerotic mastoid, hypoplastic middle ear space with a soft tissue remnant, dehiscence of facial nerve and monopodial stapes.ConclusionTreacher Collins syndrome in Sgaw Karen patients has not been previously documented. This is the first report of monopodial stapes in a TCS patient who had a TCOF1 mutation. The absence of a common facial phenotype and/or the presence of monopodial stapes may be the effects of this novel TCOF1 mutation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156466/2/coa13560.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156466/1/coa13560_am.pd

Dental Anomalies in Ciliopathies: Lessons from Patients with BBS2, BBS7, and EVC2 Mutations

Objective: To investigate dental anomalies and the molecular etiology of a patient with Ellis–van Creveld syndrome and two patients with Bardet–Biedl syndrome, two examples of ciliopathies. Patients and Methods: Clinical examination, radiographic evaluation, whole exome sequencing, and Sanger direct sequencing were performed. Results: Patient 1 had Ellis–van Creveld syndrome with delayed dental development or tooth agenesis, and multiple frenula, the feature found only in patients with mutations in ciliary genes. A novel homozygous mutation in EVC2 (c.703G>C; p.Ala235Pro) was identified. Patient 2 had Bardet–Biedl syndrome with a homozygous frameshift mutation (c.389_390delAC; p.Asn130ThrfsTer4) in BBS7. Patient 3 had Bardet–Biedl syndrome and carried a heterozygous mutation (c.389_390delAC; p.Asn130ThrfsTer4) in BBS7 and a homozygous mutation in BBS2 (c.209G>A; p.Ser70Asn). Her clinical findings included global developmental delay, disproportionate short stature, myopia, retinitis pigmentosa, obesity, pyometra with vaginal atresia, bilateral hydronephrosis with ureteropelvic junction obstruction, bilateral genu valgus, post-axial polydactyly feet, and small and thin fingernails and toenails, tooth agenesis, microdontia, taurodontism, and impaired dentin formation. Conclusions: EVC2, BBS2, and BBS7 mutations found in our patients were implicated in malformation syndromes with dental anomalies including tooth agenesis, microdontia, taurodontism, and impaired dentin formation

A Mutation in CACNA1S Is Associated with Multiple Supernumerary Cusps and Root Maldevelopment

Background: Enamel knots and Hertwig epithelial root sheath (HERS) regulate the growth and folding of the dental epithelium, which subsequently determines the final form of tooth crown and roots. We would like to investigate the genetic etiology of seven patients affected with unique clinical manifestations, including multiple supernumerary cusps, single prominent premolars, and single-rooted molars. Methods: Oral and radiographic examination and whole-exome or Sanger sequencing were performed in seven patients. Immunohistochemical study during early tooth development in mice was performed. Results: A heterozygous variant (c. 865A>G; p.Ile289Val) in CACNA1S was identified in all the patients, but not in an unaffected family member and control. Immunohistochemical study showed high expression of Cacna1s in the secondary enamel knot. Conclusions: This CACNA1S variant seemed to cause impaired dental epithelial folding; too much folding in the molars and less folding in the premolars; and delayed folding (invagination) of HERS, which resulted in single-rooted molars or taurodontism. Our observation suggests that the mutation in CACNA1S might disrupt calcium influx, resulting in impaired dental epithelium folding, and subsequent abnormal crown and root morphology

FAM20A Mutation in a Patient with Enamel-Renal-Gingival Syndrome: A Case Report

Abstract: Objectives: Amelogenesis imperfecta with Gingival fibromatosis syndrome (AIGFS), amelogenesis imperfecta with nephrocalcinosis or Enamel-Renal syndrome (ERS), and Enamel- Renal-Gingival syndrome have been associated with mutations in the FAM20A gene. A number of cases in the literature have described patients with three important findings, including amelogenesis imperfecta (AI), gingival fibromatosis and nephrocalcinosis. This study was aimed to identify FAM20A mutations in an 11-year-old Turkish male affected with enamel-renal-gingival syndrome. Methods: Clinical and radiographic examinations and mutational analysis of the coding exons of FAM20A gene were performed. Results: The patient was the first child of non-consanguineous parents. Oral examination revealed AI and generalized gingival fibromatosis. A panoramic radiograph showed generalized absence of enamel, delayed eruption of permanent teeth, intrapulpal calcification and multiple unerupted teeth. No calcification was observed with renal ultrasound. Mutation analysis of FAM20A revealed a novel missense mutation in exon 10 (NM_017565.3: c.1307G>A; g.61999G>A; p.Gly436Glu). This is notable because G436 is highly conserved among FAM20A homologues. Conclusions: Our study reports a novel FAM20A mutation and confirms that AIGFS and ERS actually are the same entity with different manifestations. Patients with AI, hypoplastic type with unerupted teeth and gingival fibromatosis are advocated to have renal ultrasonography to rule out nephrocalcinosis or nephrolithiasis. Keywords: FAM20A, Amelogenesis imperfecta, Gingival hyperplasia,  Nephrocalcinosi