Clinical relevance of postzygotic mosaicism in Cornelia de Lange syndrome and purifying selection of NIPBL variants in blood.

Postzygotic mosaicism (PZM) in NIPBL is a strong source of causality for Cornelia de Lange syndrome (CdLS) that can have major clinical implications. Here, we further delineate the role of somatic mosaicism in CdLS by describing a series of 11 unreported patients with mosaic disease-causing variants in NIPBL and performing a retrospective cohort study from a Spanish CdLS diagnostic center. By reviewing the literature and combining our findings with previously published data, we demonstrate a negative selection against somatic deleterious NIPBL variants in blood. Furthermore, the analysis of all reported cases indicates an unusual high prevalence of mosaicism in CdLS, occurring in 13.1% of patients with a positive molecular diagnosis. It is worth noting that most of the affected individuals with mosaicism have a clinical phenotype at least as severe as those with constitutive pathogenic variants. However, the type of genetic change does not vary between germline and somatic events and, even in the presence of mosaicism, missense substitutions are located preferentially within the HEAT repeat domain of NIPBL. In conclusion, the high prevalence of mosaicism in CdLS as well as the disparity in tissue distribution provide a novel orientation for the clinical management and genetic counselling of families.

Complex nutritional deficiencies in a large cohort of Italian patients with Cornelia de Lange syndrome spectrum.

Cornelia de Lange syndrome Spectrum (CdLSp) is characterized by intellectual disability, facial dysmorphisms, and growth impairment. Although eating difficulties are a well-known feature of the disease, there is no data regarding the nutritional deficiencies of these patients. The food intake was tracked using a dietary transcription provided by the family/caregivers, biochemical nutritional parameters were measured with laboratory tests and through an accurate clinical evaluation of the incidence of qualitative and quantitative imbalances in a cohort of 73 patients with CdLSp ware determined. Of these 73, 62 (85%) subjects provided a complete and detailed dietary transcription. In the studied population, a quantitative caloric imbalance in 47/62 (76%) subjects was observed. The caloric intake was low in 27/62 (43%) subjects whereas excessive in 20/62 (33%). Only 15/62 (24%) had an optimum caloric intake. Regarding micronutrients, a calcium intake deficiency in 32% of the patients (20/62) was observed. Blood tests revealed a low iron level in 22/73 (30%) of the patients and 25(OH)D deficiency in 49/73 (67%). Serum hypocalcemia was not evidenced. Qualitative and quantitative imbalances resulted in more frequent than expected in CdLSp patients. A qualitative imbalance was more prevalent in younger patients while in older patients prevailed mainly a quantitative disproportion. We found no statistically meaningful correlation between dietary imbalances, genetic, or clinical parameters. Our findings highlight the need for further studies to evaluate the basal metabolic rate of CdLSp patients and find a correlation with their growth impairment.

Second-trimester pregnancy associated plasma protein-A levels are reduced in Cornelia de Lange syndrome pregnancies.

Maternal serum samples were collected from 19 pregnancies which resulted in the birth of a child with the classical Cornelia de Lange syndrome phenotype ascertained by careful clinical review. Using specific immunoassays, the serum levels of pregnancy associated plasma protein-A, free-beta human chorionic gonadotrophin and inhibin A were investigated. Pregnancy associated plasma protein-A was detectable in all cases but the levels were significantly reduced in second-trimester maternal serum from 18 affected pregnancies. Expressed as multiples of the median (MOM), the results ranged from 0.03 MOM to 0.71 MOM with an overall median value of 0.21 MOM (Mann-Whitney p<0.001). From these data it is possible to estimate a probability that any given level of this serum marker is associated with an affected pregnancy. One further sample taken in the first trimester from an affected pregnancy at 11 weeks' gestation had a normal pregnancy associated plasma protein-A level (1.22 MOM). Less markedly reduced levels were found for free beta human chorionic gonadotrophin and inhibin A. We conclude that second-trimester maternal serum pregnancy associated plasma protein-A measurements may be of value as an adjunct to ultrasonography in the prenatal diagnosis of Cornelia de Lange syndrome. A table of likelihood ratios is presented.

Oxygen desaturation of selected term infants in car seats.

OBJECTIVES: Premature infants are known to be at risk for oxygen (O2) desaturation and/or apnea in car seats. Since 1990, the American Academy of Pediatrics has recommended a period of monitoring in car seats before hospital discharge for infants born at < 37 weeks gestation. The objective of this report is to determine if selected term infants are also at risk for O2 desaturation, apnea, or bradycardia while in an infant car seat. METHODS: MetroWest Medical Center is a community hospital with a level II neonatal unit. Term infants who in the judgment of their pediatrician were felt to be at risk for O2 desaturation or apnea were monitored for a 90-minute period in a car seat and observed for transcutaneous O2 desaturation, apnea, or bradycardia. In addition, several infants who were admitted to the pediatric inpatient unit after discharge from the nursery were monitored in a similar fashion. RESULTS: Eight of 28 monitored infants (28.6%) had a period of O2 desaturation < 90%. In addition, five of 28 monitored infants (17.8%) had borderline results (O2 saturation, 90 to 93%). All four infants monitored because of genetic syndromes had abnormal results. O2 desaturation was also observed in two term infants who had been observed to be apneic by a parent after discharge from the nursery. CONCLUSIONS: In selected circumstances (eg, genetic disorders or observed apnea) term infants may be at risk for O2 desaturation in an upright car seat and monitoring these infants in car seats before nursery discharge should be considered. Because not all infants at risk for O2 desaturation can be identified at birth, an alternative approach would be to recommend, unless medically contraindicated (eg, gastroesphogeal reflux when supine), that infants should routinely be transported in a supine position car seat in the early months of life.