Congenital Infantile Fibrosarcoma Involving Pelvic Wall and Thigh Soft Tissues and Placenta, Presenting with Coagulopathy.

Infantile fibrosarcoma (IF) is a well characterized pediatric malignancy marked by gene rearrangements involving members of the NTRK family. In this report, we present a case of IF that presented in the inguinal region-proximal thigh and was initially thought to be a kaposiform hemangioendothelioma (KHE) because it presented with a bleeding diathesis thought to be Kasabach-Merritt phenomenon (KMP). Subsequently, the placental examination showed a neoplasm in the perivascular-subendothelial space of stem villi, initially thought to be myofibromatosis. Ultimately, a biopsy of the thigh mass showed IF with an NTRK3-ETV6 fusion. Subsequent FISH analysis of the placenta showed an ETV6 rearrangement confirming that it was also IF. Review of the laboratory studies suggests that disseminated intravascular coagulation may have been more likely than KMP, highlighting the difficulty in making this distinction in some cases. We believe this to be the first report of an IF presenting in a soft tissue site and the placenta, and discuss the possible mechanisms that could have allowed the IF in the leg to spread to the placenta.

Neonatal respiratory failure due to novel compound heterozygous mutations in the ABCA3 lipid transporter.

The ATP-binding cassette transporter member A3 (ABCA3) is a lipid transporter with a critical function in pulmonary surfactant biogenesis. Biallelic loss-of-function mutations in ABCA3 result in severe surfactant deficiency leading to neonatal respiratory failure with death in the first year of life. Herein, we describe a newborn with severe respiratory distress at birth progressing to respiratory failure requiring transplant. This patient was found to have a maternally inherited frameshift loss-of-function ABCA3 mutation and a paternally inherited synonymous variant in ABCA3 predicted to create a cryptic splice site. Additional studies showed reduced ABCA3 expression in hyperplastic alveolar epithelial type II cells and lamellar body alterations characteristic of ABCA3 deficiency, leading to a diagnosis of autosomal recessive ABCA3-related pulmonary surfactant dysfunction. This case highlights the need for an integrated, comprehensive approach for the diagnosis of inherited diseases when in silico modeling is utilized in the interpretation of key novel genetic mutations.

Success of chemotherapy and a liver transplant in a pediatric patient with hepatic angiosarcoma: A case report.

Hepatic angiosarcoma is an extremely rare diagnosis in children, with fewer than 50 pediatric cases reported in the literature worldwide. This aggressive vascular sarcoma carries a very dismal prognosis and is known to be resistant to radiation, chemotherapy, and other vascular-targeted agents. Complete surgical resection is felt to provide the best chance for long-term survival. In patients with tumors not amenable to resection, a liver transplant can be considered. However, very few such transplants have been reported, given that they remain controversial due to high cancer recurrence and mortality post-transplant. Herein, we report the unique case of a 2-year-old child with localized hepatic angiosarcoma not amendable to resection who successfully underwent a liver transplant and received chemotherapy with six cycles of doxorubicin, docetaxel, and ifosfamide.

Hematopoietic cell transplantation for severe MPS I in the first six months of life: The heart of the matter.

BACKGROUND: Hematopoietic cell transplantation (HCT) is accepted therapy for severe mucopolysaccharidosis type I (MPS IH). With implementation of newborn screening (NBS) for MPS I in the US, HCT may now occur earlier than 1-2 years of age and it might be assumed that cardiac issues will be fewer. To examine this hypothesis, we reviewed our records for any MPS IH infant who underwent HCT at ≤6 months of age. STUDY PATIENTS: Pre- and (most recent) post-HCT cardiac echos and clinical courses were reviewed in all infants with MPS IH undergoing HCT at ≤6 months of age. RESULTS: 7 MPS IH infants (4 M) who were diagnosed at median (range) (MEDRNG) of 14 (3, 22) days of life (DOL) by NBS [2] or because an older sib had MPS IH [5], began enzyme replacement therapy at MEDRNG of 48 (7, 62) DOL. First pre-HCT echo was performed at MEDRNG of 45 (0, 88) DOL. HCT (6 cord blood, 1 related) occurred at MEDRNG of 131 (105, 183) DOL with most recent echo at MEDRNG of 408 (10, 1897) days after HCT. Mitral regurgitation (≥mild) occurred before (2/7) and after (2/7) HCT; LVH (2/7) occurred after HCT; PFO was common before (5/7) and after (3/7) HCT. One infant had severely decreased function at initial echo and required ICU management. Another infant with a patent foramen ovale and indwelling central line required additional neuroimaging to determine the cause of a seizure. A final infant died unexpectedly 69 days post-HCT without evidence of occlusive coronary disease at autopsy. CONCLUSIONS: In addition to the traditional phenotypic features of severe MPS I, newborns presenting for HCT have cardiac and non-cardiac problems unique to their young age. Recognition of these issues is essential for optimal outcomes.

Expanding the Spectrum of Pediatric NTRK-rearranged Mesenchymal Tumors.

Pediatric mesenchymal tumors harboring variant NTRK fusions (ETV6-negative) are being increasingly described; however, the histologic and clinical features of these variant NTRK tumors and their relationship to classic infantile fibrosarcoma are not well characterized. A better understanding of the clinicopathologic features of these tumors is necessary, and would aid in both early diagnosis and treatment. Therefore, the aim of this study was to characterize a series of pediatric NTRK-rearranged mesenchymal tumors, including classic ETV6-NTRK3 fused tumors and tumors with variant (non-ETV6) NTRK fusions. The clinical features, morphology, immunophenotype, and genetics of 12 classic ETV6-NTRK3 fused infantile fibrosarcoma and 18 variant NTRK-rearranged mesenchymal tumors were evaluated. For both classic and variant groups, the age at diagnosis ranged from birth to 15 years (median, 4 mo) with no sex predilection; the most common sites involved were the extremities and trunk. The rate of local recurrence and metastasis were not significantly different (recurrence rate: 11% classic, 40% variant; metastatic rate: 18% classic, 25% variant). Classic and variant NTRK tumors had an overlapping spectrum of histologic features, containing haphazardly arranged primitive cells in a myxoid background and/or spindle cells in long fascicles. Both groups showed diffuse pan-TRK expression by immunohistochemistry. Otherwise, the immunoprofile was nonspecific, but similar between both groups. No statistical difference was seen in any clinicopathologic feature between the classic ETV6-NTRK3 and variant fusion cohorts. Pediatric NTRK-rearranged mesenchymal tumors with both classic and variant fusions likely represent a spectrum of disease with shared, recognizable cliniopathologic features.

Plasma Cell Myeloma in Children and Young Adults: A Report of 4 Cases From a Single Institution and a Review of the Literature.

Plasma cell myeloma (PCM) is rare in children and young adults and therefore may be difficult to diagnose. Here we report the clinicopathologic findings of 4 patients under the age of 30 diagnosed with PCM at our institution and summarize the literature about 48 other cases of PCM in this age group. The male:female ratio was 1.2:1 and the number of cases increased with age. Children and young adults with PCM often present with a plasmacytoma and are less likely to have asymptomatic PCM than their adult counterparts. From the cases that reported ethnicity, the majority (55%) were non-white suggesting a possible ethnic predisposition to PCM in this age group. PCM should be included in the differential diagnosis of mass lesions, especially a destructive bony lesion, after more common causes have been ruled out in this age group. The optimal treatment for PCM in this patient population is unclear and conclusions into this are hampered by the paucity of cases and the lack of standardized follow-up.

Sporadic Insulinoma Presenting as Early Morning Night Terrors.

A 16-year-old boy with a recent diagnosis of night terrors was evaluated for recurrent early morning hypoglycemia after an early morning seizure. Evaluation in clinic with critical laboratories identified hyperinsulinemic hypoglycemia. Additional investigation revealed a sporadic insulinoma as the etiology of his hypoglycemia and all symptoms were resolved after pancreaticoduodenectomy. The importance of obtaining critical laboratory samples is highlighted and appropriate radiologic, medical, and pathologic testing is discussed. We additionally review the medical and surgical management of hyperinsulinemic hypoglycemia. A discussion of multiple endocrine neoplasia type 1 associated insulinomas is included as well. This case highlights the importance of considering hypoglycemia in the evaluation of night terrors and new-onset seizures.

Virilizing para-adrenocortical adenoma associated with idiopathic-acquired generalized anhidrosis in an adolescent girl.

Adrenocortical tumors are rare in childhood and adolescence. Virilization, alone or in combination with signs of overproduction of other adrenal hormones, is the most common clinical presentation. Here we report an unusual case of an African-American female adolescent presenting with idiopathic acquired generalized anhidrosis, dysregulation of body temperature, absence of adult body odor and dry skin in the face of a virilizing para-adrenocortical adenoma. Virilization signs regressed soon after removal of the tumor, but normalization of the 3alpha-androstenediol glucuronide (3alpha-AG) took longer compared to other measurable androgens; accompanied by anhidrosis. The association of remitting anhidrosis with normalized levels of 3alpha-AG suggests it might be a possible mechanism for anhidrosis. High 3alpha-AG levels might implicate the increased peripheral conversion of weak pro-androgens with different biochemical structure. We recommend obtaining 3alpha-AG beside other androgens in virilized patients with atypical dermatological symptoms in the face of hyperandrogenism.

Verrucous hemangioma of the glans penis.

Verrucous hemangioma (VH) is a hyperkeratotic lesion usually presenting in infancy, occurring primarily on the extremities. We report a 5-year-old boy with VH in the glans penis and discuss briefly the hyperkeratotic vascular stains, which constitute a heterogenous group. During a 7-year follow-up, the patient received various local treatments, but the lesion regrew to its original size after each treatment until the second deep excision after which no more recurrences have been observed for 3 years now. VH in this location has never been reported.

Timing, route, and dose of administration of heparin-binding epidermal growth factor-like growth factor in protection against intestinal ischemia-reperfusion injury.

PURPOSE: We have previously demonstrated that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an intestinal cytoprotective agent. The current study examined whether HB-EGF is effective as salvage therapy as well as prophylactic therapy for intestinal ischemia-reperfusion (I/R) injury, whether intravenous administration is as effective as intraluminal administration, and whether increased benefits are seen with increasing dose. METHODS: Total midgut I/R injury in rats was achieved by occlusion of a first-order branch of the superior mesenteric artery for 60 minutes, followed by reperfusion for 6 hours. Rats were treated with HB-EGF 5 minutes before ischemia, halfway through the ischemic event, or 5 minutes after ischemia. Route of administration was tested by administering HB-EGF either intraluminally or intravenously. Seven different doses of HB-EGF were tested. RESULTS: Heparin-binding, EGF-like growth factor protected the intestine from injury when administered before injury and was also effective when administered during ischemia or even after injury. Intraluminal administration of HB-EGF was superior to intravenous administration. Increasing doses of HB-EGF resulted in a greater cytoprotective effect. CONCLUSION: These data demonstrate that HB-EGF acts as an effective intestinal cytoprotective agent when administered intraluminally not only before injury, but also during injury and, most importantly, even after intestinal injury has already occurred. These findings support a basis for the prophylactic use of intraluminal HB-EGF in high-risk patients, as well as for the administration of HB-EGF to salvage patients in whom an intestinal insult has already occurred.

Endogenous production of heparin-binding EGF-like growth factor during murine partial-thickness burn wound healing.

Heparin-binding EGF-like growth factor (HB-EGF), a potent epithelial cell mitogen, has been identified in human burn blister fluid and excised human burn wounds. Topical application of HB-EGF to murine partial-thickness scald burns accelerated reepithelialization, increased keratinocyte proliferation, and enhanced production of endogenous transforming growth factor-alpha in the healing wounds. The goal of the present study was to examine the production of endogenous HB-EGF and transforming growth factor-alpha (TGF-alpha) in a murine partial-thickness scald burn model. Keratinocyte proliferation was assessed by 5-bromo-deoxyuridine incorporation, and tissue sections were examined by in situ hybridization for HB-EGF mRNA expression and by immunohistochemistry for HB-EGF and TGF-alpha production. HB-EGF mRNA expression and production of HB-EGF and TGF-alpha proteins by both marginal surface keratinocytes and hair follicle epithelial cells reached a maximum by postburn day five and decreased thereafter. This corresponded to the peak period of keratinocyte proliferation. We conclude that HB-EGF and TGF-alpha act in conjunction to stimulate wound healing following thermal injury.