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PubMed2001

Pallister-Hall syndrome with stenosis of the cricoid cartilage and microphallus without hypopituitarism.

The Pallister-Hall syndrome is characterised by a spectrum of anomalies including congenital hypothalamic "hamartoblastoma" hypopituitarism, imperforate anus, polydactyly and various visceral anomalies. Rare familial cases with an autosomal dominant inheritance pattern with variable expressivity have been reported. Cases of more mildly affected individuals with Pallister-Hall syndrome have been described, including cases of asymptomatic individuals. We report a case of Pallister-Hall syndrome with microphallus and without growth hormone deficiency that has been followed successfully for two years. The patient presented postaxial polydactyly of hands, dysplasic nails, imperforate anus, small penis, scrotum bifidum with very thin urethra, bifid epiglottis and a bilateral simian crease. There was vesico-ureteral-reflux, insertional hexadactyly of the left hand and two Y shaped metacarpal with six fingers at the right hand. Brain MR imaging revealed a large sellar and suprasellar mass. A perineal anorectoplasty and a vesicostomy were performed. Laryngeal dyspnea appeared when he was 13 months old. Bronchoscopy revealed anterior synechia of vocal cords with cricoidian stenosis. A tracheostomy was performed. Mental development was normal. No mutation of the zinc finger transcription factor gene, GLI 3 was detected.

Abnormalities, Multiple↗
PubMed2001

Bilateral tibial agenesis with ectrodactyly (OMIM 119100): further evidence for autosomal recessive inheritance.

We present further evidence for autosomal recessive inheritance of the bilateral tibial agenesis/ectrodactyly dysostosis. A consanguineous Turkish couple gave birth to three children with malformations. The first, a boy, died neonatally of pulmonary hypertension with congenital alveolar capillary dysplasia and also had tibial agenesis and ectrodactyly. A second child, a girl, died after birth with the same abnormality of the lungs without skeletal malformations. After the birth of three unaffected children, echographic examination at 15 weeks of gestation in the sixth pregnancy documented agenesis of tibiae and symmetrical ectrodactyly of hands and feet. Autopsy did not show additional malformations, and lung development was normal for gestational age. This observation also confirms the autosomal recessive inheritance pattern of congenital alveolar capillary dysplasia.

Abnormalities, Multiple↗
PubMed2001

Genetic aspects of chronic pancreatitis: insights into aetiopathogenesis and clinical implications.

The recent genetic discoveries in CP support the hypothesis that inappropriate intrapancreatic activation of zymogens by trypsin results in autodigestion and pancreatitis. Two different protective mechanisms prevent activation of the pancreatic digestive enzyme cascade. First, SPINK1 inhibits up to 20% of potential trypsin activity and, second, trypsin itself activates trypsin-like enzymes readily degrading trypsinogen and other zymogens. Pancreatitis may therefore be the result of an imbalance between proteases and their inhibitors within the pancreatic parenchyma. The discovery of PRSS1 mutations in families with CP was the first breakthrough in the understanding of the underlying genetic mechanisms. Enhanced trypsinogen activation may be the common initiating step in pancreatitis caused by these mutations. The discovery of SPINK1 mutations underlines the importance of the protease inhibitor system in the pathogenesis of CP. Thus, gain-of-function in the cationic trypsinogen resulting in an enhanced autoactivation, or loss-of-function mutations in SPINK1 leading to decreased inhibitory capacity, may similarly disturb the delicate intrapancreatic balance of proteases and their inhibitors. The recent findings of SPINK1, CFTR, and PRSS1 mutations in CP patients without a family history have challenged the concept of idiopathic CP as a non-genetic disorder and the differentiation between HP and ICP. There is a clear mode of autosomal dominant inheritance for some mutations (R122H, N291, possibly MIT), whereas the inheritance pattern (autosomal recessive, complex, or modifying) of other mutations (A16V, N34S) is controverted or unknown. The lack of mutations in the above-mentioned genes in many patients suggests that CP may also be caused by genetic alterations in yet unidentified genes. Evaluation of CP patients without an obvious predisposing factor, e.g. alcohol abuse, should include genetic testing even in the absence of a family history of pancreatitis. Finally, identification of further disease-causing genes will create a better understanding of pathogenesis and may help to develop specific preventive and therapeutic strategies.

Chronic Disease↗
PubMedDate not supplied

The Antley-Bixler syndrome: two new cases.

The Antley-Bixler syndrome is a rare multiple congenital anomaly with a high mortality rate. The characteristic manifestations include craniosynostosis, radiohumeral synostosis, midface hypoplasia, joint contractures and arachnodactyly. We report two new cases of this syndrome and address the diagnostic features, associated malformations, inheritance patterns, prenatal findings, and briefly review the literature.

Abnormalities, Multiple↗
PubMed2002

A newborn infant with sternal malformation/vascular dysplasia association.

Sternal malformation/vascular dysplasia complex was described by Hersch et al. in 1985. The principle findings include cleft of the sternum covered by an atrophic skin, a midline abdominal raphe and hemangiomatosis. The inheritance pattern seems to be sporadic. We report a newborn baby with sternal defect, cleft lip and palate, supraumbilical raphe and hemangiomas.

Abnormalities, Multiple↗
PubMed2002

Progressive external ophthalmoplegia and multiple mitochondrial DNA deletions.

Progressive external ophthalmoplegia (PEO) with secondary accumulation of multiple deletions of mitochondrial DNA (mtDNA) clinically resembles disorders due to primary mutations of mtDNA but follows a Mendelian inheritance pattern. The disorder belongs to an interesting group of diseases in which both the nuclear and the mitochondrial genome are involved in the pathology. Both autosomal dominant (adPEO) and recessive (arPEO) variants of this disorder occur. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients may have multiple mtDNA deletions and/or depletion of mtDNA. Recent reports of mutations in Thymidine Phosphorylase in MNGIE, and of mutations in adenine nucleotide translocator (ANT1), Twinkle and mitochondrial DNA polymerase gamma (POLG) in adPEO, have lead to new insights in the pathogenesis of these disorders of mtDNA maintenance. We also identified POLG mutations in two families with arPEO, which underlines the crucial role of the mtDNA replication machinery for mtDNA maintenance.

Chromosomes, Human, Pair 15↗
PubMed2002

[From gene to disease; unconjugated hyperbilirubinemia: Gilbert's syndrome and Crigler-Najjar types I and II].

Gilbert's syndrome consists of a mild unconjugated hyperbilirubinemia occurring in the absence of liver disease or haemolysis. Total plasma bilirubin can be as high as 80 mumol/l and mild intermittent jaundice does occur. The inheritance pattern is probably autosomal recessive. It has been estimated that some 10-15% of the Western population suffers from Gilbert's syndrome. Bilirubin-uridinediphosphate-glucuronosyltransferase (UGT1A1) is the only enzyme involved in the conjugation of bilirubin. In patients with Gilbert's syndrome, hepatic glucuronidation by UGT1A1 is reduced to about 30% of normal. In Western populations a variant TATAA element in the upstream promotor region of the UGT1A1 gene is firmly associated with the disease. Crigler-Najjar types I and II are autosomal recessive disorders associated with near (type II) or complete absence (type I) of UGT1A1 enzyme activity. There is a persistent unconjugated hyperbilirubinemia (range 300-850 mumol/l) with the plasma concentrations being higher in type I than in type II. Genetic mutations in exon 1-5 cause both Crigler-Najjar type I and type II.

Bilirubin↗
PubMed1975

[Erythrokeratodermia variabilis. Report of 3 clinical cases and evaluation of the topical retinoic acid treatment].

Three cases of erythrokeratodermia variabilis are presented, the first one being a female aged 16 and the two others being a woman aged 27 and her son aged 2. Familial relationship between case 1 and the others did not exist. The inheritance pattern was apparently autosomal recessive in the first case and autosomal dominant in cases 2 and 3. The dermatological lesions were the classically described for the disease. The evolution had not been influenced by puberty in cases 1 and 2 or by the pregnancy in case 2. Topical acid vitamin A (0.1 g. per cent cream) was used on hyperkeratotic areas in every patient with substantial reduction of the lesions. However these beneficial results were not long-lasting after discontinuance of that therapy.

Adolescent↗
PubMedDate not supplied

The genetics, diagnosis, and management of Prader-Willi syndrome.

The Human Genome Project, molecular genetic technology, and other ongoing research into our genetic makeup are having a profound effect on the work of primary care clinicians. New knowledge of inheritance patterns and diagnostic tests, leading to management changes, becomes available almost daily. The diagnosis and management of Prader-Willi syndrome is no exception. A few years ago diagnosis was dependent on the clinical manifestation of behavioral and physical stigmata, and a definitive diagnosis often was missed or delayed for years. Current laboratory procedures play a prominent role in confirming this condition, and diagnosis in neonates is now possible, but diagnosis is often delayed because of clinicians' lack of familiarity with the disorder. Management varies with the age of the patient and the degree to which the disease is manifest. Sensitive care with lifelong surveillance is required. Well- informed nurse practitioners working in primary care can play an important role in early detection, care coordination, education, and long-term management for persons with Prader-Willi syndrome.

Adolescent↗
PubMed2002

Partial epilepsy with prominent auditory symptoms not linked to chromosome 10q.

Autosomal dominant partial epilepsy with auditory features (ADPEAF) has been identified as a distinct genetic syndrome. Several families have been described linked to chromosome 10q24, which carries mutations in the LGI1 gene. We report a small new pedigree with partial epilepsy with auditory symptoms. We performed a detailed clinical study of the family, constructed an extended pedigree comprising 106 individuals, and obtained blood samples for genetic analysis. Individuals with seizures also underwent neurophysiological and neuroradiological investigations. Genetic analysis was performed with six microsatellite markers spanning to the critical region of chromosome 10q24. Mutation analysis of the coding sequence of LGI1 was performed in two patients. Five members of the family in generation IV had seizures. Three individuals had auditory auras, followed by generalised seizures in two and brief loss of contact in one, one had nocturnal tonic-clonic seizures with an EEG suggestive of right temporal lobe onset, and one only had febrile seizures. In addition, a deceased woman was said to have had seizures. Haplotype analysis of this region of chromosome 10q24 failed to disclose a common haplotype in affected family members and no disease-associated mutations were detected in the LGI1 gene, suggesting that this locus is not associated with the disease in our family. Our small sample with partial epilepsy with auditory symptoms, clinically resembles previously described ADPEAF families. However, the low number of patients is compatible with either autosomal dominant or other inheritance patterns. In the case of the former, the lack of segregation with 10q24 suggests that a second locus is involved in the aetiology of ADPEAF; in the latter, an epileptic syndrome also characterized by auditory features, but distinct from ADPEAF, could be transmitted in this family.

Adult↗
PubMed2002

Novel mutation in FOXC1 wing region causing Axenfeld-Rieger anomaly.

PURPOSE: To determine the possible molecular genetic defect underlying Axenfeld-Rieger anomaly (ARA) and to identify the pathogenic mutation causing this anterior segment dysgenesis in an Indian pedigree. METHODS: The FOXC1 gene was amplified from genomic DNA of members of an ARA-affected family and control subjects using four novel sets of primers. The amplicons were directly sequenced, and the sequences were analyzed to identify the disease-causing mutation. RESULTS: A heterozygous novel missense mutation was identified in the coding region of the FOXC1 gene in all three patients in this family. Consistent with the autosomal dominant inheritance pattern, the mutation segregated with the disease phenotype and was fully penetrant. The mutation was found in the wing region of the highly conserved forkhead domain of the FOXC1 gene and resulted in a very severe phenotype leading to blindness. CONCLUSIONS: This is the first study to demonstrate that a mutation in the FOXC1 wing region can cause an anterior segment dysgenesis of the eye. This mutation resulted in blindness in the ARA-affected family, and the findings suggest that the FOXC1 wing region has a functional role in the normal development of the eye. Moreover, this is the first study from India to report the genetic etiology of Axenfeld-Rieger anomaly. Genotype-phenotype correlations of FOXC1 may help in establishing the disease prognosis and also in understanding the clinical and genetic heterogeneity associated with various anterior segment dysgenesis caused by this gene.

Adult↗
PubMed1976

Cheilognathoschisis in Texel sheep.

In view of the birth of abnormal Texel lambs sired by a single ram, experimental matings were carried out to determine the extent to which the malformations shown by the lambs were clear-cut inherited defects and, if so, which was the mode of hereditary transmission. From investigations on six abnormal lambs and a study of the literature it was concluded that these were inherited defects not previously described and marked by cheilognathoschis which was almost invariably associated with an unduly light birth weight, brachycephaly and cardiac septal defects. The placenta of one of the abnormal lambs, which was studied, showed marked changes. The proportional numbers showed that, when the more complicated inheritance patterns are not taken into account, the defect is transmitted by a recessive autosomal gene.

Abnormalities, Multiple↗
PubMed1976

Bilateral renal dysplasia in three siblings: report of a survivor.

Three siblings, born nonconsectively to an unrelated couple, have had bilateral dysplastic kidneys. The first child had associated skeletal anomalies, the second, ureteral atresia, and the third, no other anomalies. The occurrence of dysplastic kidneys in three siblings is compatible with an autosomal recessive inheritance pattern. In addition the variety of presenting syndromes in the children suggests that variable pathogenetic mechansims were responsible for the appearance of dysplastic kidneys. The third child is alive with kidneys that markedly decreased in size over the neonatal period but is growing well at 41 months of age indicating that the presence of bilateral dysplastic kidneys does not necessarily preclude a favorable prognosis.

Abnormalities, Multiple↗
PubMed2000

Hypohydrotic ectodermal dysplasia: an unusual presentation and management in an 11-year-old Xhosa boy.

Ectodermal dysplasia (ED) is an inherited disorder in which two or more ectodermally derived structures fail to develop, or are abnormal in development. Hypohydrotic ectodermal dysplasia (HED) or Christ-Siemens-Touraine syndrome, is an X-linked recessive syndrome with an incidence of 1/10,000 to 1/100,000 births. Because of its X-linked inheritance pattern, it is more common in males. HED is characterised by hypohydrosis (diminished perspiration), hypotrichosis (decreased amount of hair) and microdontia (small teeth), hypodontia (lack of development of one or more teeth) or adontia (total lack of tooth development). These patients present diagnostic and treatment challenges because of variable oral manifestations. This report describes an 11-year-old Xhosa boy, who was referred to the University Dental Faculty by his general medical practitioner because of hypodontia. General facial features included: frontal bossing, a depressed nasal bridge, 'butterfly' pattern of eczema over the nasal bridge to the malar process of each cheek, thinned out hair, loss of vertical dimension of face and dry skin. Intra-oral examination revealed hypodontia with peg-shaped anterior teeth and diastemas. Radiological examination revealed no developing permanent teeth or tooth buds. Diagnosis was confirmed by doing a sweat gland count. Management included oral hygiene instruction, fluoride treatments, construction of a partial lower denture and counselling about his condition with particular reference to the danger of hyperthermia and control of allergies.

Anodontia↗
PubMed1976

Benign familial macrocephaly: report of a family and review of the literature.

Five members in two generations of one family were found to have occipitofrontal head circumferences more than 2 SD above the mean. All five had normal intelligence and neurological examinations. Three of the five had ventricular dilatation by A-mode echoencephalography. The inheritance pattern of macrocephaly in this family appears to be autosomal dominant with incomplete penetrance. Possible causes of the macrocephaly in this family are discussed and the reported cases of macrocephaly with normal intelligence and no neurological deficits are reviewed.

Cephalometry↗
PubMed2003

The antigen processing machinery of class I human leukocyte antigens: linked patterns of gene expression in neoplastic cells.

The ultimate outcome of an immune response (escape or surveillance) depends on a delicate balance of opposing signals delivered by activating and inhibitory immune receptors expressed by cytotoxic T lymphocytes and natural killer cells. In this light, loss and down-regulation of human leukocyte antigens (HLA) class I molecules, while important for keeping tumors below the T-cell detection levels, may incite recognition of missing self. Conversely, the maintenance of normal levels of expression (or even up-regulation) may be favorable to tumors, at least in certain cases. In this study, we took advantage of a previously characterized panel of 15 early passage tumor cell lines (mainly from melanoma and lung carcinoma lesions) enriched with class I-low phenotypes. These cells were systematically characterized by Northern and/or Western blotting (e.g., mini-transcriptome/mini-proteome analysis) for the expression of HLA-A, -B, -C, beta(2)-microglobulin, and the members of the "antigen processing machinery" of class I molecules (LMP2, LMP7, TAP1, TAP2, tapasin, calreticulin, calnexin, and ERp57). In addition, we established four pairs of cultures, each comprising melanoma cells and normal melanocytes from the same patient. We found that approximately 97% of the 185 tested gene products are expressed (although often weakly), and in many cases coordinately regulated in 18 of 19 tumor cell lines. Linked expression patterns could be hierarchically arranged by statistical methods and graphically described as a class I HLA "coordinome." Deviations (both down- and up-regulation) from the coordinome expression pattern inherited from the normal, paired melanocyte counterpart, were allowed but limited in magnitude, as if melanoma cells were trying to keep a "low profile" HLA phenotype. We conclude that irreversible HLA loss is a rare event, and class I expression in tumor cells almost invariably results from reversible gene regulatory (rather than gene disruption) events.

Antigens, Neoplasm↗
PubMedDate not supplied

Phenotyping of IL4-induced nuclear Stat6 activity in humans: quantitation after gel shift assay using immortalized cell lines.

The IL4-induced Stat6 signaling pathway is active in a variety of cell types, including different cancer cells, and plays an important role in the regulation of gene expression, such as CD23. There are large quantitative differences in DNA-binding activity of IL4-induced Stat6, which are useful for phenotyping activated Stat6 in normal and disease status. However, quantitation of activated Stat6 is challenging and a standardized methodology is needed. Here we have developed a semi-quantitative methodology using gel shift assay in which IL4-induced nuclear Stat6 activities are measured in human EBV-transformed lymphoblastoid cell lines. Using a DNA probe with high affinity Stat6-binding N4 motif and a specific antibody to Stat6, autoradiographs of EMSA gels are recorded by a scan imager and OD readings of antibody super-shifted Stat6 complex bands are obtained. OD readings of all test cell lines are referenced to that of a standard cell line placed in every single experiment and an OD ratio is obtained for each test cell, which allows assignment of Stat6 activational phenotypes. Using this methodology, we have been able to define three Stat6 activational phenotypes termed as Stat6high (intense banding), Stat6low (medium intensity banding), and Stat6null (very low to no discernible banding). These Stat6 phenotypes correlate well with levels of CD23 expression, but not with those of HLA-DR. Pedigree analysis has revealed a Mendelian inheritance pattern for Stat6 phenotypes. The methodology is useful in association studies in human cancer and autoimmune diseases. The Stat6null phenotype may result from a defect in Stat6 signaling which has important implications with respect to the pathogenesis of cancer and Th1/Th2 cytokine imbalance in general. In addition, the defective Stat6null lines discovered here may serve as a natural human model for comprehensive study in the same way as a Stat6 knockout null animal model does.

Amino Acid Motifs↗
PubMed2003

Corneal lattice dystrophy, a concealed ophthalmic problem in Thailand.

One single family of corneal lattice dystrophy was examined and interviewed to elucidate the variety of clinical manifestations, factors associated with visual impairment, and the impact on the patient's quality of life. Forty-three out of 88 family members (48.9%) were affected. The inheritance pattern was autosomal dominant. Corneal haze grading from 1 to 4 was 5.3 per cent, 26.3 per cent, 43.4 per cent, and 25 per cent respectively. Surface irregularity grading from 1 to 4 was 18.4 per cent, 39.5 per cent, 32.9 per cent, and 9.2 per cent respectively. Forty-five per cent of the patients had VA < or = 20/200. Corneal haziness, irregularity, corneal erosion and disease duration were significantly related to visual impairment (p < 0.05). This disturbed the patient's activities such as reading (79.1%), working (62.8%) and daily life (69.8%). Corneal lattice dystrophy within the same family may present with different manifestations depending on the severity and duration of the disease and might be misdiagnosed. Inadequate knowledge among patients was susceptible to the high prevalence of the disease leading to impaired quality of life.

Adult↗