Rapp-Hodgkin Syndrome Research Articles

A spectrum of TP63-related disorders with eight affected individuals in five unrelated families

TP63-related disdorders broadly involve varying combinations of ectodermal dysplasia (sparse hair, hypohydrosis, tooth abnormalities, nail dysplasia), cleft lip/palate, acromelic malformation, split-hand/foot malformation/syndactyly, ankyloblepharon filiforme adnatum, lacrimal duct obstruction, hypopigmentation, and hypoplastic breasts and/or nipples. TP63-related disorders are associated with heterozygous pathogenic variants in TP63 and include seven overlapping phenotypes; Ankyloblepharon‐ectodermal defects‐cleft lip/palate syndrome (AEC), Ectrodactyly‐ectodermal dysplasia‐cleft lip/palate syndrome 3 (EEC3), Limb‐mammary syndrome (LMS), Acro‐dermo‐ungual‐lacrimal‐tooth syndrome (ADULT), Rapp–Hodgkin syndrome (RHS), Split-hand/foot malformation 4 (SHFM4), and Orofacial cleft 8. We report on five unrelated families with 8 affected individuals in which the probands presented with varying combinations of ectodermal dysplasia, cleft lip/palate, split-hand/foot malformation, lacrimal duct obstruction, and ankyloblepharon filiforme adnatum. The clinical diagnosis involved AEC syndrome (2 patients), EEC3 syndrome (2 patients), and a yet hitherto unclassified TP63-related disorder. Sanger sequence analysis of the TP63 gene was performed revealing five different variants among which four were novel and three were de novo. The identificated TP63 variants co-segregated with the other affected individuals in the families. The abnormalities of ectoderm derived structures including hair, nails, sweat glands, and teeth should alert the physician to the possibility of TP63-related disorders particularly in the presence of orofacial clefting.

Adalimumab Experience in the Management of Hidradenitis Suppurativa Burdened with Rapp-Hodgkin Syndrome

Background. Rapp-Hodgkin syndrome is a rare genetic disease from the ectodermal dysplasia group. It manifests with damage of ectodermal structures — layer of embrional tissue that provides the development of many organs and tissues in the body, such as: skin, sweat glands, hair, teeth, and nails. Disease symptoms may range from mild to severe and include dental abnormalities, fragile, thin or no hair, abnormal nails, hypohidrosis (due to the reduced number of sweat glands), cleft lips and palate. Hidradenitis suppurativa is a chronic inflammatory disease that predominantly affects apocrine glands areas. This nosology is characterized by painful nodes, abscesses, and fistulas, prone to relapses and leading to scarring.Clinical case description. The authors present a clinical case demonstrating the combination of Rapp-Hodgkin syndrome and severe hidradenitis suppurativa in 17-year-old male patient.Conclusion. The heterogeneous clinical findings of hidradenitis suppurativa and history of rare genetic disease result in patients' admissions to various medical specialists. Thus, it leads to delayed verification of the diagnosis and incorrect treatment methods. As a result, patients have persistent cosmetic skin defects, possible complications of irrational treatment, and decreased quality of life by the time of diagnosis.

A novel TP63 variant in a patient with ankyloblepharon-ectodermal defect–cleft lip/palate syndrome and Rapp–Hodgkin syndrome-like ectodermal dysplasia

Ankyloblepharon-ectodermal defect–cleft lip/palate syndrome and Rapp–Hodgkin syndrome are well-known TP63-related autosomal-dominant genetic disorders with various similar ectodermal dysplasias. In this study, whole-exome sequencing revealed a novel, potentially pathogenic TP63 nonsense variant (NM_001114980.2:c.25 C > T: p.Gln9Ter) in a patient with an atypical clinical phenotype. This variant was detected near translation initiation sites and has an effect only on ΔNp63α, the short isoform protein product of the TP63 gene.

Pili Torti: A Feature of Numerous Congenital and Acquired Conditions.

Pili torti is a rare condition characterized by the presence of the hair shaft, which is flattened at irregular intervals and twisted 180° along its long axis. It is a form of hair shaft disorder with increased fragility. The condition is classified into inherited and acquired. Inherited forms may be either isolated or associated with numerous genetic diseases or syndromes (e.g., Menkes disease, Björnstad syndrome, Netherton syndrome, and Bazex-Dupré-Christol syndrome). Moreover, pili torti may be a feature of various ectodermal dysplasias (such as Rapp-Hodgkin syndrome and Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome). Acquired pili torti was described in numerous forms of alopecia (e.g., lichen planopilaris, discoid lupus erythematosus, dissecting cellulitis, folliculitis decalvans, alopecia areata) as well as neoplastic and systemic diseases (such as cutaneous T-cell lymphoma, scalp metastasis of breast cancer, anorexia nervosa, malnutrition, cataracts, and chronic graft-vs.-host disease). The condition may also be induced by several drugs (epidermal growth factor receptor inhibitors, oral retinoids, sodium valproate, and carbamide perhydrate). The diagnosis of pili torti is based on trichoscopic or microscopic examination. As pili torti is a marker of numerous congenital and acquired disorders, in every case, the search for the signs of underlying conditions is recommended.

Mutations in P63 and IRF-6 Present with Overlapping Craniofacial Defects: A study from Lebanon

Interferon Regulatory Factor 6 (IRF-6) and p63 are two vital transcription factors implicated in normal craniofacial development. In this report, we present a family with Van Der Woude Syndrome (VWS) with a mutation in exon 9 of IRF-6 gene and a phenotypically overlapping case of Rapp-Hodgkin Syndrome (RHS) resulting from a mutation in the p63 gene. Members from both families presented with congenital lip pits and cleft lip/palate. The RHS case had additional ectodermal features that underscore the upstream nature of p63 in the complex p63-IRF-6 interactive pathway.

Rapp Hodgkin Syndrome.

Rapp Hodgkin Syndrome.

Dental management of Rapp-Hodgkin syndrome associated with oral cleft and hypodontia.

Rapp-Hodgkin syndrome (RHS) is a rare type of autosomal dominant disorder characterized by association of ectodermal dysplasia (ED) with cleft lip/palate. The main features include dry, brittle hair with alopecia in adulthood, dental anomalies (hypodontia, microdontia with delayed eruption, fissured tongue, and retruded maxilla), hypohidrosis, dysplastic nails, and clefting. Palmar-plantar keratoderma is seen frequently. RHS has signs and symptoms that overlap considerably with those of ankyloblepharon-ED-clefting syndrome and ectrodactyly-ED-clefting syndrome. This manuscript discusses a case of RHS, one of the four members in three generations who had ED with variable degree of involvement of hair, teeth, nail, and sweat glands.

Clinical Variability in a Family with an Ectodermal Dysplasia Syndrome and a Nonsense Mutation in the TP63 Gene

Mutations in the TP63 gene have been associated with a variety of ectodermal dysplasia syndromes, among which the clinically overlapping Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) and the Rapp-Hodgkin syndromes. We report a multiplex nonconsanguineous family of Ashkenazi-Jewish descent, in which the index patient presented with a persistent scalp skin lesion, dystrophic nails and light thin hair. Further evaluation revealed over 10 affected individuals in the kindred, over four generations, exhibiting varying degrees of ectodermal involvement. Analysis of the TP63 gene from four of the patients and from two healthy individuals of the same family was performed. Gene sequencing of the patients revealed a nonsense mutation leading to a premature termination codon (PTC) (p.Gln16X). The same mutation was found in all tested affected individuals in the family, but gave rise to marked phenotypic variability with minor clinical manifestations in some individuals, underscoring the clinical heterogeneity associated with the recently described PTC-causing mutations.

Cicatricial External Auditory Canal Stenosis Caused by Ectodermal Dysplasia: Rapp-Hodgkin Syndrome

We present a case of recurrent cicatricial stenosis of the external ear canals caused by ectodermal dysplasia, specifically Rapp-Hodgkin syndrome, in a 45-year-old woman. No form of medical or surgical management has produced durable patency of the patient's ear canals, and her hearing loss is being managed with hearing aids. Topical management of the recurring external otitis slows the process but has been unsuccessful in preventing restenosis of both external auditory canals.

Gene p63: In ectrodactyly-ectodermal dysplasia clefting, ankyloblepharon-ectodermal dysplasia, Rapp-Hodgkin syndrome

Introduction:An analysis was made of three different syndromes associated with p63 gene mutations, known as ectrodactyly–ectodermal dysplasia-clefting syndrome (EEC), ankyloblepharon–ectodermal dysplasia clefting syndrome (AEC or Hay–Wells) and Rapp–Hodgkin syndrome (RHS). The postoperative complications associated with their cleft reconstructions were also evaluated.Materials and Methods:Extensive demographic information, in particular of the clinical appearances, associated malformations, and the types and complications of the reconstructive surgical procedures, were recorded of these syndromic cases occurring in a database of 3621 facial cleft deformity patients. The data was analyzed using the Microsoft Excel program.Results:A total of 10 (0.28%) cases of p63 associated syndromes were recorded: EEC (6), RHS (3), and AEC (1). The following clinical cleft appearances were noted – EEC = 6: CLA 1 -right side unilateral (female); CLAP 4 – right side (1) + left side (1) unilateral (male + female); bilateral (2) (males); hPsP 1 (female) (divided in 3 Black, 2 White, 1 Indian); RHS = 3: CLAP 2 (White males); hPsP 1 (White female); AEC = 1: CLAP bilateral (White male). Other features of the syndromes were: skin, hand, foot, tooth, hair and nail involvement, and light sensitivity. Postoperative complications included: (i) stenosis of nasal opening, especially after reconstruction of the bilateral cleft lip and the columella lengthening (2 cases), (ii) premaxilla-prolabium fusion (2 cases), (iii) repeated occurrence of oro-nasal fistula in the hard palate (4 cases), and (iv) dysgnathial development of midfacial structures (3 cases).Discussion:Three different p63 associated syndromes (EEC, AEC, and RHS) were diagnosed (0.27% of the total facial cleft deformities database). The majority of the cases presented with a bilateral CLAP in males only. A number of females and males had unilateral CLA. The hPsP-cleft was recorded in females only. The associated ectodermal component most probably had a profoundly negative influence on postoperatively wound healing, which was observed in particular at the nasal openings, the premaxilla sulcus and in the hard palate mucosa. The reconstruction of p63 associated syndromes is a greater challenge than the usual cleft reconstruction to the surgeon.

Two interesting cases of EEC syndrome

AimTo report two cases of EEC syndrome with oral involvement to highlight the fact that the dental surgeon may be among the first to recognise the condition. IntroductionThe EEC syndrome, a rare congenital syndrome is characterised by ectodermal dysplasia, distal limb anomaly, cleft lip and palate and lachrymal duct anomalies although the term oligosymptomatic EEC syndrome has been suggested for cases in which ectrodactyly may be absent and that such cases should not be deprived of the EEC syndrome diagnosis. It is usually inherited as an autosomal dominant trait with variable expressivity and penetrance and all these features rarely coexist in a single individual. ConclusionBoth our cases had all three characteristic features of the EEC syndrome. Other syndromes with overlapping features such as the Rapp–Hodgkin syndrome and the AEC syndrome should be considered in the differential diagnosis of incomplete forms of EEC syndrome. Clinical significanceIt is important to follow an interdisciplinary approach to attain the greatest degree of success possible in the treatment of such cases.

Skin symptoms in four ectodermal dysplasia syndromes including two case reports of Rapp-Hodgkin-Syndrome

The skin, hair and nail changes in four distinct ectodermal dysplasia syndromes are compared and reviewed. These syndromes comprise Christ-Siemens-Touraine syndrome; ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome; ankyloblepharon-ectodermal defects-cleft lip/palate syndrome and Rapp-Hodgkin syndrome. A comprehensive overview of the dermatological signs and symptoms in these syndromes was generated from the database of the Ectodermal Dysplasia Network Germany, the clinical findings in the patients seen in our department and an extensive review of the literature. The findings included abnormalities of skin, sweating, hair and nails. These clinical findings are discussed in relation to the underlying molecular defects known to play a role in these four ectodermal dysplasia syndromes.

Rapp–Hodgkin syndrome and SHFM1 patients: Delineating the p63–Dlx5/Dlx6 pathway

Rapp–Hodgkin Syndrome (RHS) is a genetic disorder resulting from mutations in the TP63 gene encoding p63 transcription factor. p63 is directly associated with a cis-regulatory element on chromosome 7q21 that controls the expression of DLX5 and DLX6 genes which are involved in craniofacial abnormalities and ectrodactyly or split hand/foot malformation (SHFM). Chromosomal deletions on 7q21 locus can result in loss of DXL5/DLX6 and/or in loss/disruption of cis-regulatory elements, at which p63 binds.We report two patients that have in common a p63–Dlx5/Dlx6 pathway dysregulation. One showed growth retardation, craniofacial dysmorphism, syndactyly, developmental delay and a de novo deletion (~8.5Mb) on chromosome 7q21.13–q21.3, including DLX5 and DLX6. The second patient with a clinical diagnosis of RHS showed a de novo heterozygous missense mutation, c. 401G>A (p.G134D), in TP63 (exon 4). Our findings may contribute to a greater understanding of the pathogenic mechanisms underlying disorders caused by TP63 mutations.

Functional characterization of a novel TP63 mutation in a family with overlapping features of Rapp‐Hodgkin/AEC/ADULT syndromes

Heterozygous mutations in TP63 cause a wide spectrum of autosomal dominant developmental disorders variably affecting skin, limbs, and face. TP63 encodes p63, a protein expressed in two main isoforms (Tap63 and ΔNp63) with critical roles in both cell differentiation and development. Some analyses suggest a relationship of the mutation site to the observed clinical picture, although this link is inconsistent. This suggests an appreciable phenotypic continuity within the TP63-related disorders. We report a 3-month-old boy ascertained for congenital scalp erosion and mild features of ectodermal dysplasia. His mother showed full-blown characteristics of Rapp-Hodgkin syndrome plus intense abdominal and popliteal freckling. Molecular investigation identified the novel TP63 mutation c.1697delG. We used a luciferase reporter assay to compare the effects on the p63 transactivation (TA) activity of c.1697delG with that of the p.Arg280Cys and p.Gln634X mutations, associated with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome and isolated split hand/foot malformation, respectively. These results demonstrated complex behavior of c.1697delG in the TA of genes involved in epidermal differentiation and development and shed further light in the physiopathology of TP63-related disorders. © 2011 Wiley Periodicals, Inc.

A newborn with overlapping features of AEC and EEC syndromes

Ectrodactyly, ectodermal dysplasia, clefting (EEC) syndrome is the prototype of several p63 conditions, which include ankyloblepharon, ectodermal dysplasia, clefting (AEC) syndrome, limb-mammary syndrome (LMS), Rapp-Hodgkin syndrome (RHS), ADULT syndrome, and others. All these disorders include combinations of ectodermal dysplasia, orofacial clefting and limb malformations in variable severity. A newborn patient is presented with diffuse erythematous and desquamating skin lesions and anal atresia. She also had sparse and lightly colored thin hair, deeply set eyes, hypoplastic alae nasi, and a short philtrum. Cleft lip/palate and ankyloblepharon were not present. Complete cutaneous syndactyly was present on both hands in between the third and fourth fingers. Mild ectrodactyly was evident on all four extremities in between first and second digits. There was post-axial polydactyly on both feet. Anal atresia was present and defecation occurred through a rectovaginal fistula. The patient represented an interesting overlapping clinical condition between AEC and EEC syndromes. Diffuse skin lesions with excoriation and desquamation suggest AEC syndrome, despite the absence of ankyloblepharon, however; ectrodactyly and polydactyly strongly suggest the EEC syndrome. C308Y mutation in exon 8 of TP63 gene was detected, which was previously described to lead only to EEC syndrome and not to any of the other allelic conditions. These data emphasize the large degree of clinical variability that may be seen for specific TP63 mutations.

Mutation in SAM domain of TP63 is associated with nonsyndromic cleft lip and palate and cleft palate

Mutations in sterile alpha motif (SAM) domain of TP63 have been reported to be associated with ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome and Rapp-Hodgkin syndrome. SAM domain, a protein-protein interaction module, is found in cytoplasmic signaling proteins and several transcriptional regulatory proteins which are involved in development and differentiation. Here, we report on a SAM domain mutation (p.Asp564His) in TP63 that predisposed the patients to have nonsyndromic cleft palate and nonsyndromic cleft lip and palate.

Recognition of p63 by the E3 ligase ITCH: Effect of an ectodermal dysplasia mutant

The E3 ubiquitin ligase Itch mediates the degradation of the p63 protein. Itch contains four WW domains which are pivotal for the substrate recognition process. Indeed, this domain is implicated in several signalling complexes crucially involved in human diseases including Muscular Dystrophy, Alzheimer's Disease, and Huntington Disease. WW domains are highly compact protein-protein binding modules that interact with short proline-rich sequences. The four WW domains present in Itch belong to the Group I type, which binds polypeptides with a PY motif characterized by a PPxY consensus sequence, where x can be any residue. Accordingly, the Itch-p63 interaction results from a direct binding of Itch-WW2 domain with the PY motif of p63. Here, we report a structural analysis of the Itch-p63 interaction by fluorescence, CD and NMR spectroscopy. Indeed, we studied the in vitro interaction between Itch-WW2 domain and p63(534-551), an 18-mer peptide encompassing a fragment of the p63 protein including the PY motif. In addition, we evaluated the conformation and the interaction with Itch-WW2 of a site specific mutant of p63, I549T, that has been reported in both Hay–Wells syndrome and Rapp–Hodgkin syndrome. Based on our results, we propose an extended PPxY motif for the Itch recognition motif (P-P-P-Y-x(4)-[ST]-[ILV]), which includes these C-terminal residues to the PPxY motif.

Rapp-Hodgkin and Hay-Wells ectodermal dysplasia syndromes represent a variable spectrum of the same genetic disorder

Rapp-Hodgkin syndrome (RHS) and Hay-Wells [also known as ankyloblepharon-ectodermal defects-cleft lip/palate (AEC)] syndrome have been designated as distinct ectodermal dysplasia syndromes despite both disorders having overlapping clinical features and the same mutated gene, TP63. To search for TP63 mutations in two unrelated cases of RHS and two of AEC syndrome and to review the TP63 mutation database and clinical descriptions of affected individuals, the goal being to refine genotype-phenotype correlation and to determine the clinical/molecular justification for RHS and AEC continuing to exist as separate entities. Clinical examination of four affected cases and sequencing of genomic DNA using TP63-specific primers. Literature review of published clinical descriptions of RHS and AEC syndrome cases containing TP63 mutation data. Cases of RHS and AEC show considerable clinical overlap, particularly with regard to hypotrichosis and mid-face hypoplasia, and the clinical feature of ankyloblepharon in AEC is often subtle, transient and a poor distinguishing clinical sign. We identified two new and two recurrent heterozygous mutations in TP63: c.1456insA (p.Leu486fsX52), RHS; c.1537T>G (p.Phe513Val), RHS; c.1787delG (p.Gly596fsX68), AEC; and c.1682G>A (p.Gly561Asp), AEC. Including this study, 42 different mutations in TP63 in RHS and AEC have now been reported, three of which are exactly the same in both syndromes. Our clinicopathological and molecular findings indicate that there is no justification for the continued use of eponyms in referring to these particular ectodermal dysplasia syndromes. We support the view that the terms ‘Hay-Wells’ and ‘Rapp-Hodgkin’ should be abandoned in favour of the all-inclusive diagnosis ‘AEC syndrome’, notwithstanding the inconsistency or often transient nature of the ankyloblepharon.

Rapp-Hodgkin Syndrome: Clinical and Dental Findings

Rapp-Hodgkin syndrome is a rare form of ectodermal dysplasia involving the hair, eyes, sweat glands, nails, teeth and palate. This syndrome is characterized by stiff sparse hair with the appearance of steel wool, sparse eyebrows and lashes, cleft palate, absence of lacrimal punctae, epiphora, a decreased number of sweat glands, and dystrophic nails. Cleft palate, hypodontia, abnormal tooth shape, multiple caries, delayed eruption of teeth are the main oral manifestations. In this paper we describe the clinical and dental findings of this syndrome in a 7 year old girl referred to the dental clinic because of severe tooth ache. The dental treatment included root canal treatment, composite restorations, extractions and removable prostheses. This paper highlights features of Rapp-Hodgkin Syndrome and its dental rehabilitation.

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.