Search

Background: The triple A syndrome is characterized by the main features adrenal insufficiency, achalasia and alacrima. Other organ systems can be involved in a variable manner., Patient: We report clinical and novel molecular findings in a 6.8-year-old Kurdish boy, who presented with relapsing vomiting and failure to thrive. He was diagnosed as having achalasia and primary adrenocortical hypofunction. History and clinical examination showed that the boy was unable to produce tears. In addition, a large number of associated neurological and dermatological features was present in this patient. Thus, the clinical diagnosis of triple A syndrome was made., Results: Initial molecular marker analysis supported linkage to the triple A critical region on chromosome 12q13. Further, a homozygous G -->A transition in exon 9 of the newly identified AAAS gene, resulting in a stop codon (W295X) and predicting a truncated protein with loss of function, confirmed the diagnosis. This new mutation was also detected in another family of Kurdish origin. In turned out that both families were related., (Copyright 2002 S. Karger AG, Basel)

Purpose: To map the disease locus of a two-generation, consanguineous Pakistani family with autosomal recessive cone-rod dystrophy (arCRD). All affected individuals had night blindness, deterioration of central vision, photophobia, epiphora in bright light, and problems with color distinction. Fundoscopy revealed marked macular degeneration and attenuation of retinal vessels. Mild pigmentary changes were present in the periphery., Methods: Genomic DNA was amplified across the polymorphic microsatellite poly-CA regions identified by markers. Alleles were assigned to individuals that allowed calculation of LOD scores using the Cyrillic (Cherwell Scientific, Oxford, UK) and MLINK (accessed from ftp://linkage. rockefeller.edu/softeware/linkage/) software programs. The cellular retinoic acid-binding protein 2 (CRABP2), cone transducin alpha-subunit (GNAT2), potassium inwardly rectifying channel, subfamily J, member 10 (KCNJ10), genes were analyzed by heteroduplex analysis and direct sequencing for mutations., Results: A new locus for arCRD (CORD8) has been mapped to chromosome 1q12-q24. A maximum two-point LOD score of 4.22 was obtained with marker D1S2635 at recombination fraction of theta = 0.00. Two critical recombinations in the pedigree positioned this locus to a region flanked by markers D1S457 and D1S2681. A region of homozygosity was observed within the loci D1S442 and D1S2681, giving a probable critical disease interval of 21 cM. Mutation screening of the three candidate genes CRABP2, GNAT2, and KCNJ10 revealed no disease-associated mutations., Conclusions: The findings therefore suggest that this phenotype maps to a new locus and is due to an as yet uncharacterized gene within the 1q12-q24 chromosomal region.

For those searching for human disease-causing genes, information on the position of genes with respect to genetic markers is essential. The physical map composed of ESTs and genetic markers provides the positional information of these markers as well as the starting point of gene identification in the form of genomic clones containing exons. To facilitate the effort of identification of genes in the region spanning D12S1629 and D12S312, we constructed a high-resolution transcript map with PAC/BAC/cosmid clones. The strategy for the construction of such a map involved utilization of STSs for the screening of the large insert bacterial chromosome libraries and a chromosome 12-specific cosmid library by hybridization. The contig was constructed based on the STS contents of the clones. The resulting high-resolution transcript map of the region between P273P14/SP6 and D12S312 spans 4.4 cM from 66.8 to 71.2 cM of the Généthon genetic map and represents approximately 2.4 Mb. It was composed of 81 BAC, 45 PAC, and 91 cosmid clones with a minimal tiling path consisting of 16 BAC and 4 PAC clones. These clones are being used to sequence this part of chromosome 12. We determined the order of 135 STSs including 74 genes and ESTs in the map. Among these, 115 STSs were unambiguously ordered, resulting in one ordered marker per 21 kb. The order of keratin type II locus genes was determined. This map would greatly enhance the positional cloning effort of the responsible genes for those diseases that are linked to this region, including male germ cell tumor as well as palmoplantar keratoderma, Bothnian-type, and triple A syndrome. This transcript map was localized at human chromosome 12q13.

Triple A syndrome (Allgrove syndrome, MIM No. 231550) is a rare autosomal recessive disorder characterised by ACTH-resistant adrenal insufficiency, achalasia of the cardia, and alacrimia. The triple A gene has been previously mapped to chromosome 12q13 in a maximum interval of 6 cM between loci D12S1629 and D12S312. Using linkage analysis in 12 triple A families, mostly originating from North Africa, we confirm that the disease locus maps to the 12q13 region (Zmax = 10.89 at theta = 0 for D12S1604) and suggest that triple A is a genetically homogeneous disorder. Recombination events as well as homozygosity for polymorphic markers enabled us to reduce the genetic interval to a 3.9 cM region. Moreover, total linkage disequilibrium was found at the D12S1604 locus between a rare allele and the mutant chromosomes in North African patients. Analysis of markers at five contiguous loci showed that most of the triple A chromosomes are derived from a single founder chromosome. As all markers are located in a 0 cM genetic interval and only allele 5 at the D12S1604 locus was conserved in mutant chromosomes, we speculate that the triple A mutation is due to an ancient Arabian founder effect that occurred before migration to North Africa. Since we also found linkage disequilibrium at D12S1604 in two patients from Southern Europe (France and Spain), the founder effect might well extend to other Mediterranean countries. Taking advantage of a YAC contig encompassing the triple A minimal physical region, the triple A gene was mapped to a 1.7 Mb DNA fragment accessible to gene cloning.

Ophthalmic manifestations are a common component of the ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome; however, few ophthalmic publications have specifically addressed these features. The authors describe a 38-year-old patient with EEC syndrome who demonstrated several associated ocular signs and symptoms. The ophthalmic findings in this patient included bilateral entropion with secondary trichiasis, and shallow inferior fornices with symblepharon. Interestingly, the patient also had vertically deficient tarsi and absence of the meibomian glands. Ophthalmologists should be aware of the ocular signs and symptoms associated with EEC because some manifestations can potentially be sight threatening.

Tumor cells from a malignant mixed tumor of the lacrimal gland were maintained in tissue culture for more than 55 generations. Comparative immunohistochemical analysis was performed on whole tumor sections and on the tumor cell culture to define the origin of the cells in culture. The cultured cells expressed cytokeratin, smooth-muscle actin, S-100 protein, and vimentin and were negative for glial fibrillary acidic protein. Tumor sections expressed cytokeratin but were negative for muscle-specific actin, vimentin, and glial fibrillary acidic protein. Through tissue culture studies of salivary gland epithelial neoplasias, which are very similar to lacrimal gland epithelial neoplasias, pluripotential stem cells have been identified. Similar tissue culture analysis of lacrimal gland epithelial neoplasms can be a valuable tool for studying the origin of these uncommon tumors.

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.

The triple A or Allgrove's syndrome (MIM*231550) is an autosomal recessive disease characterized by the triad of adrenocorticotropic hormone (ACTH) resistant adrenal insufficiency, achalasia and alacrima. Since its first description by Allgrove et al. (1978) more than 70 cases from all over the world have been reported. The syndrome manifests itself during the first decade of life with severe hypoglycaemic episodes which can cause sudden death. The frequent association with neurological disorders presenting as a mixed pattern of upper and lower motor neuropathy, sensory impairment, autonomic neuropathy and mental retardation may result in a severely disabling disease. As an additional feature some patients have hyperkeratosis of their palms and soles. We have performed a systematic genome linkage scan in eight triple A families of which three were consanguineous [including the large highly inbred kindred described by Moore et al. (1991)]. We obtained conclusive evidence for linkage of the triple A syndrome locus to markers on chromosome 12q13 (D12S368, theta max = 0, Zmax = 10.81) with no indication of genetic heterogeneity. Haplotype and multipoint analyses suggest that the gene is located on a chromosomal segment flanked by the markers D12S1629 and D12S312 which are 6 cM apart. This region harbors the type II keratin gene cluster, and potential candidate genes include SCN8A and HOXC genes.

Objective: To investigate the significance of quantitative analyses of DNA content and P53 gene product expression which are applied for pathological diagnosis of epithelial lacrimal gland tumor., Methods: Flow cytometry (FCM) and immunofluorescence staining technique were used to quantitatively measure the DNA content and expression of P53 gene product from 39 cases with epithelial lacrimal gland tumors., Results: It is indicated that the pleomorphic adenomas still possess of the properties of DNA diploid of normal lacrimal gland cell, but malignant tumors are characterized by DNA aneuploidy. There is a significant difference in the content of expression of P53 gene product between pleomorphic adenomas and malignant tumors (P < 0.001). The content of expression of P53 gene product is positively correlated to the DNA content, and both are increasing with the reduction of tumor tissue differentiation., Conclusion: Quantitative analyses of DNA content and expression of P53 gene product may provide objective indexes for the pathological diagnosis of epithelial lacrimal gland tumor.

Objective: To obtain the information about whether expression of epidermal growth factor (EGF) receptor is related to the proliferative activity of tumor., Methods: The expression of EGF receptor and DNA content of pleomorphic adenoma of lacrimal gland in 32 cases were detected by an immunohistochemical avidin biotin peroxidase complex method and determined by an image analysis technique, respectively. The relationship between the expression of EGF receptor and DNA content was analyzed., Results: 10 tumors were stained positively with anti-EGF receptor antibody, the DNA contents of 14 cases were increased, their DNA ploidy distribution pattern showed two or several peaks. Good correlation has been found between the expression of EGF receptor and DNA ploidy distribution pattern, and the DNA distribution pattern of tumor with positive EGF receptor expression showed mainly two or several peaks (P < 0.01)., Conclusion: The expression of EGF receptor of pleomorphic tumor of lacrimal gland is related to the proliferative activity of tumor cells.

This report describes two phenotypically normal sisters, each married to a phenotypically normal paternal cousin. One couple had one female and one male child with alacrima; the other couple had a similarly affected girl. The keratitis sicca was manifested by punctate staining of the conjunctiva and blotchy staining of the cornea in the interpalpebral zone with fluorescein and Rose Bengal. Apart from an associated atopy in one of the children, pharmacological testing, biochemical analysis, and clinical examination suggested dysfunction of the lacrimal glands. We propose that the alacrima in this family is inherited in an autosomal recessive fashion.

We have undertaken cytogenetic investigation of seven benign and malignant lacrimal gland neoplasms. This study showed recurrent chromosomal abnormalities involving chromosomes 3, 8, 9, and 12. These features are similar to those found in benign and malignant salivary gland tumors, which suggests possible common mechanisms involved in the neoplastic proliferation of these histologically related tumors.

Short-term cultures from 12 non-squamous cell carcinomas (NSCCs) of the head and neck were cytogenetically investigated. Three tumours were acinic cell carcinomas, two adenoid cystic carcinomas, three mucoepidermoid carcinomas, two carcinomas in pleomorphic adenoma, and two adenocarcinomas. Clonal chromosome aberrations were detected in all but one adenocarcinoma. Including our data, a total of 40 head and neck NSCCs with clonal aberrations have been described. Deletions of the long arm of chromosome 6 are the most common aberrations (11/40 cases); they have been detected in all types of NSCC except carcinoma in pleomorphic adenoma. Two aberrations seem to be closely associated with tumour type: t(6;9)(q21-24;p13-23), which has been seen in three of 11 adenoid cystic carcinomas (in two as the sole aberration), and structural rearrangements of 8q12-13, which have been detected in three of four carcinomas in pleomorphic adenoma.

The authors report a Kuwaiti Arab family in which the father and one of his two sons have severe hypolacrimation with blotchy staining of the cornea and punctate staining of the interpalpebral bulbar conjunctiva by fluorescein and Rose Bengal. Pharmacologic testing together with biochemical analysis and systemic examinations and investigations suggest an isolated dysfunction of lacrimation. The authors' small Arab family differs from the only other recorded pedigree (Irish) in which all five affected members in four generations also had atopy.

Allgrove syndrome (isolated glucocorticoid deficiency, achalasia and alacrima) was found in eight members of an inbred French Canadian/North American Indian pedigree. The high degree of consanguinity supports an autosomal recessive mode of inheritance for this disorder. Six patients presented with hypoglycaemia and other evidence of cortisol deficiency between 2.5 and 8 years of age; however, two others became cortisol deficient after initial testing showed normal cortisol responses to ACTH, evidence that the glucocorticoid insufficiency of this syndrome may not be congenital, but may develop as late as the third decade. No evidence of mineralocorticoid deficiency has been found during 65 patient-years of follow-up. Alacrima was the earliest and most consistent clinical sign of Allgrove syndrome. Other manifestations of peripheral or autonomic neuropathy were found in four patients. The patients showed similar facial features, and three had significant velo-pharyngeal incompetence. All showed oesophageal dysmotility even in the absence of symptomatic dysphagia. In-vitro studies of lymphocyte ACTH binding showed no differences from normal controls. If such lymphocyte binding, as has been suggested, reflects adrenal ACTH receptor activity, these data would suggest that the glucocorticoid deficiency of Allgrove syndrome is not the result of a defect in that receptor. However, the observation that ACTH does not elicit increased adenylate cyclase activity even in normal lymphocytes casts considerable doubt on the physiological significance of ACTH binding to lymphocytes. It seems likely, therefore, that true ACTH receptors are not expressed on peripheral lymphocytes, and any conclusions regarding a possible receptor defect in Allgrove syndrome must await studies of receptor expression on adrenal cell membranes.

We describe a single case of a 2-year, 8-month-old male child with alacrima, achalasia, and neurologic anomalies and proven clinical and laboratory evidence of normal adrenocortical function. As the child was the product of a first cousin marriage, the possibility of autosomal recessive mode of inheritance was considered. Differentiation between this syndrome and other previously described associated syndromes is illustrated. This article emphasizes the presence of multisystem anomalies as described in the presence of normal suprarenal function.

Cases of adenoid cystic carcinomas of the salivary (n = 90) and lacrimal glands (n = 6) from the years 1965-1980 were evaluated retrospectively with regard to clinical, epidemiologic and histomorphologic parameters, and in 52 cases, nuclear DNA content was assessed using a single cell scanning cytophotometry procedure in order to determine prognostic factors. Clinical courses were poor with a high incidence of recurrences, hematogenous metastases and deaths from tumor. Histology was related to prognosis, glandular tumors showing a better prognosis than solid ones. Tumor size greater than 4 cm was correlated with an unfavorable clinical course in all cases. Cytophotometry yielded various types of histograms (7 diploid, 10 proliferative, 14 triploid, 19 atypical, 2 tetraploid). Significant correlations were found as to the time of survival, tumors with diploid histograms showing the longest intervals and those with atypical ones the shortest. Although the prognosis of adenoid cystic carcinoma remains poor, cytophotometry can offer additional prognostic information in the individual case.

Familial glucocorticoid deficiency is a rare multisystem disorder characterized by glucocorticoid deficiency with normal mineralocorticoid activity, achalasia of the cardia, and alacrima. Familial hypophosphatemic rickets is characterized by selective renal phosphate wasting with subsequent hypophosphatemia and an inappropriately low 1,25-dihydroxyvitamin D concentration for the degree of hypophosphatemia. A 6-year-old girl with both disorders is described. A biochemical relationship between familial glucocorticoid deficiency and familial hypophosphatemic rickets could not be defined; the influence of cortisol on her serum calcium level, phosphorus level, and rickets, as well as the natural history of these two entities, is described.

We describe a family with markedly deficient lacrimation from infancy and punctate corneal epithelial erosions. An autosomal dominant inheritance pattern is suggested. A hypoplasia of the lacrimal gland in this family was suggested by pharmacologic testing and by histopathologic examination of the lacrimal gland of the proposita. The family investigated in this report represents the first instance of hereditary congenital alacrima without associated ocular or adnexal abnormalities and apart from systemic disorders such as the Riley-Day syndrome and anhidrotic ectodermal dysplasia.

Isolated glucocorticoid failure associated with achalasia of the cardia is described in two pairs of siblings in separate families. Defective tear production is also present in three of the patients, and one shows other signs of autonomic dysfunction. Two other families with adrenal insufficiency and achalasia are known. This unusual association probably represents a familial disorder of as yet unknown aetiology.

A kindred is presented in which several members had complaints of head movement-dependent oscillopsia due to acquired vestibular areflexia in combination with progressive hearing loss. History was noncontributory for other neurologic or otologic diseases (including infectious diseases) or use of neuro-ototoxic drugs. The pedigree suggests autosomal dominant inheritance.