Multiple Developmental Anomalies Research Articles

Specific brain MRI features of constitutional mismatch repair deficiency syndrome in children with high-grade gliomas.

Children with constitutional mismatch repair deficiency (CMMRD) syndrome have an increased risk of high-grade gliomas (HGG), and brain imaging abnormalities. This study analyzes brain imaging features in CMMRD syndrome children versus those with HGG without CMMRD. Retrospective comparative analysis of brain imaging in 30 CMMRD children (20 boys, median age eight years, 22 with HGG), seven with Lynch syndrome (7 HGG), 39 with type 1 neurofibromatosis (NF1) (four with HGG) and 50 with HGG without MMR or NF1 pathogenic variant ("no-predisposition" patients). HGG in CMMRD and Lynch patients were predominantly hemispheric (versus midline) compared to NF1 and no-predisposition patients (91% and 86%, vs 25% and 54%, p = 0.004). CMMRD-associated tumors often had ill-defined boundaries (p = 0.008). All CMMRD patients exhibited at least one developmental venous anomaly (DVA), versus 14%, 10%, and 6% of Lynch, NF1, and no-predisposition patients (p < 0.0001). Multiple DVAs were observed in 83% of CMMRD patients, one NF1 patient (3%), and never in other groups (p < 0.0001). Cavernomas were discovered in 21% of CMMRD patients, never in other groups (p = 0.01). NF1-like focal areas of high T2-FLAIR signal intensity (FASI) were more prevalent in CMMRD patients than in Lynch or no-predisposition patients (50%, vs 20% and 0%, respectively, p < 0.0001). Subcortical and ill-limited FASI, possibly involving the cortex, were specific to CMMRD (p < 0.0001) and did not evolve in 93% of patients (13/14). Diffuse hemispherically located HGG associated with multiple DVAs, cavernomas, and NF1-like or subcortical FASI strongly suggests CMMRD syndrome compared to children with HGG in other contexts. The radiologic suggestion of CMMRD syndrome when confronted with HGGs in children may prompt genetic testing. This can influence therapeutic plans. Therefore, imaging features could potentially be incorporated into CMMRD testing recommendations. Using imaging to detect CMMRD syndrome early may improve patient care. CMMRD features include: hemispheric HGG with multiple developmental venous anomalies and NF1-like or subcortical areas with high T2-FLAIR intensity. We propose novel imaging features to improve the identification of potential CMMRD patients.

De novo cerebral cavernous malformations with PIK3CA somatic mutation and EPHB4 germline mutation in a child with multiple developmental venous anomalies and cutaneous vascular malformations.

Cavernous malformations (CM) that arise in the central nervous system have long been considered congenital, while there are many reports of de novo non-familial-type CM adjacent to developmental venous anomalies (DVA) or after radiation. The mechanisms that cause de novo formations of sporadic cavernous malformation (CM) still remain unknown and purely speculative. We report a case of de novo cerebral CM in a child with multiple developmental venous anomalies and cutaneous vascular malformations. Histological examination and whole-exome sequencing (WES) was performed on a fresh-frozen tissue sample of the CM. WES revealed 2 missense non-synonymous variants in two genes, EPHB4 and PIK3CA. The mutant allele of EPHB4 (NM_004444.4: c.1840T > C, p.Y614H) appeared in 248/469 WES reads (allele frequency, 52.88%), which suggested the mutation a germline one. PIK3CA (NM_006218.2) somatic mutations were found in exon 9: c.1624G > A (p.Glu542Lys) with variant frequency of 2.2% (2/89 WES reads). We did not find any non-synonymous mutations of the three CCM genes (KRIT1, CCM2, and PDCD10) in this patient. Our findings suggested that the combination of gain of function in PIK3CA and loss of function in EPHB4 may play an important role in the pathogenesis of CM, which can develop in acquired form like tumorigenesis.

The case of determining the species, gender, age and race of the skull with congenital multiple developmental anomalies

In forensic medicine, a reconstructive victim profile is a widely used procedure for providing individual data in cases of complex identification of a person. The most valuable data such as gender, age, origin and height are obtained from skeletal and dental analyses. Deformed skulls require special expert attention during the forensic examination of bone remains. Unusual skull shapes are usually formed with certain diseases (hydrocephalus, craniostenosis, rickets), various kinds of injuries or as a result of artificial (intentional) changes in the shape of the head. The detection of cranial deformity has a great forensic importance in identifying a person, allowing you to further outline the range of diseases that an unknown person could have suffered during his lifetime. The article describes a rare forensic case of identification of a human skull with congenital multiple developmental anomalies. During the forensic medical and forensic examination, the deceased had a history of signs of a rare disease characterized by the formation of a specific deformation of the skull. A comprehensive assessment of the data is very important when conducting forensic medical studies aimed at helping investigative authorities to identify human remains.

Cerebral developmental venous anomalies in children with mismatch repair deficiency

Constitutional mismatch repair deficiency (CMMRD) is one of the rare cancer predisposition syndromes. The aim of this study was to evaluate the cerebral developmental venous anomalies in children with central nervous system tumors associated with CMMRD, an area in which there is extremely little experience. Data from children diagnosed with medulloblastoma and high grade central nervous sytem tumor were retrospectively collected. According to the European CMMRD criteria, nine patients were diagnosed as CMMRD syndrome and the others consisted of the group without CMMRD. All radiological examinations of these children were retrospectively reviewed. Whole exome sequencing was performed to index cases` germline DNA. Nine children from four families, six females and three males, were studied. The median age at the first tumor diagnosis was 4.5 years (range, 9 months to 14 years). All CMMRD patients had café au lait spots, but none fulfilled the diagnostic criteria for neurofibromatosis. The patients developed high-grade glial tumor (n: 7) and medulloblastoma (n: 2). The affected genes in the three families were MSH6 [c.478C > T (p.Gln160Ter)], MSH6 [c.2871dupC (p.Phe958LeufsTer5)] and MLH1 [c.236G > A(p.Arg79Lys)], respectively. Seven patients had multiple developmental venous anomalies; six patients had leptomeningeal enhancement; and five patients had cavernomas. None of these findings were present in the group without CMMRD. Constitutional mismatch repair deficiency should be considered when multiple developmental venous anomalies, cavernomas, and leptomeningeal enhancement are detected, especially in patients with café au lait spots.

Multiple developmental craniovertebral junction anomalies associated with fusion of the third and fourth cervical vertebrae: A case report and review of the literature

Craniovertebral junction (CVJ) is formed by the occipital condyles of the skull, atlas (C1), and axis (C2). CVJ anomalies are a complex group of disorders with a variable course and complicated line of management. A cross-sectional imaging is indispensable for the evaluation of CVJ as it may unmask pathologies unsuspected by clinical evaluation and conventional radiography. We present a case report in which we describe multiple developmental CVJ anomalies in a 25-year-old male patient. These include fusion defects of anterior and posterior arches of C1, os odontoideum, atlantoaxial subluxation (with compression of the cervical cord at the cervicomedullary junction), and fusion of C3 and C4 vertebral bodies as well as posterior elements.

Functional Versatility of the CDK Inhibitor p57Kip2.

The cyclin/CDK inhibitor p57Kip2 belongs to the Cip/Kip family, with p21Cip1 and p27Kip1, and is the least studied member of the family. Unlike the other family members, p57Kip2 has a unique role during embryogenesis and is the only CDK inhibitor required for embryonic development. p57Kip2 is encoded by the imprinted gene CDKN1C, which is the gene most frequently silenced or mutated in the genetic disorder Beckwith–Wiedemann syndrome (BWS), characterized by multiple developmental anomalies. Although initially identified as a cell cycle inhibitor based on its homology to other Cip/Kip family proteins, multiple novel functions have been ascribed to p57Kip2 in recent years that participate in the control of various cellular processes, including apoptosis, migration and transcription. Here, we will review our current knowledge on p57Kip2 structure, regulation, and its diverse functions during development and homeostasis, as well as its potential implication in the development of various pathologies, including cancer.

Expression of calretinin in odontogenic keratocysts and basal cell carcinomas: A study of sporadic and Gorlin-Goltz syndrome-related cases

Gorlin-Goltz syndrome (GGS), is an autosomal dominant inherited disorder related to germline mutation of PTCH1 gene, characterised by the presence of multiple developmental anomalies and tumours, mainly basal cell carcinomas (BCC) and odontogenic keratocysts (OKC).We analysed and compared the expression of calretinin in 16 sporadic OKCs, from 15 patients, and 12 syndromic OKCs from 11 patients; in 19 BCC's and 2 cutaneous keratocysts (CKC) belonging to 4 GGS patients, 15 sporadic BCCs and 3 steatocystomas (SC).Calretinin was negative in 10 of 12 syndromic OKCs, focally positive (<5% of cells) in 2; six sporadic OKCs were negative, 6 focally and 4 diffusely positive (p = .02, cases focally and diffusely positive vs. cases negative). All BCCs of 3 GGS patients were negative, the fourth patient presented two BCCs negative and 5 focally or diffusely positive; 7 sporadic BCCs were negative and 8 focally positive (p = NS). Two CKCs resulted negative in one GGS patient; 2 sporadic SCs were positive, and a third was negative.PTCH1 mutations produce an altered PTCH protein and an aberrant activation of Sonic hedgehog (SHH) pathway, leading to tumoral proliferation. It has been demonstrated that treatment of human foetal radial glia cells with SHH reduces, whereas the blockage of SHH increases calretinin expression. We found a lower expression of calretinin in syndromic OKCs compared to sporadic cases. Although calretinin's value in differential diagnosis between sporadic and syndromic tumours appears not crucial, our results shed light on the possible link between SHH dysfunction and calretinin expression in GGS-related tumours.

Treatment of congenital clubfoot in a patient with Jacobsen syndrome using Ponseti method: A case report

Introduction. Jacobsen syndrome, characterized by multiple developmental anomalies, is a rare genetic syndrome caused by a partial deletion of the long arm of the 11th chromosome. The incidence is 1 : 100,000 live births. Patients of this group have malformations of the heart, kidneys, gastrointestinal tract, central nervous system, and skeleton. The severity of clinical features is diverse. Jacobsen syndrome rarely combines with a congenital clubfoot.&#x0D; Case report. The clinical case of using the Ponseti method for the treatment of congenital clubfoot in combination with Jacobsen syndrome is presented. As a result, a complete primary correction of the foot was obtained, which did not relapse within 2 years.&#x0D; Discussion. Only brief references to this pathology were found in the literature. In the case of our patient, a greater number of gypsum dressings were required to complete the primary correction of the foot.&#x0D; Conclusion. Painless foot has been achieved, which has a full range of motion, which confirms the success of the application of the Ponseti method for the treatment of non-idiopathic congenital clubfoot and the need for using it as a starting method.

Pediatric Congenital Cerebrovascular Anomalies.

Congenital cerebrovascular anomalies in the pediatric age group are myriad with diverse etiologies. The purpose of this paper is to provide an imaging overview of congenital vascular malformations and vascular tumors, as these conditions are varied and the characteristic vascular abnormality may even suggest the underlying systemic condition in helping to guide further management. For example, the identification of an arterial anomaly such as agenesis/hypoplasia/duplication may warrant further evaluation for an associated syndrome. Recognition of other pertinent findings, such as persistent carotid-vertebrobasilar anastomoses for instance, would be particularly important for the planning of potential embolization/coiling of associated vascular malformation and/or aneurysm. Awareness of congenital dural sinus anomalies, including hypoplasia, aplasia, and or duplication, prevents the incorrect or overdiagnosis of sinus thrombosis. Moreover, multiple developmental venous anomalies in a patient may require further investigation for its familial association. In a similar context, there may be familial association with multiple cavernous malformations and children with central nervous system vascular malformations may have an association with other vascular conditions, eg, hereditary hemorrhagic telangiectasia, etc. An accurate description of vascular lesions is critical for understanding the natural history of the disease process and ultimately for guiding treatment. An important example of this includes Sturge-Weber syndrome, which is often incorrectly viewed as an arteriovenous malformation, but actually a type of venous malformation. Another example which is important to recognize includes the differentiation between an infantile hemangioma and a vascular malformation, particularly as the course of the pathology and the treatment is so different between the two.

Multiple Brain Developmental Venous Anomalies as a Marker for Constitutional Mismatch Repair Deficiency Syndrome.

Biallelic constitutional mutations in DNA mismatch repair genes cause a distinct syndrome, constitutional mismatch repair deficiency syndrome (CMMRD), characterized by cancers from multiple organs, most commonly brain tumors, during childhood. Surveillance protocols include total and brain MR imaging among other modalities to enable early detection of tumors. Brain surveillance scans revealed prominent brain developmental venous anomalies (DVAs) in some patients. DVAs are benign vascular anomalies, and their incidence in the general population is 2.6%-6.4%. Most developmental venous anomalies are asymptomatic and are found incidentally. Our purpose was to assess the prevalence of DVAs in CMMRD patients and describe their phenotype. A retrospective descriptive analysis of brain MR imaging studies from 10 patients from 3 families with CMMRD was performed. Analysis included the number of developmental venous anomalies, location, draining vessels, and associated vascular anomalies (ie, cavernomas), with clinical correlation of symptoms and tumors. All 10 patients had ≥2 developmental venous anomalies, and 2 had, in addition, non-therapy-induced cavernomas. There was no clinically symptomatic intracranial bleeding from developmental venous anomalies. Six patients had malignant brain tumors. The location of brain tumors was not adjacent to the developmental venous anomalies. No new developmental venous anomalies developed during follow-up. The occurrence of multiple developmental venous anomalies in all our patients with CMMRD suggests that developmental venous anomalies may be a characteristic of this syndrome that has not been previously described. If confirmed, this quantifiable feature can be added to the current scoring system and could result in early implementation of genetic testing and surveillance protocols, which can be life-saving for these patients.

Identification of circular RNAs and their alterations involved in developing male Xenopus laevis chronically exposed to atrazine

Atrazine (AZ) is an environmental endocrine disrupting chemical which can affect the development of amphibians. In our past studies, we demonstrated that chronical exposure to 100 μg/L AZ can cause abnormalities in development and related genes expression of gonads in developing male Xenopus laevis (X. laevis) tadpoles. Recent studies by others have demonstrated that circular RNAs (circRNAs) are implicated in multiple developmental anomalies. However, whether circRNAs involve in the effects in AZ-exposed X. laevis remains unknown. In this study, over 68575 circRNAs were detected by circRNA sequencing of testis tissues from control groups (n = 3) and AZ-treated X. laevis (n = 3). Treatment of AZ led to 405 circRNAs differentially expressed including 44 upregulated and 361 downregulated compared with froglets in the control groups. Two upregulated and 6 downregulated circRNAs were further validated by real-time PCR assay which displayed consistent regulation patterns as shown by the transcriptome sequencing results. Two hundreds and eighty two differentially expressed circRNAs played miRNA sponges roles. Kyoto Encyclopedia of Genes and Genomes pathway analysis of miRNA targets showed that AZ-affected circRNAs are mainly involved in 19 pathways. The Wnt signaling pathway and progesterone-mediated oocyte maturation pathway may be two involved signal pathways. This study for the first time provides evidence that AZ can alter circRNAs which play a role in AZ-induced testicular degeneration of developing male X. laevis through regulation of expressions of functional genes in the testes of X. laevis.

Anatomical variations and developmental anomalies of the thyroid gland in Ethiopian population: a cadaveric study.

Because of its embryonic origin, the thyroid gland is predisposed to multiple anatomical variations and developmental anomalies. These include the pyramidal lobe, the origin of levator glandular thyroidae, the absence of the isthmus, ectopic thyroid, accessory thyroid tissues, etc. These anatomical variations are clinically significant to surgeons, anatomists, and researchers. The present study was designed to report anatomical variations and developmental anomalies of the thyroid gland in Ethiopian population. The study was conducted on 40 cadavers used for routine dissection classes. The thyroid gland was exposed and observed for any variations and developmental anomalies. The length, width, and thickness of the lobes were measured using a vernier caliper. Differences in the incidence of pyramidal lobe and absence of the isthmus between sexes were tested using a Pearson chi-square test. The mean length, width, and thickness of the right lobe were 4.24 cm, 1.8 cm, and 1.6 cm, respectively, whereas it was 4.08 cm, 1.8 cm, and 1.6 cm, respectively for that of the left lobe. The pyramidal lobe was noted in 52.5% of the cadavers. The levator glandulae thyroidae were prevalent in 40% of the cadavers. The isthmus mainly overlies the 2nd to 4th tracheal rings and was absent in 7.5% of the cadavers. Accessory thyroid tissue and double pyramidal lobes were noted in 2.5% of the cadavers. Most of the variations of the thyroid gland were seen frequently in female but it was not statically significant. Different clinically important and rare variations of the thyroid gland were found.

Pcsk5 is required in the early cranio-cardiac mesoderm for heart development

BackgroundLoss of proprotein convertase subtilisin/kexin type 5 (Pcsk5) results in multiple developmental anomalies including cardiac malformations, caudal regression, pre-sacral mass, renal agenesis, anteroposterior patterning defects, and tracheo-oesophageal and anorectal malformations, and is a model for VACTERL/caudal regression/Currarino syndromes (VACTERL association - Vertebral anomalies, Anal atresia, Cardiac defects, Tracheoesophageal fistula and/or Esophageal atresia, Renal & Radial anomalies and Limb defects).ResultsUsing magnetic resonance imaging (MRI), we examined heart development in mouse embryos with zygotic and cardiac specific deletion of Pcsk5. We show that conditional deletion of Pcsk5 in all epiblastic lineages recapitulates all developmental malformations except for tracheo-esophageal malformations. Using a conditional deletion strategy, we find that there is an essential and specific requirement for Pcsk5 in the cranio-cardiac mesoderm for cardiogenesis, but not for conotruncal septation or any other aspect of embryonic development. Surprisingly, deletion of Pcsk5 in cardiogenic or pharyngeal mesodermal progenitors that form later from the cranio-cardiac mesoderm does not affect heart development. Neither is Pcsk5 essential in the neural crest, which drives conotruncal septation.ConclusionsOur results suggest that Pcsk5 may have an essential and early role in the cranio-cardiac mesoderm for heart development. Alternatively, it is possible that Pcsk5 may still play a critical role in Nkx2.5-expressing cardiac progenitors, with persistence of mRNA or protein accounting for the lack of effect of deletion on heart development.

P57(Kip2) knock-in mouse reveals CDK-independent contribution in the development of Beckwith-Wiedemann syndrome.

CDKN1C encodes the cyclin-CDK inhibitor p57(Kip2) (p57), a negative regulator of the cell cycle and putative tumour suppressor. Genetic and epigenetic alterations causing loss of p57 function are the most frequent cause of Beckwith-Wiedemann syndrome (BWS), a genetic disorder characterized by multiple developmental anomalies and increased susceptibility to tumour development during childhood. So far, BWS development has been attributed entirely to the deregulation of proliferation caused by loss of p57-mediated CDK inhibition. However, a fraction of BWS patients have point mutations in CDKN1C located outside of the CDK inhibitory region, suggesting the involvement of other parts of the protein in the disease. To test this possibility, we generated knock-in mice deficient for p57-mediated cyclin-CDK inhibition (p57(CK) (-) ), the only clearly defined function of p57. Comparative analysis of p57(CK) (-) and p57(KO) mice provided clear evidence for CDK-independent roles of p57 and revealed that BWS is not caused entirely by CDK deregulation, as several features of BWS are caused by the loss of CDK-independent roles of p57. Thus, while the genetic origin of BWS is well understood, our results underscore that the underlying molecular mechanisms remain largely unclear. To probe these mechanisms further, we determined the p57 interactome. Several partners identified are involved in genetic disorders with features resembling those caused by CDKN1C mutation, suggesting that they could be involved in BWS pathogenesis and revealing a possible connection between seemingly distinct syndromes. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia

The evolutionarily conserved transmembrane anterior posterior transformation 1 protein, encoded by TAPT1, is involved in murine axial skeletal patterning, but its cellular function remains unknown. Our study demonstrates that TAPT1 mutations underlie a complex congenital syndrome, showing clinical overlap between lethal skeletal dysplasias and ciliopathies. This syndrome is characterized by fetal lethality, severe hypomineralization of the entire skeleton and intra-uterine fractures, and multiple congenital developmental anomalies affecting the brain, lungs, and kidneys. We establish that wild-type TAPT1 localizes to the centrosome and/or ciliary basal body, whereas defective TAPT1 mislocalizes to the cytoplasm and disrupts Golgi morphology and trafficking and normal primary cilium formation. Knockdown of tapt1b in zebrafish induces severe craniofacial cartilage malformations and delayed ossification, which is shown to be associated with aberrant differentiation of cranial neural crest cells.

An unusual case of rib anomalies in number and morphology with association of vertebral and sternum anomalies: Computed tomography diagnosis

A significantly less number of ribs with multiple developmental anomalies in ribs, spine, and sternum is very rare anomaly. We report a case of a 50-year-old man with 15 number of ribs, absent first, second, fourth, seventh and eleventh ribs on the left and absent first, third, eight and tenth ribs on the right side, along with a bifid anterior end of the left sixth rib, fused posterior ends of right fifth and sixth ribs, and bilateral hypoplastic 12th ribs. These anomalies were also associated with thoracolumbar block and hemivertebrae as well as a small sternum. All findings were identified incidentally on computed tomography. No similar type of rib anomalies was found in previous literature. We discuss the details of this case, and suggest a perspective of morphology and developmental biology.

Concurrent occurrence of multiple developmental anomalies: A rare case report and review of literature

Talon cusp and fusion are uncommon odontogenic anomalies comprising of both primary and permanent dentition, which occur on the palatal surface of permanent maxillary incisors, while fused teeth are more common in the primary anterior dentition. This article reports an unusual case of talon cusp presenting on the lingual surface of fused permanent right mandibular central and lateral incisor in the permanent dentition in association with impacted left mandibular third molar. Recognition of this condition and early diagnosis are important to provide prophylactic measures, thereby preventing complications.

MAGNETIC RESONANCE IMAGING FINDINGS ASSOCIATED WITH LATERAL CEREBRAL VENTRICULOMEGALY IN ENGLISH BULLDOGS

Multiple congenital or developmental anomalies associated with the central nervous system have been reported in English Bulldogs. The purpose of this retrospective study was to identify and describe the prevalence and MRI characteristics of these anomalies and their association with presence and degree of cerebral ventriculomegaly. Magnetic resonance imaging studies of 50 English Bulldogs were evaluated. Forty-eight dogs had some degree of cerebral ventriculomegaly, 27 of which had an otherwise normal brain. Presence of lateral ventriculomegaly was not significantly associated with presence of another intracranial lesion. Appearance of the septum pellucidum was variable, ranging from intact to incomplete or completely absent. The corpus callosum was subjectively thinned in all but three dogs, two of which had normal lateral ventricles. Fusion of the rostral colliculi was not found in any dog. A persistent craniopharyngeal canal was identified in one dog. Aqueductal stenosis caused by fusion of the rostral colliculi was not identified in any dog. Findings indicated that cerebral ventriculomegaly is a common finding in English Bulldogs with or without other intracranial lesions, aqueductal stenosis caused by fusion of the rostral colliculi is unlikely to be a common etiology leading to obstructive hydrocephalus, and a large craniopharyngeal canal is a rare finding that has unknown clinical significance at this time.

Radiological Findings of Gorlin Syndrome-A Case Report

Basal cell nevus (Gorlin-Goltz) syndrome is a rare autosomal dominant disorder with multiple developmental anomalies and predisposition to various neoplasms. We present a 60 year old male with pigmented, ulcerated skin lesions in face, neck and trunk, histologically proved to be basal cell carcinomas. Mild exopthalmos, hypertelorism, chest wall deformity &amp; scoliosis were noted. Radiological imaging showed calcification of falx cerebri &amp; tentorium cerebelli, bridging of sella turcica, right third, fourth and fifth bifid ribs, scoliosis of lumbar spine, odontogenic keratocyst of mandible and flame shaped lucencies in hands. Nepalese Journal of Radiology / Vol.3 / No.1 / Issue 4 / Jan-June, 2013 / 94-98 DOI: http://dx.doi.org/10.3126/njr.v3i1.8821

A Case of Bilateral Submandibular Gland Aplasia

Congenital aplasia of the major salivary glands is very rare. Some authors have reported that most congenital aplasia of a major salivary gland is assosiated with multiple other developmental anomalies, especially in the case of craniofacial lesions. Other authors have reported on some cases of aplasia of the partial major salivary glands involved only the parotid glands or submandibular glands without other malformations. Here we report on a very case of aplasia of the bilateral submandibular glands and compensatory hypertrophy of the bilateral lingual glands.