Chediak-Higashi syndrome is a condition that affects many parts of the body, particularly the immune system. This disease damages immune system cells, leaving them less able to fight off invaders such as viruses and bacteria. As a result, most people with Chediak-Higashi syndrome have repeated and persistent infections starting in infancy or early childhood. These infections tend to be very serious or life-threatening.

The incidence of acute intestinal infarction approximates to the reported death rate-some 600 deaths a year in the United Kingdom. Though it may be theoretically possible to restore the intestinal circulation, late diagnosis of cases with additional cardiac, respiratory, and renal abnormalities precludes a successful outcome in the majority, and the patient is usually doomed from the start. Though the classical description is of a patient who develops sudden severe abdominal colic, passes blood and mucus per rectum, and rapidly develops peripheral circulatory failure, A. Marston' rightly emphasizes that the mode of presentation is usually atypical. The onset is often insidious with only vague abdominal pain, and the patient may remain apparently well for hours or even days. At this stage, when the diagnosis must be made or laparotomy undertaken for treatment to be effective, the patient may have mild abdominal distension with generalized tenderness but no rigidity. Bowel sounds are normal or increased until the stage when peritonitis ensues, the abdomen is silent, and irreversible gangrene is present. It requires a high degree of suspicion on the physician's part to consider a diagnosis of intestinal infarction at this stage, and the surgeon will often hesitate to undertake laparotomy for vague symptoms when the patient's general condition gives rise to doubts about the anaesthetic risk. As the ischaemic process continues, vast quantities of fluid and blood are lost, and the patient rapidly deteriorates. Marston points out that, when florid physical signs have appeared, the point of recovery for the patient has probably been passed. Investigation of the acute case yields disappointing results. Plain films of the abdomen may show intestinal distension, and aortography is of doubtful value. Leucocytosis occurs early and may be of value, but other laboratory investigations merely reflect the severity of the underlying changes. Before surgical operation resuscitation by intravenous fluids, correction of metabolic acidosis by bicarbonate, and administration of antibiotic may help to prepare the patient. Administration of heparin is unlikely to be rewarding. Though total midgut necrosis is lethal, it is sometimes possible to undertake a limited resection, the removal of a mesenteric embolus by Fogarty catheter, or revascularization of the superior mesenteric artery by bypass graft or by direct anastomosis to aorta or common iliac. Routine reoperation 24 hours later is strongly advised to assess the success of revascularization and to resect any bowel which has subsequently become gangrenous. Chronic intestinal ischaemia is a different problem, but, if the diagnosis can be made, successful revascularization may avert acute infarction. The classical history of severe, persistent, postprandial pain ("intestinal angina"), vomiting, severe loss of weight, and alteration in bowel habit is seen only infrequently, and the patient is more likely to present with vague abdominal pain and moderate loss of weight. Early enthusiasm for the investigation and treatment of cases due to atherosclerosis has waned because many patients develop a good collateral blood supply and do not require surgery.2 Recently attention has been paid to the coeliac axis compression syndrome. American reports3 are encouraging in that patients with abdominal pain, weight loss, and bowel upset have been shown to have stenosis of the coeliac axis caused by external compression from the median arcuate ligament of the diaphragm or from periarterial fibrosis. Simple division of the constricting fibres brings relief of symptoms in 70-80% of cases. J. A. Edwards and his colleagues4 are not so convinced, and there is certainly a need for further study of this problem.

To the Editor:The recommendations for diagnosis of mast cell activation syndrome proposed by Akin et al1Akin C. Valent P. Metcalfe D.D. Mast cell activation syndrome: proposed diagnostic criteria.J Allergy Clin Immunol. 2010; 126: 1099-1104Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar can significantly contribute to the identification of this frequent but underdiagnosed disease. Similar criteria have recently been proposed from the clinical perspective of internal medicine.2Homann J. Kolck U.W. Ehnes A. Frieling T. Raithel M. Molderings G.J. Systemic mastocytosis - definition of an internal disease.Med Klin (Munich). 2010; 105: 544-553Crossref PubMed Scopus (13) Google Scholar With regard to the development of a global classification of mast cell activation diseases, we have some further suggestions based on the present state of knowledge.According to recent findings,3Alvarez-Twose I. González de Olano D. Sánchez-Muñoz L. Matito A. Esteban-López M.I. Vega A. et al.Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms.J Allergy Clin Immunol. 2010; 125: 1269-1278Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, 4Teodosio C. García-Montero A.C. Jara-Acevedo M. Sánchez-Muñoz L. Alvarez-Twose I. Núñez R. et al.Mast cells from different molecular and prognostic subtypes of systemic mastocytosis display distinct immunophenotypes.J Allergy Clin Immunol. 2010; 125: 719-726Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 5Yang Y. Létard S. Borge L. Pediatric mastocytosis-associated KIT extracellular domain mutations exhibit different functional and signaling properties compared with KIT-phosphotransferase domain mutations.Blood. 2010; 116: 1114-1123Crossref PubMed Scopus (51) Google Scholar the specific biochemical and immunohistochemical pathological alterations of mast cells in systemic mastocytosis (SM) defined by the World Health Organization (WHO) criteria (SM-WHO) are a result of the presence of the D816V mutation in tyrosine kinase Kit. Other well characterized functionally activating mutations of Kit (eg, D419H, V560G) or the FIP1L1-PDGFRA fusion gene do not induce such detectable alterations of affected mast cells, and hence, normal mast cells cannot be discriminated from mast cells with those mutations. In biopsies from tissues or bone marrow from patients with mast cell activation syndrome, often an accumulation of morphologically normal mast cells is observed that is mostly interpreted as a reactive increase in mast cell number. However, this is an unproven and, currently, unverifiable assumption; morphologically normal mast cells may also express a higher state of functional activity. Such mast cells could bear a mutation different from KIT-D816V that is not associated with morphologic alterations. If so, the increased mast cell number would reflect an accumulation of pathological mast cells—that is, a mastocytosis—although the WHO criteria would not be fulfilled. In such cases, the continuous increase in the intensity of the disease may also indicate an increase in mast cell burden. Thus, the dichotomy of SM-WHO and mast cell activation syndrome seems to be only the result of the limitations of the current research techniques. Therefore, it would be appropriate to broaden the term systemic mastocytosis in that it is synonymous with systemic mast cell activation disease, with SM-WHO as 1 subclass. Alternatively, to avoid the current confusion in practice, the term systemic mastocytosis should no longer be used until the relationships among the various forms of primary mast cell activation disorders have been better characterized.It would be inappropriate to require demonstration of an elevated concentration of at least 1 mast cell mediator for diagnosis of mast cell activation syndrome for 3 reasons. First, many conditions (eg, degrading enzymes, complexing molecules, tissue pH) may attenuate or impede spillover of exocytosed mediators into the blood. Second, only a handful of the more than 60 releasable mast cell mediators can be detected by routine commercial techniques. We take care of patients presenting with an intense mast cell mediator release syndrome and functionally activating nonD816V mutations in mast cells6Molderings G.J. Meis K. Kolck U.W. Homann J. Frieling T. Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects.Immunogenetics. 2010; 62: 721-727Crossref PubMed Scopus (50) Google Scholar but lacking increased examinable mediators. Third, if liberation of mediators from mast cells is a result of a selective/differential/piecemeal release process,7Theoharides T.C. Kempuraj D. Tagen M. Conti P. Kalogeromitros D. Differential release of mast cell mediators and the pathogenesis of inflammation.Immunol Rev. 2007; 217: 65-78Crossref PubMed Scopus (330) Google Scholar only a few mediators that may not be detectable by current techniques may be released, inducing the apparent mediator release syndrome in part by the amplification cascade of basophil, eosinophil, and general leukocyte activation. To the Editor: The recommendations for diagnosis of mast cell activation syndrome proposed by Akin et al1Akin C. Valent P. Metcalfe D.D. Mast cell activation syndrome: proposed diagnostic criteria.J Allergy Clin Immunol. 2010; 126: 1099-1104Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar can significantly contribute to the identification of this frequent but underdiagnosed disease. Similar criteria have recently been proposed from the clinical perspective of internal medicine.2Homann J. Kolck U.W. Ehnes A. Frieling T. Raithel M. Molderings G.J. Systemic mastocytosis - definition of an internal disease.Med Klin (Munich). 2010; 105: 544-553Crossref PubMed Scopus (13) Google Scholar With regard to the development of a global classification of mast cell activation diseases, we have some further suggestions based on the present state of knowledge. According to recent findings,3Alvarez-Twose I. González de Olano D. Sánchez-Muñoz L. Matito A. Esteban-López M.I. Vega A. et al.Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms.J Allergy Clin Immunol. 2010; 125: 1269-1278Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, 4Teodosio C. García-Montero A.C. Jara-Acevedo M. Sánchez-Muñoz L. Alvarez-Twose I. Núñez R. et al.Mast cells from different molecular and prognostic subtypes of systemic mastocytosis display distinct immunophenotypes.J Allergy Clin Immunol. 2010; 125: 719-726Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 5Yang Y. Létard S. Borge L. Pediatric mastocytosis-associated KIT extracellular domain mutations exhibit different functional and signaling properties compared with KIT-phosphotransferase domain mutations.Blood. 2010; 116: 1114-1123Crossref PubMed Scopus (51) Google Scholar the specific biochemical and immunohistochemical pathological alterations of mast cells in systemic mastocytosis (SM) defined by the World Health Organization (WHO) criteria (SM-WHO) are a result of the presence of the D816V mutation in tyrosine kinase Kit. Other well characterized functionally activating mutations of Kit (eg, D419H, V560G) or the FIP1L1-PDGFRA fusion gene do not induce such detectable alterations of affected mast cells, and hence, normal mast cells cannot be discriminated from mast cells with those mutations. In biopsies from tissues or bone marrow from patients with mast cell activation syndrome, often an accumulation of morphologically normal mast cells is observed that is mostly interpreted as a reactive increase in mast cell number. However, this is an unproven and, currently, unverifiable assumption; morphologically normal mast cells may also express a higher state of functional activity. Such mast cells could bear a mutation different from KIT-D816V that is not associated with morphologic alterations. If so, the increased mast cell number would reflect an accumulation of pathological mast cells—that is, a mastocytosis—although the WHO criteria would not be fulfilled. In such cases, the continuous increase in the intensity of the disease may also indicate an increase in mast cell burden. Thus, the dichotomy of SM-WHO and mast cell activation syndrome seems to be only the result of the limitations of the current research techniques. Therefore, it would be appropriate to broaden the term systemic mastocytosis in that it is synonymous with systemic mast cell activation disease, with SM-WHO as 1 subclass. Alternatively, to avoid the current confusion in practice, the term systemic mastocytosis should no longer be used until the relationships among the various forms of primary mast cell activation disorders have been better characterized. It would be inappropriate to require demonstration of an elevated concentration of at least 1 mast cell mediator for diagnosis of mast cell activation syndrome for 3 reasons. First, many conditions (eg, degrading enzymes, complexing molecules, tissue pH) may attenuate or impede spillover of exocytosed mediators into the blood. Second, only a handful of the more than 60 releasable mast cell mediators can be detected by routine commercial techniques. We take care of patients presenting with an intense mast cell mediator release syndrome and functionally activating nonD816V mutations in mast cells6Molderings G.J. Meis K. Kolck U.W. Homann J. Frieling T. Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects.Immunogenetics. 2010; 62: 721-727Crossref PubMed Scopus (50) Google Scholar but lacking increased examinable mediators. Third, if liberation of mediators from mast cells is a result of a selective/differential/piecemeal release process,7Theoharides T.C. Kempuraj D. Tagen M. Conti P. Kalogeromitros D. Differential release of mast cell mediators and the pathogenesis of inflammation.Immunol Rev. 2007; 217: 65-78Crossref PubMed Scopus (330) Google Scholar only a few mediators that may not be detectable by current techniques may be released, inducing the apparent mediator release syndrome in part by the amplification cascade of basophil, eosinophil, and general leukocyte activation. Mast cell activation syndrome: Proposed diagnostic criteriaJournal of Allergy and Clinical ImmunologyVol. 126Issue 6PreviewThe term mast cell activation syndrome (MCAS) is finding increasing use as a diagnosis for subjects who present with signs and symptoms involving the dermis, gastrointestinal track, and cardiovascular system frequently accompanied by neurologic complaints. Such patients often have undergone multiple extensive medical evaluations by different physicians in varied disciplines without a definitive medical diagnosis until the diagnosis of MCAS is applied. However, MCAS as a distinct clinical entity has not been generally accepted, nor do there exist definitive criteria for diagnosis. Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyVol. 127Issue 5PreviewTo the Editor: Full-Text PDF

Systemic mast cell activation syndrome is a mast cell disorder characterized by an unregulated increased activation of mast cells leading to a pathologically enhanced release of mediators. Mutations in tyrosine kinase kit which crucially determines mast cell activity have been suggested as a necessary condition for the development of a clinically symptomatic mast cell disease. At the level of mRNA in mast cell progenitor cells of 20 patients with systemic mast cell activation syndrome and of 20 gender- and age-matched healthy volunteers, the tyrosine kinase kit was investigated for genetic alterations by means of RT-PCR and direct sequencing of the amplificates. In mast cells of 13 out of these 20 patients, multiple predominantly novel potential functionally activating point mutations or complex alterations of the mRNA sequence encoding the tyrosine kinase kit were detected. In contrast, in 19 of the 20 healthy subjects, no functionally relevant alterations of c-kit transcripts were detected. The present findings support the idea that the systemic mast cell activation syndrome is a clonal disease most commonly associated with variable activating mutations in the tyrosine kinase kit.

Disease summary: Andersen disease (GSD IV) is a rare genetic disorder of glycogen metabolism. It is caused by the deficient activity of the glycogen-branching enzyme, resulting in accumulation of abnormal glycogen in the liver, muscle, and/or other tissues. The disease is inherited as an autosomal recessive trait. Clinically, the symptoms and findings become evident in the first months of life. Such features typically include failure to thrive and hepatosplenomegaly. In such cases, the disease course is typically characterized by progressive cirrhosis and liver failure, leading to potentially life-threatening complications. In addition, several neuromuscular variants of GSD IV have been described that may be evident at birth, in late childhood, or in adulthood.