Pathogenic variants in PIK3CA are associated with clinical phenotypes of kaposiform lymphangiomatosis,generalized lymphatic anomaly,and central conducting lymphatic anomaly

Complex lymphatic anomalies are debilitating conditions characterized by aberrant development of the lymphatic vasculature (lymphangiogenesis). Diagnosis is typically made by history, examination, radiology, and histologic findings. However, there is significant overlap between conditions, making accurate diagnosis difficult. Recently, genetic analysis has been offered as an additional diagnostic modality. Here, we describe four cases of complex lymphatic anomalies, all with PIK3CA variants but with varying clinical phenotypes. Identification of PIK3CA resulted in transition to a targeted inhibitor, alpelisib. These cases highlight the genetic overlap between phenotypically diverse lymphatic anomalies.     

Complex lymphatic anomalies

Complex lymphatic anomalies include several diagnoses with overlapping patterns of clinical symptoms, anatomic location, imaging features, hematologic alterations, and complications. Lymphatic malformations likely arise through anomalous embryogenesis of the lymphatic system. Analysis of clinical, imaging, histologic, and hematologic features is often needed to reach a diagnosis. Aspiration of fluid collections can readily define fluid as chylous or not. The presence of chyle indicates dysfunction at the mesenteric or retroperitoneal level or above the cisterna chyli due to reflux. The imaging patterns of generalized lymphatic anomaly (GLA) and Gorham–Stout disease have been segregated with distinctive bone lesions and peri-osseous features. More aggressive histology (spindled lymphatic endothelial cells), clinical progression, hemorrhage, or moderate hematologic changes should raise suspicion for kaposiform lymphangiomatosis. Biopsy may be needed for diagnosis, though avoidance of rib biopsy is advised to prevent iatrogenic chronic pleural effusion. Lymphangiography can visualize the anatomy and function of the lymphatic system and may identify dysfunction of the thoracic duct in central conducting lymphatic anomalies. Local control and symptom relief are targeted by resection, laser therapy, and sclerotherapy. Emerging data suggest a role for medical therapies for complications of complex lymphatic anomalies. Outcomes include recurrent effusion, infection, pain, fracture, mortality, and rarely, malignancy. Complex lymphatic anomalies present significant diagnostic and therapeutic challenges. Results from a phase 2 study of sirolimus in these and other conditions are expected in 2014. Improved characterization of natural history, predictors of poor outcomes, responses to therapy, and further clinical trials are needed for complex lymphatic anomalies.     

Vascular anomaly cases for the pediatric hematologist oncologists—An interdisciplinary review

Vascular anomalies (VAs) are classified as tumors or malformations depending on their clinical characteristics, pathological diagnosis, and genomic information. Diagnosis can be challenging because of the heterogeneity of clinical presentation; thus, the best diagnosis and care are provided by an interdisciplinary team of specialists. Over the past 10 years, an increasing number of pediatric hematologist/oncologists are caring for patients with VAs secondary to new medical therapy options and clinical trials. This paper focuses on complicated VA issues often seen by the pediatric hematologist/oncologist. The paper reviews clinical pearls on diagnosis, histology, radiology, and treatment options.     

Scimitar syndrome: incidence,treatment, and prognosis

This study is based on a database of 16 years; we sought to define the incidence and outcome of scimitar syndrome. Of 8,771 patients, 5 (0.057%) with scimitar syndrome were identified and constituted the study population. Follow-up ranged from 1 to 16 years (median: 10 years). Diagnosis was assured by computed tomography in four patients and by cardiac catheterization in one. Two patients presented with respiratory distress soon after birth and required early pneumonectomy in one case and coil embolization of the abnormal feeding arteries to the right lower lung followed by surgical rerouting of the abnormal pulmonary vein and repair of the atrial septal defect in the other case. The former was supported by ventilator therapy for 3 years after pneumonectomy, but was finally weaned from the ventilator. Among the other three, two had repeated pneumonia that resolved after rerouting of the abnormal right pulmonary vein and cardiac repair. The asymptomatic child did not receive any intervention. In spite of the abnormal orientation of the airways, none of the four patients with detailed computed tomography imaging showed any significant compression of the airways. All five patients were doing well as of the last follow-up. In conclusion, scimitar syndrome is a very rare disease in this Asian country and the varied symptoms, such as tachypnea and repeated infection, could be improved after interventions.     

Different race, different face: minor anomalies in Chinese newborn infants

OBJECTIVE: To define the nature and incidence of minor anomalies in Chinese newborn infants and to evaluate the validity of the hypothesis that infants with three or more minor surface anomalies will also have a major malformation. METHODS: A total of 3,345 Chinese newborn infants were examined based on a list of 67 items of minor anomalies. RESULTS: About 44.9% of the newborn infants had at least one minor anomaly that was unrelated to gender, maternal age, or gestational age, but significantly associated with fetal presentation. Breech-presented newborn infants had double the risk of minor anomalies. Simian crease, upward slant and frontal bossing could be considered normal variants for Chinese newborn infants, because the incidence of each was higher than 4%. CONCLUSIONS: Although some studies have shown that approximately 90% of infants having three or more minor anomalies are associated with a major malformation, we found only a 10.1% predictive value based on this study. Nevertheless, we suggest that infants with three or more minor anomalies be carefully evaluated for the possibility of major malformation in order to provide early management.     

Current management of childhood acute lymphocytic leukemia

Despite major advances in the treatment of childhood leukmia, there remain controversies in classification, prognostic importance of clinical and laboratory investigations, intensity of induction chemotherapy, presymptomatic CNS therapy, type and duration of maintenance chemotherapy and the role of bone marrow transplantation. In this review, some of these problems are highlighted and differences between long-term results of treatment from group studies, and those reported from Melbourne are discussed.     

Identification of Lymphatic Endothelium in Pediatric Vascular Tumors and Malformations

The distinction between lymphatic and other vascular vessels on microscopic sections is a challenging task. D2-40, a novel antibody, has been reported to be selective for lymphatic endothelium. We studied the specificity and sensitivity of D2-40 in pediatric vascular tumors and malformations. Fourteen lymphatic and 11 vascular lesions were randomly selected and stained with D2-40 and CD31 antibodies. The lymphatic lesions included 6 lymphatic malformations, 5 cystic hygromas (macrocystic lymphatic malformation), 2 lymphovenous malformations, and 1 lymphangioma, and the vascular lesions comprised 3 infantile hemangiomas, 3 Kaposiform hemangioendotheliomas, 2 tufted angiomas, 1 pyogenic granuloma, 1 arteriovenous, and 1 venulocapillary malformations. The staining patterns of the vascular channels were compared. In all lesions D2-40 labeled only the endothelium of thin-walled vascular channels morphologically consistent with lymphatic vessels (25 of 25). No staining of the vascular lesions (0 of 11) or of arteries and veins (0 of 25) was observed. All lymphatic lesions had D2-40–positive vessels; however, the percentage of vessels that stained varied. Five lymphatic lesions showed more than 75% D2-40–positive channels, 5 lesions had approximately 50%, and 4 cases showed fewer than 25% D2-40–positive channels. There was a tendency of more consistent D2-40 staining of small versus large lymphatic channels. CD31 constantly labeled arteries, veins, capillaries, and lymphatics in all lesions and all endothelial cells in the vascular lesions. D2-40 is a very specific antibody for lymphatic endothelium, with variable sensitivity. CD31 more reliably identifies lymphatic endothelium. Currently, D2-40 appears to be a good marker to identify lymphatic vessels in pediatric vascular tumors and malformations.     

Aplastic anemia—An early phase preceding acute lymphatic leukemia

A rare presentation of acute lymphatic leukaemia (ALL) in three children is described. These children initially presented with fever and pallor. The bone marrow aspiration and or biopsy were consistent with aplastic anemia. Children were treated with oxymethalone, prednisone either singly or in combination. On follow up these cases developed overt ALL between 18 days to 16 months. Relative merits of oxymethalone or prednisone therapy during the aplastic phase of acute lymphatic leukaemia have been discussed.     

Incidence and Familial Occurrence of the Congenital Anomalies of the Face, Hand and Foot

We made an epidemiological study of congenital anomalies of the face, hand and foot in newborns from 1973 to 1992 in Miyagi Prefecture which has a population of about two million. In these twenty years 579,766 babies were born in Miyagi Prefecture. Out of these newborns 3,416 babies with 3,759 congenital anomalies of the face, hand and foot were registered. Of all registered congenital anomalies, face anomalies were most commonly encountered, followed by hand and foot anomalies. Among face anomalies, in order of frequency, accessory ear was the most common, next cleft lip with or without cleft palate, cleft palate alone, cryptotia and microtia. The occurrence ratio per 10,000 live births was 9.6 in accessory ear, 6.7 in cleft lip, 6.1 in cleft lip with cleft palate, 4.2 in cleft palate alone, 2.9 in cryptotia, and 1.8 in microtia. In hand and foot anomalies, polydactyly was the most common and syndactyly the next. Incidence ratio of polydactyly was 5.8 in the hand and 6.4 in the foot. Polydactyly was the most frequent in the preaxial ray in the hand and in the postaxial ray in the foot. About half of cases of postaxial polydactyly the foot was associated with syndactyly between the fourth and fifth toe. In addition, we reported on variation of the incidence ratio and familial occurrence of congenital anomalies of the face, hand and foot.     

Prader-Willi Syndrome with del(15)(q1l, q13) Associated with Hepatoblastoma

A case of Prader-Willi syndrome who later developed hepatoblastoma is reported. Prader-Willi syndrome was suspected because of hypotonia, hypopigmentation, and undescended testes when he was a newborn infant. The diagnosis was confirmed by chromosome analysis, which showed 46XY del(15)(qll, ql3). When he was 1 year 4 months old, a liver tumor and high serum AFP were found. At operation a large tumor arising from the caudate lobe was found and the tumor was totally resected. After completion of the hepatectomy, he developed circulatory collapse of unknown cause and died shortly after the operation. Histopathologic examination revealed that the tumor was composed of two components, well differentiated cells and poorly differentiated cells. The well differentiated part did not dominate the poorly differentiated part, so it was diagnosed as poorly differentiated hepatoblastoma. This is the first reported case of Prader-Willi syndrome with a pediatric malignant tumor.     

Truncus Arteriosus: Diagnostic Accuracy,Outcomes, and Impact of Prenatal Diagnosis

Limited data exist on the impact of prenatal diagnosis and outcomes of fetal truncus arteriosus (TA). We sought to assess prenatal diagnostic accuracy and prenatal outcomes in fetuses with TA and compare postnatal outcomes in neonates with prenatally and postnatally diagnosed TA. Records were reviewed for patients diagnosed with TA in utero or at ≤60 days of life from 1992 to 2007. Forty-three (32%) of 136 TA patients had prenatal diagnosis. Five patients with TA were prenatally misdiagnosed, and 5 with other congenital heart diseases were misdiagnosed with TA prenatally. Of 28 fetuses diagnosed at <24 weeks gestation, 19 (68%) did not survive to birth because of spontaneous fetal death (n = 2) or because of elective termination (n = 17). Pregnancy termination was not more likely for fetuses with extracardiac anomalies. Of 19 live-born patients with correct prenatal diagnosis of TA, 2 (11%) died before surgery, and 4 (24%) died in the early postoperative period. All patients who died presurgically had been diagnosed prenatally. Overall, early postoperative mortality was 10%. Prenatal diagnosis of TA remains challenging and is associated with a high rate of elective termination. Fetal diagnosis was associated with younger age at repair but was not associated with improved neonatal survival.     

Hirschsprung’s disease, associated rare congenital anomalies

Objective: Hirschsprung’s disease may be associated with a number of congenital anomalies of which Down’s syndrome and intestinal atresias are commonly encountered. The study aimed to assess the impact of rare associated anomalies on the diagnosis and management of Hirschsprung’s disease.Methods: A retrospective review of the clinical presentation, diagnosis and outcome of thirty five consecutive newly diagnosed cases of Hirschsprung’s disease encountered over two years was performed.Results: Besides Down’s syndrome (two), intestinal atresia (one) and pigmentary ocular defects (two), three rare anomalies (Occipital meningocele, Calcific meconium cyst with anal stenosis, Malrotation) were encountered in four of thirty five cases. The clinical features, radiologic anatomy and gross morphology of the bowel were unconventional and the diagnosis was supported by intraoperative acetylcholinesterase staining of biopsies. Though the diagnosis was relatively delayed in these cases, the outcome has been comparable to the rest. The dilemma in their diagnosis and management and their possible pathoembryology is discussed.Conclusion: Awareness of such associations and a specific investigative protocol is imperative for timely diagnosis and minimal morbidity in complex presentations of Hirschsprung’s disease.