Faculty Bibliography

BACKGROUND:The Loeys-Dietz syndrome is a recently described autosomal dominant aortic-aneurysm syndrome with widespread systemic involvement. The disease is characterized by the triad of arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate and is caused by heterozygous mutations in the genes encoding transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2, respectively). METHODS:We undertook the clinical and molecular characterization of 52 affected families. Forty probands presented with typical manifestations of the Loeys-Dietz syndrome. In view of the phenotypic overlap between this syndrome and vascular Ehlers-Danlos syndrome, we screened an additional cohort of 40 patients who had vascular Ehlers-Danlos syndrome without the characteristic type III collagen abnormalities or the craniofacial features of the Loeys-Dietz syndrome. RESULTS:We found a mutation in TGFBR1 or TGFBR2 in all probands with typical Loeys-Dietz syndrome (type I) and in 12 probands presenting with vascular Ehlers-Danlos syndrome (Loeys-Dietz syndrome type II). The natural history of both types was characterized by aggressive arterial aneurysms (mean age at death, 26.0 years) and a high incidence of pregnancy-related complications (in 6 of 12 women). Patients with Loeys-Dietz syndrome type I, as compared with those with type II, underwent cardiovascular surgery earlier (mean age, 16.9 years vs. 26.9 years) and died earlier (22.6 years vs. 31.8 years). There were 59 vascular surgeries in the cohort, with one death during the procedure. This low rate of intraoperative mortality distinguishes the Loeys-Dietz syndrome from vascular Ehlers-Danlos syndrome. CONCLUSIONS:Mutations in either TGFBR1 or TGFBR2 predispose patients to aggressive and widespread vascular disease. The severity of the clinical presentation is predictive of the outcome. Genotyping of patients presenting with symptoms like those of vascular Ehlers-Danlos syndrome may be used to guide therapy, including the use and timing of prophylactic vascular surgery.

Persistent interstitial pulmonary emphysema (PIPE) is a syndrome characterized by air-leakage in the perivascular tissues of the lung, primarily affecting mechanically ventilated neonates. Reports in the literature of infants developing PIPE with no history of respiratory distress syndrome (RDS) or mechanical ventilation are scarce. Here, we present a case of a 3-month-old former full term male infant with no history of RDS or mechanical ventilation who presented with focal cystic lung disease associated with spontaneous tension pneumothorax. He was ultimately found to have PIPE based on pathologic evaluation of the resected cystic region. We believe that focal PIPE should be included in the differential diagnosis of cystic lung disease in a full term, unventilated infant, even when spontaneous pneumothorax is the presenting entity

The investigation of sudden death of infants varies, and death rates may depend on local practices of death certification. We studied the extent of the investigation and the final cause of death (COD) in 3 regions: New York, New York, USA (NY); King County, Washington, USA (KC); and Montevideo, Uruguay (MU). We conducted a retrospective review of 543 cases (NY 258, KC 56, MU 229) of previously healthy babies who died suddenly without obvious trauma, at ages 0 to 12 months, over a 3-year period (1998 to 2001). All cases included a complete autopsy and histologic examination. Cases were assessed for completion of special studies (including radiographs, photos, toxicology and metabolic sampling, cultures, and vitreous humor chemistry), measurements, and scene investigation. Specialized pediatric measurements and testing were done less often than routine procedures, and were done less often in cases overall compared with cases certified as sudden infant death syndrome (SIDS). Fifty-five percent of SIDS cases in NYC and 12% of SIDS cases in KC had no scene investigation. Manhattan had a complete workup in 42% of SIDS cases, whereas the remaining sites had fewer that 15% of cases completely worked up. The most common non-natural COD was suffocation at all 3 sites. The overall most common COD were respiratory infection in MU (22%) and SIDS in NY (45%) and KC (86%). We conclude that the sudden death of infants requires special consideration and still lacks consistency. SIDS investigations are not done completely in all cases and rates may depend on regional differences in certifying infant deaths

Giant cell tumor of soft tissue (GCTST) has gained general acceptance as an uncommon but distinct primary soft tissue tumor since it was first described in 1972. GCTST is predominantly seen in adults and typically shows uniformly dispersed osteoclast-like giant cells admixed with oval to polygonal mononuclear cells. It usually follows a benign clinical course, although the malignant variant has been described in cases in which the mononuclear cells demonstrate obvious dysplastic features. It is still not clear whether the two variants belong to the spectrum of the same tumor. No cytogenetic chromosomal abnormalities have been reported in the literature of GCTST. Interestingly, the osseous counterpart of giant cell tumor, which shares similar histologic features, quite often displays a telomeric association at the cytogenetic level, a finding that has never been reported in GCTST. We report the case of a 12-year-old girl with GCTST of the right leg that metastasized to the lung. Cytogenetic studies from the primary tumor showed the phenomenon of telomeric association involving multiple chromosomes

Lipoblastomas are rare benign tumors of infancy that usually affect children younger than 3 years. Most lipoblastomas (70%) occur on the extremities. Lipoblastomas may mimic other infantile tumors, including hemangiomas, hibernomas, lipomas, and liposarcomas, and correct diagnosis is necessary to ensure appropriate treatment. Lipoblastomas fall under 2 discrete subtypes: well-circumscribed lipoblastomas and diffuse lipoblastomatosis. Both types present with firm, nontender masses of lobulated, well-circumscribed soft tissue. Histologically they can be highly vascularized with plexiform capillaries, often with an individual feeder artery to each lobule. Complete surgical removal is the recommended treatment. Only 2 cases of lipoblastomas of the cheek have been reported in the English-language literature. We present the case of a young child with a cheek lipoblastoma, emphasizing the importance of correct diagnosis and highlighting techniques used to provide suitable treatment

PURPOSE:: Development and differentiation of the human fetal prostate are androgen dependent and follow a specific pattern of solid bud-ductal morphogenesis, which involves stromal-epithelial interactions. Androgen receptor associated protein 55 (ARA55) an androgen receptor coactivator localized in stromal cells, binds to androgen receptor (AR) and regulates androgen receptor translocation and transcriptional activity. We investigated whether ARA55 has a role in human prostate development. MATERIALS AND METHODS:: ARA55 expression was examined in 25 human prostates from fetuses at gestational ages 10 to 40 weeks and compared to the expression of 34betaE12 (a basal cell marker), smooth muscle actin, desmin (a smooth muscle marker), vimentin (a mesenchymal marker) and Ki-67 (a proliferation marker) by immunohistochemistry. RESULTS:: Prostatic epithelium appeared as solid epithelial buds from the urogenital sinus. It underwent arborization and ductal differentiation from the center to the periphery. ARA55 was expressed in stromal cells with a zonal pattern, primarily in the peripheral zone surrounding the noncanalized acini. Most cells in solid buds were positive for 34betaE12, while only basal layer cells in the centrally located epithelial ducts stained with 34betaE12. Solid buds also had a higher proliferation index than ducts. In addition, ARA55 expressing stromal cells but not ARA55 negative stromal cells showed smooth muscle differentiation. CONCLUSIONS:: The intimate relationship between ARA55 expressing stromal cells and mitotically active, noncanalized acini suggests that ARA55 has a role in the stromal-epithelial interaction involved in fetal prostate development

Thymoma is an uncommon tumor of childhood. Stage of the tumor is an independent prognostic factor for survival. Surgery is the treatment of choice for stage I and stage II tumors. Chemotherapy is reserved for patients with refractory or metastatic disease. Thymomas are moderately radiosensitive. However, radiation therapy is not an attractive option for children due to its side-effects on developing organs. The authors describe 2 children with completely encapsulated thymoma who were successfully treated with surgery alone. Both patients remain free of disease 3 years after surgery. One of the patients also has nevus sebaceous. The authors also discuss the possible association between the two disease entities.

Thymoma is an uncommon tumor of childhood. Stage of the tumor is an independent prognostic factor for survival. Surgery is the treatment of choice for stage I and stage II tumors. Chemotherapy is reserved for patients with refractory or metastatic disease. Thymomas are moderately radiosensitive. However, radiation therapy is not an attractive option for children due to its side-effects on developing organs. The authors describe 2 children with completely encapsulated thymoma who were successfully treated with surgery alone. Both patients remain free of disease 3 years after surgery. One of the patients also has nevus sebaceous. The authors also discuss the possible association between the two disease entities.

Tuberous sclerosis complex (TSC) is a common autosomal dominant disorder in which affected patients develop a wide variety of benign and malignant tumors. We report here on a 31-week gestational age fetus with pathological features of TSC. Developmental expression of hamartin and tuberin in various tissues was studied using immunohistochemistry. There was loss of expression of hamartin in the tuber and weak expression of the tuberin. Both hamartin and tuberin were expressed in bronchial epithelial cells, cardiac muscles, renal collecting tubules, and neural tissues. The rhabdomyomas stained negatively for tuberin and hamartin. Two genetic loci are responsible for TSC-TSCI and TSC2. The TSC1 gene on chromosome 9 encodes a protein termed hamartin that lacks sequence similarity to any known proteins, whereas the TSC2 gene on chromosome 16 codes for a protein termed tuberin. These results indicate that tuberin and hamartin may play a critical role in development and thus provide a framework for understanding the developmental and hamartomatous manifestations of tuberous sclerosis.