Helen L. Storr

Paediatric Cushing's syndrome: epidemiology, investigation and therapeutic advances

Cushings syndrome (CS), which is caused by excessive circulating glucocorticoid concentrations, is rare in the paediatric age range but presents a diagnostic and therapeutic challenge. Most paediatric endocrinologists have limited experience of managing children or adolescents with CS and thus benefit from close consultation with colleagues who treat adult patients. A protocol for investigation is required that broadly follows the model for adult patients. Here, the epidemiology and diagnosis of different causes of CS are discussed according to typical age of presentation. Treatment strategies for adrenocorticotrophic hormone (ACTH)-independent and ACTH-dependent CS are described and critically appraised. The management of paediatric CS patients after cure also presents challenges for optimizing growth, bone health, reproduction and body composition from childhood into and during adult life.

Cushing's Disease in Children and Adolescents: 20 Years of Experience in a Single Neurosurgical Center

OBJECTIVE:This is a retrospective analysis of 25 consecutive pediatric patients with Cushings disease who underwent transsphenoidal surgery performed by a single neurosurgeon in a specialist center during a 20-year period. This article discusses the presentation of Cushings disease, the endocrinological investigation with particular reference to bilateral inferior petrosal sinus sampling (BIPSS), the operative management with reference to specific pediatric difficulties of the transsphenoidal approach and the use of intraoperative image guidance, and the analysis of these cases as regards postoperative complications and outcomes of this rare condition in young patients. METHODS:All patients underwent detailed endocrine investigation and imaging in the form of computed tomography and/or magnetic resonance imaging. BIPSS was performed in 19 patients (76%), with successful lateralization of the side of the microadenoma in 14 (74%) and prediction of a central tumor in four (94% total prediction rate). Surgical removal was via the sublabial, paraseptal, transsphenoidal route. RESULTS:There were 15 male and 10 female patients, with a mean age of 13.4 years (range, 6.6–17.8 yr). Weight gain was the most common presentation (100%), and then growth impairment (96%), fatigue and skin changes (64%), and hypertension (32%). Postoperative complications included growth hormone deficiency (36%), transient diabetes insipidus (12%), panhypopituitarism (4%), and transient cerebrospinal fluid rhinorrhea (4%). The median follow-up period was 59.5 months (range, 6–126 mo). Overall, 15 patients (60%) achieved surgical cure or remission, of which 14 outcomes were obtained using the results of BIPSS. Ten patients (40%) required postoperative radiotherapy to achieve “remission.” There were no cases of meningitis, no neurological deficits, no reoperations, and no mortality. CONCLUSION:Cushings disease in children and adolescents is a rare illness. The accurate preoperative localization of the adenoma is essential for achieving good results. In this series, BIPSS was far more accurate in localizing the adenoma than computed tomography or magnetic resonance imaging. Imaging, however, is useful for the exclusion of other intracranial problems. Transsphenoidal surgery was safe and efficacious in achieving cure in the majority of cases. The challenge of transsphenoidal surgery in this age group is the small pituitary fossa and the absence of sphenoid sinus aeration in some cases. We found the use of intraoperative neuronavigation to be an excellent aid in overcoming such anatomic difficulties.

Final adult height and body mass index after cure of paediatric Cushing's disease

Objective  Linear growth data after cure of paediatric Cushings disease (CD) have been reported infrequently. We evaluated final adult height (FH) and body mass index (BMI) in a cohort of paediatric patients treated successfully for CD.

Thioredoxin Reductase 2 (TXNRD2) Mutation Associated With Familial Glucocorticoid Deficiency (FGD)

Context: Classic ACTH resistance, due to disruption of ACTH signaling, accounts for the majority of cases of familial glucocorticoid deficiency (FGD). Recently FGD cases caused by mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase, have highlighted the importance of redox regulation in steroidogenesis. Objective: We hypothesized that other components of mitochondrial antioxidant systems would be good candidates in the etiology of FGD. Design: Whole-exome sequencing was performed on three related patients, and segregation of putative causal variants confirmed by Sanger sequencing of all family members. A TXNRD2-knockdown H295R cell line was created to investigate redox homeostasis. Setting: The study was conducted on patients from three pediatric centers in the United Kingdom. Patients: Seven individuals from a consanguineous Kashmiri kindred, six of whom presented with FGD between 0.1 and 10.8 years, participated in the study. Interventions: There were no interventions. Main Outcome Measure: Identification and functional interrogation of a novel homozygous mutation segregating with the disease trait were measured. Results: A stop gain mutation, p.Y447X in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 (TXNRD2) was identified and segregated with disease in this extended kindred. RT-PCR and Western blotting revealed complete absence of TXNRD2 in patients homozygous for the mutation. TXNRD2 deficiency leads to impaired redox homeostasis in a human adrenocortical cell line. Conclusion: In contrast to the Txnrd2-knockout mouse model, in which embryonic lethality as a consequence of hematopoietic and cardiac defects is described, absence of TXNRD2 in humans leads to glucocorticoid deficiency. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans.

Familial pituitary adenomas – who should be tested for AIP mutations?

Familial Isolated Pituitary Adenomas (FIPA), an autosomal dominant disease with low penetrance is being increasingly recognized. FIPA families can be divided into two distinct groups based on genetic and phenotypic features. Patients with mutations in the aryl hydrocarbon receptor‐interacting protein (AIP) gene are characterized by young‐onset somatotroph or lactotroph macroadenomas, while in the other, larger group of FIPA patients with typically adult‐onset disease and more varied adenoma types, no causative gene(s) has been identified. Young‐onset macroadenoma patients can also be identified with germline AIP mutation without an apparent family history. Further data and longer follow‐up are necessary to establish formal guidelines, but the current data suggest genetic screening of the AIP gene in patients with a pituitary adenoma and no other associated features who have (i) a family history of pituitary adenoma, (ii) childhood‐onset pituitary adenoma or (iii) a pituitary somatotroph or lactotroph macroadenoma diagnosed before the age of 30 years.

COMPARISONS IN THE EPIDEMIOLOGY, DIAGNOSTIC FEATURES AND CURE RATE BY TRANSSPHENOIDAL SURGERY BETWEEN PAEDIATRIC AND ADULT-ONSET CUSHING'S DISEASE

OBJECTIVE There are few published comparisons between paediatric and adult-onset Cushings disease (CD). We compare the epidemiology, diagnostic features and cure rate by transsphenoidal surgery (TSS) in these groups. DESIGN Retrospective review of patient databases in a single university hospital centre. PATIENTS Totally, 41 paediatric (mean age 12.3 ± 3.5 years; range 5.7-17.8) and 183 adult (mean age 40 ± 13 years; range 18.0-95.0) patients with CD were investigated. RESULTS Paediatric CD was characterised by male (63%) and adult CD by a female predominance (79%, P<0.0001). There were small but significant differences in clinical presentation. Biochemical features of CD were comparable except the serum cortisol increase during a CRH test: mean change (105%, n=39) in paediatric and (54%, n=123) in adult subjects (P<0.0001). Macroadenomas were more common in adult (15%, 28/183) than in paediatric (2%, 1/41, P=0.04) CD. Corticotroph microadenomas were more easily visualised by pituitary magnetic resonance imaging (MRI) in adult (76%, 50/66) compared with paediatric (55%, 21/38, P=0.045) CD with poorer concordance of imaging with surgical findings in children (P=0.058). The incidence of ACTH lateralisation by bilateral simultaneous inferior petrosal sinus sampling was comparable in paediatric (76%, 25/33) and adult (79%, 46/58; P=0.95) patients with good surgical concordance in both (82% paediatric and 79% adult). Cure rates by TSS were comparable, with a paediatric cure rate of 69%. CONCLUSION Several features of paediatric CD are distinct: increased frequency of prepubertal CD in males, the different clinical presentation, the decreased presence of macroadenomas and the frequent absence of radiological evidence of an adenoma on MRI.

Clinical features, diagnosis, treatment and molecular studies in paediatric Cushing's syndrome due to primary nodular adrenocortical hyperplasia

background  Primary nodular adrenocortical hyperplasia (PNAH) is a well recognized, but infrequently studied cause of paediatric Cushings syndrome (CS).

Long-term anterior pituitary function in patients with paediatric Cushing’s disease treated with pituitary radiotherapy

BACKGROUND/OBJECTIVE Pituitary radiotherapy (RT) is an effective second-line treatment for paediatric Cushings disease (CD). Although the short-term effects of pituitary RT are well documented, there are less data on possible long-term sequelae. We report the long-term anterior pituitary function in a cohort of paediatric CD patients treated with pituitary RT. PATIENTS AND METHODS Between 1983 and 2006, 12 paediatric CD patients (10 males and 2 females) of mean age 11.4 years at diagnosis (range 6.4-17.4) underwent second-line pituitary RT (45 Gy in 25 fractions), following unsuccessful transsphenoidal surgery. Out of 12, 11 patients were cured by RT (cure interval 0.13-2.86 years) defined by mean serum cortisol of <150 nmol/l on 5-point day curve and midnight sleeping cortisol of <50 nmol/l. Long-term data are available for six male patients, who received RT at the age of 7.0-17.6 years. The mean follow-up from the completion of RT was 10.5 years (6.6-16.5). RESULTS At a mean of 1.0 year (0.11-2.54) following RT, GH deficiency (peak GH <1-17.9 mU/l) was present in five out of six patients. On retesting at a mean of 9.3 years (7.6-11.3) after RT, three out of four patients were GH sufficient (peak GH 19.2-50.4 mU/l). Other anterior pituitary functions including serum prolactin in five out of six patients were normal on follow-up. All the six patients had testicular volumes of 20-25 ml at the age of 14.5-28.5 years. CONCLUSION This series of patients illustrates the absence of serious long-term pituitary deficiency after RT and emphasises the importance of continued surveillance.

Abnormal puberty in paediatric Cushing's disease: relationship with adrenal androgen, sex hormone binding globulin and gonadotrophin concentrations

Objective  Paediatric Cushings disease is frequently associated with abnormal puberty. We addressed the hypothesis that prepubertal patients show excessive virilization and pubertal patients show suppression of LH and FSH secretion.

Bone mineral density at diagnosis and following successful treatment of pediatric Cushing’s disease

Bone mineral density (BMD) is frequently reduced in children and adolescents with Cushing’s disease (CD), but there is little follow-up data after cure. BMD was determined by dual energy X-ray absorptiometry (DEXA) in two groups of patients with CD. Group 1 comprised 8 patients, 5 males and 3 females, aged 12.4 yr (8.2–16.8), assessed at diagnosis. Group 2 comprised 11 subjects, 6 males and 5 females, diagnosed at age 13.3 yr (6.4–17.4), cured by transsphenoidal surgery (TSS) (no.=7) or TSS + pituitary irradiation (no.=4). They had measurement of BMD, at mean age of 18.3 yr (11.1–28.5), i.e. 4.5 yr (0.8–11.4) after cure. Four patients, mean age 20.2 yr (17.6–22.4), had repeated DEXAscans, 1–4 times, for up to 5.8 yr. After cure, GH deficiency was present in 9 patients and treated with hGH in 8. In Group 1, patients’ L2–L4 volumetric (v)BMD Z-score was variable with a mean of −1.04 (−3.21–0.11). L2–L4 vBMD Z-score values correlated negatively with midnight cortisol (p<0.05). In Group 2, mean L2–L4 vBMD was −0.38 (−1.0–0.13); and in 7/11, mean femoral neck (FN) areal (a)BMD Z-score was 0.14 (−1.62–2.46). FN aBMD Z-score was higher than L2–L4 aBMD Z-score (p<0.05). In patients with repeated scans, mean change in L2–L4 vBMD Z-score was 0.20 (−0.15–0.45), and mean change in FN aBMD Z-score 0.03 (−0.53–0.38). These findings show variability of BMD at diagnosis and near normal BMD after cure of pediatric CD, suggesting that with appropriate replacement of pituitary hormone deficiency normal peak bone mass is achievable.