Optimizing paediatric specialist referrals for short stature in an era of multiple growth hormone indications.

The assessment of growth during infancy and childhood is an essential component of paediatric medicine, as atypical growth may point to the existence of an underlying health condition. To reduce morbidity, it is vital that treatment for growth disorders is provided in a timely fashion. However, although there are guidelines regarding referral criteria for short stature in Europe and the USA, there are no such guidelines in Canada. To address this, a series of consultations and workshops with paediatricians, paediatric endocrinologists, family physicians and nurses were held, with the aim of developing a consensus-based set of recommendations for children in Canada showing atypical growth and to identify red flags for children who might benefit from early referral. To achieve this, a referral algorithm and referral form for primary care providers were developed to ensure timely and appropriate referrals, and transmission of the most relevant details to the secondary care consultant.

Cardiac MRI evaluation of aortic biophysical properties in paediatric Turner syndrome.

BACKGROUND: Aortopathy in Turner syndrome is associated with aortic dilation, and the risk of dissection is increased when the aortic size index is ≥ 2-2.5 cm/m2. We evaluated the aortic biophysical properties in paediatric Turner syndrome using cardiac MRI to determine their relationship to aortic size index. METHODS: Turner syndrome patients underwent cardiac MRI to evaluate ventricular function, aortic dimensions, and biophysical properties (aortic stiffness index, compliance, distensibility, pulse wave velocity, and aortic and left ventricular elastance). Spearman correlation examined correlations between these properties and aortic size index. Data was compared to 10 controls. RESULTS: Of 25 Turner syndrome patients, median age 14.7 years (interquartile range: 11.0-16.8), height z score -2.7 (interquartile range: -2.92 - -1.54), 24% had a bicuspid aortic valve. Turner syndrome had increased diastolic blood pressure (p < 0.001) and decreased left ventricular end-diastolic (p < 0.001) and end-systolic (p = 0.002) volumes compared to controls. Median aortic size index was 1.81 cm/m2 (interquartile range: 1.45-2.1) and 7 had an aortic size index > 2 cm/m2. Aortic and left ventricular elastance were greater in Turner syndrome compared to controls (both p < 0.001). Increased aortic size index correlated with increased aortic elastance (r = 0.5, p = 0.01) and left ventricular elastance (r = 0.59, p = 0.002) but not aortic compliance. Higher ascending aortic areas were associated with increased aortic compliance (r = 0.44, p = 0.03) and left ventricular elastance (r = 0.49, p = 0.01). CONCLUSION: Paediatric Turner syndrome with similar aortic size index to controls showed MRI evidence of abnormal aortic biophysical properties. These findings point to an underlying aortopathy and provide additional parameters that may aid in determining risk factors for aortic dissection.

Cardiac Magnetic Resonance Imaging in Pediatric Turner Syndrome.

OBJECTIVE: To compare the detection of cardiac lesions with the use of cardiac magnetic resonance imaging (CMR) and conventional echocardiography in children with Turner syndrome. STUDY DESIGN: Twenty-four girls with Turner syndrome, 8-18 years of age, were recruited through the Pediatric Endocrinology Program. Participants underwent CMR and echocardiography within a 2-year period, and discrepancies between the results of each modality were identified. RESULTS: Fifteen of 24 (63%) girls had a cardiac lesion identified on CMR or echocardiography. Both modalities identified the same lesion in 10 of 15 (67%); however, 6 of 15 (40%) participants had a lesion identified on CMR but not echocardiography. Participants with a missed lesion had a trend towards greater body mass index. Aortic dilation and bicuspid aortic valve were the most commonly missed lesions by echocardiography. CONCLUSIONS: CMR identifies significant cardiac lesions missed by echocardiography in pediatric patients with Turner syndrome, particularly along the aorta. These findings support the current guidelines that recommend screening CMR in addition to echocardiogram. Early identification of cardiac abnormalities in patients with Turner syndrome will allow for a greater understanding of the natural history in these patients and potentially identify candidates for earlier intervention.

Neonatal diabetes and protein losing enteropathy: a case report.

BACKGROUND: Neonatal diabetes is a rare form of monogenic diabetes with onset in the first six months of life occurring in 1/100,000 to 1/400,000 births. Both permanent and transient forms have been described. Permanent neonatal diabetes results predominantly from mutations in the KCNJ11 and ABCC8 genes. Less frequently, mutations of the GATA6 gene, located on chromosome 18 cause a form of permanent neonatal diabetes resulting from pancreatic hypoplasia or agenesis. Other anomalies associated with mutations of this gene have also been reported, most commonly congenital heart disease. CASE PRESENTATION: We report the case of a Caucasian male infant diagnosed shortly after birth with neonatal diabetes, truncus arteriosus type III, ventricular septal defect, atrial septal defect, an absent gallbladder and a right inguinal hernia. His diabetes resulted from a de novo mutation of the GATA6 gene resulting in pancreatic hypoplasia. At 20 months of age he developed protein losing enteropathy. This has not previously been associated with GATA6 mutations and it is not known if this association is causal. CONCLUSION: The combination of neonatal diabetes and pancreatic agenesis/hypoplasia should alert the clinician to the possibility of a GATA6 gene abnormality. The association of protein losing enteropathy is unique to the reported case.

Large-scale prospective T cell function assays in shipped, unfrozen blood samples: experiences from the multicenter TRIGR trial.

Broad consensus assigns T lymphocytes fundamental roles in inflammatory, infectious, and autoimmune diseases. However, clinical investigations have lacked fully characterized and validated procedures, equivalent to those of widely practiced biochemical tests with established clinical roles, for measuring core T cell functions. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) type 1 diabetes prevention trial used consecutive measurements of T cell proliferative responses in prospectively collected fresh heparinized blood samples shipped by courier within North America. In this article, we report on the quality control implications of this simple and pragmatic shipping practice and the interpretation of positive- and negative-control analytes in our assay. We used polyclonal and postvaccination responses in 4,919 samples to analyze the development of T cell immunocompetence. We have found that the vast majority of the samples were viable up to 3 days from the blood draw, yet meaningful responses were found in a proportion of those with longer travel times. Furthermore, the shipping time of uncooled samples significantly decreased both the viabilities of the samples and the unstimulated cell counts in the viable samples. Also, subject age was significantly associated with the number of unstimulated cells and T cell proliferation to positive activators. Finally, we observed a pattern of statistically significant increases in T cell responses to tetanus toxin around the timing of infant vaccinations. This assay platform and shipping protocol satisfy the criteria for robust and reproducible long-term measurements of human T cell function, comparable to those of established blood biochemical tests. We present a stable technology for prospective disease-relevant T cell analysis in immunological diseases, vaccination medicine, and measurement of herd immunity.

A previously undescribed mutation detected by sequence analysis of CYP21A2 gene in an infant with salt wasting congenital adrenal hyperplasia.

The Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http:www.imm.Ki.se/CYPalleles/cyp21.htm) has created a CYP21A2 database which include a list of all reported CYP21A2 mutations and the last update of this database was in 2006. The most up to date list of the CYP21A2 mutations reported over the last four years was published in a recent article by Concolino et al. We report a previously undescribed mutation detected by sequence analysis of CYP21A2 gene in an infant resulting in salt wasting congenital adrenal hyperplasia.

Turner Syndrome and apparent absent uterus: a case report and review of the literature.

We report on a patient who initially presented with delayed puberty and an absent uterus on imaging with ultrasound and MRI. She was subsequently diagnosed with Turner Syndrome. Turner Syndrome typically presents with early loss of ovarian function and should be considered when primary ovarian insufficiency is present with apparent absent uterus on imaging. Follow-up imaging of the apparent absent uterus post-estrogen replacement therapy is important to confirm a normal uterus. A diagnosis of an absent uterus can be psychologically traumatic for patients and families, and can have significant implications for future fertility options.

Postnatal virilization mimicking 21-hydroxylase deficiency in 3 very premature infants.

Premature infants are known to have elevated 17-hydroxyprogesterone and adrenal androgen concentrations immediately after birth, but the levels decrease rapidly. Virilization of normal premature female infants as a result of these high androgens has not been described. Three premature female infants born at 24 to 25 weeks' gestation, with birth weights 550 to 880 g and significant neonatal complications were noted to develop clitoromegaly 2 weeks to 3 months after birth. All 3 had elevated 17-hydroxyprogesterone >100 nmol/L and testosterone >3 nmol/L concentrations. All were treated as simple virilizing 21-hydroxylase deficiency, but subsequent genetic analysis revealed no CYP21 mutations. Follow-up after discontinuation of treatment revealed no recurrent virilization and normal adrenal steroid levels. Postnatal virilization in sick premature girls may occur, and investigations may suggest 21-hydroxylase deficiency. Genetic analysis of CYP21 should be performed before the diagnosis is confirmed. Further studies are needed to better document the natural history and possible causes of postnatal adrenal androgen secretion in sick premature infants.

Growth hormone (GH) insensitivity and insulin-like growth factor-I deficiency in Inuit subjects and an Ecuadorian cohort: functional studies of two codon 180 GH receptor gene mutations.

CONTEXT: Among more than 250 cases of GH insensitivity syndrome (GHIS) reported to date, the largest cohort was identified in southern Ecuador. In the Ecuadorian GHIS cohort, a sense mutation (GAA>GAG) at codon E180 of GH receptor [GHR (E180sp)] results in deletion of codons 181-188. No functional studies of this mutation have been performed, nor have different mutations at codon 180 been reported. OBJECTIVE: We now report identification of a novel GHR mutation, also within codon E180, in two distantly related GHIS subjects of Inuit origin and provide mechanistic insights into the defects caused by the Inuit and Ecuadorian GHR mutations. PATIENTS: The two Inuit subjects, with heights of -5 sd score and -7 sd score, respectively, had elevated circulating levels of GH but low levels of GH-binding protein, IGF-I, and IGF-binding protein-3. RESULTS: Both Inuit subjects carry the same novel nonsense homozygous GHR mutation at codon E180 (GAA->TAA, E180X). In vitro reconstitution experiments demonstrated that GHR (E180sp), but not GHR (E180X), could be stably expressed. GHR (E180sp), however, could not bind GH and could neither activate signal transducer and activator of transcription-5b nor induce -5b-dependent gene expression on GH treatment. Furthermore, the GHR (E180sp), which has a deletion of eight amino acid residues within the GHR dimerization domain, although retaining the ability to homodimerize, was defective in trafficking to the cell surface. CONCLUSIONS: The E180X mutation identified in two Inuit patients resulted in a truncated, unstably expressed GHR variant, whereas the E180 splicing mutation previously identified in the Ecuadorian cohort, affected both GH binding and GHR trafficking and rendered the abnormal GHR nonfunctional.

Testicular mixed germ cell tumor in an adolescent with cowden disease.

Cowden disease (also known as Cowden syndrome) is characterized by multiple organ hamartomatous tumors and an increased risk of malignancy, in particular of the breast, thyroid and endometrium. Testicular tumors including seminoma have previously been reported in adult patients. We are reporting, for the first time, a case of testicular mixed germ cell tumor in an adolescent with Cowden disease. An association of testicular malignancy in Cowden disease could be explained by the previous observation of strong PTEN gene expression in the basal cell layer around seminiferous tubules and increased frequency of PTEN mutations in cultured testicular cancer cell lines. Surveillance for breast, thyroid, endometrial and renal cancer has been recommended for individuals with Cowden disease. The association of Cowden disease and testicular malignancy in our case suggests the need for additional screening of testes.