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The histiocytoses are a heterogeneous group of disorders characterised by an excessive number of histiocytes. In most cases the pathophysiology is unclear and treatment is nonspecific. Faisalabad histiocytosis (FHC) (MIM 602782) has been classed as an autosomal recessively inherited form of histiocytosis with similarities to Rosai-Dorfman disease (RDD) (also known as sinus histiocytosis with massive lymphadenopathy (SHML)). To elucidate the molecular basis of FHC, we performed autozygosity mapping studies in a large consanguineous family and identified a novel locus at chromosome 10q22.1. Mutation analysis of candidate genes within the target interval identified biallelic germline mutations in SLC29A3 in the FHC kindred and in two families reported to have familial RDD. Analysis of SLC29A3 expression during mouse embryogenesis revealed widespread expression by e14.5 with prominent expression in the central nervous system, eye, inner ear, and epithelial tissues including the gastrointestinal tract. SLC29A3 encodes an intracellular equilibrative nucleoside transporter (hENT3) with affinity for adenosine. Recently germline mutations in SLC29A3 were also described in two rare autosomal recessive disorders with overlapping phenotypes: (a) H syndrome (MIM 612391) that is characterised by cutaneous hyperpigmentation and hypertrichosis, hepatomegaly, heart anomalies, hearing loss, and hypogonadism; and (b) PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus) syndrome. Our findings suggest that a variety of clinical diagnoses (H and PHID syndromes, FHC, and familial RDD) can be included in a new diagnostic category of SLC29A3 spectrum disorder., Competing Interests: The authors have declared that no competing interests exist.

In most children presenting with the common signs and symptoms of leukemia, the diagnosis is readily made. However, unusual features of the disease and the absence of abnormalities on the complete blood count may render the diagnosis problematic, especially if this malignancy is not suspected. The current report focuses on the unusual presentation of leukemia and the difficulties in the diagnosis of the malignancy.

Composite tumors are extremely rare. Such tumors in adrenal glands are usually of neuroendocrine-neural type and occur mostly in adults. Their pathogenesis remains elusive. We report a patient with composite neuroblastoma (NB), adrenocortical tumor (ACT), and Li-Fraumeni syndrome (LFS) with germline TP53 R248W mutation. LFS predisposes to the development of leukemia, sarcomas, adrenocortical and breast carcinomas, brain tumors and, questionably, NB. A unique correlation between a single TP53 mutation (R337H) and ACT has been reported in southern Brazilian children. It remains unclear at this time whether a similar association of NB and R248W in patients with LFS exists., ((c) 2007 Wiley-Liss, Inc.)

Numerous metabolic disorders, teratogenic agents, and in utero infections lead to congenital bone disease and malformation. This review focuses on hereditary and familial disorders of bone with particular emphasis on impaired hematopoiesis, myelofibrosis, pathologic fractures, and dysmorphology of the forearm and craniofacial structures. The severity of bone disease and marrow dysfunction of any given disorder may vary considerably from one affected individual to the next, and intrapersonal variability over time may be substantial as well. Both can impart difficulty to the appropriate evaluation and delay the correct diagnosis. Many of these disorders are phenotypically quite similar but require very different therapeutic intervention.

Rosai-Dorfman disease (RDD) is a rare, sporadic histiocytic disorder characterized by painless but protracted lymphadenopathy. Its etiology remains unclear. The observation of congenital disease and reports of familial cases with seven pairs of siblings including three sets of identical twins suggests a genetic predisposition in some patients with this condition. We now report two brothers of consanguineous Palestinian parents, whose lymphadenopathy, lymph node histology, and polyclonal hypergammaglobulinemia indicated RDD. The presence of intrauterine fractures, short stature, and sensorineural hearing impairment suggested a rare familial form of the disorder. Moynihan et al. recently described a Pakistani family with a familial histiocytic disorder highly reminiscent of the brothers reported here, whose lymph node morphology was apparently consistent with RDD as well. The presence of sensorineural deafness, short stature, and joint contractures, however, suggested a separate, rare autosomal recessive syndrome referred to as Faisalabad histiocytosis, after the family's place of origin. We believe that the brothers described here represent a second family with Faisalabad histiocytosis, which mimics RDD histologically., (Copyright (c) 2005 Wiley-Liss, Inc.)

Sickle cell intrahepatic cholestasis (SCIC) is a rare complication seen in sickle cell patients who present with sudden onset of RUQ pain, progressive hepatomegaly, mild elevation of transaminases, coagulopathy, and extreme hyperbilirubinemia. Early recognition of this entity is essential to avoid life-threatening complications. Diagnosis can be challenging given the overlap in clinical presentation with other conditions affecting the hepatobiliary biliary system in sickle cell anemia such as hepatitis, cholecystitis, and hepatic crisis. Treatment is currently limited to exchange transfusion. The authors present two patients with SCIC and cholelithiasis; the clinical picture of one is complicated by choledocholithiasis.

The "Rule of Four" facilitates a rapid and focused approach to the diagnosis of the common hematologic and oncologic disorders encountered in general pediatric practice. This system relies on four recurrent but different clinical entities or laboratory tests relevant to the diagnosis of children with anemia, excessive bleeding or clotting, and common malignancies. For each disorder, there is a discussion of a variety of four lab tests or factors pertinent to a differential diagnosis.

We describe four individuals of an African-American family with a predominantly diaphyseal bone disease associated with familial gigantiform cementoma (FGC), a disorder typically seen in Caucasians. The mother and her children presented with deformities of the jaws, abnormalities of the long bones, and pre-pubertal pathologic fractures. The index patient carried the diagnosis of osteosarcoma (OS). In addition, we provide a possible explanation for the jaw abnormalities of King Tutankhamen's father in the 18th dynasty in Egypt around 1350 BC.

The authors report a child younger than age 15 years with a rare hepatosplenic gamma/delta T-cell lymphoma, which is highly aggressive and primarily seen in young men. A 9-year-old girl presented with thrombocytopenia and hepatosplenomegaly. Bone marrow analysis revealed a metastatic pleomorphic lymphoma of peripheral T-cell phenotype, with rearrangement of the T-cell receptor gamma/delta and expression of CD3 and CD16/56. Instead of the previously reported primary, nonrandom, chromosomal abnormalities, isochromosome 7q and trisomy 8, this patient had four copies each of chromosome 7q, including isochromosome 7[i(7)(q10)] and der(21)t(7;21), as well as chromosome 8. This entity needs to be considered in women and children with lymphoma. Conventional therapy appears to be inadequate for cure.

This case suggests that typhlitis may cause delayed abdominal pathology. A history of this condition should be considered in the work-up of any patient with gastrointestinal or genitourinary pathology.

The authors report the concomitant occurrence of Duchenne muscular dystrophy (DMD) and alveolar rhabdomyosarcoma (RMS). A 4-year-old boy presented with symptoms involving his neuromuscular system that affected primarily his left hip and leg. Duchenne muscular dystrophy was diagnosed. Seven months later, metastatic alveolar RMS in the ipsilateral pelvis was documented. The diagnosis of one major disorder affecting striated muscle (DMD) may have prevented the early detection of another (RMS).

A patient with aplastic anemia failed to respond to immunosuppressive therapy and first marrow transplantation (BMT). Recovery of autologous hematopoiesis was rapid following a second stem cell transplant with a non-myeloablative preparatory regimen. The autologous immune response to infectious mononucleosis (IM) 4 weeks post-transplant was normal despite recent and ongoing severe immunosuppression.

Purpose: A large cell anaplastic lymphoma that developed after treatment of a Ewing sarcoma (ES) is described., Patient: An 11-year-old girl with a pelvic ES developed a large cell, Ki-1+, anaplastic lymphoma in the same anatomic location 10 months after multimodal therapy., Results: ES recurred in the primary site 16 months after allogeneic marrow transplantation and 3.5 years after initial diagnosis, but the patient remains in remission from her lymphoma., Conclusion: The occurrence of lymphoma and ES in a short time interval in the same patient is very unusual. Whether etiologic factors other than chemoradiotherapy, including genetic disposition, play a role remains to be elucidated.

Purpose: Myelodysplastic syndromes in children commonly evolve into acute leukemia, usually acute myelogenous leukemia (AML) and rarely acute lymphoblastic leukemia (ALL). The lineage of the leukemia can be predicted based on characteristic morphologic and cytogenetic findings of the marrow and peripheral blood., Patient and Methods: A 3-year-old boy had refractory anemia with excess blasts and abnormalities suggestive of pre-AML with highly unusual cytogenetic changes. ALL of pre-B phenotype developed., Results: Leukoerythroblastic anemia, pseudo Pelger-Huet neutrophils, and dysmyelopoietic hyperplasia of the marrow suggested likely early progression to AML. Complex cytogenetic abnormalities (monosomy 17 and 20, ring chromosome 11 with deletion of bands q23, and a derivative dicentric chromosome 12) were present in both the myelodysplastic marrow and the subsequent ALL., Conclusion: This case presents cytogenetic evidence of common early progenitor cell ontogeny of both malignancies (refractory anemia with excess blasts and ALL).

Purpose: Agnogenic myeloid metaplasia (AMM) is a myeloproliferative disorder characterized by marrow fibrosis, extramedullary hematopoiesis, splenomegaly, and leukoerythroblastosis with abnormalities of red blood cell morphology. This is rarely encountered in children. No conventional curative therapy is known; however, allogeneic bone marrow transplantation (BMT) may eradicate the underlying stem cell abnormality with subsequent normal hematopoiesis., Results: We report a 3-year-old Arab boy who had AMM and who had normal marrow hematopoiesis and markedly reduced fibrosis after high-dose chemotherapy and matched sibling BMT., Conclusions: Allogeneic BMT offers a potential cure for patients with agnogenic myeloid metaplasia. A preparatory regimen containing busulfan and cyclophosphamide appears promising for patients with the disease.

Monoclonal antibody S5, which is specific for CD44, facilitates engraftment of major histocompatibility complex (MHC)-mismatched canine bone marrow (BM) when infused into recipient animals before total body irradiation (TBI) and marrow infusion. The precise mechanism by which S5 facilitates engraftment is not known. Previously published data in a murine long-term bone marrow culture (LTBMC) model with other anti-CD44 monoclonal antibodies (mAbs) demonstrated an abrogation of myelo- and lymphopoiesis in LTBMC. To address this issue in an in vitro setting, the effect of S5 on canine myelopoiesis in LTBMC was investigated. The data indicate that treatment of LTBMC with S5 causes an absolute increase in the number of progenitor cells as measured by a colony-forming unit-granulocyte/macrophage (CFU-GM) assay compared to cultures treated with control mAb (p < 0.0001). This effect was not observed with three other anti-CD44 mAbs used (Hermes-1, S3, and IM7). In addition, a concomitant decrease in the production of nonadherent cells was noted (p < 0.0001). These effects were evident in both autologous and allogeneic LTBMC systems. mAb S5 has been shown to enhance natural killer (NK) activity, and more recent data indicate the increased cytoxic effect to be partially mediated through CD18. Thus, a possible role for modulation of the CD18 antigen in LTBMC by S5 was assessed by addition of the anti-CD18 mAb 60.3. While the S5-induced reduction in total nonadherent cell production was not changed by addition of 60.3, the increase in progenitor cells stimulated by S5 was abrogated. These findings suggest a role for anti-CD44 antibody in changes in the marrow microenvironment that may be responsible for facilitation of donor engraftment and, at least in part, CD18 may be involved in this phenomenon. The establishment of this in vitro LTBMC model will enable the mechanism to be further dissected.

Two brothers with presumed Baller-Gerold syndrome, one of whom was previously diagnosed with the association of vertebral, cardiac, renal, limb anomalies, anal atresia, tracheo-esophageal fistula (VACTERL) association with hydrocephalus, were evaluated for chromosome breakage because of severe thrombo cytopenia in one of them. Spontaneous and clastogen-induced breakage was markedly increased in both patients as compared to control individuals. Clinical manifestations and chromosome breakage, consistent with Fanconi anemia, in patients with a prior diagnosis of either Baller-Gerold syndrome, reported earlier in one other patient [Farrell et al., 1994: Am J Med Genet 50:98-99], or with VACTERL association with hydrocephalus, recently reported in 3 patients [Toriello et al., 1991: Proc Greenwood Genet Center 11:142; Porteus et al., 1992: Am J Med Genet 43:1032-1034], underline the clinical heterogeneity of Fanconi anemia and raise the question of whether these syndromes are distinct disorders or phenotypic variations of the same disease.

In this study, we examined the in vitro effect of an anti-CD44 mAb, S5, on NK function using canine PBMC as effectors. S5 enhanced NK activity in a dose-dependent and rapid fashion as did IM7, another anti-CD44 mAb that recognizes a common epitope(s) on CD44. Other anti-CD44 mAb (Hermes-1 and S3) that recognize epitopes distinct from S5 and IM7 had a variable effect on NK activity. The activation of increased killing by S5 only occurred when NK-sensitive targets were used, suggesting that lymphokine-activated killer cells were not being induced. Antibody-dependent cell cytotoxicity was not the mechanism involved in the augmentation of NK activity, nor was it Fc receptor-dependent, inasmuch as S5 F(ab')2 was able to increase NK activity. F(ab') fragments of S5 were equivalent to intact S5 in their ability to stimulate NK activity, demonstrating that cross-linking of CD44 was not a necessary component of stimulation, and that nonspecific agglutination of target and effector cells was not occurring via the two F(ab) arms. The enhancement of NK function was monocyte-independent and mediated by radioresistant cells, indicating that the antibody enhanced NK cells directly. This finding would suggest that CD44 can direct a transmembrane signal for NK cell activation.

Fetal echocardiography is the most practical method for diagnosing prenatal arrhythmias. Because some prenatal tachyarrhythmias have been shown to respond to antiarrhythmic drugs, correctly diagnosing fetal arrhythmias has assumed new importance. With the aid of two-dimensional echocardiographic imaging, an M-mode cursor can be aligned to record atrial and ventricular wall motion--either independently or simultaneously. A consistent feature in the fetus is prominent atrial wall contractions that can be readily recorded on the M-mode tracing. By matching atrial and ventricular wall contractions with assumed P waves and QRS complexes, the fetal electrocardiogram can be reconstructed. In 57 fetuses studied, recurrent atrial and ventricular ectopic beats were the most common prenatal arrhythmias. However, atrial flutter, ventricular tachycardia, atrial and ventricular bigeminy and atrial and ventricular bradyarrhythmias have been correctly identified and in some instances appropriately treated. Marked fetal bradycardia in the midtrimester of pregnancy is shown for the first time to be caused by transducer pressure on the maternal abdominal wall.