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ICF syndrome

In medicine, immunodeficiency, centromere instability and facial anomalies syndrome (ICF syndrome) is a very rare recessive autosomal disorder.

It is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood. ICF syndrome patients exhibit facial anomalies which include hypertelorism, low-set ears, epicanthal folds and macroglossia.

ICF syndrome
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Medical follow-up of Persian Gulf war Veterans with severe medically unexplained fatigue: A preliminary study
From Military Medicine, 12/1/01 by Natelson, Benjamin H

An important question for researchers interested in long-term consequences of military service is the health outcome of symptomatic Persian Gulf War Veterans. From an original group of 76 Gulf War Veterans who received the diagnosis of severe fatiguing illness, we attempted to get 58 veterans to return to our center for a second evaluation. Thirteen returned. Two had recovered by the time of revisit, but the rest remained ill; however, only one was so ill as to be unable to work. The data suggest that the medical consequences of serving in the Persian Gulf are not transient. The difficulty in getting veterans to return to our center suggests potential problems in the proposed nation-wide longitudinal health outcome study of Persian Gulf War Veterans.


It is now a well acknowledged fact that service in the Persian Gulf affected the health of some Gulf War Veterans (GWVs).1-4 In previous work from our Department of Veterans Affairs-- funded Gulf War Research Center,5 we reported that an appreciable subset of symptomatic GWVs fulfilled case definitions for chronic fatigue syndrome (CFS) or its slightly less severe variant, idiopathic chronic fatigue (ICF). An important question in the minds of the veterans is whether they will get better or worse over time. The Department of Veterans Affairs and the Department of Defense, as well as the Congress, have raised this question as a critical one to answer,fi and these interested parties have asked the Institute of Medicine to devise a plan to allow the longitudinal follow-up of GWVs over time. As part of the activities of our center, we have performed a small, preliminary follow-up study of GWVs initially evaluated from 1995 through 1998 and report here outcome information concerning their subsequent clinical status.


Initial Center Visit

Based on a history and physical examination by a physician trained to apply the case definitions of CFS7,8 and blood tests to eliminate the usual medical causes of fatigue, we made the diagnosis of CFS in 65 GWs and ICF in 11. Thus, these veterans had at least 6 months of fatigue severe enough to produce a substantial decrease in their everyday activity plus medically unexplained rheumatological, infectious, and neuropsychiatric symptoms (those with CFS had four or more symptoms from a list of eight). In evaluating these veterans, we applied a scale that categorizes patients along the severity spectrum of medically unexplained fatiguing illness. The scale has eight severity categories (see Pollet et al.5 for a detailed breakdown of this categorization system). The determination of category number depended on the self-reported severity of the rheumatological, infectious, and neuropsychiatric symptoms whose presence constitutes one of the criteria for the diagnosis of CFS or ICF. For each of the symptoms from the extended list published in the 1988 case definition,7 veterans were asked to indicate how much of a problem that symptom had been in the past month on a scale from 0 to 5 (0 was no problem, 1 indicated a mild problem, 2 indicated a moderate problem, 3 indicated a substantial problem, 4 indicated a severe problem, and 5 indicated a very severe problem).

Veterans in category 1 had the most severe illness and fulfilled both the 19881 and 19948 case definitions for CFS; they also reported symptom seventies in the month before evaluation of >=3 on the symptom severity scale described above. Veterans in categories 2 through 6 had sequentially less severe CFS. Those in category 6 had the mildest CFS. These veterans fulfilled only the 1994 case definition for CFS and had symptom severities of

All GWVs also underwent psychiatric diagnostic interviews.9 Of the 76 GWs, 34 reported symptoms consistent with a Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, axis I psychiatric illness beginning before their service in the Persian Gulf. Thirty-one of these GWVs continued to have a psychiatric diagnosis after returning from the Persian Gulf. Of the 42 GVs with no axis I diagnosis before their service in the Persian Gulf, 21 continued to be in good emotional health and the remaining 21 developed symptoms consistent with a DSM-III-R psychiatric diagnosis after their return from the Persian Gulf.

Follow-Up Protocol

Our plan was to ask as many of these veterans as possible to return to our center to participate in further studies. The first step of this process was our sending informational packets to all of the veterans from the initial group of 76 whom we could contact and who had expressed continued interest in participating in research (see below). The packets were designed to provide us information about the veterans' current health state (i.e., symptom frequency/severity, effects of illness on work and social activities, and specifics about fatigue/vigor from the Profile of Mood States [POMS] and the Multidimensional Fatigue Inventory).

We did not send these forms to 10 veterans who either were no longer interested in our work or had no available current address. The remaining veterans all received these packets. Twenty-two veterans did not return their packets despite at least three phone calls and a follow-up letter to each. The remaining 44 veterans did return their packets. Five of the 44 veterans did not respond to multiple efforts on our part to schedule their return to our center, and 8 informed us that they were no longer interested in participating in Gulf War-related research. We elected not to ask 18 subjects to return to the center because their responses indicated that they would not be suitable for a planned challenge study evaluating cardiopulmonary variables (12 with cardiorespiratory complaints; 2 taking medications that would interfere with physiological recording; 1 with new onset of alcoholism; 2 with new onset of bipolar disorder; and 1 with rheumatoid arthritis).


Thirteen veterans returned to our center for a second evaluation with an average of 22.1 +/- 9.5 (SD) months since their initial visit. Fisher tests revealed no significant differences in education, marital status, or race between veterans who returned to the center and those who did not return, nor was there any significant difference in age (37.8 +/- 8.0 years vs. 34.1 +/- 8.6 years). There were no significant differences in the results of any of the questionnaire material between veterans who returned to the center and those who did not return (Le, the group that did return their packets but were not willing or not eligible to return for a second visit).

Because there were no major differences between those GWVs who returned to the center and those who did not, we pooled available data from both groups. Our purpose in doing this was to evaluate self-reported data on symptoms, symptom severity, and the effects of illness on job and social activities. The sample size for these comparisons between time 1 and time 2 ranged from 38 to 43. No significant changes in any of these variables was found (i.e., median differences for all comparisons were 0). Thus, for the larger group, specifics related to illness did not change over time.

Table I shows each patient's category of illness on his or her initial visit and on follow-up. One patient who had category 5 CFS (i.e., relatively mild but still fulfilling the 1994 case definition) and one who had ICF no longer fulfilled case definitions for either CFS or ICF on follow-up. The other 11 patients maintained their diagnosis of CFS, although the severity of their illness as represented by their category did change. One patient in category 2 improved to category 6; this patient had originally fulfilled the more demanding 1988 case definition as well as the less rigorous 1994 case definition, but on re-evaluation, he no longer fulfilled the 1988 case definition and the magnitude of his self-reported symptoms were on the low side.

Of the six patients who had milder CFS at the time of their first visit (i.e., categories 5 or 6), one recovered, four either did not change or changed by only one category, and one got substantially worse (going to category 2). One of the patients who initially fulfilled the case definition for ICF also got substantially worse (going to category 2). Although the severity of individual symptoms for this group of patients did not change significantly from time 1 to time 2, scores for fatigue and vigor on the POMS improved significantly (median changes were -3 and 3; p = 0.06 and 0.03, respectively). However, this apparent improvement was not robust enough to manifest itself as a significant change over time for the subcomponents of the Multidimensional Fatigue Inventory.

Only 1 of the 13 patients was disabled from his illness, and this patient was in category 1 on intake and on revisit.


The results of this preliminary study are important for two reasons. First, they indicate that for the grog ip of GVs with fatiguing illness who returned to our center for a second visit, most continue to be symptomatic with a symptom complex severe enough to fulfill case definitions for CFS/ICF. Although this outcome is discouraging, there are some encouraging points. First, as assessed on the POMS, fatigue did diminish and vigor improved.

Next, the rate of inability to work for symptomatic GWVs is not high. In an earlier study, we compared the characteristics of GWVs who fulfilled the case definition for CFS with civilians who also had CFS.5 The major demographic difference between these two patient populations is that the veteran population is predominately male with the expected proportion of minorities. In contrast, the civilian population is predominately female and white. Nonetheless, comparing the two patient groups on disability status and the need for bed rest, we concluded that GWVs were less severely ill and less disabled from their illness than civilians.5 In our civilian center, nearly 50% of our patients are unable to work. Thus, finding only 1 of 13 GWVs who returned to our center to be disabled supports our previous interpretation. This bodes well for the long-term prognosis of the symptomatic GWV.

Other data also support this interpretation that CFS in GWVs is less severe than in nonveterans. In a previous outcome study of 23 nonveterans who entered our civilian CFS center with severe CFS (i.e., category 1), only one recovered during a 4-year period.10 Although that study evaluated only the sickest group of patients, the results did not differ much from those of other studies of CFS outcome. A review of a number of studies looking at the prognosis of CFS in adults suggests that fewer than 10% recover.11 In contrast, 2 GWVs from our group of 13 recovered during the 22 months between their two visits. It may be important that these patients had relatively milder disease on intake (Table I).

The second important point concerns the difficulty of getting even committed veteran volunteers to continue their participation in research. We tried to gain the renewed participation of 66 of the 76 GWVs who had come to our center for our original set of studies. Twenty-two of this group did not respond to recruitment efforts despite multiple phone calls and a letter. We excluded 18 of the remaining veterans as being unsuitable for our studies and focused our recruitment efforts on those remaining. Of the remaining 26 symptomatic veterans, only 13 were willing to continue their participation in our Persian Gulf War-related research. We feel that these data are important in the governmental interdepartmental planning that is currently under way to design a longitudinal study of outcome for symptomatic GWVs. Our data suggest that improved participation will require a different design from the one we used. Specifically, we think that the researchers will have to go to the subject rather than use our approach of asking the veteran to come to the research facility.

In conclusion, our data suggest that GWVs with severe unexplained fatigue continue to fulfill case definitions for CFS/ICF but that these diagnoses do not produce the same level of disability as seen in civilian women with this disorder. However, a country-wide longitudinal study of outcome from unexplained symptoms related to service in the Persian Gulf will require additional resources and new approaches to be successful.


The work reported here was supported by Department of Veterans Affairs research funds establishing a Center for Environmental Hazards Research in New Jersey.


1. Stretch RH, Bliese PD, Marlowe DH, Wright KM, Knudson KH, Hoover CH: Physical health symptomatology of Gulf War-era service personnel from the states of Pennsylvania and Hawaii. Milit Med 1995; 160: 131-6.

2. Persian Gulf Veterans Coordinating Board: Unexplained illness among Desert Storm veterans: a search for causes, treatment and cooperation. Arch Intern Med 1995; 155: 262-8.

3. Roy MJ, Koslowe PA, Kroenke K, et al: Signs, symptoms, and ill-defined conditions in Persian Gulf war veterans: findings from the comprehensive clinical evaluation program. Psychosom Med 1998; 60: 663-8.

4. Fukuda K, Nisenbaum R, Stewart G, et al: Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA 1998; 280: 981-8.

5. Pollet C, Natelson BH, Lange G, et al: Medical evaluation of Persian Gulf veterans with fatigue and/or chemical sensitivity. J Med 1998; 29: 101-13.

6. Institute of Medicine: Gulf War Veterans: Measuring Health. Washington, DC, National Academy Press, 1999.

7. Holmes GP, Kaplan JE, Gantz NM, et al: Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108: 387-9.

8. Fukuda K, Straus SE, Hickie I, et al: The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994; 121: 953-9. 9. Marcus S, Robins LN, Bucholz IK Quick Diagnostic Interview Schedule 3R, Ver

sion 1. St. Louis, MO, Washington University School of Medicine, 1990.

10. Hill NF, Tierksy LA, Scavella VR, Lavietes M, Natelson BB: Natural history of severe chronic fatigue syndrome. Arch Phys Med Rehabil 1999; 80: 1090-4.

11. Joyce J, Hotopf M, Wessely S: The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review. Q J Med 1997; 90: 223-33.

Guarantor: Benjamin H. Natelson, MD

Contributors: Jennifer J. Nelson, MS; Benjamin H. Natelson, MD; Arnold Peckerman, PhD; Claudia Pollet, MD; Gudrun Lange, PhD; Lana Tiersky, PhD; Richard J. Servatius, PhD; Theresa Policastro, BS; Nancy Fiedler, PhD; John E. Ottenweller, PhD

Center for Environmental Hazards Research, Department of Veterans Affairs Medical Center, East Orange, NJ 07018.

This manuscript was received for review in September 2000 and was accepted for publication in December 2000.

Reprint & Copyright by Association of Military Surgeons of U.S., 2001.

Copyright Association of Military Surgeons of the United States Dec 2001
Provided by ProQuest Information and Learning Company. All rights Reserved

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