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Sudden infant death syndrome (SIDS) "gray zone" or borderline cases are those in which it is challenging to define whether the pathological findings are sufficiently severe to lead to death. We report a case of a 17-day old male newborn who came to our attention for unexplained death. A complete autopsy was performed, including close examination of the cardiac conduction system. Lungs presented diffuse alveolar damage and interstitial inflammation, the cardiac conduction system showed fetal dispersion, resorptive degeneration, junctional tissue islands and cartilaginous hypermetaplasia of the central fibrous body. The final cause of death was a "gray zone" SIDS. This case report will highlight the intersection of SIDS and pneumonia in newborns, exploring the challenges and controversies surrounding the diagnosis and management of this complex condition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: We describe the prenatal ultrasound findings and autopsy of three fetuses with multiple congenital anomalies (MCA) whose diagnostic workup suggested the same genetic etiology. We conducted a literature review to corroborate the molecular results and find evidence that the identified variants are responsible for the phenotype seen., Methods: Trio-based Exome Sequencing (ES) analysis was performed on chorionic villus samples. We reviewed available reports dealing with prenatal manifestations of genes involved in the Glycosylphosphatidylinositols (GPI) biosynthesis defects (GPIBDs)., Results: Prenatal findings shared by all the three pregnancies included facial dysmorphisms, brain malformations of the posterior fossa, skeletal and genitourinary anomalies. ES analysis identified homozygous variants of uncertain significance in PIGW in the three fetuses. Prenatal findings of the three pregnancies overlapped with those previously described for PIGW variants and with those associated with PIGN, PIGV and PIGA variants., Conclusion: Based on the phenotypic overlap between the prenatal findings in our three cases and other cases with pathogenic variants in other genes involved in GPIBDs, we speculate that the variants identified in the three fetuses are likely causal of their phenotype and that the PIGWclinical spectrum might extend to MCA, mainly involving brain, skeletal and genitourinary systems. Moreover, we suggest that also PIGW could be involved in Fryns/Fryns-like phenotypes., (© 2022 John Wiley & Sons Ltd.)

Introduction: Glypican-3 (GPC3) is an oncofetal protein involved in cellular signaling, strongly expressed in the placenta, absent or diminished in postnatal life, but often increased in human malignancies. Germline loss-of-function variants of GPC3 gene are associated with Simpson-Golabi-Behmel syndrome type 1 (SGBS1), a rare recessive X-linked overgrowth disease characterized by typical facial features, congenital abnormalities, and an increased risk of developing childhood cancers., Methods: A clinical suspicion of SGBS1 was postulated for a newborn with prenatal history of overgrowth and polyhydramnios, presenting with neonatal weight and length >99th percentile, coarse facies, iris and retinal coloboma, supernumerary nipples, and splenomegaly. While waiting for whole-genome sequencing (WGS) results, we investigated placental GPC3 immunohistochemical expression in the proband, in three additional cases of SGBS1, and disorders commonly associated with fetal macrosomia and/or placentomegaly., Results: WGS in the proband identified a likely pathogenic maternally inherited missense variant in GPC3: c.1645A > G, (p.Ile549Val), and GPC3 immunohistochemistry demonstrated full-thickness loss of stain of the placental parenchyma. The same pattern ("null") was also present in the placentas of three additional cases of SGBS1, but not in those of unaffected controls., Discussion: Immunohistochemical expression of GPC3 in the placenta is highly reproducible. Our findings showed that a "null pattern" of staining is predictive of SGBS1 and represents a valuable aid in the differential diagnosis of fetal macrosomias, allowing targeted genetic testing and earlier diagnosis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: To reach a molecular diagnosis for a family with two consecutive fetuses presenting with multiple congenital anomalies., Methods: The two fetuses underwent prenatal ultrasound, autopsy, radiologic, and genetic investigation. Genetic analysis included karyotype and array-CGH for both fetuses and trio-based whole exome sequencing (WES) only for the second fetus., Results: WES results, initially focusing on recessive or dominant de novo variants, were negative.However, as a result of new relevant information regarding family history, the variant c.648_651dup in the PTCH1 gene was identified as causative of the fetal phenotype., Conclusions: This case further highlights how WES data analysis and interpretation strongly rely on family history and robust genotype-phenotype correlation. This is even more relevant in the prenatal setting, where access to fetal phenotype is limited and prenatal recognition of many morbid genes is not fully explored. We also provide a detailed description of the prenatal manifestations of Basal Cell Nevus Syndrome., (© 2022 John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

Purpose: To describe normal foetal brain development with high resolution post-mortem MRI (PMMRI) of non-fixed foetal brains., Methods: We retrospectively collected PMMRIs of foetuses without intracranial abnormalities and chromosomal aberrations studied after a termination of pregnancy due to extracranial abnormalities or after a spontaneous intrauterine death. PMMRIs were performed on a 3-T scanner without any fixation and without removing the brain from the skull. All PMMRIs were evaluated in consensus by two neuroradiologists., Results: Our analysis included ten PMMRIs (median gestational age (GA): 21 weeks; range: 17-28 weeks). At 19 and 20 weeks of GA, the corticospinal tracts are recognisable in the medulla oblongata, becoming less visible from 21 weeks. Prior to 20 weeks the posterior limb of the internal capsule (PLIC) is more hypointense than surrounding deep grey nuclei; starting from 21 weeks the PLIC becomes isointense, and is hyperintense at 28 weeks. From 19-22 weeks, the cerebral hemispheres show transient layers: marginal zone, cortical plate, subplate, and intermediate, subventricular and germinal zones., Conclusion: PMMRI of non-fixed in situ foetal brains preserves the natural tissue contrast and skull integrity. We assessed foetal brain development in a small cohort of foetuses, focusing on 19-22 weeks of gestation., Key Points: • Post-mortem magnetic resonance imaging (PMMRI) of non-fixed head is feasible. • PMMRI of unfixed in situ foetal brains preserves the natural tissue contrast. • PMMRI provide a good depiction of the normal foetal brain development. • PMMRI of unfixed in situ foetal brains preserves the skull integrity. • PMMRI pattern of foetal brain development at early gestational age is described.

Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth syndrome and it is usually diagnosed postnatally, on the basis of phenotype. Prenatal ultrasonography may show fetal alterations, but they are not pathognomonic and most of them are frequently detectable only from the 20th week of gestation. Nevertheless, early diagnosis is important to avoid neonatal complications and make timely and informed decisions about the pregnancy. We report on four fetuses from two unrelated families, in whom the application of whole exome sequencing and array-CGH allowed the identification of GPC3 alterations causing SGBS. The careful follow up of pregnancies and more sophisticated analysis of ultrasound findings led to the identification of early prenatal alterations, which will improve the antenatal diagnosis of SGBS. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objective: To better clarify the pathogenesis of linezolid-induced lactic acidosis., Design: Case report., Setting: ICU., Patient: A 64-year-old man who died with linezolid-induced lactic acidosis., Interventions: Skeletal muscle was sampled at autopsy to study mitochondrial function., Measurements and Main Results: Lactic acidosis developed during continuous infusion of linezolid while oxygen consumption and oxygen extraction were diminishing from 172 to 52 mL/min/m and from 0.27 to 0.10, respectively. Activities of skeletal muscle respiratory chain complexes I, III, and IV, encoded by nuclear and mitochondrial DNA, were abnormally low, whereas activity of complex II, entirely encoded by nuclear DNA, was not. Protein studies confirmed stoichiometric imbalance between mitochondrial (cytochrome c oxidase subunits 1 and 2) and nuclear (succinate dehydrogenase A) DNA-encoded respiratory chain subunits. These findings were not explained by defects in mitochondrial DNA or transcription. There were no compensatory mitochondrial biogenesis (no induction of nuclear respiratory factor 1 and mitochondrial transcript factor A) or adaptive unfolded protein response (reduced concentration of heat shock proteins 60 and 70)., Conclusions: Linezolid-induced lactic acidosis is associated with diminished global oxygen consumption and extraction. These changes reflect selective inhibition of mitochondrial protein synthesis (probably translation) with secondary mitonuclear imbalance. One novel aspect of linezolid toxicity that needs to be confirmed is blunting of reactive mitochondrial biogenesis and unfolded protein response.

The diagnosis of VACTERL syndrome can be elusive, especially in the prenatal life, due to the presence of malformations that overlap those present in other genetic conditions, including the Fanconi anemia (FA). We report on three VACTERL cases within two families, where the two who arrived to be born died shortly after birth due to severe organs' malformations. The suspicion of VACTERL association was based on prenatal ultrasound assessment and postnatal features. Subsequent chromosome breakage analysis suggested the diagnosis of FA. Finally, by next-generation sequencing based on the analysis of the exome in one family and of a panel of Fanconi genes in the second one, we identified novel FANCL truncating mutations in both families. We used ectopic expression of wild-type FANCL to functionally correct the cellular FA phenotype for both mutations. Our study emphasizes that the diagnosis of FA should be considered when VACTERL association is suspected. Furthermore, we show that loss-of-function mutations in FANCL result in a severe clinical phenotype characterized by early postnatal death., (© 2015 WILEY PERIODICALS, INC.)

Parental balanced translocation is one of the traditional indications for invasive prenatal diagnosis. Usually, the diagnostic process is straightforward. Sometimes, however, results are not entirely clear and may reveal unexpected biological processes. We performed chorionic villi sampling for a paternal 8;15 reciprocal translocation in the sixth pregnancy of a Caucasian woman. Cytogenetic analysis of chorionic villi, after both short- and long-term cultures, revealed the presence of the same rearrangement found in the father as well as a trisomy 15. Surprisingly, the trisomy, which was initially expected to derive from aberrant segregation during paternal meiosis, resulted instead from maternal nondisjunction. Although a sonogram of the fetus appeared to be normal, follow-up amniocentesis demonstrated a low-level mosaic trisomy 15 in cells extracted from the amniotic fluid, while 10% of cells from fetal tissues sampled after termination of the pregnancy were also found to be trisomic. Fetal autopsy showed dysmorphic features, confirming the diagnosis of mosaic trisomy 15 and enabled deeper insight into the prenatal phenotype of this rare condition., (© 2015 S. Karger AG, Basel.)

We report a fatal case of fulminant myocarditis (FM) in a five-year-old male child. He presented to our Emergency Department having complained fever, vomiting, nausea and abdominal pain from the previous day. The ECG showed broad complex tachycardia unresponsive to treatment with both drugs and all other resuscitation measures and the child died four hours after admission. Post-mortem histological examination showed diffuse infiltration of the myocardium although no viral material could be identified. FM is relatively uncommon and late presentation at an almost irreversible stage unusual. This case indicates the necessity of a rapid transfer to a center with ECMO or MCS, when FM is diagnosed.

Objectives: Congenital heart defects may be associated with various extracardiac and chromosomal anomalies, and complex cardiac defects may occur in the presence of heterotaxy syndromes, in which both lungs are bilobate, in left isomerism, or both trilobate, in right isomerism. Lung lobation defects are otherwise very rare. Lung lobation is recognisable only at autopsy; however, its definition is fundamental for evaluation of the visceroatrial arrangement, together with other characteristic signs., Method: We report seven cases of congenital heart defects diagnosed prenatally at 14-31 weeks of gestation (wg), 5 females and 2 males, in which autopsy revealed lung lobation defects in the presence of normal visceroatrial arrangement, in association with other extracardiac anomalies or dysmorphism., Results: Three foetuses had hypoplastic left heart syndrome, one had corrected transposition of great arteries, one had tricuspid atresia, one Ebstein's anomaly and one had ventricular septal defect in trisomy 21. In six cases, pregnancy had been terminated, while the foetus with Ebstein's anomaly died in utero at 32 wg for supraventricular tachycardia. Monolobate, bilobate, trilobate and quadrilobate lungs were found in these foetuses, together with other minor extracardiac anomalies or dysmorphism., Conclusions: Autoptic analysis in cases with prenatal diagnosis is needed to confirm echographic findings and reveal other minor anomalies, undetectable by ultrasound imaging that may complete the malformation pattern, which is useful to the couple for genetic counselling.

Background: Pseudomonas aeruginosa is an opportunistic pathogen that causes chronic endobronchial infections in cystic fibrosis (CF) patients. The role of bacterial internalization in the clearance of P. aeruginosa from the airways is controversial., Material/methods: A xenograft model was used to study P. aeruginosa strain PAO-1 clearance and internalization by the human airways in vivo. Human lung and tracheal rudiments, obtained from therapeutic abortions (20±2 weeks of gestation), were subcutaneously implanted in the flanks of SCID mice and infected after 14-22 weeks of engraftment. Lungs were surgically exposed and P. aeruginosa was injected in the pulmonary parenchima. Opercula closing the tracheal openings were excised, mucus removed, and bacterial inoculum was injected into the lumen. Internalization was studied at 4 hours post-infection on single-cell suspensions, while clearance was evaluated after 24-72 hours from the infection on homogenized tissues., Results: Tracheae and lungs were morphologically identical to the adult human tissues, as evaluated by standard histology. Both types of xenografts showed a very low level of bacterial internalization (0.004-0.25% of total recovered bacteria), although tracheal xenografts presented more than 100 times greater internalization than did lung xenografts. Both lung and tracheal xenografts did not clear the injected bacteria for each inocolum, even at very low doses (100 colony forming units)., Conclusions: P. aeruginosa internalization by epithelial cells occurs, albeit at very low levels, and is not sufficient to clear bacteria in the airway xenograft model. This model could be used for studying chronic respiratory infections in CF patients.

Fibrosarcoma (FS) is a malignant mesenchymal neoplasm of the fibroblasts that rarely affects the oral cavity. Two cases of primary FS of the jaws with intraosseous growth (2 men, aged 53 and 71 years) are described. Microscopically, in one case the tumor showed an intense proliferation of spindle-shaped cells, varying little in size and shape and arranged in parallel bands, partly crossing each other, with significant mitotic activity and nuclear pleomorphism; the second case was characterized by low cellularity comprising spindle-shaped cells, deposited in a variably fibrous and myxoid stroma. On immunohistochemistry, cells in both cases were strongly immunoreactive for MIB-1 and vimentin, focally positive for CD68, and negative for S-100 protein, pancytokeratin, HMB45, CD34, desmin, smooth muscle actin (SMA) and epithelial membrane antigen (EMA). Based on clinical, histological and immunohistochemical findings, the final diagnosis was FS in the first case, myxofibrosarcoma in the second. Treatment was radical surgery with mandibular reconstruction. After two years, the first patient displayed multiple metastases and died during the third year after the initial diagnosis; the second patient was still alive and doing well five years after treatment. We discuss the differential diagnosis versus other forms of sarcoma, examining the morphological appearance that is frequently very similar, the immunohistochemical expression of MIB-1, vimentin, S-100, CD-34, CD68, EMA, as well as conventional clinicopathological features that may help to distinguish FS from other sarcomas.

Purpose: Our purpose is to describe the prenatal manifestation of Norman-Roberts syndrome and to expand the knowledge of the fetal phenotype of this rare condition. The recurrence in two sibs might contribute to the hypothesis of a recessive condition., Methods: Three cases are presented in which the diagnosis was suggested by a prenatal ultrasound examination and confirmed by pathology of the fetuses, after termination of pregnancy. The major sign was the ultrasound detection of microcephaly at the 22nd and 23rd week of gestation. Fetal Magnetic Nuclear Resonance, the pathological examination with histological studies, was applied to arrive at the diagnosis of Norman-Roberts syndrome., Conclusion: To the best of our knowledge, this is the second description of prenatal cases of Norman-Roberts syndrome. The combined clinical and pathological data is a contribution that might help to increase the identification of this rare condition and to correctly define the risk of its recurrence., ((c) 2007 John Wiley & Sons, Ltd.)

Vasculogenesis, the formation of blood vessels in embryonic or fetal tissue mediated by immature vascular cells (ie, angioblasts), is poorly understood. We report the identification of a population of vascular progenitor cells (hVPCs) in the human fetal aorta composed of undifferentiated mesenchymal cells that coexpress endothelial and myogenic markers. Under culture conditions that promoted cell differentiation, hVPCs gave rise to a mixed population of mature endothelial and mural cells when progenitor cells were stimulated with vascular endothelial growth factor-A or platelet-derived growth factor-betabeta. hVPCs grew as nonadherent cells and, when embedded in a three-dimensional collagen gel, reorganized into cohesive cellular cords that resembled mature vascular structures. hVPC-conditioned medium contained angiogenic substances (vascular endothelial growth factor-A and angiopoietin-2) and strongly stimulated the proliferation of endothelial cells. We also demonstrate the therapeutic efficacy of a small number of hVPCs transplanted into ischemic limb muscle of immunodeficient mice. hVPCs markedly improved neovascularization and inhibited the loss of endogenous endothelial cells and myocytes, thus ameliorating the clinical outcome from ischemia. We conclude that fetal aorta represents an important source for the investigation of the phenotypic and functional features of human vascular progenitor cells.

Objectives: To analyse the data of fetal cases with rhabdomyomatosis, the growth of masses in utero, and the relative outcome., Material and Methods: Thirteen cases of cardiac/pericardial tumours with characteristics suggesting rhabdomyomatosis were found in our centre on fetal echocardiography, five before 24 wg (group A) and eight (group B) at 25 to 36 wg. Four patients terminated the pregnancy, nine continued the pregnancy and were followed-up until delivery and after birth (median postnatal follow-up of 4.2 years, range 18 months-16 years)., Results: In six/nine cases that continued the pregnancy (66.7%), the growth of smaller tumor masses was proportional with gestational age until 30 to 32 wg and was stable after that. In three cases, larger masses grew disproportionally and other small masses were revealed, causing a partial obstruction of outflow tracts. After birth, no case required surgery and no serious rhythm problems occurred. Cardiac masses regressed at least partially in all cases. Tuberous sclerosis was diagnosed in 9/11 cases (81.1%) investigated by magnetic resonance imaging in utero or postnatally. One case also had bilateral polycystic kidneys., Conclusions: Multiple and larger noduli progressed disproportionally in utero, until 30 to 36 wg. No relevant cardiac problems occurred after birth and the masses regressed in all cases. The high frequency of association with tuberous sclerosis is confirmed in our series., (Copyright 2004 John Wiley & Sons, Ltd.)

The development of layer I was studied in the human frontal cortex from 21 weeks of gestation (GW) to 2.5 postnatal months in series of adjacent sections processed for thionin staining, Bodian silver staining, and immunocytochemical labeling of neurons and glia. In addition, the terminal dUTP nick-end labeling (TUNEL) method was used to label in situ DNA fragmentation. A progressive decrease of cell density and the disappearance of the subpial granular layer (SGL) appeared as distinctive developmental features of human layer I, consistently with previous investigations. The neuronal antigen microtubule-associated protein2 was found to label preferentially Cajal-Retzius cells and dendritic processes extending from the cortical plate. At midgestation, the calcium binding protein calretinin stained in the marginal zone numerous neurons, including the Cajal-Retzius cells and their processes. Calretinin-immunoreactive neurons decreased during the subsequent maturation: such decline was abrupt in the SGL, whereas bipolar calretinin-immunopositive cells accumulated in the inner marginal zone to be presumably incorporated into the cortical plate. Cajal-Retzius cells expressed calretinin throughout the examined developmental stages. The glial antigen vimentin was already expressed at midgestation, and vimentin immunopositivity decreased progressively in cell bodies and fibers of layer I during development. Glial fibrillary acidic protein-positive elements gradually matured, and the positive cell bodies displayed the features of mature astrocytes at the end of gestation. Moreover, a decrease of free glial cells was observed in layer I, suggesting their progressive incorporation into the cortical plate. TUNEL-positive cells were detected at midgestation in the marginal zone, and they were concentrated in the SGL until its disappearance; their number decreased dramatically throughout layer I after 30 gestational weeks. TUNEL-positive nuclei or regressive changes were not detected in Cajal-Retzius cells throughout the examined developmental stages. Thus, our data point out that naturally occurring cell death is an active mechanism contributing to the disappearance of the SGL but not to the subsequent developmental reshaping of human layer I, in which, instead, migratory phenomena should play a major role. In addition, our findings argue against a disappearance of Cajal-Retzius cells due to regressive processes.

Two women without a specific risk had fetuses with multiple malformations diagnosed by ultrasound; extensive biochemical investigations on fetal blood revealed clues which would have allowed the correct diagnosis of a genetic condition: Pallister-Killian syndrome in one with increased fetal LDH, and Smith-Lemli-Opitz type II syndrome in the other with low fetal cholesterolaemia. When compared with chorionic villus sampling and amniocentesis, rapid karyotyping in women with multiple fetal malformations by fetal blood sampling allows the collection of additional data which may lead to the diagnosis of specific genetic syndromes.