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.

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain–containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (–7), deletions of 7q (7q–), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with –7 and 7q– developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.

Environmental enrichment (EE) was shown recently to accelerate brain development in rodents. Increased levels of maternal care, and particularly tactile stimulation through licking and grooming, may represent a key component in the early phases of EE. We hypothesized that enriching the environment in terms of body massage may thus accelerate brain development in infants. We explored the effects of body massage in preterm infants and found that massage accelerates the maturation of electroencephalographic activity and of visual function, in particular visual acuity. In massaged infants, we found higher levels of blood IGF-1. Massage accelerated the maturation of visual function also in rat pups and increased the level of IGF-1 in the cortex. Antagonizing IGF-1 action by means of systemic injections of the IGF-1 antagonist JB1 blocked the effects of massage in rat pups. These results demonstrate that massage has an influence on brain development and in particular on visual development and suggest that its effects are mediated by specific endogenous factors such as IGF-1.

Of the 10,730 neonates born in the period 1978-1997 and examined for cryptorchidism (C) at birth, 1387 were pre-term (gestational age <37 wk), and 9343 were full-term. At birth, a total of 737 neonates (6.9%) were cryptorchid, 487 had bilateral C and 250 unilateral C. The C rate of pre-terms was 10 times higher than that of the full-terms (30.1 and 3.4%, respectively). Comparing the two studied decades, a significant decrease of C rate was found in the second decade in full-term neonates. The rates of C at birth were significantly elevated for low birth weight, babies born from mothers with an age <20 or >35 yr, newborns from mothers with A Rh positive and B Rh positive blood group. Of the 737 cryptorchid newborns at birth, 613 (83%) were re-examined after 12 months from the expected date of delivery, and those born in the period 1988-1997 were also re-evaluated at 6 months of life. Late spontaneous descent occurred in 464 cases (75.7%), while 149 (24.3%) were still cryptorchid. The incidence of C at 12 months from the expected date of delivery, after survival curve calculation, in term and pre-term infants, was 1.53 and 7.31%, respectively, in the period 1978-1987, and 1.22 and 3.13% respectively, in the 2nd decade (1988-1997). In the groups also examined at 6 months of life, spontaneous descent occurred almost completely within the first 6 months of life in term infants, but not in pre-terms. No evidence of seasonal cyclicity was found. Medical and/or surgical treatment was generally started within 2-4 yr of age earlier in the second decade of the study. In conclusion, the main risk factor for C at birth and at 12 months of life seems to be pre-term birth and low birth weight. If this is associated itself to a higher risk of infertility too, it remains to be defined.

AIM Early intervention programmes based on the manipulation of the extra-uterine environment have been used in preterm infants with the aim of improving development and functional outcome. Infant massage, among them, has proved effective for weight gain and reduced length of stay in the neonatal intensive care unit. We have recently shown that infant massage accelerates brain maturation of low-risk preterm infants without brain abnormalities as measured by global parameters of electroencephalography (EEG) activity. In the present study we further analyse the same cohort of preterm infants, testing the hypothesis that massage determines changes in EEG spectral activity, a highly sensitive index of brain maturation. METHOD Infants were randomly allocated to a massage or comparison group. Intervention consisted of standard care only (comparison group) or standard care plus infant massage (massage group). Massage was started at around 10 days after birth and was provided for 12 days during a 2-week period. EEG was performed at around 1 and 4 weeks, i.e. before and after intervention. Spectral EEG analysis was performed on 80 seconds of active sleep, applying the fast Fourier transform on the signal obtained from eight monopolar derivations. RESULTS The modification in global EEG spectral power between the two assessments was significantly different for the two groups, especially for the delta band activity; the spectral power did not change in massaged infants although, not surprisingly, it decreased significantly in the comparison group, as shown by previous studies. INTERPRETATION We propose that massage intervention affects the maturation of brain electrical activity and favours a process more similar to that observed in utero in term infants