Rapp-Hodgkin Syndrome Research Articles

Spectrum of p63 mutations in a selected patient cohort affected with ankyloblepharon‐ectodermal defects‐cleft lip/palate syndrome (AEC)

Heterozygous mutations in the p63 gene underlie a group of at least seven allelic syndromes, including ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC) and Rapp Hodgkin syndrome (RHS), which involves varying degrees of ectodermal dysplasia, orofacial clefting and limb malformations. Mutations in the AEC and Rapp Hodgkin syndromes cluster in the 3' end of the p63 gene. Previously reported mutations are mainly missense and frameshift mutations in exons 13 and 14, affecting the p63alpha-specific SAM (sterile alpha motif) and TI (transactivation inhibitory) domains. A patient cohort affected by AEC syndrome was evaluated during International Research Symposium supported by the National Foundation for Ectodermal Dysplasias. Nineteen patients underwent full clinical evaluations and 18 had findings consistent with a diagnosis of AEC syndrome. These 19 patients, along with 5 additional relatives had genomic DNA analysis. Twenty-one of the 24 participants from 12 families were found to have mutations in the p63 gene. Eleven different mutations were identified; 10 were novel mutations. Eight were missense mutations within the coding region of the SAM domain. Three other mutations were located in exon 14 sequences, which encode the TI domain. The effects of the mutations in the SAM and TI domains are poorly understood and functional studies are required to understand the pathological mechanisms. However, AEC and RHS mutations in the 5' and 3' ends of the p63 gene point towards a critical role of the DeltaNp63alpha isoform for the AEC/RHS phenotype.

Craniofacial and anthropometric phenotype in ankyloblepharon–ectodermal defects–cleft lip/palate syndrome (Hay–Wells syndrome) in a cohort of 17 patients

Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome and Rapp-Hodgkin syndrome are well-characterized clinical entities caused by mutations in the TP63 gene. While AEC and Rapp-Hodgkin had been thought to be clinically distinct entities, the elucidation of their molecular etiology confirmed that they are a clinical continuum as opposed to distinct disorders. We have evaluated 17 patients with AEC syndrome using a systematic clinical approach. In our study, we have identified new features and others that were thought to occur only rarely. These include short stature and poor weight gain with preservation of head circumference in nearly all subjects, trismus in 35% and hypospadias in 78% of males. In addition, we describe the frequency of phenotypic features and demonstrate the extreme clinical variability in the largest cohort of AEC individuals reported in the literature thus far.

A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes

Missense mutations in the 3' end of the p63 gene are associated with either RHS (Rapp-Hodgkin syndrome) or AEC (Ankyloblepharon Ectodermal defects Cleft lip/palate) syndrome. These mutations give rise to mutant p63alpha protein isoforms with dominant effects towards their wild-type counterparts. Here we report four RHS/AEC-like patients with mutations (p.Gln9fsX23, p.Gln11X, p.Gln16X), that introduce premature termination codons in the N-terminal part of the p63 protein. These mutations appear to be incompatible with the current paradigms of dominant-negative/gain-of-function outcomes for other p63 mutations. Moreover it is difficult to envisage how the remaining small N-terminal polypeptide contributes to a dominant disease mechanism. Primary keratinocytes from a patient containing the p.Gln11X mutation revealed a normal and aberrant p63-related protein that was just slightly smaller than the wild-type p63. We show that the smaller p63 protein is produced by translation re-initiation at the next downstream methionine, causing truncation of a non-canonical transactivation domain in the DeltaN-specific isoforms. Interestingly, this new DeltaDeltaNp63 isoform is also present in the wild-type keratinocytes albeit in small amounts compared with the p.Gln11X patient. These data establish that the p.Gln11X-mutation does not represent a null-allele leading to haploinsufficiency, but instead gives rise to a truncated DeltaNp63 protein with dominant effects. Given the nature of other RHS/AEC-like syndrome mutations, we conclude that these mutations affect only the DeltaNp63alpha isoform and that this disruption is fundamental to explaining the clinical characteristics of these particular ectodermal dysplasia syndromes.

Hay‐Wells syndrome in a child with mutation in the TP73L gene

Hay-Wells syndrome is a rare form of ectodermal dysplasia, also known as AEC syndrome (Ankyloblepharon filiforme adnatum, Ectodermal effects, Cleft lip/palate). It is inherited in an autosomal dominant fashion with variable expression, featuring congenital abnormalities of skin, hair, teeth, nail, eccrine and mucous glands. We present a three-month-old boy, born to unaffected parents, with typical clinical findings of AEC syndrome. In this boy, a mutation Ile537Thr (c.1610C>T) in the sterile alpha motive (SAM) domain of the TP73L (p63) gene was detected. Because of the broad spectrum of related syndromes such as Rapp-Hodgkin syndrome, Bowen-Armstrong syndrome, CHAND syndrome and epidermolysis bullosa hereditaria, the diagnosis of AEC should be base don both clinical findings and genetic analysis.

A new mutation in TP63 is associated with age-related pathology

Increases in the number of allelic malformation syndromes have led to their classification according to their pathogenesis rather than their clinical specific phenotype. TP63 (also known as TP73L) mutations have been identified in several such syndromes characterized by autosomal dominant transmission and various combinations of ectodermal dysplasia, limb malformations and orofacial clefting. TP63 has not yet been implicated in early aging phenotype in humans, even though p63 activates a program of cellular senescence and p63-compromised mice display features of accelerated aging. We report on a family with four affected adult females presenting with Rapp-Hodgkin syndrome (RHS), an autosomal dominant clinical entity that associates anhidrotic ectodermal dysplasia with cleft lip and palate. Features between RHS and EEC syndrome (ectrodactyly, ectodermal dysplasia and cleft lip/palate) have led to the recent identification of mutations in the TP63 gene, located on 3q27, in this condition. Our patients present typical clinical features of RHS, but also ophthalmic anomalies such as corneal dystrophy and premature menopause (around 30 years). The latter findings have never been reported in this condition, and could be secondary to a new TP63 deletion that has been identified in this family.

Rapp–Hodgkin ectodermal dysplasia syndrome: The clinical and molecular overlap with Hay–Wells syndrome

We report on the clinical and molecular abnormalities in a 7-month-old girl and her mother with an ectodermal dysplasia disorder that most closely resembles Rapp-Hodgkin syndrome (RHS). At birth, the child had bilateral cleft palate, a narrow pinched nose, small chin, and hypoplastic nipples, and suffered from respiratory distress, feeding difficulties, and poor weight gain, although developmental progress was normal. Her mother had a cleft palate, sparse hair, high forehead, dental anomalies, a narrow nose, dysplastic nails, and reduced sweating. Sequencing of the p63 gene in genomic DNA from both individuals revealed a heterozygous frameshift mutation, 1721delC, in exon 14. This mutation has not been described previously and is the seventh report of a pathogenic p63 gene mutation in RHS. The frameshift results in changes to the tail of p63 with the addition of 90 missense amino acids downstream and a delayed termination codon that extends the protein by 21 amino acids. This mutation is predicted to disrupt the normal repressive function of the transactivation inhibitory domain leading to gain-of-function for at least two isoforms of the p63 transcription factor. The expanding p63 mutation database demonstrates that there is considerable overlap between the molecular pathology of RHS and Hay-Wells syndrome, with identical mutations in some cases, and that these two disorders may in fact be synonymous.

Rapp-Hodgkin syndrome: A review of the aspects of hair and hair color

Rapp-Hodgkin syndrome (RHS) is characterized by hypohidrotic ectodermal dysplasia and cleft lip/palate. This combination of clinical findings is also seen in ankyloblepharon–ectodermal dysplasia–clefting syndrome (AEC) and ectrodactyly–ectodermal dysplasia–clefting syndrome (EEC). 1 Rapp R.S. Hodgkin W.E. Anhidrotic ectodermal dysplasia: autosomal dominant inheritance with palate and lip anomalies. J Med Genet. 1968; 5: 269-272 Crossref PubMed Google Scholar , 2 Priolo M. Lagana C. Ectodermal dysplasias: a new clinical-genetic classification. J Med Genet. 2001; 38: 579-585 Crossref PubMed Scopus (129) Google Scholar , 3 Neilson D.E. Brunger J.W. Heeger S. Bamshad M. Robin N.H. Mixed clefting type in Rapp-Hodgkin syndrome. Am J Med Genet. 2002; 108: 281-284 Crossref PubMed Scopus (10) Google Scholar Although there is much clinical overlap, the presence of ectrodactyly (absence or deficiency of digits) is considered to be unique to EEC and ankyloblepharon (fusion of the eyelid margins) is unique to AEC. The presence of ectodermal dysplasia and oral clefting in combination with a distinctive facies, such as narrow or pinched nose and small mouth, suggests RHS. 4 Bjorklund L. Felding I. Rapp-Hodgkin ectodermal dysplasia. Acta Paediatr Scand. 1991; 80: 93-94 Crossref PubMed Google Scholar , 5 Fosko S.W. Stenn K.S. Bolognia J.L. Ectodermal dysplasias associated with clefting: significance of scalp dermatitis. J Am Acad Dermatol. 1992; 27: 249-256 Abstract Full Text PDF PubMed Scopus (63) Google Scholar , 6 Kantaputra P.N. Pruksachatkunakorn C. Vanittanakom P. Rapp-Hodgkin syndrome with palmoplantar keratoderma, glossy tongue, congenital absence of lingual frenum and of sublingual caruncles: newly recognized findings. Am J Med Genet. 1998; 79: 343-346 Crossref PubMed Scopus (17) Google Scholar , 7 Kantaputra P.N. Hamada T. Kumchai T. McGrath J.A. Heterozygous mutation in the SAM domain of p63 underlies Rapp-Hodgkin ectodermal dysplasia. J Dent Res. 2003; 82: 433-437 Crossref PubMed Scopus (58) Google Scholar The phenotypic similarities have led to much speculation about a genetic relationship among AEC, EEC, and RHS. There is an overlap between RHS and AEC with characteristic RHS facies 8 Cambiaghi S. Tadini G. Barbareschi M. Menni S. Caputo R. Rapp-Hodgkin syndrome and AEC syndrome: are they the same entity?. Br J Dermatol. 1994; 130: 97-101 Crossref PubMed Scopus (50) Google Scholar , 9 Rowan D.M. Scalp dermatitis, ectodermal dysplasia and cleft lip and palate: Rapp-Hodgkin or AEC syndrome. Australas J Dermatol. 1996; 37: 102-103 Crossref PubMed Scopus (20) Google Scholar , 10 Sahin M.T. Turel-Ermertcan A. Chan I. McGrath J.A. Ozturkcan S. Ectodermal dysplasia showing clinical overlap between AEC, Rapp-Hodgkin and CHAND syndromes. Clin Exp Dermatol. 2004; 29: 486-488 Crossref PubMed Scopus (18) Google Scholar and there has been a report 11 Moerman P. Fryns J.P. Ectodermal dysplasia, Rapp-Hodgkin type in a mother and severe ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC) in her child. Am J Med Genet. 1996; 63: 479-481 Crossref PubMed Scopus (28) Google Scholar of a family whose mother has RHS and a son has EEC. Recent genetic molecular studies have shown that AEC, EEC, and RHS represent a wide phenotypic spectrum of a single genetic disorder associated with mutations in the TP63 gene. 7 Kantaputra P.N. Hamada T. Kumchai T. McGrath J.A. Heterozygous mutation in the SAM domain of p63 underlies Rapp-Hodgkin ectodermal dysplasia. J Dent Res. 2003; 82: 433-437 Crossref PubMed Scopus (58) Google Scholar , 12 Bougeard G. Hadj-Rabia S. Faivre L. Sarafan-Vasseur N. Frebourg T. The Rapp-Hodgkin syndrome results from mutations of the TP63 gene. Eur J Hum Genet. 2003; 11: 700-704 Crossref PubMed Scopus (40) Google Scholar , 13 Dianzani I. Garelli E. Gustavsson P. Carando A. Gustafsson B. Dahl N. et al. Rapp-Hodgkin and AEC syndromes due to a new frameshift mutation in the TP63 gene. J Med Genet. 2003; 40: e133 Crossref PubMed Scopus (38) Google Scholar , 14 Bertola D.R. Kim C.A. Albano L.M. Scheffer H. Meijer R. van Bokhoven H. Molecular evidence that AEC syndrome and Rapp-Hodgkin syndrome are variable expressions of a single genetic disorder. Clin Genet. 2004; 66: 79-80 Crossref PubMed Scopus (46) Google Scholar

Spectrum of Phenotypic Manifestations from a Single Point Mutation of the p63 Gene, Including New Cutaneous and Immunologic Findings

Mutations in the p63 gene have been identified in five human disorders characterized by varying degrees of limb anomalies, ectodermal dysplasia, and facial clefts. We report a new point mutation in the p63 gene in a family in which the mother was initially diagnosed with Rapp-Hodgkin syndrome and her two offspring manifested ankyloblepharon, ectodermal defects, cleft lip and palate, syndrome. These three patients are the first to be reported with this particular mutation, which consists of a change from glycine to aspartic acid at position 506 on exon 14. The clinical spectrum observed in the three family members highlights the wide range of phenotypic variations that result from a single point mutation in the p63 gene. The mother lacks certain features classically associated with AEC, dermatitis of the scalp in particular. Severe erosive dermatitis of the scalp developed in both offspring, along with previously undescribed poikilodermatous skin changes and a deficiency of CD4 T lymphocytes. The new and varied phenotypic features noted in these patients emphasize the spectrum of disease caused by mutations in the p63 gene and raise the possibility of a role for it in maintaining immunocompetence.

De novo missense mutation, S541Y, in the p63 gene underlying Rapp-Hodgkin ectodermal dysplasia syndrome

Rapp-Hodgkin syndrome (RHS) is an autosomal dominant disorder characterized by ectodermal dysplasia and cleft lip/cleft palate. Very recently, mutations in p63 have been identified as a cause of RHS; to date five such mutations have been identified. We describe a Thai girl with RHS. She had short stature, ectodermal dysplasia, epiphora, cleft lip, cleft palate, and normal development. Mutation analysis for the entire coding region of p63 identified a novel and de novo mutation, 1622C--> A (S541Y), in the SAM domain, predicting an abnormal alpha tail of the p63alpha protein isotypes. This observation supports that majority of patients with RHS are caused by mutations affecting the tail of p63alpha, a region that also contains most of the pathogenic mutations in ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome.

Rapp-Hodgkin syndrome and the tail of p63

We report the clinical and molecular abnormalities in a 19-year-old woman with Rapp-Hodgkin ectodermal dysplasia syndrome. The physical features include mid-facial hypoplasia, uncombable hair, cleft palate and bifid uvula, lacrimal duct obstruction and dry skin. Sequencing of the p63 gene reveals a new heterozygous frameshift mutation, 1787delG, in exon 14. The frameshift results in changes to the tail of p63 with the addition of 68 missense amino acids downstream and a delayed termination codon that extends the protein length by 21 amino acids. These changes are predicted to disrupt the normal repressive function of the transactivation inhibitory domain leading to gain-of-function for at least two isoforms of the p63 transcription factor. The expanding p63 mutation database demonstrates that there is overlap between Rapp-Hodgkin syndrome and several other ectodermal dysplasia syndromes, notably Hay-Wells syndrome, and that characterization of the functional consequences of these p63 gene mutations at a molecular and cellular level is likely to provide further insight into the clinical spectrum of these developmental malformation syndromes.

Rapp-Hodgkin syndrome

A 5-year-old boy with a history of a bifid uvula and a submucosal cleft palate presented for evaluation of brittle nails. The physical examination demonstrated cup-shaped ears, a broad nasal root, thin upper lip, mid-facial hypoplasia, coarse hair, and twenty-nail dystrophy. The clinical presentation of ectodermal dysplasia with cleft palate was consistent with Rapp-Hodgkin syndrome, which is one of several allelic diseases associated with mutations in the TP63 gene. The clinical manifestations of Rapp-Hodgkin as well as other ectodermal dysplasias with clefting are discussed.

The Rapp-Hodgkin syndrome results from mutations of the TP63 gene.

The Rapp-Hodgkin syndrome (RHS, MIM 129400) corresponds to a rare form of anhydrotic ectodermal dysplasia, which shares some features with the ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome (EEC, MIM 604292) resulting from TP63 mutations. We report here, in two unrelated patients with RHS, the identification of two distinct TP63 mutations, corresponding to a novel frameshift mutation (1709DelA, exon 14) located downstream the sterile alpha motif (SAM) domain and to a missense mutation (R279H, exon 7) within the DNA binding domain. Functional analysis of the R279H mutation, which had previously been reported in several EEC families, shows that this mutation disrupted the dominant negative activity of the DeltaNp63alpha and gamma isoforms on the transcriptional activity of TP53. This report shows, on a molecular basis, that RHS is also an EEC-like syndrome resulting from mutations of the TP63 gene, and highlights the wide phenotypic spectrum associated to TP63 mutations.

Síndrome EEC

Abstract—EEC syndrome is an ectodermal dysplasia with primary involvement of the ectodermal oral and epidermal appendages. It is an autosomal, dominantly inherited condition which has three cardinal signs: ectrodactyly, ectodermal dysplasia, and cleft palate and/or harelip. Skin, hair, teeth, and nails can be affected. In addition to the cardinal symptoms, anomalies in the lacrimal ducts or urogenital anomalies can be part of the syndrome. The differential diagnosis includes other ectodermal dysplasias with cleft palate and with or without harelip such as the Rapp-Hodgkin syndrome and the AEC (ankyloblepharon, ectodermal dysplasia, and cleft palate with or without harelip) syndrome.

Mixed clefting type in Rapp‐Hodgkin syndrome

Mixed clefting type (MCT) is the rare occurrence of cleft lip, with or without cleft palate, and cleft palate alone in the same pedigree. Here we present a family with Rapp-Hodgkin syndrome (RHS) that manifests MCT, and use this rare finding to suggest that RHS may be related not only to phenotypically similar syndromes, but seemingly dissimilar ones as well. RHS has obvious phenotypic overlap with other ectodermal dysplasia-clefting syndromes (EDCS), such as ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC) and ankyloblepharon-ectodermal dysplasia-clefting syndrome (AEC), all of which show MCT. MCT is also found in the allelic disorders van der Woude syndrome (VDW) and popliteal-pterygium syndrome (PPS). Therefore, while VDW and PPS have little clinical overlap with the EDCS, the common finding of MCT may indicate closer relationships at the developmental or genetic level.

A Rapp-Hodgkin like syndrome in three sibs

Rapp-Hodgkin ectodermal dysplasia is an autosomal dominant disorder characterized by distinctive craniofacies, cleft lip or palate, oligodontia or anodontia, hypoplasia of the nails, and a decrease in or absence of the sweat glands and hair follicles. We have identified a family in which three children display clinical features similar to Rapp-Hodgkin syndrome. The father and two other sisters of the patient had normal facial features, but had short stature and had dental anomalies, the latter suggestive of ectodermal dysplasia. The overall clinical, dental, and dermatoglyphic findings of these patients are discussed in relation to reports of families with Rapp-Hodgkin syndrome.

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.

Cephalometric analysis of Rapp-Hodgkin syndrome.

Rapp-Hodgkin syndrome (RHS) is a rare form of ectodermal dysplasia with variable involvement of the hair, eyes, sweat glands, nails, and teeth. Oral findings may include hypodontia, hypoplastic enamel, cleft...

Rapp-Hodgkin syndrome and AEC syndrome: are they the same entity?

Rapp-Hodgkin syndrome and AEC syndrome are two disorders in which ectodermal dysplasia and clefting are associated. Rapp-Hodgkin syndrome is an autosomal dominant condition characterized by cleft lip and palate, peculiar craniofacial features, and ectodermal dysplasia, consisting of abnormalities of teeth, hair, nails and sweating. AEC syndrome manifests the same defects plus ankyloblepharon and a higher frequency of scalp dermatitis. A child affected by ectodermal dysplasia associated with clefting, ankyloblepharon, severe scalp dermatitis, and the characteristic Rapp-Hodgkin facies is reported. The overlap between Rapp-Hodgkin syndrome and AEC syndrome is discussed. Critical review of both disorders suggest that AEC syndrome and Rapp-Hodgkin syndrome represent the same entity.

Rapp-Hodgkin ectodermal dysplasia

Rapp-Hodgkin syndrome is a rare condition that is characterized by ectodermal dysplasia and palatal abnormalities. We describe a 24-year-old white woman who has Rapp-Hodgkin syndrome that is associated with a chronic palmar keratoderma, which is a rinding that has not been previously reported. We review the literature, assign the clinical features into major and minor categories, and suggest therapeutic interventions to limit the significant sequelae of this autosomal dominant syndrome.

Ectodermal dysplasias associated with clefting: Significance of scalp dermatitis

Several clinical syndromes are characterized by ectodermal dysplasia (ED) in association with clefting of the lip and/or palate. The three most commonly recognized entities are (1) the EEC syndrome (ectodermal dysplasia, ectrodactyly, cleft lip/palate); (2) the Rapp-Hodgkin syndrome with ectodermal dysplasia, cleft lip/palate, and mid facial hypoplasia; and (3) the Hay-Wells or AEC syndrome (ankyloblepharon, ectodermal defects, cleft lip/palate). The clinical characteristics of these entities as well as several less common syndromes are reviewed and summarized. The presence of scalp dermatitis in patients with the AEC syndrome and less often the Rapp-Hodgkin syndrome is emphasized.