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Background: Oropharyngeal teratoma may occur by itself or together with other craniofacial malformations, most commonly cleft palate. Oropharyngeal teratoma may be also seen in association with frontonasal dysplasia and/or various degrees of craniofacial duplication. The nosology of these sporadic disorders is poorly defined., Case and Review: We report on a 22-week fetus with a protruding nasopharyngeal teratoma, partial oral duplication, anencephaly, multiple costo-vertebral segmentation defects, and cervical diplomyelia. A review of the literature identified 48 patients published from 1931 to 2013 with co-existing clefting and duplication anomalies of the cephalic pole. Thoracic and abdominal midline anomalies were reported 13 times., Conclusion: The term "craniofacial teratoma syndrome" is introduced to define this phenotype as a recognizable developmental field defect of the cephalic pole. Developmental pathogenesis is discussed with a focus on pleiotropy and stereotaxis. The observation of midline findings suggestive of holoprosencephaly in a few previously reported cases suggests a role for the sonic hedgehog signaling pathway in this malformation pattern., (© 2014 Wiley Periodicals, Inc.)

Purpose: The objective of this paper is to analyze the structure of the ureter in normal and anencephalic human fetuses., Materials and Methods: We studied 16 ureters from 8 human fetuses without congenital anomalies aged 16 to 27 weeks post-conception (WPC) and 14 ureters from 7 anencephalic fetuses aged 19 to 33 WPC. The ureters were dissected and embedded in paraffin, from which 5 μm thick sections were obtained and stained with Masson trichrome, to quantify smooth muscle cells (SMC) and to determine the ureteral lumen area, thickness and ureteral diameter. The samples were also stained with Weigert Resorcin Fucsin (to study elastic fibers) and Picro-Sirius Red with polarization and immunohistochemistry analysis of the collagen type III fibers to study collagen. Stereological analysis of collagen, elastic system fibers and SMC were performed on the sections. Data were expressed as volumetric density (Vv-%). The images were captured with an Olympus BX51 microscope and Olympus DP70 camera. The stereological analysis was done using the Image Pro and Image J programs. For biochemical analysis, samples were fixed in acetone, and collagen concentrations were expressed as micrograms of hydroxyproline per mg of dry tissue. Means were statistically compared using the unpaired t-test (p < 0.05)., Results: The ureteral epithelium was well preserved in the anencephalic and control groups. We did not observe differences in the transitional epithelium in the anencephalic and control groups. There was no difference in elastic fibers and total collagen distribution in normal and anencephalic fetuses. SMC concentration did not differ significantly (p = 0.1215) in the anencephalic and control group. The ureteral lumen area (p = 0.0047), diameter (p = 0.0024) and thickness (p = 0.0144) were significantly smaller in anencephalic fetuses., Conclusions: Fetuses with anencephaly showed smaller diameter, area and thickness. These differences could indicate that anencephalic fetal ureters tend to have significant structural alterations, probably due to cerebral lesions with consequent brain control damage of ureter nerves.

The authors report a rare case of multiple intracranial fetuses in fetu, fulfilling Willis' traditional criteria, which include an axial and appendicular skeleton with surrounding organized tissue. This case was ascertained from studies of a full-term female neonate who presented with ventriculomegaly. A CT scan showed intracranial calcifications that were suggestive of an axial skeleton. Her birth weight was 3.176 kg (50th-75th percentile), length was 52 cm (90th percentile), head circumference was 35 cm (50th-75th percentile), and Apgar scores were 7 and 8 at 1 and 5 minutes, respectively. Prenatal ultrasonography studies performed at 12 weeks and 5 days, and 19 weeks and 6 days revealed normal findings. A 37-week prenatal ultrasonography study showed ventriculomegaly and obstructive hydrocephalus, with a possible intracranial teratoma. Cranial imaging at birth with ultrasonography, CT and MR imaging, and MR angiography demonstrated 2 complex intraventricular masses with cystic, solid, and bony elements. A craniotomy with resection of the masses was performed at 3 months of age. The infant survived and is now 12 months old with some developmental progress. Two axial skeletons, with accompanying rib cage and extremities, including well-formed feet and toes, were noted. Both anencephalic structures had skin with hair, fat, skeletal and smooth muscle, and bony structures with bone marrow and focal areas of calcification. Multiple viscera were present and included thymus, bowel, stomach, salivary gland, kidney, adrenal gland, lung, and presumed adnexal structures. A diagnosis of fetuses in fetu was rendered. Chromosomal studies of the child and tissue from the 2 fetuses in fetu showed normal female karyotypes. A single nucleotide polymorphism array analysis from the proband infant and tissue from the 2 identified fetuses in fetu appeared to be genetically identical. These results are consistent with a monozygotic twin embryonic origin of the fetus in fetu tissue, which is a mechanism that has been suggested in previous reports in which karyotypes, blood types, and limited genetic loci have been studied. This is the first report of a rare example of intracranial intraventricular twin fetuses in fetu for which a genome-wide single nucleotide polymorphism assay has confirmed their genetic identity.

A critical role of the FOX transcription factors in the development of different tissues has been shown. Among these genes, FOXN1 encodes a protein whose alteration is responsible for the Nude/SCID phenotype. Recently, our group reported on a human Nude/SCID fetus, which also had severe neural tube defects, namely anencephaly and spina bifida. This led to hypothesize that FOXN1 could have a role in the early stages of central nervous system development. Here we report on a second fetus that carried the R255X homozygous mutation in FOXN1 that has been examined for the presence of CNS developmental anomalies. At 16 postmenstrual weeks of gestation, the abdominal ultrasonography of the Nude/SCID fetus revealed a morphologically normal brain, but with absence of cavum septi pellucidi (CSP). Moreover, after confirmation of the diagnosis of severe Nude/SCID, the fetus was further examined postmortem and a first gross examination revealed an enlargement of the interhemispheric fissure. Subsequently, a magnetic resonance imaging failed to identify the corpus callosum in any section. In conclusion, our observations did not reveal any gross abnormalities in the CNS anatomy of the Nude/SCID fetus, but alteration of the corpus callosum, suggesting that FOXN1 alterations could play a role as a cofactor in CNS development in a similar fashion to other FOX family members., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Cranial neural tube defect, or anencephaly, is the absence of normal brain development because of severe developmental defect in the fetus. While the current incidence of human anencephaly ranges between 1 to 5 per 1000 births, and was higher prior to folic acid supplementation, there is no discussion of anencephaly diagnosis in the forensic literature and only one published example from the archeological record. This article presents both qualitative observations of abnormal cranial elements and an osteometric method to quantitatively determine anencephaly from forensic recovery contexts where taphonomic variables may otherwise mask diagnostic characteristics. Evidence is presented for only the second case of anencephaly diagnosed from a burial context, and the first not involving soft tissue mummification. The initial recognition and accurate prediction of anencephaly is a significant contribution to investigators recovering found human fetal remains.

In the study, stereological, histological, and anatomical techniques were used to investigate structural and morphometrical features of anencephalic and normal fetal kidneys. Twenty human fetal kidneys (5 male and 5 female anencephalic fetuses, and 5 male and 5 female normal fetuses) at gestational ages 30 to 35 weeks were examined. Our study used two basic research methods. One was conventional anatomical measurement at the macroscopic level, such as volume, length, weight, etc. The other consisted of conventional and modern microscopic techniques. The microscopic techniques were based on two research methods: histopathological examination at light microscopic level and stereological estimations, including mean kidney volumes, obtained by the Cavalieri method, and the total number and mean height of the glomeruli via the physical dissector method. There was no statistical difference between the two groups in terms of width, height, weight, and fluid replacement volumes. Microscopic quantitative assessment found no statistical differences either, in terms of the kidney volumes and the number and height of the glomeruli. Our findings suggest that kidneys from anencephalic infants may be a suitable alternative for renal transplantation.

Introduction: We hypothesized that magnetic resonance imaging (MRI) can assess fetuses with sonographically (ultrasonography (US))-suspected neural tube defects (NTD) that might influence their diagnoses and management decision., Methods: Institutional review board approval and informed consents were obtained to perform MRI for 19 fetuses referred with US-suspected NTD. Prenatal imaging findings were correlated with management decision, postnatal clinical, postnatal imaging, and pathology., Results: Prenatal MRI correctly ruled out US diagnosis of cephalocele in a fetus. In the other 18 fetuses, MRI detected detailed topography and contents of NTD sacs in five, added central nervous system (CNS) abnormalities that were not apparent on US in three, and confirmed non-CNS findings in three fetuses. MRI changed diagnosis of 3/19 fetuses (15.8%), caused minor change in diagnosis of 5/19 (26.3%), and did not influence US diagnosis of 11/19 fetuses (57.9%). MRI findings changed/modified management decision in 21% of the fetuses., Conclusion: Fetal MRI is an important adjunct to US in assessing NTD. It can identify topography and contents of sacs, add CNS and non-CNS findings, and influence management decision.

Exencephaly/anencephaly is a rare neural tube defect occurring early in embryogenesis. We report a 14-week-old fetus with exencephaly in whom central nervous system tissue was developed and preserved. There were 2 symmetrical structures grossly resembling cerebral hemispheres, which on histologic and ultrastructural study, consisted of a combination of ependymoblastomatous rosettes and canals and primitive neural tissue. The brainstem and spinal cord were partially normally formed, although descending tracts were not apparent. No cerebellar tissue was found. The eyes were formed. This appears to represent a rare example of exencephaly not covered by skin, which did not undergo necrosis and early transformation into a residual area cerebrovasculosa, characteristic of anencephaly. It may be appropriate to regard this as a unique neural tube closure defect that might be termed "ependymoblastomatous exencephaly."

Anomalies of the extraocular muscles have been suspected to be present frequently in patients with craniofacial malformations. We studied the extraocular musculature in the orbits of 15 anencephalic human fetuses between the 5th and 10th months after gestation, and in one fetus with an occipital meningocele and a large defect of the left cranial base. The findings were compared to those in nine normal age-matched fetuses. All malformed fetuses exhibited special features of the levator palpebrae superioris muscle, either its absence, an anomaly of the muscle belly, or an anomalous insertion. In addition, deficient or aberrant muscle bellies of the oblique and rectus muscles were found. In anencephaly, the frontal bone is condensed, forming narrowed orbital cavities with hypotelorism. Frequent disturbance of extraocular muscle development in fetuses with craniofacial malformations is implicated. The presented specimens are examples of extreme variants of cranial and craniofacial malformation syndromes. Thus, similar findings of extraocular muscles might also be regularly found in clinically relevant craniofacial malformations. This would force new considerations about diagnostic and therapeutic approaches to patients with craniofacial malformations.

Neural tube defects (NTDs) are congenital malformations of the central nervous system (CNS) secondary to abnormal closure of the neural tube during embryonic development. This study provides information on NTD rate, distribution, associated morphologic anomalies and organ weights in a Danish fetal and perinatal autopsy series during a 16 year period. The data were extracted from the autopsy reports of a consecutive series of 1984 fetal and perinatal autopsies from the Copenhagen area performed in the period 1989-2004. Registered parameters included: The location and morphology of the NTD, associated morphological anomalies, and organ weights. Organ weights were evaluated according to new fetal autopsy standards and grouped as low, normal or high. Ninety-seven NTD cases were found (4.9%): Spina bifida (38 cases), cephalocele (17 cases) and anencephaly (42 cases). 63% of NTD cases had associated morphologic anomalies. Among the most common were hydrocephalus, NTD in another region, and anomalies in the urogenital system. 58% of the NTD cases had abnormal weight of one or more organs. Most notable was low adrenal weight not only in anencephalic fetuses but also in cases with cephalocele, suggesting a possible association.

A genetic theory of "multifactorial" malformations, i.e., anomalies of blastogenesis or organogenesis, involving polygenic predisposition with morphogenetic threshold effect, was developed by Sewall Wright in the 1920s and remains an essential basis of birth defects biology. Because of the phenomenon of universality, i.e., the deployment of identical inductive, or pattern-forming, upstream molecular mechanisms during the earliest stages of mammalian morphogenesis, Wright's work on guinea pig otocephaly is highly pertinent to "corresponding," i.e., homologous malformations in humans. This concept is illustrated on the hand of a human fetus in the Vilnius (Lithuania) Pathological Museum with anotocephaly, i.e., anencephaly and otocephaly so severe as to correspond to Wright's guinea pig otocephaly grade 11 or 12. The observation also supports our apology for old museums and old books as repositories for anomalies, no less important for their rarity., (Copyright 2001 Wiley-Liss, Inc.)

In a significant proportion of cases, anencephaly is associated with thymic enlargement, suggesting a possibility that anencephalic fetuses have a functional disturbance in thymocyte differentiation and development. In this report, we demonstrated that CD99 expression was consistently reduced in cortical thymocytes of all anencephalic fetuses. In addition, the CD99-dependent aggregation of immature cortical thymocytes was almost completely impaired and apoptosis of thymocytes was markedly reduced in several cases. These results are in agreement with previous findings that CD99 regulates the aggregation and apoptosis of various types of cells. These data strongly suggest that functional disturbance of thymocytes and thymic hyperplasia are related to the reduced expression of CD99 molecule in anencephalic fetuses.

Comparative stereological studies were performed on zonation of adrenal glands in 10 anencephalic and 11 normal fetuses, aged between 24 and 39 postovulatory weeks. The development of adrenal fetal zone (FZ) is the main factor responsible for normal adrenal gland growth during the intra-uterine life. At the end of fetal period volume of this zone attains over 8200 mm3 and constitutes 69-70% of the total gland volume, while respective values for zona glomerulosa (ZG), zona fasciculata (ZF) and medulla (M) are 1665 mm3 (14%), 833 mm3 (7%) and 1071 mm3 (9%). These data were in striking contrast with those found in adrenals of anencephalic fetuses, in which volume of the gland attained only ca 35% of that in normal fetuses. In the oldest anencephalic fetus studied (39 weeks) the volume of the fetal zone was 962 mm3 (ca 8-folds lower than in normal fetus) comprising only 25% of the total gland volume. For the remaining zones the values were: ZG-1501 mm3 (ca 90% of the normal value and 39% of the total gland volume); ZF-770 mm3 (ca 92% and 20% respectively), and M-539 mm3 (ca 50% and 14%, respectively). This stereological study provides the first systemic description of the development of adrenal gland of anencephalic fetuses in comparison with the normally developing gland. Moreover, evidence is given that the growth of adrenal medulla is also retarded in anencephaly while the growth of the zona glomerulosa remains rather unaffected.

In our previous paper (Bocian-Sobkowska et al., 1997) we demonstrated a striking difference in development of zonation in adrenals of normal and anencephalic human fetuses. The purpose of the present study was to characterize, by means of stereology, the cellular composition of developing adrenals in the same case. Studies were performed on 11 pairs of adrenal glands from normal fetuses and 10 from anencephalic fetuses. In the studied period of development (24 to 39 weeks of intra-uterine life) the average volume of cells in normal glands increased as follows: zona glomerulosa (ZG) from 355 to 870 microns3; zona fasciculata (ZF) from 779 to 1200 microns3; fetal zone (FZ) from 2004 to 2380 microns3: and medulla (M) from 600 to 970 microns3. In anencephalic fetuses, the appropriate values were: ZG-380-680 microns3; ZF-460-680 microns3; FZ-1820-1680 microns3; and M-870-1400 microns3. At the end of the studied period the number of ZG cells in normal fetuses was two fold higher than in anencephalics, ZF cells-6-fold and in FZ-5-fold higher, while in the M the number of cells was nearly equal in both groups. During the whole investigated period of intra-uterine development the total number of adrenocortical cells in normal glands increased ca 2.5-fold, while in anencephalic glands only ca 0.5-fold, reaching at the end ca 40% of normal value. In both normal and anencephalic adrenals the number of ZG and M cells was highly correlated with ZG/M cell ratio, being slightly higher in normal glands. No such relation was demonstrated for cells of the remaining adrenocortical zones.

Anencephalic fetuses provide a model of pituitary development in the absence of the hypothalamus. We studied pituitaries of 10 anencephalic fetuses at various stages of gestation using formalin-fixed paraffin-embedded tissue with immunocytochemistry for known adenohypophysial hormones, the transcription factors Pit-1 and SF-1, cytokeratins and S-100 protein. Ten age- and sex-matched fetuses with no endocrine abnormality were controls. At 17-18 weeks of gestation, pituitaries of 4 anencephalics had no posterior lobe; the number and size of cells containing adenohypophysial hormones and the transcription factors were indistinguishable from controls, however, juxtanuclear cytokeratin-positive fibrous bodies were inconspicuous in anencephalics and were prominent in the adenohypophyses of controls. At 26-28 weeks of gestation, there was a marked reduction in number and staining intensity of cells containing SF-1, alpha-subunit of glycoprotein hormones and both gonadotropin beta-subunits in the adenohypophyses of 2 anencephalics. After 32 weeks, corticotropes were reduced in number and size, and gonadotropes were almost entirely absent; in contrast, somatotropes, lactotropes and thyrotropes were numerous. S-100 protein immunoreactivity was increased in anencephalic pituitaries after 32 weeks, when it was found in numerous cells that did not have the usual morphology of folliculo-stellate cells. These data indicate that adenohypophysial cells can differentiate in the absence of the hypothalamus, and that the transcription factors implicated in cytodifferentiation are expressed in anencephalic pituitaries, but that hypothalamic factors are essential for maintenance of gonadotropes and corticotropes. The functional role of fibrous bodies in somatotropes is unknown, but these structures are inconspicuous in the adenohypophyses of anencephalics. Finally, the appearance of S-100 protein-immunoreactive cells is abnormal in anencephalic fetuses.

We studied the development of the pharynx in human embryos and fetuses. Embryos and fetuses from 4.5 mm crown-rump length (CRL) to 40 mm CRL were processed for microscopic examination. Normal fetuses from 32 mm CRL to 250 mm CRL and fetuses with malformations of the central nervous system (CNS) were cut sagittally through the midline and their pharyngeal regions were examined macroscopically. Our observations suggested that, at an early embryonic stage, the notochord and basicranium might play important roles in the formation of the human pharynx. At a later stage, the growth of the maxillomandibular portion also appears to be important in the formation of the pharynx. The finding of malformation of the pharynx in fetuses with maldevelopment of the CNS suggests that the brain may play an important role in the formation of the pharynx.

Changeability of major + arteries and their main branches has been studied in 159 preparations of the upper extremities of fetuses, newborns and children of suckling age with trisomies of 13, 18, and 21 chromosomes, anencephaly in newborns, died at asphyxia or birth injury without any visible developmental defects. Manifestation of anatomical changeability in the human being is under an essential influence of peculiarities of genotypes. In morphogenesis of the upper extremity arteries genes of 13, 18 and 21 chromosomes participate. Trisomies of 13, 18 chromosomes cause more manifested and specific changes in morphogenesis of some structures, and trisomy 21 and mutant genes, producing anencephaly , only increase variability of their structure.

The influence of the hypothalamus on the development of the anterior pituitary cells was studied in normal and anencaphalic human fetuses. An immunocytological method was applied to study the quantitative evolution of the size of the cells during gestation. The somatotropic and corticotropic cells appeared at the end of the 2nd month of gestation. After the 3rd month of gestation their normal development required the presence of brain. The results suggest that hypothalamic factors are needed for the normal development of cells containing these pituitary hormones.

In 42 cases, fetal abnormalities were diagnosed by obstetric ultrasonography and the pregnancy was terminated. The malformations included: anencephaly (22), severe hydrocephaly (4, one with a spina bifida), encephalocele and meningocele (2) amniotic band syndrome (4; a correct prenatal diagnosis was performed during the second trimester in two cases), major anterior abdominal wall defects (2), Pena-Shokeir syndrome type I? (I), severe renal abnormalities (2), conjoined twins, dicephalus type (2), cystic hygroma and hydrops fetalis (2), osteogenesis imperfecta, type II (I). Thus, there were 23 fetuses with a polygenetically determined status; five fetuses could be affected by an autosomal recessive disorder.

In order to confirm the functional status of adrenal gland in human anencephalic fetuses, an enzyme histochemical and ultrastructural approach was used to study the adrenocortical cells of normal and anencephalic human fetuses. In the adrenal gland of the anencephalic fetuses (32nd, 34th and 36th week of gestation), enzyme histochemical activities of alkaline phosphatase and acid phosphatase was weaker than those in normal human fetuses (20th and 26th week of gestation). Ultrastructurally, a large number of lipid droplets, rough endoplasmic reticulum, tubular or vesicular profiles of smooth endoplasmic reticulum and mitochondria with poorly developed cristae were noted in the cytoplasm. In addition, Golgi complexes and microvilli were very poorly developed. Based on these findings, functional aspects of the adrenal gland in anencephalic fetuses were discussed.