Noina Abid

Clinical and metabolic effects of gluten free diet in children with type 1 diabetes and coeliac disease

Abid N, McGlone O, Cardwell C, McCallion W, Carson D. Clinical and metabolic effects of gluten free diet in children with type 1 diabetes and coeliac disease.

Clinical Experience in the Screening and Management of a Large Kindred With Familial Isolated Pituitary Adenoma Due to an Aryl Hydrocarbon Receptor Interacting Protein (AIP) Mutation

CONTEXT Germline AIP mutations usually cause young-onset acromegaly with low penetrance in a subset of familial isolated pituitary adenoma families. We describe our experience with a large family with R304* AIP mutation and discuss some of the diagnostic dilemmas and management issues. OBJECTIVE The aim of the study was to identify and screen mutation carriers in the family. PATIENTS Forty-three family members participated in the study. SETTING The study was performed in university hospitals. OUTCOME We conducted genetic and endocrine screening of family members. RESULTS We identified 18 carriers of the R304* mutation, three family members with an AIP-variant A299V, and two family members who harbored both changes. One of the two index cases presented with gigantism and pituitary apoplexy, the other presented with young-onset acromegaly, and both had surgery and radiotherapy. After genetic and clinical screening of the family, two R304* carriers were diagnosed with acromegaly. They underwent transsphenoidal surgery after a short period of somatostatin analog treatment. One of these two patients is in remission; the other achieved successful pregnancy despite suboptimal control of acromegaly. One of the A299V carrier family members was previously diagnosed with a microprolactinoma; we consider this case to be a phenocopy. Height of the unaffected R304* carrier family members is not different compared to noncarrier relatives. CONCLUSIONS Families with AIP mutations present particular problems such as the occurrence of large invasive tumors, poor response to medical treatment, difficulties with fertility and management of pregnancy, and the finding of AIP sequence variants of unknown significance. Because disease mostly develops at a younger age and penetrance is low, the timing and duration of the follow-up of carriers without overt disease requires further study. The psychological and financial impact of prolonged clinical screening must be considered. Excellent relationships between the family, endocrinologists, and geneticists are essential, and ideally these families should be managed in centers with specialist expertise.

Diagnostic value of exome and whole genome sequencing in craniosynostosis

Background Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ∼1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. Methods We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative. Results We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). Conclusions This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results.

Increased Population Risk of AIP-related Acromegaly and Gigantism in Ireland.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304*; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027–0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011–0.0047) and zero in ROI (0–0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non‐Irish patients (0–2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275–5,000) years. tMRCA‐based simulations predicted 432 (90–5,175) current carriers, including 86 affected (18–1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP‐related disease.

Mortality in type 1 diabetes diagnosed in childhood in Northern Ireland during 1989-2012: A population-based cohort study

To investigate long‐term mortality rates and causes of death in individuals diagnosed with type 1 diabetes before the age of 15 years during the period 1989‐2012 or known to paediatric diabetes teams in 1989, in Northern Ireland.

The need for preoperative α-adrenergic blockade for ganglioneuroma excision

ting position, arms rested on a table. When she reported fullness in her back and easing of pressure behind her eyes, further injection of blood in the epidural space was stopped. After the blood patch, she reported that her double vision resolved completely in standing position and she was discharged home without any complications. Abducens nerve, which has a long intracranial course, is often stretched with caudal sagging of brain structures due to intracranial hypotension. Prolonged stretching of abducent nerve can result in ischemia, palsy, and persistent diplopia despite correction of intracranial hypotension. Although adult literature reports that epidural blood patch consistently fails to relieve diplopia when performed more than 1 day after the onset of sixth cranial nerve palsy (2), we report an adolescent who developed diplopia for 3 days without positional headache following multiple lumbar punctures, having complete resolution of diplopia immediately after epidural blood patch. Clinicians need to be aware of atypical symptoms of intracranial hypotension such as positional diplopia in the absence of spinal headache following intentional (e.g. diagnostic lumbar punctures) or accidental (e.g. epidural catheter placement) dural punctures as these procedures are frequently carried out in children and adolescents. In children, lumbar epidural blood patches might be useful in relieving diplopia following intracranial hypotension due to CSF leak following dural punctures. Learning points

A novel IGSF1 mutation in a large Irish kindred highlights the need for familial screening in the IGSF1 deficiency syndrome

Loss‐of‐function mutations in IGSF1 result in X‐linked central congenital hypothyroidism (CeCH), occurring in isolation or associated with additional pituitary hormone deficits. Intrafamilial penetrance is highly variable and a minority of heterozygous females are also affected. We identified and characterized a novel IGSF1 mutation and investigated its associated phenotypes in a large Irish kindred.

Thermal dysregulation in Prader-Willi syndrome: a potentially fatal complication in adolescence, not just in infancy

A 13-year-old boy with a background of Prader-Willi syndrome (PWS) was admitted to the regional paediatric intensive care unit, with community-acquired pneumonia. Despite a week of intravenous antibiotics, resolution of inflammatory markers and resolving consolidation on radiograph, he remained feverish. Fever of unknown origin investigations were negative and he was diagnosed with central thermal dysregulation secondary to hypothalamic dysfunction in PWS. Following a hyperpyrexia period, secondary rhabdomyolysis and renal failure developed. This was successfully managed with active cooling, ventilation and haemofiltration. After weaning from haemofiltration, the patient was successfully extubated to non-invasive respiratory support.

G104(P) Audit of Endocrine Late Effects in Survivors of Childhood Brain Tumours

Brain tumours are the most common solid tumour in children, affecting 400 children in the UK each year. The aggressive treatment required for cure, may have serious consequences, of which endocrine late effects are the most prevalent. This aim of this audit is to ascertain the frequency and nature of endocrine late effects; in a cohort of 30 survivors, diagnosed over a fourteen year period. Data was collected on tumour site, histology, treatments used & endocrine complications. 70% of children underwent surgery, 87% received chemotherapy, 40% received cranial radiotherapy, 23% received craniospinal radiotherapy and 16% children received both cranial and craniospinal radiotherapy. 36% of survivors were diagnosed with growth hormone deficiency (all of these children had received radiotherapy). Impaired spinal growth was seen in all children who had received craniospinal radiotherapy, exacerbating short stature. 23% of children were found to have a suboptimal cortisol response; necessitating emergency hydrocortisone treatment. 20% of survivors developed hypothyroidism. Onset of hypothyroidism ranged from 1 to 5 years following treatment. 11% of survivors were diagnosed with precocious puberty; which in 1 case had masked a growth hormone deficiency. In conclusion, this audit confirms the high prevalence of endocrine late effects in survivors of childhood brain tumours. Growth hormone deficiency was the most common, however there was a high percentage of multiple hormone deficiencies. Data support the establishment of a joint oncology and endocrinology late effects clinic; to ensure early identification and treatment of these serious complications.