Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth.Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic β cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.

Age-related changes in uterine and ovarian morphology and size were studied in 114 normal premenarcheal girls using a real-time mechanical sector scanner. Reference growth values were obtained for total uterine length, anteroposterior diameters of the corpus and cervix, corpus/cervix ratio, and uterine and ovarian volumes. Up to 7 years of age uterine size was not influenced by age and there was a relative predominance of the cervix over the corpus. Thereafter the uterus underwent a regular increase in size and the corpus gradually became larger than the cervix. Ovarian volume was relatively stable up to 5 years, when regular age-related growth started, associated with an increase in cystic functional changes in the ovary. As uterine and ovarian morphology and size are reliable indicators of the degree of sex-hormone stimulation, real-time ultrasound offers a rapid method of studying normal and abnormal pubertal development in girls.

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