Diagnosis and Management of Gaucher Disease in India – Consensus Guidelines of the Gaucher Disease Task Force of the Society for Indian Academy of Medical Genetics and the Indian Academy of Pediatrics

Justification

Gaucher disease (GD) is amongst the most frequently occurring lysosomal storage disorder in all ethnicities. The clinical manifestations and natural history of GD is highly heterogeneous with extreme geographic and ethnic variations. The literature on GD has paucity of information and optimal management guidelines for Indian patients.

Process

Gaucher Disease Task Force was formed under the auspices of the Society for Indian Academy of Medical Genetics. Invited experts from various specialties formulated guidelines for the management of patients with GD. A writing committee was formed and the draft guidelines were circulated by email to all members for comments and inputs. The guidelines were finalized in December 2016 at the annual meeting of the Indian Academy of Medical Genetics.

Objectives

These guidelines are intended to serve as a standard framework for treating physicians and the health care systems for optimal management of Gaucher disease in India and to define unique needs of this patient population.

Recommendations

Manifestations of GD are protean and a high index of suspicion is essential for timely diagnosis. Patients frequently experience diagnostic delays during which severe irreversible complications occur. Leucocyte acid β-glucosidase activity is mandatory for establishing the diagnosis of Gaucher disease; molecular testing can help identify patients at risk of neuronopathic disease. Enzyme replacement therapy for type 1 and type 3 Gaucher disease is the standard of care. Best outcomes are achieved by early initiation of therapy before onset of irreversible complications. However, in setting of progressive neurological symptoms such as seizures and or/neuroregression, ERT is not recommended, as it cannot cross the blood brain barrier. The recommendations herein are for diagnosis, for initiation of therapy, therapeutic goals, monitoring and follow up of patients. We highlight that prevention of recurrence of the disease through genetic counseling and prenatal diagnosis is essential in India, due to uniformly severe phenotypes encountered in our population.

     

Newborn Screening Guidelines for Congenital Hypothyroidism in India: Recommendations of the Indian Society for Pediatric and Adolescent Endocrinology (ISPAE) – Part I: Screening and Confirmation of Diagnosis

The Indian Society for Pediatric and Adolescent Endocrinology has formulated locally relevant Clinical Practice Guidelines for newborn screening, diagnosis and management of primary congenital hypothyroidism (CH). Recommendations: Screening should be done for every newborn using cord blood, or postnatal blood, ideally at 48 to 72 h of age. On this screen sample, neonates with TSH?>?20 mIU/L serum units (or >34 mIU/L for samples taken between 24 to 48 h of age) should be recalled for confirmation. For screen TSH?>?40 mIU/L, immediate confirmatory venous T4/FT4 and TSH, and for milder elevation of screen TSH, a second screening TSH at 7 to 10 d of age, should be taken. Preterm and low birth weight infants should undergo screening at 48–72 h postnatal age. Sick babies should be screened at least by 7 d of age. Venous confirmatory TSH >20 mIU/L before age 2 wk and >10 mIU/L after age 2 wk, with low T4 (<10 μg/dL) or FT4 (<1.17 ng/dL) indicate primary CH and treatment initiation. Imaging is recommended by radionuclide scintigraphy and ultrasonography after CH is biochemically confirmed but treatment should not be delayed till scans are performed. Levothyroxine is commenced at 10 to 15 μg/kg in the neonatal period. Serum T4/FT4 is measured at 2 wk and TSH and T4/FT4 at 1 mo, then 2 monthly till 6 mo, 3 monthly from 6 mo-3 y and every 3–6 mo thereafter. Babies with the possibility of transient congenital hypothyroidism should be re-evaluated at age 3 y, to assess the need for lifelong therapy.     

Do the length-based (Broselow) Tape, APLS, Argall and Nelson's formulae accurately estimate weight of Indian children?

This study was aimed at validating the usefulness of a length based pediatric emergency tape (Broselow) in an Indian population. The secondary objective was to validate age based weight estimation formulae (Nelson, Argalls, APLS) for emergency needs (doses, sizes). This cross sectional study was done at a tertiary teaching hospital on a sample of 500 children attending outpatient clinic. Inclusion criteria was age between 1 month to 12 years. Children who were unstable, uncooperative or critically ill requiring emergency care and those measuring more than 145 cm in length or weighing more than 35 kg weight were excluded from the study. Measurement of actual weights, calculation of weight, adrenaline dose, fluid bolus and endotracheal tube size was done by all four methods. Results indicated good positive correlation between actual measured weights and weights estimated using Broselow Tape (r = 0.974), APLS (r = 0.902), Argalls modification (r = 0.902), and combined Nelson formulae (0.935). However, specific Nelson formulas for 7-12 yr and 3-12 mo were especially poor in correlation. Bland-Altman Plots comparing actual weight showed least mean bias for Broselow Tape estimations in < 15 kg group (0.080 +/- 0.96 kg) and maximum bias with Nelsons formula for 7 to12 yr (5.204 +/- 4.272 kg). For adrenaline doses and fluid bolus calculations, Broselow estimations were valid estimates. Broselow tape did underestimate endotracheal tube size (mean bias -0.53 +/- 0.18). To conclude, length based pediatric emergency tape (Broselow) correlates well with overall emergency decision making process in our setting. This is especially validated in the age group 0.1 to 6.7 yr weighing less than 15 kg.     

Translation and cultural adaptation of the Hirschsprung’s Disease/Anorectal Malformation Quality of life Questionnaire (HAQL) into Swedish

Purpose

Children with anorectal malformation or Hirschsprung’s Disease (HD) often have functional problems with constipation or incontinence. The Hirschsprung’s Disease/Anorectal malformation Quality of life Questionnaire (HAQL) developed in the Netherlands is a disease-specific instrument measuring the quality of life (QoL) of children and adolescents with fecal incontinence. HAQL includes several domains with questions concerning diet, laxatives, constipation, diarrhea, urine and fecal incontinence, in addition to social and emotional functioning, body image, and physical symptoms. The purpose of the study was to translate and culturally adapt the HAQL questionnaire into Swedish.

Method

The translation was carried out according to accepted translation guidelines and a backward/forward translation method was used.

Results

The translation correlated well with the original. All in all the Swedish and the Dutch versions agreed well. The Swedish translators chose to use a more simplified language in the questionnaires intended for the children, but used another choice of words in the proxy version and the adolescents’ version.

Conclusions

The translation of the HAQL instrument into Swedish gives us a disease-specific QoL instrument for children and adolescents born with HD and anorectal malformations (ARM). The translated and culturally adapted HAQL instrument is included in a survey regarding children and adolescents born with ARM.     

The role of insulin like growth factor (IGF) — 1 and IGF — binding protein-3 in diagnosis of Growth Hormone Deficiency in short stature children

Objective  The purpose of this study was to evaluate the role of IGF-1 and IGFBP-3 in diagnosis of short stature children and adolescents in whom Growth Hormone Deficiency (GHD) was found. Methods  In this cross sectional study the referred short stature children and adolescents to Namazi Hospital in Shiraz- Iran, in 2003–2005 were studied. The inclusion criteria were proved short stature based on the physical examination, weight, height, standard deviation score (SDS) of height < −2, with considering stage of puberty and predicted height in children without any genetic or chronic disorders. The exclusion criteria were any positive physical or laboratory data suggesting hypothyroidism, rickets or liver disorders. For all patients a provocative growth hormone test was performed with propranolol and L-dopa and serum IGF-1 and IGFBP-3 were measured. GHD defined as peak(cutoff) serum GH level under 10 ìg/L and low IGF-1 and IGFBP-3 considered as cutoff serum level under −2 standard deviation. Results  Eighty one short stature patients (39 boys and 42 girls) with mean age of 10.6 ± 3.5 years completed the study. Seventeen patients with GHD were found and in 18 patients IGF-1 level were low. Only in 6 patients both GH and IGF-1 were low and 2 of them had low IGFBP-3. There were no correlations between the levels of GH,IGF-1 and IGFBP-3 in children with short stature due to GHD. The sensitivity and specifity of IGF-1 and IGFBP-3 in assessment of GHD were 35% and 81% for IGF-1 and 12% and 94% for IGFBP-3, respectively. Conclusion  No correlations were found between GH level and serum levels of IGF-1 and IGFBP-3 in short patients and the sensitivity of those tests in assessment of GHD were poor.     

Immunogenicity and safety of a DTaP-IPV//PRP～T vaccine (Pentaxim) booster dose during the second year of life in Indian children primed with the same vaccine

Objective

To evaluate the immunogenicity and safety of a pentavalent (diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Hib polysaccharide-conjugate) combination vaccine booster dose.

Design

Multicenter, open, Phase III clinical study.

Setting

Two tertiary-care hospitals in Delhi and Vellore, India.

Participants/patients

207 healthy Indian children.

Intervention

The DTaP-IPV//PR～NT vaccine (Pentaxim) was given at 18–19 months of age to children who had been primed with the same vaccine at 6,10,14 weeks of age.

Main outcome measures

Immunogenicity was assessed before and 1 month after the booster. Safety was evaluated from parental reports, and investigator assessments.

Results

At 18–19 months of age, before boosting, the SP rates against diphtheria, tetanus, poliovirus and PRP were 82.3–100%; 90.0% of participants had anti-PRP ≥0.15 μg/mL. Anti-poliovirus titers were ≥1:8 dilution in 97.9–98.4% of participants. Anti-PT and FHA titers ≥5 EU/mL) were detectable in 82.5% and 90.8% of participants, respectively. One month after the booster dose, SP rates were 99.5% for PRP (≥1.0 μg/mL), 100% for diphtheria, tetanus (≥0.1 IU/mL) and polioviruses (≥8:1/dilution). Seroconversion (4 fold post-booster increase in anti-PT and -FHA concentration) occurred in 96.8% and 91.7%, respectively. Geometric mean concentrations (GMC) increased from 11.7 to 353.1 EU/mL and from 18.2 to 363.4 EU/mL for anti-PT and anti-FHA, respectively. Anti-PRP GMC increased from 1.75 to 70.5 μg/mL. Vaccine reactogenicity was low; severe solicited reactions were reported by <1.4% of participants.

Conclusion

The DTaP-IPV//PRP-T vaccine booster at 18–19 months of age was well tolerated and induced strong antibody responses.     

Acute Myeloid Leukemia (AML-M2) with Translocation (8;21) (q22;q22) and Abnormal Eosinophilic Precursors in the Bone Marrow—A Case Report

The translocation (8;21)(q22;q22) is frequently associated with M2 subtype of AML. The authors herein present a case of AML-M2 in a nine-year-old boy without hepatosplenomegaly, lymphadenopathy or any bleeding diathesis. Bone marrow examination revealed high number of eosinophilic precursors (60%) among the total nucleated bone marrow cells. Cytogenetic study with G- banding method showed 46, XY, t (8;21)(q22;q22). The morphological abnormalities in eosinophils observed in AML suggested that eosinophils may be a part of leukemic process.     

Indian Academy of Pediatrics (IAP) recommended immunization schedule for children aged 0 through 18 years — India, 2013 and updates on immunization

Justification

There is a need to review/revise recommendations about existing vaccines in light of recent developments in the field of vaccinology where new developments are taking place regularly at short intervals.

Process

Following an IAP ACVIP meeting on 3rd and 4th August, 2013, a draft of revised recommendations for the year 2013 and updates on certain new vaccine formulations was prepared and circulated among the meeting participants to arrive at a consensus.

Objectives

To review and revise recommendations for 2013 Immunization timetable for pediatricians in office practice and issue statements on new vaccine formulations.

Recommendations

The major change in the 2013 Immunization timetable was made in the recommendations pertaining to pertussis immunization. Taking in to the consideration of recent outbreaks of pertussis in many industrialized countries using acellular pertussis (aP) vaccines and subsequent finding of faster waning of the same in comparison to whole-cell pertussis (wP) vaccines and superior priming with wP vaccines than aP vaccines, the committee has now recommended wP vaccines for the primary series of infant vaccination. Guidelines are now also issued on the preference/selection of a particular aP vaccine in case it is not feasible to use wP vaccine, and use of Tdap vaccine during pregnancy. The administration schedule of monovalent human rotavirus vaccine, RV1 has been revised to 10 and 14 weeks from existing 6 and 10 weeks. Recommendation is made for the need of booster dose of live attenuated SA-14-14-2 JE vaccine. Updates and recommendations are issued on new typhoid conjugate vaccine, inactivated vero-cell culture derived SA-14-14-2 JE vaccine, inactivated vero-cell derived Kolar strain, 821564XY JE vaccine, and new meningococcal conjugate vaccines. This year the recommended immunization schedule with range for persons aged 0 through 18 years is being published together instead of two separate schedules. A subcategory of ‘general instruction’ is added in footnotes. The comments and footnotes for several vaccines are revised and separate instructions for ‘routine vaccination’ and ‘catch-up vaccination’ are added in the footnotes section wherever applicable.     

Familiarity with current practices of granting and maintaining privileges in pediatric interventional radiology—a worldwide survey of the members of the Society for Pediatric Interventional Radiology (SPIR)

Background

Physician credentialing is a complex process driven by the demand for quality improvement in health care. In the U.S., the Joint Commission Standard of 2007 has tied hospital accreditation to credentialing through mandated use of the Focused Professional Practice Evaluation (FPPE) and Ongoing Professional Practice Evaluation (OPPE).

Objective

To assess pediatric interventional radiologists’ knowledge of how institutions grant them privileges.

Materials and methods

Members of the Society for Pediatric Interventional Radiology (SPIR) were sent a web-based survey regarding credentialing.

Results

Of 122 members from 19 countries, 81 (66%) responded, and of these 81, 59 (73%) were familiar with their hospital’s privileging process. Of 49 U.S. respondents and 32 non-U.S. respondents, 37 (76%) and 17 (53%), respectively, stated that interventional radiology credentialing was different from diagnostic radiology credentialing. Of the 49 U.S. respondents, 24 (49%) reported an OPPE, and of the 32 non-U.S. respondents, 8 (25%) reported an ongoing evaluation. The U.S. OPPE is performed at shorter intervals than its international equivalent.

Conclusion

Four years after the Joint Commission defined the FPPE and OPPE, separate credentialing of pediatric interventional radiology from pediatric diagnostic radiology is more likely in the U.S. than internationally, and U.S. pediatric interventional radiologists are more likely to have a defined ongoing professional evaluation and to be evaluated every 6?months or more frequently. There are many SPIR members who do not know how they obtain privileges and/or are not knowingly subject to an OPPE. This lack of knowledge may affect future education of interventional radiologists as well as the definition of pediatric interventional radiology practices within individual institutions.     

Is there an intrauterine influence on obesity? Evidence from parent–child associations in the Avon Longitudinal Study of Parents and Children (ALSPAC)

Background

It has been suggested that increasing obesity levels in young women lead to intrauterine environments that, in turn, stimulate increased obesity among their offspring, generating an intergenerational acceleration of obesity levels. If this mechanism is important, the association of maternal body mass index (BMI) with offspring BMI should be stronger than the association of paternal with offspring BMI.

Objective

To compare the relative strengths of association of maternal and paternal BMI with offspring BMI at age 7.5, taking into account the possible effect of non‐paternity.

Methods

We compared strength of association for maternal–offspring and paternal–offspring BMI for 4654 complete parent–offspring trios in the Avon Longitudinal Study of Parents and Children (ALSPAC), using unstandardised and standardised regression analysis. We carried out a sensitivity analysis to investigate the influence of non‐paternity on these associations.

Results

The strength of association between parental BMI and offspring BMI at age 7.5 was similar for both parents. Taking into account correlations between maternal and paternal BMI, performing standardised rather than unstandardised regression and carrying out a sensitivity analysis for non‐paternity emphasised the robustness of the general similarity of the associations. The associations between high parental BMI (top decile) and offspring BMI are also similar for both parents.

Conclusion

Comparison of mother–offspring and father–offspring associations for BMI suggests that intergenerational acceleration mechanisms do not make an important contribution to levels of childhood BMI within the population. Associations at later ages and for different components of body composition now require study.The increasing prevalence of obesity among children and adults in many countries constitutes a potentially serious threat to the future health of these populations.^1,2,3 The importance of a shift in the balance of energy intake to energy expenditure as the proximal determinant of rising obesity levels is generally recognised,¹ with changes in social organisation and local, national and international economic forces being seen to underlie this pattern.⁴ In addition, there is evidence to support a role for prenatal influences on childhood and adulthood obesity.^5,6,7 Maternal obesity may lead to greater placental transfer of nutrients during embryonic and fetal development, leading to permanent changes in appetite, metabolism and the neuroendocrine function of offspring.⁵ Studies in animal models have provided some support for the existence of such mechanisms.⁸The consequence of this influence of maternal body composition on offspring body composition, mediated through the intrauterine environment, would be an intergenerational acceleration in obesity levels.^1,7 Changes in the balance of energy intake and energy expenditure, leading to an increase in obesity in mothers, would, through such intrauterine processes, generate increases in obesity among offspring. When the female offspring in turn produce their own offspring, the latter will be destined to experience further increases in obesity through the influence of the obesity levels of their mothers on the intrauterine environment they encounter. This feed‐forward mechanism would lead to an intergenerational acceleration of obesity levels, over and above the acute effects of shifts in the balance between energy intake and energy expenditure within populations.There is clear evidence that mothers with gestational diabetes have offspring with increased obesity levels in childhood and adolescence,⁹ although the degree to which this persists into adulthood is uncertain.¹⁰ The strongest evidence for a specific effect of diabetes during pregnancy on offspring body mass index (BMI) comes from a study of siblings discordant for maternal diabetes during pregnancy.¹¹ At age 22, the sibling exposed to a maternal diabetic environment had, on average, higher BMI than the unexposed sibling. No influence of paternal diabetes was seen on offspring BMI, suggesting that the intrauterine environment, rather than a simple genetic mechanism, was responsible.Raised BMI will generate a lesser degree of metabolic disturbance than that seen with diabetes, and the influence of this more modest exposure on offspring BMI is not well delineated. One approach to this issue, that would allow estimation of the potential importance of any intergenerational acceleration in obesity levels, is to compare associations between maternal BMI and offspring BMI with those between paternal BMI and offspring BMI. If maternal BMI has an influence on offspring BMI through intrauterine effects, the expectation would be of a stronger correlation of maternal than paternal BMI with offspring BMI. Few studies have approached this issue, and the available data have not been presented in a way that allows formal comparison of the magnitude of associations. Existing studies have yielded conflicting findings, generally from small sample sizes.^{12,13,14,15,16,17} We have therefore examined this issue in the Avon Longitudinal Study of Parents and Children (ALSPAC), producing directly comparable estimates of maternal and paternal BMI associations with offspring BMI, while taking into account plausible degrees of non‐paternity.