RASopathies for Radiologists.

RASopathies are a heterogeneous group of genetic syndromes caused by germline mutations in a group of genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include neurofibromatosis type 1, Legius syndrome, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome, central conducting lymphatic anomaly, and capillary malformation-arteriovenous malformation syndrome. These disorders are grouped together as RASopathies based on our current understanding of the Ras/MAPK pathway. Abnormal activation of the Ras/MAPK pathway plays a major role in development of RASopathies. The individual disorders of RASopathies are rare, but collectively they are the most common genetic condition (one in 1000 newborns). Activation or dysregulation of the common Ras/MAPK pathway gives rise to overlapping clinical features of RASopathies, involving the cardiovascular, lymphatic, musculoskeletal, cutaneous, and central nervous systems. At the same time, there is much phenotypic variability in this group of disorders. Benign and malignant tumors are associated with certain disorders. Recently, many institutions have established multidisciplinary RASopathy clinics to address unique therapeutic challenges for patients with RASopathies. Medications developed for Ras/MAPK pathway-related cancer treatment may also control the clinical symptoms due to an abnormal Ras/MAPK pathway in RASopathies. Therefore, radiologists need to be aware of the concept of RASopathies to participate in multidisciplinary care. As with the clinical manifestations, imaging features of RASopathies are overlapping and at the same time diverse. As an introduction to the concept of RASopathies, the authors present major representative RASopathies, with emphasis on their imaging similarities and differences. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Aplasia cutis congénita: a propósito de un caso / Aplasia cutis congenita: case report / Aplasia congênita da cútis: relato do caso

La aplasia cutis congénita es una patología rara caracterizada por la ausencia de desarrollo de piel. Aunque puede localizarse en diferentes áreas del cuerpo, mayormente afecta el cuero cabelludo y puede extenderse a tejidos subyacentes. Presentamos aquí un caso clínico que se destaca por la extensión de la lesión. Se incluye la descripción del tratamiento y seguimiento del paciente.

Aplasia Cutis Congenita is a rare pathology characterized by the absence of development of the epidermis, and even though it can compromise any area of the body, it usually affects the scalp and it can be extended to the underlying tissues. We present a particular case due to the lesion size. It includes treatment description and follow-up.

A Aplasia Congênita da Cútis é uma patologia rara caracterizada pela ausência de desenvolvimento das epidermes, e embora possa se localizar em diferentes áreas do corpo, acomete principalmente o couro cabeludo e pode se espalhar para os tecidos subjacentes. Apresentamos aqui um caso clínico que se destaca pela extensão da lesão. Incluímos a descrição do tratamento e acompanhamento do paciente.

Dermoscopic characteristics of membranous aplasia cutis congenita: Report of 56 cases.

BACKGROUND: Membranous aplasia cutis congenita (MACC) presents at birth characterized by oval epidermis defect. Skin lesions with MACC have various clinic manifestations. In recent years, the usefulness of trichoscopy (scalp dermoscopy) has been reported for hair loss diseases. However, the dermoscopic features of MACC were mostly reported by case reports. OBJECTIVES: To summarized the obvious dermoscopic characteristics of MACC. MATERIALS & METHODS: These 56 cases met the clinical diagnostic criteria for MACC without forceps delivery complications or other birth injuries. To find the dermoscopic characteristics of MACC by summarizing 56 infants' dermoscopic pictures. RESULTS: The dermoscopic manifestation of MACC are characterized by hair follicle openings and hair deficiency in the center of skin lesions, translucent epidermis, hair root and hair bulb arranged along the margins of skin lesion. CONCLUSION: The typical dermoscopic characteristics of MACC could help clinicians to early diagnose and differential diagnosis.

Prenatal ultrasound findings of ectodermal dysplasia: a case report.

BACKGROUND: Ectodermal Dysplasia is a diverse group of inherited disorders characterized by a congenital defect in two or more ectodermal structures. Due to a fairly low incidence, to the best of our knowledge there are few clues that can assist in making an effective prenatal ultrasound diagnosis. Currently, the prenatal diagnosis of ectodermal dysplasia depends on a fetal genetic test combined with the family history. In this case report, we present a fetal case of ectodermal dysplasia with a remarkable prenatal ultrasound image, genetic testing, family history, and relevant exams of the stillbirth. CASE PRESENTATION: A multipara with a 22-week singleton male pregnancy undergoing a fetal ultrasound examination. The image showed a hypoplastic maxilla and mandible. Subsequently, the ectodermal dysplasia was defined using a family history and genetic testing. The skin pathology from the aborted fetus demonstrated a hypohidrotic type. The computed tomography (CT) reconstruction after induced labor confirmed the prenatal ultrasound findings of the maxilla and mandible. CONCLUSIONS: This case suggested that prenatal ultrasound may provide a valuable clue of ectodermal dysplasia. The diagnosis can be established using further prenatal genetic testing and a family history.

Prenatal sonographic diagnosis of X-linked hypohidrotic ectodermal dysplasia: An unusual case.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare congenital genetic disorder caused by mutations in the ectodysplasin A gene, resulting in dysplasia or complete absence of teeth, hair, and sweat glands. XLHED is rarely diagnosed prenatally. We describe a case of XLHED diagnosed with prenatal sonography and umbilical cord blood gene testing.

Enlarged spinal nerve roots in RASopathies: Report of two cases.

RASopathies are a group of genetic conditions caused by germline variants in genes encoding signal transducers and modulators of the RAS-MAPK cascade. These disorders are multisystem diseases with considerable clinical overlap, even though distinct hallmarks are recognizable for each specific syndrome. Here we report on the presence of enlarged spinal nerve roots resembling neurofibromas, a typical neuroradiological finding of neurofibromatosis type 1, in two patients with a molecularly confirmed diagnosis of Noonan syndrome and cardio-facio-cutaneous syndrome, respectively. This evidence add enlarged spinal nerve roots as features shared among RASopathies. Future studies aiming to a better understanding of the molecular mechanisms leading to neurogenic tumor development in these patients are necessary to define their biological nature, evolution, prognosis and possible treatments.

Central nervous system variations and abnormalities in anhidrotic ectodermal dysplasia (AED): neuroimaging findings.

BACKGROUND: Anhidrotic ectodermal dysplasia (AED) is a rare, mostly X-linked recessive genodermatosis, characterized by congenital defects of ectodermal derivative structures as the central nervous system (CNS) is primarily ectodermal in origin. PURPOSE: To evaluate CNS variations and abnormalities in AED. MATERIAL AND METHODS: A retrospective analysis was made of the neurological and neuroimaging findings of 17 children (12 boys, 5 girls; median age = 8 years; age range = 2-14 years) diagnosed with AED in our pediatric clinics during 2008-2016. The pattern of CNS variation and abnormalities were evaluated by comparing of these findings with an age- and gender-matched healthy control group with no family history. RESULTS: Of the 17 AED cases identified on the basis of neuroimaging findings, 6 (35.3%) were seen to be normal. Associated CNS variation and abnormalities including cavum septum pellucidum (35.3%), callosal dysgenesis (11.8%), prominent Virchow-Robin spaces (64.7%), cortical sulcal dilation (41.1%), mega cisterna magna (35.3%), focal cortical dysplasia (11.8%), and delayed myelination (58.8%) were observed in 11 (64.7%) children with AED. CONCLUSION: AED suggests a spectrum of CNS variation and abnormalities, presenting with neurological and neuroimaging findings, demonstrated in the embryonic surface- and neuro-ectoderm derived structures. The results of this study suggest that CNS variation and abnormalities might be associated with AED.

Severe forms of Johanson-Blizzard syndrome caused by two novel compound heterozygous variants in UBR1: Clinical manifestations, imaging findings and molecular genetics.

Johanson-Blizzard Syndrome (JBS) is a rare autosomal recessive genetic disorder characterized by exocrine pancreatic insufficiency, distinct abnormal facial appearance and varying degrees of growth retardation. Variants in UBR1 gene are considered to be responsible for the syndrome. Here, we describe a 3-year old boy, who visited our clinic for severe growth retardation and frequent oily diarrhea. The physical examination revealed nasal alae aplasia, scalp defect, and maldescent of left testicle. Transabdominal ultrasound and computed tomography scan of his abdomen demonstrated complete fatty replacement of the pancreas. The clinical, laboratory, and imaging findings strongly suggest the diagnosis of hereditary pancreatitis. Whole exome sequencing revealed two rare compound heterozygous variants, c.2511T > G (p.H837Q) and c.1188T > G (p.Y396X), in the UBR1 gene of this boy, so, the diagnosis of JBS was established. This is the first report of Chinese patient with JBS, and our study indicates that transabdominal ultrasound and computed tomography are two useful and noninvasive imaging methods for the diagnosis and evaluation of JBS, and identification of these two novel variants expands the database of UBR1 gene variants. Furthermore, with the availability of the identification technology for these variants, prenatal diagnosis could be offered for future pregnancies.

Reconstruction of Congenital Cranial Defect Using Autologous Bone Graft in Aplasia Cutis Congenita.

Many methods have been devised to repair cranial defects. Here, we report the use of a simple technique for the repair of a congenital cranial defect associated with aplasia cutis congenita (ACC).A newborn baby at 39 weeks of gestation was consulted with a scalp and cranial defect at the vertex measuring 3 × 1.5 cm. A 3-D CT scan of the skull confirmed the presence of a cranial defect at the sagittal suture and a normal brain structure. On the 13 day of life, the newborn was taken to an operating room. An autologous bone graft was harvested from adjacent normal parietal bone and grafted into the debrided congenital cranial defect. The soft tissue defect was then covered by rotation flaps.The postoperative 3-D CT scan presented a well-positioned autologous bone graft. At 1 month postoperatively, the skull contour was normal and there was no palpable defect.We report a successful surgical outcome for a congenital cranial and soft tissue defect in ACC treated using an autologous bone graft and rotation flaps. Although conservative therapy may be an alternative option, we recommend appropriate surgical reconstruction in patients at risk of potentially fatal complications.

Skeletal ciliopathies: a pattern recognition approach.

Ciliopathy encompasses a diverse group of autosomal recessive genetic disorders caused by mutations in genes coding for components of the primary cilia. Skeletal ciliopathy forms a subset of ciliopathies characterized by distinctive skeletal changes. Common skeletal ciliopathies include Jeune asphyxiating thoracic dysplasia, Ellis-van Creveld syndrome, Sensenbrenner syndrome, and short-rib polydactyly syndromes. These disorders share common clinical and radiological features. The clinical hallmarks comprise thoracic hypoplasia with respiratory failure, body disproportion with a normal trunk length and short limbs, and severely short digits occasionally accompanied by polydactyly. Reflecting the clinical features, the radiological hallmarks consist of a narrow thorax caused by extremely short ribs, normal or only mildly affected spine, shortening of the tubular bones, and severe brachydactyly with or without polydactyly. Other radiological clues include trident ilia/pelvis and cone-shaped epiphysis. Skeletal ciliopathies are commonly associated with extraskeletal anomalies, such as progressive renal degeneration, liver disease, retinopathy, cardiac anomalies, and cerebellar abnormalities. In this article, we discuss the radiological pattern recognition approach to skeletal ciliopathies. We also describe the clinical and genetic features of skeletal ciliopathies that the radiologists should know for them to play an appropriate role in multidisciplinary care and scientific advancement of these complicated disorders.

Cardiofaciocutaneous syndrome with KRAS gene mutation presenting as chylopericardium.

A 12-year-old female patient with cardiofaciocutaneous syndrome in the presence of a KRAS gene mutation had episodes of pericardial effusion on ultrasound, later confirmed to be chylopericardium, which resolved after a lymphangiography. We discussed herein the pathophysiological background of this rare case and the efficacy of lymphangiography in the treatment of chylopericardium.

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

OBJECTIVES: To give an overview of the genetic and structural abnormalities occurring in fetuses with nuchal translucency (NT) measurement exceeding the 95th percentile at first-trimester screening and to investigate which of these abnormalities would be missed if cell-free fetal DNA (cfDNA) were used as a first-tier screening test for chromosomal abnormalities. METHODS: This is a national study including 1901 pregnancies with NT≥95th percentile referred to seven university hospitals in the Netherlands between 1 January 2010 and 1 January 2016. All cases with unknown pregnancy outcome were excluded. Results of detailed ultrasound examinations, karyotyping, genotyping, pregnancy and neonatal outcomes, investigation by a clinical geneticist and post-mortem investigations were collected. RESULTS: In total, 821 (43%) pregnancies had at least one abnormality. The rate of abnormalities was 21% for fetuses with NT between 95th and 99th percentile and 62% for fetuses with NT≥99th percentile. Prevalence of single-gene disorders, submicroscopic, chromosomal and structural abnormalities was 2%, 2%, 30% and 9%, respectively. CONCLUSION: Although cfDNA is superior to the combined test, especially for the detection of trisomy 21, 34% of the congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic assessment, including NT measurement.

Antenatal diagnosis of cardio-facio-cutaneous syndrome: Prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. About a case and review of literature.

Antenatal diagnosis of cardio-facio-cutaneous syndrome: prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. This paper is a case study and review of literature. "RASopathies" is the term coined for a group of genetic diseases that share modulation inside the MAPKinase pathway. Mutations inside the coding sequence of any of these genes may be responsible for the upregulation of the RAS pathway, leading on the clinical level to Type 1 Neurofibromatosis (NF1), Noonan syndrome (NS), Costello syndrome (CS), Multiple Lentigines, Loose Anagen Hair syndrome, Cardio-Facio-Cutaneous syndrome (CFCS), and, more recently, Legius syndrome. While the postnatal presentation of this group is well-known, prenatal findings are less well recognized. The presence of a RASopathy during the prenatal period can be suspected on account of non-specific abnormalities: polyhydramnios, cystic hygroma or high nuchal translucency, macrosomia with proportionate short long bones, macrocephaly, renal, lymphatic, or cardiac defects. The current case report underlines the characteristic dysmorphic facial features on 3D-ultrasound (hypertelorism, down-slanting palpebral fissures, a long and marked philtrum, and low-set posteriorly rotated ears) that allow for a "RASopathy" to be postulated. After detecting a copy number variation (CNV) absence on a CGH array, we performed a RASopathy gene panel analysis, which identified a so-far unreported heterozygous de novo mutation in the BRAF gene (namely NM_004333.4 : c.1396 G > C ; p.Gly466Arg). Genetic counseling has, therefore, focused on the diagnosis of a RASopathy and predictable phenotype of CFCS, a distinct entity characterized by an increased risk of intellectual disability and early-onset feeding problems. We suggest that a more detailed prenatal facial evaluation should be performed in fetuses presenting high nuchal thickness, heart defects, or unusual findings, along with the absence of a CNV on a CGH array. Due to the dysmorphic facial features, targeted RASopathy genes are presumed to likely to be responsible for NS, CFCS, and CS.

Morfología de las glándulas de Meibomio valorada por meibografía en pacientes con displasia ectodérmica hipohidrótica / Morphology of the Meibomian gland evaluated using meibography in patients with hypohidrotic ectodermal displasia

Introducción: La displasia ectodérmica hipohidrótica (DEH) es una enfermedad rara caracterizada por la anormal formación de los tejidos derivados del ectodermo. La hipoplasia de las glándulas de Meibomio es una de las manifestaciones oftalmológicas más frecuentes en estos pacientes. Se planteó estudiar la morfología de las glándulas de Meibomio mediante meibografía en un grupo de pacientes con DEH y compararlo con un control. Métodos: Se incluyeron 14 ojos de 7 pacientes diagnosticados de DEH. Y un grupo control con 32 ojos de 16 pacientes. Se les realizó un estudio meibográfico mediante el analizador corneal CA-800 de Topcon®. Se usó una escala meibográfica para valorar el grado de atrofia glandular. Grado 0, sin alteraciones, grado 1 afectación < 25% de ácinos glandulares, grado 2 atrofia entre el 25 y 50%, grado 3, entre el 51-75% y grado 4, alteración > 75%. En la comparación estadística se utilizaron los test no paramétricos de Mann-Whitney. Resultados: Todos los pacientes con DEH mostraron algún grado de afectación. El 57% presentó atrofia severa > 75%. El 35,8% presentó un grado 3 y el 7,2% grado 2. El grado medio de atrofia glandular en DEH fue de 3 (rango 1-4). En el grupo control el 62,5% no presentaron afectación alguna, grado 0. El 28,1% grado 1 y el 9,4% un grado 2. El grado medio de atrofia glandular fue de 0 (0,2). Se encontraron diferencias estadísticamente significativas entre los grupos. Conclusiones: La meibografía es una prueba diagnóstica sencilla que permite diferenciar entre pacientes sanos y con DEH

Introduction: Hypohidrotic ectodermal dysplasia (HED) is a rare disease that results from the abnormal development of the ectodermal germ layer in early embryogenesis. In these patients, hypoplasia of Meibomian glands is one of the most frequent ophthalmological manifestations. The main aim of this study is to evaluate the usefulness of meibography for the morphology of Meibomian glands in a group of patients with HED, and to compare it with a control group. Methods: A total of 14 eyes of 7 patients diagnosed with HED were included, and 32 eyes of 16 patients were included as a control group. The meibographic study was carried out using CA-800 Corneal Analyser (Topcon®). Grading of images was assessed by a meibomian gland atrophy score: grade 0, no alterations; grade 1, ≤25% gland atrophy; grade 2, 25% to 50% gland atrophy; grade 3, 51% to 75% gland atrophy; and grade 4 >75% gland atrophy. Both groups were compared using the Mann-Whitney U non-parametric test. Results: All patients with HED showed some degree of gland atrophy, with 57% showing severe atrophy (>75% of gland atrophy), 35.8% with a grade 3, and 7.2% grade 2. The mean grade of glandular atrophy in HED was 3 (1-4). In the control group, 62.5% had no involvement (grade 0), with 28.1% showing grade 1 and 9.4% grade 2 gland atrophy. The mean glandular atrophy grade within the control group was 0 (0-2). There were statistically significant differences between both groups. Conclusions: Meibography is a simple diagnostic tool that allows to differentiate between patients without disease and those with HED

Distinct impacts of bi-allelic WNT10A mutations on the permanent and primary dentitions in odonto-onycho-dermal dysplasia.

Odonto-onycho-dermal dysplasia (OODD) is a rare autosomal recessive syndrome characterized by multiple ectodermal abnormalities. Mutations of the wingless-type MMTV integration site family member 10A (WNT10A) gene have been associated with OODD. To date, only 11 OODD-associated WNT10A mutations have been reported. In this report, we Characterized the clinical manifestations with focusing on dental phenotypes in four unrelated OODD patients. By Sanger sequencing, we identified five novel mutations in the WNT10A gene, including two homozygous nonsense mutations c.1176C>A (p.Cys392*) and c.742C>T (p.Arg248*), one homozygous frame-shift mutation c.898-899delAT (p.Ile300Profs*126), and a compound heterozygous mutation c.826T>A (p.Cys276Ser) and c.949delG (p.Ala317Hisfs*121). Our findings confirmed that bi-allelic mutations of WNT10A were responsible for OODD and greatly expanded the mutation spectrum of OODD. For the first time, we demonstrated that bi-allelic WNT10A mutations could lead to anodontia of permanent teeth, which enhanced the phenotypic spectrum of WNT10A mutations. Interestingly, we found that bi-allelic mutations in the WNT10A gene preferentially affect the permanent dentition rather the primary dentition, suggesting that the molecular mechanisms regulated by WNT10A in the development of permanent teeth and deciduous teeth might be different.

Etiología, manifestaciones clínicas y estudio por imágenes de la displasia ectodérmica: Una revisión de la literatura / Etiology, clinical manifestations and study by images of ectodermal dysplasia: a literature review

La displasia ectodérmica (DE) es un trastorno hereditario multisistémico que involucra dos o más de las estructuras ectodérmicas, que incluyen alteraciones en la piel, cabello, uñas, dientes y glándulas sudoríparas. Las manifestaciones bucales más frecuentes son alteraciones dentarias en número y forma, como anodoncias e hipodoncias en ambas denticiones, gérmenes dentarios distróficos, dientes impactados, en forma de clavija, conoides, microdoncia, diastemas, etc. El diagnóstico clínico siempre va acompañado de estudios imagenológicos y, según la edad en que se diagnostique, el tratamiento siempre estará dirigido a restablecer y mejorar la calidad de vida. El objetivo de este trabajo es revisar la etiología, las manifestaciones clínicas y las características imagenológicas observadas en radiografías panorámicas, laterales de cráneo, cefalometrías y tomografías computarizadas de haz cónico (TCHC), con la finalidad de contribuir y ser parte del manejo multidisciplinario para lograr diagnósticos y tratamientos seguros y confiables. (AU)

Ectodermal dysplasia (ED) is a multi-systemic hereditary disorder, involving two or more of the ectodermal structures, which includes alterations in the skin, hair, nails, teeth and sweat glands.The most frequent oral manifestations are dental alterations in number and form such as: anodontias and hypodontias in both primary and permanent dentitions, dystrophic tooth buds, impacted, peg-shaped, conoid teeth, microdontia, dias-tema, etc. Clinical diagnosis is always accompanied by imaging studies and depending on the age at time of diag-nosis, treatment is aimed at restoring and improving quality of life.The objective of this study is to review the etiology, clinical manifestations and imaging characteristics observed in panoramic and lateral skull radio-graphs, cephalometry and cone beam computed tomography (CBCT), in order to contribute to multidisciplinary manage-ment, diagnoses, and safe and reliable treatments. (AU)

Etiología, manifestaciones clínicas y estudio por imágenes de la displasia ectodérmica: Una revisión de la literatura / Etiology, clinical manifestations and study by images of ectodermal dysplasia: a literature review

La displasia ectodérmica (DE) es un trastorno hereditario multisistémico que involucra dos o más de las estructuras ectodérmicas, que incluyen alteraciones en la piel, cabello, uñas, dientes y glándulas sudoríparas. Las manifestaciones bucales más frecuentes son alteraciones dentarias en número y forma, como anodoncias e hipodoncias en ambas denticiones, gérmenes dentarios distróficos, dientes impactados, en forma de clavija, conoides, microdoncia, diastemas, etc. El diagnóstico clínico siempre va acompañado de estudios imagenológicos y, según la edad en que se diagnostique, el tratamiento siempre estará dirigido a restablecer y mejorar la calidad de vida. El objetivo de este trabajo es revisar la etiología, las manifestaciones clínicas y las características imagenológicas observadas en radiografías panorámicas, laterales de cráneo, cefalometrías y tomografías computarizadas de haz cónico (TCHC), con la finalidad de contribuir y ser parte del manejo multidisciplinario para lograr diagnósticos y tratamientos seguros y confiables. (AU)