Growth hormone therapy for children with Duchenne muscular dystrophy and glucocorticoid induced short stature.

OBJECTIVE: To evaluate the outcome of recombinant human Growth Hormone (rhGH) therapy in patients with Duchene Muscular Dystrophy (DMD) and glucocorticoid treatment with compromised growth. DESIGN: Four DMD patients on Deflzacort 0.6-0.85 mg/kg/day or prednisolone 0.625 mg/kg/day recieved rhGH (0.24 mg/kg/week) for 6-18 months. Primary outcomes were Growth velocity and Height for age Z-scores (Height SD). RESULTS: Growth velocity increased from 0 to 3.25 cm/year prior to GH therapy to 3.3-7.8 cm/year over a period of 6-18 months. The typical Height SD decline in DMD was reversed in two patients and blunted in one. No adverse events or deterioration in cardiac or respiratory parameters were associated with the rhGH treatment. CONCLUSIONS: rhGH appears to be safe and efficient in promoting growth of patients with glucocorticoid induced growth failure in DMD.

The utility of glucose area under the curve from the oral glucose tolerance test as a screening tool for cystic fibrosis-related diabetes.

BACKGROUND: Consistently abnormal glucose levels on oral glucose tolerance test (OGTT) are the most effective screening tool for cystic fibrosis-related diabetes (CFRD). However, some cystic fibrosis (CF) patients demonstrate abnormal glucose profiles not reaching levels required for CFRD diagnosis and are, therefore, left untreated. Since CFRD is associated with disease deterioration, early diagnosis and treatment are desirable. AIM: To explore the association between the area under the curve of glucose (G-AUC) obtained during a five-point 2-h standard OGTT and CF disease severity parameters. METHODS: All CF patients referred for an annual routine OGTT at the Hadassah CF Center between 2002 and 2018, were included. Disease severity parameters were correlated with the G-AUC. RESULTS: Two hundred forty-two OGTTs were performed in 81 patients (mean age 19.7 ± 9.0 years); 54% were normal, 14% showed impaired glucose tolerance (IGT), 5% had values in the indeterminate range (INDET), 11% had both IGT and INDET and 16% were diagnosed with CFRD. A gradual increase in mean G-AUC was observed among the groups. In multivariate regression models, G-AUC ≥ 295 mg h/dl was independently associated with an increased number of pulmonary exacerbations (PEx). Not all the patients having this value met the CFRD definition. CONCLUSION: Patients who do not fulfill the criteria for CFRD may have abnormal glucose metabolism identifiable by abnormally high G-AUC values, which may be associated with more PEx. The potential advantage of treating these patients with insulin and the subsequent reduction in PEx needs further investigation.

Increased prevalence of attention-deficit hyperactivity disorder symptomatology in patients with familial Mediterranean fever.

OBJECTIVES: Previous studies suggest that exposure to inflammation in infancy may increase the risk for attention-deficit and hyperactivity disorder (ADHD). We studied the ADHD manifestations among 124 familial Mediterranean fever (FMF) patients and examined the relationship between FMF patient characteristics and ADHD. METHODS: Clinical, demographic, and genetic data were abstracted from patients' medical records and supplemented by information obtained during clinic visits. ADHD manifestations were assessed using the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) questionnaire. RESULTS: ADHD was diagnosed in 42 (32.8%) FMF patients, a rate significantly higher than in unselected populations (∼8%). A majority (n = 27, 64.3%) had combined inattentive, hyperactive-impulsive manifestations. Eight (19%) had predominantly hyperactive-impulsive, and seven (16.6%) had predominantly inattentive symptoms. FMF patients with severe manifestations reported more ADHD symptoms. FMF patients with ADHD symptoms were less adherent to their treatment regimen, with only 61.9% of the patients with ADHD symptoms adhering to colchicine therapy compared to 92.7% of the patients without ADHD symptoms. CONCLUSION: The high prevalence of ADHD characteristics in children with FMF may support the neuroimmune hypothesis that chronic inflammation increases the risk for ADHD. Children with FMF should be screened for ADHD as its presence may adversely affect adherence to treatment.

Safety and clinical outcome of tamoxifen in Duchenne muscular dystrophy.

Patients having Duchenne muscular dystrophy (DMD) are currently being treated with corticosteroids, which slow down disease progression at the expense of serious adverse effects. Tamoxifen is a pro-drug some of whose metabolites interact with the nuclear estrogen receptor, leading to anti-fibrotic and muscle-protective effects as has been demonstrated in a murine model of DMD. Here we report the results from a monocentric single arm prospective study in 13 ambulant boys aged 6-14 years with genetically confirmed DMD, aimed to assess the safety of tamoxifen and its impact on disease progression. Boys were treated for up to 3 years with 20 mg/day of oral tamoxifen, in addition to their ongoing corticosteroid treatment. For 8 of these patients, outcome was compared to an age- and performance-matched 12-month natural history dataset. The primary end point was the 6-minute walk test. Secondary end points were the NorthStar assessment, timed function tests, pulmonary function, the biomarker creatine phosphokinase and adverse effects. No adverse effects were noticed other than mild gynecomastia in 4 boys. Tamoxifen-treated patients retained motor and respiratory function, compared with a significant deterioration of age-matched historical control patients receiving corticosteroids only. These encouraging findings warrant a larger clinical trial to substantiate the use of tamoxifen in Duchenne muscular dystrophy.

Eligibility for growth hormone therapy in children born small for gestational age is substantially lower than expected.

BACKGROUND: Growth hormone therapy is indicated for children who are both born 'small for gestational age' (SGA) and do not achieve adequate catch-up growth (ACUG). OBJECTIVE: To evaluate the actual incidence of infants born SGA and their actual ACUG. METHODS: Birth weight data from the newborn registry at two hospitals were analysed during four consecutive years. SGA was defined according to WHO parameters and the corresponding Israeli criteria. Follow-up measurements of height and weight were abstracted from either the Ministry of Health-child growth follow-up centres, or their paediatrician clinic. ACUG was declared when the height reached was above -2.5 or -2 standard deviations (SDS) from the mean for age and gender. RESULTS: Out of 43 307, only 524 babies in the cohort (1.2%) were SGA (52% of expected). This finding was consistent annually. Out of the 446 SGA born children with available growth data (85%) during 4-8 years, 405 children (90.8%) reached a height greater than -2SDS and 428 (96%!) reached a height greater than -2.5 SDS. Term children had higher rate of ACUG achievement as compared to preterm 97.2% vs 86.8% (P < .001). Birth week and birth weight were also related to achievement of ACUG (P < .001). CONCLUSION: This large representative, heterogeneous and Western Caucasian cohort indicates that the actual number of SGA newborns is nearly half of the expected and that the actual prevalence of ACUG is also significantly higher than previously reported. These findings may have an impact on morbidity, health cost planning and growth hormone requirements in SGA babies.

Aldosterone synthase (CYP11B2) deficiency among Palestinian infants: Three novel variants and genetic heterogeneity.

Aldosterone synthase deficiency (ASD) is a rare potentially life-threatening genetic disorder that usually presents during infancy due to pathogenic variants in the CYP11B2 gene. Knowledge about CYP11B2 variants in the Arab population is scarce. Here, we present and analyze five Palestinian patients and their different novel pathogenic variants. Data on clinical presentation, electrolytes, plasma renin activity, and steroid hormone levels of five patients diagnosed with ASD were summarized. Sequencing of the CYP11B2 gene exons was followed by evolutionary conservation analysis and structural modeling of the variants. All patients were from highly consanguineous Palestinian families. The patients presented at 1-4 months of age with recurrent vomiting, poor weight gain, hyponatremia, hyperkalemia, and low aldosterone levels. Genetic analysis of the CYP11B2 gene revealed three homozygous pathogenic variants: p.Ser344Profs*9, p.G452W in two patients from an extended family, and p.Q338stop. A previously described pathogenic variant was found in one patient: p.G288S. We described four different CYP11B2 gene pathogenic variants in a relatively small population. Our findings may contribute to the future early diagnosis and therapy for patients with ASD among Arab patients who present with failure to thrive and compatible electrolyte disturbances.

A Unique Presentation of XY Gonadal Dysgenesis in Frasier Syndrome due to WT1 Mutation and a Literature Review.

Frasier syndrome (FS), a rare disease caused by inherited or de novo mutation in Wilm's Tumor suppressor gene 1 (WT1), is characterized by slow progressive nephropathy, XY gonadal dysgenesis (XY-DSD), and increased risk for gonadal tumors. Early childhood (1-6 years) nephropathy progresses with age to refractory nephrotic syndrome, and end-stage renal failure in late adolescence, when delayed puberty and/or primary amenorrhea are clinically evident. We report a unique case of FS presenting initially with primary amenorrhea at 16 years, without previous or concomitant renal damage. Only subsequently she developed an extremely late-onset nephropathy. Genetic analysis revealed the IVS9 + 5 G>A mutation in intron 9 of the WT1 gene. This clinical presentation and review of WT1 literature highlights the importance of considering FS in the differential diagnosis of patients with 46,XY disorders of Sexual development, even without nephropathy. Furthermore, the identification WT1 gene mutation prior to evident renal dysfunction indicates an immediate and close surveillance of renal function enabling an optimal and timely medical response.

The novel founder homozygous V225M mutation in the HSD17B3 gene causes aberrant splicing and XY-DSD.

PURPOSE: Mutations in the gene HSD17B3 encoding the 17-beta hydroxysteroid dehydrogenase 3 enzyme cause testosterone insufficiency leading to XY disorders of sex development. In this study the clinical and molecular characteristics of three patients from consanguineous families are elucidated. METHODS: We identified three patients from two unrelated families with XY DSD and a novel homozygous HSD17B3:c. 673G>A mutation. The effect of the mutation on splicing was determined in RNA extracted from the testis of one patient. RESULTS: Three patients presented at ages 0.1, 8 and 0.7 years with ambiguous genitalia and an XY Karyotype. Endocrine workup showed normal cortisol and mineralocorticoid levels with a low testosterone/androstenedione ratio. Whole-exome sequencing, carried out in the first family, revealed a homozygous novel mutation in the HSD17B3 gene: c. 673G>A, p. V225M. The same mutation was found by Sanger sequencing in the third unrelated patient. Haplotype analysis of a 4 Mb region surrounding the HSD17B3 gene on chromosome 9 revealed that the mutation resides on the same allele in all three patients. The mutation, being the first nucleic acid on exon 10, affects splicing and causes exon 10 skipping in one of our patients' testes. CONCLUSION: The novel homozygous c. 673G>A, p. V225M mutation in the 17HSDB3 gene is likely a founder mutation and causes severe XY-DSD. It changes a conserved amino acid residue, and also alters 17HSDB3 gene transcription by causing skipping of exon 10, thereby contributing to an imbalance in the relevant protein isoforms and consequently, significant decreased 17HDSB3 enzymatic activity.

Somatic growth in cystic fibrosis.

PURPOSE OF REVIEW: Cystic fibrosis (CF) is commonly associated with compromised growth especially in severe cases when the pulmonary function (PFT) deteriorates. As growth optimization is an important aspect of CF management, this review will summarize the current knowledge on the prevalence of growth failure in CF patients, and focus on the mechanisms leading to poor growth, on the association of poor linear growth with reduced PFT and on recombinant human growth hormone (rhGH) therapy in CF patients. RECENT FINDINGS: Despite the improvement in CF care in the last 2 decades, compromised linear growth is still quite prevalent. The pathophysiology of growth failure in CF is multifactorial. Malnutrition due to decreased energy intake increased energy expenditure and malabsorption of ingested nutrients secondary to pancreatic insufficiency, all probably play a major role in growth restriction. In addition, chronic inflammation characteristic of CF may contribute to growth failure via alteration in the GH-insulin-like growth factor 1 signaling and other changes in the growth plate. rhGH and new CFTR modulators may improve some growth parameters. SUMMARY: Beyond optimizing nutrition and malabsorption, and controlling chronic inflammation, children with CF may benefit from the anabolic effects of rhGH therapy to improve their anthropometric parameters. Whether this translates into better PFT and improved long-term outcomes is yet to be determined.

Pyogenic sacroiliitis in children: don't forget the very young.

Pyogenic sacroiliitis (PS) is rare with less than 100 pediatric cases reported in the medical literature. To better characterize PS in the pediatric population, we investigated a series of children presenting with PS. Retrospective data analysis was done at an academic tertiary center between the years of 2000 and 2017. All hospitalized children ≤ 16 years of age with PS were evaluated. Of the 894 children hospitalized with osteoarticular infections, 18 were diagnosed with PS (2%) and are included in the review. Two clinically distinct groups were identified. PS in infants (n = 13, 72.2%, mean age 1.1 years) had an indolent course and a faster recovery without any bacterial source identified. In contrast, the group of older children (n = 5, 27.8%, mean age 11.6 years) had a more complicated course and a higher rate of identified bacterial infections.Conclusion: We describe an under-recognized entity of PS in infants with a mild clinical course and fast recovery that differ from the "classical" septic sacroiliitis. Infants with PS did not suffer from invasive complications, and pathogen characteristics of older children were not identified. Infants with fever, irritability, decreased range of motion in the pelvic area, and pain during diapering should alert the clinician to this diagnosis. What is Known: • Pediatric pyogenic sacroiliitis is an extremely rare condition usually caused by Staphylococcus aureus with highest incidence in adolescents. • The diagnosis of PS is challenging due to its rarity and difficulty in assessing the sacroiliac joint. What is New: • We describe an under-recognized entity of PS in infants with a mild clinical course, without invasive complications and with fast recovery that differ from "classical" septic sacroiliitis. • Infants with fever, irritability, decreased range of motion in the pelvic area and pain during diapering should raise clinical suspicion of this diagnosis.

Sudden onset unexplained encephalopathy in infants: think of cannabis intoxication.

UNLABELLED: The use of cannabis as both a therapeutic agent and recreational drug is common, and its availability is increasing as a result of legalization in many countries. Among older children, the manifestations of cannabis intoxication are numerous and include both neurological and systemic manifestations that are frequently non-specific. There have been only a few reports detailing cannabis intoxication in infants and toddlers. We describe three infants who presented to the emergency department with encephalopathic signs without prominent systemic manifestations. During the initial interview of caregivers, no history of exposure to neurotoxic agents was obtained. All three patients were subsequently diagnosed with cannabis intoxication based on urine toxic screens for delta-9-tetrahydrocannabinol (THC). The infants recovered with supportive care that included fluids and monitoring. The non-specific symptomatology of cannabis intoxication in infants together with the wide differential for unexplained acute onset encephalopathy may delay diagnosis and lead to inappropriate procedures and interventions such as antimicrobial treatments and imaging studies. CONCLUSION: Healthcare personnel of emergency rooms, urgent care centers, and general clinics should be aware of the potential risk of cannabis ingestion in young infants. A thorough medical history and toxic screen are warranted in all infants with unexplained decreased sensorium.

The Impact of Prior Antibiotic Therapy on Outcomes in Children Hospitalized for Community-Acquired Pneumonia.

Here, we review current available literature regarding the effect of prior antibiotic treatment on outcomes of children hospitalized for community-acquired pneumonia (CAP). To date, no prospective trial has reported information regarding morbidity or mortality in this group of patients. Retrospective studies have provided evidence for the advantage of treatment with broad-spectrum antibiotics in children who failed prior antibiotic therapy. We discuss the changing epidemiology of CAP in the post PCV13 and Hib vaccines era and its relevance to the outcome of pediatric patients hospitalized for CAP. Current studies still report Streptococcus pneumoniae as the most common typical bacterial causative agent in pediatric CAP. However, in children who fail to respond to guideline directed antibiotic therapy, a non-pneumococcal, possibly one of several ß-lactam resistant causative bacterial agents should be considered thus clarifying the advantage for broad-spectrum empirical antibiotic treatment in this group of patients.

Systemic steroid treatment for severe expanding pneumococcal pneumonia.

The treatment of bacterial community-acquired pneumonia (CAP) is based on appropriate antibiotic therapy and supportive care such as intravenous fluids and supplemental oxygen. There is no available data regarding the use of steroids in CAP in children. We present an unusual case of a child with severe respiratory distress, on the brink of mechanical ventilation, due to a rapidly expanding pneumococcal pneumonia. The administration of systemic steroids resulted in a dramatic response with rapid improvement of clinical and radiological abnormalities followed by improvement of laboratory abnormalities. This case report should raise the awareness of the potential benefits of steroids in the treatment of severe pneumonia in children. Prospective randomized trials are needed to confirm the efficacy of steroids in this setting and to determine which patients would benefit most from this.