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Background: Succinyl-coenzyme A ligase (SUCL) is a mitochondrial enzyme that catalyses the reversible conversion of succinyl-coenzyme A to succinate. SUCL consists of an α subunit, encoded by SUCLG1, and a β subunit, encoded by either SUCLA2 or SUCLG2. Recently, mutations in SUCLG1 or SUCLA2 have been identified in patients with infantile lactic acidosis showing elevated urinary excretion of methylmalonate, mitochondrial respiratory chain (MRC) deficiency, and mitochondrial DNA depletion. Methods: Case description of a Japanese female patient who manifested a neonatal-onset lactic acidosis with urinary excretion of methylmalonic acid. Enzymatic analyses (MRC enzyme assay and Western blotting) and direct sequencing analysis of SUCLA2 and SUCLG1 were performed. Results: MRC enzyme assay and Western blotting showed that MRC complex I was deficient. SUCLG1 mutation analysis showed that the patient was a compound heterozygote for disease-causing mutations (p.M14T and p.S200F). Conclusion: For patients showing neonatal lactic acidosis and prolonged mild methylmalonic aciduria, MRC activities and mutations of SUCLG1 or SUCLA2 should be screened for.

We present a rare case of subcutaneous lesions arising in the palm of a 4-year-old girl. Histologic examination of the biopsy specimens showed granulomatous inflammation with focal necrobiosis, which was consistent with subcutaneous granuloma annulare. Subcutaneous granuloma annulare is a self-limited disease and treatment is not required, although recurrence and/or multiple lesions are frequent.

A 1-year-6-month-old girl presented with a subcutaneous tumor of the forehead, which had developed since birth. The preoperative examinations showed nasofrontal bone defect with meningocele and subcutaneous tumor with cyst. The patient underwent excision of the tumor and reconstruction of the bone defect. Histologically, the skin tumor exhibited disordered arrangement of striated muscle fibers among normal dermal components, and the cyst was lined by cornified epithelium with a few hair adnexa and contained lamellated keratin. These findings were consistent with rhabdomyomatous mesenchymal hamartoma (RMH) and dermoid cyst. This is an interesting case of RMH co-existing with nasofrontal meningocele and dermoid cyst in the same area. We suggest embryologic errors as a possible etiology, which is incomplete dysjunction of the neural ectoderm from the cutaneous ectoderm. Failure of insertion of mesoderm between the ectoderms caused the bone defect and the disordered proliferation and differentiation of mesoderm-derived tissue, leading to formation of hamartoma.

Acute renal failure due to leukemic infiltration into the kidney is rare in childhood acute lymphoblastic leukemia (ALL). We report here a five year-old boy with ALL who presented acute renal failure caused by leukemic infiltration at onset. Treatment with predonisolone and hemodialysis was effective. However, he showed persistent or repeated relapses at extramedullary sites, such as central nervous system, testis, and pancreas, suggesting that leukemic cells of this patient may have had a high affinity to extramedullary organs. On the basis of previous reports and the experience of this patient, intensive treatment may be needed in ALL children with renal involvement.

Invasive micropapillary carcinoma (IMPCa) of the breast refers to a unique variant of invasive ductal carcinoma, but its biological behavior has not been elucidated well. We analyzed 16 IMPCa cases (10 pure type, six mixed type). The incidence of IMPCa was 1.0% of all primary breast carcinoma. High nuclear grade (75.0%), as well as poorly differentiated histological grade (81.3%), was frequently seen. Lymph node metastases were evident in 92.9% of the examined cases, and about half of them showed more than 10 positive nodes. Comparison between serially experienced invasive ductal carcinoma, not otherwise specified (IDC-NOS), revealed that both high nuclear grade and poor histological grade were significantly more frequent (P < 0001), there was a lower frequency of positive estrogen receptor/progesterone receptor (P < 0.05, P < 0.01), a higher frequency of HER-2 overexpression (P < 0.025), and more frequent lymph node metastases (P < 0.05) in IMPCa. The comparison between lymph node positive IDC-NOS did not show any statistically significant differences in frequency for positive p53, matrix metalloproteinase protein-2 (MMP-2), vascular endothelial growth factor (VEGF) or E-cadherin. However, IMPCa showed a significantly increased number of blood vessels counted by CD34 immunostains (P < 0.05). These results suggest that IMPCa is, at least, the same or more aggressive than lymph node positive cases of IDC-NOS. Hence, not only the high incidence of lymph node metastases but also distant, blood-borne metastases may be important.

Orexin-A is a neuropeptide present in the brain and is known to regulate feeding and sleeping. In this study, we examined the systemic distribution of orexin-A in human tissues. Immunoreactivity for orexin-A was detected in ganglion cells of the thoracic sympathetic trunk, myenteric plexuses and endocrine cells of the gastrointestinal tract, islet cells of the pancreas and syncytiotrophoblasts and decidual cells of the placenta. In the gastrointestinal tract, orexin-A immunoreactivity was detected in the myenteric plexuses from 26 gestational weeks to birth. In double immunostaining in the pancreas, a great majority of insulin-positive cells was simultaneously positive for orexin-A. mRNA expression for prepro-orexin was also detected in the kidney, adrenal gland, pancreas, placenta, stomach, ileum, colon and colorectal epithelial cells. These results suggest the production of orexin-A in various human peripheral tissues and orexin-A may also play important roles in some peripheral organs.

Adrenarche is considered to occur as a result of intra-adrenal changes in steroidogenic enzymes involved in C19 steroid production. The present study was conducted because developmental changes in steroidogenic enzymes have not been examined well in human postnatal adrenal. Twenty-four specimens of nonpathological human adrenals from 7 months to 62 years retrieved from autopsy files. Immunohistochemistry for P450 side-chain cleavage (P450scc), 17alpha hydroxylase (P450c17), dehydroepiandrosterone sulfotransferase (DHEA-ST), P450 oxidoreductase, cytochrome b5, and 3beta-hydroxysteroid dehydrogenase (3betaHSD) was per-formed in these specimens, and the immuno-intensity was evaluated using CAS 200 computed image analysis system. Immunoreactivity of P450scc was marked in the zona glomerulosa, fasciculata and reticularis in the adrenal glands of all the cases examined. P450c17 and DHEA-ST immunoreactivity was weak in the zona fasciculata and reticularis in the adrenals of age 7 months to 5 years, but thereafter became prominent in the zona reticularis. Immunoreactivity of P450 oxidoreductase and cytochrome b5, components of the electron transfer system hypothesized to regulate the 17-20 lyase activity of P450c17, was weak in all three zones of adrenal cortex from 7 months to 5 years, and became more marked in the zona reticularis after age 5 years. 3betaHSD immunoreactivity was marked in all three zones of the adrenal cortex from 7 months to 8 years but thereafter decreased in the zona reticularis. These data suggest that the human adrenal zona reticularis markedly begins to develop morphologically and functionally at around 5 years of age. The increased level of P450c17, DHEA-ST, P450 oxidoreductase, and cytochrome b5, and the decreased level of 3betaHSD in the reticularis is likely to contribute to increased C19 steroid production during adrenarche.

Intratumoral metabolism and synthesis of estrogens are considered to play very important roles in the pathogenesis and development of various sex steroid-dependent neoplasms including breast and endometrial carcinoma. 17β-Hydroxysteroid dehydrogenase (17β-HSD) isozymes catalyze the interconversion of estradiol (E2) and estrone (E1), and thereby serve to modulate the tissue levels of bioactive E2. 17β-HSD type 1 primarily catalyzes the reduction of E1 to E2, whereas 17β-HSD type 2 primarily catalyzes the oxidation of E2 to E1. In the human breast and its disorders, 17β-HSD type 1 is expressed in proliferative diseases without atypia, atypical ductal hyperplasia, ductal carcinoma in situ and invasive ductal carcinoma. 17β-HSD type 2 is not detected in any of the lesions. In addition, 17β-HSD type 1 coexpression is significantly correlated with estrogen receptor status in invasive ductal carcinoma cases. These results indicate that breast carcinoma can effectively convert E1, produced as a result of in situ aromatization, to E2, a biologically potent estrogen, and exerts estrogenic actions on tumor cells through the estrogen receptor. On the other hand, in the human endometrium, 17β-HSD type 2 is expressed, but not 17β-HSD type 1. 17β-HSD type 2 is expressed in the secretory phase but not in any proliferative phase in the endometrial mucosa. The enzyme is expressed in 75% of endometrial hyperplasias and 37% of carcinoma cases. In endometrial carcinoma cases, a significant inverse correlation has been detected between17β-HSD type 2 immunoreactivity and age (p < 0.02). These results indicate that oxidation of E2 to E1 is dominant in endometrial carcinoma, 17β-HSD types 1 and 2 play an important role in the regulation of in situ estrogen production in breast and endometrial carcinoma.

11Beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) catalyzes the conversion of cortisol to biologically inactive cortisone and is thought to confer specificity on mineralocorticoid receptors (MR). Cortisol is a prerequisite for surfactant synthesis and fetal lung maturation. Recently, expression of 11betaHSD2 was demonstrated in human fetal lung, but its localization and possible biological roles remain unknown. Therefore, in this study, we examined immunohistochemical localization of 11betaHSD2, MR, and glucocorticoid receptor (GR) in nonpathological human lungs from fetus to adult (8 weeks gestation to 55 yr of age; n = 40) retrieved from pathology files. Both 11betaHSD2 and MR immunoreactivities were detected in airway epithelia, from bronchiole to trachea and in fetal and neonatal ciliated collecting duct cells of tracheal and bronchial glands, but were undetectable in alveoli. On the other hand, GR was detected in all cell types. These results indicate that 11betaHSD2 colocalizes with MR in human airway epithelia and suggest that 11betaHSD2 play an important role in pulmonary mineralocorticoid activity such as sodium and fluid transport.

We describe a case of Hodgkin lymphoma developing in a 9-year-old girl with polyarticular, rheumatoid factor-positive juvenile idiopathic arthritis treated with methotrexate (MTX), prednisone, and naproxen for 5 years. Pathologic and molecular analyses revealed that the Hodgkin cells contained Epstein-Barr virus and the viral DNA was monoclonal. She achieved complete remission after MTX withdrawal, chemotherapy, and radiation. To the best of my knowledge, this is the sixth report of Hodgkin lymphoma in patients with juvenile idiopathic arthritis receiving low dose MTX therapy.

We describe 2 siblings who had interleukin-1 receptor-associated kinase 4 deficiency with a novel mutation in exon 2. They had delayed separation of the umbilical cord. The flow cytometric analysis of monocytic intracellular tumor necrosis factor-alpha production in response to lipopolysaccharide may be a useful method to screen for the disease.

The authors report a case of primary tracheal schwannoma (neurilemoma) causing symptoms of airway obstruction in a 9-year-old girl. Computerized tomography scan showed a polypoid intratracheal mass obstructing 73% of the lumen. Partial tracheal resection with primary anastomosis was performed. Histologic analysis showed a benign neurogenic tumor of Schwann cell origin.

Succinyl-coenzyme A ligase (SUCL) is a mitochondrial enzyme that catalyses the reversible conversion of succinyl-coenzyme A to succinate. SUCL consists of an α subunit, encoded by SUCLG1, and a β subunit, encoded by either SUCLA2 or SUCLG2. Recently, mutations in SUCLG1 or SUCLA2 have been identified in patients with infantile lactic acidosis showing elevated urinary excretion of methylmalonate, mitochondrial respiratory chain (MRC) deficiency, and mitochondrial DNA depletion.Case description of a Japanese female patient who manifested a neonatal-onset lactic acidosis with urinary excretion of methylmalonic acid. Enzymatic analyses (MRC enzyme assay and Western blotting) and direct sequencing analysis of SUCLA2 and SUCLG1 were performed.MRC enzyme assay and Western blotting showed that MRC complex I was deficient. SUCLG1 mutation analysis showed that the patient was a compound heterozygote for disease-causing mutations (p.M14T and p.S200F).For patients showing neonatal lactic acidosis and prolonged mild methylmalonic aciduria, MRC activities and mutations of SUCLG1 or SUCLA2 should be screened for.

We report a case of gastric adenomyoma in a 1-month-old girl. This patient presented with gastric outlet obstruction simulating infantile hypertrophic pyloric stenosis. Histologic examination of the excised specimen showed irregularly arranged glands and interlacing smooth muscle bundles surrounding the glandular elements. We suggest that this lesion is not just heterotopia, but hamartoma composed of abnormal mixture of endoderm-derived epithelial component and mesoderm-derived smooth muscle.