The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.

Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or apoptosis, of activated lymphocytes. Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3(+)CD4(-)CD8(-) T-cell-receptor alpha/beta cells by flow cytometry, nucleotide sequences of the gene encoding Fas (APT1, TNFRSF6), and the percentage of lymphocytes undergoing apoptosis in vitro. Of 223 members of 39 families, 130 individuals possessed heterozygous germline Fas mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected (each P <.001). Investigation of these 10 patients and their relatives with Fas mutations revealed that all had defective lymphocyte apoptosis and most had other features of ALPS. The tumor cells retained the heterozygous Fas mutations found in the peripheral blood and manifested defective Fas-mediated killing. These data implicate a role for Fas-mediated apoptosis in preventing B-cell and T-cell lymphomas. Inherited defects in receptor-mediated lymphocyte apoptosis represent a newly appreciated risk factor for lymphomas.

Efficient detection of thirty-seven new IL2RG mutations in human X-linked severe combined immunodeficiency.

X-linked severe combined immunodeficiency (XSCID) is a rare and potentially fatal disease caused by mutations of IL2RG, the gene encoding the interleukin-2 receptor gamma chain, a component of multiple cytokine receptors that are essential for lymphocyte development and function. To date, over 100 different mutations of IL2RG resulting in XSCID have been published. Using nonradioactive, direct DNA sequencing of a single PCR amplicon containing the whole IL2RG gene, we found IL2RG mutations in 78 previously unpublished unrelated cases of XSCID. We report 37 newly identified mutations of IL2RG, including 23 point mutations, 10 small deletions, 3 instances of the same single nucleotide insertion, 1 large deletion, and 2 complex mutations. More than half of the mutations (22 of 37) were predicted to result in unstable IL2RG mRNA. The remaining 14 mutations disrupted conserved functional motifs common to all cytokine receptor family members; changed protein conformation, charge, or hydrophobicity; or altered the intracellular portion of the protein, which is critical for proper interaction with signal-transducing molecules including Janus family tyrosine kinase 3.

Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody. Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas. Two missense Fas variants, not restricted to patients with ALPS, were identified. Variant A(-1)T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor. Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS.

Analphoid marker chromosome in a patient with hyper-IgE syndrome, autism, and mild mental retardation.

Hyper-IgE syndrome with recurrent infections (HIES) is a primary immunodeficiency disease characterized by recurrent skin and lung abscesses and extreme elevations of serum IgE, but also involving dentition, bones, and connective tissue. Although the etiology of HIES is unknown, autosomal dominant inheritance has been observed in multiple kindreds. A 17 year old male with sporadic HIES, autism, and mild mental retardation was found to have a supernumerary marker chromosome in peripheral blood lymphocytes and skin fibroblasts. Microdissection and FISH analysis of the marker chromosome showed that it was derived from a small interstitial deletion of one homologue of chromosome 4q21. Lack of hybridization of probes specific for telomeres and alphoid centromeres, including a centromere 4 specific probe, established that the marker was an analphoid ring chromosome. Comparative genotyping of transformed B-cell subclones with (M+) and without (M-) the marker chromosome showed loss of the maternal alleles in M- cells between markers D4S1569 and D4S3010. FISH using YAC clones from 4q21 confirmed the size and location of the interstitial deletion. Thus our patient's phenotypes were associated with de novo formation of a marker chromosome containing 15-20 cM of DNA deleted from his maternally derived chromosome 4. Proximal chromosome 4q therefore is a candidate region for disease genes for both HIES and autism. Identification of genes disrupted or lost during the formation of the marker chromosome as well as linkage studies in kindreds with HIES or autism may help us to understand the etiology of these complex phenotypes.

Mutation analysis of IL2RG in human X-linked severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) is a syndrome of profoundly impaired cellular and humoral immunity. In humans, SCID is most commonly caused by mutations in the X-linked gene IL2RG, which encodes the common gamma chain, gamma c, of the leukocyte receptors for interleukin-2 and multiple other cytokines. To investigate the frequency and variety of IL2RG mutations that cause SCID, we analyzed DNA, RNA, and B-cell lines from a total of 103 unrelated SCID-affected males and their relatives using a combination of molecular and immunologic techniques. Sixty-two different mutations spanning all eight IL2RG exons were found in 87 cases, making possible correlations between mutation type and functional consequences. Although skewed maternal X chromosome inactivation, single-strand conformation polymorphism, mRNA expression, and cell surface staining with anti-gamma c antibodies were all helpful in establishing IL2RG defects as the cause of SCID, only dideoxy fingerprinting and DNA sequence determination each detected 100% of the IL2RG mutations in our series. Abnormal gamma c chains may be expressed in the lymphocytes of as many as two thirds of patients with X-linked SCID. Specific mutation diagnosis thus remains technically challenging, but it is important for genetic counseling and perhaps for helping to select appropriate subjects for retroviral gene therapy trials, This is a US government work. There are no restrictions on its use.

The anal personality: self-disclosure, negativism, self-esteem, and superego severity.

Psychoanalytic implications of anal characterology were operationalized, and an experimental situation devised to test hypotheses of various aspects of interpersonal behavior. Subjects selected for the study had been found to score either high or low on Kline's (Ai3) Anality Scale. Self-disclosure and disclosure reciprocity were shown to be negative functions of anality: productivity and superego measures were also shown to be functions of anality. Self-esteem and socio-economic status did not relate to anality levels, while the hypothesis linking anality with negativism was only partially confirmed. Implications for psychoanalytic and social psychology research are discussed.

Four years of experience with cochlear prostheses.

Within the last four years, clinical as well as engineering experience has been gathered with 12 deaf persons who received several versions of an auditory prosthesis. Two years ago we settled on a system consisting of a versatile, passive 4-channel implant driving a scala tympani electrode, and a small external speech-processor. The main characteristics of the prosthetic hearing which can thus be established are: dynamic ranges vary between 12 and 20 dB, the number of discriminable amplitude steps within the dynamic range is comparable to that of a normal-hearing person; subjective pitch increases with stimulation frequency up to at least 1,000 Hz. Thresholds and dynamic ranges as well as a number of other characteristics remain stable over long periods of time. After an initial big step to good open speech understanding by one of our patients it could now be shown, that this patient is not an exemption. Several deaf patients participating in a series of speech tests have demonstrated that it is possible to reestablish some understanding of open speech through the use of the cochlear prosthesis without additional lipreading. A program has been established which aims at achieving experience with this prosthesis in a larger number of deaf people. The program includes: implant candidate selection, implantation, adjustment of speech-processor, hearing and speech rehabilitation, and the collection of comparative "psychoelectric" characteristics.

Anality: a theory of erotism and characterology.

The psychogenesis of anality is in the psychosexual events of the second year of life. An analysis of that phase of development centers on the biological determinants of psychological development, specifically on the erotization of the excretory functions. The social structures interfering with this process are examined. The interrelationship of feces, child, and penis are analyzed within the context of the total libidinal spectrum of development and object relations. Bipolarity is seen as an integral facet of the anal character, manifested in the retentive-eliminative continuum and in the aggressive-erotic divergences. These trends are examined in detail vis-à-vis the ultimate ossification of the anal adult. In this context, the percept of anal-sadism is introduced and alternate interpretations of the phenomenon are suggested. Various characteristics frequently associated with anal characterology are discussed and an attempt is made to demarcate the status (as integral or peripheral) of these traits. Sociocultural contingencies of anality are also considered, particularly with regard to Western institutions. The major pathological maladaptions related to anality are detailed. These include the obsessions and rigid superego development, paranoia, and homosexuality. The status of anality is then evaluated from the ego-psychological perspective, and interpersonal and societal factors are considered. What emerges is a unitary construct of anality which incorporates both erotism and characterology.

Cochlear prostheses in use: recent speech comprehension results.

Speech-comprehension tests were performed with several deaf volunteers who were equipped with different cochlear prostheses. These prostheses work with inductive transcutaneous signal transmission and contain a multi-channel scala tympani electrode or, in two cases, a disc electrode situated external to the cochlea in the round window niche. The external portable single-channel speech-processor/transmitter used is the same in all cases. The comprehension (stimulation only, no lip reading) of numbers between 1 and 99 on first contact with the stimulator and therefore without any training was around 38% showing that through well designed single-channel stimulation of the auditory nerve it is possible to generate hearing sensations sounding very much like nature hearing impressions. Some open speech comprehension was reached: Through the help of the stimulator, without lip reading, between 60 and 100% of sentences unknown to the completely deaf volunteer, spoken only a little more slowly than normal, are correctly understood. The percentage for isolated unknown words is 60%. Also an important improvement of word comprehension can be achieved through additional stimulation as compared to unaided lip reading. It appears that the most recent design of our cochlear prosthesis can already be regarded as a useful aid for the deaf.