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Nijmegen breakage syndrome (NBS), a rare autosomal recessive condition also known as ataxia telangiectasia (AT) variants V1 and V2, is characterised by microcephaly, typical facies, short stature, immunodeficiency, and chromosomal instability. We report the clinical, immunological, chromosomal, and cell biological findings in 42 patients who are included in the NBS Registry in Nijmegen. The immunological, chromosomal, and cell biological findings resemble those in AT, but the clinical findings are quite different. NBS appears to be a separate entity not allelic with AT.

In children with cryptogenic Lennox-Gastaut syndrome we found a functionally impaired humoral immune response to a primary antigen (haemocyanin), despite signs of a triggered immune system consisting of elevated IgG concentrations. This combination of immunological findings, considered to be the expression of a dysbalanced-triggered as well as functionally impaired-immune system, has also been described in an auto-immune disease like systemic lupus erythaematodes in humans, and in genetically epilepsy-prone rats. The interactions between the immune system and the nervous system in Lennox-Gastaut syndrome will be discussed.

Immunological disturbances may result in altered immunoglobulin concentrations and kappa/lambda light chain (kappa/lambda) ratios. We measured the kappa/lambda ratios of total serum immunoglobulins and of polyclonal IgG, A, and M separately as well as concentrations of these immunoglobulins in fourteen patients with juvenile onset mixed connective tissue disease. When comparing the patient group with a reference group the mean serum IgG and IgA concentrations were respectively 2.98 G/L (p = 0.0012) and 0.79 G/L (p = 0.0114) higher in the group of patients with juvenile onset mixed connective tissue disease. The mean IgM concentration was 0.39 G/L (p = 0.0002) lower. The mean kappa/lambda ratios of total serum immunoglobulins, serum IgG, and serum IgA were respectively 0.20 (p = 0.0226), 0.28 (p = 0.0016) and 0.10 (p = 0.0732), higher in the group of patients with mixed connective tissue disease as compared with the reference group. Mean serum IgM kappa/lambda ratio, however, was 0.21 (p = 0.0046) lower. The alterations of the serum immunoglobulin concentrations and of the kappa/lambda ratios reflect immunological disturbances in patients with juvenile onset mixed connective tissue disease. The increased concentration of serum IgG and raised IgG kappa/lambda ratio and decreased concentration of serum IgM with decreased IgM kappa/lambda ratio indicate that the synthesis of kappa-bearing immunoglobulins mainly is affected.

The relationship between human immunoglobulin administration, and human and experimental epilepsy was investigated by reviewing the literature as well as the authors' clinical and experimental studies. The focus was: 1) the possible efficacy of IVIg; 2) the possibility that IVIg significantly increases CSF IgG and could reach the brain, and 3) the interaction between the IVIg preparation and epilepsy. There is still no formal proof of efficacy of IVIg treatment in epilepsy. However, the clinical data presented suggests that IVIg is likely to be effective in a subgroup of patients with intractable and epilepsy, and may be considered as a safe add-on medication in various types of idiopathic and symptomatic intractable epilepsy. From the authors' study on cerebrospinal fluid IgG concentrations before and after IVIg treatment in patients with epilepsy, it is concluded that the main component of the IVIg preparation (the IgG molecule) crosses the blood-CSF barrier, significantly increases CSF IgG concentration, and may reach the brain and act centrally. From a review of previous reports and two immunological studies carried out by the authors it is concluded that immunogenetic mechanisms may play a role in triggering or maintaining some types of epilepsy. In view of this, IVIg could act on epilepsy by its broad immunomodulatory mechanism of action. In addition, preliminary data are reported that contribute to the hypothesis that IVIg may have a direct neuromodulating effect.

Patients with ICF syndrome can be recognized by the presence of a variable immunodeficiency, instability of the pericentromeric heterochromatin of, in particular, chromosomes 1, 9, and 16 in cultured peripheral lymphocytes, and a number of facial anomalies. Recently, aberrations at the molecular level have been described, consisting of alterations in the methylation pattern of classical satellite DNA, in a number of patients. ICF syndrome is considered to be inherited in an autosomal recessive manner and may be rare, as only 14 patients have been described thus far. We present a new case, a boy with agammaglobulinemia, who was extensively studied by means of classical cytogenetics and fluorescent in situ hybridization. All patients previously reported in the literature are reviewed.

Before and after administration of intravenous immunoglobulin (IVIg), cerebrospinal fluid (CSF) was examined in a homogeneous group of 15 patients with cryptogenic types of West syndrome (WS) and Lennox-Gastaut syndrome (LGS). The purpose of the present CSF study was: (i) to elucidate possible etiological factors and consequences of these severe forms of epilepsy, and (ii) to elucidate mechanisms of action and adverse effects of IVIg. Hypotheses concerning etiological factors like central nervous system infections, neuroimmunological disorders, or disturbances in neurotransmitter metabolites could not be confirmed. These normal CSF findings are in accordance with the concept of a cryptogenic etiology of the epilepsies in the reported patients. Nor could we confirm hypotheses concerning seizure consequences, such as increased blood-CSF permeability, increased markers of brain cell destruction, or increased metabolic components. Following IVIg administration in these patients, all with an on the whole undisturbed blood-CSF barrier permeability as measured by Q albumin, the CSF IgG concentrations increased significantly and proportionally to the Q albumin level. No signs of adverse effects of IVIg such as aseptic meningoencephalitis were found in 165 infusions of IVIg performed in the 15 children.

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A combination of humoral immunodeficiency and isolated growth hormone deficiency was observed in a girl with Mulibrey nanism. The humoral immunodeficiency consisted of subnormal concentration of serum IgG, in particular IgG2 and IgG4, and low concentration of serum IgM. Serum IgA and IgD were elevated, IgE was absent. Antibody response in vivo was very low or absent and opsonization in vitro was defective. Total B-cell number was low. In addition, the serum kappa/lambda light chain ratios within the immunoglobulin classes G, A, and M were abnormal. The defective anti-body response may be linked to the abnormal kappa/lambda light chain ratios. Endocrine functions were normal except for isolated growth hormone deficiency. Therapy with human growth hormone resulted in increased growth velocity but did not improve humoral immune functions.

Serum immunoglobulin G, A and M concentrations and their respective kappa/lambda (kappa/lambda) light chain ratios were studied in 26 children with epilepsy. Fifteen had cryptogenic West syndrome or Lennox-Gastaut syndrome and 11 had other forms of childhood epilepsy. The results were compared to the data of a reference group of healthy children. The mean serum IgG and IgM concentrations were respectively 2.2 g/l (P = 0.007) and 0.4 g/l (P = 0.016) higher in the 26 children with epilepsy compared to the reference group. The kappa/lambda ratios of total serum immunoglobulins, IgG and IgM were respectively 0.10 (P = 0.057), 0.20 (P = 0.001) and 0.14 (P = 0.005) lower in the children with epilepsy than in the reference group. IgA concentration and IgA kappa/lambda ratio were not affected. There were no significant differences between the kappa/lambda ratios of the West and Lennox-Gastaut epilepsy and the other types of childhood epilepsies. The results are further evidence of reciprocal interaction between the nervous system and the immune system in childhood epilepsy.

The total kappa/lambda immunoglobulin light chain ratio and the kappa/lambda ratios within each of the serum immunoglobulin classes G. A. and M were measured in thirteen patients with humoral immunological disorders. Of those patients, eight had common variable immunodeficiency whereas live patients had other forms of humoral immunological deficiencies. Eleven patients had abnormal antibody response in vivo. All but three of the thirteen patients had clearly abnormal light chain ratios in one or more of the immunoglobulin classes. We conclude that humoral immunological disorders, usually characterized by abnormal heavy chain production and a disturbed antibody response, may frequently have a concomitant abnormal synthesis of the light chains resulting in an abnormal kappa/lambda light chain ratio.

Longitudinal serum immunoglobulin levels were studied in 36 children with selective IgA deficiency during a median follow-up period of 5 years. Twenty-live children were "sporadic' cases, and 11 were "familiar. Serum and saliva IgA levels in 23 children remained below 2 mg/'l. Eight children with IgA levels above 2 mg/1 showed considerahle intra-individual variance in serum IgA. but remained IgA deficient. Five children at various ages developed IgA levels above 50mg/l with detectable secretory IgA in saliva- In most of the children IgG subclass levels were found to be rather high, including at younger ages. There were no obvious differences between 'sporadie' and 'familial' eases except an assoeiation between IgD deficiency and serum IgA levels below 2 mg/1, and between serum levels of IgD above 1 ItJ/ml and of IgA above 2 mg/1, which was found to be significant in the "sporadic' group but not in the "familial' group.

A girl with acute non-lymphoblastic leukaemia was treated with immunosuppressive chemotherapy. After cessation of therapy she had three consecutive episodes of infection due to Streptococcus pneumoniae from which she recovered and was shown to have developed a combined deficiency of both IgG2 and IgG4. The patient eventually relapsed and died 3 years after the initial diagnosis. The importance of measuring IgG subclasses in patients treated with immunosuppressive chemotherapy is discussed.

An enzyme-linked immunosorbent assay is described for measuring kappa and lambda light chains within each of the serum immunoglobulin classes G, A and M. The detection limit was 0.06 U/L for total IgG, IgG kappa and IgG lambda, 0.2 U/L for total IgA, IgA kappa and IgA lambda and 0.5 U/L for total IgM, IgM kappa and IgM lambda. The concentrations of kappa plus lambda light chains from the three different immunoglobulins correlated well within those of total immunoglobulin G, A and M as measured by enzyme-linked immunosorbent assay or by immunonephelometry. Adult values for the kappa/lambda light chain ratio were found to be 2.0 for IgG kappa/lambda, 1.1 for IgA kappa/lambda and 1.7 for IgM kappa/lambda.

Clinical manifestations in 40 children with selective IgA deficiency were studied during a follow-up period of 2-10 years. The patients were divided into two groups: group I consisted of 25 children with "sporadic" IgA deficiency and group II of 15 children with "familial" IgA deficiency. Respiratory tract infections including otitis media were frequent in both groups. Concomitant IgG2-IgG4 deficiency was found in two patients in group I. Longitudinal serum IgG levels were elevated significantly in both groups. Atopic complaints were observed in 10 children of the "sporadic" group, but only in two of the "familial" group. However, elevated serum IgE levels were more often found in group II. Two children of group I were mentally retarded and chromosomal examination showed abnormalities in both. Anti-IgA antibodies were detected in one child in group I and three children in group II. These three patients had an IgA deficient mother with class-specific anti-IgA antibodies. Concomitant IgG4-IgE deficiency was found in all four.

ICF syndrome (Immunodeficiency, Centromeric instability, in particular of chromosomes 1 and 16 and Facial dysmorphisms) was described in 1988 by Maraschio et al. (J Med Genet 25:173-180). Here we present another case of ICF syndrome. The boy was born at 38 weeks, small for gestational age (2055 gram, 45 cm). During the first year he had a failure to thrive and a slight psychomotor retardation. At the age of 10 months, he suffered from RS bronchiolitis. Immunological studies revealed an agamma-globulinaemia (all immunoglobulins were absent). B cells were normal, as were T cell markers (CD2 58 %, CD3 56 %, CD4, 36 %, CD8 17 %). In vitro responses of peripheral blood cells to PHA and PWM were normal. He had a typical face. Cytogenetic studies revealed a normal 46 XY male karyotype, although half of the cells showed alterations (e.g. gaps, breaks, translocations, centromeric fusions, multiradial figures) in the centromeric regions of chromosomes 1 and 16. During immunoglobulin substitution he did not suffer from infection but he ceased, growing, probably due to malabsorption. Untill now, 15 patients with ICF syndrome are recognized. All but one had facial anomalies. All had immunodeficiency varying from IgA deficiency to SCID. A review of these patients will be given.

We report on five independent families with a chromosome instability disorder that earlier had been called the Nijmegen breakage syndrome (NBS). These families, two from the Netherlands and three from Czechoslovakia, had a total of eight patients, five of whom are still alive. The main clinical manifestations were microcephaly, short stature, a ''bird-like'' face, immunological defects involving both the humoral and cellular system. In four of the five living patients it has been possible to study the chromosomes of cultured lymphocytes. The basic karyotype in these patients were normal, but in 17% to 35% of the metaphases rearrangements were found, preferentially involving chromosomes 7 and/or 14 at the sites 7p13, 7q34, and 14q11. The chromosomes of all five living patients were very sensitive to ionizing radiation. In addition, the DNA synthesis in their cultured lymphocytes and fibroblasts was more resistant to X-rays than in cells from controls. The NBS shares a number of important features with ataxia telangiectasia (AT). Both syndromes are characterized by the occurrence of typical rearrangements of chromosomes 7 and/or 14, cellular and chromosomal hypersensitivity to X-irradiation, radioresistance of DNA replication and immunodeficiency. However, there are also obvious differences: NBS patients have microcephaly but neither ataxia normore » telangiectasia, and in contrast to the situation in AT the alpha-fetoprotein level in their serum is normal.« less

Weemaes, C., (Department of Paediatrics, University Hospital, Nijmegen, The Netherlands), Leijh, P., Blusse van Oud Alblas, D., van der Meer, J. and van Furth, R. (Department of Infectious Diseases, University Hospital, Leiden, The Netherlands). Normal microbicidal function of monocytes in a girl with chronic granulomatous disease. Acta Paediatr Scand, 70:421, 1981.–The history of a 13-year-old girl with a syndrome resembling Chronic Granulomatous Disease (C.G.D.) is described. Metabolic studies in granulocytes and monocytes classified the patient as having C.G.D. The granulocytes failed to kill Staphylococcus aureus and Candida Albicans; however, the killing of these microorganisms by the patient's monocytes was nearly normal. Family studies revealed no abnormalities in the phagocytic cells of the parents and the siblings.

In most series of children treated with continuous ambulatory peritoneal dialysis (CAPO), the incidence of peritonitis is higher than in adults. This phenomenon has been insufficiently explained. In the serum of 12 young children treated with CAPO, the serum immunoglobulins IgA, IgM, and IgG, as well as the IgG subclasses, were evaluated. In 11 of them, IgG2 was not detectable. Total IgG was also slightly decreased in these patients. In control groups, consisting of children before CAPO was started, children treated with hemodialysis, and adult CAPO patients, no clear abnormalities were found. It is concluded that in young patients peritoneal dialysis causes IgG loss leading to IgG2 deficiency.

A familial occurrence of chronic inflammatory demyelinating polyneuropathy is reported. The diagnostic problems in distinguishing the progressive form of this disease in childhood from hereditary motor and sensory neuropathy types I and III are discussed. Criteria for a definite diagnosis of chronic inflammatory demyelinating polyneuropathy are proposed.

A longitudinal follow-up of two children of a mother with IgA deficiency and anti-IgA antibodies is reported. Anti-IgA antibodies were transported across the placenta and were demonstrated in the cord serum and in the serum after the first week of life. The elder boy, born at term, remained IgA deficient. The second boy, who was born prematurely, developed a normal IgA system. This discrepancy between the children is discussed.

Increased levels of serum IgD can be found in single patients with a variety of clinical syndromes and in the disease entity designated hyper-IgD syndrome which is associated with periodic fever and lymphadenopathy. We investigated 17 patients, both children and adults, with high serum IgD levels ranging from 220 to 5300 IU/ml. Eight patients had periodic fever and lymphadenopathy, four showed a humoral immunodeficiency, and the remainder had a variety of clinical abnormalities. Serum IgA levels were consistently high in all patients except in those with an immunodeficiency. Serum IgD complexes were detectable in each serum, which indicates that the occurrence is not pathognomic for the syndrome of periodic fever. Antibody formation against the primary antigen Helix pomatia hemocyanine and the secondary antigen tetanus toxoid showed no abnormalities in the patients without an immunodeficiency. Bone marrow origin of serum IgD was strongly suggested by enumeration of IgD-containing plasma cells. We conclude that no apparent relationship exists between the several clinical syndromes and increased serum IgD.

Immunological examinations of four patients with Bloom syndrome, belonging to two families, revealed some disturbances of the immune function. All patients had decreased levels of at least one class of immunoglobulins. The disturbances of the lymphocyte stimulation tests demonstrated a remarkable similarity in the siblings: decreased stimulation in vitro by phytohemagglutinin (PHA) and pokeweed mitogen (PWM), low responses on stimulation by specific antigens, and diminished responder capacity in mixed lymphocyte reaction (MLR) in both patients of family I: normal stimulation in vitro by PHA and PWM, high responses on stimulation by specific antigens, and diminished responder capacity in MLR in both patients of family II. This remarkable difference in expression of the defect between both families could be the expression of a genetic heterogeneity.

Weemaes, C. M. R., Hustinx, T. W. J., Scheres, J. M. J. C, van Minister, P. J. J., Bakkeren, J. A. J. M. and Taalman, R. D. F. M. (Departments of Paediatrics and Human Genetics, University of Nijmegen, Nijmegen, The Netherlands.) Acta Paediatr Scand, 70:557,.–A 10-year-old boy with microcephaly, stunted growth, mental retardation, cafe-au-lait spots and immunodeficiency is described. An older brother of the patient had the same clinical symptoms and a more severe immunodeficiency. Cytogenetic studies in the proband revealed a typical form of chromosome instability with multiple rearrangements of chromosomes 7 and 14. Such abnormalities were also present, though in very low frequencies, in the father and three of the phenotypically normal sibs. The similarity of the symptoms in the two sibs, the close consanguinity of their parents and the results of the cytogenetic studies in the family favour the hypothesis that the disorder is an inherited one. The clinical features and the chromosome aberrations as present in the proband are usually found in chromosomal breakage syndromes, but it was possible to exclude each of the classical chromosomal breakage syndromes on clinical and/or cytogenetic grounds.

Chromosome analysis was performed in 17 children with IgA-deficiency. In two patients a constitutional structural chromosome abnormality was found. A ring chromosome 22 was seen in one, while in the other a mosaicism of ring chromosome 18/18p+ was observed. Both patients were mentally retarded and showed distinct congenital defects. From ten asymptomatic patients, spontaneous as well as X-ray-induced chromosome instability was investigated. There was no increased spontaneous instability, and also after irradiation the induced chromosome damage was within normal control levels. A relationship between IgA-deficiency and X-ray hypersensitivity, as might be suggested by the frequently occurring coincidence of radiosensitivity and IgA-deficiency in ataxia telangiectasia patients, is not established.

The clinical and cytogenetic data are presented of four children with Bloom's syndrome, who belong to two unrelated Dutch families. The patients showed, in varying degrees, the clinical features most characteristic of the syndrome: stunted growth; telangiectatic facial erythema; sun-sensitivity of the skin; and decreased immuno-competence. In one child the skin lesions were only minor and the diagnosis would probably not have been made if her sib had not been recognized as having Bloom's syndrome. The cytogenetic characteristics of the syndrome were present in all patients. Each showed a high number of chromosomal aberrations and numerous sister-chromatid exchanges per cell.

We report a patient with chronic granulomatous disease who developed invasive pulmonary aspergillosis and a subphrenic abscess. During treatment, high levels of Aspergillus antigen were detected in the abscess, but circulating antigen and Aspergillus DNA were undetectable in the serum.

ATAXIA-TELANGIECTASIA, or the Louis-Bar syndrome, is a recessive autosomal disorder clinically characterized by progressive cerebel lar ataxia, oculocutaneous telangiectasia, immunodef ic iency, and a predisposi t ion to the deve lopment o f neoplasia. Most often pat ients die f rom pu lmona ry insufficiency or cancer in the first two decades of life. A T is one of the classical ch romosome breakage syndromes; the cells of the pat ients usually display an increased f requency of spontaneous chromosome breaks and rear rangements . C h r o m o s o m e 14 abnor malities are especially f requent and very often there is a t andem 14q/14q translocation, a so-called Dq + marker c h r o m o s o m e ; , Recent ly we have detected ano the r chromosomal abnormal i ty which might be especially associated with AT: in three subsequent ly studied patients we did not find D q + markers but typical ch romosome 7 abnormal i t ies .

In 1981 Weemaes et al.(Acta Paediatr.Scand.70:557-564 1981) reported on two Dutch children with microcephaly, stunted growth immunodeficiency and chromosome instability. Recently Seemanova et al.(Amj. Med Genetics 20:639-648 1985)described 9 patients from 6 families with microcephaly, immunodeficiency and increased risk for lymphoreticular malignancy. Both humoral and cellular immunity were disturbed in the patients. Cytogenetic studies in our Dutch patient and three Csechoslovak patients, still alive, revealed multiple rearrangements of chromosomes 7 and 14. There was also an increased sensitivity of the chromosomes to X-rays and abnormal DNArepair synthesis after irradiation of the cells. The laboratory findings of these patients are identical with those in ataxia telangiectasia. The clinical symptons are different, however, because all patients have microcephaly but neither ataxia nor telangiectasia.