Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1.

Muscle-eye-brain disease (MEB) is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities, and lissencephaly. Mammalian O-mannosyl glycosylation is a rare type of protein modification that is observed in a limited number of glycoproteins of brain, nerve, and skeletal muscle. Here we isolated a human cDNA for protein O-mannose beta-1,2-N-acetylglucosaminyltransferase (POMGnT1), which participates in O-mannosyl glycan synthesis. We also identified six independent mutations of the POMGnT1 gene in six patients with MEB. Expression of most frequent mutation revealed a great loss of the enzymatic activity. These findings suggest that interference in O-mannosyl glycosylation is a new pathomechanism for muscular dystrophy as well as neuronal migration disorder.

Two patients with 'Dropped head syndrome' due to mutations in LMNA or SEPN1 genes.

Dropped head syndrome is characterized by severe weakness of neck extensor muscles with sparing of the flexors. It is a prominent sign in several neuromuscular conditions, but it may also be an isolated feature with uncertain aetiology. We report two children in whom prominent weakness of neck extensor muscles is associated with mutations in lamin A/C (LMNA) and selenoprotein N1 (SEPN1) genes, respectively. This report expands the underlying causes of the dropped head syndrome which may be the presenting feature of a congenital muscular dystrophy.

Myogenesis within the human gubernaculum: histological and immunohistochemical evaluation.

BACKGROUND: The presence of varying amounts of smooth muscle (SM) in the patent processus vaginalis suggests that SM plays a role in the descent of the testis. Myogenesis within the gubernaculum (representing primitive mesenchymal tissue) has been evaluated. MATERIALS AND METHODS: Bilateral gubernacula of ten male and five female fetuses were obtained. Sections were stained with hematoxylin-eosin, van Gieson and Gomori trichrome. Expressions of human muscle actin, desmin, vimentin, alpha-smooth muscle actin, human myosin, fast myosin, slow myosin, and Myo-D were determined through immunohistochemistry. The structural alterations and expressions according to the fetal ages were determined within the gubernacula of both sexes. RESULTS: Gubernacula revealed striated muscle at twelve weeks of age. Despite expression of actin and desmin, those muscles did not express Myo-D. Actin and desmin expressing striated muscles ceased to exist until 22 weeks of age. Both vascular SM and cremaster muscle (CM) expressed Myo-D during the 22nd and 23rd weeks. CM additionally expressed alpha-smooth muscle actin. Detection of myofibroblasts in the 22nd week was followed by appearance of the SM in the 27th week in the gubernacula of male fetuses. The same alterations were encountered among the female fetuses at later time points. CONCLUSION: Both smooth muscle and CM develop within the gubernaculum. CM may have transdifferentiated from the vascular SM. If the gubernaculum represents primitive mesenchymal tissue, it ceases to exist after the development of muscles.

A rare malignant hepatic tumor of childhood: transitional liver cell tumor revisited.

Transitional liver cell tumor is an extremely rare entity and has a poor prognosis. It has similar histopathologic findings with hepatoblastoma and hepatocellular carcinoma. Up to now, only 10 cases have been reported in the literature. We report on an 8-year-old boy with histologically proven transitional liver cell tumor and describe the pertinent radiological findings.

Genetic identity of Marinesco-Sjögren/myoglobinuria and CCFDN syndromes.

OBJECTIVE AND BACKGROUND: To describe three Gypsy families with Marinesco-Sjögren syndrome (MSS), demyelinating neuropathy, and recurrent episodes of myoglobinuria in five of the six affected subjects. Because these families originated from the same genetically isolated founder population as did patients with congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome, and because the two syndromes have clinical manifestations in common, we hypothesized that the two related, albeit distinct, syndromes may represent clinical variants of a single genetic disorder. METHODS: Clinical studies were conducted and linkage and haplotype analyses were performed for the three families. A total of 16 individuals, including the 6 with MSS and 10 unaffected relatives, were genotyped for six polymorphic microsatellite markers from the CCFDN region on 18qter. RESULTS: Linkage analysis of markers in the 18qter region, where we previously had located the CCFDN gene, produced a lod score of 3.55, demonstrating colocalization of the gene responsible for MSS with demyelinating neuropathy and myoglobinuria with the CCFDN gene. Moreover, the patients with MSS shared the conserved marker haplotype found in CCFDN chromosomes. CONCLUSIONS: These data suggest that Marinesco-Sjögren syndrome with peripheral neuropathy and myoglobinuria, and congenital cataracts facial dysmorphism neuropathy syndrome are genetically identical and are caused by a single founder mutation.

Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease.

BACKGROUND: Three rare autosomal recessive disorders share the combination of congenital muscular dystrophy and brain malformations including a neuronal migration defect: muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD). In addition, ocular abnormalities are a constant feature in MEB and WWS. Lack of consistent ocular abnormalities in FCMD has allowed a clear clinical demarcation of this syndrome, whereas the phenotypic distinction between MEB and WWS has remained controversial. The MEB gene is located on chromosome 1p32-p34. OBJECTIVES: To establish distinguishing diagnostic criteria for MEB and WWS and to determine whether MEB and WWS are allelic disorders. METHODS: The authors undertook clinical characterization followed by linkage analysis in 19 MEB/WWS families with 29 affected individuals. With use of clinical diagnostic criteria based on Finnish patients with MEB, each patient was categorized as having either MEB or WWS. A linkage and haplotype analysis using 10 markers spanning the MEB locus was performed on the entire family resource. RESULTS: Patients in 11 families were classified as having MEB and in 8 families as WWS. Strong evidence in favor of genetic heterogeneity was obtained in the 19 families. There was evidence for linkage to 1p32-p34 in all but 1 of the 11 pedigrees segregating the MEB phenotype. In contrast, linkage to the MEB locus was excluded in seven of eight of the WWS families. CONCLUSION: These results allow the classification of MEB and WWS as distinct disorders on both clinical and genetic grounds and provide a basis for the mapping of the WWS gene(s).

Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy.

Mutations in the lamin A/C gene are found in Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy with cardiac conduction disturbances, dilated cardiomyopathy with conduction system disease, and familial partial lipodystrophy. Cases with lamin A/C mutations presenting with lipodystrophy in combination with cardiac and/or skeletal muscle abnormalities are described.

Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts unlinked to the LAMA2, FCMD and MEB loci.

We report a case of congenital muscular dystrophy with secondary merosin deficiency, structural involvement of the central nervous system and mental retardation in an 8-year-old girl from a consanguineous family. She had early-onset hypotonia, generalized muscle wasting, with weakness especially of the neck muscles, joint contractures, mental retardation and high creatine kinase. Muscle biopsy showed dystrophic changes with partial deficiency of the laminin alpha(2) chain. Cranial magnetic resonance imaging revealed multiple small cysts in the cerebellum, without cerebral cortical dysplasia or white matter changes. The laminin alpha(2) chain (6q2), Fukuyama type congenital muscular dystrophy (9q31-q33) and muscle-eye-brain disease (1p32-p34) loci were all excluded by linkage analysis. We suggest that this case represents a new entity in the nosology of congenital muscular dystrophy.

Merosin-deficient congenital muscular dystrophy with severe mental retardation and normal cranial MRI: a report of two siblings.

The evidence of severe structural brain abnormalities in association with severe mental retardation is characteristic in congenital muscular dystrophy (CMD) forms other than the 'classical' form. However, it seems that the nosology of CMD is not complete yet, as we have clinical, immunohistochemical and genetic data suggesting that there are other unclassified forms. Here we report two CMD siblings from a consanguineous family with partial merosin-deficiency in muscle biopsies, severe mental retardation and normal MRI of the brain. The disease was not linked to the LAMA2 gene (6q22-23) or to Fukuyama congenital muscular dystrophy (FCMD) (9q31-33). To our knowledge, such an association may constitute a new entity within the broad clinical spectrum of CMD.

Merosin-positive congenital muscular dystrophy with mental retardation and cataracts: a new entity in two families.

Merosin-positive congenital muscular dystrophy is a heterogenous group of disorders with varying clinical presentations and severity. In general, central nervous system involvement is not present. There is also evidence for still unclassified forms. Here we report three cases in two families with merosin-positive congenital muscular dystrophy, mild mental retardation, bilateral cataracts and normal cranial magnetic resonance imaging. To our knowledge, such an association has not been reported previously, and thus is a new entity within congenital muscular dystrophy nosology.

Differences in the morphology of the processus vaginalis with sex and underlying disease condition.

The structures of sacs from boys and girls with inguinal hernia, and from boys with undescended testis or hydrocele were evaluated and compared. Particular attention was directed to determine if a clue helpful in describing the mechanism of obliteration of processus vaginalis (PV) exists. Sacs from boys (n: 8) and girls (n: 11) with inguinal hernia, and sacs from boys with undescended testis (n: 11) and hydrocele (n: 10) were obtained and stained with hematoxylin-eosin, trichrome and elastic van Gieson. The histologic structures of each group of samples were determined and compared. Smooth muscle was presented as a layer within the sacs of girls and boys with inguinal hernia. However, smooth muscle bundles were sparsely presented in sacs associated with undescended testis and hydrocele. Myofibroblasts were commonly encountered in sacs associated with inguinal hernia. The smooth muscle was invariably presented in sacs that contained myofibroblasts. While sacs from boys only had smooth muscle, sacs from girls also had striated muscle. Since the muscle components of sacs vary, PV is sexually dimorphic. Persistence of PV seems to be associated with the presence of smooth muscle and myofibroblasts within the sac wall. Myofibroblasts may have originated from the smooth muscle, and reflect the attempts at obliteration of PV.

Clinical spectrum of muscle-eye-brain disease: from the typical presentation to severe autistic features.

Muscle-eye-brain disease (MEB) is an autosomal recessive congenital muscular dystrophy with ocular abnormalities and type II lissencephaly. MEB is caused by mutations in the protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase (POMGnT1) gene on chromosome 1q33. POMGnT1 is a glycosylation enzyme that participates in the synthesis of O-mannosyl glycan. The disease is characterized by altered glycosylation of alpha-dystroglycan. The clinical spectrum of MEB phenotype and POMGnT1 mutations are significantly expanded. We would like to present two cases with MEB disease with POMGnT1 mutations, whose clinical picture shows heterogeneity. The patient with R442H mutation had the classical form of the disease although the one with IVS17-2A-->G homozygous mutation had severe autistic features as the dominating presenting sign. These two cases represent different spectrums of one disorder. To the best of our knowledge, autistic features and stereotypical movements have not been included thus far as a part of broad and heterogeneous MEB spectrum.

Beta-sarcoglycan gene mutations in Turkey.

The term limb-girdle muscular dystrophy (LGMD) refers to a group of muscular dystrophies that, at the outset, affect primarily the muscles of the hip and shoulder girdle. Limb-girdle muscular dystrophy is genetically heterogeneous comprising autosomal dominant (types LGMD 1A-1E) as well as autosomal recessive forms (types LGMD 2A-2J known). A subgroup among the autosomal recessive forms comprises the sarcoglycanopathies (LGMD2C-2F), caused by mutations in the gamma (gamma-SG), alpha (alpha-SG), beta (beta-SG) and delta (delta-SG) sarcoglycan genes, respectively. The sarcoglycans form the sarcoglycan complex, part of the dystrophin-associated glycoproteins. Mutations in the beta-SG gene causes LGMD2E. Disease severity, in this form, varies from mild to severe phenotypes depending on the individual mutation. Homozygous missense mutations in critical locations may result in the total absence of alpha-, beta- and gamma-sarcoglycan from the muscle membrane and a phenotype as severe as null mutations. In the present study, through screening 80 unrelated LGMD2 families, we identified 13 families with LGMD2E. Mutations in the beta-SG gene were identified in 12 patients from nine families. One of these patients carried a previously reported truncating mutation (Q11X), while the other 11 carried novel missense/rameshift mutations (M1L, V89M, I92T, I92S, 739insA), some of which were seen in more than one patient and may, therefore, be more common in the Turkish population.

Renal oncocytoma: diagnostic and therapeutic aspects.

Renal oncocytoma is one of the most unusual benign lesions, which presents as a complicated mass resulting in a diagnostic and therapeutic dilemma. A new case of renal oncocytoma in a 13-year-old boy is presented. The clinocopathologic features of this rare entity are discussed, with special emphasis on diagnosis and treatment. There are no specific presumptive clinical and laboratory findings, including tumor markers, ploidy analysis, and imaging techniques that distinguish oncocytoma from other renal masses. The most important diagnostic aid is to bear this entity in mind when a child presents with an unexplained renal mass. Frozen section biopsies followed by partial nephrectomy are mandatory for the appropriate treatment after excluding bilateral or multifocal occurrence.

A comparative histopathologic evaluation of the effects of three different solutions used for whole bowel irrigation: an experimental study.

PURPOSE: Although whole bowel irrigation (WBI) is a widely used method of bowel preparation in daily surgical practice, almost nothing is known about the histopathologic alterations caused by WBI and whether these differences have any detrimental effect on the outcome of gastrointestinal surgical procedures. Therefore, an experimental study has been conducted to evaluate and compare the effects of WBI with various solutions on the histology of gastrointestinal tract. METHODS: During the experimental procedures animals were divided into 4 groups consisting of 8 animals each as follows: group A, WBI performed by using isotonic saline solution; group B, WBI performed by using an isoosmolar solution containing polyethylene glycol (PEG); group C, WBI performed by using Lactated Ringer's solution; group D, Animals that were not irrigated but sham operations that were performed served as controls. Four hours after WBI the animals underwent laparotomy and a segment of transverse colon with intact vascular peduncle was prepared. After waiting for 30 minutes, specimens from duodenum, small intestine, large bowel, colonic segment, and liver were obtained from each animal. Histopathologically, all of the specimens were evaluated and graded by 3 parameters including congestion, edema, and inflammation. RESULTS: Although varying degrees of congestion, edema, and inflammation were encountered from all of the specimens of group A, B, and C, only slight congestion was noted in all specimens of group D. The difference between group D and other groups was statistically very significant (P < .001). When the sections from duodenums of groups were evaluated, the degree of congestion, edema, and inflammation were found to be moderate in group B, mild-moderate in group A, and mild in group C. Histopathologic examinations of specimens of the small, large bowel, and isolated colonic segment showed severe congestion, edema, and inflammation in group A, moderate-mild in group B, and mild in group C. The difference between A and B, A and C, and A and D was statistically significant (P < .01). Although severe congestion was encountered in liver specimens of group A, only mild congestion was encountered in groups B and C (P= .0001). The matched durations of irrigations and total volume of irrigation solutions were found to be not related with the difference in histopathologic findings. CONCLUSIONS: WBI has induced varying degrees of histopathologic alterations from mild to severe in the rat gastrointestinal tract. Lactated Ringer's solution and PEG solution have induced the least alterations. Therefore, WBI with Lactated Ringer's solution and PEG solution seem to be safe alternatives of mechanical bowel preparation before elective large bowel surgery. Because saline solution has caused detrimental alterations in distal gastrointestinal tract histology, WBI with saline solution seems to be unadvisable.

Pulmonary lymphomatoid granulomatosis in a 4 year old.

The authors report a pulmonary lymphomatoid granulomatosis (LG) in a 4-year-old girl. The clinicopathologic and radiological features of this rare entity are discussed with special emphasis on differential diagnosis, including a brief literature review. LG is an aggressive multiorgan disease that primarily affects the adult lung. There are no specific presumptive clinical and laboratory findings, including tumor markers and imaging techniques, that distinguish LG from other pulmonary nodular lesions. The most important diagnostic aid is to bear this entity in mind when a child presents with pulmonary nodule associated with intractable long-lasting symptoms. Open lung biopsy and total excision is mandatory for the appropriate diagnosis and treatment.

Congenital epulis of the newborn. A case report.

Congenital epulis of the newborn is a rare benign tumor, also known as a congenital gingival granular cell tumor. Although it is a benign lesion, the tumor may cause feeding and respiratory problems when too large or when multiple tumors exist. In this article, a case of congenital epulis is presented and its treatment is discussed.

The role of heterotopic gastric mucosa with or without colonization of Helicobacter pylori upon the diverse symptomatology of Meckel's diverticulum in children.

The roles of heterotopic gastric mucosa either with or without colonization of Helicobacter pylori (HP) upon the diverse symptomatology of Meckel's diverticulum (MD) in children have been evaluated retrospectively. The medical records of 92 patients who underwent MD excision either incidentally or symptomatically between 1976 and 1997 were reviewed retrospectively. Age at admission and symptoms were recorded. The slides were stained with hematoxylin eosin and Giemsa to identify the presence of heterotopic tissue, ulceration, hemorrhage, inflammation and HP. Bleeding, obstruction and inflammatory groups were statistically compared with chi-square test. The age of the patients ranged between 1 day and 14 years with a mean of 3.5+/-3.8 years. The male: female ratio was 3.6:1. Among 92 MD, 18 (19.5%) were remove incidentally, one of which had heterotopic gastric mucosa. The indications fo surgical removal of MD were intestinal obstruction, diverticulitis and bleeding in 45 (48.9%), 11 (11.9%) and 18 (19.5%) patients, respectively. Heterotopic gastric mucosa was detected in 28 (30.4%) patients, of whom 8, 3, and 16 presented with intestinal obstruction, diverticulitis and bleeding, respectively. Helicobacter pylori was not detected in one patient with incidental removal of MD; with heterotopic gastric mucosa however, three patients with obstruction, one patient with diverticulitis and one patient with bleeding had HP in the heterotopic gastric mucosa located in MD. MD may become symptomatic due to a complicated course such as rectal bleeding, intestinal obstruction or diverticulitis. The presence of heterotopic gastric mucosa in MD seems to mainly associate with rectal bleeding. The presence of HP colonization in heterotopic gastric mucosa does not increase the incidence of rectal bleeding. The other complications of MD, including intestinal obstruction and diverticulitis, are not directly related to the presence of heterotopic gastric mucosa in the MD. However, colonization of heterotopic gastric mucosa by HP seems to increase the incidence of these complications.

MR imaging of pelvic and thigh muscles in congenital muscular dystrophy.

To define and compare the magnetic resonance (MR) imaging findings of pelvic and thigh muscles in merosin-deficient and merosin-positive congenital muscular dystrophy, 10 patients with merosin-positive and six patients with merosin-deficient muscular dystrophy were examined in a 0.5 T MR imaging unit. Intensity and atrophy scores were given to individual muscles by two radiologists and were calculated for three muscle groups (pelvic, anterior thigh and posterior thigh muscles). Rectus femoris was affected less than the vastus muscles in 40 percent of cases in merosin-positive patients, whereas there was no selective sparing in merosin-deficient patients. Sartorius and gracilis were relatively spared in both groups. The most consistently affected muscles were gluteus maximus, adductor magnus and brevis in merosin-positive patients. Atrophy was more prominent in the adductor muscles in the merosin-deficient group. Intensity scores of anterior thigh muscles of the merosin-positive group were significantly higher than those of the merosin-deficient group (U = 8, p = 0.016). When stepwise logistic regression model was applied, intensity score of the anterior thigh muscles was found to be the best differentiating variable. The regression analysis model formed was able to differentiate the two forms with a sensitivity of 80 percent and specificity of 83 percent.