Mohammed Didi

The role of surgery in optic pathway/hypothalamic gliomas in children.

OBJECT Optic pathway/hypothalamic gliomas (OPHGs) are generally benign tumors situated in an exquisitely sensitive brain region. The location and natural history of OPHGs has led to much debate about optimal treatment. This paper revisits the role of and optimal timing of debulking surgery in OPHG. METHODS This paper presents a series of cases managed by the neuro-oncology team at Alder Hey Childrens Hospital and a single surgeon. Data were collected retrospectively for periods prior to 2009 and prospectively thereafter. Tailored treatment strategies were used, including observation and combinations of surgery, chemotherapy, and radiotherapy. Tumor control rates and outcomes are reviewed. RESULTS Forty-two patients were treated between 1998 and 2011. Their median age at diagnosis was 5 years 7 months. Nineteen patients were positive for neurofibromatosis Type 1 (NF1) and 23 patients were negative for NF1. The median duration of follow-up was 77 months (range 21.8-142.3 months). Presenting symptoms included visual impairment (in 50% of cases), headache (in 24%), and hypothalamic/pituitary dysfunction (in 29%). Twenty-two debulking procedures were performed in 21 patients. Four biopsies (3 open, 1 endoscopic) were also performed. The histological diagnosis was pilocytic astrocytoma in 21 patients and pilomyxoid astrocytoma in 2 patients. Ten patients (Group 1) had primary surgical debulking alone and were then observed. Four patients (Group 2) had surgical debulking, plus planned chemotherapy within 3 months. Seven patients (Group 3) required surgical debulking for progressive disease following a variety of treatments. Patient age had the greatest impact on subsequent tumor progression. In total, 13 patients received chemotherapy, 4 on initial presentation, 4 in combination with surgery, and 5 for further tumor progression. Five patients were treated with radiotherapy, 3 prior to referral to Alder Hey. Eleven patients required shunt insertion for hydrocephalus. Vision was stabilized for 74% of patients. The number of patients with hypothalamic/pituitary dysfunction increased from 12 at presentation to 16 by the end of treatment. The overall survival rate was 93%. Three patients died-1 from tumor progression, 1 from infective complications from tumor biopsy, and 1 from a spontaneous posterior fossa hemorrhage. NF1 was associated with improved outcome-fewer patients required active intervention and rates of visual impairment and/or or hypothalamic/pituitary dysfunction were lower. CONCLUSIONS Good long-term survival and functional outcomes can be achieved in children with OPHG. Tumor control was achieved through an individualized approach using surgery, chemotherapy, or radiotherapy in varied combinations. The authors aim to limit radiotherapy to cases involving older children in whom other therapies have failed, due to the well-described and often devastating late effects associated with midline cranial irradiation. Surgery has a clear role for diagnosis, tumor control, and relief of mass effect. In particular, primary surgical debulking of tumor (without adjuvant therapy) is safe and effective. Recent advances in intraoperative MRI may add value and need further assessment.

Disproportionate short stature after cranial irradiation and combination chemotherapy for leukaemia.

The effect of combination chemotherapy and cranial irradiation on final height and body proportions was retrospectively examined in a cohort of 142 children treated for acute lymphoblastic leukaemia (ALL). Eighty four children (48 girls, 36 boys) received 24 Gy cranial irradiation and 58 (35 girls, 23 boys) 18 Gy. None had received testicular or spinal irradiation. A significant reduction in standing height SD score from diagnosis to final height was seen in all groups. Of the 109 children in whom sitting height measurements were available, 88 (81%) had relatively shorter backs than legs and in 25 (23%) this disproportion was of a marked degree. After mathematical correction for sitting height loss there was no longer a significant reduction in standing height SD score at final height in all except the 24 Gy group of girls. These data suggest that disproportion is a common finding after treatment for ALL and that, at least in some children, much if not all of the height loss seen is due to a reduction in sitting height. Possible explanations for this disproportion include a disturbance of puberty or an effect of chemotherapy on spinal growth, or both.

Cranial MRI scans are indicated in all girls with central precocious puberty

Aims: (1) To assess the value of cranial magnetic resonance imaging (MRI) scans in the investigation of girls with central precocious puberty (CPP); and (2) to determine the clinical predictors of abnormal cranial MRI scans in these patients. Methods: A retrospective study of 67 girls diagnosed with CPP who underwent cranial MRI scans at diagnosis. Patients with neurological signs or symptoms at presentation were excluded. Results: The mean age of onset of puberty was 6.2 years (range 2.0–7.9). Intracranial abnormalities were present in 10 (15%) patients (MR+), while 57 (85%) had no abnormalities (MR−). There was no statistical difference between MR+ patients and MR− patients at presentation with respect to age of onset of puberty, pubertal stage, bone age advance, pelvic ultrasound findings, or height or body mass index standard deviation scores (SDS). Conclusion: Girls with CPP should have a cranial MRI scan as part of their assessment since clinical features, including age, are not helpful in predicting those with underlying pathology. Implementation of such an approach may have a substantial effect on clinical practice and healthcare cost.

Phaeochromocytoma in children

Phaeochromocytoma is a rare clinical entity in children. Contrary to traditional teaching, which suggested that 10% of phaeochromocytomas are “familial”, a germline mutation has been identified in up to 59% (27/48) of apparently sporadic phaeochromocytomas presenting at 18 years or younger and in 70% of those presenting before 10 years of age. The inherited predisposition may be attributable to a germline mutation in the Von Hippel–Lindau gene, the genes encoding the subunits B and D of succinate dehydrogenase, the RET proto-oncogene predisposing to multiple endocrine neoplasia type 2, or the neurofibromatosis type 1 gene. Of these, the Von Hippel–Lindau gene is the most commonly mutated gene in children presenting with a phaeochromocytoma. Genetic counselling is recommended before gene testing and investigation of the wider family. This review provides guidance on the aetiology, investigation, management, histopathology, genetics and follow-up of children with a phaeochromocytoma.

Pituitary adenomas in childhood, adolescence and young adulthood: presentation, management, endocrine and metabolic outcomes

OBJECTIVE To elucidate the long-term outcomes of pituitary adenomas diagnosed in childhood and adolescence, knowledge of which remains sparse. DESIGN AND METHODS A retrospective review of patients aged ≤21 years at diagnosis of pituitary adenoma, attending a neuroendocrine service in Liverpool, UK, between 1984-2009. RESULTS There were 41 patients (33 female), mean age at diagnosis 17.3 years (range 11-21) and mean follow-up 9.6 years; 29 patients had prolactinomas (15 macroprolactinomas), 6 non-functioning pituitary adenomas (NFPAs), 5 Cushings disease (CD) and 1 acromegaly. All prolactinoma patients received dopamine agonists (DAs) and three also underwent pituitary surgery. Furthermore, ten patients underwent surgery: five with CD, one with acromegaly and four with NFPA. Four received radiotherapy after surgery. Another ten patients received hormone replacement: nine hydrocortisone, five thyroxine, seven sex steroids and five GH; another seven had severe asymptomatic GH deficiency. Three female patients were treated for infertility (two successfully). Thirteen patients gained significant weight (body mass index (BMI) increase >2 kg/m(2)) since diagnosis and 16 in total are now obese (BMI>30 kg/m(2)). Five were treated with orlistat and one attended a weight management service. Two received antihypertensive medications, two had type 2 diabetes and four were treated for dyslipidaemia. CONCLUSIONS This is one of the largest reviews of patients aged 21 or younger at diagnosis of pituitary adenoma followed up by a single service. Two-thirds had prolactinomas, all were treated with DAs and three underwent surgery. Increased cardiovascular risk factors (obesity and dyslipidaemia) and infertility are important sequelae and active identification and treatment are necessary.

Abnormal Neurodevelopmental Outcomes are Common in Children with Transient Congenital Hyperinsulinism

Introduction: Neuroglycopenia is recognized to be associated with abnormal neurodevelopmental outcomes in 26–44% of children with persistent congenital hyperinsulinism (P-CHI). The prevalence of abnormal neurodevelopment in transient CHI (T-CHI) is not known. We have aimed to investigate abnormal neurodevelopment and associated factors in T-CHI and P-CHI. Materials and Methods: A cohort of children with CHI (n = 67, age 2.5–5 years) was assessed at follow-up review and noted to have normal or abnormal (mild or severe) neurodevelopmental outcomes for the domains of speech and language, motor, and vision. Children were classified as P-CHI (n = 33), if they had undergone surgery or remained on medical therapy, or T-CHI (n = 34), if medical treatment for hypoglycemia was stopped. Results: Overall, abnormal neurodevelopment was present in 26 (39%) children with CHI, of whom 18 (69%) were severe. Importantly, the incidence of abnormal neurodevelopment in T-CHI was similar to that in P-CHI (30 vs. 47% respectively, p = 0.16). The prevalence of severe abnormal neurodevelopment in speech, motor, and vision domains was similar in both T-CHI and P-CHI children. For this cohort, we found that the severity of disease [based upon maximal diazoxide dose (odds ratio 95% confidence intervals) 1.3 (1.1; 1.5), p = 0.03], and early presentation of CHI <7 days following birth [5.9 (1.3; 27.8), p = 0.02] were significantly associated with abnormal neurodevelopment. There was no significant association with gender, genotype, or the histopathological basis of CHI. Conclusion: Abnormal neurodevelopment was evident in one third of children with both T-CHI and P-CHI, early presentation and severe CHI being risk factors. Early recognition and rapid correction of hypoglycemia are advocated to avoid abnormal neurodevelopment in children with CHI.

A preliminary trial of the effect of recombinant human growth hormone on short-term linear growth and glucose homeostasis in children with Crohn’s disease

Background  It is unclear whether recombinant human growth hormone (rhGH) improves linear growth in children with Crohn’s disease (CD).

Functional characterization of a novel insulin receptor mutation contributing to Rabson-Mendenhall syndrome.

Objective/Patients  Rabson–Mendenhall syndrome (RMS) is a rare, recessively inherited disorder of extreme insulin resistance due to mutations in the insulin receptor gene. We have identified a pair of siblings with RMS attributable to compound heterozygosity for two insulin receptor mutations, one previously unreported, and have characterized the novel receptor mutation functionally.

Children with congenital hypothyroidism are at risk of adult obesity due to early adiposity rebound

objective  There is some evidence that children with congenital hypothyroidism (CH) are heavier than their reference population. There are few data on adults with CH. The timing of adiposity rebound (AR) in childhood has been shown to have strong correlations with adult obesity. Our aims were to study the timing of AR and factors affecting AR in children with CH.

Early morning salivary cortisol and cortisone, and adrenal responses to a simplified low-dose short Synacthen test in children with asthma.

To examine serum cortisol responses to a simplified low‐dose short Synacthen test (LDSST) in children treated with inhaled corticosteroids (ICS) for asthma and to compare these to early morning salivary cortisol (EMSC) and cortisone (EMSCn) levels.