Cancer risk in heterozygotes for ataxia-telangiectasia.

Epidemiological studies have suggested that ataxia-telangiectasia (AT) heterozygotes have a predisposition to cancer, especially breast cancer in women. Now, haplotyping can identify heterozygotes for AT mutation (ATM) in AT families, allowing the risk of cancer associated with ATM heterozygosity status to be better assessed. We report a family study of AT patients, in which we estimated the risk of cancer according to ATM heterozygosity status. We analyzed demographic characteristics and occurrence of cancer in 1,423 relatives of AT patients. Haplotyping was performed in living relatives. The probability of being heterozygotes for ATM was calculated for deceased relatives. The risk of developing cancer was estimated in the cohort of relatives, and expected numbers of cancer cases were calculated from French age period-specific incidence rates. The number of cancers at all sites in the total population of relatives was not higher than expected. However, significant heterogeneity was found according to ATM heterozygosity status. This is mainly due to the increased risk of breast cancer previously observed in obligate heterozygotes. In obligate heterozygotes, relative risk (RR) was non-significantly increased for thyroid cancer, leukemia and liver cancer. Risks of ovarian, lung, pancreatic, kidney, stomach and colorectal cancers were non-significantly increased in the group with 0.5 probability of being heterozygotes. The RR was not significantly increased for any site of cancer, except for breast. Therefore, there is no evidence that specific screening of relatives of AT patients would be justified at particular sites other than the breast. However, the amplitude of the risk of breast cancer estimated in heterozygous women does not appear to justify a separate screening program from that already available to women with a first-degree relative affected by breast cancer.

Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families.

Epidemiological studies in ataxia telangiectasia (AT) families have suggested that AT heterozygotes could have an increased cancer risk, especially breast cancer (BC) in women. It has also been suggested that an increased sensibility of AT heterozygotes to the effect of ionizing radiation could be responsible for the increased BC risk. BC relative risk (RR) estimation in AT heterozygotes within families ascertained through AT children is presented here. Family data collected included demographic characteristics, occurrence of cancers, past radiation exposures and blood samples. DNA samples were studied using seven ATM linked microsatellites markers allowing AT haplotypes reconstitution. The relative risk of BC was assessed using French estimated incidence rates. A significant increase risk of BC is found among obligate ATM heterozygotes with a point estimate of 3.32 (P = 0.002). BC relative risk calculated according to age is significantly increased among the obligate ATM heterozygotes female relatives with an age < or = 44 years (RR = 4.55, P = 0.005). The BC relative risk is statistically borderline among the obligate ATM heterozygote female relatives with an age > or = 45 years (RR = 2.48, P = 0.08). The estimated BC relative risk among ATM heterozygotes is consistent with previously published data. However, the increased risk is only a little higher than classical reproductive risk factors and similar to the risk associated with a first-degree relative affected by BC.

Inflammation: "a natural experiment" for the systemic pathogenicity of cytokines.

It has previously been demonstrated that the overproduction of interleukin-6 (IL-6) is a key element in the clinical and biological abnormalities encountered in Castleman's disease (CD). The particular case of a male child with a localized form of CD is reported. In this patient, evidence was found of a correlation between systemic manifestations and circulating IL-6, and IL-6 gene overexpression in the germinal centers of hyperplastic lymph nodes. Circulating IL-6 levels were 10- to 100-fold higher than in all CD cases previously documented. This unique biological feature was closely associated with high levels of circulating IL-1 and tumor necrosis factor-alpha (TNF-alpha), which are known for their ability to induce and/or amplify IL-6 production. One month after surgical removal of the pathological lymph node, the clinical and biological abnormalities diminished, while circulating IL-6 levels dropped dramatically eight months later. It is worth noting that after resection, the time-course of the IL-6 decrease closely correlated with that of IL-1 and TNF-alpha. Considering that in various inflammatory diseases IL-1, TNF-alpha and IL-6 may act in a synergistic manner in inducing systemic manifestations, this case report raises new questions as to the nature of the systemic pathogenicity of cytokines in CD.

Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene.

Griscelli disease (OMIM 214450) is a rare autosomal recessive disorder characterized by pigmentary dilution, variable cellular immunodeficiency and onset of acute phases of uncontrolled lymphocyte and macrophage activation, leading to death in the absence of bone-marrow transplantation. The pigmentary dilution is characterized by a diffuse skin pigmentation, silvery hair, large clumps of pigments in the hair shafts (Fig. 1) and an accumulation of melanosomes in melanocytes, with abnormal transfer of the melanin granules to the keratinocytes. Immunological abnormalities are characterized by absent delayed-type cutaneous hypersensitivity and an impaired natural-killer cell function. A similar disorder has been described in the dilute lethal mouse--which, however, differs by the occurrence of a severe neurological disorder. The dilute locus encodes myosin-Va, a member of the unconventional myosin family. Myosins bind actin and produce mechanical force through ATP hydrolysis. Some members of this family are thought to participate in organelle-transport machinery. Because of the phenotype resulting in the dilute mouse and because of their potential role in intracellular transport, unconventional myosin-encoding genes were regarded as candidate genes for Griscelli disease. Here we report that the Griscelli disease locus co-localizes on chromosome 15q21 with the myosin-Va gene, MYO5a, and that mutations of this gene occur in two patients with the disease. Griscelli disease is therefore a human equivalent of dilute expression in the mouse.

Idiopathic disseminated bacillus Calmette-Guérin infection: a French national retrospective study.

OBJECTIVE: Disseminated bacillus Calmette-Guérin (BCG) infection after inoculation of live vaccine is considered to result from impaired immunity of the child. However, in half of the cases, regarded as idiopathic, no well-defined immunodeficiency condition can account for the infection. The objective of the present study is to report the prevalence, clinical features, associated infections, and outcomes of children with idiopathic disseminated BCG infection. DESIGN: National retrospective survey during the period from 1974 through 1994 in France. SETTING: All neonatology and pediatrics units in primary care and referral centers throughout France. PATIENTS: Data were collected from 595 (82%) of 721 units, 377 (93%) of 407 centers, and 320 (93%) of 345 cities. Selection criteria included BCG infection, dissemination to at least two areas beyond the inoculation site, and no well-defined immunodeficiency condition. Sixteen children (8 girls and 8 boys), born to families unrelated to each other but often consanguinous (5 of 16) or abroad (5 of 16). RESULTS: The minimal prevalence rate was estimated at 0.59 cases per 1 million vaccinated children born in France. Clinical features included fever and cachexia, disseminated BCG infection to lymph nodes (15 of 16), skin (13 of 16), soft tissues (11 of 16), lungs (11 of 16), spleen (11 of 16), liver (11 of 16), and bones (9 of 16). Eight children had associated or subsequent severe opportunistic infection (50%), with either nontyphi Salmonella enterica serotypes (7 of 16) or Mycobacterium abscessus (1 of 16). The outcome was poor: 8 children (50%) died; the cause of death was BCG infection for most children (7 of 8); 8 survived until the last follow-up (50%). CONCLUSIONS: Idiopathic disseminated BCG infection is a rare but severe complication of BCG vaccination. The infection probably results from an as yet unknown genetically determined immunodeficiency condition that affects the killing of intracellular bacteria such as BCG and Salmonella.

Bone marrow transplantation in 26 patients with Wiskott-Aldrich syndrome from a single center.

We retrospectively analyzed the outcome of bone marrow transplantation (BMT) performed in 26 patients with Wiskott-Aldrich syndrome (WAS) in one center. Twenty-eight transplantation procedures were performed. Ten unselected patients received unmanipulated marrow from a donor with genetically identical human leukocyte antigen (HLA). Eight patients were cured and survive 1.5 to 16.5 years after BMT. One patient successfully received a T-cell-depleted marrow from a matched unrelated donor. Sixteen patients were selected to receive a related HLA partially incompatible BMT because of the occurrence of life-threatening complications from the WAS (i.e., refractory thrombocytopenia, autoimmunity including vasculitis and sepsis). All but one received T-cell-depleted marrow after a conditioning regimen of busulfan and cyclophosphamide. One patient had two BMTs. Engraftment occurred in 12 of 17 attempts. The addition of monoclonal antibodies to lymphocyte function-associated antigen-1 and CD2 molecules appeared to improve engraftment. Six patients were long-term survivors, whereas others died of viral infections (n = 7), among which Epstein-Barr virus-induced B-lymphocyte proliferative disorder was predominant. Delay in development of full T- and B-cell functions accounted for severe infectious complications. These results confirm the excellent outcome of HLA genetically identical BMT in WAS, whereas BMT from HLA partially incompatible donors should be strictly restricted to patients with severe complications of WAS.

Skin lesions revealing neonatal acute leukemias with monocytic differentiation. A report of 3 cases.

Acute myelo-monoblastic (AMML) and acute monoblastic (AML) leukemias have a bad prognosis, especially in children when occurring in the first months of life. We report 3 cases of such leukaemias in which skin lesions preceded and revealed the leukemia. For the 3 infants, cutaneous lesions appeared about one month before the other signs of leukaemia (2 AML and 1 AMML). Skin biopsies from all 3 infants revealed a heavy dermic infiltration by large cells with round or irregular vesicular nuclei and abundant pale cytoplasm. These atypical cells did not express any lymphoid markers but reacted strongly with monocytic-macrophagic antibodies (CD68, CD13 and CD14). Two infants were treated by mitoxanthrone and cytarabine with complete remission. The third one was not treated because of a very poor general status. Skin involvement is frequent in these nonlymphoid leukaemias (30% to 50% of cases). In only 7% of cases, leukemic skin lesions precede and reveal the other signs of leukemia by weeks or months. Then, it is very important to repeat the blood cell counts and to biopsy the skin lesions in order to make a diagnosis of leukemia as early as possible.

A familial T-cell lymphoma with gamma delta phenotype and an original location. Possible role of chronic Epstein-Barr virus infection.

BACKGROUND: We describe a familial lymphoproliferative syndrome associated with Epstein-Barr Virus (EBV) infection and the gamma delta phenotype. METHODS: We reviewed clinical, pathologic, immunologic, and virologic findings in a nonconsanguineous French family, collected over a 13-year period. Specimens from the father (autopsy), son (liver, lymph nodes, and pericardial effusion), and daughter (skin, liver, and digestive tract) were studied with conventional histologic and immunohistochemical techniques. Anti-EBV latent membrane protein (LMP) antibody and T-cell receptor (TCR) gene rearrangements were also studied in the daughter. RESULTS: The father and daughter had similar clinical and histologic features with maxilofacial, nasal, laryngeal, skin, lung, gastrointestinal, and liver involvement by a high grade large cell angiocentric T-cell lymphoma. The gamma delta phenotype and clonal rearrangement were identified in the daughter's tumor. At the time of his death from pericarditis, the son had a 5-year history of a recurrent hemophagocytic syndrome and lymphadenopathy. Chronic EBV infection was found in each case. EBV infection of the son was diagnosed by means of serologic tests and detection of the EBV genome in circulating lymphocytes, and in the father and daughter by use of an anti-LMP antibody. Its pathologic role is discussed. CONCLUSION: This familial T-cell lymphoma syndrome associated with the gamma delta phenotype and an unusual location is an original clinical entity. Chronic EBV infection was present in each case, but its precise role remains to be determined.

Treatment of Omenn syndrome by bone marrow transplantation.

We report the outcome of allogeneic bone marrow transplantation (BMT) in nine consecutive patients with Omenn syndrome treated between 1980 and 1989. Five patients received unmanipulated marrow from a related matched donor, and four received T cell-depleted marrow from a haploidentical donor. The patients were conditioned with cyclophosphamide (200 mg/kg) and, except in one case, busulfan (16 mg/kg). Antithymocyte globulin and etoposide were given to three patients each; three recipients of T cell-depleted haploidentical marrow also received intravenous injections of an anti-leukocyte function-associated antigen type 1 antibody as graft rejection prophylaxis. All the patients were fed parenterally for 1 to 5 months before BMT to improve nutritional status and received topical corticosteroids (n = 8), systemic steroids (n = 2), etoposide (n = 1), or cyclosporine (n = 1) to control T-cell activation. Engraftment occurred in four of five recipients of human leukocyte antigen (HLA)-identical marrow and three of four recipients of HLA-haploidentical marrow. One patient died with cytomegalovirus infection. The other six patients are alive 4 to 11 years after BMT, with full chimerism in all but one case. Chronic graft-versus-host disease persists in one patient; the other five survivors have fully restored immune function and have no manifestations of Omenn syndrome, including failure to thrive. We conclude that both HLA-identical and haploidentical BMT can cure Omenn syndrome, provided that parenteral nutrition and immunosuppressive therapy are given before transplantation.

Treatment of Chediak-Higashi syndrome by allogenic bone marrow transplantation: report of 10 cases.

Chediak-Higashi syndrome is a rare condition characterized by susceptibility to bacterial infections, defective natural killer activity, and episodes of macrophage activation known as accelerated phases. Chemotherapy can induce transient remission of the accelerated phase, but relapses become less and less sensitive to treatment and ultimately lead to death. Allogenic bone marrow transplantation (BMT) has been proposed as a curative treatment for Chediak-Higashi syndrome. We report the outcome of BMT in 10 such children. Seven received marrow from an HLA-identical related donor and three from an HLA-nonidentical related donor. Three patients died, two from a new accelerated phase after rejection of transplanted bone marrow and one from cytomegalovirus (CMV) pneumonia. Six of seven recipients of HLA-identical marrow and one of three recipients of HLA-nonidentical marrow are alive and well without treatment 1.5 to 13 years after transplantation (median, 6.5 years). No manifestations of accelerated phases have occurred in these seven patients, and significant natural killer activity is detectable. Interestingly, BMT prevented recurrence of accelerated phases in patients with limited numbers of donor-type leukocytes after transplantation. Ocular and cutaneous albinism were not corrected after transplantation. None of the patients developed serious toxic reactions to the BMT conditioning regimen or have long-term sequelae. These results show that HLA-identical BMT is an acceptable curative treatment for Chediak-Higashi syndrome, whereas HLA-nonidentical BMT remains an experimental approach.

Bone marrow transplantation in major histocompatibility complex class II deficiency: a single-center study of 19 patients.

Major histocompatibility complex (MHC) class II deficiency (bare lymphocyte syndrome) is a rare inborn error of the immune system characterized by impaired antigen presentation and combined immunodeficiency. It causes severe and unremitting infections leading to progressive liver and lung dysfunctions and death during childhood. As in other combined immunodeficiency disorders, bone marrow transplantation (BMT) is considered the treatment of choice for MHC class II deficiency. We analyzed the files of 19 patients who have undergone BMT in our center. Of the 7 patients who underwent HLA-identical BMT, 3 died in the immediate posttransplant period of severe viral infections, whereas the remaining 4 were cured, with recovery of normal immune functions. Of the 12 patients who underwent HLA-haplo-identical BMT, 3 were cured, 1 was improved by partial engraftment, 7 died of infectious complications due to graft failure or rejection, and 1 is still immunodeficient because of engraftment failure. A favorable outcome in the HLA-non-identical BMT group was associated with an age of less than 2 years at the time of transplantation. All the patients with stable long-term engraftment had persistently low CD4 counts after transplantation (105 to 650/microL at last follow up), but no clear susceptibility to opportunistic infections despite persisting MHC class II deficiency on thymic epithelium and other nonhematopoietic cells. We conclude that HLA-identical and -haploidentical BMT can cure MHC class II deficiency, although the success rate of haploidentical BMT is lower than that in other combined immunodeficiency syndromes. HLA-haploidentical BMT should preferably be performed in the first 2 years of life, before the acquisition of chronic virus carriage and sequelae of infections.

Partial albinism with immunodeficiency (Griscelli syndrome).

Partial albinism with immunodeficiency is a rare and fatal immunologic disorder characterized by pigmentary dilution and variable cellular immunodeficiency. To define the phenotype, therapy, and outcome, we retrospectively analyzed seven consecutive patients. Primary abnormalities included a silvery-grayish sheen to the hair, large pigment agglomerations in hair shafts, and an abundance of mature melanosomes in melanocytes, with reduced pigmentation of adjacent keratinocytes. Clinical onset occurred between the ages of 4 months and 4 years and was characterized by accelerated phases (lymphohistiocytic infiltration of multiple organs, including the brain and the meninges), triggered by viral and bacterial infections. Characteristic laboratory features included pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and hypoproteinemia. Consistent immunologic abnormalities were characterized by absent delayed-type cutaneous hypersensitivity and impaired natural killer cell function. Some patients had secondary hypogammaglobulinemia, impaired major histocompatibility complex-mediated cytotoxic effects, a decreased capacity of lymphocytes to trigger a mixed lymphocyte reaction, or various functional granulocytic abnormalities. The disease seems to be invariably lethal without bone marrow transplantation; the mean age at the time of death was 5 years. Bone marrow transplantation has been performed in three cases; two patients died in the immediate posttransplantation period of infectious complications, but one patient is cured after a follow-up of 5 years. We conclude that partial albinism with immunodeficiency (Griscelli syndrome) can be differentiated from Chédiak-Higashi syndrome by pathognomonic histologic features. One of the underlying immunologic defects may be a defective function of natural killer cells, predisposing the patient to virus-associated hemophagocytic syndrome or accelerated phases. The prognosis is very poor unless early bone marrow transplantation is carried out.

Long-term itraconazole prophylaxis against Aspergillus infections in thirty-two patients with chronic granulomatous disease.

We conducted a prospective, open study of oral itraconazole therapy (5 and then 10 mg/kg per day) to assess tolerance and potential efficacy in preventing fungal infections in patients with chronic granulomatous disease. Thirty-two patients were enrolled in one center between 1985 and 1991. Tolerance was excellent in all cases. Poor compliance was suspected in three cases. Two patients were excluded from efficacy analysis because itraconazole was used as part of therapy for pulmonary aspergillosis. Of 30 patients, 3 developed a fungal (Aspergillus) lung infection, an incidence 3.4/100 patient-years versus 11.5 in a historical control group that did not receive any prophylaxis (p = 0.13) and 9.55 in a historical group of patients who received daily ketoconazole prophylaxis (p = 0.19). The percentage of patients infected with Aspergillus was significantly different: 10% in the itraconazole group versus 34.4% in the untreated group (p = 0.013). These results require further evaluation through a comparative randomized trial to assess the possible benefit of itraconazole prophylaxis in patients with chronic granulomatous disease.

Stroke and cerebral infarcts in children infected with human immunodeficiency virus.

OBJECTIVE: To study the causes of stroke and cerebral infarcts in children infected with the human immunodeficiency virus (HIV)-type 1. DESIGN: Case series. PATIENTS: Four of 380 HIV-infected children followed up in a 10-year period in our department who had a stroke with evidence of cerebral infarcts on radiological imaging. RESULTS: The four patients were severely immunodepressed, but their clinical status and outcome were different. Aneurysmal dilation of major cerebral arteries and thrombosis of these arteries or of small cortical vessels were discovered in two patients. Both patients had a history of frequent infections and had suffered repeated neurological events that resulted in severe clinical deterioration or death. An infectious causative agent was strongly suspected but was not detected. The other two patients had a more favorable outcome. An isolated cerebrovascular thrombosis was found in one patient, while in the other, HIV-1-related focal necrosis was suggested by the lack of permanent cerebrovascular abnormalities or thrombosis and by signs of necrosis in biopsy specimens of the brain. CONCLUSION: Stroke and cerebral infarcts in HIV-1 infected children have different causes and different prognoses.

Intractable infant diarrhea associated with phenotypic abnormalities and immunodeficiency.

We report on eight children with severe diarrhea beginning in the first 6 months of life (< 1 month in six cases), who had a number of features in common. All were small for gestational age and had an abnormal phenotype, including facial dysmorphism, hypertelorism, and woolly, easily removable hair with trichorhexis nodosa. Two were products of consanguineous marriages. Severe secretory diarrhea persisted despite bowel rest (n = 7). Jejunal biopsy specimens showed total or subtotal villous atrophy with crypt necrosis, and inconstant T-cell activation in some cases (n = 3). Colon biopsy specimens showed moderate nonspecific colitis. All the patients had defective antibody responses despite normal serum immunoglobulin levels, and defective antigen-specific skin tests despite positive proliferative responses in vitro. Three had monoclonal hyper-immunoglobulinemia A. The course was marked by diffuse erythroderma in two cases and mental retardation in three. Treatment included bowel rest, intravenous administration of immune globulins, administration of corticosteroids (n = 6) and cyclosporine (n = 2), and bone marrow transplantation (n = 1). Five patients died between the ages of 2 and 5 years (of sepsis or cirrhosis), two are being fed enterally, and one continues to receive total parenteral nutrition. The cause of the combined low birth weight, dysmorphism, severe diarrhea, trichorrhexis, and immunodeficiency is unclear. These features may constitute a specific syndrome within the group of intractable diarrheas of infancy.

Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course.

OBJECTIVE: To determine the variability and the natural course of children suffering from autosomal recessive osteopetrosis to allow optimal counseling and decision making with respect to therapeutic intervention. DESIGN: Retrospective and longitudinal evaluation of clinical symptoms and natural course with emphasis on survival and sensoneurologic and hematologic findings. SETTING: Two large referral-based pediatric bone marrow transplantation units in Europe. PATIENTS: Thirty-three patients with autosomal recessive osteopetrosis admitted to units in Paris and Leiden between 1972 and 1988 were analyzed until last follow-up or the time at which bone marrow transplantation was performed. The great number of patients and unprecedented amount of data make this report one of the single largest clinical studies on autosomal recessive osteopetrosis. MAIN RESULTS: Ocular involvement occurring at a median age of 2 months was the symptom at initial examination in half of the patients. A striking variability between patients was found. Retinal degeneration was present in three patients and associated generalized neurodegeneration was present in two. The probability of survival until the age of 6 years was about 30% for the group as a whole. The cumulative risk of developing visual or hematologic impairment in the first year of life was about 75% and leveled off afterward. Patients with early hematologic impairment, ie, before 3 months of age, especially when combined with early visual impairment, had a very poor prognosis regarding life expectancy. CONCLUSIONS: Autosomal recessive osteopetrosis seems to be a variable disorder with a poor prognosis, especially in children with early visual and hematologic impairment. Allogenic bone marrow transplantation remains the only curative approach.

Clinical consequences and treatment of primary immunodeficiency syndromes characterized by functional T and B lymphocyte anomalies (combined immune deficiency).

OBJECTIVE: To review the clinical presentation and outcome of patients with an unusual primary T + B lymphocyte immunodeficiency syndrome, characterized by the presence of T lymphocytes with no detectable gross phenotypic anomaly, but which are not activated in vitro or in vivo in response to antigens, although they do respond to mitogens. METHODS: A retrospective analysis of clinical and immunological data recorded in 25 cases. Acquired immunodeficiencies and known primary T cell immunodeficiency syndromes (severe combined immunodeficiency syndrome, Di-George syndrome, Wiskott-Aldrich syndrome, cartilage hair hypoplasia, Omenn's syndrome, ataxia telangiectasia, defective expression of major histocompatibility complex class II molecules, and defective expression of the CD3/T cell receptor complex) were excluded. RESULTS: The patients had severe and particularly protracted infections, mainly of the respiratory tract and gut. Severe viral infections, generally due to herpes viruses, occurred in nearly two-thirds of the patients, with a median follow-up of 54 months. Autoimmune manifestations are frequent (60%), targetting mainly marrow-derived cells, and were characterized by a tendency to relapse and by a dependence on immunosuppressive therapy. Allergic manifestations were also frequent (48% of cases). Eight of the 19 patients who had not undergone bone marrow transplantation died. All but one of the 11 survivors had moderate to severe sequelae. Bone marrow transplantation seemed to be the treatment of choice, because four of six recipients of HLA-identical (n = 2) or nonidentical (n = 4) marrow are alive and the immune deficiency has been corrected. CONCLUSION: Early recognition of these life-threatening syndromes may improve the chances of cure. Despite common clinical manifestations and prognosis, these functional immunodeficiencies appear heterogeneous regarding inheritance pattern and at least existence of a B cell immunodeficiency.

Treatment of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins, steroids, and cyclosporin A.

Familial hemophagocytic lymphohistiocytosis (FHL) is a potentially fatal disease characterized by diffuse infiltration by histiocytes and T lymphocytes. Treatment with myelotoxic drugs, such as etoposide, brings about remission in most patients, but problems of toxicity remain, and the development of disease resistance can cause secondary relapses. We have used an alternative approach, based on the suggested primary role of T-cell activation in FHL, comprising combined treatment with steroids (2 to 5 mg/kg/d methylprednisolone intravenously, followed by progressive tapering) and rabbit antithymocyte globulins (10 mg/kg/d for 5 days), followed by maintenance therapy with cyclosporine A (CSA). In a pilot study of six patients (four with a family history of FHL), all showed systemic remission within 7 days, which was complete in five cases; despite treatment with intrathecal methotrexate, one patient died of severe brain involvement. Two patients received T-cell--depleted HLA--non-identical bone marrow transplants, which was successful in one case. The other three patients, who have been on CSA maintenance therapy for periods of 6 to 24 months, are in complete remission. We have observed no side-effects (there has been no persisting T-cell immunodeficiency). These results suggest that nonmyelotoxic treatments for FHL may be safe, effective, and worthy of further investigation; they also support the key role of T lymphocytes in the disease.

Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients.

We carried out a retrospective analysis of 117 patients with severe combined immunodeficiency who were examined in a single center between Jan. 1, 1970, and Jan. 1, 1992, for the purpose of evaluating disease onset, progression, and outcome. The frequency of case referral increased from 8 from 1970 to 1975 to 56 from 1986 to 1991. The most frequent phenotype was T-/B+ (absence of T lymphocytes and presence of B lymphocytes) (n = 51); there were 36 cases of alymphocytosis, 16 of adenosine deaminase deficiency, 13 of Omenn syndrome, and 1 of reticular dysgenesis. Protracted diarrhea and lung infections were the main infectious complications; infection with bacillus Calmette-Guérin occurred in 10 of 28 vaccinated patients, but none of the six recipients of oral polio vaccine subsequently had poliomyelitis. The presence of maternal T cells was suspected or proved in half the patients with alymphocytosis or T-B+ severe combined immunodeficiency but did not occur in the other forms of the disease. Of the 117 patients, 22 died before transplantation could be performed. Adenosine deaminase deficiency and Omenn syndrome were more frequently associated with death before hematopoietic stem cell transplantation was possible. Fetal liver transplantation was successful in 1 of 10 cases. The survival rate among the 30 recipients of bone marrow with identical human leukocyte antigens (HLA) was 80%, with a median follow-up of 129 months; 23 of 25 patients recovered full immune function. The survival rate among the 50 recipients of HLA-haploidentical T cell-depleted bone marrow was 56%, with a mean follow-up of 35 months. Of the latter patients, 10 (35%) still require immunoglobulin substitution. There has been a trend toward improvement in the survival rate of haploidentical bone marrow recipients, presumably because of more effective infection-control measures and better transplantation strategy.

Growth and growth hormone secretion after bone marrow transplantation.

This study analyses the growth and the growth hormone secretion of children given various conditioning protocols before bone marrow transplantation (BMT). Twenty nine children (14 boys, 15 girls) given BMT were classified according to their conditioning protocol: total body irradiation (TBI) given as a single exposure of 10 Grays (Gy, group I, 11 cases), or 8 Gy (group II, four cases), 12 Gy given as six fractionated doses (Group III, seven cases), or chemotherapy alone (group IV, seven cases). The arginine-insulin stimulated growth hormone peak, 2-7.5 years after BMT, was > 10 micrograms/l in all patients except four from group I (6.9-8.9 micrograms/l). A second growth hormone secretion evaluation was performed in 10 group I patients because of persistent low growth velocity despite a normal growth hormone peak. There were no significant changes in the mean (SEM) stimulated growth hormone peak (18.4 (2.2) v 20.1 (3.6) micrograms/l) at 3 (0.3) to 5.2 (0.6) years after BMT. The sleep growth hormone peaks and concentrations (n = 6) were normal. The mean cumulative height changes (SD) during the three years after BMT were: -1.4 (0.2) in group I, -0.1 (0.4) in group II, -0.4 (0.2) in group III, and 1.5 (0.5) in group IV; this was significant in groups I and IV. The final heights of two monozygotic twins (BMT donor and recipient) had differed by 17.5 cm, despite them both having normal growth hormone peaks and puberty. Eight patients, treated for congenital immune deficiency syndrome, were growth retarded at the time of BMT. Of these, only those conditioned by chemotherapy alone had significant catch up growth (2(0.6)SD) while those conditioned by a single Gy exposure did not (0(0.4)SD). It is concluded that the total radiation dose is critical for growth evolution, as is the fractionation schedule. For the TBI doses and the interval since BMT studied, there was no correlation between growth hormone peak and the height loss. The rapidity of decreased growth velocity after TBI and the comparison between the monozygotic twins suggest that radiation induced skeletal lesions are partly responsible for the decreased growth.