Chronic generalized spinal muscular atrophy of infancy and childhood: Arrested Werdnig-Hoffmann disease

Recent studies have shown that the acute fatal form of infantile spinal muscular atrophy (acute Werdnig-Hoffmann disease or spinal muscular atrophy Type I) is a distinct genetic and clinical entity. This has prompted clinical re-examination of the disease known as `arrested Werdnig-Hoffmann disease'' which hitherto was thought to be a spectrum variant of the acute fatal form. A total of 18 such patients with the chronic generalized form of spinal muscular atrophy has been known to The Hospital for Sick Children over the past 10 years. Patients with this characteristic clinical syndrome comprise approximately one-fifth of children with chronic spinal muscular atrophy. Clinically, no patient was even able to crawl normally or progress further with motor milestones. Median age of clinical onset is 6 months of age, and life expectancy ranges from 2 years to the third decade. Inevitable spinal and joint deformities occur by the second decade of life. Management should be based on vigorous antibiotic therapy, orthopaedic and neurological surveillance, and a carefully planned educational programme aimed at realistic employment in late adolescence.     

Virilizing adrenal adenoma in a 2-year-old girl

A 2-year-old girl with virilization had an adrenal tumor that produced testosterone with little evidence of excessive urinary androgen excretion. Plasma testosterone concentration was 407 ng/dL and urinary 17-ketosteroid (17KS) levels were 3 and 2 mg/day. Excretion of 17KS decreased to 1.8 mg/day after suppression of dexamethasone therapy, but urinary 17-hydroxycorticosteroid excretion did not change from 1.0 to 0.7 mg/day after administration of dexamethasone. She had a blunted response to administration of metyrapone and insulin and a small diurnal variation in cortisol concentration suggesting suppression of corticotropin secretion, even though the plasma cortisol concentration was in the normal range and there were no clinical signs of cortisol excess. High-performance liquid chromatography was used to analyze the steroid content of tumor tissue. Those portions of the tumor that were rich in steroids contained predominantly testosterone.     

Precocious breast development: a case of unilateral hyperplasia of the adrenal cortex

The case of a 14-month-old girl presenting with precocious breast development due to adrenal hyperplasia is reported. The endocrine studies revealed a slight elevation of the plasma progesterone, 17-hydroxyprogesterone, testosterone and oestrone levels, and an increased urinary oestrogen excretion. The findings of the ultrasound examination and the evidence that the oestradiol concentration in the left adrenal vein was higher than in the right adrenal vein confirmed the diagnosis of left adrenal hyperfunction. Surgical exploration revealed unilateral hyperplasia of the adrenal cortex. After adrenalectomy the plasma hormone levels and urinary oestrogen excretion fell to normal, with concomitant regression of breast tissue. The girl shows no signs of recurrence of the disorder in a 2 year follow-up. This adrenal hyperplasia might be a benign adrenal disorder causing precocious breast development.     

Clinical and Neuroimaging Findings of Sydenham’s Chorea

Objective: Sydenham’s chorea (SC) is thought to be an autoimmune disorder. MRI is generally used to exclude other causes of chorea. There are no typically defined MRI features of SC. In this study we aimed to determine clinical and neuroimaging findings of SC. Methods: In this study 17 patients with acute SC were retrospectively evaluated. Sydenham’s chorea was diagnosed according to the 1992 revision of the Jones criteria. The other causes of chorea were excluded. Cranial MRI was performed in all patients during the acute phase of SC. Walking, speech and swallowing disorders, muscle weakness, behavioral disorders, treatment, symptom recovery time and recurrence were evaluated. Findings : The patients’ mean age was 11.2 years. Behavioral changes, muscle weakness and dysphagia occurred in 70%, 64% and 23% of the patients, respectively. Nonspecific signal hyperintensities were observed in the white matter, brain stem and caudate nucleus in 47% of patients. Two patients who had chorea paralytica were treated successfully with a high dose of intravenous methylprednisolone. Conclusion: Nonspecific hyperintense white matter abnormalities may be due to the inflammatory process associated with a longer duration of clinical signs. To explain the MRI findings and the pathogenesis of SC, comprehensive studies are needed.Key Words: Sydenham’s Chorea; MRI Findings; Chorea Paralytica; Corticosteroids     

Persistence of neurological damage induced by dietary vitamin B-12 deficiency in infancy

Accepted 9 April 1997
A case is reported of a 14 month old boy with severe dietary vitamin B-12 deficiency caused by his mother''s vegan diet. Cinical, electroencephalography (EEG), and haematological findings are described. Cranial magnetic resonance imaging (MRI) showed severe frontal and frontoparietal cranial atrophy. Vitamin B-12 supplements led to a rapid improvement of haematological and neurological symptoms. Serum vitamin B-12 and urinary methylmalonate excretion were normal 10 days after treatment began. After six weeks, EEG was normal and cranial MRI after 10 weeks showed complete disappearance of all structural abnormalities. Cognitive and language development, however, remained seriously retarded at the age of 2 years. It is concluded that infantile vitamin B-12 deficiency induced by maternal vegan diets may cause lasting neurodisability even though vitamin B-12 supplementation leads to rapid resolution of cerebral atrophy and electroencephalographic abnormality.

     

Cranial MRI of neurologically impaired children suffering from neonatal hypoglycaemia

Background. Metabolic disturbances such as anoxia and hypoglycaemia are important in causing maldevelopment of the neonatal brain. While there have been some pathology studies of the effects of neonatal hypoglycaemia on brain development, reports of MRI findings in such infants have been rare. Objectives. To describe the MRI findings in neurologically handicapped children who had suffered from neonatal hypoglycaemia and to evaluate the relationship between the neurological impairment and neonatal hypoglycaemia. Materials and methods. We retrospectively evaluated the MRI findings in eight full-term infants with neonatal symptomatic hypoglycaemia who later exhibited neurological handicap. The age at which the MRI scans were obtained ranged from 9 months to 8 years 10 months (mean 4 years 1 month, median 4 years). Results. The most striking findings were prolonged T1 weighting and T2 weighting in the parieto-occipital periventricular deep white matter in six patients, suggesting abnormal or delayed myelination. Dilatation of the lateral ventricles, especially of the trigones, was observed in five patients in whom the distance between the posterior horns of the lateral ventricles and the adjacent sulci was reduced. The volume of white matter relative to grey matter was reduced in two patients. In addition, four patients exhibited cerebral cortical atrophy, mainly in the occipital lobe. Conclusions. These findings suggest that neonatal hypoglycaemia may cause delayed or abnormal myelination, especially in the parieto-occipital, periventricular, deep white matter, and may cause cerebral cortical atrophy, especially in the occipital lobe. Received: 1 August 1997 Accepted: 15 June 1998     

Brain structure abnormalities in adolescent girls with conduct disorder

Background: Conduct disorder (CD) in female adolescents is associated with a range of negative outcomes, including teenage pregnancy and antisocial personality disorder. Although recent studies have documented changes in brain structure and function in male adolescents with CD, there have been no neuroimaging studies of female adolescents with CD. Our primary objective was to investigate whether female adolescents with CD show changes in grey matter volume. Our secondary aim was to assess for sex differences in the relationship between CD and brain structure. Methods: Female adolescents with CD (n = 22) and healthy control participants matched in age, performance IQ and handedness (n = 20) underwent structural magnetic resonance imaging. Group comparisons of grey matter volume were performed using voxel‐based morphometry. We also tested for sex differences using archive data obtained from male CD and control participants. Results: Female adolescents with CD showed reduced bilateral anterior insula and right striatal grey matter volumes compared with healthy controls. Aggressive CD symptoms were negatively correlated with right dorsolateral prefrontal cortex volume, whereas callous‐unemotional traits were positively correlated with bilateral orbitofrontal cortex volume. The sex differences analyses revealed a main effect of diagnosis on right amygdala volume (reflecting reduced amygdala volume in the combined CD group relative to controls) and sex‐by‐diagnosis interactions in bilateral anterior insula. Conclusions: We observed structural abnormalities in brain regions involved in emotion processing, reward and empathy in female adolescents with CD, which broadly overlap with those reported in previous studies of CD in male adolescents.     

The changing face of celiac disease

The face of celiac disease has changed significantly over the past 50 years. With the advent of new noninvasive and more sensitive screening tools, it has become increasingly apparent that this disease presents in a heterogeneous fashion, with symptomatic disease only occurring in a small number of patients. Furthermore, great insights have been made into the disease''s genetic and immunological components, thus increasing the medical community''s understanding of the disease. The current gold standard for diagnosis is histological confirmation, and the cornerstone of therapy is lifelong elimination of gluten. Further advances in immunobiological techniques will most likely aid in earlier detection and commencement of the appropriate diet, thus preventing the development of associated complications.     

Adrenal cortical tumours: epidemiological and familial aspects.

Epidemiological data on the 14 cases of adrenal cortical tumour registered with the Manchester Children''s Tumour Registry from 1954 and 1985 are presented. The incidence of adrenal cortical carcinomas was 0.3%, mainly in girls, most of whom presented with virilisation. The incidence of neoplastic disease among close relatives was ascertained, but, except in siblings, this was not significantly higher than would be expected. Evidence from extended pedigrees, however, indicates that at least four of the children could be members of families with the SBLA (sarcoma, breast and brain tumour, leukaemia, laryngeal and lung cancer, and adrenal cortical carcinoma) cancer family syndrome, and that other relatives may be at risk of developing such neoplasms.     

The role of high‐dose chemotherapy and stem cell rescue in the treatment of malignant brain tumors: A reappraisal

Abstract: The outcome for children with malignant brain tumors has improved modestly in recent years. Notable is the improved 5‐yr disease‐free survival for those children with 'standard‐risk' medulloblastoma and other primitive neuro‐ectodermal tumors (PNET) (i.e. tumors without neuraxis dissemination at presentation). For other children with newly diagnosed malignant brain tumors, especially in the absence of radical surgical resection, the outcome remains poor despite surgery, irradiation and conventional chemotherapy. Patients whose tumors recur despite initial therapy continue to experience a dismal outlook with these conventional strategies of treatment. In an attempt to improve the outlook for such brain tumor patients with poor prognoses, strategies utilizing high‐dose (potentially myeloablative) chemotherapy with autologous stem cell rescue have been developed. These studies, conducted initially in patients with recurrent tumors, were then extended to patients with newly diagnosed malignant gliomas and brain‐stem tumors, as well as to young children with various malignant brain tumors at diagnosis in an attempt to avoid irradiation to the brain. The results of several of these studies are summarized, updating information reviewed in an earlier summary in 1996, demonstrating durable disease‐free survival for a proportion of patients with recurrent malignant gliomas and medulloblastomas/PNET, as well as encouraging data in some of those patients with newly diagnosed brain tumors.     

Influence of exclusive breastfeeding on hippocampal structure,satiety responsiveness,and weight status

Longer exclusive breastfeeding duration has been associated with differences in neural development, better satiety responsiveness, and decreased risk for childhood obesity. Given hippocampus sensitivity to diet and potential role in the integration of satiety signals, hippocampus may play a role in these relationships. We conducted a secondary analysis of 149, 7–11‐year‐olds (73 males) who participated in one of five studies that assessed neural responses to food cues. Hippocampal grey matter volume was extracted from structural scans using CAT12, weight status was assessed using age‐ and sex‐adjusted body mass index (%BMI_p85), and parents reported exclusive breastfeeding duration and satiety responsiveness (Children''s Eating Behaviour Questionnaire). Separate path models for left and right hippocampus tested: (1) the direct effect of exclusive breastfeeding on satiety responsiveness and its indirect effect through hippocampal grey matter volume; (2) the direct effect of hippocampal grey matter volume on %BMI_p85 and its indirect effect through satiety responsiveness. %BMI_p85 was adjusted for maternal education, yearly income, and premature birth while hippocampal grey matter volume was adjusted for total intercranial volume, age, and study from which data were extracted. Longer exclusive breastfeeding duration was associated with greater bilateral hippocampal grey matter volumes. In addition, better satiety responsiveness and greater left hippocampal grey matter volume were both associated with lower %BMI_p85. However, hippocampal grey matter volumes were not associated with satiety responsiveness. Although no relationship was found between breastfeeding and child weight status, these results highlight the potential impact of exclusive breastfeeding duration on the hippocampal structure.     

Serial magnetic resonance imaging and neurophysiological studies in multiple sulphatase deficiency.

We present serial clinical, magnetic resonance imaging (MRI) and neurophysiological findings of a patient with multiple sulphatase deficiency (MSD), who was first admitted at the age of 9 months, because of psychomotor retardation. MRI demonstrated extensive diffuse symmetrical high signal in the deep white matter of both cerebral hemispheres, as well as of the subcortical white matter and the brainstem, while there was additional enlargement of sulci and subdural spaces and mild atrophy. Assay of arylsulphatase A activity in white blood cell homogenates at the age of 29 months disclosed a marked deficiency of the enzyme, compatible with the diagnosis of early-infantile metachromatic leukodystrophy. During the course of a later admission, the presence of ichthyosis pointed out to the possible diagnosis of MSD; further assays of sulphatases in plasma, leukocytes as well as in cultured fibroblasts, combined with an abnormal excretion of mucopolysaccharides and sulphatides in urine confirmed the diagnosis. Molecular analysis identified a homozygous disease-causing mutation (R349W) of the SUMF1 gene. Serial neurophysiological and MRI studies demonstrated the progressive nature of the disorder (regarding both central and peripheral nervous system), correlating with the clinical deterioration (spastic quadriplegia, optic atrophy and epilepsy) with subsequent death at the age of 4 years.     

Congenital Adrenal Hyperplasia and Brain Magnetic Resonance Imaging Abnormalities

A 15-yr-old male patient with congenital adrenal hyperplasia (CAH) was referred to our department with a one year history of gradual worsening of tremors. He was diagnosed with salt-wasting 21-hydroxylase deficiency CAH at 40 d old and was started on hydrocortisone, fludrocortisone and salt. He was found to have hypertension at 8 yr of age. Detailed investigations failed to detect any cause for secondary hypertension. Physical findings on the current hospitalization objectified obesity, blood pressure of 150/80 mmHg, postural and action tremor, left cerebellar syndrome, reflex tetra pyramidal syndrome and mental decline. Brain magnetic resonance imaging (MRI) showed bilateral periventricular white matter hyperintensity that was more pronounced in the posterior regions and associated with cortico-subcortical atrophy and complete agenesis of the corpus callosum. All investigations for leukoencephalopathy were negative. A diagnosis of brain MRI abnormalities related to CAH was made, and the patient received symptomatic treatment of tremors. Our case report provides evidence of an increased frequency of brain MRI abnormalities in CAH. The literature suggests hormonal imbalance and exposure to excess exogenous glucocorticoids as main probable mechanisms. Thus, in clinical practice, CAH should be considered as one of the possible causes of brain white matter involvement associated with or without cerebral atrophy.     

IgA deficiency in children: A clinical study with special reference to intestinal findings

Clinical, immunological, and intestinal studies on 26 children with IgA deficiency in the age range 2 to 16 years are reported. 9 of these children were suffering from autoimmune disease, namely thyroiditis (5), thyrotoxicosis (1), rheumatoid arthritis (2), and probable Sjögren''s syndrome (1). The last-mentioned patient had defective cellular immunity. Altogether 11 patients were subject to recurrent respiratory tract infections. The symptomatology of the remaining patients was variable. In a boy with growth retardation, a chromosome anomaly was found, and endocrinological studies indicated total absence of growth hormone.In 21 patients IgA was undetectable, while 5 had trace amounts of IgA in their sera. IgG was raised in 11 patients, and one patient had low serum IgG. IgM levels were mostly normal. Precipitating antibodies to cow''s milk proteins were present in all but one serum.Small intestinal biopsy was performed on all patients. In 3 cases total villous atrophy was detected and these probably had coeliac disease, though malabsorption symptoms were not always evident. Disaccharidase assay of biopsy specimens revealed 2 cases of isolated lactase deficiency among 8 tested.Results show that the increased incidence of autoimmune disease reported in IgA deficiency in adults also holds true in children; i.e. that there is a raised incidence of coeliac disease with or without symptoms in IgA deficiency.     

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??X-linked adrenoleukodystrophy??X-ALD?? is an inherited neurodegenerative disorder??involving mainly the white matter and axons of the central nervous system??the adrenal cortex and the testis. X-ALD is caused by a defect in the gene ABCD1 that maps to Xq 28 locus. The primary biochemical disorder is the accumulation of saturated very long chain fatty acids??VLCFA?? secondary to peroxisomal dysfunction. At least six distinct phenotypes have been described??and the most severe type is childhood cerebral adrenoleukodystrophy. When suspected??the diagnosis is established biochemically??and prenatal testing is possible in affected families. By far there is still lack of the effective treatment methods. The administration of a mixture of glyceryl trioleate and glyceryl trierucate??also referred to as Lorenzo’s Oil??has been shown to prevent disease progression in asymptomatic patients with cerebral involvement of X-ALD. Allogeneic hematopoietic stem cell transplantation??HSCT?? is the treatment of choice for individuals with early stages of the cerebral form of the disease. Once adrenal insufficiency is present??the hormonal replacement therapy is identical to that of autoimmune Addison’s disease.     

Is disomic homozygosity at the APECED locus the cause of increased autoimmunity in Down's syndrome?

AIMS—To examine the age of onset of insulin dependent diabetes mellitus (IDDM) in children with Down''s syndrome compared with non-trisomic individuals, and to assess whether differences might be related to disomic homozygosity at the autoimmune polyglandular disease type 1 (APECED) gene locus.
METHODS—Children with Down''s syndrome and IDDM were identified through the Down''s syndrome association newsletter and from paediatricians. DNA was extracted from mouthbrush preparations provided by the parents and patients using standard techniques. Mapping techniques were then used to identify areas of reduction to homozygosity, including a marker that overlaps the locus for APECED. The frequency of disomic homozygosity for all markers (n = 18) was compared with a control group of 99 patients with Down''s syndrome and their parents. The families also answered a questionnaire concerning diabetes and related autoimmune conditions in the family. Details were compared with the British Paediatric Surveillance Group 1988diabetes study.
RESULTS—Children with Down''s syndrome and IDDM were diagnosed significantly earlier than the general population (6.7 v 8.0 years) with a far higher proportion diagnosed in the first 2 years of life (22% v 7%). There was no evidence of increased disomic homozygosity in the region of the APECED locus in Down''s syndrome patients with IDDM compared with simple Down''s syndrome.
CONCLUSIONS—The natural history of IDDM in Down''s syndrome is different from that of the general population. Although children with Down''s syndrome have features similar to cases of APECED, disomic homozygosity in this region does not explain the predilection for autoimmune disease.

     

X-linked hypophosphatemia: The medical expert's challenges and the patient's concerns on their journey with the disease

X-linked hypophosphatemia (XLH) is a rare inheritable disorder of phosphate handling due to loss of function mutations of the PHEX gene, associated with increased production of FGF23 and impaired bone mineralization. In children, the disease's most common manifestations are bowing deformities of the lower limbs, short stature, and spontaneous dental abscesses. In adults, these are osteomalacia, insufficiency fractures, and enthesopathies associated with bone and joint pain. The XLH patient's journey with the disease may be difficult, reflecting concerns and experiences globally common to all patients with rare genetic diseases. Delays in diagnosis often preclude an optimal treatment outcome. Under-treatment is common as treating physicians, particularly those not familiar with the disease, tend to err on the side of caution, often choosing safety over efficacy. Physical abnormalities, pain, diminished function, and impaired mobility tend not only to isolate the XLH patient from his peers but also to have a significant psychological effect, eventually leading to significant impairment in quality of life. Significant advances in understanding the pathophysiology of XLH, the availability of a very comprehensive Evidence-based Guideline for the diagnosis and management of XLH, and the successful development of an effective and safe disease-specific novel therapy for XLH, have paved the way for a significant improvement in the management of this rare disorder of phosphate metabolism, heralding a significant improvement in the disease's outcome measures. Additional data from long-term observational studies and randomized controlled trials are eagerly awaited to consolidate these promising developments in the field of this rare disease.     

Hypoxic-ischaemic encephalopathy after near miss sudden infant death syndrome.

Between 1982 and 1985, 14 infants aged 3-26 weeks presented with severe hypoxic episodes as a result of the ''near miss'' sudden infant death syndrome (SIDS). They all had metabolic acidosis, cardiovascular instability, acute renal failure, ischaemic colitis, or acute neurological dysfunction. Investigation of the cause excluded infection and trauma, or a primary metabolic, pulmonary, cardiac, or seizure disorder. Seven infants were deeply comatose on admission, never regained consciousness, and died within 60 hours. A characteristic evolution of hypoxic-ischaemic encephalopathy not previously clearly described after near miss SIDS was seen in the seven who lived. Five of the seven were conscious within one hour of resuscitation and showed a striking interval of near normality before neurological deterioration that was characterised by status epilepticus, deep coma, and brain stem dysfunction from 36-96 hours after the event. A biphasic course was not apparent in the remaining two, each of whom was comatose on admission, though refractory seizures did develop. Computed tomograms of the brain more than a week after the event showed cortical infarction or cerebral atrophy. Six of the survivors, followed up from 16-55 months, have serious residual deficits including spastic quadriplegia, delayed development, cortical blindness, or infantile spasms.     

Cushing's Syndrome in Childhood: Postoperative Management

Of 8 children with Cushing''s syndrome, 7 had tumours and 1 bilateral adrenal hyperplasia. All had hypertension; 5 cases also showed virilization; only 3 had short stature. All excreted raised urinary 17KS and 17OHCS. Pyelography showed displaced kidneys on the affected side in 5 cases.     

A VIRILIZING ADRENAL TUMOR WITH BORDERLINE ELEVATION OF URINARY 17-KETOSTEROIDS AND HISTOCHEMICAL DEMONSTRATION OF A DEFICIENCY IN THE δ5/δ4-ISOMERASE, 3β-HYDROXYSTEROID DEHYDROGENASE ENZYMATIC SYSTEM

Abstract. A 3-year-old girl affected by a virilizing tumor of the adrenal gland, without significant elevation in the levels of 17 ketosteroids (17-KS) urinary excretion, was studied clinically. Her symptoms started abruptly at the age of 2, with progressive enlargement of the clitoris and the appearance of pubic hair. In various tests, the 17-KS levels barely exceeded the upper normal limits and at times remained within normal limits. The retropneumoperitoneum X-ray suggested an enlargement of the right adrenal gland and the presence of a neoplasm, which was actually discovered during surgery. Histopathological examination revealed a well-defined neoplasm, without capsule invasion and with accentuated cell polymorphism. Histoenzymology showed that the tissue lacked the enzymatic system involving 3β-hydroxysteroid dehydrogenase (3β-HSD). Indoxylesterase (I.EST-A) activity identified the tumor as originating from the internal layers of the adrenal cortex. The histochemical findings were correlated to the clinical picture and the levels of urinary 17-KS.