Small for gestational age: the familial perspective.

BACKGROUND: There are multiple etiologies for being born small for gestational age (SGA). However, extended familial data in idiopathic cases have been scarcely reported. OBJECTIVE: Our aim was to explore the familial history of SGA newborns and describe the proportion and distribution of SGA in their parents and parental siblings. METHODS: This was a retrospective study performed at an obstetrics clinic holding a detailed reliable electronic database. Between 2008 and 2017, data of 14,003 patients and 20,617 pregnancies were recorded. Parents of SGA infants were identified and extended familial history was obtained by questionnaires, including birth weights (BWs) and gestational age at birth of the parents and parents' siblings. SGA was defined as a BW below the 10th percentile. Proportions of maternal, paternal, and parental siblings' SGA were calculated. Chi-square test was performed to assess the relationship between SGA family member's gender and SGA infants' gender, and between the relative's gender and their family relationship to the infant. RESULTS: About 2100 women had a history of a previous infant born SGA, however, after exclusion the final cohort comprised 926 women with a previous SGA infant. In 473 cases there was at least one other family member of the infant born SGA: father, mother, aunt, or uncle of the infant, representing a prevalence of 51% (473/926) of familial SGA. Out of familial SGA cases, maternal SGA was found in 55% (260/473), and paternal SGA was found in 28.1% (133/473). 27.6% had more than one SGA relative. Eighteen infants had both an SGA father and an SGA mother (3.8%). A history of an SGA aunt or uncle was found in 44% (209/473) of familial SGA cases, which was 22.5% (209/926) of the entire cohort. Parental sibling SGA occurred almost twice in mother's siblings as compared to father's siblings. Chi-square test revealed no association between the SGA relative's gender and their family relationship to the infant. There was no association between the SGA infant's gender and the SGA relative's gender. CONCLUSIONS: A family history of SGA is common in SGA infants, and occurs most often in mothers. This study found 22% SGA in parental siblings, in maternal siblings more than paternal siblings, supporting the possibility of a genetic component in SGA trait transmission. In clinical practice, when counseling parents with a growth-restricted fetus from an unknown etiology, extended familial birthweight history should be obtained and taken into account, which may be helpful in reducing parental anxiety.

A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant.

PURPOSE: This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections. METHODS: Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses. Immunological workup included in vitro T cell studies, flow cytometry, and CyTOF analysis. RESULTS: WES revealed a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene: c.1590C>A; p.Asn530Lys which co-segregated with the disease in the nuclear family. WB and IHC analyses demonstrated reduced protein levels in patient's cells compared with controls. Moreover, comprehensive immunological workup revealed severely diminished blood-borne regulatory T cell (Treg) frequency and impaired in vitro CD4+ T cell proliferation and Treg generation. CyTOF analysis showed significant shifts in the patient's innate and adaptive immune cells compared with healthy controls and ulcerative colitis patients. CONCLUSIONS: Pathogenic variants in CARMIL2 have been implicated in an immunodeficiency syndrome characterized by recurrent infections, occasionally with concurrent chronic diarrhea. We show that CARMIL2-immunodeficiency is associated with significant alterations in the landscape of immune populations in a patient with prominent gastrointestinal disease. This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.

Rare Disease Diagnostics: A Single-center Experience and Lessons Learnt.

OBJECTIVE: The growing availability of next-generation sequencing technologies has revolutionized medical genetics, facilitating discovery of causative genes in numerous Mendelian disorders. Nevertheless, there are still many undiagnosed cases. We report the experience of the Genetics Institute at Rambam Health Care Campus in rare disease diagnostics using whole-exome sequencing (WES). METHODS: Phenotypic characterization of patients was done in close collaboration with referring physicians. We utilized WES analysis for diagnosing families suspected for rare genetic disorders. Bioinformatic analysis was performed in-house using the Genoox analysis platform. RESULTS: Between the years 2014 and 2017, we studied 34 families. Neurological manifestations were the most common reason for referral (38%), and 55% of families were consanguineous. A definite diagnosis was reached in 21 cases (62%). Four cases (19%) were diagnosed with variants in novel genes. In addition, six families (18%) had strong candidate novel gene discoveries still under investigation. Therefore, the true diagnosis rate is probably even higher. Some of the diagnoses had a significant impact such as alerting the patient management and providing a tailored treatment. CONCLUSIONS: An accurate molecular diagnosis can set the stage for improved patient care and provides an opportunity to study disease mechanisms, which may lead to development of tailored treatments. Data from our genetic research program demonstrate high diagnostic and novel disease-associated or causative gene discovery rates. This is likely related to the unique genetic architecture of the population in Northern Israel as well as to our strategy for case selection and the close collaboration between analysts, geneticists, and clinicians, all working in the same hospital.

The effect of a policy change on late termination of pregnancy in Israel.

OBJECTIVE: To compare approval rates of late termination of pregnancy (LTOP) requests before and after a policy change in Israel in late 2007. METHODS: In a retrospective study, LTOP requests and board decisions from 2002-2007 (group 1) were compared with those from 2007-2012 (group 2) at 3 university-affiliated medical centers in Israel. Reasons for application, approval, or rejection were compared between the groups. RESULTS: There were 552 applications for LTOP. The overall approval rate for LTOP and the specific approval rate per medical indication did not differ significantly between the groups. The rate of requests due to confirmed genetic anomalies decreased from 18.4% in group 1 to 11.3% in group 2 (P=0.03). Compared with group 1, the rate of rejection for intrauterine infection increased from 8.3% to 26.3% (P=0.2), and that for pregnancy complications decreased from 62.5% to 35.0% (P=0.2) in group 2 but these differences were not statistically significant. Requests due to structural anomalies were declined because they were considered to be minor cardiac, renal, cerebral, or skeletal anomalies. CONCLUSION: The more stringent 2007 criteria for approving requests for LTOP did not affect the rate of rejection of requests due to structural anomalies between the 2 time periods.

Late postnatal systemic steroids predispose to retinopathy of prematurity in very-low-birth-weight infants: a comparative study.

BACKGROUND AND OBJECTIVE: Retinopathy of prematurity (ROP) develops mostly in very-low-birth-weight (VLBW) premature infants. Besides prematurity and hyperoxia, other variables have been brought up as risk factors for ROP. We aimed to search risk factors for ROP by comparing two groups of preemies, one with and the other without ROP. PATIENTS AND METHODS: During 2004-2006, 27 VLBW premature infants developed ROP (ROP group). For each neonate in the ROP group, we chose a neonate born at similar gestational age (GA) (+/-1 week) but without ROP (control group). For each neonate of both groups, we recorded demographic, maternal, gestational, intrapartum, neonatal, interventional, growth and ophthalmologic data from patients' medical records. RESULTS: Eleven of the tested variables were significantly different between the ROP and control groups in univariate analysis. However, only seven of these variables remained significantly different between groups when controlling each variable for GA: bronchopulmonary dysplasia (BPD, p=0.04), duration of hospitalization (p=0.017), high-frequency oscillatory ventilation (HFOV, p=0.033), duration of oxygen therapy (p=0.023), surfactant therapy (p=0.045), inhaled steroids (p=0.015) and systemic steroids for BPD (p=0.007). These seven significant variables were related to respiratory morbidity and interventions. Multiple stepwise logistic regression including all significant variables in the univariate analysis showed that only systemic steroids remained significantly different between groups (p=0.007, OR 5.42, 95% CI 1.60-18.34). CONCLUSION: Significantly more neonates in the ROP group received late postnatal systemic steroids as compared to controls. We speculate that steroids, by altering insulin growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) expression, might contribute to the pathogenesis of ROP.