Bone biochemistry in children with fractures presenting with non-accidental injury.

BACKGROUND: In cases of fractures in children with suspicion of non-accidental injury (NAI), biochemical markers of calcium homeostasis should be performed. OBJECTIVES: To describe the pattern of biochemistry in children with fractures NAI is suspected. PARTICIPANTS AND SETTING: Children ≤2 years of age who had undergone a skeletal survey as part of a child protection investigation where 1/+ fracture was identified over a ten-year period (2012-2021) at the Royal Hospital for Children, Glasgow. METHODS: A retrospective review of case notes was conducted. Established criteria to classify NAI were used to distinguish confirmed NAI from non-NAI. Biochemical markers of calcium homeostasis were classified as normal or abnormal using local reference ranges. Vitamin D deficiency was classified as Vitamin D < 25 nmol/L and insufficiency as 25-50 nmol/L. RESULTS: One hundred and twenty-seven children were identified, of whom 107 (84 %) had bone biochemistry performed. Twenty-nine children (24 %) had injuries that were classified as confirmed NAI. In cases where NAI was confirmed either at case conference or by criminal conviction 14/29 (48 %) had one or more abnormal bone biochemical markers. None of the children displayed clinical or radiological evidence of rickets. Alkaline phosphatase (ALP) was higher in children with confirmed NAI (median 296 vs. 261, p = 0.01) but there were no other statistically significant differences in biochemical levels between those with confirmed NAI compared to those without. Those with confirmed NAI were from areas with lower SIMD score (2.0 vs. 3.0 p = 0.01) but no other differences were found between the groups. CONCLUSION: No clear predictors of NAI are demonstrated on biochemistry alone in young children with fractures.

Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing.

NHS genetics centres in Scotland sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. Genome sequencing was performed at Edinburgh Genomics, and phenotype and sequence data were transferred to Genomics England for variant calling, gene-based filtering and variant prioritisation. NHS Scotland genetics laboratories performed interpretation, validation and reporting. New diagnoses were made in 23% cases - 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes. Diagnostic yield varied considerably between phenotype categories and was minimal in cases with prior exome testing. Genome sequencing with gene panel filtering and reporting achieved improved diagnostic yield over previous historic testing but not over now routine trio-exome sequence tests. Re-interpretation of genomic data with updated gene panels modestly improved diagnostic yield at minimal cost. However, to justify the additional costs of genome vs exome sequencing, efficient methods for analysis of structural variation will be required and / or cost of genome analysis and storage will need to decrease.

Diagnostic and predictive value of ultrasound and isotope thyroid scanning, alone and in combination, in infants referred with thyroid-stimulating hormone elevation on newborn screening.

OBJECTIVE: To determine the diagnostic and predictive value of ultrasound and radioisotope scans of the thyroid, alone and in combination, during a single visit after initial referral by the screening laboratory with thyroid-stimulating hormone (TSH) elevation. STUDY DESIGN: Retrospective blind review of ultrasound and radioisotope images followed by final diagnosis based on clinical features, biochemistry, imaging, and molecular genetic study. RESULTS: Infants (n = 97; 61 female) with median birthweight 3.38 kg (range 2.04-4.86) and gestation 40 weeks (range 33-42), underwent successful dual thyroid ultrasound and technetium-99m pertechnetate radioisotope scan in a single center. Combined scanning at the initial visit resulted in a correct final diagnosis in 79 of 97 (81%) cases. One patient was misdiagnosed initially as having athyreosis as the result of delayed radioisotope scan and the diagnosis of ectopia made later on diagnostic challenge. The specificity/sensitivity for radioisotope scan and for ultrasound was as follows: 100%/97% and 100%/55% for ectopia (n = 39); 81%/100% and 54%/100% for athyreosis (n = 18); and 89%/90% and 80%/95% for dyshormonogenesis (n = 20). Neither modality, alone or in combination, predicted final diagnosis in eutopic glands due to hypoplasia (n = 4), transient TSH elevation (n = 12), and status still uncertain (n = 4). CONCLUSION: More than 80% of newborn infants with TSH elevation can be diagnosed correctly on initial imaging with combined radioisotope scan and ultrasound. Ultrasound cannot reliably detect thyroid ectopia. Radioisotope scan, especially if performed late, may show no uptake despite the presence of a eutopic gland.

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

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.