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Objective: Our objective was to investigate the molecular etiology of osteogenesis imperfecta type VIII and dental anomalies in 4 siblings of a Karen tribe family.Materials and Methods: Four patients and their unaffected parents were studied by clinical and radiographic examination. In situ hybridization of P3h1 during early murine tooth development, whole-exome sequencing, and Sanger direct sequencing were performed.Results: A novel homozygous missense P3H1 mutation (NM_001243246.1; c.2141A>G; NP_001230175.1; p.Lys714Arg) was identified in all patients. Their unaffected parents were heterozygous for the mutation. The mutation is hypothesized to belong to isoform c of P3H1. Mutations in P3H1 are associated with autosomal recessive osteogenesis imperfecta type VIII. Hypodontia, a mesiodens, and single-rooted permanent second molars found in our patients have never been reported in patients with P3H1 mutations. Single-rooted second permanent molars or failure to form multiple roots implies effects of the P3H1 mutation on root development.Conclusions: We report a novel P3H1 mutation as the underlying cause of osteogenesis imperfecta type VIII with dental anomalies. Our study suggests that isoform c of P3H1 is also a functional isoform of P3H1. We report, for the first time, to our knowledge, the association of P3H1 mutation and osteogenesis imperfecta type VIII with dental anomalies. [ABSTRACT FROM AUTHOR]

We report an Indian girl with split-hand/foot malformation (SHFM), sparse hair, and interrupted eyebrows, who carries a novel homozygous deletion c.695_697delACA in WNT10B . The variant is deduced to cause an in-frame deletion of Asn residue 232 (p.Asn232del). According to the protein model, this single amino acid deletion at the critical position in the protein structure is likely to severely affect the protein structure and function. This deletion is likely to lead decreased lifetime and make it unable to bind to its receptors and other ligands. The patient and all family members had normal bone density and they were not obese like some of the patients with WNT10B variants. Here we report a patient with SHFM6 who carried a novel WNT10B mutation. Sparse hair and interrupted eyebrows may be associated findings of SHFM6. [ABSTRACT FROM AUTHOR]

Al-Awadi-Raas-Rothschild syndrome (AARRS; OMIM 276820 ) is a very rare autosomal recessive limb malformation syndrome caused by WNT7A mutations. AARRS is characterized by various degrees of limb aplasia and hypoplasia. Normal intelligence and malformations of urogenital system are frequent findings. Complete loss of WNT7A function has been shown to cause AARRS, however, its partial loss leads to the milder malformation, Fuhrmann syndrome. An Indian boy affected with AARRS is reported. A novel homozygous base substitution mutation c.550A > C (p.Asn184Asp) is identified in the patient. Parents were heterozygous for the mutation. In addition to the typical features of AARRS, the patient had agenesis of the mandibular left deciduous lateral incisor. The heterozygous parents had microdontia of the maxillary left permanent third molar and taurodontism (enlarged dental pulp chamber at the expense of root) in a number of their permanent molars. Whole exome sequencing of the patient and his parents ruled out mutations in 11 known hypodontia-associated genes including WNT10A , MSX1 , EDA , EDAR , EDARADD , PAX9 , AXIN2, GREM2 , NEMO , KRT17 , and TFAP2B . In situ hybridization during tooth development showed Wnt7a expression in wild-type tooth epithelium at E14.5. All lines of evidence suggest that WNT7A has important role in tooth development and its mutation may lead to tooth agenesis, microdontia, and taurodontism. Oral examination of patients with AARRS and Fuhrmann syndromes is highly recommended. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate molecular etiologies of oral exostoses and dental anomalies in 14 patients from eight families. Oral and radiographic examinations were performed on every patient. Whole exome and Sanger sequencing were performed on DNA of the patients, the unaffected parents and unaffected siblings. LRP6 mutant proteins were modeled and analyzed. Five mutations in LRP6 , including four missense (p.Glu72Lys, p.Lys82Asn, Tyr418His, and p.Ile773Val) and one nonsense mutation (p.Arg32Ter), were identified. These mutations have not been reported to be associated with dental anomalies or oral exostoses. Oral features included a variety of oral exostoses (7 of the 14 patients), root defects (6 of the 14 patients), and tooth agenesis (5 of the 14 patients). Less common dental anomalies included microdontia, tooth fusion, odontomas, and mesiodens. Analysis of the protein models of the five LRP6 mutations shed light on their likely impact on LRP6 protein structure and function. Fourteen patients with five LRP6 mutations, including two recurrent mutations and three novel ones, are reported. Our study shows for the first time that mutations in LRP6 are associated with mesiodens, fusion of teeth, odontomas, microdontia, long roots, molars with unseparated roots, and taurodontism. • LRP6 mutations are associated with mesiodens, fusion of teeth, and microdontia. • LRP6 mutations caused root malformation. • The LRP6 gene has an important role for root development. [ABSTRACT FROM AUTHOR]

• Homozygous mutation in ESCO2 causes Juberg-Hayward syndrome. • Juberg-Hayward syndrome and Roberts syndrome are allelic. • Microcephaly is not a consistent feature of Juberg-Hayward syndrome. • Humeroradial synostosis and radial head dislocation are in the same spectrum of forearm malformations. Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, hypoplasia or aplasia of thumbs, short stature, dislocation of radial head, and fusion of humerus and radius leading to elbow restriction. A homozygous mutation in ESCO2 has recently been reported to cause Juberg-Hayward syndrome. Our objective was to investigate the molecular etiology of Juberg-Hayward syndrome in two affected Lisu tribe brothers. Two patients, the unaffected parents, and two unaffected siblings were studied. Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, Western blot analysis, and chromosome testing were performed. Two affected brothers had characteristic features of Juberg-Hayward syndrome, except for the absence of microcephaly. The elder brother had bilateral cleft lip and palate, short stature, humeroradial synostosis, and simple partial seizure with secondary generalization. The younger brother had unilateral cleft lip and palate, short stature, and dislocation of radial heads. The homozygous (c.1654C > T; p.Arg552Ter) mutation in ESCO2 was identified in both patients. The other unaffected members of the family were heterozygous for the mutation. The presence of humeroradial synostosis and radial head dislocation in the same family is consistent with both being in the same spectrum of forearm malformations. Chromosome testing of the affected patients showed premature centromere separation. Western blot analysis showed reduced amount of truncated protein. Our findings confirm that a homozygous mutation in ESCO2 is the underlying cause of Juberg-Hayward syndrome. Microcephaly does not appear to be a consistent feature of the syndrome. [ABSTRACT FROM AUTHOR]

• TRPS1 has important role in dentin mineralization. • TRPS1 mutation can cause hypoplastic mandibular condyles with long condylar necks. • Thorough oral examination is necessary for patients with TRPS1 mutations. • TRPS1 is an important gene for tooth renewal. Tricho-rhino-phalangeal syndrome type I, an autosomal dominant condition, is caused by heterozygous pathogenic variants in a zinc finger transcription factor, TRPS1 , which has important roles in development of endochondral bones, teeth, and hair. Clinical manifestations of the patients include short stature, sparse, fine and slow-growing scalp hair, bulbous nose, supernumerary teeth, hip dysplasia, brachydactyly, and cone-shaped epiphyses of the phalangeal bones. To clinically, radiographically, and molecular genetically investigate a patient with tricho-rhino-phalangeal syndrome type I. Clinical and radiographic examination and mutation analysis of TRPS1 were performed. Clinical and radiographic examination indicated the patient had tricho-rhino-phalangeal syndrome type I. Sequencing of the TRPS1 gene revealed a heterozygous pathogenic variant (c.2762G>A; p.Arg921Gln). Oral examination showed supernumerary teeth, large dental pulp spaces, dental pulp stones, microdontia of the maxillary permanent lateral incisors, absence of the mandibular left second premolar and short root of the maxillary right second premolar, and hypoplastic mandibular condyles with long condylar necks. TRPS1 has an important function in regulating bone and dentin mineralization. Having large dental pulp spaces suggests that impaired dentin mineralization was the result of the TRPS1 pathogenic variant. This is the first patient with a TRPS1 pathogenic variant who had impaired dentin mineralization. This is also the third report showing the association between TRPS1 pathogenic variants and the presence of supernumerary teeth. [ABSTRACT FROM AUTHOR]

We report a Thai girl affected with plasminogen deficiency, Type I. Ligneous conjunctivitis was first observed when she was one-month-old. The newly recognized findings include tapered incisor roots as a result of thin root dentin, generalized short tooth roots, and mandibular prognathism. Mutation analysis of PLG demonstrated homozygous c.1193G>A missense mutation. The parents were heterozygous for c.1193G>A mutation. The c.1193G>A mutation is novel and predicted to cause amino acid substitution p.Cys398Tyr. Thin root dentin in the patient who was affected with PLG mutation and immunolocalization of Plg during early root development in mice imply the role of plasminogen in root dentin formation. [ABSTRACT FROM AUTHOR]

Abstract: Turkish twin brothers affected with hereditary sensory and autonomic neuropathy type IV (HSAN IV) are reported. Their clinical findings were generally typical for HSAN IV. Interestingly they both had preserved periodontal sensation. Mutation analysis of the NTRK1 gene showed a homozygous c.2001C>T substitution in exon 15 in both twins. This base substitution is predicted to change a polar, positively charged amino acid arginine to the highly active amino acid cystein at position 654 (p.Arg654Cys). The parents were heterozygous for the mutation. This mutation has been reported previously in one Japanese and one Arab patients. The preserved periodontal sensation has not previously been reported in patients affected with HSAN IV. This preserved sensation in our patients might have been through Ruffini endings, the periodontal mechanoreceptors which have been reported to be present in TrkA knockout mice. Here we report the first twins affected with HSAN IV and the observation that periodontal sensation is not affected by mutation in NTRK1. [Copyright &y& Elsevier]