Histiocytosis X

Histiocytosis X is a spectrum of diseases which should be classified among the wide spectrum of histiocytic disorders, consisting of proliferation of the Mononuclear Phagocyte System (MPS). The clinical manifestations reflect the site of histiocytic proliferation and may vary from a solitary bone lesion discovered by chance on X-ray film to a disease with a rapidly fatal course affecting almost any organ. The classic classification into eosinophilic granuloma of bone, Hand-Schüller-Christian disease and Letterer-Siwe disease and other related classifications fail to demonstrate the variable course and the smooth transitions, and do not correlate with the histologic findings and prognosis. The features of the immature and mature macrophage and, in this connection, the histologic findings of non-cutaneous material and the histochemical studies allow a classification into:

1. Benign Histiocytosis X
2. Solitary or multiple bone lesions
3. Benign disseminated Histiocytosis X
4. Malignant Histiocytosis X.

The clinical manifestations themselves do not allow a distinction to be made between the two entities, but the latter may lead to severe dysfunction of certain organs. A survey of the clinical manifestations is given. Benign Histiocytosis X comprises a widely variable spectrum, ranging from a solitary bone lesion to disseminated disease, but mostly with favourable outcome; malignant Histiocytosis X has a uniform, rapidly fatal, acute course with severe dysfunction of organs. This classification is highly correlated with prognosis, which is based on histology, age at onset, dysfunction of liver, lung and hemopoietic system, and a score system. In differential diagnosis, malignant Histiocytosis X must be distinguished from other histiocytic disorders and combined immunodeficiency, which have very similar symptomatology, but often have a recessive inheritance. The etiology of Histiocytosis X is still unknown, but histochemical and electronmicroscopic studies point to a response of mature and immature histiocytes to an unidentified antigen. Treatment of bone lesions consists in curettage or irradiation (600–1000 rads), if the lesions give rise to symptoms. Relapses are frequent. In benign disseminated Histiocytosis X a treatment protocol similar to that of acute lymphoblastic leukemia (ALL) is proposed and a more intensive protocol in malignant Histiocytosis X. The prognosis of Histiocytosis X has substantially improved with the advent of multiple cytostatic treatment. Histiocytosis X is a spectrum of diseases of unknown etiology, consisting in a proliferation of differentiated cells of the Mononuclear Phagocyte System (MPS), known as histiocytes. The clinical manifestations are widely variable, mirroring the widespread distribution of the MPS, affecting almost any organ. As a result there are numerous smooth transitions between the three classical entities distinguished in the literature: eosinophilic granuloma, Hand-Schüller-Christian disease and Letterer-Siwe disease. Because of the variable course of Histiocytosis X, and for prognostic and therapeutic reasons, a classification based on clinical and histologic manifestations is desirable. The purpose of this report is to review the literature concerning the classification of histiocytic disorders and Histiocytosis X. On the basis of the clinical manifestations, their prognostic value and the histologic findings, a classification (Table 1) is given that will be relatively simple to use in practice as a guide to prognosis and therapy.     

Cellular reaction to Pneumocystis carinii

Two types of Pneumocystis carinii infections must be distinguished:

1. Interstitial plasmacell pneumonia, which occurs only in premature or in marasmic infants between the 10th and 24th week of life. It is most frequently associated with severe diarrhoea, atrophy of the bowel mucosa and IgG levels of below 200 mg%. Pneumocystis carinii organisms spread rapidly throughout the alveoli of all pulmonary lobes in these debilitated infants. The capsular antigen of the Pneumocystis carinii cysts elicits a massive plasmacell infiltration of the alveolar septa, which is accompanied by immuneglobulin production of IgM type. This reaction occurs within 24 to 48 hrs and leads frequently to death. Morphometric counts on 65 cases showed that up to 78% of the entire lung space was formed by septa distended with plasmacells and proplasmacells. The organisms disappear from the alveoli within 2 to 3 days due to the hosts IgM antibody response. The cellular infiltrate persists and may in itself cause suffocation. Complete clearing of the interstitial infiltrate takes 6–8 weeks. This sudden massive infiltration of the entire lung does not occur in all cases. Pneumocystis carinii organisms occur frequently in the subpleural posterior alveoli, eliciting a minor focal interstitial plasmacell response, which remains clinically undetected.
2. Hypoergic Pneumocystosis may occur at any age and is associated with congenital immunedeficiency diseases, diseases of the reticulo-endothelial system and immunosuppressive therapy leading to IgG deficiency. No host response to the organism occurs under these circumstances. Morphometric counts on 51 human lungs showed no interstitial inflammatory infiltrate. The septa may occasionally be distended by neoplastic infiltrates of reticulo-endothelial type as for instance in plasmacell myeloma, lymphoma or leukaemia, which is the cause rather than the result of the Pneumocystosis.

     

Fatal infectious mononucleosis: A case with a review of the literature

The association of Landry-Guillain-Barre syndrome and other complications with Epstein-Barr virus induced infectious mononucleosis in a 7 yr old girl is being reported from India for the first time.     

Cerebrospinal fluid concentration and urinary excretion of cyclic adenosine-3′, 5′-monophosphate in various diseases of children

Cerebrospinal fluid (CSF) concentration and urinary excretion of cyclic adenosine-3′,5′-monophosphate (cAMP) were measured in children aged from 3 days to 15 years by the protein-binding method of Gilman (1970). The mean CSF cAMP concentration (22.4±0.6 (S.E.) nmol/l) of 24 “healthy” children tended to be lower (P<0.2) than that of adult patients who revealed no pathological findings on clinical examination. No difference in the results was found between the sexes. High cAMP concentrations were found in CSF of children suffering from cerebellar glioma, hypothalamic precocious puberty, bacterial meningitis, or Cushing's disease. The urinary excretion of cAMP varied from 0.2 to 5.3 in “healthy” and from 1.3 to 7.6 μmol/24 hrs in diseased children. Two children with pheochromocytoma showed a striking decrease in the rate of urinary excretion of the nucleotide after surgical treatment.     

D-penicillamine in the treatment of Indian childhood cirrhosis—a preliminary report

A longitudinal study was carried out for evaluating the effect of D-penicillamine in the treatment of 85 biopsy proven cases of Indian childhood cirrhosis. The drug significantly (P< 0.002) reduced the serum and hepatic copper content and simultaneously there was improvement in clinical and symptomatic aspects. This therapy was compared with the conventional corticosteroid therapy. The D-penicillamine therapy was found to be superior (P< 0.002).     

Immunoglobulins in cerebrospinal fluid in central nervous system disorders

Immunoglobulins were estimated in the cerebrospinal fluid from 70 cases of nervous system diseases. Thirty childern with evidence of C.N.S. irritation without infection served as controls. The immunoglobulins were higher in cases with C.N. S infections. Within this group meningeal involvement (tubercular and pyogenic) resulted in a significant rise in IgG compared to viral encephalitis. The proportion of immunoglobulin in the CSF protein can be helpful in distinguishing TBM from PM.     

Prognostic factors of gastroesophageal reflux disease in congenital diaphragmatic hernia: a multicenter study

Purpose

Gastroesophageal reflux disease (GERD) is one of the concomitant problems in infants with congenital diaphragmatic hernia (CDH). We assessed risk factors of GERD in CDH patients.

Methods

The retrospective observational study for CDH infants was conducted. Cases of CDH who were born between January 2006 and December 2010, were operated in the 9 participating institutions, and survived to discharge were included. Completion of medical therapy for GERD and incidence of surgery were primary outcomes. Kaplan–Meier survival analysis and Cox proportional hazards regression were used.

Results

In 182 cases of CDH, the medical therapies for GERD were performed in 23.8 % (40/168), and were completed in 60.0 % (24/40). Prenatal detection of CDH (HR 5.87, CI 1.6–18.8, p = 0.012) and tube feeding at discharge (HR 5.04, 95 % CI 1.3–33.1, p = 0.016) were significantly correlated with unsuccessful weaning from medical therapy. Surgery for GERD was performed in 10.7 % (18/169). Gestational age (HR 4.78, 95 % CI 1.5–21.1, p = 0.006) and diaphragmatic defect of more than 75 % (HR 4.3, 95 % CI 1.6–12.9, p = 0.005) were significantly correlated with need for antireflux surgery.

Conclusion

Diaphragmatic defect of more than 75 % was risk factor of future need for antireflux surgery.     

Perinatal immunoglobulin levels in premature and small-for-date infants

In 100 low-birth-weight newborns divided into a group of prematures with adequate birth weight and a group of antenatal hypotrophics, the immunoglobulins in cord serum and in serum at 5 days were determined. The results are expressed in International Units/ml. A significant increase of IgM as compared with cord blood after 5 days of life was found in both groups. In prenatal hypotrophics insignificantly higher levels of IgM were detected both in cord and in 5-day blood. It could be supposed that the dystrophisation of some small-for-date newborns could result from intrauterine infection.     

Urinary excretion of Δ5-pregnenetriol (5-pregnene-3β,17α,20-triol) in healthy children

The excretion of Δ⁵pregnenetriol (Δ⁵) was determined in 24-h urine samples from 57 children of various ages. The probands were healthy regarding their endocrine states. Six groups of children were selected: Group I: neonates (n=12♂, aged 4 to 24 days), group II: infants (n=11♂, aged 1 to 8 months), group III; small children (n=7♂, 3♀, aged 11/2 to 6 years), group IV: schoolchildren (n=4♂, 5♀, aged 61/2 to 10 years), group V: preadolescents (n=5♂, 4♀, aged 101/2 to 13 years, developmental stages Tanner 2 to 3), group VI: adolescents (n=5♂, 1♀, aged 13–15 years, developmental stages Tanner 3 to 4). The completeness of the 24-h-urine collections was checked by creatinine determinations. The method used for steroid determination consisted of hydrolysis, extraction. Girard-T-reaction, paper chromatography, and photometric end-point determination using the Zimmermann reaction. Dehydroepiandrosterone (DHEA) was determined parallel to Δ⁵PT. The following results were obtained: $$\begin{gathered} Group I: \hfill \\ \Delta ^5 PT 0.01 - 0.11mg, mean:0.07mg/24h \hfill \\ DHEA 0.04 - 0.12mg, mean:0.07mg/24h \hfill \\ Group II: \hfill \\ \Delta ^5 PT 0.02 - 0.17mg, mean:0.10mg/24h \hfill \\ DHEA 0.01 - 0.10mg, mean:0.05mg/24h \hfill \\ Group III: \hfill \\ \Delta ^5 PT 0.01 - 0.07mg, mean:0.04mg/24h \hfill \\ DHEA 0.03 - 0.09mg, mean:0.05mg/24h \hfill \\ Group IV: \hfill \\ \Delta ^5 PT 0.02 - 0.37mg, mean:0.15mg/24h \hfill \\ DHEA 0.04 - 0.35mg, mean:0.16mg/24h \hfill \\ Group V: \hfill \\ \Delta ^5 PT 0.05 - 0.28 mg, mean:0.12mg/24h \hfill \\ DHEA 0.04 - 0.37mg, mean:0.17mg/24h \hfill \\ Group VI: \hfill \\ \Delta ^5 PT 0.11 - 0.36mg, mean:0.22mg/24h \hfill \\ DHEA 0.12 - 0.42mg, mean:0.22mg/24h \hfill \\ \end{gathered} $$ The excretion of Δ⁵PT was significantly correlated to the excretion of DHEA (P<0.001), which can be explained by a common metabolic pathway for both steroids.     

Association between nocturnal blood pressure dipping and insulin resistance in children affected by NAFLD

The aim of this study was to analyse the relationship between insulin–glucose metabolism, nocturnal blood pressure dipping and nonalcoholic fatty liver disease (NAFLD) in obese adolescents without diabetes. One hundred one consecutive children, with biopsy-proven NAFLD, were included in this study. Blood samples were drawn for the analyses of liver function tests, insulin–glucose metabolism and lipid profile appraisal. An ambulatory blood pressure measurement (ABPM) was performed. Seventy-six children (75.3 %) were systolic nondippers, and 23 of them were diastolic nondippers (30.3 %). No differences were found in the anthropometric parameters between the two groups. When compared to the systolic dippers, the systolic nondippers had higher medians of mean nocturnal blood pressure, glucose at 0, 60 and 120 min in the oral glucose tolerance test (OGTT), OGTT insulin at all time points and insulin-resistance values. No correlation of histopathological features with dipping/nondipping statuses was found. Conclusions: We found an association between a nocturnal blood pressure fall and measures of insulin levels, independent of obesity, or daytime blood pressure levels, among the obese patients with NAFLD. Although no association between nondipping profiles and NAFLD was observed in our study, further studies with a longer term follow-up are needed, to better elucidate the complex link between these particular entities.     

The Joubert Syndrome associated with bilateral chorioretinal coloboma

A case of the Joubert Syndrome is reported. This syndrome, of which 11 cases have hitherto been described, is characterized by aplasia of the cerebellar vermis in addition to episodic hyperpnoea, abnormal eye movements, rhythmic protrusion of the tongue, ataxia, and mental retardation. The diagnosis was made by the clinical symptoms, computerized axial tomography of the brain, and lumbar pneumencephalography. Bilateral typical colobomata of retina and choroid were an additional anomaly, described for the first time in association with the Joubert Syndrome. The possible relationship between the ocular and cerebral anomalies is discussed.     

Effect of corticosteroids and lung ventilation in the VEGF and NO pathways in congenital diaphragmatic hernia in rats

Purpose

The use of dexamethasone (Dx) stimulates growth, fetal lung maturation and can improve pulmonary hypertension in congenital diaphragmatic hernia (CDH). Our aim was to evaluate the effect of Dx on the lung after fetal pulmonary ventilation in the CDH rat model.

Methods

Some groups underwent prenatal treatment with dexamethasone (0.4 mg/kg) that was given at 18.5 gestational day (GD). Sprague–Dawley rat fetuses were divided into groups: control (C); ventilated control (CV); control exposed to dexamethasone (CDx); ventilated control exposed to dexamethasone (CVDx); congenital diaphragmatic hernia (CDH), ventilated CDH (CDHV), CDH exposed to dexamethasone (CDHDx) and ventilated CDH exposed to dexamethasone (CDHVDx). At 21.5 GD fetuses were delivered by C-section, weighed and ventilated for 30 min. We analyzed the lung morphometry by Masson’s Trichrome stain, and VEGF, VEGFR1, VEGFR2 and NOS3 expression by immunohistochemistry.

Results

All fetuses with CDH, with or without prenatal dexamethasone showed lung and body weight lower than control fetuses (p < 0.05). All groups that received dexamethasone showed a decrease in the medial muscular layer of arterioles, the internal diameter of the air spaces (Lma) and length of parenchymal transection/airspace ratio (p < 0.05). In the immunohistochemistry, VEGF decreased more in CDHDV group (p < 0.05). VEGFR1 showed no difference, whereas VEGFR2 decreased significantly in the CDHDV group (p < 0.05). NOS3 increased in the group CDHDV (p < 0.05).

Conclusion

The use of prenatal dexamethasone added to ventilation alters the VEGF and NO pathways.     

B Cell Suppression in Newborn Following Treatment of Pregnant Diffuse Large B-cell Lymphoma Patient with Rituximab Containing Regimen

Non-Hodgkin lymphoma associated with pregnancy is rare. Rituximab based chemotherapy is now considered the standard of care and considered safe for the treatment of diffuse large B-cell lymphoma (DLBCL) during pregnancy but little is known about its safety profile on the fetus. A 32 y primigravida was diagnosed as DLBCL at 20 wk of gestation. She received rituximab containing chemotherapy with successful pregnancy outcome. Though the baby was absolutely healthy, B-cell was totally absent in the cord blood.     

A case of new chondrodystrophy

A form of lethal short-limbed dwarfism (a new chondrodystrophy) has been presented. The clinical, radiological and histological characteristics of this entity have been discussed and illustrated. Its distinction from Achondrogenesis type I, both radiologically and histologically, is described.     

Spirometric Evaluation in Juvenile Idiopathic Arthritis: Data from Eastern India

Objective

To evaluate lung function in juvenile idiopathic arthritis (JIA) patients.

Methods

This was a case control study carried out at Institute of Post-Graduate Medical Education & Research, Kolkata, involving JIA patients between 5 and 12 y. They were diagnosed and classified on the basis of International League of Associations for Rheumatology (ILAR) criteria and compared with same number of age, sex, height and weight matched controls. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, forced expiratory flow between 25 and 75 % of vital capacity (FEF_25–75%) and peak expiratory flow rate (PEFR) of cases were compared to those of matched controls.

Results

Among 36 JIA patients initially recruited, 9 were excluded. Of the remaining 27 patients, male: female ratio was 17:10. Mean age, height and weight of JIA patients were 9.15 y, 124.67 cm and 23.78 kg respectively. Six patients had oligoarthritis, 3 had rheumatoid factor positive (RF+) polyarthritis, 10 had rheumatoid factor negative (RF-) polyarthritis and 8 had systemic JIA. Eleven patients had active disease and 15 patients required methotrexate. None had respiratory symptoms. Mean duration of the disease was 2.96 y. Mean FVC and FEV1 were significantly less in JIA patients compared to controls (p value?=?0.0003 and 0.0007, respectively). FEV1/FVC in both the groups was similar (p value?=?0.96). Mean Z scores for FVC and FEV1 were significantly higher in JIA patients (p value?=?0.0064 and 0.0030, respectively).

Conclusion

Spirometry in JIA patients demonstrated statistically significant restrictive pattern of alteration in pulmonary function.     

Smith-Lemli-Opitz syndrome: Review and report of two affected siblings

This paper reports two siblings with the Smith-Lemli-Opitz syndrome and reviews the literature on the subject. SLOS is a syndrome of multiple congenital anomalies with mental and growth retardation, unusual facies, genito-urinary and hand and foot abnormalities inherited as an autosomal recessive trait.     

Direct observation and focused feedback for clinical skills training

Direct observation of the medical trainee by an expert assessor and providing authentic feedback is considered an important tool for development of clinical and procedural skills. Mini-clinical evaluation exercise and Direct Observation of Procedural Skills are two important tools to observe the trainee during a clinical encounter or during a procedure, make an expert standardized (though subjective) observation, and use it to provide developmental feedback. Both can be easily integrated into routine work of clinical departments, and both provide a reliable assessment if 6-8 such encounters are used.     

Indian Children with Developmental Disabilities: Early versus Late Referral for Intervention

Objective

To study the age at referral, of children with neurodevelopmental disabilities to Child Development and Early Intervention Clinic and compare the neuromorbidity and socio-economic profile of the early and late presenters.

Methods

This retrospective observational study was conducted at Child Development and Early Intervention Clinic (CDEIC) located in Northern India. Case records of children enroled at CDEIC in last 5 y; with neurodevelopmental disabilities namely Mental Retardation/Global Developmental Delay, Cerebral Palsy, hearing and vision impairment were separated and studied.

Results

Two thousand and twenty cases were included in this study. 62.8 % presented before 3 y of age (early presenters) and 37.1 % presented at 3 y or more (late presenters). There was no difference in the overall rates and severity of mental retardation in early and late presenters. The proportion of children with quadriparetic cerebral palsy, hearing impairment, vision impairment and multiple disabilities was significantly more in early presenters. The early presenters had better parental education status, less number of siblings, better immunization status and more were delivered at a hospital and residing in urban areas.

Conclusions

Large numbers of children with neurodevelopmental disabilities are referred late for intervention services, leading to loss of opportunity for early intervention. Children with purely mental disability are the ones, most likely to be referred late. Socio-economic differences are significantly contributing to these delayed referrals.     

Nitrofen increases total retinol levels in placenta during lung morphogenesis in the nitrofen model of congenital diaphragmatic hernia

Background

It has been shown that pulmonary retinol level is decreased during lung morphogenesis in the nitrofen-induced PH in congenital diaphragmatic hernia (CDH). Placenta has a major role in the retinol homeostasis in fetal life. Since there is no fetal retinol synthesis, maternal retinol has to cross the placenta. Placenta is the main fetal retinol store where retinol is stored in retinyl-ester formation. Trophoblasts have to produce its own retinol-binding protein (RBP) for retinol transport from placenta to fetus. Recently, we demonstrated that trophoblastic RBP expression is decreased in the nitrofen model of CDH. The aim of this study was to investigate the retinol transfer from mother to the placenta in nitrofen model of CDH.

Methods

Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). Fetal placenta harvested on D21 and divided into two groups: control (n = 11) and nitrofen with CDH (n = 11). Retinoid levels in placenta were measured using HPLC. Immunohistochemistry was performed to evaluate trophoblastic expression of main RSP genes.

Results

Total retinol levels in the placenta were significantly increased in CDH placenta compared to control placenta. The retinyl-ester levels were significantly increased in CDH placenta compared to control placenta. Markedly, decreased immunoreactivity of retinoid signaling pathway was observed in trophoblast cells in CDH compared to control placenta.

Conclusions

Increased placental retinol levels show that retinol is transferred from mother to placenta and stored in the placenta in nitrofen model of CDH during lung morphogenesis. Nitrofen may disturb the mobilization of retinol from placenta to fetal circulation causing PH in CDH.