High endogenous melatonin levels in critically ill children: a pilot study.

OBJECTIVE: To evaluate the serum melatonin levels in critically ill pediatric patients and to test the effect of light on the melatonin's circadian rhythm. Data on melatonin secretion in critically ill pediatric subjects are lacking. STUDY DESIGN: We investigated the serum melatonin levels of 16 sedated and mechanically ventilated patients in a pediatric intensive care unit. Children (mean age, 5.1 ± 3.1 years) were randomly assigned to a dark-exposed or to a light-exposed group to evaluate the effects of light on serum melatonin concentrations. Blood samples for serum melatonin analysis were collected at 10 p.m., 1 a.m., 3 a.m., 5 a.m., 8 a.m., and 12 p.m. RESULTS: The melatonin circadian rhythm was severely disrupted in critically ill children; light exposure lowered serum melatonin even in a context of highly altered circadian cycle; melatonin peaks were greater for healthy age-matched children. CONCLUSION: The high melatonin levels in the critically ill children may be a response to counteract the elevated oxidative stress associated with serious diseases. Whether these elevated melatonin levels confer any beneficial effects in pediatric critically ill patients remains unknown.

Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes.

Joubert syndrome (JBTS), related disorders (JSRDs) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and CORS2 (JBTS2) loci are allelic and caused by mutations in TMEM216, which encodes an uncharacterized tetraspan transmembrane protein. Individuals with CORS2 frequently had nephronophthisis and polydactyly, and two affected individuals conformed to the oro-facio-digital type VI phenotype, whereas skeletal dysplasia was common in fetuses affected by MKS. A single G218T mutation (R73L in the protein) was identified in all cases of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in mutant fibroblasts or after knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 formed a complex with Meckelin, which is encoded by a gene also mutated in JSRDs and MKS. Disruption of tmem216 expression in zebrafish caused gastrulation defects similar to those in other ciliary morphants. These data implicate a new family of proteins in the ciliopathies and further support allelism between ciliopathy disorders.

MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement.

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the "molar tooth sign", a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.

CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders.

Joubert syndrome-related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurological, ocular, and renal manifestations. Mutations in the CEP290 gene were recently identified in families with the MTS-related neurological features, many of which showed oculo-renal involvement typical of Senior-Loken syndrome (JSRD-SLS phenotype). Here, we performed comprehensive CEP290-mutation analysis on two nonoverlapping cohorts of JSRD-affected patients with a proven MTS. We identified mutations in 19 of 44 patients with JSRD-SLS. The second cohort consisted of 84 patients representing the spectrum of other JSRD subtypes, with mutations identified in only two patients. The data suggest that CEP290 mutations are frequently encountered and are largely specific to the JSRD-SLS subtype. One patient with mutation displayed complete situs inversus, confirming the clinical and genetic overlap between JSRDs and other ciliopathies.

Nablus mask-like facial syndrome is caused by a microdeletion of 8q detected by array-based comparative genomic hybridization.

In 2000, Teebi reported on a 4-year-old boy with a distinctive pattern of malformation, which he termed the "Nablus mask-like facial syndrome" (OMIM# 608156). Characterization of this syndrome has been difficult because of the paucity of patients described in the medical literature and its unknown etiology and pathogenesis. We present two patients with Nablus mask-like facial syndrome who both display a microdeletion in the 8q21-8q22 region detected by array-based comparative genomic hybridization. Patient 1, a boy, has a distinct facial appearance characterized by severe blepharophimosis, tight-appearing glistening facial skin, sparse and unruly hair, a flat and broad nose, and distinctive ears that are triangular in shape with prominent antihelices. He also demonstrates camptodactyly, contractures, unusual dentition, cryptorchidism, mild developmental delay, and a happy demeanor. Patient 2, a girl with a strikingly similar phenotype, was previously described in a report by Salpietro et al. 2003. She has distinctive ears, dental anomalies, and developmental delay. The etiology of her pattern of malformation was not identified at that time. Although high-resolution chromosome and subtelomeric FISH analyses were normal, array-based comparative genomic hybridization revealed an approximately 4 Mb deletion involving the 8q21.3-8q22.1 region in both patients. This region encompasses a number of genes that may contribute to this unique phenotype. These results demonstrate a chromosomal microdeletion as the etiology of Nablus mask-like facial syndrome and emphasize the diagnostic utility of array-based comparative genomic hybridization in the evaluation of multiple malformation syndromes of previously unrecognized causation.

AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders.

OBJECTIVE: Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. It is characterized by hypoplasia of the cerebellar vermis and a particular midbrain-hindbrain "molar tooth" sign, a finding shared by a group of Joubert syndrome-related disorders (JSRDs), with wide phenotypic variability. The frequency of mutations in the first positionally cloned gene, AHI1, is unknown. METHODS: We searched for mutations in the AHI1 gene among a cohort of 137 families with JSRD and radiographically proven molar tooth sign. RESULTS: We identified 15 deleterious mutations in 10 families with pure JS or JS plus retinal and/or additional central nervous system abnormalities. Mutations among families with JSRD including kidney or liver involvement were not detected. Transheterozygous mutations were identified in the majority of those without history of consanguinity. Most mutations were truncating or splicing errors, with only one missense mutation in the highly conserved WD40 repeat domain that led to disease of similar severity. INTERPRETATION: AHI1 mutations are a frequent cause of disease in patients with specific forms of JSRD.

Distinguishing the four genetic causes of Jouberts syndrome-related disorders.

Jouberts syndrome-related disorders are a group of recessively inherited conditions showing cerebellar vermis hypoplasia and the molar tooth sign of the midbrain-hindbrain junction. Recent analyses have suggested at least three loci, JBTS1 (9q34.3), -2 (11p11.2-q12.3), and -3 (6q23), but the phenotypic spectrum associated with each locus has not been delineated. In addition, deletions of the NPHP1 gene, usually responsible for isolated juvenile nephronophthisis, are occasionally encountered among Jouberts syndrome-related disorder patients. Here, we describe four novel families showing evidence of linkage to two of these loci, provide a 3.6Mb refinement of the JBTS2 locus, and perform a detailed comparison of all linked families identified so far, to define the clinical and radiographical hallmarks for each genetic condition. We find that JBTS1 and -3 primarily show features restricted to the central nervous system, with JBTS1 showing largely pure cerebellar and midbrain-hindbrain junction involvement, and JBTS3 displaying cerebellar, midbrain-hindbrain junction, and cerebral cortical features, most notably polymicrogyria. Conversely, JBTS2 is associated with multiorgan involvement of kidney, retina, and liver, in addition to the central nervous system features, and results in extreme phenotypic variability. This provides a useful framework for genetic testing strategies and prediction of which patients are most likely to experience development of systemic complications.

Specific immunotherapy effect on interleukin-18 and CD30 serum levels in monosensitized patients with rhinitis.

To clarify the immunologic changes associated with specific immunotherapy (SIT), we analyzed interleukin (IL)-18 and CD30 serum levels in a group of patients with allergic rhinitis before and after SIT. IL-18 is a proinflammatory cytokine that plays an important role in the Th1 response. CD30 is a marker of Th2 lymphocytes. We selected 16 healthy donors (HDs) and 16 patients affected by allergic rhinitis, matched for sex and age. Serum IL-18 and CD30 levels were assayed by an immunoenzymatic method. IL-18 serum levels in the patients were lower than in the HDs before SIT (200.69 +/- 93.48 pg/mL versus 296.50 +/- 66.29 pg/mL; p < 0.05). After SIT, patients showed an increase of serum IL-18 levels (288.69 +/- 146.69 pg/mL versus 200.69 +/- 93.48 pg/mL; p < 0.05). On the contrary, serum CD30 levels were higher in patients before SIT with respect to HDs (14.78 +/- 8.30 IU/mL versus < 1 IU/mL; p < 0.05). SIT caused a decrease of serum CD30 levels in patients who were allergic (5.95 +/- 5.70 IU/mL versus 14.78 +/- 8.30 IU/mL; p < 0.05). In conclusion, in this study we showed for the first time the shift of IL-18 and CD30 production after SIT.

Cadmium concentration in maternal and cord blood and infant birth weight: a study on healthy non-smoking women.

The aim of our study was to measure, at delivery, maternal and cord blood cadmium levels (by means of atomic absorption spectrometry) in 45 healthy non-smoking pregnant women exposed to a low cadmium challenge, and to evaluate the relationship between these cadmium levels and the birth weight of the infants. Our results showed fairly low cadmium levels in maternal blood, in accordance with the fact that all women enrolled in this study lived in areas with low toxic metal contamination and that they did not smoke during their pregnancy. Furthermore, a highly significant direct correlation was found between maternal and cord blood cadmium concentrations. Since cadmium concentration appeared of the same order of magnitudine both in cord and maternal serum, one could speculate that cadmium is transferred easily from the mother to the fetus through the placenta. Finally, we found that birth weight is inversely correlated with maternal and cord blood cadmium concentrations; thus birth weight might be negatively influenced by cadmium levels as a result of the toxic effects of the metal on the placenta. Although preliminary, our data show that (also not-predictable) prenatal exposure to even low cadmium levels might be a risk factor for developmental impairment in infants.