Multiple Epiphyseal Dysplasia, Recessive.

Disease characteristics. Recessive multiple epiphyseal dysplasia (EDM4/rMED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have some abnormal finding at birth, e.g., clubfoot, clinodactyly, or (rarely) cystic ear swelling. Onset of articular pain is variable but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished and ranges from 150 to 180 cm. Functional disability is mild. Diagnosis/testing. Diagnosis of EDM4/rMED is based on clinical and radiographic findings. SLC26A2 is the only gene known to be associated with EDM4/rMED. Molecular genetic testing is available on a clinical basis. Management. Treatment of manifestations: physiotherapy for muscular strengthening; cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs (NSAIDs); orthopedic surgery as indicated. Surveillance: radiographs as indicated. Agents/circumstances to avoid: sports involving joint overload. Genetic counseling. EDM4/rMED is inherited in an autosomal recessive manner. At conception, each sib of a proband with EDM4/rMED has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk is possible if both disease-causing alleles in the family are known and the carrier status of the parents has been confirmed. Requests for prenatal testing for mild conditions such as EDM4/rMED are not common.

Calpain 3, the "gatekeeper" of proper sarcomere assembly, turnover and maintenance.

Calpain 3 is a member of the calpain family of calcium-dependent intracellular proteases. Thirteen years ago it was discovered that mutations in calpain 3 (CAPN3) result in an autosomal recessive and progressive form of limb girdle muscular dystrophy called limb girdle muscular dystrophy type 2A. While calpain 3 mRNA is expressed at high levels in muscle and appears to have some role in developmental processes, muscles of patients and mice lacking calpain 3 still form apparently normal muscle during prenatal development; thus, a functional calpain 3 protease is not mandatory for muscle to form in vivo but it is a pre-requisite for muscle to remain healthy. Despite intensive research in this field, the physiological substrates of the calpain 3 protein (hereafter referred to as CAPN3) and its alternatively spliced isoforms remain elusive. The existence of these multiple isoforms complicates the search for the physiological functions of CAPN3 and its pathophysiological role. In this review, we summarize the genetic and biochemical evidence that point to loss of function of the full-length isoform of CAPN3, also known as p94, as the pathogenic isoform. We also argue that its natural substrates must reside in its proximity within the sarcomere where it is stored in an inactive state anchored to titin. We further propose that CAPN3 has many attributes that make it ideally suited as a sensor of sarcomeric integrity and function, involved in its repair and maintenance. Loss of these CAPN3-mediated activities can explain the "progressive" development of muscular dystrophy.

Efficient total variation algorithm for fetal brain MRI reconstruction.

Fetal MRI reconstruction aims at finding a high-resolution image given a small set of low-resolution images. It is usually modeled as an inverse problem where the regularization term plays a central role in the reconstruction quality. Literature has considered several regularization terms s.a. Dirichlet/Laplacian energy, Total Variation (TV)- based energies and more recently non-local means. Although TV energies are quite attractive because of their ability in edge preservation, standard explicit steepest gradient techniques have been applied to optimize fetal-based TV energies. The main contribution of this work lies in the introduction of a well-posed TV algorithm from the point of view of convex optimization. Specifically, our proposed TV optimization algorithm or fetal reconstruction is optimal w.r.t. the asymptotic and iterative convergence speeds O(1/n2) and O(1/√ε), while existing techniques are in O(1/n2) and O(1/√ε). We apply our algorithm to (1) clinical newborn data, considered as ground truth, and (2) clinical fetal acquisitions. Our algorithm compares favorably with the literature in terms of speed and accuracy.

Comparison of foetal US and MRI in the characterisation of congenital lung anomalies.

OBJECTIVES: To compare the accuracy of prenatal ultrasonography (US) to magnetic resonance imaging (MRI) in the characterisation of congenital lung anomalies, and to assess their agreement with final diagnosis. To evaluate the influence of additional MRI information on therapeutic management. METHODS: 26 prenatal congenital lung anomalies detected consecutively between 2006 and 2012 were retrospectively evaluated. Lesions were initially observed at prenatal US and further investigated with MRI. Prenatal US and MRI imaging findings, and suggested diagnosis were compared with the final diagnosis, obtained from autopsies (4), pathological evaluation following surgical resection (15) and postnatal imaging studies (7). RESULTS: Postnatal diagnoses included 7 congenital pulmonary airway malformations, 8 complex lesions, 7 overinflations, 1 sequestration, 1 bronchogenic cyst, 1 blastoma and 1 bilateral lymphangioma. Suggested prenatal US and MRI diagnosis was correct in 34.6% and 46.2% of patients, respectively, mainly isolated lung lesions with typical imaging findings. Nonspecific imaging findings at US and MRI studies were observed in 38.4% of cases. In 42% of the operated anomalies, pathological dissection revealed the presence of complex anomalies. MRI changed the US diagnosis, but not the further management in 9.7% of the lesions. CONCLUSIONS: Prenatal US and MRI showed a high accuracy in the diagnosis of isolated congenital lung lesions with typical imaging findings. However, overall characterisation rates were low, because of both a high percentage of complex lesions and of lesions with nonspecific imaging findings. MRI was better than US in characterising complex lesions, but its additional information did not influence therapy decisions.

The role of epilepsy in early language development in a child with a congenital lesion in the right hemisphere

Early epilepsy is known to worsen the developmental prognosis of young children with a congenital focal brain lesion, but its direct role is often very difficult to delineate from the other variables. This requires prolonged periods of follow-up with simultaneous serial electrophysiological and developmental assessments which are rarely obtained. We studied a male infant with a right prenatal infarct in the territory of the right middle cerebral artery resulting in a left spastic hemiparesis, and an epileptic disorder (infantile spasms with transient right hemihypsarrhythmia and focal seizures) from the age of 7 months until the age of 4 years. Pregnancy and delivery were normal. A dissociated delay of early language acquisition affecting mainly comprehension without any autistic features was documented. This delay was much more severe than usually expected in children with early focal lesions, and its evolution, with catch-up to normal, was correlated with the active phase of the epilepsy. We postulate that the epilepsy specifically amplified a pattern of delayed language emergence, mainly affecting lexical comprehension, reported in children with early right hemisphere damage.

Maternal age-specific risk of non-chromosomal anomalies.

OBJECTIVES: To determine the excess risk of non-chromosomal congenital anomaly (NCA) among teenage mothers and older mothers. DESIGN AND SETTING: Population-based prevalence study using data from EUROCAT congenital anomaly registers in 23 regions of Europe in 15 countries, covering a total of 1.75 million births from 2000 to 2004. PARTICIPANTS: A total of 38,958 cases of NCA that were live births, fetal deaths with gestational age > or = 20 weeks or terminations of pregnancy following prenatal diagnosis of a congenital anomaly. MAIN OUTCOME MEASURES: Prevalence of NCA according to maternal age, and relative risk (RR) of NCA and 84 standard NCA subgroups compared with mothers aged 25-29. RESULTS: The crude prevalence of all NCA was 26.5 per 1000 births in teenage mothers (<20 years), 23.8 for mothers 20-24 years, 22.5 for mothers 25-29 years, 21.5 for mothers 30-34 years, 21.4 for mothers 35-39 years and 22.6 for mothers 40-44 years. The RR adjusted for country for teenage mothers was 1.11 (95% CI 1.06-1.17); 0.99 (95% CI 0.96-1.02) for mothers 35-39; and 1.01 (95% CI 0.95-1.07) for mothers 40-44. The pattern of maternal age-related risk varied significantly between countries: France, Ireland and Portugal had higher RR for teenage mothers, Germany and Poland had higher RR for older mothers. The maternal age-specific RR varied for different NCAs. Teenage mothers were at a significantly greater risk (P < 0.01) of gastroschisis, maternal infection syndromes, tricuspid atresia, anencephalus, nervous system and digestive system anomalies while older mothers were at a significantly greater risk (P < 0.01) of fetal alcohol syndrome, encephalocele, oesophageal atresia and thanatophoric dwarfism. CONCLUSIONS: Clinical and public health interventions are needed to reduce environmental risk factors for NCA, giving special attention to young mothers among whom some risk factors are more prevalent. Reassurance can be given to older mothers that their age in itself does not confer extra risk for NCA.

Proyecto de Estudio descriptivo basado en una encuesta de salud a una población de gestantes de la ciudad de Barcelona

El asesoramiento y control de salud de una gestación permite proporcionar un programa de cribado para clasificar el embarazo en función del riesgo. Esta clasificación se realiza mediante la identificación de “factores de riesgo” que se pueden obtener durante todo el embarazo, ya que una complicación puede aparecer incluso al final del embarazo, y convertirlo en embarazo de alto riesgo. La identificación del riesgo permite incorporar diferentes estrategias de prevención y/o tratamiento a lo largo del embarazo, incluso en el postparto inmediato y periodo neonatal precoz (primeros 28 días de vida), para evitar complicaciones maternas/fetales o minimizarlas. Es por ello, que el mejor momento para evaluar la salud de la embarazada es cuando el embarazo haya concluido, ya que si dicha evaluación ocurre antes de finalizar el embarazo, la información estará incompleta y sesgada (el bebé no ha nacido aún y no se conocen los resultados del parto, momento en el que también pueden aparacer complicaciones y cambiar el curso nomal del embarazo). El objetivo principal del estudio será identificar las complicaciones más frecuentes del embarazo, parto y postparto de una población de embarazadas de Barcelona; los objetivos secundarios incluirán la identificación de los factores de riesgo asociados a dichas complicaciones (factores demográficos pregestacionales o factores gestacionales/puerperales) y plantear medidas de prevención de estas complicaciones mediante la modificación de estos factores de riesgo, siempre que esto sea posible. El método de trabajo será el análisis del contenido del cuestionario “Maternity Experiences Survey, 2006 Questionnaire” en una muestra de gestantes de la ciudad de Barcelona. Las conclusiones esperadas contemplan conocer la incidencia de complicaciones en esta población, así como la influencia del control prenatal en dichas complicaciones; aportando un análisis exhaustivo sobre los posibles factores de riesgo y las posibles estrategias de mejora de estos resultados.

Arthrogryposis multiplexa congenita: an epidemiologic study of nearly 9 million births in 24 EUROCAT registers.

OBJECTIVE: To examine the occurrence of arthrogryposis multiplex congenita (AMC) in Europe and to identify possible risk factors. STUDY DESIGN: Retrospective population-based epidemiological study using EUROCAT congenital anomaly registries. The study population included all cases of AMC (based on WHO ICD-9 or ICD-10 codes) that were livebirths (LB), fetal deaths (FD) from 20 weeks gestation and underwent termination of pregnancy for fetal anomaly (TOPFA), 1980-2006. RESULTS: Among 8.9 million births covered by 24 EUROCAT congenital anomaly registries, 757 AMC cases were reported. This gives a prevalence of 8.5 per 100,000. Five hundred and four (67%) AMC cases were LB, 199 (26%) cases were TOPFA, and FD occurred in 54 (7%) cases. First week survival status was known for 381 of the 504 LB (76%), of whom 87 (23%) died within the first week of life. Perinatal mortality associated with AMC was 32%. Two hundred and eighty-two (37%) cases had isolated AMC, 90 (12%) had additional syndrome or chromosomal anomalies and 385 (51%) had other major malformations. The same or similar anomaly was reported in 13% of siblings and in 12% of the mother's own family background. Information on prenatal testing was available for 521 cases of which 360 tested positive for a congenital anomaly, representing a sensitivity of 69%. Information on maternal illness before and during pregnancy and medication use in the first trimester was available for approximately a third of the mothers, of whom the vast majority reported no maternal illness or medication use. CONCLUSION: AMC is a rare occurrence, with a reported prevalence of 1:12,000. In this study, while information on potential risk factors such as maternal disease or maternal use of drugs was limited, they did not appear to be associated with the occurrence of AMC. AMC was lethal in a third of cases, either in utero or during the first week of life, although this may not be solely attributed to AMC as most cases had additional malformations.

Phenotip - a web-based instrument to help diagnosing fetal syndromes antenatally.

Prenatal ultrasound can often reliably distinguish fetal anatomic anomalies, particularly in the hands of an experienced ultrasonographer. Given the large number of existing syndromes and the significant overlap in prenatal findings, antenatal differentiation for syndrome diagnosis is difficult. We constructed a hierarchic tree of 1140 sonographic markers and submarkers, organized per organ system. Subsequently, a database of prenatally diagnosable syndromes was built. An internet-based search engine was then designed to search the syndrome database based on a single or multiple sonographic markers. Future developments will include a database with magnetic resonance imaging findings as well as further refinements in the search engine to allow prioritization based on incidence of syndromes and markers.

Infant Mortality in Iowa Interim Study Committee, January 1992

The Infant Mortality in Iowa Interim Study Committee was established by the Legislative Council to review historical trends in Iowa's infant mortality rates to identify the extent of the problem on a statewide basis. Identify areas in the state with the greatest incidence of infant mortality, and research health complications. Identify factors which lead to impoverished families, and research access to health care services. Survey and review the current structure of service provided to pregnant women in Iowa health care facilities, and solicit information on the level of existing prenatal services. Recommend changes in Iowa's health care system which would lower Iowa's infant mortality rate.

Association of moderate alcohol use and binge drinking during pregnancy with neonatal health.

Background:  Heavy drinking and smoking during pregnancy are known to have a negative impact on the unborn child. However, the impact of low-to-moderate alcohol consumption and binge drinking has been debated recently. The aim of this study was to examine the relationship of moderate prenatal drinking and binge drinking with birthweight, being small for gestational age (SGA) at birth, preterm birth, and neonatal asphyxia. Methods:  Moderate alcohol drinking, binge drinking, and several possible confounders were assessed in 1,258 pregnant women; information on neonatal health was obtained at birth. Results:  Results indicate that 30.8% of the women drank at low levels (<2 glasses/wk), 7.9% drank moderately (2 to 4 glasses/wk), and 0.9% showed higher levels of drinking (≥5 glasses/wk); 4.7% reported binge drinking (defined as ≥3 glasses/occasion). 6.4% of the children were SGA (<10th percentile of birthweight adjusted for gestational age), 4.6% were preterm (<37th week of gestation), and 13.0% showed asphyxia (arterial cord pH <7.10 and/or arterial cord lactate >6.35 mmol and/or Apgar score <7 at 5 minutes). When controlling for maternal age, citizenship, occupational status, parity, smoking, use of prescription/over-the-counter drugs, illicit drug use, and child gender moderate drinking was related to lower birthweight (p < 0.01), and moderate drinking and binge drinking were associated with neonatal asphyxia at trend level (p = 0.06 and p = 0.09). Moderate drinking and binge drinking were not related to length of gestation. Conclusions:  In contrast to recent reviews in the field, our results assume that moderate drinking and binge drinking are risk factors for neonatal health.

Moderate postnatal hyperoxia accelerates lung growth and attenuates pulmonary hypertension in infant rats after exposure to intra-amniotic endotoxin.

To determine the separate and interactive effects of fetal inflammation and neonatal hyperoxia on the developing lung, we hypothesized that: 1) antenatal endotoxin (ETX) causes sustained abnormalities of infant lung structure; and 2) postnatal hyperoxia augments the adverse effects of antenatal ETX on infant lung growth. Escherichia coli ETX or saline (SA) was injected into amniotic sacs in pregnant Sprague-Dawley rats at 20 days of gestation. Pups were delivered 2 days later and raised in room air (RA) or moderate hyperoxia (O₂, 80% O₂ at Denver's altitude, ∼65% O₂ at sea level) from birth through 14 days of age. Heart and lung tissues were harvested for measurements. Intra-amniotic ETX caused right ventricular hypertrophy (RVH) and decreased lung vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) protein contents at birth. In ETX-exposed rats (ETX-RA), alveolarization and vessel density were decreased, pulmonary vascular wall thickness percentage was increased, and RVH was persistent throughout the study period compared with controls (SA-RA). After antenatal ETX, moderate hyperoxia increased lung VEGF and VEGFR-2 protein contents in ETX-O₂ rats and improved their alveolar and vascular structure and RVH compared with ETX-RA rats. In contrast, severe hyperoxia (≥95% O₂ at Denver's altitude) further reduced lung vessel density after intra-amniotic ETX exposure. We conclude that intra-amniotic ETX induces fetal pulmonary hypertension and causes persistent abnormalities of lung structure with sustained pulmonary hypertension in infant rats. Moreover, moderate postnatal hyperoxia after antenatal ETX restores lung growth and prevents pulmonary hypertension during infancy.

Case-control analysis of paternal age and trisomic anomalies.

OBJECTIVES: To determine whether older paternal age increases the risk of fathering a pregnancy with Patau (trisomy 13), Edwards (trisomy 18), Klinefelter (XXY) or XYY syndrome. DESIGN: Case-control: cases with each of these syndromes were matched to four controls with Down syndrome from within the same congenital anomaly register and with maternal age within 6 months. SETTING: Data from 22 EUROCAT congenital anomaly registers in 12 European countries. PARTICIPANTS: Diagnoses with observed or (for terminations) predicted year of birth from 1980 to 2005, comprising live births, fetal deaths with gestational age ≥ 20 weeks and terminations after prenatal diagnosis of the anomaly. Data include 374 cases of Patau syndrome, 929 of Edwards syndrome, 295 of Klinefelter syndrome, 28 of XYY syndrome and 5627 controls with Down syndrome. MAIN OUTCOME MEASURES: Odds ratio (OR) associated with a 10-year increase in paternal age for each anomaly was estimated using conditional logistic regression. Results were adjusted to take account of the estimated association of paternal age with Down syndrome (1.11; 95% CI 1.01 to 1.23). RESULTS: The OR for Patau syndrome was 1.10 (95% CI 0.83 to 1.45); for Edwards syndrome, 1.15 (0.96 to 1.38); for Klinefelter syndrome, 1.35 (1.02 to 1.79); and for XYY syndrome, 1.99 (0.75 to 5.26). CONCLUSIONS: There was a statistically significant increase in the odds of Klinefelter syndrome with increasing paternal age. The larger positive associations of Klinefelter and XYY syndromes with paternal age compared with Patau and Edwards syndromes are consistent with the greater percentage of these sex chromosome anomalies being of paternal origin.

Population based screening - the difficulty of how to do more good than harm and how to achieve it.

Screening people without symptoms of disease is an attractive idea. Screening allows early detection of disease or elevated risk of disease, and has the potential for improved treatment and reduction of mortality. The list of future screening opportunities is set to grow because of the refinement of screening techniques, the increasing frequency of degenerative and chronic diseases, and the steadily growing body of evidence on genetic predispositions for various diseases. But how should we decide on the diseases for which screening should be done and on recommendations for how it should be implemented? We use the examples of prostate cancer and genetic screening to show the importance of considering screening as an ongoing population-based intervention with beneficial and harmful effects, and not simply the use of a test. Assessing whether screening should be recommended and implemented for any named disease is therefore a multi-dimensional task in health technology assessment. There are several countries that already use established processes and criteria to assess the appropriateness of screening. We argue that the Swiss healthcare system needs a nationwide screening commission mandated to conduct appropriate evidence-based evaluation of the impact of proposed screening interventions, to issue evidence-based recommendations, and to monitor the performance of screening programmes introduced. Without explicit processes there is a danger that beneficial screening programmes could be neglected and that ineffective, and potentially harmful, screening procedures could be introduced.

Outcome of severe unilateral cerebellar hypoplasia.

Aim: Complete or subtotal absence of one cerebellar hemisphere is exceptional; only single cases have been described. We aimed to assess the long-term outcome in children with severe unilateral cerebellar hypoplasia (UCH). Method: As part of a retrospective study we describe neuroimaging features, clinical findings, and cognitive outcomes of seven children with UCH (five males, two females; age at first magnetic resonance imaging [MRI]: median 1y 3mo, range 9d-8y 10mo; age at latest follow-up: median 6y 6mo, range 2y 3mo-14y 11mo). Results: One child had abnormalities on prenatal MRI at 21 weeks' gestation. The left cerebellar hemisphere was affected in five children, and the right hemisphere in two children. The vermis was involved in five children. The volume of the posterior fossa was variable. At the latest follow-up, neurological findings included truncal ataxia and muscular hypotonia in five children, limb ataxia in three patients, and head nodding in two patients. Three children had learning disability*, five had speech and language disorders, and one had a severe behavioural disorder. Interpretation: Severe UCH is a residual change after a disruptive prenatal cerebellar insult, most likely haemorrhagic. The outcome is variable, ranging from almost normal development to marked developmental impairment. Ataxia is a frequent but not a leading sign. It seems that involvement of the cerebellar vermis is often, but not consistently, associated with a poorer cognitive outcome, whereas an intact vermis is associated with normal outcome and no truncal ataxia.