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PubMed2002

Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts.

EEC syndrome is an autosomal dominant disorder with the cardinal signs of ectrodactyly, ectodermal dysplasia, and orofacial clefts. EEC syndrome has been linked to chromosome 3q27 and heterozygous p63 mutations were detected in unrelated EEC families. In addition, homozygous p63 null mice exhibit craniofacial abnormalities, limb truncations, and absence of epidermal appendages, such as hair follicles and tooth primordia. In this study, we screened 39 syndromic patients, including four with EEC syndrome, five with syndromes closely related to EEC syndrome, and 30 with other syndromic orofacial clefts and/or limb anomalies. We identified heterozygous p63 mutations in three unrelated cases of EEC syndrome, two Iowa white families and one sporadic case in a Filipino boy. One family is atypical for EEC and has features consistent with Hay-Wells syndrome. In this family, the mutation ablates a splice acceptor site and, in the other two, mutations produce amino acid substitutions, R280C and R304Q, which alter conserved DNA binding sites. Germline mosaicism was detected in the founder of the mutation in one case. These three cases show significant interfamilial and intrafamilial variability in expressivity. We also screened p63 in 62 patients with non-syndromic orofacial clefts, identifying an intronic single nucleotide polymorphism but finding no evidence of mutations that would explain even a subset of non-syndromic orofacial clefts. This study supports a common role for p63 in classical EEC syndrome, both familial and sporadic, but not in other related or non-syndromic forms of orofacial clefts.

Abnormalities, Multiple↗
PubMed2026

Uncovering phenotypic expansion in AXIN2-related disorders through precision animal modeling.

PURPOSE: Heterozygous pathogenic variants in AXIN2 (HGNC: 904) cause oligodontia-colorectal cancer syndrome. We identified 5 individuals with de novo heterozygous variants [NM_004655.4:c.196G>A p.(Glu66Lys), c.197A>G p.(Glu66Gly), and c.199G>A p.(Gly67Arg)] in AXIN2. Common phenotypes among these individuals included ectodermal dysplasia, global developmental delay, microcephaly, and limb, ophthalmologic, and genitourinary abnormalities. METHODS: Structural modeling was performed to predict the impact of these variants on AXIN2. A prime editing N1 screen of mouse embryos was performed to test whether the p.Glu66Lys variant produces a phenotype. Drosophila models were used to test the effect of this variant on Wnt signaling. RESULTS: Structural modeling suggests that these variants disrupt AXIN2 binding to tankyrase, which regulates AXIN2 levels through poly-ADP-ribosylation. Heterozygous (p.Glu66Lys) mouse embryos were perinatally lethal with soft palate clefts and skeletal abnormalities. Modeling of the p.Glu66Lys variant in the Drosophila wing suggests gain-of-function or dominant-negative activity compared to reference AXIN2. CONCLUSION: Specific variants in the tankyrase-binding domain of AXIN2 are pathogenic, leading to phenotypic expansion with potential context-dependent effects on AXIN2 function and Wnt signaling. The N1 modeling strategy used to demonstrate variant pathogenicity may be beneficial for resolving other heterozygous variants associated with congenital anomalies.

AXIN2↗
PubMed1999

Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1.

Pachyonychia congenita (PC) is a group of inherited ectodermal dysplasias, the characteristic phenotype being hypertrophic nail dystrophy. Two main clinical subtypes, PC-1 and PC-2, are inherited as autosomal dominant disorders, but other less well characterized clinical forms also exist. The PC-1 phenotype may be distinguished by the absence of the epidermal cysts found in PC-2, and it has been shown to be caused by mutations in either keratin K16 or its expression partner, the K6a isoform of K6. Mutations in K16 have also been shown to cause a milder related phenotype, focal non-epidermolytic palmoplantar keratoderma. Recently, we have developed a long-range polymerase chain reaction (PCR) strategy which allows specific amplification of the entire functional K16 gene (KRT16A), without amplification of the two K16 pseudogenes (psiKRT16B and psiKRT16C), enabling mutation analysis based on genomic DNA. Here, using this methodology, we describe novel mutations R127P and Q122P in the helix 1A domain of K16 in two families presenting with PC-1. Both mutations were excluded from 50 normal unrelated individuals by restriction enzyme analysis of K16 PCR fragments. In one family, ultrastructural analysis was performed, revealing distinctive tonofilament abnormalities. Specifically, keratin filament bundles were greatly condensed, but did not form the dense amorphous aggregates seen in a number of other keratin disorders. In the second kindred, autosomal dominant cataract was present in some but not all members affected by PC. As the cataract phenotype did not fully cosegregate with the K16 mutation, and given that K16 is not expressed in the lens, these two phenotypes may be coincidental.

Cataract↗
PubMed2002

Different morphotypes of the tabby (EDA) dentition in the mouse mandible result from a defect in the mesio-distal segmentation of dental epithelium.

OBJECTIVES: Prenatal identification of the different dentition morphotypes, which exist in the lower molar region of tabby (Ta) adult mice, and investigation of their origin. The mouse Ta syndrome and its counterpart anhidrotic (hypohidrotic) ectodermal dysplasia (EDA) in human are characterized by absence or hypoplasia of sweat glands, hair and teeth. DESIGN: Analysis of tooth morphogenesis using serial histological sections and 3D computer aided reconstructions of the dental epithelium in the cheek region of the mandible. SETTING AND SAMPLE POPULATION: Institute of Experimental Medicine, Academy of Sciences, Prague. Heads of 75 Ta homozygous and hemizygous mice and 40 wild type (WT) control mice aged from embryonic day (ED) 14.0-20.5 (newborns), harvested during 1995-2001. OUTCOME MEASURE: Prenatal identification of five distinct morphotypes of Ta dentition on the basis of differences in tooth number, size, shape, position and developmental stage and of the morphology of the enamel knot in the most mesial tooth primordium. RESULTS: The mesio-distal length of the dental epithelium was similar in the lower cheek region in Ta and WT mice. In Ta embryos, there was altered the mesio-distal segmentation of the dental epithelium giving rise to the individual tooth primordia. Prenatally, two basic morphotypes I and II and their particular subtypes (Ia, Ib, Ic, and IIa, IIb, respectively) of the developing dentition were identified from day 15.5. The incidence of the distinct morphotypes in the present sample did not differ from postnatal data. The proportion of the morphotype I and II was dependent on mother genotype. CONCLUSION: The different dentition morphotypes in Ta mice originate from a defect in the mesio-distal segmentation of the dental epithelium in mouse embryos. This defect presumably leads to variable positions of tooth boundaries that do not correspond to those of the WT molars. One tooth primordium of Ta mice might be derived from adjacent parts of two molar primordia in WT mice.

Animals↗
PubMed2001

p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation.

p63 mutations have been associated with EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate), as well as with nonsyndromic split hand-split foot malformation (SHFM). We performed p63 mutation analysis in a sample of 43 individuals and families affected with EEC syndrome, in 35 individuals affected with SHFM, and in three families with the EEC-like condition limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cleft palate, and mammary-gland abnormalities. The results differed for these three conditions. p63 gene mutations were detected in almost all (40/43) individuals affected with EEC syndrome. Apart from a frameshift mutation in exon 13, all other EEC mutations were missense, predominantly involving codons 204, 227, 279, 280, and 304. In contrast, p63 mutations were detected in only a small proportion (4/35) of patients with isolated SHFM. p63 mutations in SHFM included three novel mutations: a missense mutation (K193E), a nonsense mutation (Q634X), and a mutation in the 3' splice site for exon 5. The fourth SHFM mutation (R280H) in this series was also found in a patient with classical EEC syndrome, suggesting partial overlap between the EEC and SHFM mutational spectra. The original family with LMS (van Bokhoven et al. 1999) had no detectable p63 mutation, although it clearly localizes to the p63 locus in 3q27. In two other small kindreds affected with LMS, frameshift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 is the major gene for EEC syndrome, and that it makes a modest contribution to SHFM. There appears to be a genotype-phenotype correlation, in that there is a specific pattern of missense mutations in EEC syndrome that are not generally found in SHFM or LMS.

Alternative Splicing↗
PubMed1987

[Cloverleaf skull associated with generalized bone defects close to asphyxiating thoracic dysplasia].

The association of cloverleaf skull and micromelia is reputed. X-ray images of the skull are typical; those of the skeleton are compatible with the thoracic dysplasia reported by Jeune, or with chondro-ectodermic dysplasia: short ribs, horizontal roof of the acetabulum with a rounded median prominence and lateral spurs, deformed long bones with broad metaphyses, absent ossification of the terminal phalanges. The mode of inheritance of the syndrome is probably autosomal recessive. The association reported is undescribed until now, although cloverleaf skull can be associated with other bone deformities. Most often the latter are thanatophoric dwarfism or a syndrome including ankylosis of the elbow joints, occasionally of the knees, club-foot, syndactyly and absent phalanges.

Abnormalities, Multiple↗
PubMed2006

Exclusion of p63 as a candidate gene for autosomal-dominant amelogenesis imperfecta.

OBJECTIVE: Mutations within the p63 gene have been shown to cause ectodermal dysplasia syndromes affecting a spectrum of developmental abnormalities, including ectodermal appendages, e.g. enamel. The affected teeth have a similar phenotype as another dental disorder, amelogenesis imperfecta (AI), a disease of genetically determined abnormal enamel formation in the absence of systemic symptoms. The genetic basis of particular forms of AI has been found, although the gene(s) responsible for the most prevalent AI types has not been identified. MATERIAL AND METHODS: DNA samples of 41 individuals (25 affected and 16 unaffected) from 6 Swedish families with autosomal-dominant AI were screened for mutations (by partially denaturing HPLC) and sequenced. RESULTS: No mutation in p63 was found in these families. CONCLUSIONS: p63 is not responsible for different forms of autosomal-dominant AI in the Swedish families studied. The roles of p63 in tooth development and in the genetic etiology of AI remain to be identified.

Amelogenesis Imperfecta↗
PubMed2000

[Etiopathogenesis of arrhythmogenic right ventricular dysplasia].

Arhythmogenic right ventricular dysplasia (ARVD) is a genetically determined cardiomyopathy with a dominant transmission mode and variable penetrance. Transdifferenciation of cardiomyocytes into adipocytes is likely to explain massive replacement of right ventricular and to a lesser extent left ventricular myocardium by adipose tissue. This phenomenon starts in the mediomural layers and extends into the epicardium. It can occur in the fetus, however youth and young adults are more frequently involved. Apoptosis defined as a programmed cell death, is likely to enhance adipogenesis and tiny fibrosis production. Inflammation can be superimposed on the genetically determined substrate and usually involves both ventricles. Myocarditis can be acute or chronic with interstitial or scar fibrosis, or active chronic. In some cases, left ventricular involvement can be as important as right ventricle, characterizing biventricular dysplasia. In Naxos disease, ARVD is associated with an ectodermic dysplasia. The transmission mode is recessive.

Adipose Tissue↗
PubMed1978

Chondroectodermal dysplasia (Ellis--van Creveld syndrome) with dysplasia of renal medulla and bile ducts.

A case of a 28-month-old boy with chondroectodermal dysplasia (Ellis-van Creveld syndrome) is reported. Besides polydactyly, ectodermal dysplasia, acromelic dwarfism and congenital heart defect, which are characteristic morphologic features of the syndrome, additional dysplastic developmental defects were discovered in the kidneys, liver, and lungs. Detailed histopathologic studies of the growth plates of tibia, femur and ribs disclosed an irregular, partly hyperplastic, partly dystrophic appearance of the epiphyseal cartilage, which was not resorbed properly by the invading blood vessels. Focal areas of necrosis occurred and barriers of tongue-shaped cartilaginous peninsulas persisted. Regular enchondral ossification was hindered and compensatory membrane ossification was found in the fibrosing metaphyseal bone marrow adjacent to the cartilage. Dysplasia and fibrosis of the renal medulla plus interstitial fibrosing nephritis in the cortex resulted in kidney contraction and renal failure. Hepatomegaly, portal fibrosis and bile duct hyperplasia and dysplasia were detected at autopsy, but did not have any clinical significance. These findings once again emphasize that derivatives of all three germ layers are involved in the Ellis-van Creveld syndrome. The possibility that a single metabolic or structural abnormality of the mesenchymal tissues could be responsible for the various organ dysplasias is discussed.

Bile Ducts↗
PubMed2002

Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar.

X-linked and autosomal forms of anhidrotic ectodermal dysplasia syndromes (HED) are characterized by deficient development of several ectodermal organs, including hair, teeth and exocrine glands. The recent cloning of the genes that underlie these syndromes, ectodysplasin (ED1) and the ectodysplasin A receptor (EDAR), and their identification as a novel TNF ligand-receptor pair suggested a role for TNF signaling in embryonic morphogenesis. In the mouse, the genes of the spontaneous mutations Tabby (Ta) and downless (dl) were identified as homologs of ED1 and EDAR, respectively. To gain insight into the function of this signaling pathway in development of skin and hair follicles, we analyzed the expression and regulation of Eda and Edar in wild type as well as Tabby and Lef1 mutant mouse embryos. We show that Eda and Edar expression is confined to the ectoderm and occurs in a pattern that suggests a role of ectodysplasin/Edar signaling in the interactions between the ectodermal compartments and the formation and function of hair placodes. By using skin explant cultures, we further show that this signaling pathway is intimately associated with interactions between the epithelial and mesenchymal tissues. We also find that Ta mutants lack completely the placodes of the first developing tylotrich hairs, and that they do not show patterned expression of placodal genes, including Bmp4, Lef1, Shh, Ptch and Edar, and the genes for beta-catenin and activin A. Finally, we identified activin as a mesenchymal signal that stimulates Edar expression and WNT as a signal that induces Eda expression, suggesting a hierarchy of distinct signaling pathways in the development of skin and hair follicles. In conclusion, we suggest that Eda and Edar are associated with the onset of ectodermal patterning and that ectodysplasin/edar signaling also regulates the morphogenesis of hair follicles.

Activins↗
PubMed1985

Ultrasonic demonstration of fetal skeletal dysplasia. Case reports.

Reports on prenatal diagnosis in cases of skeletal dysplasia have mostly been in high-risk mothers with a suspect genetic background where the fetal lesion could probably be predetermined. We deal with routine ultrasonographic appraisal of the fetal skeleton when dysplasia is not initially suspected, and relate our experience of the lethal forms of this condition. During the 4-year period 1981-1984, 6 cases of skeletal dysplasia, including thanatophoric dysplasia, achondrogenesis, the Ellis-van Creveld syndrome (chondro-ectodermal dysplasia) and osteogenesis imperfecta, were detected; the ultrasonographic findings are discussed.

Bone Diseases, Developmental↗
PubMedDate not supplied

Ellis-van Creveld Syndrome: a report of two cases.

Ellis-van Creveld syndrome (EVC) or chondroectodermal dysplasia, a rare autosomal recessive disorder, is a tetrad of chondrodysplasia, ectodermal dysplasia, polydactyly, and congenital heart disease, of which chondrodystrophy of the tubular bones is the most common feature, while central nervous system (CNS) and urinary tract anomalies are some of its rarer associations. This report describes EVC syndrome in two sisters of Indian origin, ages 8 and 6 years, the products of nonrelated, unaffected parents. The patients had chondrodysplasia of tubular bones resulting in disproportionate dwarfism, polydactyly, severely dystrophic nails, partially absent teeth, and short and bound-down upper lips with multiple frenulae. Other features noted in the girls were syndactyly and mild mitral regurgitation. All four of the classic features of EVC syndrome were present in patient 1 and three in patient 2. Additional findings were ichthyosis and plantar keratoderma in the former and absent clavicles in the latter, which have not been reported previously. The importance of prenatal diagnosis of EVC is stressed and a multidisciplinary approach for the management of these patients is highlighted.

Child↗
PubMed1997

Ocular manifestations in a father and son with EEC syndrome.

BACKGROUND: The ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is a rare disease which follows an autosomal-dominant pattern of inheritance. Due to the ectodermal dysplasia there is atresia of the lacrimal duct system and aplasia of the meibomian glands with a defective tear film. Therefore, vascularized corneal scars often form during early adult life. PATIENTS: Father aged 41 years, and son aged 23 months. Both patients: stenosis/atresia of lacrimal duct systems (the father had twice undergone dacryocystorhinostomy externally) with epiphora, lip-palate clefting, syndactylies of fingers and toes, lobster deformities of hands. Additional ophthalmological findings in the father: bilaterally extracted juvenile cataracts with implantation of intraocular lenses, bilateral extensive vascularized corneal scars. Additional dermatological findings in the father: malignant melanoma of the calf, now in complete remission following several operations on the melanoma and several cycles of chemotherapy for the metastases. DISCUSSION AND THERAPEUTIC CONCLUSIONS: Father and son show the full clinical picture of the EEC syndrome with clefting, lobster-like deformities of the hands and ectodermal dysplasia with tear duct atresia and aplasia of the meibomian glands with defective tear film. During childhood, the main handicapping features are the clefting and the hand deformities with their respective multiple operative revisions. During early adulthood, however, the ocular problems become the predominantly handicapping aspects of the EEC syndrome; due to the ectodermal dysplasia, vascularized corneal scarring develops. Tearing and secondary inflammation due to lacrimal duct atresia has to be treated by early dacryocystorhinostomy. As secondary infections promote the development of corneal scars, one should not postpone the operation too long. Infections have to be treated promptly by local antibiotics. Because of the aplasia of the meibomian glands, artificial tear substitution should be given on a regular basis to support the defective tear film. Thus, the development of vascularized corneal scars can perhaps be delayed. Once corneal scarring has developed, perforating keratoplasty has a poor prognosis due to the ectodermal dysplasia, the absence of the meibomian glands and the defective tear film. Three factors lead to the formation of vascularized corneal scars: recurrent infections of lid margins and conjunctiva due to obstructed tear ducts; defective tear film with insufficient lipid phase due to the aplasia of the meibomian glands; and primary corneal epithelial defects in the course of the generalized ectodermal dysplasia.

Adult↗
PubMed1998

[Johanson-Blizzard syndrome. A complex dysplasia syndrome with aplasia of the nasal alae and inner ear deafness].

BACKGROUND: The Johanson-Blizzard syndrome is a rare autosomal recessive syndrome with ectodermal dysplasia. ENT findings in the syndrome include profound bilateral hearing loss, aplasia of the alae nasi and dental malformations. To date approximately 30 cases have been described. CASE REPORT: We report our findings in a female patient who was born as the second child of consanguine parents. Pregnancy was normal, birth weight 3620 g and body length 52 cm. She was hospitalized immediately after birth because of anal atresia and facial dysmorphism with aplastic alae nasi, mongoloid eye slant and slightly dystopic ears. Bilateral symmetric profound hearing loss was diagnosed by subjective hearing tests and confirmed by auditory evoked brainstem potentials. Otoacoustic emissions were absent. Hearing aids were successfully fitted. Other malformations were a duplex of the uterus and vagina and exocrine pancreatic insufficiency. The anal atresia was corrected surgically. DISCUSSION: In general, the exocrine pancreatic insufficiency in the Johanson-Blizzard syndrome requires careful medical management. The aplastic alae nasi require no specific therapy, while in our case in the hearing loss could be treated with hearing aids.

Abnormalities, Multiple↗
PubMed2000

Ellis van Creveld syndrome (chondroectodermal dysplasia, MIM 22550) in three siblings from a non-consanguineous mating.

The major diagnostic features of Ellis van Creveld syndrome (EvC) includes disproportionate short stature, polydactyly, ectodermal anomalies, and structural heart defects. We describe three siblings with EvC of a non-consanguineous mating. The history of these siblings well illustrate the clinical manifestations and complications that children with EvC encounter. All three girls had short stature, narrow rib cage, polydactyly and nail hypoplasia. The first daughter died in early infancy in respiratory failure. The second daughter underwent open heart surgery for atrial septal defect repair. The third daughter, diagnosed in utero with fetal ultrasonography, currently is scheduled for surgical excision of extra-digits and extraction of neonatal teeth. Infant mortality rates among patients with EvC is strikingly high due primarily to cardiorespiratory failure. If they survive infancy morbidity is significant. The gene effected in individuals with EvC has recently been identified on the short arm of chromosome 4. Future testing for gene mutations may provide valuable information for premarital counseling and prenatal diagnosis. Three offspring with disproportionate short stature, polydactyly, and ectodermal dysplasia of a non-consanguineous mating, strongly indicate parental heterozygosity for Ellis van Creveld syndrome.

Adult↗
PubMed1982

[Congenital bilateral amastia in a mother and a daughter (author's transl)].

A 23 year-old primigravida with bilateral congenital amastia was delivered at 38 weeks gestation following early rupture of the membranes. The mature newborn female also showed congenital bilateral amastia. In addition mother and daughter showed a mild hook finger of both 5th fingers. The mother only had 19 permanent teeth. About the permanent in the infant no data were obtained. This type of manifestation of a congenital anhydrotic ectodermal dysplasia is probably due to a sex-linked recessive gene. Newer investigations in experimental embryology show that the complete inhibition of the growth of the ectodermal milkridge occurs in the 6-12 th week of intra-uterine life and may also occur as an embryopathy due to dehydroepiandrosterone.

Adult↗
PubMed2005

Ellis-van Creveld syndrome and dyserythropoiesis.

Ellis-van Creveld (EVC) syndrome or chondroectodermal dysplasia is a rare autosomal recessive disorder characterized by a variable spectrum of clinical findings. Classical EVC syndrome comprises a tetrad of clinical manifestations of chondrodystrophy, polydactyly, ectodermal dysplasia, and cardiac defects. In several case reports, dysplasia involving other organs has also been identified. Hematologic abnormalities have been rarely reported in patients with EVC syndrome. Here, we report a case of a 3-year-old Hispanic boy with EVC syndrome and marked dyserythropoiesis. The dyserythropoiesis may be part of an isolated myelodysplastic change or a primary myelodysplastic syndrome and likely represents an unusual EVC syndrome association. To our knowledge, this association has not been previously reported.

Bone Marrow↗