The molecular causes of thyroid dysgenesis: a systematic review.

BACKGROUND: Congenital hypothyroidism (CH) is a frequent disease occurring with an incidence of about 1/2500 newborns/year. In 80-85% of the cases CH is caused by alterations in thyroid morphogenesis, generally indicated by the term "thyroid dysgenesis" (TD). TD is generally a sporadic disease, but in about 5% of the cases a genetic origin has been demonstrated. In these cases, mutations in genes playing a role during thyroid morphogenesis (NKX2-1, PAX8, FOXE1, NKX2-5, TSHR) have been reported. AIM: This work reviews the main steps of thyroid morphogenesis and all the genetic alterations associated with TD and published in the literature.

Novel Munc13-4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis.

Familial haemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous disorder characterised by constitutive defects in cellular cytotoxicity resulting in fever, hepatosplenomegaly and cytopenia, and the outcome is fatal unless treated by chemoimmunotherapy followed by haematopoietic stem-cell transplantation. Since 1999, mutations in the perforin gene giving rise to this disease have been identified; however, these account only for 40% of cases. Lack of a genetic marker hampers the diagnosis, suitability for transplantation, selection of familial donors, identification of carriers, genetic counselling and prenatal diagnosis. Mutations in the Munc13-4 gene have recently been described in patients with FHL. We sequenced the Munc13-4 gene in all patients with haemophagocytic lymphohistiocytosis not due to PRF1 mutations. In 15 of the 30 families studied, 12 novel and 4 known Munc13-4 mutations were found, spread throughout the gene. Among novel mutations, 2650C-->T introduced a stop codon; 441del A, 532del C, 3082del C and 3226ins G caused a frameshift, and seven were mis sense mutations. Median age of diagnosis was 4 months, but six patients developed the disease after 5 years of age and one as a young adult of 18 years. Involvement of central nervous system was present in 9 of 15 patients, activity of natural killer cells was markedly reduced or absent in 13 of 13 tested patients. Chemo-immunotherapy was effective in all patients. Munc13-4 mutations were found in 15 of 30 patients with FHL without PRF1 mutations. Because these patients may develop the disease during adolescence or even later, haematologists should include FHL2 and FHL3 in the differential diagnosis of young adults with fever, cytopenia, splenomegaly and hypercytokinaemia.

Transplant-related toxicity and mortality: an AIEOP prospective study in 636 pediatric patients transplanted for acute leukemia.

Hematopoietic stem cell transplantation can cure high-risk acute leukemia (AL), but the occurrence of non-leukemic death is still high. The AIEOP conducted a prospective study in order to assess incidence and relationships of early toxicity and transplant-related mortality (TRM) in a pediatric population. Between 1990 and 1997 toxicities reported in eight organs (central nervous system, heart, lungs, liver, gut, kidneys, bladder, mucosa) were classified into three grades (mild, moderate, severe) and prospectively registered for 636 consecutive children who underwent autologous (216) or allogeneic (420) transplantation, either from an HLA compatible related (294), or alternative (126) donor in 13 AIEOP transplant centers. Overall, 47% of the patients are alive in CR (3-year EFS: 45.2%, s.e.: 2.1), 19% died in CR at a median of 60 days (90-day TRM: 14.3%, s.e.: 1.4), 34% relapsed. Toxicity of any organ, but mucosa and gut, was positively correlated with early death; moderate and severe toxicity to heart, lungs, liver and kidneys significantly increased early TRM, with estimated relative risks of 9.1, 5.5, 2.7 and 2.8, respectively, as compared to absent or mild toxicity. Patients with grade III-IV aGVHD experienced more than double (56% vs. 19%) TRM than patients with grade 0-II aGVHD. A higher cumulative toxicity score, estimating the impact of toxicity on TRM, was significantly associated with transplantation from an alternative donor. Quantitative assessment allowed us to describe the extent to which 'grade' of toxicity and 'type' of involved organs were related to mortality and pre-transplant characteristics and yielded a prognostic score potentially useful to compare different conditioning regimens and predict probability of early death.

Familial hemophagocytic lymphohistiocytosis: how late can the onset be?

BACKGROUND AND OBJECTIVES: Most patients with familial hemophagocytic lymphohistiocytosis (HLH) develop the disease within the first two years of age. In a minority of cases a later occurrence has been reported, with an upper age limit of eight years. A significant concordance of the age at onset within each family has also been observed. RESULTS: We report four cases of families with HLH diagnosed at an unusually late age, comprised between between 9 and 17 years; in each of these families another child developed the disease in infancy. The natural killer activity of the patients was depleted; nevertheless, we had indirect evidence that, in at least two families, mutations of the perforin gene were not causing the disease. INTERPRETATION AND CONCLUSIONS: Such a late onset is very unusual and suggests that there is a subgroup of families with HLH in which the disease may present early or late in different members. Thus in some families with HLH the siblings might remain at risk of developing the disease for several years. Their actual risk cannot be defined until the genetic mutation is identified in each family and assessed in each member.

Undertreatment of hypertension in community-dwelling older adults: a drug-utilization study in Dicomano, Italy.

OBJECTIVE: To define: (1) the prevalence of and (2) factors associated with undertreatment of hypertension in older persons; and (3) the prevalence of specific drug regimens and reasons for their selection. PARTICIPANTS: Cross-sectional survey of persons aged > or =65 years living in Dicomano, Italy. MAIN OUTCOME MEASURES: Prevalence of untreated and uncontrolled hypertension, both defined on the basis of two blood pressure (BP) cut-off points (> or =140/90 and > or =160/90 mm Hg) and of the presence of pharmacological treatment Predictors of undertreatment were analysed for the higher BP cut-off only. RESULTS: Five hundred of 692 (72.3%) and 380/692 (54.9%) participants met the 140/90 and the 160/90 mm Hg BP criterion, respectively. Of the latter, 162 (42.6%) were untreated, 119 (31.3%) had uncontrolled and 99 (26.1%) controlled hypertension. Women [odds ratio (OR), 0.4; 95% confidence interval (CI), 0.2-0.7], participants with coronary artery disease (CAD) (OR, 0.2; 95% CI, 0.1-0.6), stroke (OR, 0.3; 95% CI, 0.1-0.7), and preserved cognitive status (Mini Mental State Examination score >21: 0.3; 95% CI, 0.2-0.7) were more frequently treated. Uncontrolled hypertension was less likely in women (OR, 0.5; 95% CI, 0.3-1.0) and CAD patients (OR, 0.3; 95% CI, 0.1-0.7). Angiotensin converting enzyme (ACE)-inhibitors (55%), calcium (Ca)-antagonists (31%) and diuretics (20%) were the drugs most commonly prescribed. ACE-inhibitors were preferred, and diuretics rarely used, in diabetic subjects. Ca-antagonists were used mostly in CAD participants. CONCLUSIONS: Hypertension is undertreated in the majority of noninstitutionalized older adults, especially in men with impaired cognition and no vascular disease. Drug regimens are mostly based on ACE-inhibitors and Ca-antagonists, as a result of associated clinical conditions, requiring individualized treatment.

Pulsatile weight increases in very low birthweight babies appropriate for gestational age.

The weight increment profiles of 20 low birthweight babies measured during the first two months of extrauterine life were analysed. The babies were weighed daily, and the weight profiles showed minor irregularities when compared with an interpolated linear trend. When increments were plotted at two week intervals a linear increase in weight velocity was seen, but when increments were computed every three days, the velocity profile was non-linear and pulsatile. All cases studied showed regular pulsatile patterns of weight velocity during the first two months of life. A mean profile of the 20 babies permitted estimation of the periodicity of the pulsing: the cycle alternated every nine to 11 days. A non-linear pattern was found in the published series of unsmoothed data that have been widely adopted as standards for growth in low birthweight babies.

[Non-nutritional sucking in the preterm neonate]. / La suzione nonnutritiva nel neonato pretermine.

The authors briefly review the available data on nonnutritive sucking (NNS) in preterm infants focusing mainly on NNS as a form of intervention and on the relationship of NNS with cardiorespiratory control. The previous studies on the positive effects of NNS on weight gain and oxygenation called for deeper investigation on the mechanism involved. The authors report the main results of their work on this field. The effects of NNS on transcutaneous oxygen tension, heart rate and respiration were studied sequentially in 14 sleeping preterm infants breathing room air. Transcutaneous oxygenation tension increased during NNS in infants between 32 and 35 weeks postconceptional age, but not in those between 36 and 39 weeks. This response was not associated with a change in respiratory rate or sleep state, although heart rate tended to increase. A subsequent study however, demonstrated a small and transient increase of respiratory rate during NNS bursts. Although further longitudinal studies will be needed these data offer further support for the beneficial effects of NNS in preterm infants.