A missing kidney and a hidden congenital diaphragmatic hernia.

Congenital intrathoracic kidney (ITK) is a rare condition, which is usually discovered incidentally in asymptomatic children who do not need any intervention. However, it may be associated with congenital diaphragmatic hernia (CDH), in which case it requires urgent surgical intervention. We present a case of prenatally diagnosed ITK associated with a left CDH that was operated on day 5 of life. The neonate is currently well at 15 months of age.

Case Report: Fetal Bilateral Diaphragmatic Agenesis, Ectopic Liver and Abnormal Pancreas.

Congenital bilateral diaphragm agenesis is a very rare condition. We describe limited (abdomen only) autopsy findings of a case of bilateral diaphragm agenesis in a 27-week male fetus with unusual findings of fibrosis of the pancreatic head and ectopic liver nodules in a mass at the upper abdomen that may represent a possible diaphragm anlage. We have correlated our observations with data from experimental and embryological studies to suggest possible mechanisms for the malformations that were present and their implications for our understanding of pancreas, liver and diaphragm development in the human fetus.

Naso-oropharyngeal choristoma (hairy polyps): an overview and current update on presentation, management, origin and related controversies.

This review presents a comprehensive and updated overview of bigerminal choristomas (hairy polyps) of naso-oropharynx/oral cavity, and discusses the controversies related to nosology and origin from a clinico-embryologic perspective. English-language texts of the last 25 years (January 1989-January 2014) were collected from the PubMed/MEDLINE database using the given keywords. Of the 330 records, 64 full-text articles (mostly case reports/series) were selected, incorporating clinical data from 78 patients, after screening through duplicates and the given exclusion criteria. With the available evidence, hairy polyps appear more common than generally believed, and are increasingly being recognized as an important, often-missed cause of respiratory distress and feeding difficulty in neonates and infants. Such a child without any apparent cause should be examined with flexible nasopharyngoscope to specifically look for hairy polyps which might be life-threatening, especially when small. The female preponderance as believed today has been found to be an overestimation in this review. These lesions are characteristically composed of mature ectodermal and mesodermal tissue derivatives presenting as heterotopic masses, hence termed choristoma. However, little is known about their origin, and whether they are developmental malformations or primitive teratomas is debatable. Involvement of Eustachian tube and tonsils as predominant subsites and the speculated molecular embryogenesis link hairy polyps to the development of the first and second pharyngeal arches. They are exceptionally rare in adults, but form a distinct entity in this age-group and could be explained as delayed pluripotent cell morphogenesis or focal neoplastic malformations, keeping with the present-day understandings of the expanded "teratoma family".

Ectopic pancreas: a rare cause of abdominal pain.

We present a case of recurrent abdominal pain due to an ectopic or heterotopic pancreas. Heterotopic pancreas (HP) is the presence of histologic pancreatic tissue outside its normal location without any anatomic or vascular continuity with the pancreas. The frequency of HP has been estimated as 0.6-13.7%. Most are found in the duodenum, stomach, andjejunum. The exact mechanism remains controversial but it has been theorized that it most likely arises congenitally during embryonic development. The elevations of amylase and lipase levels are modest due to the small volume of pancreatic tissue in the HP. Therefore, diagnostic modalities including barium swallow, upper-gastrointestinal series, CT, EUS, and MRCP can be used when suspecting HP. The need for treatment is based on symptoms and definitive diagnosis, especially when the possibility of malignancy exists. Asymptomatic causes need not require treatment.

Müllerianosis: four developmental (embryonic) mullerian diseases.

The theory of müllerianosis predicts that embryonic müllerian tissue, misplaced during organogenesis, results in the formation of 4 benign müllerian diseases-developmental adenomyosis, endometriosis, endosalpingiosis, and endocervicosis-(developmental müllerian diseases) that will be identified in human female fetuses, infants, children, adolescents, and adults. Direct evidence is presented to support the existence of developmental adenomyosis, developmental endometriosis, and developmental endocervicosis in human female fetuses along with strong circumstantial evidence supporting the existence of all 4 developmental müllerian diseases in human female infants, children, adolescents, and adults. This evidence throws light upon the pathogenesis of rare müllerian lesions whose pathogenesis remains inexplicable by classical and modern theories. Furthermore, this research has scientific and clinical relevance: scientific relevance because it opens up a new field of comparative research-the 4 developmental müllerian diseases complement the 4 acquired müllerian diseases; clinical relevance because it identifies rare müllerian diseases curable by complete surgical excision.

Ectopic formation of primordial germ cells by transplantation of the germ plasm: direct evidence for germ cell determinant in Xenopus.

In many animals, the germ line is specified by a distinct cytoplasmic structure called germ plasm (GP). GP is necessary for primordial germ cell (PGC) formation in anuran amphibians including Xenopus. However, it is unclear whether GP is a direct germ cell determinant in vertebrates. Here we demonstrate that GP acts autonomously for germ cell formation in Xenopus. EGFP-labeled GP from the vegetal pole was transplanted into animal hemisphere of recipient embryos. Cells carrying transplanted GP (T-GP) at the ectopic position showed characteristics similar to the endogenous normal PGCs in subcellular distribution of GP and presence of germ plasm specific molecules. However, T-GP-carrying-cells in the ectopic tissue did not migrate towards the genital ridge. T-GP-carrying cells from gastrula or tailbud embryos were transferred into the endoderm of wild-type hosts. From there, they migrated into the developing gonad. To clarify whether ectopic T-GP-carrying cells can produce functional germ cells, they were identified by changing the recipients, from the wild-type Xenopus to transgenic Xenopus expressing DsRed2. After transferring T-GP carrying cells labeled genetically with DsRed2 into wild-type hosts, we could find chimeric gonads in mature hosts. Furthermore, the spermatozoa and eggs derived from T-GP-carrying cells were fertile. Thus, we have demonstrated that Xenopus germ plasm is sufficient for germ cell determination.

Early onset of Runx2 expression caused craniosynostosis, ectopic bone formation, and limb defects.

RUNX2 is an essential transcription factor for osteoblast differentiation, because osteoblast differentiation is completely blocked in Runx2-deficient mice. However, it remains to be clarified whether RUNX2 is sufficient for osteoblast differentiation during embryogenesis. To address this issue, Runx2 transgenic mice were generated under the control of the Prrx1 promoter, which directs the transgene expression to mesenchymal cells before the onset of bone development. The transgene expression was detected in the cranium, limb buds, and the region from the mandible to anterior chest wall. The skull became small and the limbs were shortened depending on the levels of the transgene expression. Early onset of Runx2 expression in the cranial mesenchyme induced mineralization on E13.0, when no mineralization was observed in wild-type mice, and resulted in craniosynostosis as shown by the closure of sutures and fontanelles on E18.5. Col1a1 and Spp1 expressions were detected in the mineralized regions on E12.5-13.5. The limb bones were hypoplastic and fused, and ectopic bones were formed in the hands and feet. Col2a1 expression was inhibited but Col1a1 expression was induced in the limb buds on E12.5. In the anterior chest wall, ectopic bones were formed through the process of intramembranous ossification, interrupting the formation of cartilaginous anlagen of sternal manubrium. These findings indicate that RUNX2 is sufficient to direct mesenchymal cells to osteoblasts and lead to intramembranous bone formation during embryogenesis; Runx2 inhibits chondrocyte differentiation at an early stage; and that Runx2 expression at appropriate level, times and spaces during embryogenesis is essential for skeletal development.

Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells.

The classical view of neural plate development held that it arises from the ectoderm, after its separation from the mesodermal and endodermal lineages. However, recent cell-lineage-tracing experiments indicate that the caudal neural plate and paraxial mesoderm are generated from common bipotential axial stem cells originating from the caudal lateral epiblast. Tbx6 null mutant mouse embryos which produce ectopic neural tubes at the expense of paraxial mesoderm must provide a clue to the regulatory mechanism underlying this neural versus mesodermal fate choice. Here we demonstrate that Tbx6-dependent regulation of Sox2 determines the fate of axial stem cells. In wild-type embryos, enhancer N1 of the neural primordial gene Sox2 is activated in the caudal lateral epiblast, and the cells staying in the superficial layer sustain N1 activity and activate Sox2 expression in the neural plate. In contrast, the cells destined to become mesoderm activate Tbx6 and turn off enhancer N1 before migrating into the paraxial mesoderm compartment. In Tbx6 mutant embryos, however, enhancer N1 activity persists in the paraxial mesoderm compartment, eliciting ectopic Sox2 activation and transforming the paraxial mesoderm into neural tubes. An enhancer-N1-specific deletion mutation introduced into Tbx6 mutant embryos prevented this Sox2 activation in the mesodermal compartment and subsequent development of ectopic neural tubes, indicating that Tbx6 regulates Sox2 via enhancer N1. Tbx6-dependent repression of Wnt3a in the paraxial mesodermal compartment is implicated in this regulatory process. Paraxial mesoderm-specific misexpression of a Sox2 transgene in wild-type embryos resulted in ectopic neural tube development. Thus, Tbx6 represses Sox2 by inactivating enhancer N1 to inhibit neural development, and this is an essential step for the specification of paraxial mesoderm from the axial stem cells.

Multicenter study of 19 aortopulmonary window parathyroid tumors: the challenge of embryologic origin.

BACKGROUND: Ectopic abnormal parathyroid glands are relatively common in the superior mediastinum but are rarely situated in the aortopulmonary window (APW). The embryological origin of these abnormal parathyroid glands is controversial. The purpose of this investigation was to investigate the embryological origin and the surgical management of abnormal parathyroid glands situated in the APW. METHODS: The databases of patients operated on for primary, secondary, and tertiary hyperparathyroidism at eight European medical centers with a special interest in endocrine surgery were reviewed to identify those with APW adenomas. Demographic features, localization procedures, and perioperative and pathology findings were documented. The embryological origin was determined based on the number and position of identified parathyroid glands. RESULTS: Nineteen (0.24%) APW parathyroid tumors were identified in 7,869 patients who underwent an operation for hyperparathyroidism (HPT) and 181 patients (2.3%) with mediastinal abnormal parathyroid glands. Ten patients had primary, eight had secondary, and one had tertiary HPT. Sixteen patients had undergone previous unsuccessful cervical exploration. In three patients, an APW adenoma was suspected by preoperative localization studies and was cured at the initial operation. Sixteen patients had persistent HPT of whom 15 were reoperated, resulting in 6 failures. Evaluation of 17 patients who had bilateral neck exploration allowed us to determine the most probable origin of the APW parathyroid tumors: 12 were supernumerary, 4 appeared to originate from a superior, and 1 from an inferior gland. CONCLUSIONS: Abnormal parathyroid glands situated in the APW are rare and usually identified after an unsuccessful cervical exploration. Preoperative imaging of the mediastinum and neck are essential. The origin of these ectopically situated tumors is probably, as suggested by our data, from a supernumerary fifth parathyroid gland or from abnormal migration of a superior parathyroid gland during the embryologic development.

Case report: ectopic nipple on the sole of the foot, an unexplained anomaly.

Supernumerary nipples are common congenital anomalies, most often occurring along the embryonic milk lines. We present a patient with an ectopic nipple on the foot. We are unable to explain the aetiology of this anomaly; however, several theories have been proposed. They are also associated with disorders of the renal and cardiovascular systems as well as pathology that affect normal breast tissue.

Congenital anomalies of the spleen from an embryological point of view.

The spleen is the major accumulation of lymphoid tissue in the human body, an organ which prenatally produces and postnatally controls blood cells. Normally, a developed spleen lies in the upper left quadrant in parallel with the long axis of the 10th rib. It is a mesodermal derivate which first appears as a condensation of mesenchymal cells inside the dorsal mesogastrium at the end of the fourth embryonic week. Some congenital anomalies of the spleen are common, such as splenic lobulation and accessory spleen, while other conditions are rare, such as wandering spleen and polysplenia. Splenogonadal fusion is also a rare developmental anomaly, resulting from abnormal fusion of the splenic and gonadal primordia during prenatal development. The purpose of this article is to describe the normal development of the human spleen, supplemented with our own photomicrographs and a review of congenital anomalies of the spleen with their possible embryonic basis.

Body wall morphogenesis: limb-genesis interferes with body wall-genesis via its influence on the abaxial somite derivatives.

The vertebrate body wall is regionalized into thoracic and lumbosacral/abdominal regions that differ in their morphology and developmental origin. The thoracic body wall has ribs and intercostal muscles, which develops from thoracic somites, whereas the abdominal wall has abdominal muscles, which develops from lumbosacral somites without ribs cage. To examine whether limb-genesis interferes with body wall-genesis, and to test the possibility that limb generation leads to the regional differentiation, an ectopic limb was induced in the thoracic region by transplanting prospective limb somatopleural mesoderm of Japanese quail between the ectoderm and somatopleural mesoderm of the chick prospective thoracic region. This ectopic limb generation induced the somitic cells to migrate into the ectopic limb mesenchyme to become its muscles and caused the loss of distal thoracic body wall (sterno-distal rib and distal intercostal muscle), without causing any significant effect on the more proximal region (proximal rib, vertebro-distal rib and proximal intercostal muscle). According to a new primaxial-abaxial classification, the proximal region is classified as primaxial and the distal region, as well as limb, is classified as abaxial. We demonstrated that ectopic limb development interfered with body wall development via its influence on the abaxial somite derivatives. The present study supports the idea that the somitic cells give rise to the primaxial derivatives keeping their own identity and fate, whereas they produce the abaxial derivatives responding to the lateral plate mesoderm.

Nolz1 is induced by retinoid signals and controls motoneuron subtype identity through distinct repressor activities.

The acquisition and maintenance of final neuronal identity depends in part upon the implementation of fate-specification programs in postmitotic neurons; however, the mechanisms involved remain unclear. In the developing spinal cord, retinoic acid (RA) signaling pathways specify the columnar and divisional identities of postmitotic motoneurons (MNs). Here we show that RA signals induce expression of the NET transcriptional regulator Nolz1 in differentiated chick MNs, where it regulates the progressive specification of prospective Lim3-negative motor columns. Nolz1 controls the initial formation of forelimb and thoracic Lim3-negative motor columns by downregulating Lim3 expression and maintaining the expression of key homeodomain proteins necessary for MN identity and survival. At forelimb levels, Nolz1 specifies lateral motor column (LMC) identity by inducing the expression of the postmitotic LMC determinant Hoxc6, and implements the partial specification of lateral LMC identity through Lim1 induction. The specificity of Nolz1 function depends upon distinct repressor activities that require, in part, the modulatory activity of Grg5, an atypical member of the Gro-TLE family of co-repressors. Thus, RA signals regulate diverse events in MN subtype specification by inducing the expression of a key transcriptional regulator that controls multiple developmental pathways via functionally distinct repressor complexes.

Glial heterotopia of the face.

The authors report a case of combined subcutaneous and intranasal glial heterotopia of the face in a 4-month-old boy. The pathogenesis and differential diagnoses of this rare developmental disorder are discussed as is the importance of careful radiologic findings for appropriate surgical decision.

Bilateral intrathoracic kidneys and adrenal glands associated with posterior congenital diaphragmatic hernias.

We present a case of bilateral intrathoracic kidneys and adrenal glands associated with bilateral posterior diaphragmatic defects in a symptomatic 18-month-old baby boy. The diaphragmatic defect did not appear to be the typical posterolateral diaphragmatic hernia of Bochdalek. The patient underwent primary surgical correction through an abdominal approach. Postoperatively, the patient enjoyed an uneventful course and was discharged home without any further events. We discuss this report of bilateral intrathoracic kidneys associated with bilateral diaphragmatic hernias, we describe the operative management, and we analyze the possible embryological development of this defect.

''Ectopic eyelashes'' (ectopic cilia) in a 2-year-old girl: brief report and discussion of possible embryologic origin.

Cilia, or eyelashes, are unique hair follicles normally found at the eyelid margin. The spectrum of cilial anomalies includes cilial row duplication, agenesis, and ectopic placement. Ectopic cilia are the most rare of cilial anomalies. We report a case of a 2-and-a-half-year-old girl with ectopic cilia of the anterior tarsal plate, an extremely rare, congenital anomaly that is most often not associated with other findings and likely results from an event during embryogenesis.

Fgf-dependent otic induction requires competence provided by Foxi1 and Dlx3b.

BACKGROUND: The inner ear arises from a specialized set of cells, the otic placode, that forms at the lateral edge of the neural plate adjacent to the hindbrain. Previous studies indicated that fibroblast growth factors (Fgfs) are required for otic induction; in zebrafish, loss of both Fgf3 and Fgf8 results in total ablation of otic tissue. Furthermore, gain-of-function studies suggested that Fgf signaling is not only necessary but also sufficient for otic induction, although the amount of induced ectopic otic tissue reported after misexpression of fgf3 or fgf8 varies among different studies. We previously suggested that Foxi1 and Dlx3b may provide competence to form the ear because loss of both foxi1 and dlx3b results in ablation of all otic tissue even in the presence of a fully functional Fgf signaling pathway. RESULTS: Using a transgenic line that allows us to misexpress fgf8 under the control of the zebrafish temperature-inducible hsp70 promoter, we readdressed the role of Fgf signaling and otic competence during placode induction. We find that misexpression of fgf8 fails to induce formation of ectopic otic vesicles outside of the endogenous ear field and has different consequences depending upon the developmental stage. Overexpression of fgf8 from 1-cell to midgastrula stages leads to formation of no or small otic vesicles, respectively. Overexpression of fgf8 at these stages never leads to ectopic expression of foxi1 or dlx3b, contrary to previous studies that indicated that foxi1 is activated by Fgf signaling. Consistent with our results we find that pharmacological inhibition of Fgf signaling has no effect on foxi1 or dlx3b expression, but instead, Bmp signaling activates foxi1, directly and dlx3b, indirectly. In contrast to early activation of fgf8, fgf8 overexpression at the end of gastrulation, when otic induction begins, leads to much larger otic vesicles. We further show that application of a low dose of retinoic acid that does not perturb patterning of the anterior neural plate leads to expansion of foxi1 and to a massive Fgf-dependent otic induction. CONCLUSION: These results provide further support for the hypothesis that Foxi1 and Dlx3b provide competence for cells to respond to Fgf and form an otic placode.

Bilateral cervical chondrocutaneous remnants: a case report and review of the literature.

Cervical chondrocutaneous remnants are less common lesions, which are encountered at the lateral neck. They are similar in appearance to preauricular tags, which are more frequent. Bilateral appearance of this pathology is quite uncommon. The lesions always present at birth, and are located in the middle or lower third of the lateral neck with a significant prevalence of location anterior to the sternocleidomastoid muscle. The overlying skin is similar to the surrounding neck skin and the lesion is painless, lacking any inflammation or discharge. Surgically there is no connection with deep underlying structures. The therapy of choice should be complete surgical removal. Several associated anomalies may accompany cervical chondrocutaneous remnants. Thus these patients must be evaluated carefully in order to detect any additional anomaly. We herein report a four-year-old patient with bilateral cervical chondrocutaneous remnant located at the inferior third of the lateral neck anterior to the sternocleidomastoid muscle. We also review the literature for patients with bilateral cervical chondrocutaneous remnants and discuss embryologic and diagnostic aspects.