Molecular background of polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal-recessive autoimmune disease caused by autoimmune regulator gene mutations. The aim of this study was to examine the mutation profile of Polish APECED patients, determine the carrier rate of the most frequent mutation(s) and estimate disease prevalence. While studying 14 unrelated patients, we identified three novel mutations (c.1A>T, affecting the start codon; [IVS1 + 1G>C; IVS1 + 5delG], a complex mutation affecting splice site; c. 908G>C, p.R303P, a missense mutation in plant homeodomain (PHD) and three previously reported mutations (c.769C>T, p.R257X; c.967_979del13bp, C322fsX372; c.931delT, p.C311fsX376). Eleven patients had mutations on both chromosomes, whereas in three patients only a single alteration with proven or likely pathogenic effect was detected. The most frequent was the p.R257X mutation (71% of chromosomes); its carriage rate was assessed in the background population. Analysis of 2008 samples showed eight heterozygotes, indicating the frequency of 0.40% (1:250) and the disease prevalence - 1:129,000 (95% confidence interval: 1:555,000 to 1:30,000). Comparison with an epidemiological estimate (1:619,000, derived for women) suggested that in Poland, APECED is underdiagnosed. Among the patients, no genotype/phenotype correlations were found, but we noted that women had earlier onset of hypoparathyroidism (p < 0.02) and were younger at diagnosis (p < 0.05) than men.

Small cell lung cancer is not associated with the presence of anti-fucosyl-GM1 ganglioside autoantibodies reactive in immunoenzymatic test.

The characteristic feature of small cell lung cancer carcinoma (SCLC) is the aberrant expression and abundant presentation of fucosyl-GM1 ganglioside (FucGM1). In the present study we searched for the presence of anti-FucGM1 ganglioside, as well as anti-GM1, GM2 and GD3 ganglioside autoantibodies in the sera of patients with SCLC and as a control, in sera of patients with renal cell cancer (RC) and healthy blood donors. The autoantibodies against FucGM1 were present at low titer in only three of 36 SCLC patients, and with similar titer in two of 36 RC patients and four of 36 healthy controls. Likewise, the autoantibodies against GM2 and GM3 gangliosides were found only sporadically and with the same titer and frequency in cancer patients as in healthy persons. Anti-GD3 autoantibodies could not be detected in any of the screened sera.

X-linked hypophosphatemia in Polish patients. 2. Analysis of clinical features and genotype-phenotype correlation.

Clinical and molecular data of 59 affected persons from 36 unrelated families with XLH (36 probands and 23 members of their families) were analysed. Characteristic phenotypic features (degree of leg deformities, growth failure, tooth abnormalities, tubular reabsorption of phosphate, serum phosphate and 1,25-dihydroxyvitamin D3 concentrations, head length and hearing defect in some cases) were assessed in relation to the type and localisation of 29 different PHEX gene mutations. The severity of clinical symptoms did not strictly depend upon the type and localisation of the PHEX gene mutation. A hearing defect was correlated with mutations in the beginning fragment, while tooth abnormalities and increased head length with the mutations in the beginning and the terminal fragment of the gene. Phosphate and vitamin D3 supplementation usually slowed progressive growth retardation and leg bowing. Our results point to the probability that alternative splicing occurs in the PHEX gene, producing several active forms of the PHEX protein. Some of them might be involved in bone turnover and dentin formation, others in renal phosphate uptake and vitamin D3 metabolism.

X-linked hypophosphatemia in Polish patients. 1. Mutations in the PHEX gene.

We present twenty-nine PHEX gene mutations extending our previous work, giving it to a total of 37 different mutations identified in Polish patients with familial or sporadic X-linked hypophosphatemia. Deletions, insertions and nucleotide substitutions leading to frameshift (27%), stop codon (29%), splice site (24%), and missense mutations (20%) were found. The mutations are distributed along the gene; exons 3, 4, 11, 12, 14, 15, 17, 20 and 22 are regions with the most frequent mutation events. Four mutations, P534L, G579R, R549X and IVS15+1nt, recurred in three, four, two and three unrelated patients, respectively. They have also been detected in affected persons from other countries. Twenty-eight mutations are specific for Polish population and almost all of them are unique. Most of the identified mutations are expected to result in major changes in protein structure and/or function.

Dominantly inherited isolated hyperparathyroidism: a syndromic association?

Dominantly inherited isolated hyperparathyroidism (DIIH) is rare in childhood. It may be the first biochemical abnormality in the multiple endocrine neoplasia type I (MEN I) and type II (MEN II) syndromes. Its clinical course is usually asymptomatic or of low morbidity. Radiographic examination is most often normal. We describe six members of a family with distinctive phenotype and DIIH. Limited systemic symptoms and severe radiographic osteitis fibrosa cystica were further unusual features in this family. The diagnosis of DIIH was made only after a 9-year-old girl developed hypercalcaemic crisis after a pathological femoral fracture. Distinctive phenotype, unusual clinical course and unparalleled radiographic changes suggest a not yet described syndromic association.

Expression of CEA and trophoblastic cell markers by lung carcinoma in association with histological characteristics and serum marker levels.

The study of tumour markers in lung cancer has focused mainly on serum-based analysis. The controversy about carcinoembryonic antigen (CEA), pregnancy specific glycoprotein 1 (SP1) and beta human chorionic gonadotropin (betahCG) production in lung carcinoma has been reported in several studies. The aims of this study were: to explore an expression of CEA, SP1 and betahCG in various histological types of lung carcinoma with respect to the grade of differentiation; and to define the relationship between tumour marker expression and serum marker concentration. Ninety two lung tumours (75 non-small cell carcinomas (NSCLC) and 17 small cell lung carcinomas (SCLC)) entered the study. Tumour marker expression was compared with the serum levels of CEA, SP1 and betahCG in 57 patients (pts) with NSCLC and four pts with SCLC. Positive immunostaining of CEA and SP1 was observed in 87% NSCLC, and betahCG was found in 24% NSCLC. In the SCLC group positive staining showed in 29% of tumours, SP1 in 51% and betahCG in 18%. Positive CEA expression ranged from 50-100% within the carcinomatous cell population (pcp) and was more characteristic for well and moderately differentiated adenocarcinomas. This finding was in contrast to squamous cell carcinomas, where the majority of tumours expressed CEA in 1-50% pcp. A significant negative correlation was noticed for adenocarcinoma between tumour expression and grade of histological differentiation for CEA (P < 0.001) and SP1 (P = 0.023). Results were not significant for squamous carcinoma. Significant differences of serum CEA concentration were noticed between adenocarcinoma and squamous carcinoma (P = 0.003). In addition, a statistically significant relation was found between serum CEA concentration and an early (I + II) and advanced (IIIa + IIIb + IV) stage of NSCLC (P = 0.031). A significant correlation was noticed when serum CEA and tumour CEA expression was compared for NSCLC (P < 0.001), and for serum betahCG and tumour betahCG (P = 0.019).

Persistent hypercalciuria and elevated 25-hydroxyvitamin D3 in children with infantile hypercalcaemia.

The aim of the study was to characterize abnormalities of calcium-phosphate and vitamin D3 metabolism in children with a past history of "mild" Lightwood-type idiopathic infantile hypercalcaemia. Seventeen seemingly healthy children aged 2-12 years, with long-term idiopathic hypercalcaemic syndrome since infancy were studied. Two reference groups were also included (vitamin D3 intoxication/healthy and Williams groups). Despite a long-term milk-restricted diet and a restricted vitamin D3 intake, urinary calcium excretion in the study group was 0.117 +/- 0.07 mumol/kg per 24 h. Compared with the reference groups (0.047 +/- 0.029 and 0.067 +/- 0.06 mumol/kg per 24 h, P < 0.05), there was significant hypercalciuria in the children with idiopathic hypercalcaemia since infancy. Serum concentrations of 25-hydroxyvitamin D3 in the study group were also elevated compared with the reference groups (57.4 +/- 15.5 vs. 34.6 +/- 9.3 and 22.7 +/- 10.5 ng/ml). 1,25-Dihydroxyvitamin D3 levels were at the upper limit of normal (45.9 +/- 13.1 vs. 35.0 +/- 8.1 and 30.0 +/- 13.7 pg/ml). Non-progressive, clinically silent nephrocalcinosis was visible on ultrasound examinations. The disturbances of vitamin D3 and calcium-phosphate metabolism persistent in the normocalcaemic phase of idiopathic infantile hypercalcaemia may be a primary metabolic defect of the condition. The mechanisms leading to elevation of metabolites of 1,25-dihydroxy- and 25-hydroxyvitamin D3 and the relationship between this and persistent hypercalciuria and nephrocalcinosis need pathophysiological explanation.

[Brain mapping in atonic epileptic attacks with consciousness disorders at school age]. / Mózgowy maping w padaczkowych napadach atonicznych z zaburzeniami swiadomosci, wieku szkolnego.

The paper presents the results of the analysis of atonic epileptic seizures with application of brain mapping eeg. The views to date on the pathogenesis of atonic seizures could be based on the assumptions of centrencephalic epilepsy voiced by Penfield and Jasper. The present investigations and electrophysiological-clinical observations support, however, contrary to the concept of Penfield and Jasper, the cortical origin of these seizures. The discussion on the clinical forms of atonic seizures in epilepsy, confirmed by analysis of brain mapping in the domain of frequencies and amplitude distribution, in the form of brain topograms, allows for the concept of cortical origin of these seizures with the probability of localisation of the epileptic focus, as in here presented case, in the anterior right paramedial frontal region of the brain.

[Brain mapping in Parkinson disease treated by cryothalamotomy]. / Mózgowy maping w chorobie Parkinsona u osób leczonych kriotalamotomia.

Brain mapping of the cerebral bioelectric activity was done by the BEAM method in 20 patients with Parkinson's disease treated by cryothalamotomy. Conventional egg examinations demonstrating relatively small changes of the type of local asymmetry of frequencies and/or amplitudes, sporadic focal changes, and sporadic generalized and disseminated generalized changes were analysed in a computer system in the domain of frequency and time. Brain mapping demonstrated very distinctly the asymmetry in the frequency bands alpha and beta. On the operated side a regular alpha rhythm of lower frequency but higher amplitude dominated in the brain hemisphere. On the intact side a quick beta rhythm prevailed and an irregular alpha rhythm was noticeable. This phenomenon described by analysis in the domain of frequency confirms the unilateral synchronizing influence of thalamotomy on the bioelectric activity of the operated brain hemisphere and may correlate with the functional motor improvement noted in the operated subjects. In three cases with a longer course of the disease analysis in the frequency domain demonstrated the presence of generalized diffused slow waves in both frontal regions. These changes correlated with mental insufficiency of the examined patients.

Growth rate in children with vitamin-D-dependent rickets in relation to 1-alpha-hydroxyvitamin D3 dosage.

Growth rate of five children with vitamin D-dependent rickets was analyzed during the long-term treatment with an active analog of vitamin D3. Considerable increase in growth rate together with the improvement of biochemical values and radiological pattern took place during the initial phase of administration of 1-hydroxyvitamin D3. During the maintenance treatment of long duration with 1-hydroxyvitamin D3 both the acceleration of growth and catch-up growth persisted. However, in 4 among 5 children studied an inhibition of growth was observed during different periods of time. Only in one boy was this connected with the conclusion of the process of physiological growth. In three remaining children a slow-down in growth rate appeared during the pre-pubertal period or was the effect of lowering the dose of 1-hydroxyvitamin D3 as an countermeasure to hypercalciuria. In such cases inhibition of growth was caused by the administration of too small a dose of 1-hydroxyvitamin D3 in relation to the requirement. In all cases the appearance of biochemical features of rickets aggravation, such as low blood serum phosphate concentration and elevated alkaline phosphatase activity, preceded the observable inhibition of growth. The results obtained allow us to conclude that the inhibition of growth observed during the long-term treatment of rickets with 1-hydroxyvitamin D3 may be regarded as the first signal of inadequate dosage of 1-hydroxy vitamin D3.

Urinary succinylacetone presence and delta-aminolaevulinic acid excretion in patients with type I tyrosinaemia during treatment.

In a group of 5 patients it was found that the presence of succinylacetone in urine as well as increased urinary excretion of delta-aminolaevulinic acid are a good criterion for the diagnosis of type I tyrosinaemia, and may serve for monitoring of the effectiveness of treatment with low-tyrosine diet. Determination of tyrosine levels in blood and urine by the semiquantitative method may be deceptive.

[Two cases of epileptiform attacks due to hypocalcemia in a child with hypoparathyroidism]. / Dwa przypadki padaczko-podobnych napadów hipokalcemii u dzieci z niedoczynnoscia przytarczyc.

Two cases are described of epileptiform convulsive seizures and consciousness disturbances in girls. The diagnosis of hypocalcaemia due to hypoparathyroidism was considerably delayed, and was made only when irreversible brain damage developed. The pathological mechanism, principles of diagnosis and treatment of hypoparathyroidism are discussed.

Abolished phosphaturic response to parathormone in adult patients with Fahr disease and its restoration after propranolol administration.

The similar localization of intracranial calcification in hypoparathyroidism and in Fahr disease without parathyroid gland disorder suggests that in these two disorders the pathomechanism of calcium phosphate deposition in the brain may be similar. It may be that in Fahr disease some factors, such as chronic respiratory alkalosis, could lead to hypoparathyroidism-like changes in the brain tissue. Abolition of the phosphaturic response to parathormone (PTH) was recently demonstrated in acute experimental hypocapnia. In three adult patients with Fahr disease, a tendency towards compensatory respiratory alkalosis and arterial hypocapnia was found. The parathormone test revealed a marked decrease in phosphaturia response to PTH, but normal cAMP response. In one patient, the parathormone test was repeated during propranolol administration and showed a considerable improvement in the phosphaturic response to parathormone. It is postulated that chronic hyperventilation and hypocapnia as well as phosphaturic resistance to PTH, intracellular increase of phosphate concentration and development of hypoparathyroidism-like intracranial calcification in patients with Fahr disease could all be caused by disturbance of adrenergic receptors and their relationship to PTH receptors.

[Role of the parathyroid glands in the pathogenesis of intracerebral calcifications]. / Udzial przytarczyc w patogenezie zwapnien sródmózgowych.

Investigations of calcium-phosphate metabolism were carried out in a group of 11 children and adults with intracerebral calcifications. It was possible to isolate three different pathogenetic types of calcifications in the striatum and dentate nuclei in the cerebellum. The authors suggest restriction of the term "Fahr's syndrome" to cases without true of false hypoparathyroidism. The assessment of the calcium-phosphate metabolism, and particularly, the test with parathyroid hormone, seem to be an indispensable element in the differential diagnosis of this type of intracerebral calcifications.