Lifelong Replacement Therapy Research Articles

Newly identified common variable immunodeficiency in an elderly patient with rheumatoid arthritis

Common variable immunodeficiency is a group of heterogeneous diseases that are primary immunodeficiencies with a predominant lack of antibody synthesis. The most common manifestation is chronic infectious pathology of the respiratory tract, less often of the gastrointestinal tract, as well as septic arthritis. Non-infectious manifestations include autoimmune diseases, non-infectious diarrhea, cancer, benign lymphoid hyperplasia. In one patient, a combination of several syndromes is possible. Unlike most other primary immunodeficiencies that debut in early childhood, this pathology often manifests in the third or fourth decade of life, and sometimes later in apparently healthy people. Although the routine laboratory method for determining the concentration of the main classes of immunoglobulins makes it quite easy to identify patients with common variable immunodeficiency, often the diagnosis is made many years after the onset of the first clinical symptoms, when serious complications have already developed. The disease is characterized by a gradual onset, chronic progressive course and ineffectiveness of standard therapy. The main method of treatment is lifelong replacement therapy with intravenous immunoglobulins. The article considers a clinical case when an elderly patient with seronegative rheumatoid arthritis with a juvenile onset was diagnosed many years later. The results of immunological studies, including immunophenotyping of peripheral blood and bone marrow lymphocytes, are presented. Issues of differential diagnosis with secondary hypogammaglobulinemia and lymphoproliferative diseases are highlighted. It has been stated that until now, doctors of various specialties are not sufficiently familiar with the problem of primary immunodeficiencies, especially when it comes to adults, and non-infectious manifestations dominate in the clinical picture.

Reduced serum concentrations of biomarkers reflecting Leydig and Sertoli cell function in male patients with congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is a recessive condition that affects the adrenal glands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids, adult patients with CAH often experience impaired gonadal function. In pubertal boys and in men with CAH, circulating testosterone is produced by the adrenal glands as well as the testicular, steroidogenic cells. In this European two-center study, we evaluated the function of Leydig and Sertoli cells in 61 boys and men with CAH, primarily due to 21-hydroxylase deficiency. Despite conventional hormone replacement therapy, our results indicated a significant reduction in serum concentrations of both Leydig cell-derived hormones (i.e. insulin-like factor 3 (INSL3) and testosterone) and Sertoli cell-derived hormones (i.e. inhibin B and anti-Müllerian hormone) in adult males with CAH. Serum concentrations of INSL3 were particularly reduced in those with testicular adrenal rest tumors. To our knowledge, this is the first study to evaluate circulating INSL3 as a candidate biomarker to monitor Leydig cell function in patients with CAH.

Functional calcium-responsive parathyroid glands generated using single-step blastocyst complementation

Patients with permanent hypoparathyroidism require lifelong replacement therapy to avoid life-threatening complications, The benefits of conventional treatment are limited, however. Transplanting a functional parathyroid gland (PTG) would yield better results. Parathyroid gland cells generated from pluripotent stem cells in vitro to date cannot mimic the physiological responses to extracellular calcium that are essential for calcium homeostasis. We thus hypothesized that blastocyst complementation (BC) could be a better strategy for generating functional PTG cells and compensating loss of parathyroid function. We here describe generation of fully functional PTGs from mouse embryonic stem cells (mESCs) with single-step BC. Using CRISPR-Cas9 knockout of Glial cells missing2 (Gcm2), we efficiently produced aparathyroid embryos for BC. In these embryos, mESCs differentiated into endocrinologically mature PTGs that rescued Gcm2-/- mice from neonatal death. The mESC-derived PTGs responded to extracellular calcium, restoring calcium homeostasis on transplantation into mice surgically rendered hypoparathyroid. We also successfully generated functional interspecies PTGs in Gcm2-/- rat neonates, an accomplishment with potential for future human PTG therapy using xenogeneic animal BC. Our results demonstrate that BC can produce functional endocrine organs and constitute a concept in treatment of hypoparathyroidism.

Modern possibilities and prospects in the treatment of adrenal insufficiency

Adrenal insufficiency (AI) is a life-threatening disease characterized by a decrease in the production of hormones by the adrenal cortex and requires lifelong replacement therapy with glucocorticoids (GCs) and, in some cases, mineralocorticoids (MCs). The number of individuals with primary and secondary AI in Europe is estimated at 20-50 per 100 thousand people, the increase in the number of cases of this disease in the world may be partly due to the rapid increase in the frequency of use of GC in various clinical strategies, including in oncological diseases.In AI, hormone replacement therapy is vital, but long-term use of GC may be associated with various adverse effects, especially at non-physiological concentrations of GC. This review provides a brief overview of the current therapeutic possibilities of AI hormone therapy, which contributes to the prevention of the development of adrenal crises, as well as promising opportunities for more effective imitation of the physiological profile of cortisol, aimed at preventing the development of undesirable effects of therapy. Several different forms of AI are currently available, differing in profile, duration of action, and route of administration. The most preferred currently in the treatment of AI are GCs with a short half-life, which provides a more manageable action profile and a lower risk of side effects. Promising substitution therapy options include modified-release hydrocortisone preparations, as well as new methods of drug administration using an insulin pump, which will better mimic the physiological effects of endogenous cortisol.

Hypothyroidism: The difficulty in attributing symptoms to their underlying cause.

Common symptoms of overt hypothyroidism are non-specific and include fatigue, lethargy, and dry skin. Although the diagnosis is considered to be straightforward, no single symptom can be used to identify patients with overt hypothyroidism, while many patients with subclinical hypothyroidism are asymptomatic. A large population-based study on the spectrum of symptoms in subclinical hypothyroidism showed similar rates of thyroid disease-related symptoms compared with euthyroid subjects, while the TSH concentration had no impact on symptom score. Together, these findings make it challenging to attribute symptoms to their underlying cause. This is also true in the case of unexplained persistent symptoms in levothyroxine-treated patients. Although generally considered a life-long replacement therapy, successful thyroid hormone discontinuation resulting in euthyroidism has been reported in approximately one third of patients. Thus, we overtreat patients with (subclinical) hypothyroidism, highlighting the importance of reliable diagnostic criteria. The diagnostic process, including the implementation of robust TSH and FT4 reference intervals, is especially challenging in specific situations including aging, pregnancy, non-thyroidal illness, and central hypothyroidism. There is a clear need for improved adherence to current guidelines from scientific societies and for willingness to manage symptoms without a clear pathological correlate, especially in the case of mild TSH elevations. This review will highlight recent literature on this topic and offers some practice points.

Семейный случай наследственной агаммаглобулинемии типа Брутона

Aim. To update the information about hereditary agammoglobulinemia, to describe a clinical case. Key Points. The frequency of hereditary agammaglobulinemia varies from 1:100,000 to 1:200,000. The cause of this disease is a gene mutation on the long arm of the X chromosome that codes for B-cell tyrosine kinase. The disease is characterized by a sharp decrease in all classes of serum immunoglobulins and the number of circulating B - lymphocytes. Hereditary agammaglobulinemia manifested by repeated bacterial infections during the first two years of life. Patients require lifelong replacement therapy with intravenous immunoglobulins. In this article we included 3 own clinical observations. Conclusion. The quality of life and prognosis of the patients with Bruton's disease depends on the early detection of the disease and the quality of medical care provided. Keywords: hereditary agammaglobulinemia, Bruton's disease, primary immune deficiencies, X-linked agammaglobulinemia

Trabecular bone score and sclerostin concentrations in patients with primary adrenal insufficiency

Patients with primary adrenal insufficiency need lifelong replacement therapy with glucocorticoids and mineralocorticoids, which may influence their bone quality. The aim of the study was to evaluate densitometry parameters, trabecular bone score and sclerostin concentrations in patients with primary adrenal insufficiency in comparison to control group. We included 29 patients (62% females) with diagnose of autoimmune primary adrenal insufficiency (mean age 49.7 ± 11.7 years, mean duration of the disease 13.2± 13.6 years) and 33 healthy subjects (adjusted with age, sex and body mass index). Bone mineral density at the femoral neck, lumbar spine, total body and trabecular bone score were evaluated. Serum sclerostin concentrations were measured. There were no significant differences in densitometry parameters (T-score, Z-score, bone mineral density in all locations) as well as in trabecular bone score in patients with adrenal insufficiency in comparison to control group. Mean serum sclerostin concentration was significantly higher in patients with adrenal insufficiency than in control group (44.7 ± 23.5 vs 30.7 ± 10.4 pmol/l, p=0.006). There was a negative correlation between trabecular bone score and the duration of adrenal insufficiency and age, also a negative correlation between femoral neck and total densitometry parameters and 24-hour urine cortisol as a marker of hydrocortisone daily dose in patients with adrenal insufficiency. The bone status in patients with primary adrenal insufficiency was not impaired in comparison to control group, while sclerostin concentration was higher. The duration of the disease and higher hydrocortisone doses may affect negatively bone status.

Gene and cell therapy of adrenal pathology: achievements and prospects

Our current understanding of the molecular and cellular mechanisms in tissues and organs during normal and pathological conditions opens up substantial prospects for the development of novel approaches to treatment of various diseases. For instance, lifelong replacement therapy is no longer mandatory for the management of some monogenic hereditary diseases. Genome editing techniques that have emerged in the last decade are being actively investigated as tools for correcting mutations in affected organs. Furthermore, new protocols for obtaining various types of human and animal cells and cellular systems are evolving, increasingly reflecting the real structures in vivo. These methods, together with the accompanying gene and cell therapy, are being actively developed and several approaches are already undergoing clinical trials. Adrenal insufficiency caused by a variety of factors can potentially be the target of such therapeutic strategies. The adrenal gland is a highly organized organ, with multiple structural components interacting with each other via a complex network of endocrine and paracrine signals. This review summarizes the findings of studies in the field of structural organization and functioning of the adrenal gland at the molecular level, as well as the modern approaches to the treatment of adrenal pathologies.

Lifelong immunoglobulin replacement therapy for agammaglobulinaemia too costly in the USA

Lifelong immunoglobulin replacement therapy for agammaglobulinaemia too costly in the USA

Safety and Effectiveness of Total versus Subtotal Thyroidectomy in Management of Simple Multinodular Goiter

Abstract Background: Disorders of the thyroid gland constitute the second most common endocrine disease following diabetes mellitus. The prevalence of nodular goiter and thyroid auton-omy is increased in regions with chronic Iodine Deficiency (ID). It has been documented that the thyroid gland adjusts to ID in the early stages by diffuse hyperplasia, while chronic exposure to ID results in nodular hyperplasia, increased colloid content and increased height of the follicular cells. Aim of Study: To compare between total and subtotal thyroidectomy in management of Multinodular Goiter as regard safety and effectiveness and post-operative complica-tions like: Hypocalcaemia, recurrent laryngeal nerve injury and hypoparathyroidism. Material and Methods: This prospective study was done at Ain Shams University Hospitals and Banha teaching hospital during the period between March and September 2019. This study included 40 cases of SMNG. Their age was between 30 to 45 years, consent was taken from each patient pre-operatively. Agreement of ethical committee was done. Results: Our study showed the advantages of total thy-roidectomy include adequate eradication of the disease, prevention of recurrent goiter and avoidance of the need for completion surgery in case of occult malignancy, but it is associated with higher morbidity (postoperative thyroidectomy complications: RLN palsy and hypoparathyroidism) and the need for lifelong replacement therapy (L-thyroxin supplemen-tation). Conclusion: In MNG, there are a high percentage of cases with disease involving the entire gland; many areas of appar-ently healthy tissue are found to be microscopically involved with variable grade of chronic lymphocytic thyroiditis or follicular hyperplasia or even lobular dysplasia with tendency to form nodules. These signs of disease of this organ tend to recurrence if not treated.

Joint disease and its medical and socio-economic impact on haemophilia care in Romania

Hemophilia is a congenital, hereditary, rare bleeding disorder, which fortunately has nowadays an optimal therapeutical solution, namely a life-long replacement therapy (RT) with the missing coagulation factor VIII (hemophilia A) or IX (hemophilia B). Inappropriate treatment results in secondary morbidity, dominated by the chronic hem arthropathy, with high medical and socioeconomic burden. Objectives: As in our country, RT has been started only in 1997 and a real prophylactic replacement (PR) only in 2016/2017, we aimed at conducting a study of persons mainly with prophylactic RT and of those mainly with on-demand (OD) regimen for obtaining a comparative evaluation of the medical and socio-economic outcomes. Material and methods: This observational cross-sectional patient-reported outcome (PRO) survey included 122 patients with a severe form of the disease, willing to answer to a large questionnaire with 56 items focused on 4 domains: socio-demographic, medical, quality of health and life, and direct costs of care. Results: There have been assessed striking, statistically different results, concerning the markers which reveal clinical severity (annualized joint and non-joint bleeding rate, target joints, hem arthropathy), the need for chronic analgesic therapy and orthopedic interventions, frequency of deficiency, disability, handicap and social assistance in the group of persons with OD treatment vs. PR. The high costs related to surgical interventions and occurrence of inhibitors have been underlined, related to a secondary morbidity of hemophilia. Conclusions: The favorable effects of PR are evident also in our country; its high costs are counterbalanced by the deleterious health and quality of life results of OD treatment, and also by its high costs for the specific secondary morbidity, pleading in the favor of PR, in accordance with the principles of care in Europe.

Practice patterns and outcomes in the management of Thai patients with Graves\u2019 disease

BackgroundThe treatment of hyperthyroid Graves’ disease (GD) varies considerably among geographic areas. In this study, we aimed to evaluate practice patterns and treatment outcomes in Thai patients with hyperthyroid GD.MethodsA retrospective cohort study over 35 years (1985–2019) in patients with hyperthyroid GD was conducted. The trends of treatment options were compared periodically during the study period and the overall remission rate from each option was determined.ResultsA total of 2736 hyperthyroid GD patients were treated and followed-up for at least 3 months over the study period (female 82.0%, mean age at diagnosis 36.3 ± 12.0 years, median duration of follow-up 74.5 months). Anti-thyroid drug (ATD) was the most commonly used treatment (78.0%), followed by RAI (21.0%), and surgery (1.0%). There was a significant downward trend for surgery, from 12.3% in the 1980s to only 0.2% in last phase of the study period. The preference for RAI therapy has also decreased in the last 5 years. Among ATD-treated patients, the remission rate was achieved only in 30.7 and 16.0% of all ATD-treated patients were eventually treated with RAI. Spontaneous hypothyroidism developed in 2.7% of the ATD-treated patients during a follow-up period. Almost all RAI-treated patients (97.1%) developed hypothyroidism.ConclusionsOur present study highlighted the changing landscape of primary treatments for hyperthyroid GD toward ATD and the sharp downward trend in the surgical option. Even though ATD was associated with a low remission rate, it was preferred by many patients and physicians. The use of RAI as the primary treatment decreased in the last decade. However, RAI was a very effective treatment for Graves’ hyperthyroidism but will inevitably induce hypothyroidism and a requirement for life-long replacement therapy.

Clinical Outcomes After Discontinuation of Thyroid Hormone Replacement: A Systematic Review and Meta-Analysis.

Background: Levothyroxine (LT4) is one of the most commonly prescribed medications. Although considered a life-long replacement therapy, LT4 therapy can be discontinued for some patients. This study aims at: (i) reviewing the evidence on clinical outcomes of patients undergoing thyroid hormone replacement discontinuation, (ii) identifying the predictors of successful discontinuation, and (iii) systematically appraising frameworks used for deprescribing thyroid hormone. Methods: We searched multiple bibliographic databases, including Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus, from inception to February 2020 for studies in which thyroid hormone replacement was discontinued. Clinical outcomes assessed included: proportion of patients that remained euthyroid or needed to restart thyroid hormone replacement after discontinuation and frequency of clinical symptoms of hypothyroidism and adverse effects. We also evaluated predictors for discontinuation and deprescribing frameworks. Reviewers (F.J.K.T., N.B., N.M.S.O., S.M.) evaluated studies for inclusion, extracted data, and assessed methodological quality independently and in duplicate. Results: Seventeen observational studies at moderate to high risk of bias met inclusion criteria, including a total of 1103 patients (86% women) with an age range of 2-81 years. Approximately a third of patients undergoing thyroid hormone discontinuation remained euthyroid at follow-up (37.2%, 95% confidence interval [CI 24.2-50.1%], I2 97.5%). Subgroup analysis showed that patients with a previous diagnosis of overt hypothyroidism (OH) were less likely to remain euthyroid (11.8% [CI 0.4-23.2%], I2 90.3%) than patients with a prior diagnosis of subclinical hypothyroidism (SCH) (35.6% [CI 8.2-62.9%], I2 94.0%). No study followed a framework for systematically deprescribing LT4. Conclusions: Low-quality evidence suggests that up to a third of patients remained euthyroid after thyroid hormone discontinuation, with a higher proportion of patients with an initial diagnosis of SCH remaining euthyroid than patients with an initial diagnosis of OH. A deprescribing framework focusing on adequate selection of patients for deprescribing LT4 and a systematic process is warranted to guide clinicians in re-evaluating the need for LT4 in their patients.

Effect of glucocorticoids on bone metabolism in replacement therapy of adrenal insufficiency. Literature review

Adrenal insufficiency (AI) is a syndrome caused by disturbance in the synthesis and secretion of hormones of the adrenal cortex, which ensure the vital activity, energy and water-salt homeostasis. The widest hormonal deficiency is observed in primary hypocorticism, when the synthesis of not only glucocorticoids (GC) and adrenal androgens, but also mineralocorticoids is disrupted. Lifelong replacement therapy with GCs for this pathology may be associated with a risk of bone loss and osteoporosis. However, at present, there are no clear guidelines for diagnosis of bone condition, including and bone mineral density (BMD) monitoring during treatment with GCs in patients with AI. This review summarizes collected data on the key pathogenetic links of glucocorticoid-induced osteoporosis, incidence of decreased BMD and fractures in patients with AI. In this review factors that influence bone metabolism in this cohort of patients are considered: the type and the dose of prescribed GCs, the type (primary, secondary, HH in congenital adrenal cortex dysfunction) and the duration of AI, age, gender, and the presence of concomitant endocrine disorders (hypogonadism, growth hormone (GH) deficiency). In addition, the review presents data on the effect of adrenal androgen replacement therapy and recombinant GH therapy on bone metabolism in secondary AI.

Experience of Idursulfase Beta Administration in the Child with Mucopolysaccharidosis Type II: Clinical Case

Background. Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a rare hereditary lysosomal storage disease associated with iduronate-2-sulfatase deficiency. Patients with MPS II require life-long enzyme replacement therapy (ERT) to replace the deficiency of endogenous enzyme. There are two medications — idursulfase and idursulfase beta — that are licensed and recommended for these patients in Russian Federation. However, it is well known that ERT can cause hypersensitivity reactions development.Clinical Case Description. The ERT (idursulfase in the dose of 0.5 mg/kg once per week) onset in the male patient with severe MPS II was at the age of 2.5 years. Hypersensitivity reactions (urticaria, fever) were noted incidentally, thus, the premedication with antihistamines and antipyretics was performed. The ERT side effects has aggravated at the age of 8 years despite the glucocorticosteroids admission and infusion rate reduction up to 8–16 ml/h. That is why we have changed the medication on idursulfase beta with major clinical response: we have achieved control on both disease itself and hypersensitivity reactions.Conclusion. The availability of two ERT medications for patients with MPS II expands treatment opportunities. In case of any allergic reactions due to idursulfase, the change on idursulfase beta reduces the risk of any ERT complications with sufficient control of MPS II course.

Clinical characteristics and prenatal diagnosis for 22 families in Henan Province of China with X-linked agammaglobulinemia (XLA) related to Bruton\u2019s tyrosine kinase (BTK) gene mutations

BackgroundX-linked agammaglobulinaemia (XLA) is a rare immunodeficiency disease for which recurrent severe infection is the major clinical symptom. BTK is the main causative gene, with X chromosome recessive inheritance. However, the mutations reported to date do not fully explain the disorder.MethodsWe detected the percentage of CD19+ B cells and serum immunoglobulin (IgG, IgA, and IgM) levels by flow cytometry and rate scatter immunoturbidimetry, and investigated the BTK mutation profile in 22 XLA patients using Sanger sequencing and real-time PCR .ResultsWe evaluated the clinical symptoms of 22 XLA patients and investigated genetic mutations present, identifying six novel mutations in the BTK gene: 2 missense mutations (c.23G > T and c.112 T > C), 2 frameshift mutations (c.522_523insC and c.1060delA), 1 large deletion (deletion of exon 2 to 5), and 1 splice-site mutation (c.1631 + 2 T > C). Prenatal diagnoses were performed in six families (F10, F11, F15, F18, F20 and F21), with the following results: the male fetus in Family 10 (F10) did not carry the c.922_923delGA mutation; the male fetus in Family 15 (F15) did not carry the c.1631 + 1G > T splicing mutation; the female fetus in Family 20 (F20) did not carry the c.1931 T > C mutation; the female fetus in Family 21 (F21) did not carry the large deletion mutation. Hence, these four fetuses are not likely to develop XLA. Male fetuses with c.1060delA and c.1684C > T mutations were identified in Family 11 and Family 18, respectively. The pregnant woman in F18 chose to terminate the pregnancy, whereas the pregnant woman in F11 chose to continue the pregnancy.ConclusionWe confirmed the diagnosis of 22 XLA patients from 22 unrelated families and detected six new pathogenic mutations. Prenatal diagnosis was performed in six families. Early genetic diagnosis and routine lifelong immunoglobulin replacement therapy can prevent and treat infections in XLA children, saving their lives.

MON-174 Circadian Misalignment of the 24-H Profiles of Melatonin and Cortisol in Adrenal Insufficiency

Patients with adrenal insufficiency (AI), in whom cortisol release is absent, need to be on lifelong replacement therapy. Depending on the modality of glucocorticoid replacement, the resulting 24-h profile of circulating cortisol levels maybe dampened, enhanced, abnormally timed or inconsistent. The 24-h cortisol profile is a major internal synchronizing signal between central and peripheral circadian clocks. Misalignment between central and peripheral clocks has a host of adverse effects, particularly on metabolism and cardiovascular function. Melatonin, normally secreted by the pineal gland exclusively at night and considered a robust marker of central circadian timing, also plays a role as an internal synchronizing signal. Conditions like AI, where the 24-h profile of glucocorticoid levels deviates from normality, could produce misalignment between central and peripheral oscillators.We examined whether AI patients are at higher risk of disturbances of the circadian system. Participants were 13 AI patients (11 females, 2 men; mean age 45.8 yrs old; mean BMI 25.5) and 13 controls (11 females, 2 males; mean age 48.5 yrs old, mean BMI 26.4) matched for age, sex, and BMI. 10 of the AI patients were on hydrocortisone treatment (total dose range: 20 to 40mg/day, number of doses: 1-5 doses/day) and 3 of the AI patients were on prednisone treatment. Cortisol and melatonin were measured over a 24-h period every 30-60 minutes in all patients and controls.The 24-h profile of cortisol was quite variable across patients, dependent on replacement therapy. Those on prednisone had very little detectable cortisol with small peaks that occurred around dosing. Those on hydrocortisone, had multiple peaks across the 24-h cycle dependent on medication regime and dosing. As expected, control subjects had a quiescent period of cortisol release from early evening to mid-sleep (18:00 to 02:00) and a mid-sleep rise in serum cortisol that peaks in the morning and subsequently dissipates across the day. In contrast, AI patients have low levels of cortisol across the entire sleep period, with a sharp morning rise, delayed compared to controls. Unexpectedly, we observed a marked difference in the melatonin profile in AI subjects compared to controls. Indeed, a significant daytime phase of elevated melatonin levels was detected in 7 of the 13 AI patients. The nocturnal elevation in the patients was similar to that observed in controls albeit advanced.In conclusion, the abnormalities of the circadian profile of glucocorticoid levels in AI are associated with an abnormal 24-hr profile of melatonin release, a marker of central circadian function, suggesting that the disruption of the glucocorticoid rhythm may affect central circadian function. It is possible that this circadian dysfunction contributes to the well-known adverse cardio-metabolic outcomes in AI.

Clinical features and partial proportional molecular genetics in neonatal diabetes mellitus: a retrospective analysis in southwestern China.

To explore the relationship of phenotype and genotype of neonatal diabetes mellitus (NDM) in southwestern China. Sixteen cases of NDM admitted to Children's Hospital of Chongqing Medical University from May 2009 to May 2019 were included in this study. The clinical features of the included infants were retrospectively analyzed. Peripheral blood samples of the patients and their parents were collected for mutation detection. Among the 16 cases of NDM, 8 cases were permanent neonatal diabetes mellitus (PNDM) (including 3 clinical syndromes), and 3 cases were transient neonatal diabetes mellitus (TNDM). Mutation detection was performed in six cases. The mutation genes and their loci were FOXP3 p.V408M, KCNJ11 p.C166Y, ABCC8 p.S830P, KCNJ11 p.I182T, KCNJ11 p.G334D, and ZFP57 p.R125X,412. ABCC8 p.S830P was the new found pathogenic site of gene mutation. According to the clinical features and follow-up results, one case was diagnosed as IPEX syndrome, two as DEND syndrome, two as simple PNDM, and one as TNDM. All the TNDM could spontaneously alleviate and then insulin was withdrawn. In PNDM, 75% of those with KATP channel gene mutation could be completely or partially converted to oral sulfonylureas treatment, however, the rest cases needed lifelong insulin replacement therapy. The clinical manifestations and treatment regimens of patients with NDM vary according to the type of gene mutation. Even the same mutant genotype has differences in phenotype and response to treatment.

Inherited Bleeding Disorders in North Indian Children: 14years' Experience from a Tertiary Care Center.

Inherited bleeding disorders are not uncommon in pediatric practice: most of them being chronic, require lifelong replacement therapy. To frame a management policy, it is essential to assess the load and pattern of bleeding disorders in the local population. However, there is paucity of data reporting the clinical spectrum of coagulation and platelet function disorders in Indian children. Hence to find out the exact burden and clinico-investigational profile of these patients we conducted this study. In this retrospective case review, detailed clinical information was extracted from case records in 426 children with a suspected diagnosis of hereditary bleeding disorder registered in the Pediatric Hematology clinic of a tertiary referral centre over a period of 14years (1998-2011) and pooled for analysis. In our cohort prevalence of hemophilia A, hemophilia B, platelet function disorders, von Willebrand disease and other rare factor deficiencies were 72%, 11%, 7%, 4% and 4% respectively. Common clinical spectrum included skin bleeds, arthropathy, mucosal bleeds. 10% had deeper tissue bleeding and 16% received replacement therapy at the first visit. Nearly 3/4th of cases were lost for follow up after the initial visit. Hemophilia A was the commonest inherited bleeding disorder in our population. Skin bleeds and arthropathy were common clinical presentations. Factor replacement therapy was restricted to a minority. There is an urgent need for establishing centresof excellence with administrative commitment for factor replacement therapy for comprehensive management of such children in resource-limited countries.

Quality of Life Differences for Primary Immunodeficiency Patients on Home SCIG versus IVIG

BackgroundPatients with primary immunodeficiency disease (PIDD) and antibody deficiency require lifelong immunoglobulin replacement therapy. While both subcutaneous immunoglobulin (SCIG) and intravenous immunoglobulin (IVIG) replacement therapy are effective in preventing infection, patients with PIDD still experience worse health-related quality of life (hrQOL) outcomes.ObjectiveAssess differences in hrQOL for PIDD patients receiving home SCIG versus IVIG.MethodsSF-36 surveys were administered by a specialty pharmacy to 630 PIDD patients receiving home SCIG and IVIG at baseline and then every 3 months between 2014 and 2016. Results were analyzed using two-sample t tests and linear mixed effects model. Analysis was repeated for different age categories and trended over time.ResultsPatients receiving SCIG reported statistically significant higher energy fatigue scores (+ 9 points, p < 0.001) but lower perceived role limitations due to physical health scores (− 14 points, p < 0.001). These differences were only observed in patients > 36 years of age. There were no differences in the composite SF-36 score for patients receiving SCIG versus IVIG (+ 1, p = 0.66). Immunoglobulin-naïve patients all improved their hrQOL, but a larger improvement was seen in those initiating SCIG versus IVIG.ConclusionPatients with PIDD on home IVIG versus SCIG have similar composite hrQOL scores as measured by the SF-36. In the adult population, initiating immunoglobulin replacement with SCIG may result in more hrQOL improvement compared with IVIG, although personal preferences should also be considered.Clinical ImplicationsPatients with PIDD on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36.Capsule SummaryPatients with primary immune-deficiency on home IVIG versus SCIG have similar composite health-related quality of life scores as measured by the SF-36. Personal preferences are important in deciding whether to treat with IVIG or SCIG.