WNT10A has been associated with various syndromes with ectodermal dysplasia from severe autosomal recessive SchO?pf-Schulz-Passarge syndrome to odonto-onycho-dermal dysplasia and autosomal dominant hypodontia. We report WNT10A mutations in an American family of which four members are affected with isolated hypodontia or microdontia. Here we demonstrate that in addition to MSX1, PAX9, AXIN2, and EDA, mutations in WNT10A can cause isolated hypodontia.

Several ectodermal dysplasia syndromes, including Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) and Ankyloblepharon-Ectodermal Dysplasia-Clefting (AEC) syndromes, are known to result from mutations in the p63 gene. We investigated whether Rapp-Hodgkin syndrome (RHS) is also caused by mutations in the p63 gene. We identified a heterozygous de novo germline missense mutation, S545P, in the sterile-alpha-motif (SAM) domain of p63, in a Thai patient affected with RHS. This is the first genetic abnormality to be described in RHS. The amino acid substitution is the most downstream missense mutation in p63 reported thus far. Histological assessment of a skin biopsy from the patient's palm showed hyperkeratosis and keratinocyte cell-cell detachment in the upper layers of the epidermis, along with numerous apoptotic keratinocytes. Collectively, these investigations demonstrate that RHS is also caused by mutations in p63 and that the clinical similarities to AEC syndrome are paralleled by the nature of the inherent mutation.

Analysis of the literature yielded 42 examples of the combination of sternal non-union and supraumbilical raphé without evidence of sex predilection. However, among an additional 31 cases in which the triad included facial hemangioma, there was almost exclusive female occurrence. Another condition involves extensive unilateral hemangioma of the face, absence of ipsilateral carotid and vertebral vessels, mental retardation, and Dandy-Walker malformation. Still another disorder has been proposed which includes facial hemangioma and dilatation of the carotid syphon. Both of these conditions exhibit marked female predilection. Examples of overlap of all three "disorders" cause the authors to question the independence of these disorders, hypothesizing instead that they represent a spectrum.

The enamel-renal syndrome of amelogenesis imperfecta (AI) and nephrocalcinosis, and the amelogenesis imperfecta-gingival fibromatosis syndrome have both been associated with mutations in FAM20A. We report on two unrelated Thai patients with three novel and one previously reported mutations in FAM20A with findings suggesting both disorders, including hypoplastic AI, gingival fibromatosis, unerupted teeth, aggressive periodontitis, and nephrocalcinosis/nephrolithiasis. Additional findings consisted of a supernumerary premolar, localized aggressive periodontitis, thin alveolar bone, vitamin D deficiency-associated hyperparathyroidism, and heterotopic calcification in other tissues, including lungs, dental pulp, gingiva, dental follicles, and periodontal tissues, and early cessation of limited menstruation. Greater promotory activity of urine on calcium oxalate crystal growth compared to controls may help to explain the pathogenesis, and suggest that FAM20A mutations can contribute to nephrocalcinosis/nephrolithiasis. Our findings expand the phenotypic spectrum of FAM20A mutations. Since both of our patients and a large number of previously reported cases had all the important features of both syndromes, including AI, renal anomalies, and gingival fibromatosis, we are convinced that these two disorders actually are the same entity. The name of enamel-renal-gingival syndrome is suggested.

Isolated or nonsyndromic tooth agenesis or hypodontia is the most common human malformation. It has been associated with mutations in MSX1, PAX9, EDA, AXIN2, EDAR, EDARADD, and WNT10A. GREMLIN 2 (GREM2) is a strong bone morphogenetic protein (BMP) antagonist that is known to regulate BMPs in embryogenesis and tissue development. Bmp4 has been shown to have a role in tooth development. Grem2(-/-) mice have small, malformed maxillary and mandibular incisors, indicating that Grem2 has important roles in normal tooth development. Here, we demonstrate for the first time that GREM2 mutations are associated with human malformations, which include isolated tooth agenesis, microdontia, short tooth roots, taurodontism, sparse and slow-growing hair, and dry and itchy skin. We sequenced WNT10A, WNT10B, MSX1, EDA, EDAR, EDARADD, AXIN2, and PAX9 in all 7 patients to rule out the effects of other ectodermal dysplasias and other tooth-related genes and did not find mutations in any of them. GREM2 mutations exhibit variable expressivity even within the same families. The inheritance is autosomal dominant with incomplete penetrance. The expression of Grem2 during the early development of mouse teeth and hair follicles and the evaluation of the likely effects of the mutations on the protein structure substantiate these new findings.

Dominant mutations in TP63 cause ankyloblepharon ectodermal dysplasia and clefting (AEC), an ectodermal dysplasia characterized by skin fragility. Since DNp63a is the predominantly expressed TP63 isoform in postnatal skin, we hypothesized that mutant DNp63a proteins are primarily responsible for skin fragility in AEC patients. We found that mutant DNp63a proteins expressed in AEC patients function as dominant-negative molecules, suggesting that the human AEC skin phenotype could be mimicked in mouse skin by downregulating DNp63a. Indeed, downregulating DNp63 expression in mouse epidermis caused severe skin erosions, which resembled lesions that develop in AEC patients. In both cases, lesions were characterized by suprabasal epidermal proliferation, delayed terminal differentiation, and basement membrane abnormalities. By failing to provide structural stability to the epidermis, these defects likely contribute to the observed skin fragility. The development of a mouse model for AEC will allow us to further unravel the genetic pathways that are normally regulated by DNp63 and that may be perturbed in AEC patients. Ultimately, these studies will not only contribute to our understanding of the molecular mechanisms that cause skin fragility in AEC patients, but may also result in the identification of targets for novel therapeutic approaches aimed at treating skin erosions.

Our study provides the most comprehensive study of oral manifestations in patients with MPS VI. Receiving ERT at very young ages may lessen craniofacial malformations including hypoplasic mandibular condyles and anterior open bite. Oral manifestations can be used as diagnostic features for MPS VI prior to assessing leukocyte ARSB activity or urinary excretion of dermatan sulfate.

Tricho-rhino-phalangeal syndromes (TRPS) are caused by mutation or deletion of TRPS1, a gene encoding a GATA transcription factor. These disorders are characterized by abnormalities of the hair, face, and selected bones. Rare cases of individuals with TRPS displaying supernumerary teeth have been reported, but none of these has been examined molecularly. We used two different approaches to investigate a possible role of TRPS1 during tooth development. We looked at the expression of Tprs1 during mouse tooth development and analyzed the craniofacial defects of Trps1 mutant mice. In parallel, we investigated whether a 17-year-old Thai boy with clinical features of TRPS and 5 supernumerary teeth had mutation in TRPS1. We report here that Trps1 is expressed during mouse tooth development, and that an individual with TRPS with supernumerary teeth has the amino acid substitution A919V in the GATA zinc finger of TRPS1. These results suggest a role for TRPS1 in tooth morphogenesis.