Ultrastructure and immunocytochemistry of hepatic peroxisomes in rhizomelic chondrodysplasia punctata

Peroxisomes were studied in the liver of two rhizomelic chondrodysplasia punctata patients using electron microscopy and catalase cytochemistry. Immuno-electron microscopy was carried out on the liver of one of these patients using antibodies to catalase, acyl-CoA oxidase, bifunctional protein, 3-ketoacyl-CoA thiolase and a 68 kDa peroxisomal membrane protein, in conjunction with protein-A colloidal gold. Moderately to markedly enlarged, flocculent peroxisomes were found in both patients. In one patient they were very heterogeneous with regard to the number per hepatocyte. The peroxisomes had very low levels of catalase as indicated by cytochemistry and immunocytochemistry. The three -oxidation enzymes were localised normally within the peroxisomes. The 68 kDa membrane protein was localised to the peroxisomal membranes. Some extra membrane loops were also identified using this antibody.     

Colonic perforation in the first few hours of life associated with rhizomelic chondrodysplasia punctata

Rhizomelic chondrodysplasia punctata (RCP), a rare autosomal recessive disease characterized by a disorder of peroxisome metabolism, has been shown to affect multiple organ systems. A neonate presenting with a colonic perforation in the first few hours of life was subsequently diagnosed with RCP. A literature search revealed no previous reports of intestinal perforation associated with RCP. Intestinal perforation should be added to the list of medical complications associated with RCP.     

Severe tracheobronchial stenosis and cervical vertebral subluxation in X-linked recessive chondrodysplasia punctata

Radiologic manifestations of X-linked chondrodysplasia punctata (CDPX1) typically include chondrodysplasia, epiphyseal stippling, punctate calcification of cartilage, distal phalangeal hypoplasia, and nasal/midface hypoplasia. We present an infant with CDPX1 demonstrating calcification and stenosis of the entire trachea and mainstem bronchi, as well as possible anterior C1 subluxation due to progression of congenital vertebral dysplasia.     

Brachytelephalangic chondrodysplasia punctata with severe spinal cord compression: report of four new cases

Brachytelephalangic chondrodysplasia punctata (CDPX1, OMIM: #302950) is a rare congenital skeletal dysplasia caused by arylsulfatase E deficiency (OMIM: #300180). Although the symptoms are usually mild, severe spinal cord compression by dysplastic vertebras may develop. We report four new cases with severe cervical spinal canal narrowing documented by radiography, magnetic resonance imaging (MRI), and autopsy. In all, nine cases of CDPX1 with severe cervical spinal cord compression have now been described. Because these cases account for a large proportion of all reported CDPX1 cases, we believe that an antenatal suspicion of CDPX1 should lead to genetic counseling and to investigations for spinal cord compression. After birth, this complication must be routinely anticipated, and we suggest spinal MRI in all CDPX1 infants. Unless spinal cord compression is confidently ruled out, we recommend that these newborns receive the same care as trauma patients suspected of craniocervical junction disruption. No conflicts of interest occurred for this work.     

Prenatal diagnosis of cervical spinal cord compression in chondrodysplasia punctata brachytelephalangic type: A case report and literature review

Chondrodysplasia punctata brachytelephalangic type is a common subset of a heterogeneous group of chondrodysplasia punctata. Most affected children generally do not have significant physical disabilities; however, a small number of patients are at risk of cervical canal stenosis with cervical cord compression leading to serious morbidity and early mortality. Very little is known about the in utero manifestation of severe complications. We report an affected child in whom the Binder phenotype was found on antenatal ultrasound and cervical spinal cord compression on fetal magnetic resonance imaging. Prenatal diagnosis of chondrodysplasia punctata brachytelephalangic type and its complications are beneficial for timely, prompt medical intervention.     

A distinct chondrodysplasia resembling Kniest dysplasia: clinical, roentgenographic, histologic, and ultrastructural findings

Two sibs, one girl and one boy, were observed in infancy with a severe lethal skeletal dysplasia syndrome that radiologically and histologically resembled Kniest dysplasia but clearly differed in clinical course and inheritance. Kniest dysplasia is a nonlethal syndrome, whereas both of these infants died in the neonatal period. Kniest dysplasia appears to be inherited as an autosomal dominant trait; the likely transmission in this family was autosomal recessive. Roentgenograms revealed dumbbell-shaped long bones superficially similar to Kniest dysplasia, but with markedly shortened diaphyses and metaphyseal irregularities. Chondro-osseous morphology demonstrated a superficially similar foamy "Swiss cheese" appearance to the cartilage matrix, as seen in Kniest dysplasia, but there were distinctly different changes in the growth plate and resting cartilage. Ultrastructurally, the chondrocytic endoplasmic reticulum was found to have an appearance different from that observed in either normal or Kniest cartilage. These cases likely represent a distinct chondrodysplasia.     

Treatment of infantile phytanic acid storage disease: clinical,biochemical and ultrastructural findings in two children treated for 2 years

Two patients with infantile phytanic acid storage disease (infantile Refsum disease), one of whom showed the presence of morphologically normal peroxisomes in a liver biopsy, were treated with a low phytanic acid diet for more than 2 years and the effects of treatment on certain clinical, biochemical and ultrastructural parameters were examined. Both patients showed evidence of either an improvement or stabilisation in their clinical condition. Plasma phytanic acid levels decreased to near normal values in approximately 6 weeks after the introduction of the diet; plasma pipecolic acid also declined markedly but the decrease was not so rapid and its level remained abnormal. C₂₆C₂₂ fatty acid ratios decreased very slowly and even after 2 years the values remained grossly abnormal. Despite the marked reduction of phytanic acid in the liver, there was an increase in the C₂₆C₂₂ fatty acid ratios and this appeared to be paralleled by an increase in inclusion bodies. Our data suggest that some patients with the infantile form of Refsum disease may show some clinical benefit from dietary management and this is reflected biochemically by decreases in the plasma levels of phytanic acid and pipecolic acid.Abbreviations VLCFA very long chain fatty acids - ALD adrenoleukodystrophy     

Isolated gonadotropin deficiency in boys: clinical characteristics and growth

Analysis of the clinical findings and growth in 20 boys with isolated gonadotropin deficiency revealed a heterogeneous group of physical abnormalities. Ten of these patients were hyposmic or anosmic (Kallmann syndrome). Abnormalities found in our patients included undescended testes, gynecomastia, and ocular or skeletal anomalies. Regardless of the presence of hyposmia, patients without testicular enlargement (less than 2 cm3), had serum luteinizing hormone (LH) responses to luteinizing hormone-releasing factor (LRF) that were the same as in prepubertal boys. By contrast, five boys with testicular enlargement (greater than 2 cm3), some of whom had hyposmia, had a greater serum LH response to LRF than did prepubertal boys. Adrenarche was moderately delayed; although all boys initially had normal serum levels of dehydroepiandrosterone-sulfate, four boys eventually developed elevated serum levels. Bone ages were delayed compared with chronologic age in boys who had the condition after 15 years of age. The rate of linear growth was normal, and final adult heights were normal with testosterone therapy, although linear growth continued longer in these boys than in boys with normal pubertal progression. Although none of the patients was obese at the time of diagnosis, three patients developed obesity after initiation of testosterone therapy.     

Isolated glucocorticoid deficiency: metabolic and endocrine studies in a 5-year-old boy

A 5-year-old boy is described who presented with episodes of hypoglycaemia triggered by mild infections or fever. Subnormal glucocorticoid production was confirmed by demonstrating low urinary excretion of free cortisol, low plasma cortisol concentrations that did not rise after glucagon and ACTH stimulation, and by elevated plasma ACTH levels. The selective nature of the abnormality was confirmed by demonstrating normal plasma electrolyte concentrations and blood pressure on a salt-restricted diet. Plasma renin activity and plasma aldosterone levels were also normal and responded appropriately to salt restriction and to frusemide-induced diuresis. Starvation-induced hypoglycaemia was associated with raised levels of blood ketone bodies and low blood alanine concentrations. Catecholamine secretion during hypoglycaemia was reduced. Glucocorticoid replacement therapy was effective in restoring normal glucose homeostasis.Smith and Nephew Research Fellow     

Cerebro-hepato-renal syndrome of zellweger: Clinical symptoms and relevant laboratory findings in 16 patients

The clinical features of 16 patients suffering from cerebro-hepato-renal syndrome are presented. Five of these children lived beyond 2 years. Four of them are still alive. The increase of pipecolic acid in serum and cerebrospinal fluid (CSF), the abnormality of the bile acids and the increased excretion of p-OH-phenyl lactate were a consistent finding. The concentration of pipecolic acid in urine was not always distinctly elevated. A loading test with DL-pipecolic acid was always abnormal.     

Interstitial lung disease in infants: new classification system, imaging technique, clinical presentation and imaging findings

Interstitial lung disease (ILD) is defined as a rare, heterogeneous group of parenchymal lung conditions that develop primarily because of underlying developmental or genetic disorders. Affected infants typically present with clinical syndromes characterized by dyspnea, tachypnea, crackles and hypoxemia. Until recently, the understanding of ILD in infants has been limited largely owing to a lack of evidence-based information of underlying pathogenesis, natural history, imaging findings and histopathological features. However, ILD in infants is now better understood and managed because of (1) advances in imaging methods that result in rapid and accurate detection, (2) improved thoracoscopic techniques for lung biopsy, (3) a consensus regarding the pathological criteria for these particular lung conditions and (4) a new classification system based on the underlying etiology of ILD. This article reviews the new classification system, imaging technique, clinical presentation and imaging findings of ILD in infants. Specialized knowledge of this new classification system in conjunction with recognition of characteristic imaging findings of ILD in infants has great potential for early and accurate diagnosis, which in turn can lead to optimal patient management.     

Autoimmune hepatitis in 828 Brazilian children and adolescents: clinical and laboratory findings,histological profile,treatments, and outcomes

ObjectiveThis large study with a long-term follow-up aimed to evaluate the clinical presentation, laboratory findings, histological profile, treatments, and outcomes of children and adolescents with autoimmune hepatitis.MethodsThe medical records of 828 children and adolescents with autoimmune hepatitis were reviewed. A questionnaire was used to collect anonymous data on clinical presentation, biochemical and histological findings, and treatments.ResultsOf all patients, 89.6% had autoimmune hepatitis-1 and 10.4% had autoimmune hepatitis-2. The female sex was predominant in both groups. The median age at symptom onset was 111.5 (6; 210) and 53.5 (8; 165) months in the patients with autoimmune hepatitis 1 and autoimmune hepatitis-2, respectively. Acute clinical onset was observed in 56.1% and 58.8% and insidious symptoms in 43.9% and 41.2% of the patients with autoimmune hepatitis-1 and autoimmune hepatitis-2, respectively. The risk of hepatic failure was 1.6-fold higher for autoimmune hepatitis-2. Fulminant hepatic failure occurred in 3.6% and 10.6% of the patients with autoimmune hepatitis-1 and autoimmune hepatitis-2, respectively; the risk was 3.1-fold higher for autoimmune hepatitis-2. The gamma globulin and immunoglobulin G levels were significantly higher in autoimmune hepatitis-1, while the immunoglobulin A and C3 levels were lower in autoimmune hepatitis-2. Cirrhosis was observed in 22.4% of the patients; biochemical remission was achieved in 76.2%. The actuarial survival rate was 93.0%. A total of 4.6% underwent liver transplantation, and 6.9% died (autoimmune hepatitis-1: 7.5%; autoimmune hepatitis-2: 2.4%).ConclusionsIn this large clinical series of Brazilian children and adolescents, autoimmune hepatitis-1 was more frequent, and patients with autoimmune hepatitis-2 exhibited higher disease remission rates with earlier response to treatment. Patients with autoimmune hepatitis-1 had a higher risk of death.     

Auxological, clinical and MRI findings in Taiwanese children with growth hormone deficiency

Growth hormone deficiency (GHD) may be classified into partial isolated GHD (partial IGHD), severe IGHD or multiple pituitary hormone deficiency (MPHD) by the severity of GHD or associated with deficiency of one or more other anterior pituitary hormones during provocative tests. Morphological alterations on magnetic resonance imaging (MRI) in patients with GHD include pituitary hypoplasia, absence or interruption of pituitary stalk, and absence or ectopic posterior lobe. This study investigated the auxological, clinical severity, and anatomical characteristics of the pituitary hypothalamic region by MRI and correlated their relationships. We evaluated these parameters in 45 Taiwanese children with GHD (31 males and 14 females), aged from 3.13 to 17.91 years (10.5+/-2.5), who were divided into diagnostic subgroups of partial IGHD (18 patients), severe IGHD (13 patients), and MPHD (14 patients). We found that BA-CA, peak GH, IGF-I, IGF-I SDS, and height SDS were significantly different among these three groups. The partial IGHD group had significantly higher IGF-I than the MPHD group. There was no significant difference in prematurity, cesarean delivery, birth order, neonatal jaundice, and target height among these three groups. On MRI, patients with MPHD had significantly smaller pituitary height (PHt) SDS (p = 0.0012) and higher frequency of pituitary hypoplasia, pituitary stalk interruption, and ectopic posterior lobe (p = 0.026, 0.008, 0.005, respectively) than the other two groups. Furthermore, PHt SDS was correlated not only with peak GH (r = 0.40, p = 0.0058), but also with basal IGF-I SDS (r = 0.49, p = 0.0007) and body height SDS (r = 0.44, p = 0.025). In conclusion, morphological alterations on MRI of the hypothalamic-pituitary area are correlated with the severity of hypopituitarism. Meticulous evaluation of auxological, clinical and MRI findings can help evaluation of the severity of hypopituitarism and facilitate appropriate treatment in children with GHD.     

Auxological, clinical and neuroradiological findings in infants with early onset growth hormone deficiency

Sixteen infants less than 2 years of age with apparently idiopathic hypopituitarism were studied. At birth, 11 of 16 patients (69%) had subnormal length associated with relative adiposity and 10 of 16 (62%) showed significant deterioration in length deficiency from birth onwards. These findings suggest that: (a) growth hormone deficiency, in a number of patients, had started well before delivery; (b) growth hormone may play a role in intrauterine growth; and (c) growth hormone may also be involved in early postnatal growth. Magnetic resonance imaging in these patients was very similar to that described in hypopituitarism of later onset. This suggests that even in the latter case, hypopituitarism may have a prenatal onset. Finally, the severity of growth failure and the coexistence of other hypopituitary symptoms at the time of diagnosis in 31 % of our patients indicate that early clinical screening of hypopituitarism is possible.     

Surfactant protein B deficiency: Clinical, histological and molecular evaluation

Congenital alveolar proteinosis due to surfactant protein B deficiency is an inherited disease which results in severe respiratory failure in term infants soon after birth. The pathophysiologic basis of this disease is now known to be an inability to synthesise adequate quantities of normally functioning surfactant protein B. We report a male infant with fatal respiratory failure of neonatal onset, and histopathological features typical of those seen in congenital alveolar proteinosis. Molecular analysis of genomic DNA revealed two mutations, the 'common' 121ins2 mutation in exon 4, and a novel 2bp frameshift mutation in exon 5. We believe this is the first Australian case of surfactant protein B deficiency confirmed by molecular analysis.     

Mastoiditis in children: a prospective, observational study comparing clinical presentation, microbiology, computed tomography, surgical findings and histology

The aim of this study was to obtain comprehensive data on clinical presentation, microbiology, computed tomography, surgical findings and histology in acute, sub-acute and chronic mastoiditis. We performed a prospective, observational study in children under 16 years of age presenting to our institution during the 2-year period beginning in April 2000. The children were examined and their condition treated in accordance with a standardized protocol elaborated by the paediatric, otolaryngology (ORL) and radiology departments. Thirty-eight patients were hospitalized (22 with acute mastoiditis, seven with sub-acute mastoiditis, nine with chronic mastoiditis). There were 30 complications present in 21 patients (55%). Streptococcus pyogenes was the most common pathogen (7/24 cases), followed by Streptococcus pneumoniae (4/24 cases). Mastoid surgery was performed in 29 patients. Histology of mastoid tissue revealed predominantly acute inflammation in two cases, mixed acute/chronic inflammation in 19 cases and predominantly chronic inflammation in seven cases. Radiologic data were evaluated retrospectively. Spiral, volume-based high-resolution (HR) computed tomography (CT) of the temporal bone had a sensitivity of 100%, specificity of 38%, positive predictive value (PPV) of 50% and negative predictive value (NPV) of 100% in detecting coalescence of mastoid trabeculae. Cranial CT with contrast had a sensitivity of 80%, specificity of 94%, PPV of 80% and NPV of 94% in identifying intra-cranial extension. Conclusion: histological evidence suggests that sub-acute/chronic infection underlies not only sub-acute and chronic mastoiditis, but most cases of acute mastoiditis as well. HR-CT of the temporal bone is effective in ruling out coalescence. Cranial CT is valuable in identifying intra-cranial extension. Cranial and HR-CT are recommended in the examination of children with mastoiditis.     

Morphologic findings in children with acquired immune deficiency syndrome: pathogenesis and clinical implications

The lesions observed in biopsy and autopsy material from children with the acquired immunodeficiency syndrome (AIDS) can be divided into three pathogenetic categories: primary lesions related to infection by human immunodeficiency virus (HIV) (e.g., lymphoreticular system and brain); lesions due to the sequelae of HIV infection (e.g., opportunistic infections, pulmonary lymphoid lesions, etc.); and lesions of undetermined pathogenesis (e.g., renal lesions, cardiomyopathy, etc.). The role of morphologic studies in AIDS in understanding the pathogenesis of the various lesions and their clinical implications are discussed by describing the following examples among others. Study of the thymus enabled us to distinguish AIDS from some congenital immune deficiency syndromes. Thymic injury contributes to immunodeficiency in AIDS. Its apparent irreversibility will have to be considered in the long-term management of children with AIDS when specific effective therapy for HIV becomes available. Demonstration of HIV--like particles in the characteristic giant cells in the brain has been instrumental in the recognition of HIV encephalopathy. Biopsy is helpful in the rapid diagnosis of opportunistic infections (OIs). Autopsy study of OIs has shown involvement of clinically unsuspected organs, such as the adrenals. Characterization of the pulmonary lymphoid lesions led to their inclusion as a diagnostic criterion for AIDS in children. Progression of pulmonary lymphoid lesions to a lymphoproliferative disorder was demonstrated at autopsy. Recognition of lesions such as cardiomyopathy and arteriopathy at autopsy should alert clinicians to suspect these disorders during life.