Centrally mediated obstructive apnoea and restenosis of the foramen magnum in an infant with achondroplasia.

Achondroplasia is associated with foramen magnum stenosis. We report a male infant with achondroplasia and centrally mediated obstructive apnoea who underwent two foramen magnum decompression due to bone regrowth. He presented at six weeks of age with breath holding and apnoeic episodes associated with significant desaturation, requiring non-invasive ventilation. Craniospinal imaging revealed a narrow foramen magnum without signal change in the spinal cord. Sleep studies showed obstructive, but not central, apnoea. Respiratory abnormalities persisted and reimaging at two months showed development of significant signal changes at the cervicomedullary junction (CMJ). He underwent emergency foramen magnum decompression with initial clinical improvement. Ten days later he relapsed with further apnoeic episodes requiring respiratory support. After extensive re-investigations including CT and MRI, incomplete initial decompression and foramen magnum restenosis were considered and confirmed with a CT head scan 15 weeks after the initial operation. Repeat decompression of bone and removal of thickened dural bands resulted in complete resolution of the apnoeic episodes. Obstructive sleep apnoea can be centrally mediated and further decompression of foramen magnum stenosis should be considered, especially if significant respiratory compromise persists or recurs.

Processing of Positive Newborn Screening Results for Congenital Hypothyroidism: A Qualitative Exploration of Current Practice in England.

The objective of this research was to explore current communication practices for positive newborn bloodspot screening results for congenital hypothyroidism from the newborn bloodspot screening laboratory to clinicians and then families, in order to (i) understand how the pathway is implemented in practice, (ii) highlight regional differences and (iii) identify barriers and facilitators. A qualitative exploratory design was employed using semi-structured interviews across 13 newborn bloodspot screening laboratories in England. Participants included 35 clinicians and 17 NBS laboratory staff across the 13 laboratories and 18 members of relevant clinical teams. Findings illuminated variations in how positive newborn bloodspot screening results for congenital hypothyroidism are communicated in practice. This included regional variations due to historical arrangements and local resources. Contacting the appropriate person could be challenging and obtaining feedback from clinical teams to the laboratory after the child has been seen could be time consuming for those involved. Standardised communication model(s) for positive newborn bloodspot screening results for congenital hypothyroidism, which include named contact individuals, defined pathways of care and processes for feeding back to laboratories, may help to ensure the process is less labour intensive, particularly from a laboratory perspective.

Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era.

BACKGROUND: Skeletal dysplasia (SD) conditions are rare genetic diseases of the skeleton, encompassing a heterogeneous group of over 400 disorders, and represent approximately 5% of all congenital anomalies. Developments in genetic and treatment technologies are leading to unparalleled therapeutic advances; thus, it is more important than ever to molecularly confirm SD conditions. Data on 'rates-of-molecular yields' in SD conditions, through exome sequencing approaches, is limited. Figures of 39% and 52.5% have been reported in the USA (n = 54) and South Korea (n = 185) respectively. METHODS: We discuss a single-centre (in the UK) experience of whole-exome sequencing (WES) in a cohort of 15 paediatric patients (aged 5 months to 12 years) with SD disorders previously molecularly unconfirmed. Our cohort included patients with known clinical diagnoses and undiagnosed skeletal syndromes. Extensive phenotyping and expert radiological review by a panel of international SD radiology experts, coupled with a complex bioinformatics pipeline, allowed for both gene-targeted and gene-agnostic approaches. RESULTS: Significant variants leading to a likely or confirmed diagnosis were identified in 53.3% (n = 8/15) of patients; 46.7% (n = 7/15) having a definite molecular diagnosis and 6.7% (n = 1/15) having a likely molecular diagnosis. We discuss this in the context of a rare disease in general and specifically SD presentations. Of patients with known diagnoses pre-WES (n = 10), molecular confirmation occurred in 7/10 cases, as opposed to 1/5 where a diagnosis was unknown pre-test. Thus, diagnostic return is greatest where the diagnosis is known pre-test. For WGS (whole genome sequencing, the next iteration of WES), careful case selection (ideally of known diagnoses pre-test) will yield highest returns. CONCLUSIONS: Our results highlight the cost-effective use of WES-targeted bioinformatic analysis as a diagnostic tool for SD, particularly patients with presumed SD, where detailed phenotyping is essential. Thorough co-ordinated clinical evaluation between clinical, radiological, and molecular teams is essential for improved yield and clinical care. WES (and WGS) yields will increase with time, allowing faster diagnoses, avoiding needless investigations, ensuring individualised patient care and patient reassurance. Further diagnoses will lead to increased information on natural history/mechanistic details, and likely increased therapies and clinical trials.

KIAA0753-related skeletal ciliopathy: a ninth case, extending the phenotype and reporting a novel variant.

KIAA0753-related skeletal ciliopathy is a recently described recessive disorder causing skeletal dysplasia and overlapping features of certain ciliopathies; Joubert, Jeune and Oro-facial-digital syndromes. We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia. Testing for FGFR3 achondroplasia-related hotspots and mucopolysaccharidosis were negative. Whole-exome sequencing, aged eight, via skeletal dysplasia panel analysis and subsequent whole-genome sequencing (via the 100,000 genomes project) found no cause. WGS data reanalysis using exomiser uncovered compound heterozygous pathogenic KIAA0753 variants (frameshift and splice site). Further clinical and radiological surveys were consistent with the expected phenotype. We discuss the emerging phenotype of this uncommon disorder. This report details the sixth published case of skeletal dysplasia in all cases of KIAA0753-related disease and the first case to describe a novel c.1830-2A>G splice variant. Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression.

The Evidence for Fertility Preservation in Pediatric Klinefelter Syndrome.

Klinefelter syndrome (KS) is a common cause of non-obstructive azoospermia (NOA). Advances in fertility preservation (FP) techniques, such as the use of microdissection testicular sperm extraction (micro-TESE), have improved sperm retrieval rates (SRR) up to 40-50% in this population. Age has been suggested to have an impact on FP, postulating that sperm production may deteriorate over time due to germ cell loss. As such, sperm retrieval for patients with KS at a younger age has been proposed to further improve SRR; however, whether such practice pragmatically improves SRR is yet to be determined, and controversy remains with concerns over trauma caused by FP procedures on further impairment of testicular function. There has also been a debate on the ethics of performing FP procedures in the pediatric population. Optimizing FP for patients with KS invariably requires a holistic multidisciplinary approach. This review aimed to evaluate the latest evidence in performing FP in pediatric patients with KS, and discuss the controversy surrounding such practice. Hormonal changes in patients with KS during childhood and the use of hormonal manipulation to optimize SSR in this population have also been reviewed.

Earlier detection of hypochondroplasia: A large single-center UK case series and systematic review.

Hypochondroplasia (HCH) is a rare autosomal dominant skeletal dysplasia condition caused by FGFR3 mutations leading to disproportionate short stature. Classically HCH presents in toddlers or school-age children, as limb-to-trunk disproportion and is often mild and easily overlooked during infancy. We report experiences from a single-center UK HCH-cohort of 31 patients, the rate of antenatal HCH detection in our cohort (13/31, 41.9%) and describe relevant case-data for this subset of 13 patients. Inclusion criteria were patients with confirmed molecular HCH diagnosis (by age 3 years) and presenting with short long-bones or large head size on antenatal ultrasound scan. We then conducted a systematic literature review using PUBMED and MEDLINE, analyzing patients with HCH and related antenatal findings. Antenatally suspected (with subsequent molecular confirmation) HCH has been reported 15 times in the literature (2004-2019). Key markers (consistent in both groups) included reduced; femur length, humeral length and increased; biparietal diameter and head circumference. HCH is increasingly detected both antenatally and in infancy, contrary to previous descriptions. This is likely due to greater HCH awareness, improved imaging, and easier molecular testing. Thus, one should consider HCH outside the classical presenting period. Studying the natural history of younger patients with HCH is important with the advent of several targeted FGFR3 therapies currently in trials for Achondroplasia, that may soon be trialed in HCH.

Achondroplasia Foramen Magnum Score: screening infants for stenosis.

BACKGROUND: Achondroplasia is associated with foramen magnum stenosis (FMS) and significant risk of morbidity and sudden death in infants. A sensitive and reliable method of detecting infants who require decompressive surgery is required. This study aims to describe the incidence and severity of FMS in an unselected, sequential series of infants using a novel MRI score and retrospectively correlate severity with clinical examination and cardiorespiratory sleep (CRS) studies. METHODS: The Achondroplasia Foramen Magnum Score (AFMS) was developed and scores were retrospectively correlated with clinical and CRS data over a 3-year period. RESULTS: Of 36 infants (M:F, 18:18), 2 (5.6%) did not have FMS (AFMS0); 13 (36.1%) had FMS with preservation of the cerebrospinal fluid (CSF) spaces (AFMS1); 3 (8.3%) had FMS with loss of the CSF space but no spinal cord distortion (AFMS2); 13 (36.1%) had FMS with flattening of the cervical cord without signal change (AFMS3); and 5 (13.9%) had FMS resulting in cervical cord signal change (AFMS4). Mean Total Apnea and Hypopnea Index (TAHI) for AFMS0-4 was 3.4, 6.41, 2.97, 10.5 and 25.8, respectively. Severe TAHI had a specificity of 89% but only a 59% sensitivity for AFMS3-4. Neurological examination was normal in 34/36 (94%) patients. Overall, 9/36 (25%) infants required neurosurgery with minimal surgical complications. CONCLUSIONS: Clinical examination and CRS have a low sensitivity for predicting the effects of foramen stenosis on the spinal cord. Routine screening with MRI using AFMS can aid in detecting early spinal cord changes and has the potential to reduce infant morbidity and mortality.

Demystifying the Pizza Bolus: The Effect of Dough Fermentation on Glycemic Response-A Sensor-Augmented Pump Intervention Trial in Children with Type 1 Diabetes Mellitus.

Background: Glycemia following pizza consumption is typically managed with a dual-wave insulin bolus. This study evaluated the effect of a simple bolus on glycemia following consumption of traditionally prepared pizzas with long (24 h) or short (8 h) dough fermentation periods. Research Design and Methods: On two separate evenings, children with type 1 diabetes (n = 38) receiving sensor-integrated pump therapy consumed traditionally prepared pizza with either short (pizza A) or long (pizza B) dough fermentation, and blood glucose was monitored over 11 h. A simple insulin bolus was administered 15 min preprandially. The carbohydrate and amino acid contents of the two types of pizza were analyzed by liquid chromatography and high-resolution mass spectrometry (LC-HRMS). Results: The mean (±standard deviation) time in range 3.9-10.0 mmol/L was 73.2% ± 23.2%, and 50.8% ± 26.7% of glucose measurements were within the range 3.9-7.8 mmol/L. However, during the 2 h after bolus administration, the mean time in range 3.9-7.8 mmol/L was significantly greater with pizza B than with pizza A (73.3% ± 31.5% vs. 51.8% ± 37.4%, respectively, P = 0.009), and the time in hyperglycemia (>10 mmol/L) was significantly shorter (mean percentage 6.1% ± 19.0% vs. 17.7% ± 29.8%, respectively, P = 0.019). LC-HRMS analysis showed that long fermentation was associated with a lower carbohydrate content in the pizza, and a higher amino acid content. Conclusions: Glycemia following consumption of traditionally prepared pizza can be managed using a simple bolus 15 min before eating. Glycemic control can be further improved by increasing the dough fermentation time. Study registration: NCT03748251, Clinicaltrials.gov.

Continuous subcutaneous insulin infusion in preschool children: butt or tummy, which is the best infusion set site?

BACKGROUND: Choosing the right infusion set site can be an important factor in obtaining good glycemic control, especially in very young children. In an attempt to identify the best infusion site, we performed a crossover study in six preschool children with type 1 diabetes using insulin pump therapy. SUBJECTS AND METHODS: We enrolled six patients 5.2±0.7 years old (range, 4-6 years), with type 1 diabetes for more than 1.5 years, using insulin pump therapy for at least 6 months. For each patient, body mass index, glycated hemoglobin, and all data downloaded from the system were evaluated on two occasions: the first with the infusion set placed on the buttock and the second on the abdomen, each for 3 days. The order of infusion set placement was randomized. Mean capillary blood glucose, mean continuous glycemia, mean area under the curve (AUC) using the trapezoidal rule for both >140 mg/dL and <70 mg/dL, insulin daily dose, carbohydrate/insulin ratio, total basal insulin, total bolus insulin, and mean amplitude of glucose excursions (MAGE) were evaluated. RESULTS: Mean glycemic values, mean AUC >140 mg/dL, and MAGE were significantly lower when the infusion set was placed on the buttock versus the abdomen (144.6±31.9 mg/dL vs. 166.0±34.8 mg/dL [P=0.000], 28.4±18.3% vs. 48.8±28.2% [P=0.000], and 32±10 vs. 60±15 mg/dL [P<0.001], respectively), whereas mean AUC <70 mg/dL was higher (1.47±2.77% vs. 0.87±1.03% [P<0.001]). CONCLUSIONS: The present findings suggest that preschool children with type 1 diabetes using insulin pump therapy could benefit from inserting the infusion set in the buttock instead of the abdomen.

Chat line for adolescents with type 1 diabetes: a useful tool to improve coping with diabetes: a 2-year follow-up study.

BACKGROUND: We evaluated the impact of a 2-year chat line involving adolescents with type 1 diabetes regarding quality of life and metabolic control. METHODS: We enrolled 193 children, 10-18 years of age (mean ± SD, 13.6 ± 2.7 years), with type 1 diabetes for 1.2-6 years (3.6 ± 2.4 years), body mass index of 23.2 ± 4.1 kg/m(2), insulin requirement of 0.7 ± 0.3 U/kg/day, and glycated hemoglobin (HbA1c) of 7.8 ± 1.1%, who participated in a weekly physician-moderated chat line for a 2-year follow-up period. Each patient completed the Diabetes Quality of Life for Youth Inventory (DQOLY) at baseline and after 1 and 2 years. A measure of glycemic control (HbA1c) was also collected. Data from 17 patients who discontinued using the chat line were not included in the analysis. As controls, 203 patients with type 1 diabetes, age- and sex-matched, with similar HbA1c at baseline and socioeconomic status, were randomly selected among 834 patients who refused to participate in the chat sessions. RESULTS: DQOLY responses from youth with type 1 diabetes showed a significant improvement (P = 0.0001) only in patients who participated in chat sessions. We observed a decrease of 0.4% in HbA1c in patients who participated in chat session (7.8 ± 1.1% vs. 7.4 ± 0.5%, P < 0.0001) compared with the 0.1% of the controls (7.9 ± 1.9% vs. 7.8 ± 1.8%, P = 0.668). No difference was observed in HbA1c between the two groups (P = 0.056). CONCLUSIONS: A chat line is also a cheap and effective tool that helps improve diabetes compliance. The chat line could help the diabetes team understand and treat their patients more comprehensively; moreover, it could help patients cope better with their daily life.