Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a heterogeneous disorder characterized by profound hypoglycaemia due to inappropriate hypersecretion of insulin. An important ...diagnostic goal is to distinguish patients with a focal hyperplasia of islet cells of the pancreas (FoPHHI) from those with a diffuse abnormality of islets (DiPHHI), because the management differs significantly. The intriguing similarity between islet cell hyperplasia and tumourigenesis prompted us to investigate whether the imprinted genes in the 11p15 region are involved. Results showed that diffuse forms are caused by constitutional homozygous or compound heterozygous mutations of the SUR1 gene. In contrast, focal forms are caused by loss of the maternally inherited 11p15 region, resulting in both loss of the maternally expressed tumour suppressor genes accounting for hyperplasia and somatic reduction to hemizygosity or homozygosity of the paternally inherited SUR1, limited to the lesion. Thus, this somatic disorder, which leads both to beta-cell proliferation and to hyperinsulinism, can be considered the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation.
Cellualar adhesion molecules are newly identified mediators of angiogenesis. Infantile hemangiomas, characterized in the early stages by a proliferation of poorly differentiated vessels followed in ...the late stages by a vascular differentiation and regression of the tumor, represent an interesting model to study angiogenesis. We studied by immunohistochemistry the distribution of HLA‐DR and three adhesion molecules ICAM‐3. E‐selectin and VCAM‐I on endothelial cells in different stages of vessel differentiation in infantile hemangiomas. We found high levels of ICAM‐3 expression on proliferating vessels, while its expression was low or undetectable on well differentiated vessels. A different set of E‐selection antibodies showed a more heterogenous pattern of distribution and VCAM‐1 antigens were found in both proliferating and differentiated vessels. HLA‐DR expression on endothelial cells was inversely correlated to the vascular differentiation. Our results are consistent with the hypothesis that ICAM‐3 plays a role in the early stages of vessel formation. Our results also suggest that variation of E‐selectin and HLA‐DR expression may be related either to vessel differentiation or may reflect the acquisition of an activated endothelial cell status.
Congenital hyperinsulinism (CHI), previously named persistent hyperinsulinemic hypoglycemia of infancy, is characterized by profound hypoglycemia because of excessive insulin secretion. CHI presents ...as two different morphological forms: a diffuse form with functional abnormality of islets throughout the pancreas and a focal form with focal islet cell adenomatous hyperplasia, which can be cured by partial pancreatectomy. Recently, we have shown that focal adenomatous hyperplasia involves the specific loss of the maternal 11p15 region and a constitutional mutation of a paternally inherited allele of the gene encoding the regulating subunit of the K
+
ATP channel, the sulfonylurea receptor (ABCC8 or SUR1). In the present study on a large series of 31 patients, describing both morphological features and molecular data, we report that 61% of cases (19 out of 31) carried a paternally inherited mutation not only in the ABCC8 gene as previously described but also in the second gene encoding the K
+
ATP channel, the inward rectifying potassium channel (KCNJ11 or KIR6.2), in 15 cases and 4 cases, respectively. Moreover our results are consistent with the presence of a duplicated paternal 11p15 allele probably because of mitotic recombination or reduplication of the paternal chromosome after somatic loss of the maternal chromosome. In agreement with the loss of the maternal chromosome, the level of expression of a maternally expressed tumor suppressor gene, H19, was greatly reduced compared to the level of expression of the paternally expressed growth promoter gene, IGF2. The expression of IGF2 was on average only moderately increased. Thus, focal forms of CHI can be considered to be a recessive somatic disease, associating an imbalance in the expression of imprinted genes in the 11p15.5 region to a somatic reduction to homozygosity of an ABCC8- or KCNJ11-recessive mutation. The former is responsible for the abnormal growth rate, as in embryonic tumors, whereas the latter leads to unregulated secretion of insulin.
Gastrointestinal symptoms are common and often reveal primary immunodeficiency. Although they mimic gastrointestinal diseases observed in immunocompetent patients, there have diagnostic and ...therapeutic specificities that should be known for optimal management of these patients. This review describes the gastrointestinal diseases found in primary immunodeficiency and proposes some diagnostic and therapeutic strategies.
Les manifestations gastro-intestinales des déficits immunitaires primitifs (DIP) sont fréquentes et souvent révélatrices du déficit immunitaire. Si elles miment, pour la plupart, les maladies ...digestives de l’immunocompétant, elles comportent des spécificités diagnostiques et thérapeutiques qui doivent être connues pour la prise en charge adaptée de ces patients. Cette revue établit la description des atteintes digestives des DIP en proposant notamment une démarche diagnostique et fait état des thérapeutiques disponibles.
Gastrointestinal symptoms are common and often reveal primary immunodeficiency. Although they mimic gastrointestinal diseases observed in immunocompetent patients, there have diagnostic and therapeutic specificities that should be known for optimal management of these patients. This review describes the gastrointestinal diseases found in primary immunodeficiency and proposes some diagnostic and therapeutic strategies.
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