Tpit is a highly cell-restricted transcription factor that is required for expression of the pro-opiomelanocortin (POMC) gene and for terminal differentiation of the pituitary corticotroph lineage. Its exclusive expression in pituitary POMC-expressing cells has suggested that its mutation may cause isolated deficiency of pituitary adrenocorticotropin (ACTH). We now show that Tpit-deficient mice constitute a model of isolated ACTH deficiency (IAD) that is very similar to human IAD patients carrying TPIT gene mutations. Through genetic analysis of a panel of IAD patients, we show that TPIT gene mutations are associated at high frequency with early onset IAD, but not with juvenile forms of this deficiency. We identified seven different TPIT mutations, including nonsense, missense, point deletion, and a genomic deletion. This work defines congenital early onset IAD as a relatively homogeneous clinical entity caused by recessive transmission of loss-of-function mutations in the TPIT gene.

Tpit is a T box transcription factor important for terminal differentiation of pituitary proopiomelanocortin-expressing cells. We demonstrated that human and mouse mutations of the TPIT gene cause a neonatal-onset form of congenital isolated ACTH deficiency (IAD). In the absence of glucocorticoid replacement, IAD can lead to neonatal death by acute adrenal insufficiency. This clinical entity was not previously well characterized because of the small number of published cases. Since identification of the first TPIT mutations, we have enlarged our series of neonatal IAD patients to 27 patients from 21 unrelated families. We found TPIT mutations in 17 of 27 patients. We identified 10 different TPIT mutations, with one mutation found in five unrelated families. All patients appeared to be homozygous or compound heterozygous for TPIT mutations, and their unaffected parents are heterozygous carriers, confirming a recessive mode of transmission. We compared the clinical and biological phenotype of the 17 IAD patients carrying a TPIT mutation with the 10 IAD patients with normal TPIT-coding sequences. This series of neonatal IAD patients revealed a highly homogeneous clinical presentation, suggesting that this disease may be an underestimated cause of neonatal death. Identification of TPIT gene mutations as the principal molecular cause of neonatal IAD permits prenatal diagnosis for families at risk for the purpose of early glucocorticoid replacement therapy.

In four children from the same family, we have observed an association of mental retardation, dwarfism, hypertelorism, facial clefting and urogenital abnormalities. Clinical and laboratory data suggest that it is a previously undescribed genetic syndrome, ie, a pleiotropic autosomal recessive trait.

We report the data of 19 children with neuroblastoma (NB) or Ewing's sarcoma (EW) who had peripheral blood stem cells (PBSCs) harvested after mobilization by: (1) cyclophosphamide (CY) + etoposide + G-CSF, (2) CY + GM-CSF, or (3) G-CSF alone. There were no consistent differences in the number of PBSCs collected following these three different mobilization regimens as assessed by CFU-GM. 17 patients were reinfused with PBSCs after myeloablative therapy and had successful haemopoietic recovery. These results show that in children with solid tumours such as NB or EW a sufficient number of PBSCs can be collected after G-CSF alone, and that PBSCs collected following stimulation by G-CSF alone are as effective in reconstituting haemopoiesis as those collected after mobilizing chemotherapy + HGFs.

The relative contribution of diarrheagenic Escherichia coli was examined during a 1-year prospective study of hospitalized children in Clermont-Ferrand, France, including 220 case patients (with diarrhea) and 211 matched controls. Fecal isolates were characterized by means of their pattern of adherence to HEp-2 cells and by colony hybridization with DNA probes specific for the six categories of diarrheagenic E. coli. No enteroinvasive or enterotoxigenic E. coli isolates were isolated. Twenty-eight (6.5%) eae-positive isolates and 39 (9%) enteroaggregative E. coli isolates characterized with the aggregative adherence probe and/or by their adherence pattern were detected; they were equally distributed among the patients and the controls. Diffusely adhering E. coli was the predominant pathotype: 30.7% were detected by their adherence pattern and 13.7% were detected with the daaC probe. They were isolated with similar frequencies from the patients and the controls, thereby showing no association with diarrhea. However, daaC-positive strains were significantly associated with a past record of urinary tract infections. These results suggest that the diffusely adhering E. coli organisms isolated in the present study are not true intestinal pathogens but may be regarded as resident colonic strains. Escherichia coli strains associated with diarrheal disease have been divided into categories on the basis of pathogenic mechanisms. By using an assay measuring mannose-resistant bacterial adherence to the HEp-2 cell line, three pathotypes of E. coli have been distinguished so far (39). The localized adherence (LA) pattern refers to the formation of distinct microcolonies or bacterial clusters on the HEp-2 cell surface. This phenotype is characteristic of enteropathogenic E. coli (EPEC) responsible for infantile diarrhea in developing countries (9). The second pattern, called aggregative adherence (AA) refers to a pattern whereby bacteria adhere to each other and form a stacked brick-like lattice on the epithelial cells and on glass coverslips (39). Several epidemiological studies with infants and children in developing countries have noted an association between this adherence pattern and persistent diarrhea (6, 10, 52). The last group is referred to as diffusely adhering E. coli (DAEC). Many epidemiological studies concerning the involvement of this last group in infantile diarrhea have been conducted, but they led to contradictory results (2,