Untreated Siblings Research Articles

Do conditional cash transfers improve intergenerational gains in educational achievement?: Evidence from Brazil’s Bolsa Familia Program

Conditional cash transfer programs are designed to interrupt the intergenerational cycle of poverty by improving health and educational outcomes. We evaluate the efficacy of the world’s largest CCT program utilizing educational outcomes from the complete administrative records at the intra-family level of Brazil’s Bolsa Família program (PBF). Although we find that younger siblings subject to the Bolsa Família conditionalities outperform their older, untreated siblings in educational attainment within the same household, the overall effect size remains substantively small. We consider the educational attainment of 15–17 year old beneficiaries with siblings who were above the age of 18 at the time of family enrollment. Our findings show precisely estimated positive effects due to the large sample, indicating that the program yields minimal improvements in educational outcomes for ‘treated’ children compared to their ‘untreated’ siblings. Additionally, we find modest differences across boy and girl sibling pairs, but consistent regional effects, underscoring the importance of local public goods provision for enhancing program efficacy.

Family-Based Interventions for Pediatric Obesity: A Comprehensive Systematic Review and Meta-Analysis of Their Effectiveness.

Genetics can influence obesity, and when it affects both parents and children, there is a high risk of developing cardiometabolic diseases. Studies have indicated that family-based treatment (FBT) is a cost-effective and successful option for achieving significant weight changes in both children and parents. While specialized clinics offer FBT, primary care settings, where most pediatric care takes place, may not have the necessary resources or expertise to provide intensive behavioral interventions for childhood obesity. Based on early findings, FBT could potentially have a positive impact on siblings as well, as when treated children and parents experience behavioral changes, it can also have a beneficial effect on their untreated siblings. Parents play a crucial role in shaping their children's behavior, and siblings often have a stronger influence on them than their parents or friends. For our meta-analysis, we utilized three graphical models created using RevMan 5.4, based on the selected articles. To develop our systematic review, we thoroughly analyzed a total of 10 articles. The subgroup analysis within these studies assessed the effectiveness of FBT for overweight children, revealing no significant differences between groups (p=0.77). This suggests that based on their BMI, FBT may not have a statistically significant impact on weight loss in overweight children. However, each study reviewed showed statistical significance (p<0.05). The findings of our meta-analysis underscore the need for more robust evidence and larger randomized controlled trials (RCTs) to enhance our understanding of FBT's benefits in pediatric obesity. This will be crucial for reducing the rising prevalence of obesity and maintaining lower incidence rates.

Does anti-HPA-1a affect birthweight in fetal and neonatal alloimmune thrombocytopenia?

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) ensues from parental incompatibility for platelet alloantigens with maternal sensitization. HPA-1a/1b incompatibility is the most common cause of FNAIT in Caucasians. Placental villitis and lower birthweight in FNAIT suggest anti-HPA-1a may have effects beyond inducing thrombocytopenia. Does FNAIT secondary to anti-HPA-1a result in smaller newborns and, the corollary, does antenatal management of FNAIT increase birthweight? Birthweights of 270 FNAIT-affected newborns from a randomized clinical trial and a NAITbabies.org survey (135 paired siblings) were compared with those of published controls and treated to untreated FNAIT-affected siblings. Birthweights were converted to percentiles to account for gestational age, sex, and role of birth order in birth weight. Body weights of FNAIT-affected and -unaffected pups in a mouse FNAIT model were analyzed. Untreated siblings in both the clinical trial and NAITbabies.org cohorts were not small, compared with normal controls. However, treated siblings in both cohorts had significantly higher birthweight percentiles compared with their previous untreated affected sibling. After accounting for gestational age, sex, and birth order, increased birthweight percentile in treated compared with the untreated siblings remained significant in both cohorts. FNAIT-affected neonatal mice had lower bodyweights than FNAIT-unaffected pups. Untreated FNAIT-affected newborns were not small; however, treatment of FNAIT-affected pregnancies increased newborn birthweights despite corrections to account for other factors that might have influenced the results. High dose IVIG is believed to "block" FcRn and lower maternal anti-HPA-1a levels, and thus increase birthweights by reducing levels of maternal anti-HPA-1a and reducing placental villitis.

Divalent metal content in diet affects severity of manganese toxicity in Drosophila.

Dysregulation of manganese (Mn) homeostasis is a contributing factor in many neuro-degenerative diseases. Adult Drosophila are sensitive to excessive levels of dietary Mn, dying relatively early, and exhibiting biochemical and mobility changes reminiscent of Parkinsonian conditions. To further study Mn homeostasis in Drosophila, we sought to test lower levels of dietary Mn (5 mM) and noted a striking difference in Canton-S adult survivorship on different food. On a cornmeal diet, Mn-treated flies live only about half as long as untreated siblings. Yet, with the same Mn concentration in a molasses diet, adults survive about 80% as long as untreated siblings, and adults raised on a sucrose-yeast diet are completely insensitive to this low dose of dietary Mn. By manipulating metal ion content in the cornmeal diet, and measuring the metal content in each diet, we traced the difference in lifespan to the levels of calcium and magnesium in the food, suggesting that these ions are involved in Mn uptake and/or use. Based on these findings, it is recommended that the total dietary load of metal ions be considered when assessing Mn toxicity.

Phenotypic variation between siblings with Metachromatic Leukodystrophy

BackgroundMetachromatic Leukodystrophy (MLD) is a rare autosomal-recessive lysosomal storage disorder caused by mutations in the ARSA gene. While interventional trials often use untreated siblings as controls, the genotype-phenotype correlation is only partly understood, and the variability of the clinical course between siblings is unclear with some evidence for a discrepant clinical course in juvenile patients. The aim of this study was to systematically investigate the phenotypic variation in MLD siblings in comparison to the variability in a larger MLD cohort and to case reports published in literature.ResultsDetailed clinical information was available from 12 sibling-pairs (3 late-infantile, 9 juvenile) and 61 single patients (29 late-infantile, 32 juvenile). Variability of age at onset was similar between the siblings and randomly chosen pairs of the remaining cohort (no statistically different Euclidean distances). However, in children with juvenile MLD both the type of first symptoms and the dynamic of the disease were less variable between siblings compared to the general cohort. In late-infantile patients, type of first symptoms and dynamic of disease were similarly homogeneous between siblings and the whole MLD cohort. Thirteen published case reports of families with affected siblings with MLD are presented with similar findings.ConclusionsIn a systematic analysis of phenotypic variation in families with MLD, siblings with the late-infantile form showed a similar variability as unrelated pairs of children with late-infantile MLD, whereas siblings with juvenile MLD showed a more homogeneous phenotype regarding type of first symptoms and disease evolution in comparison to unrelated children with juvenile MLD, but not regarding their age at onset. These results are highly relevant with respect to the evaluation of treatment effects and for counseling of families with affected siblings.

The effects of a nutrient supplementation intervention in Ghana on parents' investments in their children.

A child’s endowment is a reflection of his/her genetic makeup and the conditions faced in early life. Parents build on their child’s endowment by investing resources in their child, and together, a child’s endowment and subsequent investments act as input into important later-life outcomes. A positive or negative shock to a child’s endowment can have a direct biological effect on a child’s long-term outcomes but may also affect parents’ decisions about investments in the health and human capital of their children. Using follow-up data collected several years after a randomized trial in Ghana, we explored whether maternal and child supplementation with small-quantity lipid-based nutrient supplements (SQ-LNS) throughout much of the first 1,000 days influenced parental investments in the health and human capital of their children. Across the domains of family planning, breastfeeding, health, education, and paternal financial support, we found that, in general, the intervention did not affect investments in the treated child nor his/her untreated siblings. These results suggest that given production technologies, constraints, and preferences, the intervention either did not change parents’ optimal investment strategies or that the effects of the intervention, namely increased birth size and attained length at 18 months of age, were too small for parents to perceive or to have any meaningful impact on parents’ expectations about the returns to investments in their children.

Early-life social environment predicts social network position in wild zebra finches.

Early-life experience can fundamentally shape individual life-history trajectories. Previous research has suggested that exposure to stress during development causes differences in social behaviour later in life. In captivity, juvenile zebra finches exposed to elevated corticosterone levels were less socially choosy and more central in their social networks when compared to untreated siblings. These differences extended to other aspects of social life, with 'stress-exposed' juveniles switching social learning strategies and juvenile males less faithfully learning their father's song. However, while this body of research suggests that the impacts of early-life stress could be profound, it remains unknown whether such effects are strong enough to be expressed under natural conditions. Here, we collected data on social associations of zebra finches in the Australian desert after experimentally manipulating brood sizes. Juveniles from enlarged broods experienced heightened sibling competition, and we predicted that they would express similar patterns of social associations to stress-treated birds in the captive study by having more, but less differentiated, relationships. We show striking support for the suggested consequences of developmental stress on social network positions, with our data from the wild replicating the same results in 9 out of 10 predictions previously tested in captivity. Chicks raised in enlarged broods foraged with greater numbers of conspecifics but were less 'choosy' and more central in the social network. Our results confirm that the natural range of variation in early-life experience can be sufficient to predict individuals' social trajectories and support theory highlighting the potential importance of developmental conditions on behaviour.

Indirect Effect of Azithromycin Use on the Intestinal Microbiome Diversity of Untreated Children: A Randomized Trial.

Cohabiting children may share components of their intestinal microbiome. We evaluated whether receipt of azithromycin in one sibling confers changes to the intestinal microbiome in an untreated sibling compared with placebo in a randomized controlled trial. We found no evidence of an indirect effect of antibiotic use in cohabiting children. Clinical Trials Registrations: NCT03187834.

Serotonergic stimulation induces nerve growth and promotes visual learning via posterior eye grafts in a vertebrate model of induced sensory plasticity

The major goal of regenerative medicine is to repair damaged tissues and organ systems, thereby restoring their native functions in the host. Control of innervation by re-grown or implanted structures, and integration of the nascent nerves into behavioral/cognitive programs of the host, remains a critical barrier. In the case of sensory organs, this is particularly true, as afferent neurons must form connections with the host to communicate auditory, visual, and tactile information. Xenopus embryos and tadpoles are powerful models for such studies, as grafting techniques allow for the creation of eyes and other sensory structures along the body axis, and the behavior of the resulting organism can be quantitatively analyzed. Previous work has demonstrated that ectopic eyes could be grafted in blinded tadpoles, allowing some of the animals to learn in a simple light-preference assay. Here, we show that it is possible to improve the efficiency of the process in the context of a novel image-forming vision assay, using a drug already approved for human use. Innervation of the host by ectopic eyes can be increased by targeting a serotonergic signaling mechanism: grafts treated with a 5-HT1B/D agonist strongly innervate the recipient compared with untreated grafts, without large-scale disruption of the host nervous system. Blind animals possessing eye grafts with the augmented innervation demonstrate increased performance over untreated siblings in wavelength-based learning assays. Furthermore, treated animals also exhibit enhanced visual pattern recognition, suggesting that the increased innervation in response to 5-HT1B/D activation leads to enhanced functional integration of the ectopic organ with the host central nervous system and behavioral programs. These data establish a model system and reveal a new roadmap using small molecule neurotransmitter drugs to augment innervation, integration, and function of transplanted heterologous organs in regenerative medicine.

Ewes Direct Most Maternal Attention towards Lambs that Show the Greatest Pain-Related Behavioural Responses.

Although neonatal farm animals are frequently subjected to painful management procedures, the role of maternal behaviour in pain coping, has not been much studied. We investigated whether ewes were able to distinguish between lambs in pain and those that were not, and whether their behaviour altered depending on the severity of lamb pain. Eighty male lambs were allocated to one of 4 pain treatments within 24 hours of birth. Lambs were either handled only (C), bilaterally castrated with tight rubber rings (RR), as for RR but with the application of a Burdizzo clamp immediately proximal to the ring (Combined) or subjected to short scrotum castration (SSC) where the testicles were retained within the abdomen and only the scrotum removed. The behaviour of the ewe, treated lamb and untreated sibling where present (n = 54) were recorded for 30 minutes after treatment. Castration treatment increased the expression of abnormal standing and lying postures, specific pain-related behaviours (head-turning, stamping/kicking, easing quarters, tail wagging) and composite pain scores (P<0.001 for all). The greatest expression of pain-related behaviours was shown by lambs in the RR group, which were the only group to show rolling responses indicative of severe pain, followed by the SSC group. Ewes expressed more licking/sniffing responses to the RR and SSC lambs than towards the Combined and C lambs (P<0.05), and oriented most to RR lambs and least to C lambs (P<0.001). Ewes with two lambs also directed more attention towards the treated than the untreated lamb (P<0.001). The quantity of maternal care directed towards the lamb was positively correlated with the expression of active pain behaviours. The data demonstrate that ewes are able to discriminate between lambs in pain and those that are not, and that their response is increased with a greater severity of pain.

Design of a regulated lentiviral vector for hematopoietic stem cell gene therapy of globoid cell leukodystrophy

Globoid cell leukodystrophy (GLD) is a demyelinating lysosomal storage disease due to the deficiency of the galactocerebrosidase (GALC) enzyme. The favorable outcome of hematopoietic stem and progenitor cell (HSPC)-based approaches in GLD and other similar diseases suggests HSPC gene therapy as a promising therapeutic option for patients. The path to clinical development of this strategy was hampered by a selective toxicity of the overexpressed GALC in the HSPC compartment. Here, we presented the optimization of a lentiviral vector (LV) in which miR-126 regulation was coupled to codon optimization of the human GALC cDNA to obtain a selective and enhanced enzymatic activity only upon transduced HSPCs differentiation. The safety of human GALC overexpression driven by this LV was extensively demonstrated in vitro and in vivo on human HSPCs from healthy donors. No perturbation in the content of proapoptotic sphingolipids, gene expression profile, and capability of engraftment and mutlilineage differentiation in chimeric mice was observed. The therapeutic potential of this LV was then assessed in a severe GLD murine model that benefited from transplantation of corrected HSPCs with longer survival and ameliorated phenotype as compared to untreated siblings. This construct has thus been selected as a candidate for clinical translation.

Leptin monotherapy rescues spermatogenesis in male Akita type 1 diabetic mice.

Type 1 diabetes is associated with subfertility in humans. The current treatment for type 1 diabetes, insulin monotherapy, is suboptimal to fully stabilize glycemia, potentially leading to this subfertility. Recent work has demonstrated that treatment with the energy-regulating hormone leptin, alone or in combination with insulin, can more effectively control glycemia in mouse models of type 1 diabetes. Here, we sought to determine whether the fertility defects in a type 1 diabetic mouse model, the Akita mouse, can be rescued with leptin monotherapy in the absence of any exogenous insulin. Akita homozygous mice treated with leptin alone had a larger total body size, testes, and seminal vesicles than their untreated siblings. Leptin treatment prevented testicular degeneration and rescued sperm motility to wild-type levels. Furthermore, sperm obtained from leptin-treated mice could successfully fertilize ooctyes in vitro. Despite completely rescuing spermatogenesis, the critical reproductive hormones LH and testosterone were only modestly higher than in untreated mice, indicating that a minimum threshold of these hormones must be met to maintain spermatogenesis. Cumulatively, these findings implicate the importance of leptin in maintaining fertility and support the use of leptin therapy in the treatment of type 1 diabetes.

Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation For Metachromatic Leukodystrophy

Metachromatic Leukodystrophy (MLD) is a rare demyelinating disease caused by deficient lysosomal arylsulfatase-A (ARSA) activity and resulting pathologic sulfatide excess. Signs and symptoms vary with the age of disease onset. In early phenotypes (“late infantile” and “early juvenile”; onset < 6 years; E-MLD) rapid neurologic regression and death are observed. In late disease (“late juvenile” and “adult”; onset ≥ 6 years; L-MLD) a neuropsychiatric prodrome often precedes frank neurologic decline. For over 30 years, allogeneic hematopoietic stem cell transplantation (HSCT) has been used to halt or curb MLD progression. Yet published outcome data are scant and mixed. We report characteristics of and outcomes for 42 MLD patients following HSCT at the University of Minnesota, the largest such report to our knowledge.From 1984 to 2008, 17 E-MLD and 25 L-MLD patients were transplanted. The median age at HSCT in the E-MLD group was 5 years (range, 0 – 8 years); the median age at transplant in the L-MLD group was 20 years (range, 6 – 44 years). Twelve (29%) patients were male. Preparative regimens varied. Twenty-seven (64%) patients received myeloablative busulfan/cyclophosphamide conditioning; 11 (26%) received a cyclophosphamide/TBI regimen; 4 (10%) underwent reduced-intensity conditioning. Allograft sources also varied. 10 (24%) patients received an HLA-matched sibling marrow graft; 16 (38%) had an unrelated marrow donor (HLA-mismatched = 6); 16 (38%) received UCB grafts (HLA-mismatched = 14).Thirty-three (79%) patients were symptomatic at HSCT. The median time from symptom onset to diagnosis was 17 months in E-MLD and 50 months in L-MLD patients. Pre-HSCT brain MRI data was available for 37 patients; 36 (97%) demonstrated white-matter abnormalities. Of 40 patients with evaluable pre-HSCT nerve conduction velocity (NCV) studies, 37 (93%) had measurable peripheral neuropathy. Non-neuropsychological clinical involvement was scored per a neurologic function scale (NFS, 0 = no neurologic findings, 25 = maximal neurologic findings) spanning the domains of auditory processing, vision, motor, swallowing, incontinence, and seizures. Of 40 patients evaluable for pre-HSCT NFS, 25 (63%) had a non-zero score (range, 1 - 4) and 15 (37%) a zero score.Five-year survival was 58%. Greatest survival (70%) was seen in recipients of HLA-matched, sibling marrow. Among alternative graft recipients (n = 32), favorable survival followed UCB transplantation compared to unrelated marrow (62% versus 47%). Ten patients (24%) died of transplant-related causes by day 180 (3 from hepatic veno-occulsive disease; 2 each from graft-versus-host disease (GvHD) and sepsis; 1 each from graft failure, thrombotic thrombocytopenic purpura, and multiple organ failure syndrome). Four additional patients died within 1 year of transplant, all from infection. Four patients (all E-MLD) died from disease progression (range, 1.5 – 7.1 years post-HSCT). Fourteen patients (33%) developed grade II-IV acute GvHD; 6 (14%) developed chronic GvHD.The median survivor follow-up was 10 years; 74% demonstrated ≥ 80% donor engraftment at most recent observation. Of 30 evaluable patients, only 9 (31%) demonstrated progression of white-matter disease at median MRI follow-up of 1.26 years. For 22 patients with post-HSCT NCV studies, 17 (77%) evidenced worsening peripheral neuropathy at median follow-up 2.9 years. Twenty-four patients had evaluable post-transplant NFS scores. In E-MLD, the median increase in NFS score was 9 (range, 1 - 10) at median follow-up of 3.4 years. In L-MLD, the median increase was 3 (range, 0 - 22) at median follow-up of 3 years. Symptom status (present versus absent) at the time of HSCT neither impacted survival nor post-transplant NFS. Of 15 L-MLD patients surviving past one year, 7 had an evaluable verbal IQ (VIQ, average range 80 - 120) on both pre- and post-HSCT neuropsychological evaluations. In this subgroup, the mean pre- and post-HSCT VIQ were 83 and 75, respectively; mean follow up was 4.1 years post-HSCT.In summary, we report outcomes following HSCT for a large MLD cohort. Preliminary analysis suggests favorable clinical neurologic and neuropsychological performance following transplant for L-MLD. Ongoing analysis of the entire cohort, including comparisons against untreated siblings, aims to further define the neurological and neuropsychological benefit of HSCT for MLD. Disclosures:No relevant conflicts of interest to declare.

Lipoprotein-associated phospholipase A2 mass and activity in children with heterozygous familial hypercholesterolemia and unaffected siblings: Effect of pravastatin

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an independent risk factor of cardiovascular disease and a target of treatment. Lp-PLA(2) levels in children have not been previously reported. The effect of statin therapy on Lp-PLA(2) mass and activity in children with familial hypercholesterolemia (FH) is also not known. Lp-PLA(2) mass and activity levels were measured at baseline and after 2 years in 178 children with FH randomized to pravastatin or placebo and in 78 unaffected and untreated siblings. At the end of the randomized period, all FH children were then placed on pravastatin for an additional 2 years, and Lp-PLA(2) mass and activity levels were correlated with changes in carotid intima-media thickness during 4 years of follow-up. Baseline levels of Lp-PLA(2) mass and activity were significantly greater in children with FH compared with unaffected siblings (mass: 240.3 ± 41.6 vs 222.1 ± 36.5 ng/mL, P = .002; activity: 205.7 ± 41.6 vs 124.3±23.0 nmol/min/mL, P < .0001). In the randomized FH cohort, after 2 years treatment, Lp-PLA(2) mass (217.8 ± 35.0 vs 231.5 ± 34.8 ng/mL, P = .001) and activity (178.8 ± 37.3 vs 206.2 ± 33.5 nmol/min/mL, P < .0001) were significantly reduced by pravastatin compared with placebo. Change in Lp-PLA(2) activity was related to change in low-density lipoprotein cholesterol (pravastatin: r = 0.53, P < .0001, placebo: r = 0.23, P < .001) but change in Lp-PLA(2) mass was not related to change in low-density lipoprotein cholesterol. Baseline levels of Lp-PLA(2) mass and activity were not significantly associated with carotid intima-media thickness at baseline or at 4 years. Lp-PLA(2) mass and activity are significantly elevated in children with heterozygous FH compared with unaffected siblings and are significantly reduced by pravastatin therapy.

A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers

How cell numbers are determined is not understood. Hedgehog-Gli activity is involved in precursor cell proliferation and stem cell self-renewal, and its deregulation sustains the growth of many human tumours. However, it is not known whether GLI1, the final mediator of Hh signals, controls stem cell numbers, and how its activity is restricted to curtail tumourigenesis. Here we have altered the levels of GLI1 and p53, the major tumour suppressor, in multiple systems. We show that GLI1 expression in Nestin+ neural progenitors increases precursor and clonogenic stem cell numbers in vivo and in vitro. In contrast, p53 inhibits GLI1-driven neural stem cell self-renewal, tumour growth and proliferation. Mechanistically, p53 inhibits the activity, nuclear localisation and levels of GLI1 and in turn, GLI1 represses p53, establishing an inhibitory loop. We also find that p53 regulates the phosphorylation of a novel N' truncated putative activator isoform of GLI1 in human cells. The balance of GLI1 and p53 functions, thus, determines cell numbers, and prevalence of p53 restricts GLI1-driven stem cell expansion and tumourigenesis.

Giving children a better start: Preschool attendance and school-age profiles

We study the effect of pre-primary education on children's subsequent school outcomes by exploiting a unique feature of the Uruguayan household survey (ECH) that collects retrospective information on preschool attendance in the context of a rapid expansion in the supply of pre-primary places. Using a within household estimator, we find small gains from preschool attendance at early ages that get magnified as children grow up. By age 15, treated children have accumulated 0.8 extra years of education and are 27 percentage points more likely to be in school compared to their untreated siblings. Instrumental variables estimates that attempt to control for non random selection of siblings into preschool lead to similar results. Pre-primary education appears as a successful and cost-effective policy to prevent early grade failure and its long lasting consequences in low income countries.

Giving Children a Better Start: Preschool Attendance and School-Age Profiles

The authors study the effect of pre-primary education on children's subsequent school outcomes by exploiting a unique feature of the Uruguayan household survey (ECH) that collects retrospective information on preschool attendance in the context of a rapid expansion in the supply of pre-primary places. Using a within household estimator, they find small gains from preschool attendance at early ages that magnify as children grow up. By age 15, treated children have accumulated 0.8 extra years of education and are 27 percentage points more likely to be in school compared with their untreated siblings. Instrumental variables estimates that control for nonrandom selection of siblings into preschool lead to similar results. The authors speculate that early grade repetition harms subsequent school progression and that pre-primary education appears as a successful policy option to prevent early grade failure and its long lasting consequences.

Long-Term Effects of Fetal and Neonatal Alloimmune Thrombocytopenia and Its Antenatal Treatment on the Medical and Developmental Outcomes of Affected Children

Alloimmune thrombocytopenia (AIT) is characterized by severe thrombocytopenia, usually diagnosed after birth, which may result in intracranial hemorrhage (ICH) in as many as 20% of cases. The course of AIT typically worsens in subsequent pregnancies. Administration to mother of intravenous gammaglobulin (IVIG) and/or corticosteroids to increase the fetal platelet counts of a subsequent affected fetus is widely used to avoid ICH. The objective of this study was to evaluate the long-term effects of AIT and its antenatal treatment on the medical and developmental outcomes of affected children. Seventy-one pairs of untreated (older) and antenatally treated (younger) siblings with AIT were compared. A medical questionnaire and the Behavioral Assessment System for Children (BASC) were completed over the telephone by mothers. In this sample, birth platelet counts of treated fetuses were significantly higher than those of the untreated fetuses. Treated children were born at significantly lower gestational ages and with significantly lower birthweights than untreated children. No treated child suffered a perinatal ICH compared with 12 untreated siblings. Treated siblings also had fewer vision problems (three versus 14 in the untreated group). Children treated as fetuses received higher scores on the BASC Adaptive Skills Composite than their untreated siblings. The antenatal regimen of IVIG and/or corticosteroids did not affect the results. Children with AIT treated as fetuses had better long-term developmental-behavioral outcomes than their untreated siblings, perhaps because of higher in utero platelet counts. We speculate that platelets may possibly play a role in neurodevelopmental processes in the fetus.

OP06.12: Use of middle cerebral artery Doppler velocity to time the first invasive procedures in pregnancies affected by red cell alloimmunisation

Group B included 24 subsequent pregnancies, that were managed by weekly administration of IVIG without monitoring platelet counts. The treatment started in the 18th–24th gestational week and was continued until delivery. Group C included 6 pregnancies, in which the women refused treatment despite our counselling. Results: All treated fetuses were delivered by elective c/s, except for three cases, in which vaginal delivery was achieved, after confirming a fetal platelet count above 50,000. The mean platelet count at birth after IVIG treatment was 118,000 (range 11,000–320,000), compared to 25,000 (range 8000–70,000) among the 17 first affected siblings and 24,000 (range 10,000–44,000) among the 6 infants whose mothers refused treatment (p < 0.005). Only 8% (2/24) of the treated fetuses had platelet counts of less than 30,000 at birth compared to 70% (16/23) of the untreated siblings (p < 0.05). None of the treated and nontreated fetuses had an abnormal brain ultrasonographic findings or an intracranial hemorrhage. Conclusions: Non-invasive management of alloimmune thrombocytopenia consisting of only immunoglobulin administration is highly effective and seems safe in women without a history of intracranial hemorrhage. Therefore, the value of performing cordocentesis and platelet transfusions is doubtful in view of its risk for the fetus, and the fact that IVIG therapy so effectively improves the fetal platelet count

Variable presentation of precocious puberty associated with the D564G mutation of the LHCGR gene in children with testotoxicosis

We report on a family with familial male-limited precocious puberty (FMPP) due to a D564G mutation of the LHCGR gene. Family members show a varied phenotypic expression from severe precocity unresponsive to therapy with compromise of the predicted final height in some members, to attainment of tall final stature in other members who never received medical treatment. DNA amplification and sequencing of exon 11 of the LHCGR gene was done for the three affected male members and their mother. DNA analysis revealed a D564G mutation in the third cytoplasmic loop of the LHCGR receptor. All three males had precocious puberty with elevated testosterone levels. The index case developed central precocious puberty and evidence of compromised final height while on therapy. In contrast, the untreated older siblings attained a tall final height. This report underscores the possibility that the effects of the mutant luteinizing hormone/choriogonadotropin receptor on phenotypic expression of FMPP, such as adult final height, are modified by other factors.