Antenatal Onset Research Articles

Periventricular hemorrhagic infarction in preterm neonates: Etiology and time of development.

To find the obstetrical and delivery associated risk factors of antenatal and postnatal grade III intraventricular hemorrhage (IVH) or periventricular hemorrhagic infarction (PVHI) in preterm neonates. A retrospective study of obstetric and delivery associated risk factors included neonates (<35 gestational weeks) with severe IVH/PVHI (n = 120) and a prospectively collected control group (n = 50). The children were divided into: (1) antenatal onset group (n = 27) with insult visible on cerebral ultrasonography within the first 12 hours of birth or periventricular cystic changes visible in PVHI within the first 3 days; (2) neonatal onset group (n = 70) with insult diagnosed after initial normal findings or I-II grade IVH, and (3) unknown time-onset group (n = 23) with insult visible at > 12 h of age. The mothers of the antenatal onset group had significantly more bacterial infections before delivery compared to the neonatal onset group: 20/27 (74.1%) versus 23/69 (33.3%), (odds ratio (OR) 5.7 [95% confidence interval 2.1-16]; p = 0.0008) or compared to the control group (11/50 (22%); OR 11 [2.8-42]; p = 0.0005). Placental histology revealed chorioamnionitis more often in the antenatal compared to the neonatal onset group (14/21 (66.7%) versus 16/42 (38.1%), respectively; OR 3.7 [1.18-11]; p = 0.025). Neonates with neonatal development of severe IVH/PVHI had significantly more complications during delivery or intensive care. Bacterial infection during pregnancy is an important risk factor for development of antenatal onset severe IVH or PVHI. In neonates born to mothers with severe bacterial infection during pregnancy, cerebral ultrasonography is indicated for early detection of severe IVH or PVHI.

Fetal heart rate evolution and brain imaging findings in preterm infants with severe cerebral palsy

Cerebral palsy is more common among preterm infants than among full-term infants. Although there is still no clear evidence that fetal heart rate monitoring effectively reduces cerebral palsy incidence, it is helpful to estimate the timing of brain injury leading to cerebral palsy and the causal relationship with delivery based on the fetal heart rate evolution patterns. Understanding the relationship between the timing and the type of brain injury can help to identify preventive measures in obstetrical care. This study aimed to examine the relationship between the timing of insults and the type of brain injury in preterm infants with severe cerebral palsy. This longitudinal study was based on a nationwide database for cerebral palsy. The data of infants with severe cerebral palsy (equivalent to levels 3-5 of the Gross Motor Function Classification System-Expanded and Revised), born between 2009 and 2014 at 28 to 33 weeks of gestation, were included. The intrapartum fetal heart rate evolution patterns were evaluated by 3 obstetricians blinded to clinical information other than gestational age at birth, and these were categorized after agreement by at least 2 of the 3 reviewers into (1) continuous bradycardia, (2) persistently nonreassuring (prenatal onset), (3) reassuring-prolonged deceleration, (4) Hon's pattern (intrapartum onset), (5) persistently reassuring (pre- or postnatal onset), and (6) unclassified. Infant brain magnetic resonance imaging findings at term-equivalent age were assessed by a pediatric neurologist blinded to the background details, except for gestational age at birth and corrected age at image acquisition, and these were categorized as (1) basal ganglia-thalamus, (2) white matter, (3) watershed cortex or subcortex, (4) stroke, (5) normal, and (6) unclassified based on the predominant site involved. The risk factors for the basal ganglia-thalamus group were compared with those of the combined white matter and watershed injuries group. Among 1593 infants with severe cerebral palsy, 231 were born at 28 to 33 weeks of gestation, and 140 met the eligibility criteria. Fetal heart rate evolution patterns were categorized as bradycardia (17% [24]); persistently nonreassuring (40% [56]); reassuring-prolonged deceleration (7% [10]); reassuring-Hon (6% [8]); persistently reassuring (7% [10]); and unclassified (23% [32]). Cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in 13% of infants. Magnetic resonance imaging showed that 34% (n=48) of infants developed basal ganglia-thalamus-dominant brain injury. Of the remaining 92 infants, 43% (60) showed white matter injuries, 1% (1) showed watershed injuries, 4% (5) showed stroke, 1% (1) had normal findings, and 18% (25) had unclassified findings. Infants with continuous bradycardia (adjusted odds ratio, 1033.06; 95% confidence interval, 15.49-68,879.92) and persistently nonreassuring fetal heart rate patterns (61.20; 2.09-1793.12) had a significantly increased risk for basal ganglia-thalamus injury. Severe cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in only 13% of infants born at 28 to 33 weeks of gestation. Although the white matter-watershed injury was predominant in the study populations, severe acute hypoxia-ischemia may be an important prenatal etiology of severe cerebral palsy in preterm infants.

Special Report: Women’s Reproductive Mental Health—A Clinical Framework

Special Report: Women’s Reproductive Mental Health—A Clinical Framework

Magnetic Resonance Imaging in (Near-)Term Infants with Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a major cause of neurological sequelae in (near-)term newborns. Despite the use of therapeutic hypothermia, a significant number of newborns still experience impaired neurodevelopment. Neuroimaging is the standard of care in infants with HIE to determine the timing and nature of the injury, guide further treatment decisions, and predict neurodevelopmental outcomes. Cranial ultrasonography is a helpful noninvasive tool to assess the brain before initiation of hypothermia to look for abnormalities suggestive of HIE mimics or antenatal onset of injury. Magnetic resonance imaging (MRI) which includes diffusion-weighted imaging has, however, become the gold standard to assess brain injury in infants with HIE, and has an excellent prognostic utility. Magnetic resonance spectroscopy provides complementary metabolic information and has also been shown to be a reliable prognostic biomarker. Advanced imaging modalities, including diffusion tensor imaging and arterial spin labeling, are increasingly being used to gain further information about the etiology and prognosis of brain injury. Over the past decades, tremendous progress has been made in the field of neonatal neuroimaging. In this review, the main brain injury patterns of infants with HIE, the application of conventional and advanced MRI techniques in these newborns, and HIE mimics, will be described.

Modified Grading of Postnatal Urinary Tract Dilation

Source: Melo FF, Vasconcelos MA, Mak RH, et al. Postnatal urinary tract dilatation classification: improvement of the accuracy in predicting kidney injury [pubished online ahead of print August 28, 2021]. Pediatr Nephrol. doi: 101007/s00467-021-05254-xInvestigators from the Federal University of Minas Geraos (UFMG), Belo Horizonte, Brazil, and Rady Children’s Hospital, San Diego, CA, conducted a study to assess the accuracy of multiple classification systems for urinary tract dilatation (UTD) on postnatal ultrasound (US) in predicting future need for surgical intervention and/or kidney injury among neonates diagnosed with antenatal hydronephrosis (ANH). Study participants were infants with isolated ANH, defined as anteroposterior renal pelvis diameter ≥5 mm on a third trimester ultrasound, who were seen at the Pediatric Nephrology Unit at UFMG and followed prospectively from 1989 to 2019. The initial postnatal US was performed at approximately 14 days of age. A standard protocol was used to manage these patients. Study outcomes were surgical intervention and kidney injury. The need for surgery was determined using a protocol with markers indicative of severe obstruction, and kidney injury was defined as the presence of significant proteinuria, hypertension, or presence of chronic kidney disease (CKD). Using the results of the first postnatal US, severity of UTD was categorized using 5 grading systems: renal pelvic diameter (RPD), renal parenchyma thickness (RPT), a grading system developed by the Society of Fetal Urology (SFU), the UTD grading system, and a modified UTD system (UTDm). The accuracy of each system for predicting each outcome was assessed by generating receiver operating curves (ROC) and measuring the area under the curve (AUC). In addition, using the ROC analysis, the threshold (measurement with RPD and RPT and grade with the other tests) that maximized sensitivity and specificity was identified.Data were analyzed on 447 children, including 318 (71.1%) boys. Median follow-up was 9 years. Overall, 131 (29%) underwent surgical intervention at a median age of 8 months. The AUC for all grading systems in predicting surgical intervention were all >0.90, but the AUC for RPT statistically was significantly worse than that of the other tests. Using a threshold of >grade 2 with UTDm, the sensitivity for surgery was 85.5% and specificity was 89.9%. For RPD, a cutoff value of >15 mm had a sensitivity of 99.2% and specificity of 82.3%. A total of 26 children (5.8%) met criteria for kidney injury. The highest AUCs for predicting kidney injury were achieved with RPT (AUC = 0.921) and UTDm (AUC = 0.913); RPD and SFU had significantly worse AUCs. The sensitivity and specificity of UTDm, with a threshold at grade 2 or higher for predicting kidney injury, were 100% and 71.9%, respectively, and for RPT, with a cutoff at ≤8.9 mm, 96.1% and 80.0%, respectively.The authors conclude that several grading systems for UTD in newborns with ANH have good accuracy in predicting need for surgery and/or kidney injury.Dr Sanchez-Kazi has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Hydronephrosis as a congenital anomaly of the kidney and urinary tract can affect up to 14% of all pregnancies.1 Kidney and bladder US is used for grading the degree of UTD and for measurement of the RPT. Several grading systems are used today, including the SFU, UTD Consensus Recommendations, and Onen’s (2–4). The researchers in the current study combined the grading systems with some modifications to enhance the sensitivity and specificity of using hydronephrosis and RPT in predicting long-term kidney injury.The current study is 1 of the few with long-term follow-up of the hydronephrotic kidney and the participants’ blood pressure, urine protein, and kidney function. As with previous reports, kidney outcomes are easier to predict with mild and severe hydronephrosis (See AAP Grand Rounds. 2020;43[4]:42.)5 Moderate degree of hydronephrosis needs more follow-up and requires further imaging to assess if and when surgical intervention is required. Quantitative information such as RPT is useful in addition to grading of UTD. The difficulty in using the grading systems, however, is not the quantification, but standardization of where the measurements should be obtained since dilation can be affected by hydration and bladder fullness.Past studies have shown significant intra- and interobserver variability between clinicians.6,7 It is interesting to note that the number of surgical interventions was higher in the early years of the current study period. Does this reflect changes in indications for surgery, improvement in grading and measurement of the urinary dilation, or changing attitudes toward early surgical intervention?Modifications of the current postnatal US grading systems are useful in prognostication of kidney health in infants with antenatal onset of hydronephrosis.Recall that isolated ANH has a high rate of spontaneous resolution, thus abrogating the need for extensive imaging or urological intervention.5

WS-5. Proposal for a novel classification based on onset of HDP; antenatal onset, labor onset, and postpartum onset

Elevated progesterone on the day of human chorionic gonadotropin (hCG) administration is associated with decreased live birth rates in IVF cycles. The association with adverse pregnancy outcomes is unknown.Assess the association between serum progesterone on the day of hCG administration and the risk of ischemic placental disease [IPD; preeclampsia, placental abruption, and/or small for gestational age (SGA)].We conducted a retrospective cohort study of autologous fresh IVF cycles resulting in delivery between 2005 and 2018. All IVF procedures were conducted at a large, university-affiliated infertility center. Patients were divided into tertiles based on their serum progesterone level on the day of hCG administration; the lowest tertile served as the reference group. We identified pregnancies complicated by preeclampsia and placental abruption using ICD-9/10 codes and medical record review. We defined SGA as < 10th percentile using U.S. growth curves.The cohort included 166 deliveries in the lowest tertile of progesterone (0.2–0.73 ng/ml), 166 deliveries in the middle (0.64–1.05 ng/ml) and 167 deliveries in the highest tertile (1.05–5.6 ng/ml). Compared with the lowest tertile, the risk of IPD was greater in the middle (RR 1.6; 95% CI 1.1–2.5) tertile after adjustment for age, parity, number of oocytes retrieved, and estradiol. The highest tertile was also not associated with an increased risk of IPD.In an IVF population, elevated serum progesterone in the range of 0.64–1.05 ng/mL on the day of hCG administration was associated with a small increased risk of IPD.

LBSL: Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations.

ObjectiveLeukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes.MethodsWe reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function.ResultsWe found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5′-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function.ConclusionsDARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.

How could we suspect life-threatening perinatal group A streptococcal infection?

AimPerinatal group A streptococcal infection is a rare but life‐threatening condition. Few reports have focused on its clinical characteristics and how to prevent deterioration. We report our experience with two antenatal fatal cases and reviewed 96 cases in the literature to assess the clinical characteristics of group A streptococcal infection.MethodsEnglish‐language clinical reports of antenatal and postnatal group A streptococcal infection in 1974–2019 were retrieved and examined. Relationships between clinical characteristics and maternal outcomes were assessed.ResultsUnivariate analysis revealed that antenatal group A streptococcal infection was significantly associated with an age of ≤19 or ≥ 35 years, cesarean section, sore throat as an initial symptom, positive throat culture, maternal death and fetal death. Multivariate analysis revealed that antenatal onset (odds ratio = 7.922, 95% confidence interval = 1.297–48.374; P = 0.025) and a quick sepsis‐related organ‐failure assessment score (qSOFA; low blood pressure, high respiratory rate or altered mental status) of ≥2 (odds ratio = 6.166, 95% confidence interval = 1.066–35.670; P = 0.042) were significantly related to maternal death.ConclusionPer our findings, antenatal group A streptococcal infection was significantly associated with maternal and fetal death. Further, the antenatal infection was revealed as a more critical risk factor. We suggest that the presence of any sign related to the qSOFA is a potential clue suspecting perinatal group A streptococcal infection in primary obstetric facilities.

Foetal onset of EIF2B related disorder in two siblings: cerebellar hypoplasia with absent Bergmann glia and severe hypomyelination

Bi-allelic pathogenic variants in genes of the EIF2B family are responsible for Childhood Ataxia with Central nervous system Hypomyelination/Vanishing White Matter disease, a progressive neurodegenerative disorder of the central white matter. Only seven molecularly proven cases with antenatal onset have been reported so far. We report for the first time the neuropathological findings obtained from two foetuses harbouring deleterious variants in the EIF2B5 gene who presented in utero growth retardation and microcephaly with simplified gyral pattern that led to a medical termination of the pregnancy at 27 and 32 weeks of gestation. Neuropathological examination confirmed microcephaly with delayed gyration, periventricular pseudo-cysts and severe cerebellar hypoplasia. Histologically, the cerebellar cortex was immature, the dentate nuclei were fragmented and myelin stains revealed almost no myelination of the infratentorial structures. Bergmann glia was virtually absent associated to a drastic decreased number of mature astrocytes in the cerebellar white matter, multiple nestin-positive immature astrocytes as well as increased numbers of PDGRFα-positive oligodendrocyte precursors. Whole exome sequencing performed in the two foetuses and their parents allowed the identification of two EIF2B5 compound heterozygous variants in the two foetuses: c.468C > G p.Ile156Met and c.1165G > A p.Val389Met, the parents being heterozygous carriers. These variants are absent in the genome Aggregation Database (gnomAD r2.0.2). Contrary to the variant Ile156Met already described in a patient with CACH syndrome, the variant p.Val389Met is novel and predicted to be deleterious using several softwares. Neuropathological findings further expand the phenotypic spectrum of the disease that very likely occurs during early gestation and may manifest from the second half of pregnancy by a severe impairment of cerebral and cerebellar development.

Outcomes of patients admitted to the intensive care unit for complications of hypertensive disorders of pregnancy at a South African tertiary hospital - a 4-year retrospective review.

Hypertensive disorders of pregnancy (HDP) are a major cause of maternal mortality and adverse outcomes. A previous study in the intensive care unit (ICU) at King Edward VIII Hospital, Durban, South Africa, in 2000 found 10.5% mortality among eclampsia patients. To describe the mortality and adverse neurological outcomes associated with HDP in a tertiary ICU, compare these with results from 2000 and describe factors associated therewith. The data of 85 patients admitted with HDP to ICU at King Edward VIII Hospital from 2010 to 2013 were retrospectively reviewed. Mortality and adverse neurological outcome (Glasgow Coma Scale (GCS) ≤14 on discharge from ICU) were assessed. Two sets of analyses were conducted. The first compared those alive on discharge from ICU with those who died in ICU. The second compared good neurological outcome with poor outcome (adverse neurological outcome, or death). The mortality was 11.6%, and overall, 9% had adverse neurological outcomes. There was no significant difference in mortality between patients with eclampsia in 2010 - 2013 (11.0%) and those in 2000 (10.5%) (p=0.9). Factors associated with mortality were: intra- or postpartum onset of seizures; twins; failure to perform operative delivery when indicated; lowest GCS score <10; failure to use magnesium sulphate when indicated; respiratory failure; and lower respiratory tract infections. Factors associated with poor outcomes (adverse neurological outcome, or death) were: parity (better outcomes in primiparous patients); time of antenatal onset of hypertension (worse if earlier onset); HIV infection; failure to perform operative delivery when indicated; lowest GCS score <10; failure to use magnesium sulphate when indicated; use of anticonvulsants other than magnesium sulphate or benzodiazepines in eclampsia. The lack of improvement in ICU eclampsia mortality demonstrates a need to develop and implement a protocol for HDP management. The study provides a comparison of present mortality among eclamptic patients with hyperensive disorders of pregnancy (HDP) with the mortality of eclamptic patients described in an article from the year 2000. It further looks at adverse maternal outcomes, specifically adverse neurological outcomes.In addition, it analyses other factors that may affect outcomes in HDP patients. This information is useful in making recommendations in an attempt to improve the outcomes.

Neonatal tremor episodes and hyperekplexia‐like presentation at onset in a child with SCN8A developmental and epileptic encephalopathy

SCN8A encephalopathy is a newly defined epileptic encephalopathy caused by de novo mutations of the SCN8A gene. We report herein a four-year-old boy presenting with severe non-epileptic abnormal movements, of possibly antenatal onset, progressively associated with pharmacoresistant epilepsy and regression, associated with a de novo heterozygous missense mutation of SCN8A. This case shows that paroxysmal non-epileptic episodes of severe tremor and hyperekplexia-like startles and a striking vegetative component can be the first early symptoms of severe SCN8A developmental and epileptic encephalopathy. Clinicians should be aware of these symptoms in order to avoid misdiagnosis and ensure early appropriate therapeutic management. [Published with video sequences on www.epilepticdisorders.com].

Pontocerebellar hypoplasia type 1 for the neuropediatrician: Genotype-phenotype correlations and diagnostic guidelines based on new cases and overview of the literature.

Pontocerebellar hypoplasia type 1 (PCH1) is a major cause of non-5q spinal muscular atrophy (SMA). We screened 128 SMN1-negative SMA patients from Bulgaria for a frequent mutation -p.G31A in EXOSC3, and performed a literature review of all genetically verified PCH1 cases. Homozygous p.G31A/EXOSC3 mutation was identified in 14 Roma patients, representing three fourths of all our SMN1-negative Roma SMA cases. The phenotype of the p.G31A/EXOSC3 homozygotes was compared to the clinical presentation of all reported to date genetically verified PCH1 cases. Signs of antenatal onset of disease present at birth were common in all PCH1 sub-types except in the homozygous p.D132A/EXOSC3 patients. The PCH1sub-types with early death (between ages 1 day and 17 months), seen in patients with p.G31A/EXOSC3 or SLC25A46 mutations have a SMA type 1-like clinical presentation but with global developmental delay, visual and hearing impairment, with or without microcephaly, nystagmus and optic atrophy. Mutations with milder presentation (homozygous p.D132A/EXOSC3 or VRK1) may display additionally signs of upper motor neuron impairment, dystonia or ataxia and die at age between 5 and 18 years. Other EXOSC3 mutations and EXOSC8 cases are intermediate - SMA type 1-like presentation, spasticity (mostly in EXOSC8) and death between 3 months and 5 years. There is no correlation between neurological onset and duration of life. We add marble-like skin and congenital laryngeal stridor as features of PCH1. We show that imaging signs of cerebellar and pontine hypoplasia may be missing early in infancy. EMG signs of anterior horn neuronopathy may be missing in PCH1 patients with SLC25A46 mutations. Thus, there is considerable phenotypic variability in PCH1, with some cases being more SMA-like, than PCH-like. Detailed clinical evaluation and ethnicity background may guide genetic testing and subsequent genetic counseling.

Autopsy findings in EPG5-related Vici syndrome with antenatal onset.

Vici syndrome is one of the most extensive inherited human multisystem disorders and due to recessive mutations in EPG5 encoding a key autophagy regulator with a crucial role in autophagosome-lysosome fusion. The condition presents usually early in life, with features of severe global developmental delay, profound failure to thrive, (acquired) microcephaly, callosal agenesis, cataracts, cardiomyopathy, hypopigmentation, and combined immunodeficiency. Clinical course is variable but usually progressive and associated with high mortality. Here, we present a fetus, offspring of consanguineous parents, in whom callosal agenesis and other developmental brain abnormalities were detected on fetal ultrasound scan (US) and subsequent MRI scan in the second trimester. Postmortem examination performed after medically indicated termination of pregnancy confirmed CNS abnormalities and provided additional evidence for skin hypopigmentation, nascent cataracts, and hypertrophic cardiomyopathy. Genetic testing prompted by a suggestive combination of features revealed a homozygous EPG5 mutation (c.5870-1G>A) predicted to cause aberrant splicing of the EPG5 transcript. Our findings expand the phenotypical spectrum of EPG5-related Vici syndrome and suggest that this severe condition may already present in utero. While callosal agenesis is not an uncommon finding in fetal medicine, additional presence of hypopigmentation, cataracts and cardiomyopathy is rare and should prompt EPG5 testing.

Analysis of antenatal-onset cerebral palsy secondary to transient ischemia in utero using a national database in Japan.

We conducted a retrospective analysis of summary medical reports of children diagnosed with cerebral palsy (CP) to identify clinical features of antenatal onset of CP secondary to transient ischemia in utero. The 658 brief summary reports available in the Japan Obstetric Compensation System for Cerebral Palsy were screened, and we identified cases of singleton pregnancy, delivered at gestational age ≥ 33 weeks and those with cord blood gas pH≥7.20. Of the 137 cases identified, 84 were excluded for the following reasons: no evidence of ischemic brain lesion, clear post-natal causative factor of CP, presence of a congenital condition, and sentinel hypoxic event, such as uterine rupture. The demographic profiles of the 53 cases included in our analysis were compared to identify those with and without an abnormal variability in fetal heart rate. Between-group comparison identified an association between abnormal heart rate variability and a lower Apgar score at 1 min (2 vs 6; P < 0.001) and 5 min (5.5 vs 8; P = 0.002), and more frequent episodes of fetal movement loss (41% vs 10%; P = 0.027). An hypoxic event≤1 week before delivery was more likely to be associated with abnormal heart rate variability (89%) and low Apgar score (82%), while events at>1 week were associated with development of polyhydramnios (44%). In utero transient ischemic events can contribute to term or near-term CP. Careful follow-up is recommended for fetuses with a history of fetal movement loss, abnormal variability in heart rate, and polyhydramnios of unknown causes.

An unusual association of microcephalic osteodysplastic primordial dwarfism type I with cardiac and brain anomalies.

Less than 100 cases of primordial dwarfism have been reported worldwide out of which Microcephalic osteodysplastic primordial dwarfism type I comprise about <30 cases. We report a rare case of extreme growth failure in a neonate with primordial dwarfism of antenatal onset due to Microcephalic osteodysplastic primordial dwarfism type I. Our case is also unique in being associated with hitertho unreported association of subpulmonic ventricular septal defect and a dorsal interhemispheric cyst in the brain.

A rare chronic progressive leukoencephalopathy of childhood: Two newborn cases with vanishing white matter disease

Vanishing white matter disease, which is one of the most prevalent inherited childhood leukoencephalopathies, has an extremely wide phenotypic variation. The classical phenotype is characterized by early childhood onset of chronic neurological deterioration, dominated by cerebellar ataxia. However cases with antenatal onset, severe clinical course in the neonatal period and early demise have been also defined in the literature. Almost all diagnosed newborns present with rapid neurological deterioration and unexplained coma soon after birth. Other symptoms include feeding intolerance, hypotonia, seizures, apnea and severe respiratory distress. The exact pathogenesis is not known. Cerebral magnetic resonance imaging and spectroscopy are diagnostic. Differential diagnosis is difficult in the neonatal period and the disease may be misdiagnosed as hypoxic ischemic encephalopathy, congenital infections and inborn errors of metabolism. Here we present two premature infants with unexplained comatose state and severe neurological symptoms whose cerebral imaging studies were indicative of rarefaction and cystic degeneration of the cerebral white matter, and particularly emphasize on the differential diagnosis and the importance of cerebral imaging studies in the newborn period.

Mevalonate kinase deficiency, a metabolic autoinflammatory disease

Mevalonate kinase deficiency is a rare autosomal recessive inborn error of metabolism with an autoinflammatory phenotype. In this review we discuss its pathogenesis, clinical presentation and treatment. Mutations in both copies of the MVK-gene lead to a block in the mevalonate pathway. Interleukin-1beta mediates the inflammatory phenotype. Shortage of a non-sterol isoprenoid product of the mevalonate pathway, Geranylgeranylpyrophosphate leads to aberrant activation of the small GTPase Rac1, and inflammasome activation. The clinical phenotype ranges widely, depending on the severity of the enzyme defect. All patients show recurrent fevers, lymphadenopathy and high acute phase proteins. Severely affected patients have antenatal disease onset, dysmorphic features, growth retardation, cognitive impairment and progressive ataxia. Diagnosis relies on mutation analysis of the MVK-gene. There is no evidence based therapy. IL-1 blockade is usually effective. Severe cases require allogeneic stem cell transplantation. Targeted therapies are needed.

C.P.6 Study of a novel autosomal recessive minicore disease

Minicore disease is a congenital myopathy of early onset, defined pathologically by the presence of multiple areas of reduced mitochondrial oxidative activity in muscle biopsies. There are currently three types of minicore disease defined; minicore myopathy with external ophthalmoplegia, caused by mutations in the RYR1 gene; minicore disease, severe classic form, caused by mutations in the SEPN1 gene and minicore myopathy, antenatal onset with arthrogryposis, with no associated disease gene. A family with three affected sibs was studied. The parents are unaffected and not known to be related, and the phenotype is consistent. The affected sibs presented at birth with extreme generalised hypotonia. There was marked delay in motor milestones, with walking only achieved after 2years of age. Neck, trunk and facial weakness was moderate, and there was moderate reduction in respiratory muscle strength. The heart was unaffected and intelligence preserved. Muscle biopsy of the quadriceps showed minicores on oxidative stains. This phenotype was not consistent with the described phenotypes of minicore disease, suggesting that this is a novel minicore disease phenotype. We combined linkage analysis with exome capture and next generation sequencing to attempt to identify the causative mutation in this family. SNP linkage analysis under a recessive model eliminated all known congenital myopathy, minicore disease and muscular dystrophy genes except for TTN, POMT1, SGCA, DMN2, and COL6A1. Subsequently, whole exome sequencing data eliminated all genes in the list except for TTN, in which two heterozygous variants were identified. Further investigation of these variants in the family found that both variants were inherited from the unaffected father, suggesting that these variants are not the cause of the disease in this family. Thus, it is suspected that a novel disease gene is the cause of this family’s disease.

Atypical timing and presentation of periventricular haemorrhagic infarction in preterm infants: the role of thrombophilia

Periventricular haemorrhagic infarction (PVHI) is a complication of preterm birth associated with cardiorespiratory instability. To date, the role of thrombophilia as a possible additional risk factor in infants with atypical timing and presentation of PVHI has not been investigated. This was a retrospective cohort study of preterm infants who developed PVHI with an atypical timing and presentation either of antenatal onset or late in the postnatal course in the absence of a preceding sudden deterioration of their clinical condition. In infants with atypical PVHI mutation analysis of the factor V Leiden (G1691A), prothrombin (G20210A) gene, and C677T and A1298C polymorphisms in the MTHFR gene was performed, and plasma lipoprotein(a) and homocysteine levels were measured. Sixty-two preterm infants who presented with a PVHI were studied. Seventeen had an atypical presentation (seven males, 10 females; median birthweight 1170g [range 580-1990g]; median gestational age 30.6wks [range 28.7-33.7wks]). The typical PVHI group comprised 28 males and 17 females (median birthweight 1200g [range 670-2210g]; median gestational age 29.6wks [range 25.3-33.6wks]). Among the 17 infants with atypical presentation, the factor V Leiden mutation was found in seven infants (41%) as well as in the mothers of six of these seven infants; in one infant this was concomitant with a prothrombin gene mutation. A polymorphism in the MTHFR gene was also present in these infants. In two infants with an atypical presentation who were tested for this, a mutation in the COL4A1 gene was found (reported previously). All but two of the infants with an atypical presentation developed spastic unilateral cerebral palsy. An atypical presentation of PVHI in preterm infants tends to occur more often in the presence of thrombophilia. Testing of thrombophilia, especially factor V Leiden and prothrombin gene mutation, is recommended in these infants.

Atypical Presentation of Periventricular Haemorrhagic Infarction in the Presence of Thrombophilia

Introduction: Periventricular haemorrhagic infarction (PVHI) is a complication of preterm birth associated with cardiorespiratory instability. The role of thrombophilia as a possible additional risk factor in infants with an atypical presentation when PVHI was of presumed antenatal onset or > 96 h after birth in the absence of a preceding sudden deterioration, has not been investigated extensively.Objective: To report thrombophilic mutations in preterm infants with an atypical presentation of PVHI.Methods: From January 2005 - December 2010 data of infants (gestational age 28.7 to 36.7 weeks, median 30.6 weeks; birth weight 580 to 3090 gram, median 1300 gram) who developed an atypical PVHI were collected. Mutation analysis of the factor V Leiden (G1691A), prothrombin (G20210A) gene and C677T and A1298C polymorphisms in the MTHFR gene was performed, as well as the plasma lipoprotein(a) and homocysteine levels.Results: Twenty-one preterm infants presented with an atypical PVHI. Among these infants a heterozygous factor V Leiden mutation was found in seven (33%) infants and their mothers (population incidence is 3-5%), in one concomitant with a heterozygous prothrombin gene mutation and one had an isolated heterozygous prothrombin gene mutation. C677T or A1298C polymorphism in the MTHFR gene was present in all these 8 infants. In two siblings, a mutation in COL4A1 gene was found.Conclusions: An atypical presentation of PVHI in preterm infants is often associated with gene mutations, especially the factor V Leiden mutation.