Piranit Nik Kantaputra

WNT10A and isolated hypodontia.

WNT10A has been associated with various syndromes with ectodermal dysplasia from severe autosomal recessive SchÖpf–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.

ΔNp63 Knockdown Mice: A Mouse Model for AEC Syndrome

Dominant mutations in TP63 cause ankyloblepharon ectodermal dysplasia and clefting (AEC), an ectodermal dysplasia characterized by skin fragility. Since ΔNp63α is the predominantly expressed TP63 isoform in postnatal skin, we hypothesized that mutant ΔNp63α proteins are primarily responsible for skin fragility in AEC patients. We found that mutant ΔNp63α 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 ΔNp63α. Indeed, downregulating ΔNp63 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 ΔNp63 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.

THE GENE FOR MESOMELIC DYSPLASIA KANTAPUTRA TYPE IS MAPPED TO CHROMOSOME 2Q24-Q32

AbstractMesomelic dysplasia Kantaputra type (MDK) (MIM *156232) is a new autosomal dominant skeletal dysplasia characterized by dwarfism, shortening of the forearms/lower-legs, carpal/tarsal synostosis, and dorsolateral foot deviation. We studied a Thai family in which 15 members in 3 generations were affected with MDK. With reference to the breakpoints of a balanced translocation [t(2;8)(q31;p21)] in patients from a previously reported Italian family with a skeletal dysplasia that appears similar to MDK, a linkage analysis was performed in the Thai family using 50 CA-repeat markers mapped to nearby regions (2q22-q34 and 8p24-p21) of the translocation breakpoints. The results clearly ruled out a linkage of MDK to marker loci at the 8p24-p21 region, whereas all nine affected members available for the study shared a haplotype at four loci (D2S2284, D2S326, D2S2188, and D2S2314) spanning about 22.7 cM in the 2q24-q32 region. The computer-assisted two-point linkage analysis revealed maximum logarithm of odds (lod) scores of 4.82, 4.21, 4.82, and 4.21 (θ = 0) at these loci, respectively. These data indicated that the MDK locus is in the vicinity of D2S2284 and D2S2188 loci that are most likely mapped to 2q24-q32.

Enamel-renal-gingival syndrome and FAM20A mutations

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.

Cleft Lip with Cleft Palate, Ankyloglossia, and Hypodontia are Associated with TBX22 Mutations

X-linked cleft palate and ankyloglossia (CPX) are caused by mutations in the TBX22 transcription factor. To investigate whether patients with ankyloglossia alone or in the presence of other craniofacial features including hypodontia or CLP might be caused by TBX22 mutations, we analyzed 45 Thai patients with isolated ankyloglossia, 2 unusual CPA families, and 282 non-syndromic Thai and UK patients with CLP. Five putative missense mutations were identified, including 3 located in the T-box binding domain (R120Q, R126W, and R151L) that affects DNA binding and/or transcriptional repression. The 2 novel C-terminal mutations, P389Q and S400Y, did not affect TBX22 activity. Mutations R120Q and P389Q were identified in patients with ankyloglossia only, while R126W and R151L were present in families that included CLP. Several individuals in these families were also found to have micro/hypodontia. This study has expanded the phenotypic spectrum of TBX22-related mutations to include dental anomalies and cleft lip.

A novel gene is disrupted at a 14q13 breakpoint of t(2;14) in a patient with mirror-image polydactyly of hands and feet

AbstractMirror-image polydactyly of hands and feet (MIP) is a very rare congenital anomaly characterized by mirror-image duplication of digits. To isolate the gene responsible for MIP, we performed translocation breakpoint cloning from an MIP patient with t(2;14)(p23.3;q13). We isolated a good candidate gene for MIP that was disrupted by the translocation of the patient. We had previously constructed a 1.2-megabase bacterial artificial chromosome (BAC)/P1-derived artificial chromosome (PAC) contig covering the 14q13 breakpoint of t(2;14)(p23.3;q13). From a 500-kb segment consisting of seven BAC/PAC clones in the contig, we isolated a novel gene (the mirror-image polydactyly 1 gene, designated as MIPOL1, GenBank Accession No. AY059470), in addition to the hepatocyte nuclear factor 3 alpha gene (HNF3A, GenBank Accession No. XM 007360). MIPOL1 spans about 350-kb, comprises 15 exons, and encodes 442 amino acids. Northern blot analysis revealed that MIPOL1 expression is definite but very weak in adult heart, liver, skeletal muscle, kidney, and pancreas, and in fetal kidney. In view of the genome sequence and the contig map constructed, the 14q13 breakpoint of the patient was identified as located in intron 11 of MIPOL1, indicating that the gene was disrupted by the translocation, and that the breakage resulted in MIPOL1 protein truncation. Whole-mount in situ hybridization in mouse resulted in mouse Mipol1 signals all over E10.5–E13.5 mouse embryos. Two other unrelated patients with limb anomalies similar to MIP were subjected to mutation analysis of MIPOL1, but none had any mutations. We then isolated BAC clones from the other breakpoint, 2p23.3. A search for genes and expressed sequence tags in a more than 300-kb region around the 2p23.3 breakpoint found only the neuroblastoma-amplified protein gene (NAG, GenBank Accession No. NM 015909), which is located at least 50kb centromeric to the breakpoint and is not likely to be related to MIP. MIPOL1 is a good candidate gene for the MIP type of anomaly.

A novel homozygous Arg222Trp missense mutation in WNT7A in two sisters with severe Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome†‡

Al‐Awadi/Raas‐Rothschild/Schinzel phocomelia (AARRS) syndrome, a rare autosomal recessive disorder, comprises malformations of upper and lower limbs with severely hypoplastic pelvis and abnormal genitalia. Mutations in WNT7A have been reported as cause of the syndrome. We report on two sisters in a Thai family with short and malformed long bones, absent fibulae, flexion contracture of digits, and a/hypoplastic nails. Fusion between severely malformed femora and slender tibiae has never been reported in patients with WNT7A mutations. Lower limbs were more severely malformed than the upper ones and the pelvis was also severely affected. Multiple fusions of long bones and of the femoral heads to the acetabula were evident. A novel homozygous missense mutation in coding exon 4 of the WNT7A was detected in both affected daughters (c.664C > T) leading to an amino acid exchange from arginine to tryptophan (p.Arg222Trp; R222W). The phenotype is likely to result from an abnormality of all three signaling centers in the developing limb resulting in ventralization with a loss of dorsal structures (aplasia/hypoplasia of nails) a loss of anterior–posterior identity (single distal bones in lower limb without polarity) and an outgrowth defect resulting in distal truncations.

Laurin‐Sandrow syndrome with additional associated manifestations

A Thai man with Laurin-Sandrow syndrome (LSS, MIM 135750), the ninth reported case, is described. He had an underdeveloped nasal bone, scar-like seams under the nose, large heads of mandibular condyles, and brachymesophalangy of toes as newly observed findings of the syndrome. He also had mental retardation. The patient had duplication of ulna, with triphalangeal thumbs, and polydactyly of one finger. The triphalangeal thumbs were non-opposable. Carpal bones were malformed. Mirror image polydactyly of the toes was present. There were nine toes on the right and eight on the left. Joint abnormalities were observed at his elbows, wrists, knees, ankles, fingers, and toes. Synostosis of severely malformed tarsal bones was noted. This appears to be the first case of LSS with anomalies not limited to the nose and limbs. The relationship between LSS, tibial hemimelia-polysyndactyly-triphalangeal thumbs syndrome, triphalangeal thumb-polysyndactyly syndrome, preaxial polydactyly types 2 and 3, and Haas-type syndactyly is discussed.

The smallest teeth in the world are caused by mutations in the PCNT gene

We report a follow up study on two MOPD II Thai families with severe dental anomalies and hypoplastic alveolar bone. Striking dental anomalies comprise severe microdontia, opalescent and abnormally shaped teeth, and rootless molars. As a result of severe hypoplastic alveolar bone, most permanent teeth have been lost. Mutation analysis of PCNT revealed 2 novel mutations (p.Lys3154del and p.Glu1154X) and a recurrent mutation (p.Pro1923X). Teeth of the patient who carried a homozygous novel mutation of p.Glu1154X are probably the smallest ever reported. The sizes of the mandibular permanent incisors and all premolars were approximately 2‐2.5 mm, mesiodistally. All previously reported, PCNT mutations have been described to cause premature truncation of the pericentrin protein. p.Lys3154del mutation was unique as it was pathogenic as a result of missing only a single amino acid. In situ hybridization of Pcnt shows its expression in the epithelium and mesenchyme during early stages of rodent tooth development. It is evident that PCNT has crucial role in tooth development. The permanent dentition is more severely affected than the one. This implies that PCNT appears to have more role in the development of the permanent dentition. As pericentrin is a critical centrosomal protein, the dental phenotype found in MOPD II patients is postulated to be the consequence of loss of microtubule integrity which leads to defective centrosome function.

Rapp-Hodgkin syndrome with palmoplantar keratoderma, glossy tongue, congenital absence of lingual frenum and of sublingual caruncles: Newly recognized findings

We report on a boy with Rapp-Hodgkin syndrome (RHS) or Rapp-Hodgkin ectodermal dysplasia. He had sparse, wiry, slow growing and uncombable hair, but no pili torti or pili canaliculi characteristic of RHS. He also had sparse eyelashes and eyebrows, and obstructed lacrimal puncta and epiphora. Bilateral bony external auditory canal stenosis led to hearing loss. The mouth was small with repaired bilateral cleft lip and palate. Oral manifestations included hypodontia, microdontia, unerupted mandibular premolars with well formed roots, large dental pulp spaces, enamel hypoplasia, multiple caries, glossy tongue, and congenital absence of lingual frenum and of sublingual caruncles including submandibular and sublingual salivary duct openings. Palmo-plantar keratoderma, unerupted premolars, congenital absence of lingual frenum, sublingual caruncles, glossy tongue, and pili canaliculi seen in the patient are newly recognized findings of this syndrome. Overlapping findings of RHS ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC), and ankyloblepharon-ectodermal defects-cleft lip and palate syndrome (AEC) are discussed.