Peripheral neuropathy in the first 2 years of life: diagnostic evaluation including molecular genetics.

Inherited polyneuropathies present in the first 2 years of life are discussed with emphasis on clinical, pathologic, and molecular data. Early-onset polyneuropathies are relatively rare, sometimes life-threatening conditions that demand early recognition by clinical and pathologic examination. Histologic and ultrastructural overlaps among the various conditions are sometimes resolved by molecular genetic analysis. The growth in disease identification by genetic localization allows a more comprehensive understanding of the clinical and morphologic heterogeneity involving rearrangements of the same gene. Molecular mechanisms explaining the acquisition of such gene rearrangements are beginning to be unraveled. Peripheral myelin disorders may be confused with primary axonal disorders, and electrophysiologic examination often helps to distinguish between these two. Furthermore, early-onset central nervous system disorders may present as peripheral polyneuropathies and confound the clinical picture. A tentative diagnosis can often be offered by pathologic examination and confirmed by biochemical enzyme analysis later. The differential clinical diagnostic considerations of early-onset polyneuropathies are offered, to help clinicians sort out these diseases in the most efficient manner.

Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.

Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other. There are skeletal muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both actin and myosin. Inherited diseases in humans have been associated with defects in cardiac actin (dilated cardiomyopathy and hypertrophic cardiomyopathy), cardiac myosin (hypertrophic cardiomyopathy) and non-muscle myosin (deafness). Here we report that mutations in the human skeletal muscle alpha-actin gene (ACTA1) are associated with two different muscle diseases, 'congenital myopathy with excess of thin myofilaments' (actin myopathy) and nemaline myopathy. Both diseases are characterized by structural abnormalities of the muscle fibres and variable degrees of muscle weakness. We have identified 15 different missense mutations resulting in 14 different amino acid changes. The missense mutations in ACTA1 are distributed throughout all six coding exons, and some involve known functional domains of actin. Approximately half of the patients died within their first year, but two female patients have survived into their thirties and have children. We identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family showing dominant inheritance comprised a 33-year-old affected mother and her two affected and two unaffected children. In another family, the clinically unaffected father is a somatic mosaic for the mutation seen in both of his affected children. We identified recessive mutations in one family in which the two affected siblings had heterozygous mutations in two different exons, one paternally and the other maternally inherited. We also identified de novo mutations in seven sporadic probands for which it was possible to analyse parental DNA.

Rapid autologous marrow recovery and eradication of infectious mononucleosis despite severe immunosuppression following second transplantation for aplastic anemia.

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.

Tubulointerstitial nephritis induced by the leukotriene receptor antagonist pranlukast.

A 7-year-old boy with asthma was receiving the leukotriene receptor antagonist pranlukast (Ultair; SmithKline Beecham; Pittsburgh) as part of an open-label clinical trial. The patient's asthma improved, and he remained asymptomatic; but routine study evaluations 9 to 12 months into therapy showed microhematuria, proteinuria, glucosuria, anemia, and renal insufficiency. Renal biopsy demonstrated changes classic for acute allergic tubulointerstitial nephritis (ATIN), with mixed interstitial inflammatory infiltrate including eosinophils. Within 6 months of pranlukast withdrawal, anemia resolved and urinary sediment and renal function normalized. The case demonstrates that hypersensitivity reaction to pranlukast and resultant ATIN is possible, and that periodic urine testing in patients receiving pranlukast should be considered.

Embryo-associated immunosuppressor factor is produced at the maternal-fetal interface in human pregnancy.

PROBLEM: To study whether embryo associated immunosuppressor factor (EASF) is synthesized at the maternal-fetal interface. METHOD: Anti-EASF monoclonal antibody H5D12 was used to identify EASF. Paraffin-embedded sections were prepared from placental and fetal tissues and immunohistochemistry was done by the avidin-biotin-peroxidase technique. EASF was affinity purified using H5D12-Sepharose 4B from culture media of placental villi and analyzed for immunosuppressive activity (by Concanavalin A-induced lymphocyte proliferation assay) and molecular weight identity (by metabolic labeling studies with 35S-methionine followed by immunoprecipitation and SDS-PAGE). RESULTS: Immunohistochemical studies demonstrates intense immunostaining of villous syncytiotrophoblast and cytotrophoblast cells of first trimester placental tissues. Hoffbauer cells and decidual cells stained positive. The same cells in second and third trimester placental tissues stained weakly. However, the endothelium and smooth muscle cells of fetal blood vessels, fetal ovarian stroma and primordial follicles, kidney epithelium, cerebral neurons, and glial cells all stained negative. The affinity-purified EASF from the conditioned media of placental villi (less than 12 wk gestational age) was identified as a 37-kDa molecule with immunosuppressive activity. Metabolic labeling studies revealed that placental villi from early gestational age secretes a major factor of 37-kDa and minor factors of 41-kDa and 47-kDa molecular weight. CONCLUSIONS: Monoclonal antibody H5D12 identifies a factor that is produced by the pre-implantation embryo and also synthesized by decidua and trophoblast cells.

Cardiac tamponade as a terminal event in the hemolytic uremic syndrome in childhood.

The case of a 6-year-old Inuit female with the epidemic form of hemolytic uremic syndrome (HUS) with myocardial involvement and probable cardiac tamponade is presented. This case illustrates the multisystemic nature of the syndrome, and to our knowledge, cardiac tamponade as a probable terminal event in HUS has not been reported previously.

Autosomal recessive, fatal infantile hypertonic muscular dystrophy among Canadian Natives.

We describe eleven mid-western Canadian aboriginal infants with a unique, progressive muscle disorder. All except one had muscle biopsy and/or autopsy. The infants were normal newborns who rapidly developed rigidity of all skeletal muscles, with early, respiratory insufficiency. Death occurred before 18 months of age. Electromyography showed increased insertion activity and profuse fibrillation potentials; motor unit potentials and interference pattern are normal until late in the course. Pathologic features include progressive, granular to powdery Z-band transformation, myofibrillar loss, and muscle regeneration. SDS-gel electrophoresis of one muscle sample revealed increased 54kDa and reduced 80kDa protein fractions. This disease differs from other conditions with Z-band alterations because of continuous muscle activity and relentless clinical progression. The clinical features, elevated serum creatine kinase, electromyographic and muscle biopsy findings suggest a dystrophic process. The recognition of this condition as an autosomal recessive disorder allows appropriate genetic counselling.

Heterotopic ossification in children after iliopsoas release.

Heterotopic calcification or ossification of the soft tissues adjacent to the lesser trochanter was observed in the radiographs of 4 patients during a retrospective review of the records of 68 patients with Perthes' disease. This abnormality has since been seen in one other patient with Perthes' disease and in five with spastic quadriplegia. All 10 patients are known to have undergone iliopsoas release as part of adductor tenotomy. The authors believe that the heterotopic ossification is related to the surgery.

Secondary massive ovarian edema with Meig's syndrome.

Primary massive ovarian edema is uncommon, particularly when it involves both ovaries before puberty. Ovarian edema secondary to a preexisting ovarian lesion is one of the postulated mechanisms. A prepubertal girl presented with bilateral massive ovarian edema with stromal hyperthecosis, which may have predisposed both ovaries to undergo partial torsion. The associations with Meig's syndrome, greatly elevated hormone levels and presence of omental and retroperitoneal nodules, raised a suspicion of malignancy.

Malignant mixed germ-cell-sex cord-stromal tumors of the ovary associated with isosexual precocious puberty.

Two cases of hormonally active, metastasizing malignant mixed germ cell-sex cord-stromal tumors are described in otherwise normal prepubertal girls. Isosexual precocity was noted 5 months and 1 month before surgery. One child died 1 year after presentation, and the other was alive, with no apparent tumor, 1 year after diagnosis. These two cases represent the first recorded instance of a unique tumor in which metastases of several cell types were encountered.

Neu-Laxova syndrome: report of two cases.

Two cases of Neu-Laxova syndrome are reported. The pathological features are described. There is marked swelling of the palms and soles, which is due to massive fat and myxomatous connective tissue proliferation in addition to edema. Lissencephaly with hypoplasia of cortical descending fibers is observed, along with cerebellar hypoplasia. The occurrence of 2 microcephalic male and female infants dying shortly after birth in the same sibship with 1 normal baby in between confirms similar findings by others and supports an autosomal-recessive inheritance. The relevance of pathological examination in further delineation of the phenotypic appearance is discussed.

Echocardiography of intracardiac filling defects in infants and children.

Intracardiac masses are rare in infants and children. Early detection is essential to their successful management. We present seven patients in whom echocardiography established the diagnosis and was crucial in the management. Three of the masses were primary cardiac tumors and four were thrombi. Patient 1: an infant with a calcified left ventricular fibroma. Patient 2: a neonate who presented with cyanosis due to obstruction of the right ventricular inflow tract by a fibroblastic tumor. Patient 3: an infant with a right atrial myxoma presenting as sepsis. Patient 4: a child who had a pulmonary embolus after a pulmonary valvotomy and was found to have a right ventricular thrombus. Patient 5: a child with a right atrial thrombus following a Fontan procedure for univentricular atrioventricular connection. Patient 6: a child with a left ventricular thrombus due to a dilated cardiomyopathy in association with epidermolysis bullosa. Patient 7: An infant with bilateral lobar emphysema, an aorticopulmonary window with left ventricular fibroelastosis, who developed a left ventricular thrombus.

Childhood Köhlmeier-Degos disease with atypical skin lesions.

We report clinical and pathologic findings in a 16-year-old boy whose disease began in infancy with maculopapular skin lesions, followed by cyclic nodular cutaneous eruptions, intermittent enlargement of liver and spleen, episodic abdominal pain, and sporadic unexplained fever. Subsequently, various ophthalmologic disturbances, along with a multitude of neurologic signs and symptoms, dominated the clinical picture. The CNS bore the brunt of pathologic changes, characterized by widespread leptomeningeal fibrosis, ventricular enlargement, and multiple brain infarcts. Striking intimal thickening led to narrowing or occlusion of almost all the medium-sized and small extraparenchymal arteries.