Exome sequencing reveals a novel COL2A1 mutation implicated in multiple epiphyseal dysplasia.

Mutations in the COMP, COL9A1, COL9A2, COL9A3, MATN3, and SLC26A2 genes cause approximately 70% of multiple epiphyseal dysplasia (MED) cases. The genetic changes involved in the etiology of the remaining cases are still unknown, suggesting that other genes contribute to MED development. Our goal was to identify a mutation causing an autosomal dominant form of MED in a large multigenerational family. Initially, we excluded all genes known to be associated with autosomal dominant MED by using microsatellite and SNP markers. Follow-up with whole-exome sequencing analysis revealed a mutation c.2032G>A (p.Gly678Arg) in the COL2A1 gene (NCBI Reference Sequence: NM_001844.4), which co-segregated with the disease phenotype in this family, manifested by severe hip dysplasia and osteoarthritis. One of the affected family members had a double-layered patella, which is frequently seen in patients with autosomal recessive MED caused by DTDST mutations and sporadically in the dominant form of MED caused by COL9A2 defect.

SMD Kozlowski type caused by p.Arg594His substitution in TRPV4 reveals abnormal ossification and notochordal remnants in discs and vertebrae.

Spondylometaphyseal dysplasia Kozlowski type (SMDK) is a monogenic disorder within the TRPV4 dysplasia spectrum and has characteristic spinal and metaphyseal changes. We report skeletal MR imaging in a two-year-old patient who manifested typical clinical and radiographic features of SMDK. The diagnosis was confirmed by molecular analysis which revealed a mutation NM_021625.4:c.1781G > A - p.(Arg594His) in exon 11 of the TRPV4 gene. We have documented abnormalities in endochondral formation of the long and short tubular bones as well as round bones of the wrists and feet. The vertebral bodies had increased thickness of hyaline cartilage which enveloped ossification centers. The vertebrae and discs also had abnormalities in size, shape and structure. These anomalies were most likely the consequence of notochordal remnants presence within the intervertebral discs and in the vertebral bodies. The advantages of MR imaging in bone dysplasias caused by TRPV4 mutations are emphasized in this article.

[Cranial ultrasound through posterolateral fontanelle in visualization of posterior fossa abnormalities in preterm and term neonates]. / Ultrasonografia glowy przez ciemiaczko tylno- boczne w ocenie nieprawidlowosci tylnego dolu czaszki u wczesniaków i noworodk>w donoszonych.

OBJECTIVES: The aim of the study was to evaluate the usefulness of US in the diagnosis of posterior fossa abnormalities in neonates by posterolateral fontanelle as compared with the anterior fontanelle approach and MRI. MATERIAL AND METHODS: US studies were performed on 1337 neonates, including 512 preterm infants, through the anterior and posterolateral fontanelles. Abnormalities were detected in 134 patients. Among them, abnormalities in posterior fossa were visualized with the posterolateral approach in 14 neonates. MR images were obtained in that subgrqup. RESULTS: The lesions consisted of cerebellar hemorrhage and congenital cerebellar malformations. Foci of hemorrhage were visualized by US in preterm neonates (n = 5), only through the posterolateral approach and on MRI. Dandy-Walker malformations (n = 2) were detected by US with both approaches and confirmed on MRI. In pontocerebellar hypoplasia (n =2), US with both approaches, showed hypoplastic cerebellar hemispheres and fluid in the posterior fossa. MRI, additionally visualized pontine hypoplasia. Fluid collection in the posterior fossa and translocation of cerebellar hemispheres were observed in the other 6 neonates by US with both approaches. MRI revealed arachnoid cysts (n = 2), mega cisterna magna (n = 3) and Blake's pouch (n = 1). CONCLUSIONS: US using posterolateral fontanelle is the method of choice for the diagnosis of cerebellar hemorrhage. These lesions are not visualized through anterior fontanelle. US visualization of the abnormal structures in some cerebellar malformations has similar effectiveness for both approaches. MRI plays the crucial role in identification and differential diagnosis of these malformations.

[Ultrasound examination in diagnosis and monitoring of necrotizing enterocolitis in a group of newborns with birth weight below 2000 g--a preliminary report]. / Ultrasonografia w ocenie martwiczego zapalenia jelit u noworodków z urodzeniowa masa ciala ponizej 2000 g--donlesienie wstepne.

OBJECTIVES: Necrotizing enterocolitis (NEC) is a common cause of morbidity in the neonatal care units, especially in cases of preterm neonates with low and very low birth weight. Plain abdominal radiography remains to be the main diagnostic tool in the diagnosis and follow-up of NEC. However; it is sometimes impossible to depict all pathological findings in the radiographs. Furthermore, radiography exposes the youngest, most sensitive patients to consecutive episodes of radiation. Ultrasound examination seems to be an interesting alternative to current standard usage of radiography and its role is still underestimated. The aim of the paper was to assess the applicability of ultrasound examination in the diagnosis and monitoring of neonates suffering from NEC. MATERIAL AND METHODS: The study group consisted of 12 neonates (gestational age 25-36 weeks, weight 540-1900 g), suspected of NEC development. Abdominal radiographs obtained with the use of anterior-posterior and lateral projections, as well as ultrasound examination, were performed. During bowel sonography attention was paid to the presence of intraabdominal fluid, free intraperitoneal gas, bowel wall thickness and bowel wall perfusion. Intramural gas, free intraperitoneal gas and signs of bowel distension were evaluated on the radiographs. RESULTS: Bowel distension was found in all patients. The presence of intraluminal gas was detected in 3 neonates, whereas the signs of bowel perforation were present in only 2 patients. Ultrasound evaluation revealed bowel wall thickening together with increased bowel wall perfusion in 9 patients. Only one neonate presented thinning of the bowel wall, decreased bowel wall perfusion and presence of free intraperitoneal fluid. These findings were connected with a poor outcome of that patient. CONCLUSIONS: Ultrasound examination can be extremely helpful for the initial diagnosis as well as the follow-up of patients developing NEC. It allows to depict the majority of pathological findings for NEC, even those not visible on plain abdominal radiography It is important to emphasize that abdominal sonography (with special reference to the bowel sonography), together with plain abdominal radiography should be considered as standard imaging modalities for the assessment of necrotizing enterocolitis.

Three new patients with FATCO: fibular agenesis with ectrodactyly.

We document three new patients with fibular agenesis, tibial campomelia, and oligosyndactyly (FATCO). Two of these individuals had tetramelic manifestations while the third had bilateral abnormalities of the lower limbs. These patients and others reported as FATCO seem to belong to the phenotype "fibular aplasia with ectrodactyly." Genetic screening for CNVs and mutations in the TP63 and WNT10B genes did not show any genetic abnormalities. ©

IAEA survey of pediatric CT practice in 40 countries in Asia, Europe, Latin America, and Africa: Part 1, frequency and appropriateness.

OBJECTIVE: The purpose of this study was to assess the frequency of pediatric CT in 40 less-resourced countries and to determine the level of appropriateness in CT use. MATERIALS AND METHODS: Data on the increase in the number of CT examinations during 2007 and 2009 and appropriate use of CT examinations were collected, using standard forms, from 146 CT facilities at 126 hospitals. RESULTS: The lowest frequency of pediatric CT examinations in 2009 was in European facilities (4.3%), and frequencies in Asia (12.2%) and Africa (7.8%) were twice as high. Head CT is the most common CT examination in children, amounting to nearly 75% of all pediatric CT examinations. Although regulations in many countries assign radiologists with the main responsibility of deciding whether a radiologic examination should be performed, in fact, radiologists alone were responsible for only 6.3% of situations. Written referral guidelines for imaging were not available in almost one half of the CT facilities. Appropriateness criteria for CT examinations in children did not always follow guidelines set by agencies, in particular, for patients with accidental head trauma, infants with congenital torticollis, children with possible ventriculoperitoneal shunt malfunction, and young children (< 5 years old) with acute sinusitis. In about one third of situations, nonavailability of previous images and records on previously received patient doses have the potential to lead to unnecessary examinations and radiation doses. CONCLUSION: With increasing use of CT in children and a lack of use of appropriateness criteria, there is a strong need to implement guidelines to avoid unnecessary radiation doses to children.

Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia.

Sclerosteosis and Van Buchem disease are related recessive sclerosing bone dysplasias caused by alterations in the SOST gene. We tested the hypothesis that craniodiaphyseal dysplasia (CDD) (MIM 122860), an extremely rare sclerosing bone dysplasia resulting facial distortion referred to as "leontiasis ossea", could also be caused by SOST mutations. We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) two children with CDD. As these mutations are located in the secretion signal of the SOST gene, we tested their effect on secretion by transfecting the mutant constructs into 293E cells. Intriguingly, these mutations greatly reduced the secretion of SOST. We conclude that CDD, the most severe form of sclerotic bone disease, is part of a spectrum of disease caused by mutations in SOST. Unlike the other SOST-related conditions, sclerosteosis and Van Buchem disease that are inherited as recessive traits seem to be caused by a dominant negative mechanism.

New intermediate phenotype between MED and DD caused by compound heterozygous mutations in the DTDST gene.

DTDST mutations cause a spectrum of diastrophic dysplasia disorders characterized by defects of proteoglycans sulfation. Reduction of sulfate/chloride antiporter activity is manifested by lower sulfate uptake and depends on a combination of mutations in DTDST. We analyzed a family with an autosomal recessive form of bone dysplasia. Three affected brothers from this family are compound heterozygotes for C653S/A715V mutations. We classified their phenotype as a new intermediate form between diastrophic dysplasia and multiple epiphyseal dysplasia, manifested by shortening of stature, metatarsus adductus/club foot, mild brachydactyly, proximally placed thumbs and clinodactyly of the fifth fingers. Radiographs document platyspondyly most marked in the lower thoracic and upper lumbar spine, epiphyseal dysplasia affecting predominantly the femoral heads, widening of the metaphyses, narrow growth cartilage and multilayered patellae. Exaggerated lesser trochanters of femur, that is, "monkey wrench" sign, elevated greater trochanters, thin upper pubic rami, grossly normal carpal/tarsal bones and severe, early onset osteoarthritis were other notable features.

Severe neonatal spondylometaphyseal dysplasia in two siblings.

We report on two siblings with a severe neonatal form of spondylometaphyseal dysplasia (SMD). Similar cases have been reported in four publications. Analysis of pedigree data from the original and present families suggests an autosomal recessive mode of inheritance, although parental gonadal mosaicism is also possible. The similarities in the phenotype between our patients and spondyloepimetaphyseal dysplasia congenita (SEMDC) and spondyloepimetaphyseal dysplasia Strudwick (SEMDS) type, indicated that these patients could have a defect in the COL2A1 gene. Molecular analysis of genomic DNA of these patients excluded this gene. Another potential candidate gene PTHR1, was also analyzed in the selected regions and no mutation was found. This gene is probably causative in the Jansen type of SMD, which shares some phenotypic features with the siblings whom we documented. Our results indicate that a new candidate gene for the reported form of SMD should be sought.

[Diaphragmatic hernia in reference hospital ICZMP--diagnostic problems and outcome]. / Problemy diagnostyczne i losy plodów z przepuklina przeponowa w osrodku referencyjnym ICZMP w latach 1994-2006.

OBJECTIVES: The aim of the study was to analyze US/ECHO examinations in fetuses with diaphragmatic hernia (DH) diagnosed and treated in our institution from 1994-2006, and their follow-up. MATERIAL AND METHODS: Retrospective analysis of the data base from Department for Diagnoses & Prevention of Fetal Malformations, Research Institute of the Polish Mother's Memorial Hospital: 14,481 fetal echo/ultrasound examinations in 10,077 fetuses have been analyzed to retrieve 115 fetuses with DH. RESULTS: The mean gestational age at the targeted US/ECHO examination was 30 wks. There were 8 terminations of pregnancies (at mean 21 wks), 6 intrauterine demises, 60 neonatal deaths after delivery (in 1-3rd day of postnatal life), 8 deaths after surgery, 19 neonates were discharged home and in 14 cases the follow-up could not be monitored. The most common anomalies accompanying DH have been central nervous system anomalies (20%), polyhydramnion (16%) and cong heart defects (10%). In this subgroup, there was 100% mortality. Isolated DH has been diagnosed in every third case. In this subgroup, 27 neonates had undergone surgery and the survival rate was 70%, however since 2004 there was not a single death on record. CONCLUSIONS: Late gestational age of US/ECHO examinations in our tertiary center suggests that DH has been relatively difficult to detect during ultrasound screening. DH and the other structural malformations have been a lethal disease in our series in 100%. Isolated DH was much less frequent and was present in every third case (29%), and in this group the survival rate was 70%, regardless of the way of the delivery (CS or Vaginal).

A boy with severe craniodiaphyseal dysplasia and apparently normal mother.

We describe a boy and his mother affected with craniodiaphyseal dysplasia (CDD). The boy had a very severe form of the disease with extensive osteosclerosis already at birth. Facial diplegia, bilateral hearing loss and optic nerve atrophy were early, severe complications of the disease. At age 7 years progressive genu valgum and unusual epimetaphyseal radiographic appearances suggested hyperparathyroidism. This was confirmed by biochemical tests. Because of some facial similarity between the asymptomatic mother and the propositus, a limited skeletal survey of the mother was performed. It demonstrated cranial osteosclerosis and hyperostosis. It is possible that the mother has somatic mosaicism for a mutation of the genes causing CDD.

Low-dose protocol for head CT in monitoring hydrocephalus in children.

BACKGROUND: Children with hydrocephalus and increased intracranial pressure are treated with ventricular shunts. Multiple head CT is used to assess shunt malfunction and changes in ventricular size (volume). Because of the naturally high contrast of the head structures in CT imaging, a low-dose protocol for hydrocephalic pediatric patients was proposed. The aim of the study was to assess the implemented protocol in categories of radiation risk to the patients. MATERIAL/METHODS: Head CT examinations were performed using the fourth-generation single-slice scanner PQ-2000 (Picker). Exposure parameters of the routine head procedure stored in the scanner software were the starting point for the investigation. The acceptable ranges of the modified parameters were found on the basis of earlier published results. The effect of the new protocol on image quality was tested using a CATPHAN phantom. The organ doses were evaluated experimentally. The clinical images were evaluated by two experienced and independent radiologists. RESULTS: Head CT examinations were performed in 380 children with hydrocephalus during a 10-year period at the Department of Diagnostic Imaging Polish Mother's Memorial Hospital. Until 2005 these children were examined according to the routine protocol of the scanner, i.e. 10 mm contiguous axial, 120 kVp, and 225 mAs. Then the protocol was modified to 10 mm contiguous axial, 100 kVp, and 150 mAs. Reductions in patient doses to 70% were found while the clinical images maintained sufficient diagnostic value. CONCLUSIONS: The low-dose protocol for head CT can be recommended for the monitoring of pediatric hydrocephalus patients.

Severe, atypical form of dyschondrosteosis (report of two cases).

UNLABELLED: We report a mother and her son with unique mesomelic dysplasia. The mesomelic shortening in the upper extremities presents features of Leri-Weill syndrome (dyschondrosteosis) (OMIM 127300), that of the lower extremities is consistent with Langer mesomelic dysplasia (OMIM 249700). Molecular studies showed a heterozygous short stature homeobox gene ( SHOX)deletion in both patients. A second genetic defect in the other SHOX allele was not found. CONCLUSION: Our study broadens the phenotypic spectrum associated with short stature homeobox gene functional haploinsufficiency.

[Difficulties in diagnosis of battered child syndrome in infant]. / Trudnosci diagnostyczne u niemowlecia z zespolem maltretowanego (bitego) dziecka.

The diagnosis of battered child syndrome in infants was reached on the basis of the risk factors appraisal in social and family history, combined with clinical and roentgenographic examinations; the difficulties in establishing the diagnosis are presented. Long hospitalisation also revealed that the observed injuries are due to child abuse. The interdisciplinary approach is needed when non-accidental injuries are considered.

[Usefulness of Doppler ultrasound imaging in monitoring of hypoxic-ischemic encephalopathy in preterm infants]. / Wartosc ultrasonografii dopplerowskiej w ocenie zmian niedokrwienno-niedotlenieniowych u wczesniaków.

Cerebral blood flow disregulation could be one of the main causes of hypoxic-ischaemic encephalopathy (HIE). It is difficult to differentiate between sonographic appearance of immature periventricular white matter of premature neonate and changes of HIE type. Therefore the diagnostic and prognostic value of doppler ultrasound resistance index (RI) examination in anterior cerebral arteries of premature infants with early sonographic signs of periventricular white matter hyperechogenicity was the aim of the study. The study group consisted of 23 premature infants: birth weight 1550 +/- 570 g, gestational age 24-32 weeks, Apgar score 2-7 points, of which 19 were ventilated. Doppler ultrasound imaging was performed twice: during the first 24 hours of life and 3 weeks later. As not all infants survived to the time of control examination, the final study group consisted of 17 subjects. Doppler examination of premature infants having finally sonographic signs of HIE (n = 12) revealed that RI value in this group of infants was increased during initial as well as the next examination. In the group of premature infants having finally normal sonographic scan (n = 5), doppler examinations showed that RI value stayed in normal limits or was slightly decreased all the time. We conclude that doppler imaging of premature infants could be important diagnostic and prognostic tool in differentiating between the ultrasonographic view of immature periventricular white matter and real HIE. Doppler imaging is useful in identification of patients having increased risk of HIE and supplements routine transfontanellar ultrasound in estimation of HIE progression.