Small Thorax Research Articles

Antenatal Diagnosis of Achondrogenesis Type II

Achondrogenesis is a lethal congenital chondrodystrophy characterized by extreme micromelia, small thorax and polyhydramnios. We describe a case of achondrogenesis type II (Langer-Saldino achondrogenesis). Prenatal ultrasonography at 22-weeks gestation revealed a fetus with large head, short neck and chest, prominent abdomen and short limbs. Pregnancy was terminated. Radiologic examination of neonate revealed features of achondrogenesis type II. Routine ultrasound screening made early detection and timely management possible.

Letters to the Editor

Letters to the Editor

Airway Evaluation and Management in 7 Children With Malignant Infantile Osteopetrosis Before Hematopoietic Stem Cell Transplantation

Malignant infantile osteopetrosis (MIOP) is a rare disorder caused by dysfunctional osteoclasts. The classic MIOP features, such as frontal bossing, micrognathia, and small thorax, may place these children at risk for developing obstructive sleep apnea (OSA) and chronic hypoxemia. To objectively document OSA, airway evaluations were performed; results impacted management. We reviewed the records of 7 MIOP patients treated at St Jude. Six underwent polysomnograms during prehematopoietic stem cell transplantation (HSCT) evaluation. To determine the existence of a relationship between OSA and radiologic imaging, initial chest radiographs and bone mineral density studies were reviewed. Pre-HSCT patients had a median apnea-hypopnea index of 17.51 (normal, 0 to 2), with <25% being central events, thus indicating OSA. The median minimal oxygen saturation was 79%, indicating intermittent hypoxemia. Neither chest radiographs nor bone mineral density correlated with severity of OSA. Four patients received tracheostomies before or during HSCT. Three surviving children underwent polysomnograms 1 year after HSCT, and median apnea-hypopnea index was 1.3, indicating near to complete resolution of OSA. Resolution of OSA may have been multifactorial. Using a quantitative approach, we demonstrate that MIOP children have OSA and hypoxemia; thus, these children should have airway evaluations and treatments to potentially reduce the risk of life-threatening pulmonary complications.

Phenotypic Characterization of the 7H24 Mutant in O‐xylosyltransferase

Formation of morphogenetic gradients is a fundamental mechanism of developmental signaling. Establishment of the gradient dictates how tissues respond to extracellular signals to elicit appropriate cellular responses to a secreted ligand. Recently, we have identified a novel mutation in the Drosophila O‐xylosyltransferase (oxt) that encodes a key enzyme required for heparan and chondroitin sulfate (HS and CS) biosynthesis, named 7H24. In Drosophila, HS has been shown to be essential for Wingless (Wg)/Wnt, Hedgehog (Hh) and Decapentaplegic (Dpp)/Bone Morphogenic Protein (BMP) extracellular ligand movement and gradient formation. When HS is absent downstream signaling of these elemental pathways that drive the Drosophila and human developmental program is disrupted. The 7H24 mutation in oxt is a functional null and removal of maternal and zygotic oxt is embryonic lethal with terminal segment polarity cuticle phenotypes suggesting disruption of the Wg and/or Hh signaling pathway. Removal of zygotic oxt causes homozygous mutants to die as pharate adults with small rough eyes and thorax defects that cannot close from the pupal case. We find deficiencies in Wg, Hh and Dpp signaling in the mutant larval wing imaginal discs and evaluation of larval eye phenotypes suggests they do not arise because of defects in cell type specification.

Paternal deletion 6q24.3: A new congenital anomaly syndrome associated with intrauterine growth failure, early developmental delay and characteristic facial appearance

Deletions of the long arm of chromosome 6 are relatively uncommon and to date minimal genotype-phenotype correlations have been observed. We report on three unrelated patients with de novo paternal interstitial deletions of 6q24.3. FISH mapping was used to delineate the minimal region of overlap between these three patients. Although all three patients had different size deletions and different breakpoints, two of the patients shared a 2.5 Mb region of overlap and strikingly similar facial features including a triangular face, frontal bossing with metopic prominence, short and upward-slanting palpebral fissures, asymmetry of upper eyelids, hooded eyelids, shallow orbits, prominent inferior orbital crease, wide mouth, and long and flat philtrum. They also had redundant skin, joint laxity, a small thorax, and early developmental delay. The smallest region of overlap between all three patients was a region of deletion less than 1 Mb; all had a history of IUGR and postnatal short stature without overt radiologic skeletal anomalies. The dysmorphic features, early developmental and growth delay may be due to the hemizygous state for one of the genes in the deleted region of two of the patients or to a long range effect of the deletion on expression of other genes. In addition, since imprinted genes have been reported in this region, paternal deletion of an imprinted gene in all three patients may contribute to the growth phenotype. We propose that this is a new congenital malformation syndrome associated with a paternal deletion of 6q24.3.

Paternal uniparental isodisomy for chromosome 14 with mosaicism for a supernumerary marker chromosome 14

Uniparental disomy (UPD) describes the inheritance of two homologous chromosomes from a single parent. Disease phenotypes associated with UPD and chromosomal imprinting, rather than with mutations, include Beckwith-Wiedemann syndrome (paternal UPD11p), Angelman syndrome (paternal UPD15), Prader-Willi syndrome (maternal UPD15), and transient neonatal diabetes (paternal UPD6). Here we report on the first case of paternal uniparental isodisomy of chromosome 14 with a mosaicism for a supernumerary marker chromosome 14. The patient demonstrated a small thorax with a 'coat hanger' shape of the ribs, kyphoscoliosis, hypoplasia of the maxilla and mandible, a broad nasal bridge with anteverted nares, contractures of the wrists with ulnar deviation bilaterally, diastasis recti, and marked muscle hypotonia. Vertical skin creases under the chin and stippled epiphyses of the humeri were features not previously described in patients with paternal UPD14. This case illustrates that as with the finding of an isochromosome, a supernumerary marker chromosome can be an important clue to the presence of UPD14.

Diagnóstico prenatal en el segundo trimestre de displasia torácica asfixiante

A case of prenatal diagnosis of Jeune’s syndrome is described. Because the incidence of this syndrome is low, diagnosis in the 21st week of pregnancy is exceptional. Jeune’s syndrome, or asphyxiating thoracic dysplasia, is a skeletal dysplasia with autosomal recessive inheritance. Prenatal diagnosis can be established by ultrasonographic findings of a small thorax, short ribs, pelvic abnormalities, rhizomelic brachymelia, and renal and liver anomalies, among others. In the present case, the prenatal diagnosis was confirmed at necropsy.

Evaluation of 3D Monte Carlo-Based Scatter Correction for 201Tl Cardiac Perfusion SPECT

(201)Tl-Chloride ((201)Tl) is a myocardial perfusion SPECT agent with excellent biochemical properties commonly used for assessing tissue viability. However, cardiac (201)Tl SPECT images are severely degraded by photons scattered in the thorax. Accurate correction for this scatter is complicated by the nonuniform density and varied sizes of thoraxes, by the additional attenuation and scatter caused by female patients' breasts, and by the energy spectrum of (201)Tl. Monte Carlo simulation is a general and accurate method well suited to modeling this scatter. Statistical reconstruction that includes Monte Carlo modeling of scatter was compared with statistical reconstruction algorithms not corrected for scatter. In the ADS method, corrections for attenuation, detector response, and scatter (Monte Carlo-based) were implemented simultaneously via the dual-matrix ordered-subset expectation maximization algorithm with a Monte Carlo simulator as part of the forward projector. The ADS method was compared with the A method (ordered-subset expectation maximization with attenuation correction) and with the AD method (a method like the A method but with detector response modeling added). A dual-head SPECT system equipped with two (153)Gd scanning line sources was used for simultaneously acquiring transmission and emission data. Four clinically realistic phantom configurations (a large thorax and a small thorax, each with and without breasts) with a cardiac insert containing 2 cold defects were used to evaluate the proposed reconstruction algorithms. We compared the performance of the different algorithms in terms of noise properties, contrast-to-noise ratios, the contrast separability of perfusion defects, uniformity, and robustness to anatomic variations. The ADS method provided images with clearly better visual defect contrast than did the other methods. The contrasts achieved with the ADS method were 10%-24% higher than those achieved with the AD method and 11%-37% higher than those achieved with the A method. For a typical contrast level, the ADS method exhibited noise levels around 27% lower than the AD method and 34% lower than the A method. Compared with the other 2 algorithms, the ADS reconstructions were less sensitive to anatomic variations and had better image uniformity in the homogeneously perfused myocardium. Finally, we found that the improvements that can be achieved with Monte Carlo-based scatter correction are stronger for (201)Tl than for (99m)Tc imaging. Our results indicate that Monte Carlo-based scatter correction is suitable for (201)Tl cardiac imaging and that such correction simultaneously improves several image-quality metrics.

Winged queens replaced by reproductives smaller than workers in Mystrium ants

In ants, winged queens that are specialized for independent colony foundation can be replaced by wingless reproductives better adapted for colony fission. We studied this shift in reproductive strategy by comparing two Mystrium species from Madagascar using morphometry, allometry and dissections. Mystrium rogeri has a single dealate queen in each colony with a larger thorax than workers and similar mandibles that allow these queens to hunt during non-claustral foundation. In contrast, Mystrium 'red' lacks winged queens and half of the female adults belong to a wingless 'intermorph' caste smaller and allometrically distinct from the workers. Intermorphs have functional ovaries and spermatheca while those of workers are degenerate. Intermorphs care for brood and a few mate and reproduce making them an all-purpose caste that takes charge of both work and reproduction. However, their mandibles are reduced and inappropriate for hunting centipedes, unlike the workers' mandibles. This together with their small thorax disallow them to perform independent colony foundation, and colonies reproduce by fission. M. rogeri workers have mandibles polymorphic in size and shape, which allow for all tasks from brood care to hunting. In M. 'red', colonial investment in reproduction has shifted from producing expensive winged queens to more numerous helpers. M. 'red' intermorphs are the first case of reproductives smaller than workers in ants and illustrate their potential to diversify their caste system for better colonial economy.

Prenatal diagnostic indicators of paternal uniparental disomy 14

To present clinical findings of a child with paternal uniparental isodisomy 14 (pat UPD14) focusing on relevant prenatal characteristics. Ultrasonography at 23 weeks of gestation of a 37-year-old multigravid woman revealed a fetus with polyhydramnios, small thorax, and short, distinctively angled ribs. Fetal karyotype was 46,XY. The child was born spontaneously at 35 weeks with poor neonatal adaptation. From birth, he presented with severe respiratory insufficiency due to severe thoracic malformation. Clinical examination revealed a small, bell-shaped thorax, redundant lax skin, mild contractures of the fingers and dysmorphic facial features. Chest X rays showed short, abnormally curved ribs that suggested the possibility of pat UPD14, which was confirmed by molecular analysis. Pat UPD14 is associated with a distinct clinical phenotype. Prognosis is poor because of severe respiratory insufficiency and neurodevelopmental retardation. Our report confirms salient postnatal signs of previous descriptions, especially the characteristic radiological abnormalities with ribs showing a 'coat-hanger' configuration. Retrospective fetal ultrasound of our case allowed the identification of this pathognomonic feature prenatally, which makes it possible to consider pat UPD14 at routine prenatal sonography, in particular in combination with a small bell-shaped thorax and polyhydramnios.

Segmental and full paternal isodisomy for chromosome 14 in three patients: Narrowing the critical region and implication for the clinical features

We report on segmental and full paternal isodisomy for chromosome 14 in three previously unreported Japanese patients. Patient 1 was a 5(6/12)-year-old girl, Patient 2 was a male neonate, and Patient 3 was a -year-old girl. Physical examination at birth showed various somatic features characteristic of paternal uniparental disomy for chromosome 14 (upd(14)pat) such as hairy forehead, protruding philtrum, micrognathia, small thorax, and abdominal wall defects in Patients 1-3, and the constellation of somatic features was persistently observed in Patients 1 and 3. Radiological studies at birth delineated unique bell-shaped thorax with coat-hanger appearance of the ribs in Patients 1-3, but the thoracic deformity ameliorated in Patients 1 and 3 by mid childhood. Chromosome analysis showed a 46,XX karyotype in Patients 1 and 3 and was not performed in Patient 2. Microsatellite analysis indicated full paternal isodisomy for chromosome 14 in Patients 1 and 2 and segmental paternal isodisomy for chromosome 14 distal to D14S981 at 14q23.3 in Patient 3. Methylation specific PCR assay for the differentially methylated region (DMR) of GTL2 at 14q32 yielded positive products with methylated allele specific primers and no products with unmethylated allele specific primers in Patients 1-3. Since clinical phenotype was similar between Patient 3 with segmental upd(14)pat and Patients 1 and 2 with full upd(14)pat, the results are keeping with the 14q32 localized imprinted genes as the critical components of the phenotype observed in upd(14)pat and help narrow the search for additional genes to the approximately 40 Mb region distal to D14S981. Furthermore, it is likely that the characteristic thoracic deformity ameliorates with age.

P102a: Ultrasonographic diagnosis of Jarcho-Levin syndrome at 20 weeks' gestation in a without previous family history. A case report

Jarcho-Levin syndrome (or spondylothoracic dysplasia) is a congenital disease characterized by multiple vertebral and rib malformations, causing a short trunk dwarfism commonly leading to respiratory insufficiency and death during the first years of life. Prenatal sonographic diagnosis of Jarcho-Levin syndrome has been reported in both the first and second trimester. But always in families at risk. The most characteristic sonographic features were malaligned vertebrae, disorganization of vertebral bodies, and posteriorly fused ribs. We describe a case diagnosed during the second trimester ultrasound scan for screening of fetal anomalies in a couple without history of affected children. This was the first pregnancy of a 24-year-old woman. The course of the pregnancy was uneventful until a structural defect of the fetal spine was detected at the 20 weeks’ scan. Fetal karyotype by cordocentesis was 46 XY, and major cardiac malformations were excluded by detailed fetal echocardiography. The fetus had a severe disorganization of the spine and ribs, skeletal kyphosis, with several hemivertebrae and a small thorax. The ultrasonographic findings allowed us making a reliable diagnosis of a variety of Jarcho-Levin syndrome, and adequate genetic counselling to the couple, even though no other malformations were associated and there was no family history for the syndrome. All of the findings at postmortem examination confirmed the ultrasound features and were consistent with the Jarcho-Levin syndrome. Our case illustrates the importance of an accurate ultrasound examination at both first and second trimester in order to detect any rare congenital syndromes.

Hepatic manifestations of Jeune syndrome (asphyxiating thoracic dystrophy).

Asphyxiating thoracic dystrophy, or Jeune syndrome, is an autosomal recessive skeletal dysplasia with multiorgan involvement. Most patients develop progressive respiratory insufficiency related to the abnormally small thorax and renal insufficiency. Other clinical manifestations include cystic lesions of the pancreas and retinal abnormalities. Hepatic abnormalities have been described both clinically and at autopsy, but the pathogenesis of the liver disease is not clear. A patient with Jeune syndrome developed complications because of progressive portal hypertension necessitating transplantation. We present a discussion of the gross and histopathologic findings in the explanted liver, along with a review of the pathology of liver disease in Jeune syndrome.

Prenatal sonographic diagnosis of Neu‐Laxova syndrome

We report the sonographic diagnosis of Neu-Laxova syndrome in a fetus at 27 weeks' menstrual age. The parents were first cousins. Sonography revealed microcephaly, a sloping forehead, exophthalmos, a small thorax and abdomen, hypoplastic lungs, syndactyly, hyperextended knees, polyhydramnios, a small placenta, and intrauterine growth restriction. The long bones were normal. The calvaria was hyperechoic and associated with shadowing, obscuring any intracranial abnormalities. This sonographic finding was presumed to represent calvarial calcification, not previously described with this syndrome. We believe that Neu-Laxova syndrome can be reliably diagnosed prenatally by demonstrating the sonographic features described, although other conditions with similar sonographic features need to be considered in the differential diagnosis.

2D/3D sonographic imaging of thanatophoric dysplasia type I at 19 weeks of gestation

Thanatophoric dysplasia is a sporadic, lethal congenital skeletal dysplasia. There are two major subtypes: (1) a short, curved femur characterizes type I; and (2) a straighter femur with cloverleaf skull characterizes type II. We, here, present a case of type I disease. A 30‐year‐old pregnant woman was referred to the ultrasound unit due to fetal short extremities at 19 weeks and 4 days of gestation. Ultrasound revealed short limbs and a severely small thorax. Every limb bone was markedly short, and the femur, tibia, fibula and humerus were remarkably curved. 3D ultrasound demonstrated the abnormal appearance of extremities. Cranial and intracranial structures were normal. One week later, no growth of limb bones was seen. Thanatophoric dysplasia type I was strongly suspected and counseling of the couple was done. Pregnancy was terminated at 21 weeks of gestation and a female fetus was aborted. Short and curved limb bones were confirmed by postnatal X‐ray. Genomic DNA obtained by cord blood showed a point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene; a C to T substitution at position 742 in the FGFR3 gene, resulting in a Arg248Cys substitution, known to be associated with type I disease. By ultrasound in the second trimester, prenatal diagnosis of skeletal dysplasia can be feasible. However, differentiating this lethal disease from non‐lethal skeletal disorders should be done prudently.

Non-cardiac thoracic ultrasound in 75 feline and canine patients.

The purpose of this study was to describe the ultrasonographic appearance of non-cardiac diseases of the small animal thorax. Ultrasound images from a total of 75 animals (26 cats and 49 dogs) were compared to cytologic, histopathologic, and necropsy findings. Clinical diagnoses included neoplasia of the mediastinum, pleura, or lungs (43); idiopathic mediastinal cyst (3); diaphragmatic or peritoneopericardial hernia (4); lung lobe torsion (1); pulmonary eosinophilic infiltrates (1); and idiopathic, chylous, congestive heart failure, or lymphangiectasia associated pleural effusion (14). In the remaining 9 patients, a definitive diagnosis was not obtained. Ultrasound-guided fine needle aspirate was performed in 56 patients; 1 of these also had an ultrasound-guided tissue core biopsy. Of the fine needle aspirates, 51 (91%) were diagnostic. Ultrasound examination, particularly when accompanied by guided tissue sampling, can be a valuable tool in the diagnosis of non-cardiac intrathoracic lesions.

Prenatal Diagnosis of Thoracopelvic Dysplasia: A Case Report

Thoracopelvic dysplasia, a variant of asphyxiating thoracic dysplasia (Jeune syndrome), is an uncommon skeletal disorder characterized by a small thorax, pelvic abnormalities and other complex, combined anomalies, including hypomelia, polydactyly and renal anomalies.A 32-year-old woman, gravida 1, para 0, was referred at 27 weeks' gestation due to polyhydramnios. Sonography revealed hydramnios, low fetal thoracic circumference (TC) and abdominal circumference (AC) ratio (0.78), skull and skin edema, increased nuchal translucency (7 mm), micrognathia, low-set ears, left cardiac deviation (66 degrees), overriding fingers, and club and rock-buttock feet. Amniocentesis revealed a normal karyotype (46, XY). Asphyxiating thoracic dysplasia was considered. At 40 weeks' gestation, a male infant was delivered vaginally. Besides the prenatal findings, cryptorchidism and high-arched palate were noted. Radiography of the infant revealed a narrow, funnel-shaped thorax and small pelvis with short, flared iliac bones; poorly developed acetabulum; and small, shallow sciatic notch. No dyspnea was observed at five months postpartum.Thoracopelvic dysplasia should be considered when a low TC/AC ratio (< 0.8) is observed. In this case the final diagnosis was made after detailed exclusion of other disorders combined with observation of a small thorax. Prenatal diagnosis of thoracopelvic dysplasia is possible.

Short-limb dwarfism and hypertrophic cardiomyopathy in a patient with paternal isodisomy 14: 45,XY,idic(14)(p11).

Uniparental disomy (UPD) has been shown to result in specific disorders either due to imprinting and/or homozygosity of mutant alleles. Here we present the findings in a child with paternal UPD14. Ultrasound evaluation was performed at 30 weeks of gestation because of abnormally large uterine size. Pertinent ultrasound findings included polyhydramnios, short limbs, abnormal position of hands, small thorax, and nonvisualization of the fetal stomach. Post-natally the infant was found to have a low birth weight, short birth length, contractures, short limbs, and a small thorax with upslanting ribs. Assisted ventilation and gastrostomy were required. At age 6 months, the infant required hospitalization for hypertrophic cardiomyopathy which responded to Atenolol. Initial cytogenetic studies demonstrated an apparently balanced de novo Robertsonian translocation involving chromosomes 14 and a karyotype designation of 45,XY,t(14q14q). No indication of mosaicism for trisomy 14 was observed in metaphase spreads prepared from peripheral blood lymphocytes or skin-derived fibroblasts. C-band and fluorescence in situ hybridization results demonstrated that the chromosome was dicentric. DNA analyses showed paternal uniparental isodisomy for chromosome 14. Based on the cytogenetic and DNA results a final karyotype designation of 45,XY,idic(14)(p11) was assigned to this infant with paternal isodisomy of chromosome 14.

A Case of Jeune Syndrome (Asphyxiating Thoracic Dystrophy)

A Case of Jeune Syndrome (Asphyxiating Thoracic Dystrophy)

Campomelic Syndrome Associated with Potter's Syndrome and Car diosplenic Syndrome

ABSTRACT Campomelic syndrome is a heterogeneous group of disorders characterized by short‐limbed dwarfism with congenital bowing or bending of the long bones particularly in the lower limbs and is frequently associated with a variety of non‐skeletal manifestations. Two distinct types are (1) long‐limbed campomelic dysplasia with bent bones of normal length and width: (2) short‐limbed campomelic dysplasia in which the bent bones are short and wide. We reported an autopsy case of this syndrome.This male baby with gestational age of 32 weeks was born to a mother with placenta previa, showing abdominal distention and short‐limbed appearance. Postmortem examination revealed bilaterally enlarged Potter type 1 polycystic kidneys, a pancreatic cyst, and two spleens in the abdominal cavity. Both lungs were hypoplastic and the heart exhibited multiple congenital anomalies such as double outlet right ventricle, pulmonary artery hy‐poplasia, mitral atresia, absence of ductus arteriosus, and inferior vena cava draining into the left atrium. Characteristically both femur bones were curved at proximal two‐thirds with slightly shortened lengths. Both humeri also showed bending of distal one‐third. Other chondro‐osseous abnormalities such as small epiglottis, narrow thorax, dolichoce‐phaly, and bilateral equinovarus deformity were noted. These findings were compatible with campomelic dysplasia of long‐limbed type accompanying unusual sets of non‐skeletal manifestations of Potter's syndrome and cardiosplenic syndrome. Key words: campomelic syndrome, Potter's syndrome, cardiosplenic syndrome