A propósito de un caso de síndrome de Fraser. Autopsia de un feto de 37 semanas de gestación con múltiples malformaciones / About a case of Fraser syndrome. Autopsy of a 37 weeks gestation fetus with multiple malformations

El síndrome de Fraser o síndrome criptoftalmos/sindactilia es una enfermedad genética rara, cuyo diagnóstico se basa en una serie de criterios clínicos mayores y menores, y que puede apoyarse en pruebas genéticas. En este artículo se presenta el caso de una autopsia fetal de 37 semanas de gestación con sospecha de síndrome de CHAOS (síndrome obstructivo congénito de las vías aéreas altas). (AU)

Fraser syndrome or cryptophthalmos-syndactyly syndrome is a rare genetic disease, the diagnosis of which is based on a series of major and minor clinical criteria and that can be supported by genetic tests. This article presents the case of a fetal autopsy at 37 weeks of gestation with suspicion of CHAOS syndrome (congenital obstructive syndrome of the upper airways). (AU)

A propósito de un caso de síndrome de Fraser. Autopsia de un feto de 37 semanas de gestación con múltiples malformaciones / About a case of Fraser syndrome. Autopsy of a 37 weeks gestation fetus with multiple malformations

El síndrome de Fraser o síndrome criptoftalmos/sindactilia es una enfermedad genética rara, cuyo diagnóstico se basa en una serie de criterios clínicos mayores y menores, y que puede apoyarse en pruebas genéticas. En este artículo se presenta el caso de una autopsia fetal de 37 semanas de gestación con sospecha de síndrome de CHAOS (síndrome obstructivo congénito de las vías aéreas altas). (AU)

Fraser syndrome or cryptophthalmos-syndactyly syndrome is a rare genetic disease, the diagnosis of which is based on a series of major and minor clinical criteria and that can be supported by genetic tests. This article presents the case of a fetal autopsy at 37 weeks of gestation with suspicion of CHAOS syndrome (congenital obstructive syndrome of the upper airways). (AU)

Fraser syndrome with limb reduction defect: a rare and unique anatomic variation.

INTRODUCTION: Fraser syndrome, named after George Fraser, is an autosomal recessive disorder showing a highly variable interfamilial phenotypic variation, with malformations ranging from minor symptoms to lethal anomalies like renal agenesis, incompatible with survival. Limb reduction defects have not been reported to be associated with it. CASE PRESENTATION: A 21-year-old primigravida presented to the antenatal outpatient department with a level two targeted anomaly scan report suggestive of severe oligohydramnios with suspected renal agenesis. The cranial vault bones were compressed, and orbital globes and lenses could not be visualized. Renal agenesis was confirmed due to sleeping adrenals sign, non-visualization of the urinary bladder, and Doppler of renal arteries. A detailed examination of the fetal head in the sagittal section showed the absence of an eye globe and lens, arousing suspicion of Fraser syndrome. After pregnancy termination, a complete fetal autopsy was done to look for any additional findings. CONCLUSION: Patients who have a syndromic mix of acrofacial and urogenital abnormalities with or without cryptophthalmos should be evaluated for Fraser syndrome, which can be diagnosed by clinical examination and perinatal autopsy.

Whole exome sequencing identifies a novel FRAS1 mutation and aids in vitro fertilization with preimplantation genetic diagnosis in Fraser syndrome.

OBJECTIVE: To demonstrate the picture of a woman who had three times of pregnancies but fetuses were complicated with Fraser syndrome, a rare genetic disorder with multiple congenital anomalies. CASE REPORT: Here are three complicated pregnancies with predominant features of severe oligohydramnios and other variable intrafamilial presentations. We made a definite diagnosis, Fraser syndrome, with the assistance of whole exome sequencing (WES) via umbilical blood of the second and third fetus. The provision of a preimplantation diagnosis helped contribute a healthy newborn in this family. CONCLUSION: This paper provides insights into obscure antenatal presentations of Fraser syndrome with intrafamilial variance. Clinical uncertainty at the fetal stage suggests the role of WES to reach a final diagnosis, and a preimplantation diagnosis is applicable to avoid recurrence of genetic disorders in subsequent pregnancies.

Oral and Craniofacial Anomalies of Fraser Syndrome:Prosthetic Management.

Fraser syndrome (FS, MIM 219000) is a rare autosomal disorder characterized by systemic and oro-facial malformation, usually comprising cryptophthalmos, laryngeal malformations, syndactyly, and urogenital defects. We presented a 21-year-old FS case with partial missing teeth seeking aesthetic dental treatment. Clinical examination revealed bilateral cryptophthalmos, extensive syndactyly of hands and feet broad nose with the depressed nasal bridge, and surgically corrected bilateral cleft lip. She presented class III jaw relation and reduced the vertical height of the face. Prosthetic rehabilitation of the patient was done with upper and lower overlay dentures made from acrylic resin (VIPI BLOCK TRILUX®, VIPI Industria, Pirassununga, SP, Brazil) using computer-aided design (CAD) and computer-aided manufacturing (CAM) process. At the follow-up visit, the patient presented improved aesthetics and function. Proper management and rehabilitation of FS patients are challenging, but standard guidelines for oral health management are currently lacking. This article presents a case of Fraser syndrome presenting oral and craniofacial anomalies, and prosthetic rehabilitation was done. We also provided recommendations for the optimal oral health care for the FS patients. Functional adaptation and rehabilitation have significant roles in the various functions, survival, and quality of the life of FS patients. Integrated medicaldental care is needed in such patients with support from family members, friends, and colleagues.

Excluding embryos with two novel mutations in FREM2 gene by the next-generation sequencing-based single nucleotide polymorphism haplotyping.

Fraser syndrome is a rare autosomal recessive malformation disorder. It is characterized by cryptophthalmos, syndactyly, urinary tract abnormalities and ambiguous genitalia. This condition is due to homozygous or heterozygous mutations in the FRAS1, FREM1, FREM2, and GRIP1 genes. In the present study, we recruited a Chinese family with Fraser syndrome. Two novel mutations c.7542_7543insG and c.2689C>T in the FREM2 gene were detected in this Fraser syndrome family by PCR-based sequencing. The next-generation sequencing-based single nucleotide polymorphism haplotyping method was applied to exclude these two mutations in 9 blastocysts obtained from the patient. After obtaining consent and informing the risk, the patient received in vitro fertilization and embryo transfer treatment with an embryo carrying a heterozygous mutation. Finally, she delivered a healthy baby without any complications on March 17, 2019. In conclusion, we first reported two novel mutations in the FREM2 gene associated with the risk of Fraser syndrome. Moreover, we described a next-generation sequencing-based single nucleotide polymorphism haplotyping method to select the 'right' embryos from patients with Fraser syndrome for in vitro fertilization and embryo transfer treatment.

Bilateral anophthalmia and intrahepatic biliary atresia, two unusual components of Fraser syndrome: a case report.

BACKGROUND: Fraser syndrome or "cryptophthalmos syndrome" is a rare autosomal recessive disease. It is characterized by a group of congenital malformations such as: crytophthalmos, syndactyly, abnormal genitalia, and malformations of the nose, ears, and larynx. Although cryptophthalmos is considered as a main feature of Fraser syndrome, its absence does not exclude the diagnosis. Clinical diagnosis can be made by Thomas Criteria. Here we present the first documented case of Fraser Syndrome in Aleppo, Syria that is characterized by bilateral anophthalmia and intrahepatic biliary atresia. CASE PRESENTATION: During pregnancy, several ultrasound scans revealed hyperechoic lungs, ascites, and unremarkable right kidney at the 19th-week visit; bilateral syndactyly on both hands and feet at the 32nd-week visit. On the 39th week of gestation, the stillborn was delivered by cesarean section due to cephalopelvic disproportion. Gross examination showed bilateral anophthalmia, bilateral syndactyly on hands and feet, low set ears, and ambiguous genitalia. Microscopic examination of the lung, spleen, liver, ovary, and kidneys revealed abnormalities in these organs. CONCLUSION: The diagnosis of Fraser syndrome can be made prenatally and postnatally; prenatally by ultrasound at 18 weeks of gestation and postnatally by clinical examination using Thomas criteria. Moreover, intrahepatic biliary atresia was not described previously with Fraser syndrome; this recommends a more detailed pathologic study for Fraser syndrome cases.

Diagnosis of Fraser syndrome missed out until the age of six months old in a low-resource setting: a case report.

BACKGROUND: Fraser syndrome is a rare genetic disorder that often presents with ocular, renal, genital and limb's congenital anomalies. The prognosis of this genetic disorder depends on the severity of the combination of congenital malformations, some of which may be fatal. The diagnosis of Fraser syndrome is based on established clinical criteria and genetic tests. The criteria enabling clinical diagnosis are visible dysmorphic features present at birth, hence, Fraser syndrome can easily diagnosed at birth, except when health professionals are inexperienced in clinical recognition. Herein, we report a case of Fraser syndrome missed out at birth and fortuitously diagnosed at the age of six months in a bid to raise clinicians' awareness, particularly in resource-limited settings. CASE PRESENTATION: We report a case of a six-month-old Cameroonian female infant, born at home and taken the following day to a primary healthcare facility for neonatal care. Her mother had no antenatal care until birth. She presented at our health center with respiratory distress and fever. She had a temperature of 38.8 °C and signs of left lung basal consolidation, suggestive of a left lower lober pneumonia, confirmed on chest x-ray. Other incidental clinical findings were several dysmorphic features like bilateral cryptophthalmos, nasal malformation, anal imperforation (with a perianal fistula), an external genital anomaly and syndactyly characteristic of Fraser syndrome associated with pneumonia. The patient responded well to intravenous antibiotics for the treatment of her pneumonia. Thereafter, she was referred to a pediatric surgeaon for surgical corrections of her bilateral cryptophthalmos, anal imperforation, external genital defect and syndactyly. CONCLUSION: Here we presented a case of Fraser syndrome in a Cameroonian infant whose diagnosis was missed out at birth and fortuitously made at six months of age. In view of the serious and potentially fatal complications of this genetic disorder, we draw clinicians' attention, especially obstetricians, midwives and pediatricians for a high index of clinical suspicion geared at a timely diagnosis and management. Also, for a timely diagnosis, health education on regular antenatal and postnatal follow ups of  the mother-infant couple respectively, cannot be overemphasized.

Loss-of-function mutations in FREM2 disrupt eye morphogenesis.

Cryptophthalmos is a rare congenital disorder characterized by ocular dysplasia with eyelid malformation. Complete cryptophthalmos is characterized by the presence of continuous skin from the forehead over the eyes and onto the cheek, along with complete fusion of the eyelids. In the present study, we characterized the clinical manifestations of three patients with isolated bilateral cryptophthalmos. These patients shared the same c.6499C > T missense mutation in the FRAS1-related extracellular matrix protein 2 (FREM2) gene, while each individual presented an additional nonsense mutation in the same gene (Patient #1, c.2206C > T; Patient #2, c.5309G > A; and Patient #3, c.4063C > T). Then, we used CRISPR/Cas9 to generate mice carrying Frem2R725X/R2156W compound heterozygous mutations, and showed that these mice recapitulated the human isolated cryptophthalmos phenotype. We detected FREM2 expression in the outer plexiform layer of the retina for the first time in the cryptophthalmic eyes, and the levels were comparable to the wild-type mice. Moreover, a set of different expressed genes that may contribute secondarily to the phenotypes were identified by performing RNA sequencing (RNA-seq) of the fetal Frem2 mutant mice. Our findings extend the spectrum of FREM2 mutations, and provide insights into opportunities for the prenatal diagnosis of isolated cryptophthalmos. Furthermore, our work highlights the importance of the FREM2 protein during the development of eyelids and the anterior segment of the eyeballs, establishes a suitable animal model for studying epithelial reopening during eyelid development and serves as a valuable reference for further mechanistic studies of the pathogenesis of isolated cryptophthalmos.

Reconstruction of Unilateral Incomplete Cryptophthalmos in Fraser Syndrome.

A full-term baby girl with Fraser syndrome was born with right incomplete cryptophthalmos. On examination, the globe was completely covered with skin with partially formed eyelids laterally. At 3 years of age, she underwent an evisceration with orbital implant and reconstruction of the eyelids and fornices using the pre-existing scleral remnant. Custom ocular prosthetic fitting was performed 5 weeks postoperatively. At 4 years follow up, she continued to successfully retain an ocular prosthesis.

Variable presentation of Fraser syndrome in two fetuses and a novel mutation in FRAS1.

We report on a consanguineous family with three pregnancies affected with Fraser syndrome. We note severe brachydactyly is a manifestation of Fraser syndrome and found a novel homozygous splice site variation c.3293-2A>T in FRAS1. We would like to highlight variable manifestations of Fraser syndrome and the presence of oligohydramnios in the antenatal period often makes prenatal diagnosis clinically challenging.

Fraser syndrome: features suggestive of prenatal diagnosis in a review of 38 cases.

OBJECTIVE: Fraser syndrome (FS) is a rare malformation recessive disorder. Major criteria are cryptophtalmos, syndactyly, respiratory, genital and urinary tract anomalies. Few prenatal presentations have been reported. METHOD: We analyzed the prenatal and postnatal fetal phenotype in 38 cases of FS, including 25 pregnancy termination cases, 8 intra-uterine death cases and 4 cases that died after birth. RESULTS: Including both prenatal and postnatal fetal phenotypic evaluation, all cases presented dysmorphic features with nose and ear dysplasia. Renal anomalies and syndactyly were present in 37/38 cases, cryptophtalmos in 36/38, airways anomalies in 30/37 and genital anomalies in 30/35 cases. Anomalies of the abdominal wall such as low set umbilicus and omphalocele were found in 31 cases. Among the 26 cases for which ultrasound data were available, detectable anomalies included oligohydramnios (22), ascites/hydrops (9), renal anomalies (20), evidence for high airways obstruction (11), ophthalmologic anomalies (4), ear dysplasia (2) and syndactyly (2). CONCLUSION: This study shows that the postnatal phenotype of FS is very specific, whereas oligohydramnios hampers the prenatal recognition of the cardinal FS diagnosis criteria. Association of oligohydramnios, kidney agenesis and CHAOS should lead to consider this diagnosis. © 2016 John Wiley & Sons, Ltd.

Prenatal diagnosis of Fraser syndrome: a matter of life or death?

BACKGROUND: Fraser Syndrome is a rare, autosomal recessive syndrome. It's characterized primarily by cryptophthalmos, syndactyly and urogenital malformation. Respiratory malformations are frequently present and not taken into account. To better manage childbirth at the time of delivery it is crucial to get prenatal diagnosis early on in the pregnancy. CASE PRESENTATION: We are reporting a female infant born by natural birth with 46,XX. She was characterized phenotypically by cryptophthalmos, syndactyly, bilateral microtia and ambiguous genitalia. A prenatal ultrasound didn't revealed or raised any suspects for the Fraser Syndrome. It only discovered a unilateral kidney agenesis. At birth the infant showed a severe respiratory distress, intubation was attempted but it failed. The baby was transferred to Santobono-Pausilipon III level hospital. A tracheostomy was performed successfully and saved her life. Computerized Tomography revealed left microphthalmos and a malformation like-coloboma into right ocular globe with cysts and a small calcification parietal anterior. Genetic test revealed the typical mutations in the gene FREM2 confirming the diagnosis of Fraser Syndrome. In her fourth month, after birth, the infant was subjected to an operation to reconstruct eyelids with a mucous membrane graft. The left renal function was normal. The baby showed a delay in motor milestones for visual impairment. At the 19(th) month fallow-up, during a magnetic resonance it was revealed: a normal morphologic brain development, a thin presence in the right optic nerve and the visual cortex were developing. CONCLUSIONS: The prenatal diagnosis of Fraser Syndrome is frequently possible. The prenatal ultrasound can reveal features like polyhydramnios or oligohydramnios, echogenic lungs, renal abnormalities or agenesis and cryptophthalmos that are pathognomonic of the Fraser Syndrome. The health providers must keep in mind that if there are suspects of the Fraser Syndrome during prenatal exams, the infants could have a severe malformation in the respiratory tract.

Fraser Syndrome.

Fraser's Syndrome (FS) is a rare autosomal recessive disorder with a spectrum of malformations. The most consistent features are Cryptophthalmos (CO), syndactyly, genitourinary tract abnormalities, laryngeal and tracheal anomalies, craniofacial dysmorphism, malformations of the ear and nose, orofacial clefting and musculoskeletal defects. FS is genetically heterogeneous; so far mutations in FRAS1, FREM2 and GRIP1 genes have been linked to FS. FS can be diagnosed on clinical examination, pre-natal ultrasound or perinatal autopsy. We present a case of a 3 months old child born to consanguineous healthy parents with bilateral complete CO, unilateral microphthalmia, hypertelorism, syndactyly (hands and feet bilaterally), ambiguous genitalia with cryptorchidism and an umbilical hernia. We also present the criteria for diagnosing FS and the significant features on pre-natal ultrasonography. Around 200 case reports of patients with FS and CO have been published. To our knowledge, this is the first reported case of FS in Pakistan.

Fraser syndrome with laryngeal webs: Report of two cases and a review of the literature.

Fraser syndrome is a rare genetic disorder characterized by cryptophthalmos, syndactyly and laryngeal atresia. Although laryngeal webs occur uncommonly, they are the main cause of death in the first week of life in these patients. In this paper, we report two cases of Fraser syndrome with laryngeal webs. One of them was a twelve-year-old girl, primarily diagnosed with a supraglottic laryngeal web. In the course of treatment, a second web was also identified at the level of vocal cords, which is to our knowledge the first case of Fraser syndrome with two laryngeal webs in different levels.