First-Trimester Diagnosis of Agnathia-Otocephaly Complex: A Series of 4 Cases and Review of the Literature.

First-trimester ultrasound findings in 4 fetuses with agnathia-otocephaly complex are described. In addition, information from 3 cases reported in the literature was also reviewed, for a total of 7 cases analyzed. All 7 fetuses presented with agnathia and 6 with ventrocaudal displacement of the ears (melotia/synotia). Four fetuses had holoprosencephaly. In 6 cases, the parents opted for termination of pregnancy. The remaining case resulted in premature delivery at 26 weeks due to severe polyhydramnios and early neonatal death. This report highlights the important role of ultrasound in the identification of agnathia-otocephaly complex in the first trimester of pregnancy.

[Frequency of holoprosencephaly in Chile]. / ECLAMC: 41 años de vigilancia de la holoprosencefalia en Chile. Período 1972-2012.

BACKGROUND: Holoprosencephaly is a structural anomaly of the brain that consists in a defect of the prosencephalon development that leads to face and neurological defects of variable intensity. AIM: To estimate holoprosencephaly prevalence at birth. PATIENTS AND METHODS: All cases of holoprosencephaly, born alive or stillbirths, registered in the 15 Chilean Hospitals of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) between 1972 and 2012, were studied. Craniofacial and other anomalies found in newborns affected by holoprosencephaly are described. RESULTS: Fifty five cases of holoprosencephaly (58% males) were found among the 798.222 registered births (rendering a prevalence at birth of 0.69 per 10.000 newborns). The most common cranial defect was medial cleft lip with cleft palate (27.3%), bilateral cleft lip (11%) or both (38.2%), cyclopia (14%), single nostril (10.9%) and proboscis (9.1%). Eleven percent cases had a trisomy 13. A slight increase in prevalence over time was observed. CONCLUSIONS: Holoprosencephaly has a low frequency in Chile and is associated to trisomy 13. The increase in prevalence could be explained by a better prenatal diagnosis (ultrasonography).

ECLAMC: 41 años de vigilancia de la holoprosencefalia en Chile. Período 1972-2012 / Frequency of holoprosencephaly in Chile

Background: Holoprosencephaly is a structural anomaly of the brain that consists in a defect of the prosencephalon development that leads to face and neurological defects of variable intensity. Aim: To estimate holoprosencephaly prevalence at birth. Patients and Methods: All cases of holoprosencephaly, born alive or stillbirths, registered in the 15 Chilean Hospitals of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) between 1972 and 2012, were studied. Craniofacial and other anomalies found in newborns affected by holoprosencephaly are described. Results: Fifty five cases of holoprosencephaly (58% males) were found among the 798.222 registered births (rendering a prevalence at birth of 0.69 per 10.000 newborns). The most common cranial defect was medial cleft lip with cleft palate (27.3%), bilateral cleft lip (11%) or both (38.2%), cyclopia (14%), single nostril (10.9%) and proboscis (9.1%). Eleven percent cases had a trisomy 13. A slight increase in prevalence over time was observed. Conclusions: Holoprosencephaly has a low frequency in Chile and is associated to trisomy 13. The increase in prevalence could be explained by a better prenatal diagnosis (ultrasonography).

Limitación/adecuación del esfuerzo terapéutico en pediatría / Limitation/adequacy of therapeutic effort in pediatrics

En niños con condiciones de salud que amenazan sus vidas, el trayecto de la enfermedad puede llevar, en ocasiones, a que los profesionales de la salud y las familias se pregunten si continuar los tratamientos representa la mejor opción para el niño. A veces, limitar o suspender las medidas de soporte vital resulta más apropiado, especialmente si el tratamiento sólo preserva la existencia biológica o si el objetivo global del cuidado ha cambiado a “solamente mantener el confort”. Se presenta el caso de un niño portador de encefalopatía crónica en etapa terminal, en el cual se implementaron medidas de adecuación del esfuerzo terapéutico con el objetivo de permitir una muerte digna. Se describe el proceso de toma de decisiones conjunta con los padres, la forma de registro médico y las principales medidas de cuidado al final de la vida.

Limitación/adecuación del esfuerzo terapéutico en pediatría / Limitation/adequacy of therapeutic effort in pediatrics

En niños con condiciones de salud que amenazan sus vidas, el trayecto de la enfermedad puede llevar, en ocasiones, a que los profesionales de la salud y las familias se pregunten si continuar los tratamientos representa la mejor opción para el niño. A veces, limitar o suspender las medidas de soporte vital resulta más apropiado, especialmente si el tratamiento sólo preserva la existencia biológica o si el objetivo global del cuidado ha cambiado a “solamente mantener el confort”. Se presenta el caso de un niño portador de encefalopatía crónica en etapa terminal, en el cual se implementaron medidas de adecuación del esfuerzo terapéutico con el objetivo de permitir una muerte digna. Se describe el proceso de toma de decisiones conjunta con los padres, la forma de registro médico y las principales medidas de cuidado al final de la vida.

Sometimes, the disease trajectory in children with life threatening conditions can lead health professionals and families to wonder whether continuing treatment is the best option for the child. Occasionally, limiting or discontinuing life support measures is advisable, especially if treatment only preserves biological existence or the overall goal of care has shifted to just “maintaining comfort”. The study presents the case of a child with chronic encephalopathy in terminal stadium, for whom measures of therapeutic adequacy were implemented with the aim of allowing a quite death. The shared decision-making process, the medical record document and the main measures of care at end of life are described.

Dysgnathia complex sine holoprosencephaly nor synotia: a case report and discussion of its nosology.

A severe mandibular hypoplasia and microstomy with intraoral anomalies including hypoglossia, fused gums, persistence of buccopharyngeal membrane, and laryngeal hypoplasia were noted in a female newborn with the dysgnathia complex (DC). Additionally, our proposita also presented natal teeth as a probably new finding. These clinical manifestations overlapped with those of the fourth report of hypomandibular faciocranial syndrome (HFS) (31), and given that both lack for craniosynostosis (pathognomonic of HFS), we considered that both represent a subtype of DC proposed as DC sine holoprosencephaly nor synotia (DCSHS). Differential characteristics between the DCSHS, the HFS, and the DC with holoprosencephaly sine synotia are reviewed and additionally, we discussed some aspects about the nosology of the DC.

A novel heterozygous missense mutation G316D of SIX3 gene in a Brazilian patient with holoprosencephaly-like phenotype and Langerhans cell histiocytosis.

Here we report on a Brazilian female patient with the clinical manifestations of the holoprosencephaly-like phenotype who also presented with a retroocular granuloma diagnosed as Langerhans cell histiocytosis in early infancy. Mutation analysis showed a missense mutation (G316D) in the exon 2 of SIX3 gene, which was predicted as damaged by the PolyPhen program. We discuss the clinical and genetic aspects of this unusual case.

Solitary median maxillary central incisor syndrome and holoprosencephaly: a case report.

Solitary median maxillary central incisor syndrome (SMMCIS) is a rare anomaly that affects 1 in 50,000 live births. Of unknown etiology, SMMCIS is characterized by the presence of a single central incisor located on the maxillary midline and may be associated with developmental defects and systemic alterations. SMMCIS also is associated with short stature, mild forms of deviation in craniofacial morphology, and intellectual disability. The purposes of this paper were to: describe the clinical case of an 8-year-old boy with a permanent central incisor located at the midline in association with holoprosencephaly; and highlight the most important aspects related to diagnosis and treatment of solitary median maxillary central incisor syndrome.

Moebius syndrome and holoprosencephaly following exposure to misoprostol.

Moebius syndrome is a rare disease characterized by congenital facial paralysis and abducens palsy. Involvement of other cranial nerves, orofacial dysmorphism, and limb abnormalities are frequently associated. Reported here is the case of a 10-month-old child born with Moebius syndrome and presenting with holoprosencephaly, following exposure in utero to misoprostol. To our knowledge, this is the first published case report describing this association. The etiologic hypotheses of Moebius syndrome are also discussed.

Síndrome de incisivo central superior mediano: relato de caso / Syndrome of the single median maxilarry central incisor: case report

A síndrome do incisivo central superior mediano inclui uma variedade de sinais clínicos decorrentes de defeitos de desenvolvimento das estruturas medianas da face e da parte anterior do cérebro. A agenesia de um dos incisivos centrais superiores é um dos sinais clínicos que caracteriza essa síndrome e, por se tratar de anomalia presente na cavidade bucal, institui o cirurgião dentista como um dos primeiros profissionais a ter contato com esses pacientes. O presente trabalho tem por objetivo apresentar um paciente com tal síndrome, buscando promover o embasamento dos profissionais para que estejam qualificados a diagnosticar, orientar e tratar esses pacientes.

Holoprosencephaly and genitourinary anomalies in fetal methotrexate syndrome.

Prenatal exposure to methotrexate (MTX) in the first trimester may lead to fetal death, and surviving children have increased risks for cranial dysostosis, dysmorphic facies, skeletal malformations, limb defects, growth retardation, and, in some cases, developmental delay, a pattern of defects recognized as fetal MTX syndrome (FMS). We report on a male infant who, in addition to severe FMS, showed previously undescribed central nervous system (CNS) and genitourinary anomalies that contributed to the further delineation. The propositus was born to a G2, 20-year-old mother with an irregular menstrual history. The unplanned pregnancy was complicated by oral MTX treatment (5 mg/day) for suspected systemic lupus erythematosus for 14 days at the 5th week post-conception, as dated by the first trimester sonogram. In addition to the typical features of the FMS, our propositus exhibited congenital penile curvature, vesicoureteral reflux, hydronephrosis, and severe CNS anomalies including semilobar holoprosencephaly (HPE). A single previous report of lobar-type HPE in an infant with FMS led us to confirm that the HPE observed in the propositus is a feature attributable to MTX teratogenicity, although the exact mechanisms of the HPE production need to be further elucidated. Also, this case serves to highlight the presence of genitourinary anomalies in patients with FMS, a fact that requires intentional searches in future patients in order to confirm this as being characteristic of the entity.

Holoprosencephaly and holoprosencephaly-like phenotypes: Review of facial and molecular findings in patients from a craniofacial hospital in Brazil.

Here we report on the clinical and genetic data for a large sample of Brazilian patients studied at the Hospital de Reabilitação de Anomalas Craniofaciais-Universidade de São Paulo (HRAC-USP) who presented with either the classic holoprosencephaly or the holoprosencephaly-like (HPE-L) phenotype. The sample included patients without detected mutations in some HPE determinant genes such as SHH, GLI2, SIX3, TGIF, and PTCH, as well as the photographic documentation of the previously reported patients in our Center. The HPE-L phenotype has been also called of HPE "minor forms" or "microforms." The variable phenotype, the challenge of genetic counseling, and the similarities to patients with isolated cleft lip/palate are discussed.

Holoprosencephaly in Mexico: first reported autopsy case by Dr. Agustín Arellano.

INTRODUCTION: Holoprosencephaly with cyclocephaly is an early disturbance of organogenesis and has been classified as a severe brain malformation starting in 1755 by Eller in Germany, then in 1822 by Etienne Geoffroy de Saint-Hilaire in France, and finally in 1828 by Tiedemann in Germany. In 1839, Dr. Arellano published in Mexico a necropsy case of holoprosencephaly. This was the fourth publication worldwide on this kind of pathological alteration. Furthermore, in reference to diaphragmatic herniation, Arellano's paper is the fourth world report, having appeared 9 years before Bochdalek's publication. We have not found any other report that appeared before 1839 in the Americas on this particular malformation, and we consider that Arellano's paper was the first of its kind on the American continent. CONCLUSION: As is well known, the publications of this Mexican medical researcher were, for his time, at the level of those of the most developed countries. It is also important to know that the medical journal where Arellano's work was published, the "Periódico de la Academia de Medicina de Mégico(sic)," founded and directed by Dr. Manuel Carpio in 1836, is the direct forerunner of the present Gaceta Médica de México, the oldest currently published journal in the Americas.

Endocrinopathies associated with midline cerebral and cranial malformations.

We systematically reviewed a series of patients (n = 85) with midline cerebral and cranial malformations to correlate the endocrinopathy with the neuroanatomic defect. Midline cleft lip and palate was associated not only with growth hormone deficiency (GHD) but also with diabetes insipidus (DI); holoprosencephaly and optic nerve hypoplasia with absence of the septum pellucidum had a similar incidence of GHD and DI. Optic nerve hypoplasia with absence of the septum pellucidum had the highest incidence of multiple pituitary endocrinopathies and of neonatal hypoglycaemia. Unilateral, although more commonly bilateral, optic nerve hypoplasia was associated with GHD.

Holoprosencefalia: cebocefalia y ciclopadia: aspectos clínicos / Holoprosencephaly: cebocephaly and cyclopia: clinical aspect

Se presenta un estudio retrospectivo sobre la incidencia de las holoprosencefalias más frecuentes: cíclopes y cebocéfalos en la Maternidad "Concepción Palacios" desde 1949 a 1996. Se encontró que la incidencia global de holoprosencefalia es de 1 x 40 691 partos. La incidencia de cíclopes es de 1 x 51 115 partos y las de los cebocéfalos es de 1 x 31 712 partos. Se describen las malformaciones externas e internas asociadas y el diagnóstico pre y posnatal

Holoprosencefalia: reporte de un caso: actualización bibliográfica / Holopresencephaly: report of a case: bibliographical bring up to date

La holoprosencefalia comprende un espectro de malformaciones que se originan como consecuencia de una falla en el clivaje del cerebro anterior o prosencéfalo. Es una patologia de muy baja incidencia, estimandose cifras entre 1/5000 a 1/16000 nacidos vivos obsevándose una incidencia más alta en casos de embriones de huevo abortados. Se presenta el caso clínico de una paciente de 25 años, cuartigesta, tres cesáreas anteriores, quien comenzó a controlar su embarazo a partir de las 34 semanas. A las 35 semanas se le realiza una ecografía de control en la cual se detecta a nivel del polo cefálico una dilatación ventricular, sin visualizarse el cuerpo calloso; diagnóstico que se confirma a través de una nueva ecografía a las 39 semanas. Se decide programar cesárea dado los antecedentes obtétricos de la paciente...(AU)

Diagnóstico prenatal: trisomía 13 y holoprosencefalia

Se presenta un caso de diagnóstico prenatal de trisomía 13 y holoprosencefalia, durante el segundo trimestre de embarazo. Se practica una revisión de la literatura existente, incluyendo criterios de diagnóstico sonográfico y aspectos genéticos asociados. Se insiste en la importancia del diagnóstico sonográfico y genético antenatal, en la determinación de un pronóstico para el manejo ante e intraparto de estos casos