Kate Davies

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.

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.

Linear growth and body mass index in pediatric patients with Cushing's disease or simple obesity.

Background: Increasing prevalence of childhood obesity has resulted in an accelerating rate of referrals of overweight patients to pediatric clinics for exclusion of endocrine or metabolic etiologies. The exclusion of Cushing’s disease (CD) requires complex and potentially invasive investigations. Objective: to evaluate the sensitivity of accurate measurements of height, weight and body mass index (BMI) in discriminating between simple obesity and CD. Methods and patients: Height, weight and BMI were measured at diagnosis in 25 patients with CD; 14 males, 11 females, mean age 12.9 yr (6.4–17.8) and 41 patients with simple obesity (SO), defined as BMI >2.0 SD; 20 males, 21 females, mean age 9.4 yr (3.5–15.6). Results: Mean (±SE) BMI SDS in the CD patients was 2.41±0.5 and in the SO patients 3.71±1.3. Height SDS in the CD patients was −1.88±0.24 and in the SO patients 1.18±0.19 (p<0.05). The mean (±SE) BMI SDS to height SDS ratio was significantly decreased in the CD compared with the SO patients; −1.81±0.54 vs +0.90±1.17 (p<0.0001). Conclusions: Simple, accurate measurement of height and BMI SDS values provides a quick, and sensitive diagnostic discriminator in pediatric patients with CD or SO, thus potentially avoiding complex investigations.

Factors influencing skeletal maturation at diagnosis of paediatric cushing's disease

Background/Aims: Growth retardation is a recognised complication of paediatric Cushing’s disease (CD), but there are few published data on skeletal maturation at diagnosis. We assessed factors contributing to skeletal maturation in patients with paediatric CD. Patients/Methods: 17 patients, 12 males, 5 females (median age 12.1 years, range 5.8–17.4) were studied. The bone age (BA) of each child was determined by a single observer using the TW3 RUS method. BA delay, i.e. the difference between chronological age (CA) and BA, was compared with clinical and biochemical variables. Results: BA delay was present in 15/17 patients (mean delay 2.0 years, range –0.5 to 4.1 years) and correlated negatively with height SDS (r = –0.70, p < 0.01) and positively with duration of symptoms (r = 0.48, p = 0.05) and CA (r = 0.48, p = 0.05). No relationships were found with midnight cortisol, ACTH, DHEA-S or cortisol suppression during the low-dose dexamethasone suppression test. Conclusions: BA in most children with CD was delayed and related to length of symptoms and height SDS at diagnosis. Early diagnosis will reduce delay in skeletal maturation and thus contribute to optimal catch-up growth.

WHOLE EXOME SEQUENCING GIVES ADDITIONAL BENEFITS COMPARED TO CANDIDATE GENE SEQUENCING IN THE MOLECULAR DIAGNOSIS OF CHILDREN WITH GROWTH HORMONE OR IGF-1 INSENSITIVITY

BACKGROUND GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown. OBJECTIVE To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect. METHODS We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS. RESULTS A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver-Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in FANCA and PHKB in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect. CONCLUSIONS Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres.

Disorders of Sex Development–Ambiguous Genitalia

Disorders of sex development (DSD) encompass a wide range of congenital conditions with diverse features and pathophysiology, which usually present in the newborn period or during adolescence (Ahmed et al., 2015), where the development of chromosomal, gonadal or anatomic sex is atypical (Rothkopf & John, 2014). Ambiguous genitalia is a term to describe how a babys genitals look different than the genitals of most other boys and girls (Achermann, Eugster, & Shulman, 2011). It may mean that parents and healthcare professionals may not be able to correctly identify the sex of the baby. In some cases, it may be that a girls clitoris is so enlarged that it may look like a small penis, or the labia may be so fused together that it looks like a boys scrotum. It has been estimated that in around 1 in every 4500 live births, babies have genitalia that is ambiguous enough to not be able to assign a sex immediately (Michala, Liao, Wood, Conway, & Creighton, 2014), but some types of genital abnormalities may occur in as many as 1 in every 300 births (Rothkopf & John, 2014). True cases of absolute ambiguous genitalia are rare, but it is likely that the pediatric nurse will come across a case in their career.