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.

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.

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".

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.

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.

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.

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.

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.

Rescue of ataxia and preplate splitting by ectopic expression of Reelin in reeler mice.

The gene mutated in reeler (reelin) encodes a protein secreted by neurons in the developing brain that controls laminar positioning of migrating cells in the CNS by an unknown mechanism. To investigate Reelin function, we used the nestin promoter to express Reelin ectopically in the ventricular zone and other brain regions in transgenic mice. In the presence of the endogenous protein, ectopic Reelin did not alter cell migration in the neocortex or the cerebellum. However, in the reeler background, ectopic Reelin induced tyrosine phosphorylation of Dab-1 in the ventricular zone and rescued some, but not all, of the neuroanatomic and behavioral abnormalities characteristic of reeler. These results indicate that Reelin does not function simply as a positional signal. Rather, it appears to participate in multiple events critical for neuronal migration and cell positioning.

Neuronal heterotopias in the developing cerebral cortex produced by neurotrophin-4.

The marginal zone (MZ) of embryonic neocortex is crucial to its normal development. We report that neurotrophin-4 (but not NT3 or NGF), applied to embryonic rodent cortex in vitro or in vivo, produces heterotopic accumulations of neurons in the MZ. Although heterotopia production is TrkB mediated, BDNF is >10-fold less effective than NT4. Heterotopic neurons have the same birth date and phenotype as normal MZ neurons; they are not the result of NT4-induced proliferation or rescue from apoptosis. We suggest that NT4 causes excess neurons to migrate into the MZ and thus may play a role in normal MZ formation as well as in the pathogenesis of certain human cortical dysplasias.

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.

Loss of orphan receptor germ cell nuclear factor function results in ectopic development of the tail bud and a novel posterior truncation.

The dynamic embryonic expression of germ cell nuclear factor (GCNF), an orphan nuclear receptor, suggests that it may play an important role during early development. To determine the physiological role of GCNF, we have generated a targeted mutation of the GCNF gene in mice. Germ line mutation of the GCNF gene proves that the orphan nuclear receptor is essential for embryonic survival and normal development. GCNF(-/-) embryos cannot survive beyond 10.5 days postcoitum (dpc), probably due to cardiovascular failure. Prior to death, GCNF(-/-) embryos suffer significant defects in posterior development. Unlike GCNF(+/+) embryos, GCNF(-/-) embryos do not turn and remain in a lordotic position, the majority of the neural tube remains open, and the hindgut fails to close. GCNF(-/-) embryos also suffer serious defects in trunk development, specifically in somitogenesis, which terminates by 8.75 dpc. The maximum number of somites in GCNF(-/-) embryos is 13 instead of 25 as in the GCNF(+/+) embryos. Interestingly, the tailbud of GCNF(-/-) embryos develops ectopically outside the yolk sac. Indeed, alterations in expression of multiple marker genes were identified in the posterior of GCNF(-/-) embryos, including the primitive streak, the node, and the presomitic mesoderm. These results suggest that GCNF is required for maintenance of somitogenesis and posterior development and is essential for embryonic survival. These results suggest that GCNF regulates a novel and critical developmental pathway involved in normal anteroposterior development.

''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.

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.

Dissection of the cellular and molecular events that position cerebellar Purkinje cells: a study of the math1 null-mutant mouse.

Granule cell precursors in the external germinal layer (EGL) of the cerebellum have been proposed to be a major player in the migration and positioning of Purkinje cells through the expression of the Netrin-like receptor Unc5h3 and the extracellular matrix molecule Reelin. To explore the role of the EGL on these processes, we made use of the math1 null-mutant mouse in which the EGL does not form. In the absence of the EGL, we find three populations of ectopic Purkinje cells. First, we find 1% of all Purkinje cells in a supracerebellar position at the dorsal midline. Second, we find 7% of all Purkinje cells in the inferior colliculus, similar to what is seen in the Unc5h3 mutant. Our finding that Unc5h3 expression is not disrupted in these cells supports the proposed role of EGL granule cell precursors in establishing the anterior cerebellar boundary through the expression of Unc5h3. Third, we find 20% of all Purkinje cells positioned deep to the cerebellar cortex as seen in the reeler mutant. However, unlike the reeler mutant, where 5% of the Purkinje cells migrate successfully, we find that in the math1 null that 72% of the Purkinje cells migrate successfully. This finding demonstrates that Purkinje cell migration is not solely dependent on Reelin signaling from the EGL and is likely caused by Reelin signals emanating from the nuclear transitory zone or the ventricular zone, or both.

Limb deficiency and splenogonadal fusion.

We report a 10-year-old boy with tetramelic limb deficiencies, splenogonadal fusion, and mild mandibular and oral abnormalities. This patient is quite typical of 14 reported cases with this combination of findings. This association must be nosologically closely related to the Hanhart syndrome and other syndromes of limb deficiency and orofacial abnormalities. Recent experience does not support the idea that limb reduction with splenogonadal fusion is an invariably lethal dominant disorder.

Pathogenic mechanisms of heterotopic neural tissue associated with anencephaly.

Central nervous tissue was found in both the lung and the abdominal surface of the diaphragm in an anencephalic baby with gastroschisis. These findings support the hypothesis that the heterotopic neural tissue in anencephalic babies is due to transamniotic implantation. It thus appears that the pathogenic mechanism of the heterotopic neural tissue in the lung is aspiration.

Malformations of cranial base structures and pituitary gland in prenatal Meckel syndrome.

The sella turcica region, including the clivus and the pituitary gland, was studied histologically in five human fetuses with Meckel syndrome (MS). All cases had malformed sella turcica and malformed clivus with irregularly shaped notochordal remnants. We consider that these three characteristics are constant phenotypic traits in MS. The adenohypophysis was present in three cases. In one of these, ectopia of the gland occurred with adenopituitary tissue overlying the dorsum sella, and in another remnants were found in the pharyngeal submucosa. In two fetuses the neurohypophysis was not found. The findings in the region were compared to normal findings and to findings in trisomy 18, where cranial base structures radiographically appeared similar to those in MS. We conclude that in MS specific characteristics are found in the cranial base region and that radiographic analysis needs to be supplemented by histological analysis when studying this specific region.

Ectopic vestigial lesions of the neck and shoulders.

A series of five vestigial lesions of the shoulder and back is reported. Their derivation is discussed and in four cases a branchial rather than a bronchial origin is favoured. The fifth case is held to represent skin involvement by thyroglossal duct elements.