SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
In this communication, we describe the otologic and audiometric findings of a rare congenital syndrome associated with profound hearing loss. We offer a hypothesis of the possible inner ear pathologic condition. The major anomalies of this syndrome represent features of an ectodermal dysplasia syndrome.
Papillon-Lefevre syndrome (PLS) is an autosomal recessive form of palmoplantar ectodermal dysplasia, characterized by palmoplantar hyperkeratosis and severe early-onset periodontitis. The presence of severe periodontitis distinguishes PLS from other palmoplantar keratodermas. As part of our efforts to study the genetic basis of periodontitis susceptibility, we performed a genome-wide search to identify major loci for PLS in 44 individuals (14 affected) from 10 consanguineous PLS families. We have identified evidence for linkage of a PLS gene on 11q14-q21. A maximum two-point logarithm of the odds (LOD) score of 8.24 was obtained for D11S1367 at a recombination fraction of theta=0.00. Multipoint analysis resulted in a LOD score of 10.45 and placed the gene for PLS within a 4-5 cM genetic interval. This genetic interval, flanked by D11S4197 and D11S931, contains more than 50 cDNAs and 200 expressed sequence tags (ESTs). This refinement of the candidate region for a PLS gene is in agreement with other recent reports of linkage for PLS to chromosome 11q14-q21 and should help in identification of the gene for PLS.
In this article, the contribution of Rudolf Happle to the understanding of X-linked skin diseases is reviewed. In 1977 he proposed functional X-chromosomal mosaicism as the genetic mechanism underlying cutaneous anomalies that were seen in a number of X-linked skin diseases such as incontinentia pigmenti or focal dermal hypoplasia. Moreover, he recognized that these cutaneous anomalies followed the lines of Blaschko and thus he could tie in the development of the lines of Blaschko with a datable embryonic event. Convincing proof for the concept of functional X-chromosomal mosaicism was later provided by his group from functional sweat studies in female carriers of the X-linked gene defect hypohidrotic ectodermal dysplasia showing again on the back of the patient a gross, fountain-like mosaic typical of the lines of Blaschko. Moreover, in the years 1977 to 1981 he recognized the mosaic pattern in a syndrome of chondrodysplasia punctata, linear ichthyosis, patchy cicatricial alopecia, unilateral cataracts, and short stature again as a functional X-chromosomal mosaic becoming manifest exclusively in women and proposed that this syndrome, which is today named after him, is because of an X-linked dominant gene defect. Finally, the puzzling molecular genetics of the Happle syndrome are reviewed. Most likely, the Happle syndrome gene is not lethal for hemizygously affected males but rather similar to the example of epilepsy with mental retardation limited to females, the gene actually spares male gene carriers.
We examined the lateral cephalograms of Russian patients in the following categories: control with acceptable occlusions (group 1); severe hypodontia with absence of six or more teeth (group 2); and severe hypodontia associated with hypohidrotic ectodermal dysplasia (HED) (group 3). Analysis was in a cross-sectional manner, comparing dimensions at the start of the mixed dentition phase (age 6-10) and in the permanent dentition (age 12-18). The groups were matched for age and sex. Thirty-one hard- and soft-tissue landmarks were traced, and 35 linear, 19 angular, and 7 ratioed measurements were taken and compared, using analysis of variance to compare the means of each group. A reduced anterior face height was found in groups 2 and 3 as a consequence of a reduced anterior lower face height. In group 2 in the mixed dentition, the posterior face height was also reduced. The inclination of the mandible (<Se S Go Gn) was significantly reduced to 28.22 degrees +/- 0.71 degrees in group 2 and to 24.07 degrees +/- 0.97 degrees in group 3. The facial profile appeared flat or concave (<se pn pg was increased up to 8.42 degrees +/- 1.56 degrees in children and 16.81 degrees +/- 2.18 degrees in adolescents). The subnasion point was behind the aesthetic line (EL), and in group 2 patients the naso-labial angle was obtuse when compared to nonaffected patients. In group 3 patients, the naso-labial angle became acute and lips were protuberant and everted as a consequence of the reduced vertical height. Groups 2 and 3 have the typical facial characteristics unique to hypodontia, with reduced vertical dimensions as a consequence of limited alveolar bone growth. However, group 3 patients have a unique abnormal craniofacial development.
The IVIC syndrome is an autosomal dominant condition affecting mainly the upper limbs. It is described from 19 living members of one family of mostly Caucasoid descent; it came to Venezuela from the Canary Islands 140 years ago. The new mutation appeared six generations ago. It has complete penetrance and wide expressivity for a radial ray defect which may vary from an almost normal thumb to a severely malformed upper limb. When present, the thumb has a long/slender metacarpal and a short distal phalanx, reflected in a typical metacarpophalangeal (MP) pattern profile. Anthropometry reveals delayed growth in the forearms, clavicles, and cranium during adolescence, and permanently in the spine; the maturation of the face, tibiae, and feet is normal. The radial carpal bones are always affected, some being still hypoplastic at advanced ages. Constant palmar dermatoglyphic anomalies are a high a-b ridge count, a distally placed or absent t triradius, and an increased frequency of patterns in the second interdigital area. Extraocular muscles are involved almost always, producing strabismus. Hearing is bilaterally impaired due to a mixed congenital loss, either total or partial. Mild thrombocytopenia and leukocytosis are present before the age of 50 years. There is neither associated ectodermal dysplasia nor heart involvement [except for occasional mild, incomplete right bundle branch block (IRBBB)]; imperforate anus occurs in about 10% of affected persons. The possible pathogenetic relationship to the thalidomide embryopathy and to the Holt-Oram syndrome, among others, is discussed.
A 14-year-old girl with ichthyosis and severe liver disease is compared to 35 reported cases of KID or Senter syndrome. Common manifestations such as ichthyosis (35/35 patients), sensorineural deafness (33/34), "ectodermal dysplasia" (25/28), corneal abnormality (26/31) were present in the proposita, while less common manifestations such as chronic infections (15/20) and neuromuscular disease (12/35) were absent. Two families with vertical transmission and 28 sporadic cases are compatible with an autosomal dominant form of KID syndrome, while one inbred sibship with liver disease suggests the existence of an autosomal recessive form. The proposita was similar to the latter patients in having progressive cirrhosis necessitating liver transplantation; she also had short stature (10/35 patients) and mental retardation (3/35). Hepatic findings included micronodular cirrhosis, cholestasis, hyperplastic Kupffer cells, abundant Mallory's hyaline, copper accumulation without steatosis, and normal peroxisomes.
We treated 4 infants with ankyloblepharon filiforme adnatum (AFA), an uncommon anomaly in which the apposing eyelid margins are connected by abnormal tissue strands. One infant had AFA alone, one had Hay-Wells syndrome, characterized by ectodermal dysplasia, and the other 2 had chromosome abnormalities, trisomy 18, and complex chromosome rearrangement, with visceral malformations. Despite heterogeneity and phenotypic variability, these developmental abnormalities shared (1) involvement of tissues growing in apposition and (2) temporal overlap of their occurrence. This suggests a common defect in the mechanism(s) that regulate tissue fusion at multiple sites during development.
A new ectodermal dysplasia syndrome was reported by Bork et al. in 1987 (Hautarzt 38:342-347). The syndrome consisted of hypotrichosis with the typical SEM (scanning electron microscopy) changes of uncombable hair, retinal pigmentary dystrophy, juvenile cataract, oligodontia, brachydactyly with brachymetacarpia; it was inherited as an autosomal dominant trait. We describe a sporadic case and add further clinical findings to expand the spectrum of this rare syndrome.
The fifteenth known case of GAPO syndrome is presented: a probable autosomal-recessive condition of growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and optic atrophy. This article contains the clinical report of a 9-year-old girl and a short review of the hitherto-known cases. The syndrome could be attributed to either ectodermal dysplasia or perhaps an accumulation of extracellular connective tissue matrix.
We report on unusual manifestations in 2 unrelated children with interstitial deletion of 6q, with nearly identical breakpoints of 6q16.2q23.1 and 6q16.3q22.3. Major findings include growth retardation, profound developmental delay, microcephaly, facial anomalies, sparse hair, congenital heart defects, and striking hand malformations. Discordant anomalies were duodenal atresia and hypoplastic genitalia in 1 child. Split-hand defect, polydactyly, gastrointestinal anomalies, and ectodermal dysplasia have not been described previously in children with 6q deletion. The presence of hand malformations in 2 children with similar deletion breakpoints strongly suggests that this is a candidate region for one or more genes involved in limb development. Comparison of the clinical findings of other patients with 6q2 deletion suggests a recognizable phenotype.
In 1983, Johnson et al. described 16 related individuals with alopecia, anosmia or hyposmia, conductive hearing loss, microtia and/or atresia of the external auditory canal, and hypogonadotrophic hypogonadism inherited in an autosomal dominant pattern. Other less constant manifestations included facial asymmetry, mental retardation, congenital heart defect, cleft palate, and choanal stenosis. An isolated case was reported later (Johnston et al. [1987: Am J Med Genet 26: 925-927]) and thereafter an affected mother and son (Hennekam and Holtus [1993: Am J Med Genet 47: 714-716]). We describe an additional unrelated female patient with features resembling those of the previously reported cases. She presented with intrauterine growth deficiency, microcephaly, alopecia, bilateral microtia with canal atresia, conductive hearing loss, partial left facial palsy, posterior cleft palate, left choanal stenosis, tetralogy of Fallot, developmental delay, and right thumb polydactyly. Because the phenotypic abnormalities in this syndrome affect the brain, facial structures, ectoderm and its derivatives, outflow tract of the heart, and Rathke's pouch derivatives, this has suggested to previous authors etiologic involvement of the ectoderm and neuroectoderm of the first and second branchial arches, Rathke's pouch, and the diencephalon. Microtia with conductive hearing loss differentiates the condition from other ectodermal dysplasias. In the initial report, females appeared somewhat less affected than males, and there was male-to-male transmission. The mother of our patient manifests subtle features, which suggest she may be a mildly affected female. Additionally, there is a family history of early-onset alopecia in the maternal grandfather's relatives.
Genitopatellar syndrome is a recently described disorder with characteristic facies, genital anomalies, absent patella, flexion contractures, microcephaly, renal anomalies, and mental retardation. The presence of affected siblings in two of the original families suggests autosomal recessive inheritance. We report a new patient that exhibits all of these cardinal features and is also the second case to have additional, more severe findings including a congenital heart defect, anal anomalies, and features of an ectodermal dysplasia, thus expanding the phenotype to include these manifestations.
We conducted a clinical population study to examine the incidence and epidemiology of split hand foot-malformation (SHFM) in Manitoba from 1957 to 2003. The total number of births during this period was 850,742. Forty-three patients with SHFM were identified, resulting in an incidence of 1 in 19,784 births. Most patients were ascertained through referrals to the Section of Genetics and Metabolism at the Children's Hospital, Winnipeg, Manitoba. Overall, 22 (51.2%) of affected individuals were females and 21 (48.8%) were male. The left upper limb (LUL) was the most frequently affected, (in 46.5% of patients). The right hand was involved in 39.5%. In 4 patients (9.3%) all four limbs were affected. SHFM is classified as a failure of formation of parts according to the International Federation of Surgical Societies of the Hand (IFSSH) and has also been categorized as Typical or Atypical. Individuals in the Manitoba cohort were classified into two main categories: Typical (29 cases) and Atypical (3 cases). However, 11 patients were not easily placed into either group and comprised a distinct category termed "difficult to classify." Patients in the three groups were then further subdivided depending on whether or not they had additional congenital anomalies. These complex patients included those with single gene disorders in which SHFM has been reported (e.g., ectodermal dysplasia Ectrodactyly Clefting (EEC), tibial aplasia with SHFM, fibular aplasia with SHFM), as well as those with other recognized or unknown patterns of anomalies. Two had deletions involving 9q and 5p respectively. Unlike some other studies, we did not find an excess of males or right-sided defects and only two of the cases--two sisters--were related.
Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio-ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.
Heterozygous mutations in the transcription factor gene p63 cause at least six different syndromes with various combinations of ectodermal dysplasia, orofacial clefting and limb malformations. Here we will present an update of mutations in the p63 gene together with a comprehensive overview of the associated clinical features in 227 patients. These data confirm the previously recognized genotype-phenotype associations. Moreover, we report that there is a large degree of clinical variability in each of the p63-associated disorders. This is illustrated by the different phenotypes that are seen for the five-hotspot mutations that explain almost 90% of all EEC syndrome patients.
Hair and nail development have many similarities and are likely to share many developmental pathways. This is evident from the ectodermal dysplasias that affect both appendages. Of special interest are syndromic disorders as they show the effects of disturbances in molecular pathways that are essential for normal embryonic development. In this review, recent results from studies of syndrome affecting hair and nail development will be discussed.
Plakophilins (pkp-1, -2, and -3) comprise a family of armadillo-repeat containing proteins that are found in the desmosomal plaque and in the nucleus. Plakophilin-1 is most highly expressed in the suprabasal layers of the epidermis and loss of plakophilin-1 expression results in skin fragility-ectodermal dysplasia syndrome, which is characterized by a reduction in the number and size of desmosomes in the epithelia of affected individuals. To investigate the role of plakophilin-1 during desmosome formation, we fused plakophilin-1 to the hormone-binding domain of the estrogen receptor to create a fusion protein (plakophilin-1/ER) that can be activated in cell culture by the addition of 4-hydroxytamoxifen. When plakophilin-1/ER was expressed in A431 cells it was incorporated into endogenous desmosomes and did not disrupt desmosome formation. A derivative of A431 cells (A431D) do not form desmosomes, even though they express all the components believed to be necessary for desmosome assembly. Expression and activation of plakophilin-1/ER in A431D cells resulted in punctate desmoplakin staining on the cell surface. Co-expression of a classical cadherin (N-cadherin) and plakophilin-1/ER in A431D cells resulted in punctate desmoplakin staining at cell-cell borders. These data suggest that plakophilin-1 can induce assembly of desmosomal components in A431D cells in the absence of a classical cadherin; however a classical cadherin (N-cadherin) is required to direct assembly of desmosomes between adjacent cells. The activatable plakophilin-1/ER system provides a unique culture system to study the assembly of the desmosomal plaque in culture.
Tabby and downless mutant mice have identical phenotypes characterized by deficient development of several ectodermally derived organs such as teeth, hair, and sweat glands. Edar, encoded by the mouse downless gene and defective in human dominant and recessive forms of autosomal hypohidrotic ectodermal dysplasia (EDA) syndrome, is a new member of the tumor necrosis factor (TNF) receptor superfamily. The ligand of Edar is ectodysplasin, a TNF-like molecule mutated in the X-linked form of EDA and in the spontaneous mouse mutant Tabby. We have analyzed the response of Edar signaling in transfected cells and show that it activates nuclear factor-kappaB (NF-kappaB) in a dose-dependent manner. When Edar was expressed at low levels, the NF-kappaB response was enhanced by coexpression of ectodysplasin. The activation of NF-kappaB was greatly reduced in cells expressing mutant forms of Edar associated with the downless phenotype. Overexpression of Edar did not activate SAPK/JNK nor p38 kinase. Even though Edar harbors a death domain its overexpression did not induce apoptosis in any of the four cell lines analyzed, nor was there any difference in apoptosis in developing teeth of wild-type and Tabby mice. Additionally, we show that the subcellular localization of dominant negative alleles of downless is dramatically different from that of recessive or wild-type alleles. This together with differences in NF-kappaB responses suggests an explanation for the different mode of inheritance of the different downless alleles.