Monitoring Skull Base Abnormalities in Children with Osteogenesis Imperfecta - Review of Current Practice and a Suggested Clinical Pathway.

OBJECTIVES: In the context of a lack of national consensus on the benefits of skull base imaging in children with osteogenesis imperfecta (OI), this study aims to analyse and correlate the clinical symptoms and radiological images of children with severe OI. METHODS: A retrospective case notes and image analysis was carried out on children with complex OI between 2012 and 2018 at a specialist tertiary centre. Data were collected on patient demographic factors, clinical data, imaging findings (presence of Wormian bones, platybasia, basilar impression (McGregor's technique) and basilar invagination (McRae's technique)), and clinical features at the time of imaging. RESULTS: Of the 127 patients in the OI database, 94 were included. A total of 321 radiographs, 21 CT scans and 39 MRI scans were analysed. Average frequency of radiographs was 8 per 10 years. Of the 94 patients, 58 (62%), 10 (11%), 1 (1%) demonstrated platybasia, basilar impression, and basilar invagination, respectively. Of the radiographs analysed, platybasia, basilar impression, basilar invagination, and the presence of Wormian bones, could not be evaluated in 71 (22.3%), 48 (15.2%), 61 (19.5%) and 28 (9.4%) radiographs respectively (due to poor positioning, anatomical abnormalities, and poor image quality). Of the 140 radiographs with platybasia, 17 (12%) also demonstrated basilar impression compared to only 3 (2.9%) out of the 99 without platybasia (p = 0.03). No significant associations were seen between the presence of Wormian bones and basilar impression. Of the 39 MRIs, additional information on CSF flow rate, spinal cord signal and cerebellar morphology was reported in 14 (36%). There was a lack of concordance between MRI and matched radiographs in 7.1% (1/14) and 36% (5/14) for platybasia and basilar impression respectively, with full concordance for basilar invagination. Fewer than 5% had positive clinical symptoms/signs at the time of imaging; 2% (7/321) had macrocephaly, 0.6% (2/321) headache, all other neurological features were absent). Clinical features were not documented in >85% of patients. CONCLUSION: The apparent low prevalence of clinical symptoms and signs and of radiologically identified cranio-cervical abnormalities, suggests that current levels of serial imaging may be excessive. Until larger prospective studies clarify these issues, we suggest a clinical pathway for base of skull imaging which proposes a risk stratification approach to radiographic frequency and suggests parameters for proceeding to MRI.

Growth arrest despite growth hormone replacement, post-craniopharyngioma surgery.

Children with growth failure, whether secondary to an endocrinopathy such as growth hormone deficiency or secondary to neurological handicap with poor nutrient intake, grow at a subnormal rate but it is most unusual for a child to have complete growth arrest.

Hydrocortisone replacement therapy in children and adolescents with hypopituitarism.

OBJECTIVE: Appropriate replacement doses of glucocorticoid are important to determine in primary and secondary adrenal deficiency in children, both to avoid the risks of hypoglycaemia and adrenal crisis associated with undertreatment, and to avoid growth suppression and reduced final height potential associated with steroid excess. The aim of this study was to assess how closely conventional twice daily hydrocortisone administration mimics physiological cortisol secretion in a group of ACTH-deficient children and adolescents. PATIENTS: Fifty children and adolescents (aged 3-20 years) were studied who had had surgery +/- radiotherapy to the hypothalamopituitary region for removal of a craniopharyngioma. The patients were subdivided into two groups: group I comprised 44 patients known to be ACTH deficient (as determined by glucagon or insulin provocation tests of anterior pituitary function performed after surgery) and maintained on twice daily oral hydrocortisone replacement; group II comprised six patients known to be ACTH sufficient at their last assessment of pituitary function and not on hydrocortisone replacement. A third group of 10 boys (aged 7-13 years) who had no known endocrinopathy were used as controls (group III). MEASUREMENTS: After intravenous cannula insertion, blood samples were taken every 2h for measurement of plasma cortisol and glucose over a period of 24h. Patients in group I continued on their usual doses of hydrocortisone, prescribed at 0800 and 1800 h. RESULTS: The mean total daily replacement dose of hydrocortisone for patients in group I was 12.3 mg/m2/ day (range, 5.5-18.5). On the conventional twice daily dose regimen, there was a supraphysiological medium plasma cortisol level (629 nmol/l, range 185-1600; z = -3.76, P = 0.0002) 2 h after the morning dose relative to the control group, and a prolonged and unphysiological nadir from 1400-1800 h (median at 1600 h 42 nmol/l, range 13-1170; z = -3.13, P < 0.002) before the second dose of hydrocortisone was administered. Cortisol values were low, and often negligible, during the early hours of the morning (median at 0600 h 15 nmol/l, range 13-277, z = -4.87, P < 0.00001) and spontaneous hypoglycaemia was documented in one patient on a single 0800 h sample. One patient in group II was shown to be unequivocally cortisol deficient and median cortisol values for the remaining five suggested a suboptimal rise in plasma cortisol during the early hours of the morning. CONCLUSION: Our cohort of patients provides an excellent model for the study of glucocorticoid replacement in cortisol-deficient children and adolescents and shows, as in adults, that the aim of mimicking the physiological nyctohemeral secretion of cortisol is difficult to achieve in practice and raises a number of important considerations unique to steroid substitution therapy in this age group.

New challenges in the growth field.

When unlimited supplies of biosynthetic human growth hormone (hGH) became available in the late 1980s, the envisaged potential of its therapeutic applications was enormous in that it was hoped that perhaps most short children would be able to be made taller. However, this seems to have been far too simplistic a view and certainly in those children with various growth disorders treated with pharmacological doses of growth hormone (GH), the potential for increased final height does not appear to be fulfilled, with the exception of girls with Turner's syndrome. Further challenges in the growth field involve the manipulation of pubertal development during concomitant GH therapy.

Growth and endocrine sequelae of craniopharyngioma.

The growth and endocrine sequelae of 75 children (33 girls and 42 boys) with craniopharyngioma, treated from 1973 to 1994, were studied by retrospective review and by follow up assessment in 66 survivors, with a mean time from initial surgery of 6.7 years (range 1.5 to 19.8 years). Although infrequently complained of, 71% of patients had symptoms to suggest an endocrinopathy at diagnosis. After surgery, multiple endocrinopathies were almost universal, such that 75% of children had panhypopituitarism at follow up. Hypoadrenal crises in association with intercurrent illness contributed significantly to morbidity and mortality, as did the metabolic consequences of concomitant antidiuretic hormone (ADH) insufficiency and absent thirst. Final height in 25 patients was significantly below genetic target height, particularly in the girls, with loss of height potential occurring during the pubertal years. The endocrine morbidity associated with craniopharyngioma and its treatment remains high but manageable with appropriate hormone replacement. However, the combination of ADH insufficiency and an impaired sense of thirst following aggressive surgery and severe hypothalamic injury remains one of the most complex management problems.