Prenatal diagnosis and clinical significance of cephalocele-A single institution experience and literature review.

OBJECTIVES: To determine the frequency of genetic and additional structural abnormalities as well as pregnancy outcomes in fetuses with prenatally diagnosed cephalocele. METHODS: A retrospective analysis of data retrieved from ultrasound examinations and genetic testing in fetuses with cephalocele diagnosed between 2006 and 2018 in a tertiary referral hospital along with a systematic literature search in the PubMed database on fetuses with prenatally diagnosed cephalocele. RESULTS: Twenty-one out of 36 fetuses were found to have additional structural anomalies (58.3%). In four fetuses, anomalies were consistent with limb-body wall complex, in five with Meckel-Gruber syndrome, and in one with amniotic band syndrome. Genetic abnormalities were present in 11.1% of fetuses (trisomy 6; microdeletion 22q11.21; microduplication 16p13.11; pathogenic variant in gene CC2D2A). Twenty-eight pregnancies were terminated (77.8%; 28/36); two were miscarried (5.6%; 2/36). All six children from pregnancies that continued were liveborn but only two survived the surgery and developed neurological sequence. Overall survival rate was 25% (2/8) with 0% intact survival. CONCLUSIONS: Additional structural anomalies are common in fetuses with cephalocele. A significant number of fetuses have genetic abnormalities, and a detailed genetic testing should be performed in all cases. The prognosis is poor with high mortality rate and 0% intact survival.

Expanding the phenotype in Adams-Oliver syndrome correlating with the genotype.

RATIONALE: Adams-Oliver syndrome (AOS) is a genetic disorder characterized by the association of aplasia cutis congenita (ACC), terminal transverse limb defect (TTLD), congenital cardiac malformation (CCM), and minor features, such as cutaneous, neurological, and hepatic abnormalities (HAs). The aim of the study is to emphasize phenotype-genotype correlations in AOS. METHODS: We studied 29 AOS patients. We recorded retrospectively detailed phenotype data, including clinical examination, biological analyses, and imaging. The molecular analysis was performed through whole exome sequencing (WES). RESULTS: Twenty-nine patients (100%) presented with ACC, the principal inclusion criteria in the study. Seventeen of twenty-one (81%) had cutis marmorata telangiectasia congenita, 16/26 (62%) had TTLD, 14/23 (61%) had CCM, 7/20 (35%) had HAs, and 9/27 (33%) had neurological findings. WES was performed in 25 patients. Fourteen of twenty-five (56%) had alterations in the genes already described in AOS. CCM and HAs are particularly associated with the NOTCH1 genotype. TTLD is present in patients with DOCK6 and EOGT alterations. Neurological findings of variable degree were associated sometimes with DOCK6 and NOTCH1 rarely with EOGT. CONCLUSION: AOS is characterized by a clinical and molecular variability. It appears that degrees of genotype-phenotype correlations exist for patients with identified pathogenic mutations, underlining the need to undertake a systematic but adjusted multidisciplinary assessment.

Amniotic band sequence in paternal half-siblings with vascular Ehlers-Danlos syndrome.

Familial amniotic band sequence (ABS) is rare but has been reported in the offspring of mothers with connective tissue disorders. We present a family of two half-siblings with ABS who share the same biological father. Following a serious vascular event a de novo pathogenic variant in COL3A1 was detected in the father, confirming a diagnosis of vascular Ehlers-Danlos syndrome (vEDS). The same variant was found in both his ABS-affected children but not in his unaffected child. The amniotic membrane is derived from fetal tissue, type III collagen being a component. As the affected children are paternal half-siblings, ABS was less likely due to maternal factors. Rather, the amniotic bands may have resulted from decreased type III collagen production as seen in people with vEDS, causing fragility of the amniotic membrane. Consequently, it is important to consider vEDS in patients with ABS.

Chromosome 2 Microdeletion Syndrome in a Newborn with Amniotic Band Sequence.

We report a case of amniotic band sequence (ABS) with a 5 kilobase microdeletion at 2p15. The newborn was delivered with absence of the right hand and distal segments of the left digits, consistent with amniotic band sequence. The clinical findings included a lumbar meningocele, bilateral clubfeet, adrenal hypertrophy, microcephaly, and facial dysmorphism. Due to these congenital anomalies not directly associated with ABS, a SNP chromosomal microarray was ordered and identified a 51 kilobase deletion at 2p15, which includes two known genes, USP34 (ubiquitin specific protease 34) and SNORA70B (small nucleolar RNA H/ACA box 70B). The clinical significance of this specific deletion is unknown at this time; however, there have been several case reports with a larger deletion which include these two genes and have been shown to affect neurodevelopment.

Síndrome de Bartsocas-Papas y secuencia de bridas amnióticas: Semejanzas clínicas sugieren un factor etiopatogénico común / Bartsocas-Papas syndrome and amniotic bands sequence: Clinical similarities suggest a common etiopathogenic factor

Introducción: el síndrome de Bartsocas-Papas (SBP) es una entidad letal causada por una mutación homocigota del gen RIPK4, el cual, formando parte de una compleja red molecular, está involucrado en la diferenciación del queratinocito. Las principales manifestaciones del síndrome, parcialmente compartidas por otras displasias ectodérmicas monogénicas son: pterigium en miembros inferiores, fisuras faciales, defectos de reducción distal de miembros y apéndices cutáneos. Por otro lado, la secuencia de bridas amnióticas (SBA), de etiopatogenia desconocida, se caracteriza por un espectro variable de anomalías consideradas disruptivas, incluyendo fisuras faciales y defectos de reducción de miembros. Objetivo: describir los hallazgos clínicos y anatomopatológicos de un paciente con SBP y de otro con SBA, remarcando sus semejanzas. Casos clínicos: 1) Recién nacida con fisura facial, pterigium poplíteo y crural, reducción de dedos y ortejos, y apéndices cutáneos. Placenta con zonas desprovistas de epitelio amniótico. 2) Feto femenino de 27 semanas, fisura facial atípica, reducción distal de miembros, pterigium poplíteo, defecto de cierre de pared tóracoabdominal y polo cefálico, apéndices cutáneos y presencia de bridas amnióticas. Placenta y cordón umbilical con extensas zonas de desprendimiento del epitelio amniótico. Conclusiones: algunos hallazgos similares en el SBP y la SBA permitirían especular acerca de la existencia de un factor intrínseco, relacionado al desarrollo de la piel, y común a ambas entidades.

Introduction: Bartsocas-Papas syndrome (BPS) is a lethal condition caused by a homozygous mutation of the RIPK4 gene, which, being part of a complex molecular network, is involved in keratinocyte differentiation while. The main clinical manifestations are webbing of lower limbs, facial clefts, distal limb reduction defects, and skin tags, and some of these are shared with other monogenic ectodermal dysplasia syndromes. Similarly, amniotic bands sequence (ABS), a condition of unknown etiopathogenesis, is characterized by a variable spectrum of anomalies considered as disruptive, such as facial clefts and limb reduction defects. Objective: to describe clinical and autopsy findings of a patient with BPS and of a fetus with ABS, emphasizing on their similarities. Case reports: 1. Female liveborn with atypical facial clefts, popliteal and crural webbing, distal reduction defects of hands and feet, and multiple skin tags. The placenta showed regions lacking amniotic epithelium. 2. Female fetus of 27 gestational weeks, atypical facial clefts, distal limb reduction defects, popliteal webbing, thoracoabdominal and cephalic closure defects, skin tags, and amniotic bands. Placenta and umbilical cord showed broad regions lacking amniotic epithelium attachment. Conclusions: the observation of a number of findings with remarkable similarities between BPS and ABS allows considering the existence of an intrinsic factor, involved in skin development which is common to both conditions.

The amniotic band syndrome in the rat is associated with the activation of transforming growth factor-ß.

Amniocentesis in rats is associated with different malformations, such as cleft palate and limb deformation, resembling the human congenital amniotic band syndrome (ABS). Despite many human cases reported in the literature, little is known about the mechanisms involved in ABS. This study addressed if the activation of the transforming growth factor-ß1 (TGF-ß1) pathway is, in part, associated with amniotic band formation and growth restriction induced in rats by amniocentesis, as by a previously published model. For this purpose, quantification of TGF-ß1, α-smooth muscle actin, and collagen type I mRNA and protein levels were determined by quantitative PCR and Western blot analysis, respectively, in the fetus, its amniotic membrane, and the uterus of experimental and control rats. We found that TGF-ß1 mRNA levels are increased in the fetus and the amniotic membrane at 6 hours, whereas α-smooth muscle actin, phosphorylated Smad3, and collagen type I increased at 48 hours, suggesting that a fibrotic response is induced after the amniotic sac puncture. Furthermore, fetuses had hemorrhages, syndactyly, and amputation of limbs, similar to human ABS.

Amniotic band sequence: prenatal diagnosis, phenotype descriptions, and a proposal of a new classification based on morphologic findings.

OBJECTIVE: The aim of this study is to describe the phenotype of fetuses affected by amniotic band sequence (ABS) that were diagnosed at the Instituto Nacional de Perinatología Isidro Espinosa de los Reyes and to propose a new classification based on morphologic findings. MATERIAL AND METHODS: Cases with a final diagnosis of amniotic band sequence, diagnosed between January 1993 and July 2010 in the Department of Maternal Fetal Medicine, were reviewed. Demographic, clinical, and periconceptional data were collected, and the defects were described and classified. The association frequencies of the defects were also determined. RESULTS: We included 50 cases with prenatal diagnosis of amniotic band sequence. The mean maternal age was 25.7 ± 6.9 years. Of these patients, 54% (27/50) were primiparous compared to 22% (11/50) who had three or more previous pregnancies. Craniofacial defects were seen in 78% (39/50) of the cases, followed by defects of the extremities 70% (35/50), abdominal wall, spine, and/or thorax 52% (26/50). The most frequent defects were the following: a) Encephalocele and facial clefts in the craniofacial group. b) Shortening at any level in the limb defects group, and c) Alterations of the spinal column curvature in the group of "other" defects. CONCLUSIONS: The amniotic band sequence shows a tendency to affect women who are in their earlier years of reproduction. We observed an inverse relationship between the number of pregnancies and the frequency of presentation of this pathology. The majority of affected fetuses showed a phenotype that fit into one of many groups. Therefore, we propose classifying the amniotic band sequence phenotypes into the following groups: I. Craniofacial defect + limb defect. II. Craniofacial defect + limb defect + abdominal wall, spinal column, and/or thoracic defects. III. Limb defect + abdominal wall, spinal column, and/or thoracic defects; and IV. Isolated defect (craniofacial, limb, or thoraco-abdominal wall). This classification system will be helpful in diagnosing amniotic band sequence. Based on future research studies, we hope that we can use this classification system as a prognosis fetal factor to establish a more accurate fetal prognosis and recurrence probability. Finally, we created a flowchart describing all of the steps that were followed by our Department from the moment an amniotic band was found by ultrasound until the definitive diagnosis was made and the follow up according to the fetal findings.

Síndrome de bridas amnióticas: caso clínico y revisión del tema / Amniotic band syndrome: case report and review of the literatura

El síndrome de bridas amnióticas (SBA) es un conjunto de anomalías congénitas, que asocia lesiones por constricción o amputación de miembros o dedos, asociado a la presencia de bridas amnióticas. Es una entidad con baja incidencia y suele ser de aparición esporádica. Suele cursar con anillos de constricción en la parte distal de los miembros o en los dedos o en casos más graves presentar amputación completa de miembros u asociación con otras malformaciones. El diagnóstico prenatal se produce sólo en el 29-50% de los casos. Presentamos el caso de una paciente con diagnóstico ecográfico de brida amniótica en la semana 12 de gestación (AU)

Amniotic band syndrome is a set of congenital birth defects consisting of constriction rings and limb or digit amputations, associated with the presence of amniotic bands. The incidence of this complication is low and its occurrence is sporadic. This syndrome usually causes constriction rings in the distal end of limbs or digits, which, in severe cases, can lead to complete amputation of the limbs or other malformations. Only 29-50% of cases are diagnosed prenatally. We report the case of a patient with an ultrasonographic diagnosis of amniotic band syndrome in week 12 of pregnancy (AU)

Limb malformations with associated congenital constriction rings in two unrelated Egyptian males, one with a disorganization-like spectrum and the other with a probable distinct type of septo-optic dysplasia.

In this report, we describe two unrelated Egyptian male infants with limb malformations and constriction rings. The first case is developing normally but has severe limb anomalies, congenital constriction rings, scoliosis because of vertebral anomalies, a left accessory nipple, a small tumor-like swelling on his lower back with tiny skin tubular appendages, a hypoplastic scrotum, and an anchored penis. The second case is developmentally delayed with limb malformations, congenital constriction rings, a lumbar myelomeningeocele, hemangioma, and tiny tubular skin appendages on the back. The patient also had bilateral optic atrophy. The constellation of features in our patients cannot be fully explained by the amniotic disruption complex. The first patient may represent an additional case of the human homolog of the mouse disorganization mutant. The presence of bilateral optic atrophy in the second case, although without an absent septum pellucidum nor other brain anomalies resembles the infrequently reported disorder of septo-optic dysplasia with limb anomalies. Both cases were sporadic and could be caused by a new dominant mutation because of the high paternal age of case 1 and the history of paternal occupational exposure to heat for both fathers. We draw attention to the phenotypic overlap between the disorganization-like syndrome and septo-optic dysplasia with limb anomalies.

Amniotic band sequence and limb defects: data from a population-based study.

Cases with amniotic bands were analysed separately as part of an ongoing study of limb defects occurring among 1,213,913 liveborn infants in British Columbia during the years 1952 to 1984. A total of 24 cases with this specific condition was identified among 659 cases with limb defects. The calculated incidence for amniotic band sequence with significant limb involvement was 0.19 in 10,000 livebirths. This is a minimal incidence, as cases without defects of the limbs, but with constriction rings were not identified with this approach. Familial cases and cases with additional anomalies were found.

Michelin tire baby syndrome: familial constriction bands during infancy and early childhood in four generations.

We report on an infant with an unusual pattern of transitory familial constriction bands distributed symmetrically and circumferentially over the neck, forearms, and lower legs. Family history showed the occurrence of similar bands among individuals in 4 generations transmitted as an autosomal dominant trait. Neck and limb distribution in the other affected family members was also symmetrical and circumferential, with spontaneous resolution taking place during childhood. This case represents another example of the Michelin tire baby syndrome, also known as multiple benign circumferential skin creases of the limbs, and further demonstrates its autosomal dominant mode of inheritance.

Multiple circumferential skin folds and other anomalies: a problem in syndrome delineation.

Three patients with multiple ring creases of the extremities are reported. Evidence to date points to aetiological heterogeneity. The skin folds may occur as an isolated abnormality or together with other patterns of malformation, making-up various syndromes that need to be further delineated. One type is associated with autosomal dominant inheritance. This striking abnormality usually resolves with time.

A counseling dilemma involving anencephaly, acrania and amniotic bands.

A suggested fetal anencephaly on routine office ultrasound examination resulted in a diagnosis of fetal acrania when targeted ultrasonography was performed by a consultant. Following pregnancy termination, examination of the abortus revealed partial cranial destruction secondary to an amniotic band. It is often difficult to distinguish between anencephaly, acrania, and amniotic band sequence prenatally, but postnatal differentiation is imperative for accurate risk assessment in genetic counseling.