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PubMed1998

Sequence characterization of a newly identified human alpha-tubulin gene (TUBA2).

We report on the isolation and initial characterization of a human alpha-tubulin gene named TUBA2. This gene is located in the 13q11 region and has been considered a candidate gene for two nonsyndromic deafnesses, DFNB1 and DFNA3. The gene, with a minimum size of 6.5 kb, contains five exons and four introns starting at codon positions 1, 76, 125, and 352, one of which is inserted between the initiation methionine codon and the codon specifying the second amino acid, arginine 2. Neither rearrangement nor point mutation was found in the coding region of the gene in DFNB1- and DFNA3-affected patients. The gene was therefore unlikely to be responsible for either of these deafnesses. During the characterization of TUBA2, the gene encoding connexin 26 was proven to be responsible for both DFNB1 and DFNA3 (D. P. Kelsell et al., 1997, Nature 387: 80-83). However, the present data offer the possibility of testing the involvement of the TUBA2 gene in the Clouston hidrotic ectodermal dysplasia and the Kabuki syndrome, two genetic diseases that have recently been mapped to the 13q11 region.

Amino Acid Sequence↗
PubMed1987

Prenatal diagnosis of X-linked choroideremia with mental retardation, associated with a cytologically detectable X-chromosome deletion.

We describe a family in which an X-chromosome deletion is segregating with choroideremia, and X-linked recessive condition. The DNA sequences DXYS1 and DXS3, defined by the probes pDP34 and 19.2 respectively, are absent in the affected male (who is also mentally retarded), and hemizygous in his mother and in his carrier sister, who presented early in pregnancy. Analysis of chorionic villus DNA formed the basis of prenatal exclusion of choroideremia in her male fetus. In three female relatives, studied with late-labelling techniques, the deleted X was preferentially inactivated in 86-100% of cells studied. This family confirms the localisation of the choroideremia locus to within Xq13----21, and places the loci for anhidrotic ectodermal dysplasia and the X-linked immunodeficiencies outside this region.

Choroid↗
PubMed1980

Monodactylous splithand-splitfoot. A malformation occurring in three distinct genetic types.

Monodactyly is a sign of at least 3 different types of autosomal dominant ectrodactyly. In the first type only the 1st and the 5th or only the 5th toes are present on both feet. The trait is fully expressed in all affected children of patients. No skipping of a generation has been observed. Both parents of several affected children may be normal, or one parent may show minor manifestations only. Single strand mutation is suggested as an explanation of these exceptional cases. Monodactyly is seen less frequently in the second type, ectrodactyly, ectodermal dysplasia and cleft lip and palate (the EEC syndrome), than in the first type. The limb defects are more variable. The third type of ectrodactyly shows extreme intrafamilial variability, comprising various degrees of ectrodactyly, monodactyly and adactyly, defects of the ulna and/or of the tibia. Minor manifestations often occur in affected children of patients. Skipping of a generation is not uncommon.

Abnormalities, Multiple↗
PubMed1987

X-chromosomally inherited split-hand/split-foot anomaly in a Pakistani kindred.

A Pakistani kindred comprising seven generations and 36 members with the split-hand/split-foot anomaly is described. The full expression of the trait, monodactylous or split hand and split foot, mainly of the lobster-claw type, was present in 33 males and 3 females. Other females showed a distinctly milder expression of the trait, usually in the form of partial syndactyly, metacarpal and phalangeal hypoplasia, and malformation. The distribution of the affected members in the pedigree is compatible with X-chromosomal inheritance. Hemizygous males and presumably homozygous females exhibit the typical split-hand/split-foot anomaly, whereas only a part of the obligatory heterozygous females show the milder expression. There were no associated anomalies, such as ectodermal dysplasia, cleft lip/palate, macular degeneration, malformations of the long bones or internal organs, and overt mental retardation.

Abnormalities, Multiple↗
PubMed1998

[Familial juvenile macular dystrophy with congenital hypotrichosis capitis].

BACKGROUND: Our knowledge about the pathogenesis of hereditary macular diseases is still very circumscript. For genetic determination, a knowledge of the coincidence of eye symptoms and other defined common symptoms is helpful. The purpose of this paper was to present two sisters of a family of consanguineous parents with the combination of hypotrichosis of the head and macular dystrophy in the context of a tricho-ocular malformation of an ectodermal dysplasia. A review of the recent literature is included. PATIENTS AND METHODS: Two 13- and 17-year-old sisters presented at our hospital with reduced visual acuity because of symmetrical central changes of the retinal pigment epithelium and chorioatrophic scars according to macular dystrophy combined with hypotrichosis capitis. We performed fundus perimetry and histological examinations of the hair. RESULTS: The 13-year-old patient exhibited central changes of the retinal pigment epithelium leading to a relative central scotoma for Goldmann 1/4 during fundus perimetry in both eyes (visual acuity 0.125 and 0.4). We found central chorioatrophic scars, followed by absolute central scotomas, with unstable fixation in the upper retinal hemisphere in her 17-year-old sister with reduced visual acuity (0.16 and 0.2). CONCLUSION: There are few descriptions of the association of macular dystrophy and hypotrichosis. The combination of hypotrichosis and macular dystrophy could make genetical analysis easier. Mutational analysis of the TIMP-3 gene that has previously been associated with Sorsby fundus dystrophy did not reveal any disease-causing mutations in our patients.

Adolescent↗
PubMed2006

The contribution of associated congenital anomalies in understanding Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a complex congenital disorder which, from a molecular perspective, appears to result due to disruption of normal signalling during development of enteric nerve cells, resulting in aganglionosis of the distal bowel. Associated congenital anomalies occur in at least 5-32% (mean 21%) of patients and certain syndromic phenotypes have been linked to distinct genetic sites, indicating underlying genetic associations of the disease and probable gene-gene interaction in its pathogenesis. Clear-cut associations with HSCR include Down's syndrome, dominant sensorineural deafness, Waardenburg syndrome, neurofibromatosis, neuroblastoma, phaeochromocytoma, the MEN type IIB syndrome and other abnormalities. Individual anomalies vary from 2.97% to 8%, the most frequent being the gastrointestinal tract (GIT) (8.05%), the central nervous system (CNS) and sensorineural anomalies (6.79%) and the genito-urinary tract (6.05%). Other associated systems include the musculoskeletal (5.12%), cardiovascular systems (4.99%), craniofacial and eye abnormalities (3%) and less frequently the skin and integumentary system (ectodermal dysplasia) and syndromes related to cholesterol and fat metabolism. In addition to associations with neuroblastoma and tumours related to MEN2B, HSCR may also be associated with tumours of neural origin such as ganglioneuroma, ganglioneuroblastoma, retinoblastoma and tumours associated with neurofibromatosis and other autonomic nervous system disturbances. The contribution of the major susceptibility genes on chromosome 10 (RET) and chromosome 13 (EDNRB) is well established in the phenotypic expression of HSCR. Whereas major RET mutations may result in HSCR by haploinsufficiency in 20-25% of cases, the etiology of the majority of sporadic HSCR is not as clear, appearing to arise from the combined cumulative effects of susceptibility loci at critical genes controlling the mechanisms of cell proliferation, differentiation and maturation. In addition, potential "modifying" associations exist with chromosome 2, 9, 20, 21 and 22, and we explore the importance of certain flanking genes of critical areas in the final phenotypic expression of HSCR.

Animals↗
PubMed2001

Suppression of hair follicle development inhibits induction of sonic hedgehog, patched, and patched-2 in hair germs in mice.

Embryonic induction of hair follicles is a fascinating model of localized morphogenesis from a simple homogeneous epithelial cell sheet. Accumulating evidence indicates that Sonic hedgehog (Shh) signaling plays a central role in hair follicle formation. We quantitated the expression levels of Shh and its receptor genes, Patched (Ptc) and Patched-2 (Ptch2), in two distinct experimental systems in which the development of hair follicles was suppressed. Shh, Ptc, and Ptch2 were induced about six- to tenfold in normal embryonic hair germs in vivo as well as in developing skin tissue maintained in organ culture. This induction was almost completely inhibited both in the developing skin tissue of ICR mice cultured with 30ng/ml epidermal growth factor and in embryos of Tabby mutant mice (a model of hypohidrotic ectodermal dysplasia) at 14.5-15.5 days postcoitus. Expression of Shh, Ptc and Ptch2 was induced in the Tabby embryos at 16.5 days postcoitus, indicating that Shh signaling may be involved in the formation not only of the well-studied guard hair but also of the awl hair. The potential of the two biological systems for studying molecular mechanisms in hair follicle formation, particularly at an early phase including Shh signaling, is discussed.

Animals↗
PubMed2005

A new mutation in exon 7 of NEMO gene: late skewed X-chromosome inactivation in an incontinentia pigmenti female patient with immunodeficiency.

Incontinentia pigmenti is an X-linked genodermatosis, lethal in males. Affected females survive because of X-chromosome dizygosity and negative selection of cells carrying the mutant X-chromosome, and for this reason the skewed X inactivation pattern is often used to confirm the diagnosis. The most frequent mutation is a deletion of part of the NEMO gene (NEMODelta4-10), although other mutations have been reported. Mutations of NEMO which do not abolish NF-kappaB activity totally permit male survival, causing an allelic variant of IP called hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). We present a non-classical IP female patient who also suffered transient immunodeficiency because of a late and progressive selection against peripheral blood cells carrying an active mutated X-chromosome. This finding suggests that in the absence of known mutation the X-inactivation studies used in genetic counselling can induce mistakes with some female patients. At the age of 3 years and 6 months, all immunodeficiency signs disappeared, and the X-chromosome inactivation pattern was completely skewed. The low T cell proliferation and CD40L expression corroborate the important role of NEMO/ NF-kappaB pathway in T cell homeostasis. The decreased NEMO protein amount and the impaired IkBalpha degradation suggest that this new mutation, NM_003639: c.1049dupA, causes RNA or protein instability. To our knowledge, this is the first time that selection against the mutated X-chromosome in X-linked disease has been documented in vivo.

Age of Onset↗
PubMed2006

A novel missense mutation of the EDA gene in a Mongolian family with congenital hypodontia.

X-linked hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by the hypoplasia or absence of eccrine glands, dry skin, scant hair, and dental abnormalities. Here, we report a Mongolian family with congenital absence of teeth inherited in an X-linked fashion. The affected members of the family did not show other HED characteristics, except hypodontia. We successfully mapped the affected locus to chromosome Xq12-q13.1, and then found a novel missense mutation, c.193C>G, in the ectodysplasin A (EDA) gene in all affected males and carrier females. The mutation causes arginine to be replaced by glycine in codon 65 (R65G) in the juxtamembrane region of EDA. In addition, 33% (3/9) of female carriers have a skewed X-chromosome inactivation pattern. Our result strongly suggests that the c.193C>G mutation is the disease-causing mutation in this family.

Anodontia↗
PubMed2002

White blood cell defects: molecular discoveries and clinical management.

In this review, we present the most recent discoveries at the molecular level in white blood cell defects, and explain how their identification helped us to understand the underlying pathophysiology and directed our approach in clinical management. These lately discovered genes, relevant to immune disorders of mononuclear phagocytes and neutrophils, include defects in the interferon gamma (IFNg)/interleukin 12 (IL-12) pathway, such as IFNg receptor (IFNgR) defects, IL-12 defect, IL-12 receptor (IL-12R) defect, and signal transducer and activator of transcription 1 (STAT-1) defect. We have also included NF-kappaB essential modifier (NEMO) defects, which lead to X-linked ectodermal dysplasia, with or without lymphedema and osteopetrosis, and a wide range of involvement of the immune system, which can mimic the hyper-IgM phenotype. Neutrophil-specific granule deficiency and neutrophil elastase deficiency are discussed, the latter being the molecular defect in both cyclic neutropenia and in some sporadic cases of severe congenital neutropenia.

Hematologic Diseases↗
PubMed1993

A severe case of Beare-Stevenson syndrome and associated congenital deformities.

A severe case of congenital anomalies is described, with several characteristics of Beare-Stevenson syndrome, such as cutis gyrata, acanthosis nigricans, craniofacial anomalies, ear defects, enlarged umbilical stump and anogenital anomalies. He does not have craniosynostosis or clover leaf skull, which has also been described in this syndrome. This patient also shows hands and feet anomalies, absence of skin adnexa in several locations and dental anomalies, which could suggest an associated ectodermal dysplasia.

Abnormalities, Multiple↗
PubMed1975

Von Recklinghausen's disease presenting as scrotal tumor.

A five-year-old boy had an asymptomatic, periurethral, scrotal-perineal mass. An unusual associated urethral defect was subsequently discovered. The locally aggressive lesion was excised and urethroplasty accomplished. The histopathologic diagnosis proved to be plexiform neurofibroma. This is a forme fruste example of ectodermal dysplasia known as neurofibromatosis. I believe this is the first report of similar scrotal, perineal, or periurethral involvement in the syndrome.

Child, Preschool↗
PubMed1991

Trichothiodystrophy with chronic neutropenia and mild mental retardation.

Trichothiodystrophy is a feature of several diseases that consist of characteristic hair shaft abnormalities and a wide spectrum of other developmental defects. Detection of sulfur-deficient hairs identifies this disorder and separates it from other similar ectodermal dysplasias with normal sulfur content. Detection of low sulfur hair syndrome is also important for genetic counseling, because the disease appears to be an autosomal recessive trait. We report a patient with chronic neutropenia, mild mental retardation, and low sulfur content in hair. Our case expands the spectrum of disorders associated with trichothiodystrophy.

Child↗
PubMed2006

Towards subtlety: understanding the role of Toll-like receptor signaling in susceptibility to human infections.

Recent years have seen a dramatic improvement in our understanding of the role of innate immunity, and particularly Toll-like receptor (TLR) signaling, in human host defense. Appreciation of how defects in human TLR signaling enhance susceptibility to infection began with the identification of patients with monogenic immunodeficiencies, such as hypohydrotic ectodermal dysplasia with immunodeficiency and IRAK4 deficiency. Empowered by technological advances in genotyping and bioinformatics, we are now beginning to appreciate how common genetic variation in the genes controlling the innate immune response alters infectious susceptibility in a subtle but specific fashion. This review highlights the mechanisms of infectious susceptibility that result from complex interactions between the genetically variable host and microbe and explores how this new knowledge may ultimately translate into better care for our patients.

Disease Susceptibility↗
PubMed2005

The use of the Montgomery T-tube in difficult paediatric airways.

OBJECTIVE: We report our experience of using Montgomery T-tubes in children. METHOD: A retrospective review of medical records was performed. Data collected included particular clinical circumstances, the details of usage of the tube, and the eventual outcome. RESULTS: Between January 1999 and October 2003, our unit performed 293 tracheostomies, 76 laryngotracheal reconstructions and 31 other major airway procedures in children. 10 children have had a Montgomery T-tube inserted. Nine were boys. In eight cases, the T-tube was used because of severe granulations and subsequent fibrotic narrowing in the subglottis after laryngotracheal reconstruction surgery. These children had undergone between one and four major procedures prior to T-tube placement. In the other two cases, the T-tube was used to stent severe glottic and supraglottic stenosis (due to previous laser surgery for papillomas in one case and congenital ectodermal dysplasia in the other). At the time of T-tube placement the children were aged 2-18 years (median 8 years). The tube was initially fitted so as to protrude above the glottis in all cases. In one case, the T-tube was removed on the first post-operative day. One tube was removed after a week due to severe crusting. One tube blocked after 2 weeks. One child had re-stenosis in the supraglottis necessitating the placement of a T-tube with a longer upper limb. Two children have subsequently died from non-airway causes. Two children still have their T-tube in situ, one of whom is due to have it removed in the next few weeks. Six have been successfully decannulated and are well. CONCLUSIONS: The Montgomery T-tube provides a useful adjunct to the management of a small number of children with the most difficult airway problems. Its use can be problematic, however, and requires awareness of its specific complications. We have confined usage to complex stenoses where a reconstruction would be inappropriate, or (in one instance) to stent an unsupported larynx after revision reconstruction (tracheal resection).

Adolescent↗
PubMed2004

The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation.

BACKGROUND: An increasing number of rare genetic defects are associated with immunodeficiency and impaired ability to activate gene transcription through nuclear factor (NF) kappaB. Hypomorphic mutations in the NFkappaB essential modulator (NEMO) impair NFkappaB function and are linked to both immunodeficiency and ectodermal dysplasia (ED), as well as susceptibility to atypical mycobacterial infections. OBJECTIVE: We sought to investigate the clinical and immunologic natural history of patients with NEMO mutation with immunodeficiency (NEMO-ID). METHODS: Patients with severe bacterial infection and ED or unexplained mycobacterial sensitivity were evaluated for NEMO mutation. Laboratory investigations and clinical data were retrospectively and prospectively accumulated and reviewed. RESULTS: We have given a diagnosis of NEMO-ID to 7 boys; 6 had ED, and 5 had gene mutations in the 10th exon of NEMO. Our resulting estimated incidence of NEMO-ID is 1:250,000 live male births. All patients had serious pyogenic bacterial illnesses early in life, and the median age of first infection was 8.1 months. Most boys had mycobacterial disease (median age, 84 months), and a minority had herpesviral infections. Initial immunologic assessments showed hypogammaglobulinemia (median IgG, 170 mg/dL) with variable IgM (median, 41 mg/dL) and IgA (median, 143 mg/dL) levels. Two patients had increased IgM levels, and 5 had increased IgA levels. All patients evaluated had normal lymphocyte subsets with impaired proliferative responses, specific antibody production, and natural killer cell function. Two patients died from complications of mycobacterial disease (ages 21 and 33 months). CONCLUSION: NEMO-ID is a combined immunodeficiency with early susceptibility to pyogenic bacteria and later susceptibility to mycobacterial infection. Specific features of particular NEMO mutations in these patients provide insight into the role of this gene in immune function.

Agammaglobulinemia↗
PubMed2005

Ectodysplasin-1 deficiency in a German Holstein bull associated with loss of respiratory mucous glands and chronic rhinotracheitis.

A 2-year-old German Holstein bull was identified as a carrier of a mutation within the X-chromosomal ED1 gene, which encodes a TNF-related signalling molecule mainly involved in ectodermal development. The clinicopathological appearance was associated with hypotrichosis, hypodontia, and a reduced number of eccrine glands, in addition to chronic rhinotracheitis and partial squamous metaplasia. Furthermore, for the first time in an ED1-deficient animal, a complete lack of respiratory mucous glands was observed. This suggests that the ED1 gene plays a role in the development of mucous glands, the absence of which resembles a feature of X-linked anhidrotic ectodermal dysplasia (ED1) in human patients.

Animals↗
PubMed2006

Glucocorticoid pretreatment suppresses chemokine expression and inflammatory cell infiltration in cholestatic rats receiving biliary intervention.

AIM: Biliary intervention may augment chemokine expression and inflammatory cell infiltration and aggravates liver injury in cholestatic rats. We tested the efficacy of glucocorticoid pretreatment to prevent the complications. METHODS: A model of biliary intervention was established in rats without (sham) or with bile duct ligation (BDL). Before biliary intervention, rats were randomly assigned to receiving intravenous injection of dexamethasone (DX group) or normal saline (NS group). Plasma levels of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) were measured with enzyme-linked immunosorbent assay, and liver messenger RNA of these chemokines was quantified with real-time quantitative reverse transcriptase-polymerase chain reaction. Monocytes, Kupffer cells, and neutrophils in the rat liver were characterized with antibodies to ectodermal dysplasia 1 (ED1), ED2, and myeloperoxidase, respectively. RESULTS: By 3 hours after biliary intervention, plasma MCP-1 and MIP-2 proteins in BDL-NS rats were significantly higher than in BDL-DX. At 3 hours, liver MCP-1 and MIP-2 messenger RNA levels were significantly upregulated in BDL-NS than in BDL-DX. The amount of ED1-, ED2- and myeloperoxidase-staining cells were significantly greater in BDL-NS than in BDL-DX. Most of the changes returned to baseline levels by 24 hours. CONCLUSION: Glucocorticoid pretreatment suppresses chemokine expression and inflammatory cell infiltration, which may consequently alleviate liver injury in cholestatic rats receiving biliary intervention.

Animals↗