Shwachman-Diamondin oireyhtymän kliiniset, geneettiset ja radiologiset piirteet

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder in which the cardinal symptoms arise from exocrine pancreatic insufficiency and bone marrow dysfunction. Previous studies have suggested increased risk of fatal complications among Finnish SDS infants. The genetic defect responsible for the disease was recently identified; the SBDS gene is located at chromosome 7q11 and encodes a protein that is involved in ribosome biosynthesis. The discovery of the SBDS gene has opened new insights into the pathogenesis of this multi-organ disease. This study aimed to assess phenotypic and genotypic features of Finnish patients with SDS. Seventeen Finnish patients with a clinical diagnosis of SDS were included in the study cohort. Extensive clinical, biochemical and imaging assessments were performed to elucidate the phenotypic features, and the findings were correlated with the SBDS genotype. Imaging studies included abdominal magnetic reso-nance imaging (MRI), brain MRI, cardiac echocardiography including tissue Doppler examination, and cardiac MRI. The skeletal phenotype was assessed by dual-energy X-ray absorptiometry and bone histomorphometry. Twelve patients had mutations in the SBDS gene. In MRI, a characteristic pattern of fat-replaced pancreas with occasional enhancement of scattered parenchymal foci and of pancreatic duct was noted in the SBDS mutation-positive patients while the mutation-negative patients did not have pancreatic fat accumulation. The patients with SBDS mutations had significantly reduced bone mineral density associated with low-energy peripheral fractures and vertebral compression fractures. Bone histomorphometry confirmed low-turnover osteoporosis. The patients with SBDS mutations had learning difficulties and smaller head size and brain volume than control subjects. Corpus callosum, cerebellar vermis, and pos-terior fossa structures were significantly smaller in SDS patients than in controls. Patients with SDS did not have evidence of clinical heart disease or myocardial fibrosis. However, subtle diastolic changes in the right ventricle and exercise-induced changes in the left ventricle contractile reserve were observed. This study expanded the phenotypic features of SDS to include primary low-turnover osteoporosis and structural alterations in the brain. Pancreatic MRI showed characteristic changes in the SBDS mutation-positive patients while these were absent in the mutation-negative patients, suggesting that MRI can be used to differentiate patients harbouring SBDS mutations from those without mutations. No evidence for clinical cardiac manifestations was found, but imaging studies revealed slightly altered myocardial function that may have clinical implications. These findings confirm the pleiotropic nature of SDS and underscore the importance of careful multidisciplinary follow-up of the affected individuals.Shwachman-Diamondin oireyhtymä on harvinainen autosomissa peittyvästi periytyvä sairaus, jonka pääpiir-teet ovat imeytymishäiriöön johtava haiman ulkoeritystoiminnan vajaatoiminta sekä verenkuvamuutoksiin, tulehdusherkkyyteen ja kohonneeseen leukemiariskiin johtava luuytimen häiriö. Oireyhtymään liittyvä geeni (SBDS geeni) kromosomissa 7q11 on hiljattain tunnistettu ja siinä on kuvattu useita mutaatioita. Tutkimuksen tavoitteena oli kartoittaa Shwachman-Diamondin oireyhtymän ilmentymistä ja geneettistä taustaa suomalaisilla potilailla. Väitöskirjatyöhön on kerätty suomalaiset oireyhtymää sairastavat potilaat, yhteensä 17 potilasta, ja he ovat osallistuneet laajoihin kliinisiin, biokemiallisiin ja kuvantamistutkimuksiin. Kuvantamismenetelminä käytettiin vatsan, aivojen ja sydämen magneettitutkimuksia. Sydäntä tutkittiin lisäksi kaikukuvauksella ja siihen liitetyllä kudos Doppler mittauksella. Selkärangan röntgenkuvauksella ja luuston mineraalitiheysmittauksella selvitettiin osteoporoosin ja osteoporoottisten nikamamuutosten esiintyvyyttä. Tutkimus osoitti, että haiman magneettikuvauksessa kaikilla SBDS-geenimutaatioita omaavilla potilailla oli tyypillisenä löydöksenä rasvoittunut haimakudos, kun taas potilailla, jolla mutaatioita ei todettu, haiman alueella ei rasvoittumista todettu. Tämän perusteella haiman vajaatoiminnasta kärsiville lapsipotilaille kannattaa tehdä haiman magneettikuvaus diagnostiikan tueksi. Kaikilla SBDS-mutaatioita kantavilla potilailla luuntiheys oli alentunut ja osalla oli lisääntynyt murtuma-alttius, mutta luukudosnäytteen perusteella osteoporoosi ei johtunut imeytymishäiriöstä. Näin ollen on mahdollista, että todetut osteoporoosimuutokset ovat yhteydessä oireyhtymään liittyvään luuytimen toimintahäiriöön. Aivojen magneettitutkimuksessa aivokurkiaisen ja aivojen takakuopan rakenteet olivat SBDS-mutaatioita kantavilla potilailla pienempiä kuin ikä- ja sukupuoli-vakioiduilla verrokkihenkilöillä. Lisäksi aivojen kokonaistilavuus oli verrokkihenkilöitä pienempi. Löydöksillä saattaa olla yhteyttä potilaiden raportoimiin oppimishäiriöihin. Kaikki potilaat olivat sydämen toiminnan osalta oireettomia. Potilailla todettiin kuvantamistutkimuksissa normaali sydämen anatomia ja sydänlihaksen rakenne, mutta sydämen toimintaa mittaavilla menetelmillä havaitiin kuitenkin lieviä oikean kammion diastolisen toiminnan muutoksia ja alentunut vasemman kammion supistuvuus rasituksessa. Nämä lievät muutokset saattavat altistaa potilaita sydänperäisiin oireisiin elimistön stressitilanteissa

A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant

Skeletal dysplasias comprise a heterogenous group of developmental disorders of skeletal and cartilaginous tissues. Several different forms have been described and the full spectrum of their clinical manifestations and underlying genetic causes are still incompletely understood. We report a three-generation Finnish family with an unusual, autosomal dominant form of osteochondrodysplasia and an empty sella. Affected individuals (age range 24-44 years) exhibit unusual codfish-shaped vertebrae, severe early-onset and debilitating osteoarthritis and an empty sella without endocrine abnormalities. Clinical characteristics also include mild dysmorphic features, reduced sitting height ratio, and obesity. Whole-exome sequencing excluded known skeletal dysplasias and identified a novel heterozygous missense mutation c.899C>T (p.Thr300Met) in TBX2, confirmed by Sanger sequencing. TBX2 is important for development of the skeleton and the brain and three prior reports have described variations in TBX2 in patients portraying a complex phenotype with vertebral anomalies, craniofacial dysmorphism and endocrine dysfunctions. Our mutation lies near a previously reported disease-causing variant and is predicted pathogenic with deleterious effects on protein function. Our findings expand the current spectrum of skeletal dysplasias, support the association of TBX2 mutations with skeletal dysplasia and suggest a role for TBX2 in development of the spinal and craniofacial structures and the pituitary gland.Peer reviewe

Profile of minor neurological findings after perinatal asphyxia

Aim To characterise the spectrum of findings in sequential neurological examinations, general movements (GM) assessment and magnetic resonance imaging (MRI) of infants with perinatal asphyxia. Methods The prospective cohort study of term infants with perinatal asphyxia treated at Helsinki University Hospital's neonatal units in 2016-2020 used Hammersmith Neonatal Neurological Examination (HNNE) and brain MRI at 2 weeks and Hammersmith Infant Neurological Examination (HINE) and GM assessment at 3 months of age. Results Analysis included 50 infants: 33 displaying perinatal asphyxia without hypoxic-ischaemic encephalopathy (HIE), seven with HIE1 and 10 with HIE2. Of the infants with atypical HNNE findings, 24/25 perinatal asphyxia without HIE cases, 5/6 HIE1 cases and all 10 HIE2 cases showed atypical findings in the HINE. The HINE identified atypical spontaneous movements significantly more often in infants with white matter T2 hyperintensity. Conclusion In this cohort, most infants with perinatal asphyxia, with or without HIE, presented atypical neurological findings in sequential examinations. The profile of neurological findings for children with perinatal asphyxia without HIE resembled that of children with HIE. White matter T2 hyperintensity was associated with atypical spontaneous movements in the HINE and was a frequent MRI finding also in perinatal asphyxia without HIE.Peer reviewe

Compromised Peak Bone Mass in Patients with Inflammatory Bowel Disease-A Prospective Study

Peer reviewe

Towards multimodal brain monitoring in asphyxiated newborns with amplitude-integrated EEG and simultaneous somatosensory evoked potentials

Background: Somatosensory evoked potentials (SEPs) offer an additional bedside tool for outcome prediction after perinatal asphyxia. Aims: To assess the reliability of SEPs recorded with bifrontoparietal amplitude-integrated electroencephalography (aEEG) brain monitoring setup for outcome prediction in asphyxiated newborns undergoing therapeutic hypothermia. Study design: Retrospective observational single-center study. Subjects: 27 consecutive asphyxiated fullor near-term newborns (25 under hypothermia) that underwent median nerve aEEG-SEPs as part of their clinical evaluation at the neonatal intensive care unit of Helsinki University Hospital. Outcome measures: aEEG-SEP classification (present, absent or unreliable) was compared to classification of SEPs recorded with a full EEG montage (EEG-SEP), and outcome determined from medical records at approximately 12-months-age. Unfavorable outcome included death, cerebral palsy, or severe epilepsy. Results: The aEEG-SEP and EEG-SEP classifications were concordant in 21 of the 22 newborns with both recordings available. All five newborns with bilaterally absent aEEG-SEPs had absent EEG-SEPs and the four with outcome information available had an unfavorable outcome (one was lost to follow-up). Of the newborns with aEEG-SEPs present, all with follow-up exams available had bilaterally present EEG-SEPs and a favorable outcome (one was lost to follow-up). One newborn with unilaterally absent aEEG-SEP at 25 h of age had bilaterally present EEG-SEPs on the next day, and a favorable outcome. Conclusions: aEEG-SEPs recorded during therapeutic hypothermia on the first postnatal days are reliable for assessing brain injury severity. Adding SEP into routine aEEG brain monitoring offers an additional tool for very early outcome prediction after birth asphyxia.Peer reviewe

Milloin kannattaa aloittaa kaikututkimuksella?

Vertaisarvioitu.• Kaikukuvaus eli ultraäänitutkimus on usein ensisijainen kuvantamis¬ menetelmä lapsia tutkittaessa. • Näkyvyys on yleensä parempi kuin aikuisia tutkittaessa, eikä diagnoosiin pääsemiseksi välttämättä tarvita muita kuvantamismenetelmiä. • Lasten ultraäänidiagnostiikassa tarvitaan tietämystä eri kehitysvaiheissa ilmenevistä tyypillisistä sairauksista ja normaalilöydöksistä.Peer reviewe

Neonatal neuroimaging and neurophysiology predict infantile onset epilepsy after perinatal hypoxic ischemic encephalopathy

Correction: Volume88, Page158-158 DOI10.1016/j.seizure.2021.04.001 PublishedMAY 2021Purpose: To evaluate the accuracy of hypoxic ischemic encephalopathy (HIE) grade, and neonatal neurophysiological and neuroimaging measures for predicting development of infantile spasms syndrome (IS) or other postneonatal, infantile onset epilepsy after perinatal HIE. Methods: We examined a population-based cohort of 92 consequent infants with moderate-to-severe HIE. The HIE grade and neonatal neuroimaging (MRI) and neurophysiology (EEG and somatosensory evoked potentials, SEPs) findings were compared to the development of IS or other epilepsy within the first year of life. Results: Out of 74 surviving infants with follow-up information, five developed IS and one developed a focal onset epilepsy. They all had recovered from severe HIE. All survivors with inactive neonatal EEG (recorded within the first few postnatal days, n = 4) or the most severe type of brain injury in MRI (n = 3) developed epilepsy (positive predictive value, PPV 100 %). Bilaterally absent SEPs had 100 % sensitivity and 75 % PPV for epilepsy. A combination of absent SEPs and a poor MRI finding (combined deep and cortical gray matter injury) resulted in higher PPV (86 %) without lowering sensitivity (100 %). Follow-up EEGs showed recurrent epileptiform activity already between 1- and 2-months age in those that developed epilepsy, distinguishing them from those surviving without epilepsy. Conclusions: Poor neonatal neuroimaging and neurophysiological findings provide accurate prediction for development of infantile onset epilepsy after HIE. Of the neonates with severe HIE, the ones with severe neonatal MRI and neurophysiological abnormalities need frequent follow-up, including repeated EEGs, for early detection of IS.Peer reviewe

Letrozole Monotherapy in Pre- and Early-Pubertal Boys Does Not Increase Adult Height

Background: Aromatase inhibitors (Als) have been used in boys with idiopathic short stature (ISS) to promote growth despite the lack of actual data regarding treatment effect on adult height. In this study, we characterized adult heights and long-term follow-up in Al-treated boys with ISS. Methods: Adult heights and long-term follow-up data, including spine MRIs, of a randomized, double-blind, placebo-controlled trial of boys who were treated with letrozole (Lz) (2.5 mg/d) or placebo (PI) for 2 years during prepuberty and early puberty. The mean bone ages at treatment cessation were 10.2 and 10.8 years, respectively. Results: Adult heights were similar between the boys treated with Lz (n = 10) and those who received PI (n = 10) (164.8 +/- 4.0 vs. 163.7 +/- 3.7 cm, p = 0.49, respectively). In either group, the adult heights did not differ from predicted adult heights at start of the study [PI: 163.7 (3.7) cm vs. 166.9 (3.3), p = 0.06; Lz: 164.8 (4.0) cm vs. 167.6 (7.9), p = 0.20, respectively]. Long-term follow-up data showed that the frequency of subjects with a vertebral deformity was similar between the groups (Lz, 29% and PI, 22%, p = 0.20), and no single comorbidity was clearly enriched in either group. Conclusions: The Lz-treated boys had similar adult heights with the subjects who received PI for 2 years, which indicates that the treatment is not beneficial when given to pre- or early-pubertal boys. Previously observed vertebral deformities ameliorated during follow-up, which supports the skeletal safety of Lz therapy in children and adolescents.Peer reviewe

High prevalence of bronchiectasis in patients with cartilage-hair hypoplasia

Non peer reviewe

PLS3Mutations Cause Severe Age and Sex-Related Spinal Pathology

Objective:Mutations in the X-chromosomalPLS3-gene, encoding Plastin 3, lead to severe early-onset osteoporosis, suggesting a major role for PLS3 in bone metabolism. However, the consequences of abnormal PLS3 function in bone and other tissues remain incompletely characterized. This study evaluated spinal consequences of aberrant PLS3 function in patients withPLS3mutations. Design:A cross-sectional cohort study with spinal magnetic resonance imaging of 15PLS3mutation-positive (age range 9-77 years) and 13 mutation-negative (9-70 years) subjects. Images were reviewed for spinal alignment, vertebral heights and morphology, intervertebral disc changes and possible endplate deterioration. Results:Vertebral changes were significantly more prevalent in the mutation-positive subjects compared with the mutation-negative subjects; they were most abundant in upper thoracic spine, and in all age groups and both sexes, although more prominent in males. Difference in anterior vertebral height reduction was most significant in T5 and T6 (p= 0.046 andp= 0.041, respectively). Mid-vertebral height reduction was most significant in T3 and T5 (p= 0.037 andp= 0.005, respectively), and, for male mutation-positive subjects only, in T4 and T6-10 (p= 0.005-0.030 for each vertebra). Most of the abnormal vertebrae were biconcave in shape but thoracic kyphosis or lumbar lordosis were unchanged. Vertebral endplates were well-preserved in the mutation-positive subjects with even fewer Schmorl nodes than the mutation-negative subjects (10 vs. 16). Conclusions:Compromised PLS3 function introduces severe and progressive changes to spinal structures that are present already in childhood, in both sexes and most abundant in upper thoracic spine. Cartilaginous structures are well-preserved.Peer reviewe