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Mycophenolate mofetil (MMF) is probably the most common employed immunosuppressant drug in recipients of solid organ transplant and in many autoimmune diseases. In vitro studies, a significant number of single clinical observations and a recent study from a group of different European teratogen information services, have provided very consistent data supporting the existence of a specific MMF embryopathy. The typical malformative pattern of MMF embryopathy includes external ear anomalies ranging from hypoplastic pinna (microtia) to complete absence of pinna (anotia); cleft lip, with or without cleft palate, and ocular anomalies as iris or chorioretinal coloboma and anophthalmia/microphthalmia. Other less frequent features are congenital heart defects, distal limbs anomalies, esophageal atresia, vertebral malformations, diaphragmatic hernia, and kidney and central nervous system anomalies. Neurodevelopmental outcome seems favorable in the small number of patients where information about this issue is available, but neurological deficits have been documented. Physicians in charge of women under MMF therapy should be aware of the potential risk of this drug to cause a specific embryopathy and the need of interrupting the treatment at least six weeks before becoming pregnant. (C) 2016 Elsevier Masson SAS. All rights reserved.

Resumen Objetivos Describir los hallazgos clinicos y moleculares de 11 pacientes espanoles con sindrome cardiofaciocutaneo (CFC), y compararlos con una serie de 130 pacientes con otros trastornos neurocardiofaciocutaneos (111 pacientes con sindrome de Noonan [SN] y 19 con sindrome LEOPARD). Pacientes y metodos Se obtuvieron datos clinicos de los pacientes remitidos para estudio genetico. Se estudiaron los genes PTPN11, SOS1, RAF1, BRAF y MAP2K1 mediante secuenciacion bidireccional de los exones donde se localizan las mutaciones mas recurrentes, y todos los exones del gen KRAS. Resultados Se identificaron 6 mutaciones en BRAF en 9 pacientes, y 2 mutaciones en MAP2K1. La talla baja, el retraso psicomotor, los trastornos del lenguaje y las anomalias ectodermicas fueron mas frecuentes en el CFC que en el resto de los sindromes (p Discusion Los pacientes con CFC muestran un fenotipo mas grave, si bien se describe un paciente sin retraso psicomotor, lo que ilustra la variabilidad del espectro fenotipico asociado a las mutaciones en BRAF. El estudio genetico es una herramienta util en el diagnostico diferencial del CFC y de los trastornos relacionados con el SN.

Preterm infants are at high risk for both early-onset and late-onset, hospital-acquired bloodstream infections. Aminoglycoside antibiotics are commonly used in the empiric treatment of suspected infection among these infants. A number of mutations in mitochondrial deoxyribonucleic acid (mtDNA) are known to increase the risk of developing irreversible hearing loss after exposure to aminoglycoside antibiotics. These mutations modify the mitochondrial ribosome, increasing the binding affinity of aminoglycosides and resulting in inhibition of mitochondrial protein synthesis. The mitochondrial m.1555A>G mutation in the gene encoding the mitochondrial 12S ribosomal ribonucleic acid (rRNA) subunit is the most common mutation mediating aminoglycoside ototoxicity. The opportunity for effective prevention may be limited by the fact that an aminoglycoside, such as gentamicin, is frequently used in the first few days after birth to prevent possible early-onset sepsis. Screening at-risk mothers might overcome this problem, if there is clinical evidence that it can be performed in a timely manner to be clinically useful.

The presence of a single umbilical artery (SUA) is a fetal soft marker of congenital abnormalities. Among the most common related malformations, there are cardiological, nephrourological and digestive anomalies, most of which are considered to have a vascular etiology. There is an association between increased incidence of intrauterine growth retardation and adverse perinatal indicators, but whether this association is due to related anomalies or isolated SUA (iSUA) is controvisal. We reviewed 96 cases of iSUA and non-isolated SUA (niSUA), diagnosed in a period of two years in a referral hospital for high-risk pregnancies. Data on prenatal explorations, including fetal ultrasonography and karyotyping, were obtained. niSUA was diagnosed when no malformations were found prenatally or in postnatal evaluation. Sixty-six newborns (68.8%) had no other anomalies and 30 (31.3%) presented with a variety of malformations including heart diseases, urophaties, digestive, nervous and musculoskeletal disorders, genetic abnormalities and complex malformations. Cardiological and nephrourological abnormalities were found to be the most frequent association with a SUA (both in 23.8% of malformed SUA newborns). Intrauterine growth restriction was not higher in iSUA newborns than in a normal population. Ultrasound allowed optimal prenatal diagnosis in most cases. The prognosis of the fetus with a SUA is determined by the presence of other malformations observed by an expert sonographer. If no other findings are made, only a routine physical examination should be performed in newborns, but no other complementary examinations are required.

Introduccion y objetivos La caracterizacion molecular de cardiopatias incluye una entidad congenita no infrecuente, el sindrome de Noonan. Presentamos el estudio de seis genes de la via RAS-MAPK en pacientes espanoles: perfil genotipico, impacto de la cardiopatia y expresividad clinica. Metodos Compusieron la poblacion en estudio 643 pacientes (y 182 familiares) diagnosticados por dismorfologos, cardiologos y endocrinopediatras de 74 hospitales (11 comunidades). Estudio primario de PTPN11 y complementario de SOS1, RAF1, BRAF, KRAS y HRAS, estratificado y orientado por signos clinicos, mediante secuenciacion de exones recurrentes (un 80-95% de mutaciones descritas). Resultados Se documento mutacion en 230 pacientes (91 mujeres, 139 varones) de 200 familias (31%), 172 PTPN11 +, 14 SOS1 +, 9 RAF1 + y 5 BRAF +, con referencia explicita a la cardiopatia padecida en 156 casos indice; 103 presentaban estenosis de la valvula pulmonar; 12, estenosis de la valvula pulmonar y miocardiopatia hipertrofica; 18, miocardiopatia hipertrofica y 14, otra cardiopatia; en solo 9 casos se encontraba ausente. En 23/30 familiares positivos no habia o no constaba cardiopatia. El rendimiento diagnostico fue superior (p = 0,016) para las muestras de algunos centros (53%; 14/32), y alcanzo el 64% (9/14; p = 0,019) en profesionales concretos. El rendimiento cayo al 18% en los pacientes sin datos clinicos facilitados. El dato genotipico reoriento el diagnostico clinico en 26 pacientes. Conclusiones El 94% de los pacientes portadores de mutacion presentaban cardiopatia, el 79% estenosis de la valvula pulmonar y el 12% miocardiopatia hipertrofica. En el 76% de los familiares positivos con rasgos clinicos compatibles, no se habia documentado la cardiopatia. El estudio molecular es una herramienta util en estos sindromes, aunque debe progresarse en la objetivacion del diagnostico clinico

Mycophenolate mofetil (MMF) and its active metabolite mycophenolic acid (MPA) are both very effective immunosuppressive agents widely used for the prevention of organ rejection following transplantation and in the therapy of autoimmune diseases. In experimental studies performed in pregnant animals, MMF exhibited teratogenicity, which later was confirmed in humans, as documented in the United States National Transplantation Pregnancy Registry (NTPR). In 2008, a specific pattern of malformations associated with in utero exposure to MMF was suggested. Subsequently, numerous reports in the scientific literature of newborns having similar patterns of malformations born to mothers who had undergone transplantation and were receiving immunosuppressive therapy provided supporting evidence for the existence of a specific MMF embryopathy. The most consistent characteristics of the MMF embryopathy phenotype include cleft lip and palate, microtia and aural atresia, and ocular anomalies (hypertelorism, arching eyebrows). Perinatal clinicians should be aware of the potential teratogenicity of MMF. Importantly, effective contraception measures should be recommended to fertile women who have received transplants before they become pregnant. Given the cumulative effect of MMF, contraceptive measures should be continued for at least 6 months after discontinuing MMF therapy.

BACKGROUND: Diabetes is the most common endocrinologic complication during pregnancy, and poor control can lead to a variety of congenital anomalies in the fetus. However, it is often difficult to differentiate between diabetes-related anomalies and an underlying genetic syndrome. In the 1990s it was proposed that preaxial hallucal polydactyly, particularly when proximally placed, was a distinguishing feature of diabetic embryopathy. METHODS: We summarize the clinical findings in 18 patients (five previously reported in abstract form) with diabetic embryopathy and preaxial hallucal polydactyly to determine which features are most suggestive of diabetic embryopathy. RESULTS: All 18 patients had preaxial hallucal polydactyly (seven bilateral, 11 unilateral), of which 15 patients had proximal implantation of the extra hallux. Further skeletal findings included the following: segmentation anomalies of the spine, equinovarus deformity of the feet, tibial hemimelia, hip dysplasia, and femoral hypoplasia. Upper limb malformations were rare. Eleven of the 18 mothers had prepregnancy insulin-dependent diabetes, while one mother had prepregnancy type 2 diabetes that required insulin therapy in the 3rd trimester. Five mothers had gestational diabetes that required insulin and one mother had gestational diabetes that was controlled by diet. The majority of mothers had poorly controlled diabetes during the pregnancy. CONCLUSIONS: Proximally placed preaxial hallucal polydactyly, particularly when coupled with segmentation anomalies of the spine and tibial hemimelia, is highly suggestive of diabetic embryopathy. Varying degrees of diabetes in the mothers point to a possible genetic predisposition interacting with the teratogenic effects of poor glycemic control leading to specific limb anomalies. Birth Defects Research (Part A), 2009. © 2008 Wiley-Liss, Inc.

Deficiency of carbohydrate sulfotransferase 3 (CHST3; also known as chondroitin-6-sulfotransferase) has been reported in a single kindred so far and in association with a phenotype of severe chondrodysplasia with progressive spinal involvement. We report eight CHST3 mutations in six unrelated individuals who presented at birth with congenital joint dislocations. These patients had been given a diagnosis of either Larsen syndrome (three individuals) or humero-spinal dysostosis (three individuals), and their clinical features included congenital dislocation of the knees, elbow joint dysplasia with subluxation and limited extension, hip dysplasia or dislocation, clubfoot, short stature, and kyphoscoliosis developing in late childhood. Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed markedly decreased 6-O-sulfation but enhanced 4-O-sulfation, confirming functional impairment of CHST3 and distinguishing them from diastrophic dysplasia sulphate transporter (DTDST)-deficient cells. These observations provide a molecular basis for recessive Larsen syndrome and indicate that recessive Larsen syndrome, humero-spinal dysostosis, and spondyloepiphyseal dysplasia Omani type form a phenotypic spectrum.

Mycophenolate mofetil (MMF) is a widely prescribed immunosuppressive agent after solid organ transplantation. Potential teratogenic effects after in utero exposure to MMF in experimental studies and clinical observations in humans has been postulated in recent literature. However, a specific pattern of malformation has not been identified yet. We present a newborn patient, born to a recipient of renal transplantation, who became pregnant while taking MMF as immunosuppressive therapy. The newborn exhibited cleft lip and palate, bilateral microtia and atretic external auditory canals, chorioretinal coloboma, hypertelorism, and micrognathia. An extensive review of the literature documented six other cases with similar malformations after in utero exposure to MMF. A consistent pattern of malformations comprising cleft lip and palate, microtia and external auditory canals could be observed in five of the six cases. A different malformative pattern observed in one of the patients could be attributed to a different agent rather than MMF. The possible teratogenic effects of other immunosuppressive drugs, such as tacrolimus and prednisone, to which this patient was also exposed, are discussed herein. In addition, the differential diagnosis with other dysmorphic syndromes that can present with a similar phenotype, such as CHARGE syndrome, 18q deletion and hypertelorism-microtia-clefting (HMC) syndrome, is presented. We conclude that in utero exposure to MMF can cause a characteristic phenotype and propose the existence of a mycophenolate-associated embryopathy whose main features are: cleft lip and palate, microtia with atresia of external auditory canal, micrognathia and hypertelorism. Ocular anomalies, corpus callosum agenesis, heart defects, kidney malformations, and diaphragmatic hernia may be part of the phenotypic spectrum of MMF embryopathy. The human teratogenicity of MMF is reinforced by this report, and the current contraceptive recommendations about its use in fertile women are stressed.

Microcephaly-lymphoedema-chorioretinal dysplasia (MIM 152950) has been described as a distinct clinical entity. The mode of inheritance is uncertain, but male to male transmission has been observed supporting autosomal dominant inheritance. A characteristic facial phenotype has recently been suggest

Objectives To describe 11 patients with cardiofaciocutaneous syndrome (CFC) and compare them with 130 patients with other RAS-MAPK syndromes (111 Noonan syndrome patients [NS] and 19 patients with LEOPARD syndrome). Patients and methods Clinical data from patients submitted for genetic analysis were collected. Bidirectional sequencing analysis of PTPN11, SOS1, RAF1, BRAF, and MAP2K1 focused on exons carrying recurrent mutations, and of all KRAS exons were performed. Results Six different mutations in BRAF were identified in 9 patients, as well as 2 MAP2K1 mutations. Short stature, developmental delay, language difficulties and ectodermal anomalies were more frequent in CFC patients when compared with other neuro-cardio-faciocutaneous syndromes (p Discussion CFC patients showed a rather severe phenotype but at least one patient with BRAF mutation showed no developmental delay, which illustrates the variability of the phenotypic spectrum caused by BRAF mutations. Molecular genetic testing is a valuable tool for differential diagnosis of CFC and NS related disorders.

We describe a 1,000-g twin fetus with absent kidneys and ureters, anal atresia and minimal evidence of external genitalia, and hypoplastic lower limbs with absent feet. A postmortem arteriogram showed a large single umbilical artery in direct continuation with the abdominal aorta, a unique anomaly almost always related to sirenomelia. We discuss the possible diagnosis of this case as sirenomelia or caudal dysgenesis, and the controversy as to whether they are two related or separate entities.

Introduction and objectives Molecular characterization of congenital heart diseases now includes the not infrequent dysmorphic Noonan syndrome. A study of 6 genes of the RAS-MAPK pathway in Spanish patients is presented: the impact of heart disease, clinical expressivity, and diagnostic yield are investigated. Methods The study included 643 patients (and 182 family members) diagnosed by dysmorphologists, cardiologists, and pediatric endocrinologists from 74 tertiary hospitals. Bidirectional sequencing analysis of PTPN11, SOS1, RAF1, BRAF, KRAS and HRAS focused on exons carrying recurrent mutations accounting for 80% to 95% of previously described mutations. Results Mutations were detected in 230 patients (91 women and 139 men) in 200 (31%) families (172 PTPN11 +, 14 SOS1 +, 9 RAF1 +, 5 BRAF +). There was specific reference to the heart defect suffered in 156 index cases: 103 patients had shown pulmonary stenosis, 12 pulmonary stenosis with hyperthrophic cardiomyopathy, 18 hypertrophic cardiomiopathy, and 14 other cardiopathies; heart disease was absent in 9 index cases. Heart disease had not been documented in 23 of 30 family members with positive genotype and compatible clinical signs. Diagnostic yield was higher ( P =.016) for samples from some centers (53%; 14/32) and even from certain professionals (64%; 9/14; P =.019). Characterization rate was 18% in patients for whom clinical data were not available. Genotyping led to a more precise diagnosis in 26 patients. Conclusions Most patients (94%) with a positive genotype had known congenital heart disease, 79% pulmonary stenosis and 12% hyperthrophic cardiomyopathy. Cardiopathy had not been documented in 76% of family members carrying the mutation. Molecular study is a useful tool in these syndromes but a more rigorous clinical diagnosis should be intended as well.

International transplant registries have accounted for more than 14000 deliveries in solid organ transplant recipient women up to 2002; thus, the possibility of becoming pregnant has been considered an additional benefit of organ transplantation.1 Improvement in organ transplantation outcome has been linked with the development of more effective immunosuppressive drugs. Hence, in recent years new pharmacologic agents have been incorporated into the armamentarium for organ transplant recipients and patients with autoimmune diseases. Among the new drugs, mycophenolate mofetil (MMF) has acquired special relevance.1 In addition, MMF has also been added to the treatment of autoimmune diseases such as lupus, because its use has been found to be more effective than cyclophosphamide, the standard treatment modality, in inducing remission of lupus nephritis and has a more favorable safety profile.2 MMF is a newly available ester derived from mycophenolic acid. After oral ingestion, MMF is hydrolyzed rapidly to mycophenolic acid, the active compound (a potent noncompetitive reversible inhibitor of inosine monophosphate … Address correspondence to Maximo Vento, PhD, MD, Neonatal Research Unit, Servicio de Neonatologia, Hospital Universitario Materno Infantil La Fe, Avenida de Campanar, 21, E46009 Valencia, Spain. E-mail: maximo.vento{at}uv.es or maximovento{at}telefonica.net

Introduccion. El sindrome de Noonan (SN) y otros sindromes con fenotipo similar, como LEOPARD, cardiofaciocutaneo, Costello y Legius, estan asociados a mutaciones en genes incluidos en la via RAS/MAPK (rasopatias), una importante via de senalizacion relacionada con la proliferacion celular. El descenso de las amigdalas cerebelares dentro del canal medular cervical, conocido como malformacion de Arnold-Chiari (MAC), se ha descrito en pacientes afectos de SN, lo que ha llevado a sugerir que la MAC podria formar parte del espectro fenotipico del SN. Presentamos dos casos con SN y MAC. Casos clinicos. Caso 1: mujer de 29 anos con fenotipo de Noonan. Fue intervenida a los 9 anos de estenosis valvular pulmonar. A los 27 anos, presento MAC sintomatica que preciso descompresion quirurgica. Presentaba mutacion c.922A>G (N308D) en el gen PTPN perteneciente a la via RAS/MAPK. Caso 2: nina de 10 anos con fenotipo de Noonan y MAC asintomatica detectada en resonancia magnetica cerebral. Era portadora de la mutacion c.923A>G (N308S) en el gen PTPN11. Conclusiones. Hemos encontrado en la bibliografia seis pacientes con esta asociacion, cuatro con fenotipo Noonan y dos con LEOPARD. Nuestros dos pacientes aportan evidencia suplementaria a la hipotesis de que la MAC formaria parte del espectro fenotipico del SN. El escaso numero de pacientes publicados con esta asociacion no permite extraer recomendaciones sobre el momento y la frecuencia de estudio de neuroimagen; no obstante, una exploracion neurologica cuidadosa deberia incluirse en la guia anticipatoria de salud en los sindromes de la via RAS/MAPK.

A large intrapericardial teratoma was found at necropsy in a 38-week stillborn fetus, in which prenatal diagnosis of hydrops fetalis and an echogenic cardiac mass had been made. Clinical and pathological data are reported. In utero intrapericardial teratomata lead to different outcomes depending on whether fetal hydrops is associated. When generalized fetal hydrops is not present, the outcome is good, even in cases with large pericardial effusions. When generalized fetal hydrops occurs, it often results in a poor outcome. In our literature review, we have found eight perinatal deaths in nine similar cases reported.

We reviewed five unreported examples and 23 previously reported cases of urethral obstruction sequence with associated lower limb deficiency. There was no evidence of amniotic bands or exposure to vasoactive drugs during pregnancy in any case. In three infants a gangrenous lesion at the distal part of the affected leg was found; in another three infants, necrotic tissue was noted in the stump of the affected leg. This type of lesion can be explained only on a vascular ischemic basis. In five cases, signs of compression of the external iliac artery by the grossly distended bladder, by grossly distended ureters, or both were found. A vascular disruption in the territory of the external iliac artery caused by compression by the distended urinary tract is the proposed mechanism for the associated limb deficiency.

7 cases of acute subdural hematomas diagnosed and surgically treated during the first week of life are presented. 5 of them are alive and well at 6 and 7 months and 3, 4 and 6 years of follow-up. Free interval, raised intracranial pressure, lateralizing signs, fall of hematocrit and pressence of blood in CSF were constant. Subdural puncture was negative in 6 cases, including a hemophilic patient (hemophilia B). Clinical diagnosis was ratified by means of neuroradiological procedures. The authors conclude that craniectomy is the treatment of choice and subdural tapping a useless procedure.