Angela Lucas-Herald

Understanding the genetic aetiology in patients with XY DSD

BACKGROUND Disorders of sex development (DSD) consist of a wide range of disorders and are commoner in those with an XY karyotype. In over half of these cases who have a 46,XY karyotype and who are raised as boys, the underlying aetiology remains unclear. AREAS OF AGREEMENT Identification of the underlying genetic abnormality may predict long-term outcome. However, genetic abnormalities that are associated with XY DSD manifest themselves with a wide range of phenotype. To understand the aetiology as well as the phenotypic variation, there is a need to harness the advanced genetic technology that is now available. AREAS OF CONTROVERSY The point at which genetic analysis should be undertaken in the course of investigations is unclear. In addition, there is little agreement on the most effective approach for genetic analysis that will be of clinical benefit to the patient. AREAS TIMELY FOR DEVELOPING RESEARCH There is a need to understand and improve the clinical utility of genetic analysis in the clinical setting of the patient with a suspected DSD. This will be even more important when parallel gene sequencing identifies variations in multiple genes.

Prevalence and Characteristics of Rib Fractures in Ex-preterm Infants

OBJECTIVES: This study aimed to identify the prevalence and characteristics of rib fractures in ex-preterm infants. METHODS: Infants born at <37 weeks’ gestation and admitted before 2011 to 3 regional neonatal units were identified from admission registers. For 2 centers, these data were available from 2000 onward and, for another center, from 2005. Electronic records were searched to identify chest radiographs performed up to age 1 year. Chest radiograph reports were then reviewed for evidence of rib fractures, and the case notes of all affected individuals were scrutinized. RESULTS: Of the 3318 eligible preterm infants, 1446 had a total of 9386 chest radiographs. Of these infants, 26 (1.8%) were identified as having a total of 62 rib fractures. Their median (range) gestation at birth was 26 weeks (23–34). The median chronological age of these infants at the time of the radiograph was 14 weeks (5 weeks to 8 months). The median corrected gestational age at the time of the radiograph was 39 weeks (34 weeks to 4 months). Of the 62 fractures, 27 (36%) were sited posteriorly, and 15 (53%) of the infants with posterior rib fractures were diagnosed with osteopathy of prematurity. Classic risk including conjugated hyperbilirubinemia and diuretics, were present in 23 of 26 (88%) infants. A full skeletal survey was performed in 8 of 26 (31%). Investigations for nonaccidental injury occurred in 4 of 26 (15%) cases. CONCLUSIONS: Evidence of rib fractures is present in ∼2% of ex-preterm infants. The evaluation of these fractures in infancy requires a detailed neonatal history irrespective of the site of rib fracture.

A Case of Functional Growth Hormone Deficiency and Early Growth Retardation in a Child With IFT172 Mutations

CONTEXT Ciliopathies are a group of rare conditions that present through a wide range of manifestations. Given the relative common occurrence of defects of the GH/IGF-I axis in children with short stature and growth retardation, the association between ciliopathies and these defects needs further attention. CASE Our patient is a boy who was born at term and noted to have early growth retardation and weight gain within the first 18 months of life. Biochemical tests demonstrated low IGF-I but a normal peak GH on stimulation and an adequate increase in IGF-I on administration of recombinant human growth hormone (rhGH). A magnetic resonance imaging scan revealed pituitary hypoplasia and an ectopic posterior pituitary. His growth responded well to rhGH therapy. Subsequently he also developed a retinopathy of his rods and cones, metaphyseal dysplasia, and hypertension with renal failure requiring renal replacement therapy. Whole-exome sequencing demonstrated compound heterozygous mutations of IFT172, thus consistent with a ciliopathy. CONCLUSIONS This is the first reported case of a child with a mutation in IFT172 who presented with growth retardation in early childhood and was initially managed as a case of functional GH deficiency that responded to rhGH therapy. This case highlights the importance of ciliary function in pituitary development and the link between early onset growth failure and ciliopathies.

Disorders of sex development: advances in genetic diagnosis and challenges in management

Disorders of sex development (DSD) are a group of rare conditions that usually present with atypical genitalia in the newborn period or as delayed puberty in an adolescent. Although a concern about the development of external genitalia may exist in one in 300 newborn infants, discrete genetic conditions that underlie DSD are generally rarely identified. It is likely that this diagnostic gap exists for a number of reasons and these include an inadequate knowl- edge of the pathogenesis and underlying mechanisms that lead to DSD, variation in assessment and in-depth phenotyping of these rare conditions, inadequate availability of quality accredited laboratories and, lastly, limited awareness of the value of a molecular genetic diagnosis for improving short-term and long-term care of the affected person.

Novel heterozygous thyrotropin receptor mutation presenting with neonatal hyperthyrotropinaemia, mild thyroid hypoplasia and absent uptake on radioisotope scan.

Abstract Hyperthyrotropinaemia [mildly elevated thyrotropin (TSH) with normal thyroxine (T4) levels] demands a full assessment, including clinical examination, thyroid imaging and, where indicated, molecular genetic investigations. A male infant, both of whose parents were on T4 treatment, was referred at age 57 days with mild but persistent TSH elevation (12.7 mU/L) and normal free T4 (19.6 pmol/L), following notification by the screening laboratory of a capillary TSH of 10.7 mU/L (reference range, 1.7–9.1 mU/L) on day 8. Assessment showed a venous free T4 level of 15 pmol/L, venous TSH of 20.9 mU/L, serum thyroglobulin of 63 μg/L (reference range, <50 μg/L), and negative thyroglobulin and thyroid peroxidase antibodies. Thyroid ultrasound showed a eutopic, slightly small gland with heterogeneous texture; however, there was no uptake on radioisotope scan. Molecular genetic studies demonstrated a novel missense heterozygous mutation in the TSH receptor (TSHR) gene (c.1169G>T;p.Cys390Phe) in the child, mother and maternal grandmother, but not in the father. The infant was treated with T4 but this was discontinued at age 3 years when repeat testing showed a free T4 of 16.7 pmol/L (reference range, 9–23 pmol/L) and TSH of 8.5 mU/L (reference range, 0.3–5.5 mU/L). A heterozygous TSHR mutation should be considered in the context of hyperthyrotropinaemia and reduced/absent uptake on radioisotope scan. Detection of this mutation has allowed our patient to discontinue T4 treatment for the moment, with a view to staying off treatment in the long-term.

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function.

Prevalence of endocrine and genetic abnormalities in boys evaluated systematically for a disorder of sex development

Abstract STUDY QUESTION What is the likelihood of identifying genetic or endocrine abnormalities in a group of boys with 46, XY who present to a specialist clinic with a suspected disorder of sex development (DSD)? SUMMARY ANSWER An endocrine abnormality of the gonadal axis may be present in a quarter of cases and copy number variants (CNVs) or single gene variants may be present in about half of the cases. WHAT IS KNOWN ALREADY Evaluation of 46, XY DSD requires a combination of endocrine and genetic tests but the prevalence of these abnormalities in a sufficiently large group of boys presenting to one specialist multidisciplinary service is unclear. STUDY, DESIGN, SIZE, DURATION This study was a retrospective review of investigations performed on 122 boys. PARTICIPANTS/MATERIALS, SETTING, METHODS All boys who attended the Glasgow DSD clinic, between 2010 and 2015 were included in the study. The median external masculinization score (EMS) of this group was 9 (range 1–11). Details of phenotype, endocrine and genetic investigations were obtained from case records. MAIN RESULTS AND THE ROLE OF CHANCE An endocrine abnormality of gonadal function was present in 28 (23%) with a median EMS of 8.3 (1–10.5) whilst the median EMS of boys with normal endocrine investigations was 9 (1.5–11) (P = 0.03). Endocrine abnormalities included a disorder of gonadal development in 19 (16%), LH deficiency in 5 (4%) and a disorder of androgen synthesis in 4 (3%) boys. Of 43 cases who had array-comparative genomic hybridization (array-CGH), CNVs were reported in 13 (30%) with a median EMS of 8.5 (1.5–11). Candidate gene analysis using a limited seven-gene panel in 64 boys identified variants in 9 (14%) with a median EMS of 8 (1–9). Of the 21 boys with a genetic abnormality, 11 (52%) had normal endocrine investigations. LIMITATIONS, REASONS FOR CAUTION A selection bias for performing array-CGH in cases with multiple congenital malformations may have led to a high yield of CNVs. It is also possible that the yield of single gene variants may have been higher than reported if the investigators had used a more extended gene panel. WIDER IMPLICATIONS OF THE FINDINGS The lack of a clear association between the extent of under-masculinization and presence of endocrine and genetic abnormalities suggests a role for parallel endocrine and genetic investigations in cases of suspected XY DSD. STUDY FUNDING/COMPETING INTEREST(S) RN was supported by the James Paterson Bursary and the Glasgow Childrens Hospital Charity Summer Scholarship. SFA, RM and EST are supported by a Scottish Executive Health Department grant 74250/1 for the Scottish Genomes Partnership. EST is also supported by MRC/EPSRC Molecular Pathology Node and Wellcome Trust ISSF funding. There are no conflicts of interest. TRIAL REGISTRATION NUMBER None.

The outcome of prenatal identification of sex chromosome abnormalities

Objective The outcome of a pregnancy following identification of a sex chromosome abnormality (SCA) is unclear. The aims of this study were to ascertain the prevalence of SCA detected prenatally in Scotland and to determine the outcomes for these cases. Design Following retrospective identification of all prenatal karyotypes performed in Scotland between 2000 and 2012, data linkage was performed to obtain information regarding maternal characteristics and pregnancy outcomes. Detailed outcome data were also collected for all affected offspring in the West of Scotland and Grampian regions within Scotland. Results Of the 28 145 pregnancies that had a karyotype over the study period, records were available for 27 152 (96%). Karyotype abnormalities were identified in 2139 (8%), with SCA being identified in 321(1%) tests. 45,X was identified as the commonest SCA in 135 pregnancies. Of 121 pregnancies with SCA in the West of Scotland and Grampian, 64 (53%), 52 (43%) and 5 (4%) led to a live birth, termination and intrauterine death, respectively. Of the 64 live births, 21 (33%) had a postnatal karyotype and 35 (54%) received specialist follow-up for the SCA that was identified prenatally. Conclusions Abnormalities of sex chromosomes are identified in approximately 1% of all pregnancies that undergo a prenatal karyotype. There is a need to review the prenatal as well as postnatal care of the affected mother and offspring.

Metformin with insulin does not improve the glycaemic control of overweight/obese adolescents with type 1 diabetes

Design: Placebo-controlled randomised controlled trial. Allocation: Via computer generated sequence. Blinding: Double-blind. Setting: 26 paediatric endocrinology clinics in the Type 1 Diabetes Exchange Clinic Network between 2013 and 2014. Patients: 140 adolescents aged between 12.1 and 19.6 years (mean (SD) 15.3 (1.7)) with type 1 diabetes for >1 year and a body mass index >85th centile for age, total daily insulin dose >0.8 units/kg and three times daily self-monitoring of blood glucose. Intervention : 2000 mg daily dose metformin compared with placebo. Outcomes : Primary outcome: change in haemoglobin A1c (HbA1c) from baseline to 26 weeks. Prespecified secondary outcomes: total daily dose (TDD) insulin per kg body weight, total basal insulin per kg body weight, anthropometry, blood pressure, metabolic profile. Follow-up period …

Review of growth hormone therapy in adolescents and young adults with Prader–Willi syndrome

Consensus guidelines from the Growth Hormone Research Society Workshop recommend growth hormone therapy in all children with genetically confirmed Prader–Willi syndrome (PWS) in combination with dietary, lifestyle and environmental interventions. As yet, however, there are limited published data regarding the use of growth hormone therapy in adolescents and young adults with PWS. This review focuses on the advantages and disadvantages of growth hormone therapy in this particular group. The risk of complications, challenges with consent for therapy, the need for contraception in females with PWS and the appropriate monitoring required are all factors which must be carefully considered in this challenging patient group. Transition from paediatric to adult services can be difficult for most adolescents, but especially so for PWS adolescents and should be undertaken under the care of experienced paediatric and adult endocrinologists and a multidisciplinary team approach. Further research is, however, still required in the management of PWS patients during adolescence.