Expression of DNA-PKcs and Ku86, but not Ku70, differs between lymphoid malignancies

We have investigated the role of DNA-dependent protein kinase (DNA-PK) and related it to proliferation and maturation of different lymphoid malignancies. DNA-PK and Ki-67 protein content was investigated in tumour samples of lymphoid malignancies, obtained from patients with low- and high-grade lymphomas, acute lymphoblastic leukaemia and multiple myeloma. All patients were untreated before sampling. Normal bone marrow, reactive tonsillar tissue and ordinary lymph node tissue were used as controls. We show here that lymphoid malignancies display differences in DNA-PK protein expression. Low-grade lymphoma, appearing as chronic lymphocytic leukaemia (CLL) displayed a significantly lower frequency of cells staining positive for DNA-PKcs and Ku86, but surprisingly not for Ku70, compared with acute lymphoblastic leukaemia (ALL) cells. When material from individual CLL patients was investigated, cells from lymph nodes showed a higher frequency of positive cells with respect to all DNA-PK subunits, compared with CLL cells infiltrating the bone marrow. High-grade lymphoma lymph node samples showed an increased frequency of cells staining positive for DNA-PKcs, Ku86 and Ki-67 compared with lymph node samples from low-grade lymphoma patients. Again, no difference in the Ku70 levels between the two lymphoma entities was noted. In multiple myeloma, the frequency of cells with positive staining for DNA-PKcs was similar to that detected in ALL and high-grade lymphoma. We conclude that with the exception of multiple myeloma, expression of DNA-PK coincides with the degree of maturation of lymphoid malignancies. In low- and high-grade lymphoma, DNA-PK is associated with the proliferation rate.     

Mental retardation, Robin sequence, and brachydactyly: further confirmation of a new syndrome

Recently we reported two sibs, brother and sister, with a new multiple congenital anomalies/mental retardation (MCA/MR) syndrome characterized by mild to moderate psychomotor delay, Robin sequence, distinctive facial appearance, and brachydactyly. We have subsequently observed a similar pattern of anomalies in two unrelated patients who also showed additional clinical findings. This new observation supports the existence of a new syndrome and expands the phenotypic spectrum of the condition.     

Acute hemolytic transfusion reactions due to multiple alloantibodies including anti-E, anti-c and anti-Jkb

We report a case of two consecutive episodes of acute hemolytic transfusion reactions (HTRs) due to multiple alloantibodies in a 34-yr-old man who suffered from avascular necrosis of left femoral head. He received five units of packed red blood cells (RBCs) during surgery. Then the transfusion of packed RBCs was required nine days after the surgery because of the unexplained drop in hemoglobin level. The transfusion of the first two units resulted in fever and brown-colored urine, but he received the transfusion of another packed RBCs the next day. He experienced even more severe symptoms during the transfusion of the first unit. We performed antibody screening test, and it showed positive results. Multiple alloantibodies including anti-E, anti-c and anti-Jkb were detected by antibody identification study. Acute HTRs due to multiple alloantibodies were diagnosed, and the supportive cares were done for 6 days. We suggest the antibody screening test should be included in the panel of pretransfusion tests for safer transfusion, and it is particularly mandatory for the patients with multiple transfusions, pregnant women, and preoperative patients.     

Patient with double heterozygosity for achondroplasia and pseudoachondroplasia,with comments on these conditions and the relationship between pseudoachondroplasia and multiple epiphyseal dysplasia,Fairbank type

We present a 7½-year-old girl with achondroplasia and pseudoachondroplasia. Her mother has achondroplasia and her father has pseudoachondroplasia. Radiographic manifestations of these two conditions from infancy to age 6 years are outlined. The findings in this patient are compared with those of achondroplastic patients and pseudoachondroplastic patients of similar ages. Our review of radiographs of many pseudoachondroplastic patients and subsequently of those of patients with multiple epiphyseal dysplasia (MED), Fairbank type, reinforced our opinion that pseudoachondroplasia and multiple epiphyseal dysplasia, Fairbank type, are closely related conditions. MED, Fairbank type, may be the mildest form of pseudoachondroplasia. Recently published electron microscopic findings also suggest this. © 1993 Wiley-Liss, Inc.     

Disproportionate elevation of the immunoglobulin G1 concentration in cerebrospinal fluids of patients with multiple sclerosis

We determined immunoglobulin G (IgG) subclass concentrations and studied their distributions in the cerebrospinal fluids of patients suffering from multiple sclerosis, other inflammatory neurological diseases, and non-inflammatory diseases of the nervous system in comparison with a control group. In addition, the four subclass concentrations were measured in serum specimens of the multiple sclerosis and control groups. These data were correlated with the extent of local IgG synthesis in the subarachnoid spaces of the patients belonging to the different groups. We found a selective elevation of the IgG1 subclass in the cerebrospinal fluids of multiple sclerosis patients, and there was only a very small overlap of the IgG1 ranges of the multiple sclerosis and control groups. No major differences were detected between the IgG subclass distributions in different courses of multiple sclerosis nor between multiple sclerosis and control sera. The group with non-inflammatory diseases showed a uniform elevation of all four subclasses and a greater overlap with the normal range. This latter feature was combined with an elevated IgG1 concentration in the group with other inflammatory diseases. It is concluded that locally synthesized IgG in the cerebrospinal fluids of multiple sclerosis patients consists mainly of IgG1.     

Myoglobinuria caused by multiple deletions of mitochondrial DNA

We report two brothers with inherited recurrent myoglobinuria associated with distinct morphological abnormalities of muscle mitochondria and multiple deletions of muscle mitochondrial DNA. Patient 1 (26 years old) and Patient 2 (21 years old) had recurrent episodes of myoglobinuria provoked by strenuous exercise or alcohol intake. Histochemistry of their biopsied limb muscles showed ragged-red fibers and cytochrome c oxidase-negative fibers as well as degenerating and regenerating fibers. Electron microscopy showed a pronounced accumulation of abnormal mitochondria containing paracrystalline inclusions and moderate increases of glycogen particles. Southern blot analysis revealed multiple deletions of mitochondrial DNA, some of which were common to both patients. By the primer shift polymerase chain reaction method, we detected multiple abnormal fragments indicating mitochondrial DNA deletions. Nucleotide sequencing of the deleted regions disclosed directly repeated sequences of 1 to 12 bp on each side of the deletions. Since the end points of mitochondrial DNA deletions were within 20 bp of the major non-coding region, probable mutations in this region contribute to the pathogenesis of multiple mitochondrial DNA deletions found in these patients. We propose that a defect of the mitochondrial energy-transducing system due to multiple mitochondrial DNA deletions is a novel genetic cause of inherited recurrent myoglobinuria.     

A new lethal syndrome of exomphalos, short limbs, and macrogonadism

We report a new lethal multiple congenital abnormality (MCA) syndrome of exomphalos, short limbs, nuchal web, macrogonadism, and facial dysmorphism in seven fetuses (six males and one female) belonging to three unrelated families. X rays showed enlarged and irregular metaphyses with a heterogeneous pattern of mineralisation of the long bones. Pathological examination showed adrenal cytomegaly, hyperplasia of Leydig cells, ovarian stroma cells, and Langherans cells, and renal microcysts. We suggest that this condition is a new autosomal recessive MCA syndrome different from Beckwith-Wiedemann syndrome, especially as no infracytogenetic deletion or uniparental disomy of chromosome 11 was found.     

Association of hypokalemia, aldosteronism, and renal cysts

The recognition of renal cysts in two patients with chronic hypokalemia and the renal effects of hypokalemia in certain species of animals prompted this study of the possible association of hypokalemia and renal cysts in patients with primary aldosteronism or primary renal potassium wasting. Using CT scans, we studied 55 patients with primary aldosteronism, of whom 24 had cysts (44 percent). The cysts were more frequent in patients with adrenal tumors than in those with idiopathic adrenal hyperplasia. Sixteen of the 26 patients with tumors (62 percent) had renal cysts, which were often multiple and located in the medulla. Lower plasma potassium levels and higher serum aldosterone levels, urinary aldosterone excretion, and plasma renin activity were correlated with the extent of the cystic disease. Sequential observations indicated that prolonged hypokalemia can be accompanied by the development of renal scarring and that the size and number of cysts can decrease markedly in some patients after the removal of an adrenal adenoma. The association of hypokalemia, aldosteronism, and renal cysts was also supported by the finding of multiple medullary cysts in two patients with primary renal potassium wasting. We conclude that chronic hypokalemia is accompanied by enhanced renal cytogenesis and may lead to interstitial scarring and renal insufficiency. Renal cysts are thus dynamic structures whose growth can be influenced by hormonal or pharmacologic interventions.     

Different clonal origin of bilateral papillary thyroid carcinoma, with a review of the literature

Papillary thyroid carcinoma (PTC) often presents with two or more anatomically separate foci. A long-standing argument is whether this multifocality is the result of multiple independent tumors (“multicentricity”) or of intrathyroidal spread originating from a single tumor mass, presumably through permeation of intrathyroidal lymph vessels. We reexamined this issue with a clonality assay and compared our results with those in the literature. A total of 27 nodules from 11 female patients with bilateral PTC treated with total thyroidectomy were investigated for clonality using the HUMARA assay. Eight of 11 cases were informative (72.7 %). All but one of tumor foci showed a monoclonal population. The outlier sample gave a value indicative of balanced X-inactivation in one nodule. The monoclonality was concordant in three patients, discordant in three, and mixed in two (with both concordant and discordant results). Interestingly, in both of the latter cases (composed of over two samples per case), the contralateral nodules were discordant. Moreover, all four ipsilateral nodules were concordant. The results of our study suggest that some cases of multifocal PTC are the result of true multicentricity, whereas others are the consequence of intrathyroid spread by an originally single tumor mass. These conclusions support those made in the past years on the basis of morphologic considerations. Specifically, the incidental finding of two or more microscopic foci of PTC widely separate from each other was felt to favor multicentricity, whereas the finding of multiple ipsilateral foci of PTC within vascular spaces, often accompanied by multiple lymph node metastases, suggested intrathyroid spread; the most striking manifestation of this phenomenon being seen in the diffuse sclerosing variant of PTC.     

Apparently novel genetic syndrome of pachygyria, mental retardation, seizure, and arachnoid cysts

We report on an apparently new syndrome in a consanguineous family with seven members, three of whom have cerebral anomalies including pachygyria and arachnoid cysts along with mental retardation and seizures. The two patients with seizure disorders also had multiple enlarged perivascular spaces seen in the white matter of the centrum semiovale. Our data provide a contribution to the accumulating knowledge on familial cerebral anomalies including arachnoid cysts and lissencephaly. Given the lack of mutation in known lissencephaly genes such as LIS1, 14-3-3epsilon, and DCX, this syndrome may constitute a new phenotype with autosomal recessive inheritance.     

Amyloidosis presenting in the lower respiratory tract. Clinicopathologic, radiologic, immunohistochemical, and histochemical studies on 48 cases

We studied 48 cases of amyloidosis localized to the lower respiratory tract. Fourteen cases were classified as tracheobronchial amyloidosis. Twenty-eight cases showed solitary or multiple nodules, and six cases had a diffuse interstitial parenchymal pattern. Almost all patients with tracheobronchial and diffuse interstitial amyloidosis had respiratory symptoms (usually dyspnea), whereas most with nodular amyloidosis were asymptomatic. Nodular parenchymal and, less frequently, tracheobronchial amyloidosis had contiguous cellular infiltrates of plasma cells, lymphocytes, and giant cells. Immunohistochemical staining of specimens from 18 cases showed these plasma cells to be polytypic, except for two tracheobronchial lesions that had a disproportionate number of lambda light chain-bearing plasma cells. Permanganate oxidation of specimens from 19 cases showed patterns in keeping with immunoglobulin-derived amyloid in 12. Local deposits of amyloid in lung may arise from deposition of circulating precursor proteins.     

Treatment of pathologic laughing and weeping with amitriptyline

Patients with bilateral forebrain disease may commonly manifest the syndrome of pathologic laughing and weeping. We investigated the efficacy of low-dose amitriptyline in 12 patients in whom this syndrome was a consequence of multiple sclerosis. In a double-blind crossover study comparing amitriptyline with placebo, eight patients experienced dramatic and significant improvement with amitriptyline (P = 0.02). The mean dose of amitriptyline was 57.8 mg per day and did not exceed 75 mg per day in any patient. Concurrent measurements of depression showed no change during the study. We conclude that amitriptyline is effective in the treatment of this disturbance of affective expression, and that this effect is distinct from the antidepressant effect of the medication.     

Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation

We have observed over 25 different mutations in the diastrophic dysplasia sulphate transporter gene (DTDST) in association with the recessive disorders achondrogenesis 1B, atelosteogenesis 2, and diastrophic dysplasia. The c862t (R279W) transition is the most common mutation in non-Finnish patients, but in these disorders it is usually combined with other DTDST mutations. We had not seen a case of homozygosity for c862t (R279W) until we analysed DNA from a 36 year old male with tall-normal stature (180 cm) who asked for genetic counselling for suspected multiple epiphyseal dysplasia. He was treated for club foot and hip dysplasia at birth. Skeletal changes consistent with multiple epiphyseal dysplasia, with the peculiar finding of a double layered patella, were recognised during childhood. Cleft palate, swelling of the ear pinna, and hitch hiker thumb were absent. He was found to be homozygous, and both healthy parents heterozygous, for the R279W mutation in DTDST, and his fibroblasts showed a sulphate incorporation defect typical of DTDST disorders. Counselling was given for a recessive disorder, thereby considerably reducing the probability of affected offspring. Multiple epiphyseal dysplasia is more frequently caused by dominant mutations in the COMP (EDM1, McKusick 132400) and COL9A2 genes (EDM2, McKusick 600204). A few other patients and families with features similar to our proband have been described previously and considered to have autosomal recessive MED (EDM4, McKusick 226900). This observation confirms the existence of this entity and assigns it to the phenotypic spectrum associated with mutations at the DTDST locus.     

A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications

PHACE (OMIM no. 606519) is a neurocutaneous syndrome that refers to the association of large, plaque-like, "segmental" hemangiomas of the face, with one or more of the following anomalies: posterior fossa brain malformations, arterial cerebrovascular anomalies, cardiovascular anomalies, eye anomalies, and ventral developmental defects, specifically sternal defects and/or supraumbilical raphe. The etiology and pathogenesis of PHACE is unknown, and potential risk factors for the syndrome have not been systematically studied. The purpose of this study was thus to determine (1) the incidence of PHACE and associated anomalies among a large cohort of hemangioma patients, (2) whether certain demographic, prenatal or perinatal risk factors predispose infants to this syndrome, and (3) whether the cutaneous distribution of the hemangioma can be correlated to the types of anomalies present. We undertook a prospective, cohort study of 1,096 children with hemangiomas, 25 of whom met criteria for PHACE. These 25 patients represented 20% of infants with segmental facial hemangiomas. Compared to previous reports, our PHACE patients had a higher incidence of cerebrovascular and cardiovascular anomalies. Two developed acute arterial ischemic stroke during infancy, while two with cardiovascular anomalies showed documented evidence of normalization, suggesting that both progressive and regressive vascular phenomena may occur in this syndrome. Correlation to the anatomic location of the hemangioma appears to be helpful in determining which structural abnormalities might be present. A comparison of demographic and perinatal data between our PHACE cases and the hemangioma cohort overall showed no major differences, except a trend for PHACE infants to be of slighter higher gestational age and born to slightly older mothers. Eighty-eight percent were female, a finding which has been noted in multiple other reports. Further research is needed to determine possible etiologies, optimal evaluation, and outcomes.     

Pathologic findings in adenosine deaminase-deficient severe combined immunodeficiency. I. Kidney, adrenal, and chondro-osseous tissue alterations.

The authors have reviewed the autopsies of 8 patients with adenosine-deaminase-deficient severe combined immunodeficiency disease (ADA-SCID). Several new findings in nonlymphoid organs, including kidney and adrenal gland, and chondro-osseous tissue indicate the multisystem nature of this disorder. Examination of renal tissue in 7 of 8 cases showed mesangial sclerosis. This was confirmed in 3 cases by electron microscopy. One case, treated with multiple erythrocyte partial exchange transfusions for several years, had no mesangial sclerosis. Six of 8 cases showed adrenal-gland cortical sclerosis. Chondro-osseous tissue from vertebrae and costochondral junctions of 4 cases examined showed typical alterations previously reported in ADA-SCID such as short growth plates with few proliferating and some hypertrophic chondrocytes. The authors report the new observations of necrotic chondrocytes, as well as large amounts of cellular debris. These changes were not observed in the 2 other patients examined, who received bone marrow or multiple partial exchange transfusions. The distribution and severity of these lesions, their relationship to ADA replacement therapy, and their homology to mice treated with a potent ADA inhibitor suggests that, in addition to lymphoid dysfunction, disordered nucleoside metabolism due to absent ADA activity in ADA-SCID may be the cause of diverse multi-system pathologic changes in tissues which continue to differentiate or mature after birth.     

New syndrome of mental retardation, Robin sequence, and brachydactyly

We report on two sibs, brother and sister, affected with a multiple congenital anomalies/mental retardation (MCA/MR) syndrome, characterized by mild to moderate psychomotor delay, Robin sequence, peculiar facial appearance, and brachydactyly. To our knowledge, this combination of anomalies has not been reported previously. The occurrence of a similar pattern of anomalies in brother and sister suggests autosomal recessive inheritance; however, dominant transmission with reduced penetrance cannot be ruled out in our patients, since minor clinical signs, such as brachydactyly, are also present in the father.     

Multiple congenital anomalies syndrome: growth and mental retardation, microcephaly, preauricular skin tags, cleft palate, camptodactyly, and distal limb anomalies. Report on two unrelated Brazilian patients.

We report on 2 unrelated Brazilian patients, born to non-consanguineous parents, both with multiple anomalies including growth and mental retardation, microcephaly, telecanthus, cleft palate, preauricular skin tags/pit, camptodactyly, and foot anomalies. To our knowledge, this is a previously undescribed formal genesis syndrome. Clinical and genetic aspects are discussed.     

Results of chromosome studies and their relation to morphology, course, and prognosis in 120 patients with de novo myelodysplastic syndrome

Cytogenetic studies were performed in 120 patients with de novo myelodysplastic syndrome (MDS) classified according to FAB criteria. Twenty-eight patients had refractory anemia (RA), 14 had refractory anemia with ring sideroblasts (RARS), 45 had refractory anemia with blast excess (RAEB), 19 had refractory anemia with blast excess in transformation (RAEB-t), and 14 had chronic myelomonocytic leukemia (CMMoL). Fifty patients (42%) had clonal chromosome anomalies at initial analysis. The most common cytogenetic anomalies were: 5q- (11 patients), trisomy 8 (nine patients), -7/7q- (6 patients), 12p- (five patients), followed by structural anomalies of chromosome 17 (four patients), and loss of Y chromosome (three patients). The prognostic value of chromosome anomalies was examined by comparison of the significance of single chromosome anomalies (34 patients) versus multiple cytogenetic changes (16 patients). Patients with multiple anomalies had a shorter survival (8 months) than patients with single anomalies (18 months) or those with a normal karyotype (36 months). All these differences were significant. The incidence of multiple anomalies was higher in patients with RAEB and RAEB-t than in those with RA, RARS, and CMMOL (p less than 0.05). However, no chromosome anomaly was specifically associated with any group of FAB classification. Transformation to acute leukemia was observed in 25% of patients with normal karyotype, 41% of patients with single anomalies, and 50% of patients with multiple changes. The incidence of leukemic transformation was significantly higher in patients with multiple anomalies than in those with a normal karyotype (p less than 0.05). Thus, in the present study, FAB classification and chromosome anomalies were of independent prognostic significance. Sequential cytogenetic studies were performed in 23 patients to correlate the cytogenetic and clinical findings during the course of the disease. Six of seven patients with transformation to acute leukemia showed a karyotypic evolution. These findings agree with the view that an unstable karyotype can be associated with a poor prognosis.     

Lack of association between 5HT2A receptor gene haplotype, bipolar disorder and its clinical subtypes in a West European sample.

Bipolar affective disorder (BPAD) is a complex psychiatric disorder with a major genetic contribution. Abnormalities in serotonergic function have been implicated in its aetiology. The 5HT2A receptor (5HT2AR) gene is a strong candidate gene for involvement in BPAD, but previous association studies have reported conflicting results. These data are difficult to interpret because most negative results were obtained with small samples. The aim of this study was to test the association between the 5HT2AR gene and BPAD in a large West European sample. We studied the -1438G/A and the His452Tyr polymorphisms, for haplotype analysis to increase both informativity and the likelihood of detecting an association between BPAD and the 5HT2AR gene. We analysed the genotype, allele and haplotype distributions of two 5HT2AR gene variants in a population of 356 BPAD patients, which we compared with 208 healthy controls. We also carried out exploratory analysis in clinical subgroups of patients defined according to personal history of mood disorders, suicidal behaviour, comorbid psychiatric disorders and family history of affective disorders. We found no difference between BPAD patients and controls for allele, genotype and haplotype distributions. Exploratory analysis in subgroups of BPAD patients showed only a marginal difference in haplotype distribution between controls and BPAD patients with antidepressant-induced mania (P = 0.018). This difference was not significant after correction for multiple testing. Our study suggests that the 5HT2AR gene is unlikely to be involved in genetic susceptibility to BPAD but should be further investigated in a pharmacogenetic study.