Acro-dermato-ungual-lacrimal-tooth Research Articles

P63 Mutation Impacts the Structure of Cardiopharyngeal Field Derived Muscles in Mice

The cardiopharyngeal field (CPF) includes anterior lateral mesoderm of the first heart field and the contiguous pharyngeal mesoderm. The latter gives rise to second‐heart‐field‐derived heart regions and branchiomeric head muscles. Neural crest cells (NCCs) surround and infiltrate mesoderm cells, forming connective tissue of head and heart musculature. NCCs are also involved in the septation of the cardiac outflow tract, the patterning of pharyngeal arch arteries, and in the proper development of attachments of branchiomeric muscles to skull, jaw, hyoid bone, and laryngeal cartilages.The p63 (aka Trp63) transcription factor is essential for the differentiation of epithelial tissue (ectoderm and endoderm) during embryogenesis. To form the correct amount of mature ectodermal, mesodermal, and NCC populations and to control the differentiation of the CPF, p63 interacts with downstream transcription factors, such as Tbx1, Isl1, and nkx2.5. We analyzed how the loss of p63 expression in p63−/− mice affected the mesodermal derivatives of the CPF. We hypothesized that the loss of p63 decreases the number of mesodermal cells differentiating from the CPF, causing a smaller mesodermal cell population in the CPF. We expected to see smaller CPF derived muscles in the p63 mutant mice, as well as deficient connective tissue in head and heart musculature as well as weakened attachments of craniofacial muscles.To determine if and when certain muscular defects appear, we performed muscle antibody staining and dissected wildtype littermates and p63−/− mice (B6.129S7‐Trp63tm2Brd/J strain) aged embryonic day (E) 12–18. We have collected minimum of five specimens for each age. We studied craniofacial, laryngeal, as well as cardiac musculature by analyzing the antibody stained specimens under the microscope and by performing microdissections under a stereomicroscope. We used 3D computed tomography scan images (taken with a uCT scanner, Skyscan 1172) to compare the craniofacial skeletons between wildtype and mutant mice.In p63−/− mice, branchiomeric muscles such as the masseter, buccinator, and nasolabialis were properly attached to bony elements but were smaller than what was seen in the wildtype mice. The p63−/− head is flexed and the chin is closer to the chest than in the wildtype specimens: this posture could be caused by the shortened and less dense sternocleidomastoid muscle in the p63−/− mice. Corresponding with previous reports, our p63 −/− mice also showed several malformations (e.g., poorly developed limbs, cleft palate, cardiac abnormalities) stereotypical of this mouse mutant and which are also seen in humans with p63 mutations such as in ADULT (acro‐dermatoungual‐lacrimal‐tooth) and EEC (Ectrodactyly‐Ectodermal Dysplasia‐Cleft Lip /Palate) syndromes. Despite that p63 expression is restricted to epithelium, the described defects reveal that p63 expression is important to much earlier, and shared developmental processes, notably NCC proliferation and differentiation, that do impact tissues derived from mesoderm as well as from epithelium. Analyzing the influence of p63 on CPF differentiation will contribute to a better understanding of regulatory mechanisms during head and heart development including the role of these mechanisms in human congenital syndromes.

Clinical, Biological and Therapeutic Features of a Patient with Acro Dermato Ungual Lacrimal Tooth Syndrome

Clinical, Biological and Therapeutic Features of a Patient with Acro Dermato Ungual Lacrimal Tooth Syndrome

ADULT (acro-dermato-ungual-lacrimal-tooth) Syndrome: A Case Report from India.

ADULT (acro-dermato-ungual-lacrimal-tooth) Syndrome: A Case Report from India.

A novel c.1037C > G (p.Ala346Gly) mutation in TP63 as cause of the ectrodactyly-ectodermal dysplasia and cleft lip/palate (EEC) syndrome.

Ectrodactyly – ectodermal dysplasia and cleft lip/palate (EEC) syndrome (OMIM 604292) is a rare disorder determined by mutations in the TP63 gene. Most cases of EEC syndrome are associated to mutations in the DNA binding domain (DBD) region of the p63 protein. Here we report on a three-generation Brazilian family with three individuals (mother, son and grandfather) affected by EEC syndrome, determined by a novel mutation c.1037C > G (p.Ala346Gly). The disorder in this family exhibits a broad spectrum of phenotypes: two individuals were personally examined, one presenting the complete constellation of EEC syndrome manifestations and the other presenting an intermediate phenotype; the third affected, a deceased individual not examined personally and referred to by his daughter, exhibited only the split-hand/foot malformation (SHFM). Our findings contribute to elucidate the complex phenotype-genotype correlations in EEC syndrome and other related TP63-mutation syndromes. The possibility of the mutation c.1037C > G being related both to acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome and SHFM is also raised by the findings here reported.

ADULT syndrome due to an R243W mutation in TP63

Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome is a rare, autosomal dominant form of ectodermal dysplasia due to TP63 mutations. ADULT syndrome is much less common than the more classical forms of TP63-associated ectodermal dysplasias, such as ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome and ankyloblepharon-ectodermal defects-cleft lip/palate syndrome. ADULT syndrome is characterized by ectrodactyly, syndactyly, and excessive freckling, in addition to more typical ectodermal defects, including hypodontia, lacrimal duct anomalies, hypotrichosis, and onychodysplasia. Unlike some of the other TP63-associated ectodermal dysplasias, ADULT syndrome lacks clefting and ankyloblepharon. Here, we report a three-generation family with ADULT syndrome due to an R243W mutation in TP63, a mutation that has previously been described in one patient with ADULT syndrome and eight unrelated patients with EEC syndrome.

Cleft palate and ADULT phenotype in a patient with a novel TP63 mutation suggests lumping of EEC/LM/ADULT syndromes into a unique entity: ELA syndrome

Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome is a rare condition belonging to the group of ectodermal dysplasias caused by TP63 mutations. Its clinical phenotype is similar to ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) and limb-mammary syndrome (LMS), and differs from these disorders mainly by the absence of cleft lip and/or palate. We report on a 39-year-old patient who was found to be heterozygous for a c.401G > T (p.Gly134Val) de novo mutation of TP63. This patient had the ADULT phenotype associated with cleft palate. Our findings, rather than extend the clinical spectrum of ADULT syndrome, suggest that cleft palate can no longer be considered an element for differential diagnosis for ADULT, EEC, and LMS. Our data, added to other reports on overlapping phenotypes, support the combining of these three phenotypes into a unique entity that we propose to call "ELA syndrome," which is an acronym of ectrodactyly-ectodermal dysplasia-cleft lip and palate, limb-mammary, and ADULT syndromes.

ADULT Syndrome Caused by a Mutation Previously Associated with EEC Syndrome

Acro-Dermato-Ungual-Lacrimal-Tooth (ADULT) syndrome is a rare autosomal dominant syndrome characterized by ectrodactyly or syndactyly, excessive freckling and dry skin, dysplastic nails, lacrimal duct atresia, primary hypodontia and early loss of permanent teeth. ADULT syndrome is one of five such syndromes that result from mutations in TP63, encoding the transcription factor p63. Until now, only four families and three individuals with ADULT syndrome have been reported in the English literature. We present a 14-year-old female patient with ADULT syndrome and discuss phenotype-genotype correlations in the p63 syndromes.

Further phenotypic and genetic variation in ADULT syndrome

ADULT (Acro-dermato-ungual-lacrimal-tooth) syndrome is characterized by ectrodactyly, syndactyly, fingernail and toenail dysplasia, hypoplasia of the breast and nipple, excessive freckling, lacrimal duct atresia, frontal alopecia, primary hypodontia, and/or early loss of permanent teeth. It is a rare autosomal dominant disorder which has been linked to mutation in the p63 gene. The p63 gene has been described in five overlapping limb malformation syndromes including the EEC syndrome (ectodermal ectrodactyly clefting). We report on the first case of ADULT syndrome of a mother and daughter with a new mutation R227Q in exon 6 of the p63 gene. This has not been previously associated with ADULT syndrome but only seen in EEC. In addition to the previously reported features of ADULT syndrome this report also describes some additional findings including hyperextensibility at the distal interphalageal joints, bilateral thumb duplication, bifid toenails, symptoms of urinary retention, vesicoureteric reflux, prominent ears, conductive hearing loss, and an overgrowth of a patch of hair in the midline of the neck. This report expands the knowledge of genotype-phenotype data on the p63 gene and suggests there may be a considerable overlap between the EEC syndrome and the ADULT syndrome.

The Hay Wells Syndrome-Derived TAp63αQ540L Mutant has Impaired Transcriptional and Cell Growth Regulatory Activity

P63 mutations have been associated with several human hereditary disorders characterized by ectodermal dysplasia such as EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome, ADULT (acro, dermato, ungual, lacrimal, tooth) syndrome and AEC (ankyloblepharon, ectodermal dysplasia, clefting) syndrome (also called Hay-Wells syndrome). The location and functional effects of the mutations that underlie these syndromes reveal a striking genotype-phenotype correlation. Unlike EEC and ADULT that result from missense mutations in the DNA-binding domain of p63, AEC is solely caused by missense mutations in the SAM domain of p63. In this paper we report a study on the TAp63α isoform, the first to be expressed during development of the embryonic epithelia, and on its naturally occurring Q540L mutant derived from an AEC patient. To assess the effects of the Q540L mutation, we generated stable cell lines expressing TAp63α wt, δNp63α or the TAp63αQ540L mutant protein and used them to systematically compare the cell growth regulatory activity of the mutant and wt p63 proteins and to generate, by microarray analysis, a comprehensive profile of differential gene expression. We found that the Q540L substitution impairs the transcriptional activity of TAp63α and causes misregulation of genes involved in the control of cell growth and epidermal differentiation.

Acro‐dermato‐ungual‐lacrimal‐tooth (ADULT) syndrome: Report of a child with phenotypic overlap with ulnar‐mammary syndrome and a new mutation in TP63

We report on a new patient with clinical findings consistent with acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome. The child had sparse hair, extensive freckling, lacrimal duct stenosis, oligodontia, dystrophic nails, reduced sweating, and bilateral athelia. Examination of his hands showed ulnar ray hypoplasia with bilateral fifth finger brachydactyly and camptodactyly. He also had surgical repair of an imperforate anus. Mutation analysis of TP63 showed a single nucleotide substitution, c.G518A, predicting a novel missense mutation, p.V114M in exon 4. This is the third mutation to be reported in TP63 in ADULT syndrome.

ADULT ectodermal dysplasia syndrome resulting from the missense mutation R298Q in the p63 gene

Several ectodermal dysplasia syndromes have been shown to result from mutations in the gene that encodes the transcription factor p63. We describe an 11-year-old boy, with clinically normal parents, who had a developmental disorder that resembled EEC (ectrodactyly ectodermal dysplasia-clefting) syndrome (OMIM 604292). He had ectrodactyly and missing middle fingers bilaterally, onychodysplasia, hypodontia with missing teeth, hypohidrosis and lacrimal duct obstruction. DNA sequencing disclosed a heterozygous G-->A substitution at nucleotide 893, that converts an arginine residue (CGA) to glutamine (CAA), the mutation being designated R298Q. This mutation occurs within the DNA-binding domain of p63, and is close to many of the published EEC syndrome mutations. However, R298Q has been described once previously in a large German pedigree, not with EEC syndrome, but another ectodermal dysplasia disorder, ADULT (acro-dermato-ungual-lacrimal-tooth) syndrome (OMIM 103285). Further clinical assessment in our patient revealed that, apart from not having cleft lip and/or palate, he had an exfoliative dermatitis of his hands and feet, and some freckling on his face and shoulders. Collectively, these features support a diagnosis of ADULT syndrome. This study has identified a specific genotype-phenotype correlation in a rare ectodermal dysplasia syndrome and the findings are useful in improving genetic counselling in this family.

Gain-of-function mutation in ADULT syndrome reveals the presence of a second transactivation domain in p63

The transcriptional co-activator p63 is of crucial importance for correct development of the limbs, ectodermal appendages (skin, nails, teeth, hair, glands), lip and palate. Mutations in the p63 gene are found in a number of human syndromes, including ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome, limb-mammary syndrome (LMS), Hay-Wells syndrome and in non-syndromic split-hand/split-foot malformation (SHFM). Each syndrome has a specific pattern of mutations with different functional effects in in vitro functional assays. We report a mutation R298Q in acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome, another EEC-like condition. The mutation is located in the DNA binding domain of p63, which harbors almost all EEC associated mutations. However, unlike mutations in EEC syndrome, the R298Q ADULT syndrome mutation does not impair DNA binding. Rather, the mutation confers novel transcription activation capacity on the DeltaN-p63gamma isoform, which normally does not possess such activity. These results confirm that ADULT syndrome is a clinically as well as molecularly distinct member of the expanding p63 mutation family of human malformation syndromes. Our results further show that p63 contains a second transactivation domain which is normally repressed and can become activated by mutations in the DNA binding domain of p63.

ADULT‐syndrome: An autosomal‐dominant disorder with pigment anomalies, ectrodactyly, nail dysplasia, and hypodontia

We describe a family with at least seven living persons who are affected by an hitherto undescribed autosomal-dominant syndrome with variable expression, bearing close resemblance to the EEC syndrome and related disorders. The main manifestations are hypodontia and/or early loss of permanent teeth, ectrodactyly, obstruction of lacrimal ducts, onychodysplasia, and excessive freckling. We propose the acronym ADULT (acro-dermato-ungual-lacrimal-tooth)-syndrome for this condition.