Asphyxiating Thoracic Dystrophy Research Articles

Clinical variability in DYNC2H1-related skeletal ciliopathies includes Ellis-van Creveld syndrome.

Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly unsolved families with different SCs. Deleterious DYNC2H1 variants were found in six sporadic patients and two monozygotic (MZ) twins. Clinical diagnoses included short rib-polydactyly type 3 in two cases, and asphyxiating thoracic dystrophy (ATD) in one case. Remarkably, clinical diagnosis fitted with EvC, mixed ATD/EvC and short rib-polydactyly/EvC phenotypes in three sporadic patients and the MZ twins. EvC/EvC-like features always occurred in compound heterozygotes sharing a previously unreported splice site change (c.6140-5A>G) or compound heterozygotes for two missense variants. These results expand the DYNC2H1 mutational repertoire and its clinical spectrum, suggesting that EvC may be occasionally caused by DYNC2H1 variants presumably acting as hypomorphic alleles.

Lateral Thoracic Expansion for Jeune's Syndrome, Surgical Approach, and Technical Details

Jeune's syndrome, or asphyxiating thoracic dystrophy (ATD), is a rare autosomal recessive disorder characterized by skeletal dysplasia. Ribs are typically short and horizontal resulting-in lethal variant-in severe lung hypoplasia, progressive respiratory failure, and death. Lateral thoracic expansion (LTE) consists in staggered bilateral ribs osteotomy leading to chest expansion and lung development. Studies on LTE in ATD patients report encouraging data, but the rarity of ATD implies the lack of a standardized surgical path. The aim of this report is to present our experience with LTE, the technical modification we adopted, and patients' clinical outcome. We retrospectively reviewed data of 11 LTE performed in 7 ATD patients with lethal variant. Information regarding pre- and postoperative clinical conditions and surgical details was collected. We adopted a single-stage or a two-stage approach based on patient clinical condition. Computed tomography (CT) scan was performed before and after surgery and lung volume was calculated. Five patients are alive, while two died in intensive care unit for other than respiratory cause (sepsis). Most patients experienced clinical improvement in terms of decreased respiratory infections rate, need for ventilation, and improved exercise tolerance. Postoperative CT scan demonstrated a median lung volume increase of 88%. Mortality in ADT patients is high. However, LTE is a feasible and safe surgical approach, which could improve clinical conditions and survival rate. Survived patients showed postoperatively less oxygen requirement and improved clinical conditions.

Laparoscopic gastrostomy in a patient with asphyxiating thoracic dystrophy

Asphyxiating thoracic dystrophy (ATD), also known as Jeune syndrome, is an autosomal recessive disease which causes thoracic insufficiency. Complications and life expectancy vary based on specific mutations. Infants with this condition may require operative feeding access in addition to surgery for other associated anomalies. No prior cases of laparoscopic surgery in ATD have been recorded in the literature. This case demonstrates that with proper technique, laparoscopic surgery can be accomplished safely. Newborn diagnosed with ATD prenatally with anatomical 20-week ultrasound who required long term enteral feeding access due to inability to tolerate oral feeds secondary to tachypnea. Patient underwent laparoscopic gastrostomy tube placement at 2 weeks of age. This was well tolerated, and no complications arose from insufflation pressure despite small thoracic volumes. Pressure control ventilation was used along with frequent desufflation breaks. Patient tolerated tube feeds at goal until expiration at 8 weeks of age. Laparoscopic surgery can be safely performed in patients with ATD with appropriate monitoring and ventilatory support. Although ATD is commonly fatal, this type of palliative surgery can improve patients’ quality of life and allow them to discharge home safely so they can spend more time with family.

Distrofia torácica asfixiante o Síndrome de Jeune

La distrofia torácica asfixiante (DTA), también denominada Síndrome de Jeune, es una enfermedad genética autosómica recesiva, cuya causa se desconoce en muchos casos. Sin embargo, se han identificado mutaciones en al menos 11 distintos genes.[1,2] Su frecuencia se estima en 1:130000 recién nacidos vivos.[3] La afección clínica se manifiesta en los huesos, principalmente en el tórax y las costillas. El tórax pequeño y las costillas cortas, son causa de la cavidad torácica, característicamente en “forma de campana” que, restringe el crecimiento y la expansión de los pulmones, lo que causa dificultad respiratoria.[3,4] La forma letal de este síndrome se debe a insuficiencia respiratoria secundaria a la hipoplasia pulmonar y al estrechamiento de la caja torácica.[4] La DTA se puede asociar también con brazos y piernas cortas, formas inusuales de los huesos pélvicos, dedos adicionales de pies o manos y problemas renales, cardíacos, hepáticos y oculares.[1,2,3] El objetivo es reportar un caso clínico de la forma letal de DTA.

Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling

Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms responsible for functional primary cilia. We identified two families with ATD caused by loss‐of‐function mutations in the gene encoding adrenergic receptor kinase 1 (ADRBK1 or GRK2). GRK2 cells from an affected individual homozygous for the p.R158* mutation resulted in loss of GRK2, and disrupted chondrocyte growth and differentiation in the cartilage growth plate. GRK2 null cells displayed normal cilia morphology, yet loss of GRK2 compromised cilia‐based signaling of Hedgehog (Hh) pathway. Canonical Wnt signaling was also impaired, manifested as a failure to respond to Wnt ligand due to impaired phosphorylation of the Wnt co‐receptor LRP6. We have identified GRK2 as an essential regulator of skeletogenesis and demonstrate how both Hh and Wnt signaling mechanistically contribute to skeletal ciliopathies.

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.

Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.

Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short-rib polydactyly type I, Saldino-Noonan type.

The short-rib polydactyly syndromes (SRPS) are autosomal recessively inherited, genetically heterogeneous skeletal ciliopathies. SRPS phenotypes were historically categorized as types I-IV, with type I first delineated by Saldino and Noonan in 1972. Characteristic findings among all forms of SRP include short horizontal ribs, short limbs and polydactyly. The SRP type I phenotype is characterized by a very small thorax, extreme micromelia, very short, poorly mineralized long bones, and multiple organ system anomalies. To date, the molecular basis of this most severe type of SRP, also known as Saldino-Noonan syndrome, has not been determined. We identified three SRP cases that fit the original phenotypic description of SRP type I. In all three cases, exome sequence analysis revealed compound heterozygosity for mutations in DYNC2H1, which encodes the main component of the retrograde IFT A motor, cytoplasmic dynein 2 heavy chain 1. Thus SRP type I, II, III and asphyxiating thoracic dystrophy (ATD), which also result from DYNC2H1 mutations. Herein we describe the phenotypic features, radiographic findings, and molecular basis of SRP type I.

Destabilization of the IFT-B cilia core complex due to mutations in IFT81 causes a Spectrum of Short-Rib Polydactyly Syndrome.

Short-rib polydactyly syndromes (SRPS) and Asphyxiating thoracic dystrophy (ATD) or Jeune Syndrome are recessively inherited skeletal ciliopathies characterized by profound skeletal abnormalities and are frequently associated with polydactyly and multiorgan system involvement. SRPS are produced by mutations in genes that participate in the formation and function of primary cilia and usually result from disruption of retrograde intraflagellar (IFT) transport of the cilium. Herein we describe a new spectrum of SRPS caused by mutations in the gene IFT81, a key component of the IFT-B complex essential for anterograde transport. In mutant chondrocytes, the mutations led to low levels of IFT81 and mutant cells produced elongated cilia, had altered hedgehog signaling, had increased post-translation modification of tubulin, and showed evidence of destabilization of additional anterograde transport complex components. These findings demonstrate the importance of IFT81 in the skeleton, its role in the anterograde transport complex, and expand the number of loci associated with SRPS.

Jeune syndrome - asphyxiating thoracic dystrophy and its prenatal diagnosis: a rare case report

Jeune syndrome is an extremely rare condition representing Asphyxiating Thoracic Dystrophy (ATD) and it is potentially lethal congenital dwarfism with estimated incidence of 1 per 100000-130000 live births. 1 A term male neonate, born by vaginal delivery to a primigravida with polyhydramnios, presented to our NICU with birth asphyxia and severe respiratory distress since birth along with multiple characteristic skeletal anomalies including small bell shaped thorax and short limbs leading to diagnosis of Jeune syndrome. Follow up of the mother in her second pregnancy with prenatal sonographic examination at 17 and 19 weeks revealed the same type of skeletal dystrophy in this pregnancy. Diagnosis was made on ultrasonographic findings and detected abnormalities were confirmed by X-ray following termination of her second pregnancy. This is a case of Jeune syndrome in siblings.

DYNC2H1 Mutations Cause Asphyxiating Thoracic Dystrophy and Short Rib-Polydactyly Syndrome, Type III

Jeune asphyxiating thoracic dystrophy (ATD) is an autosomal-recessive chondrodysplasia characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and trident acetabular roof. ATD is closely related to the short rib polydactyly syndrome (SRP) type III, which is a more severe condition characterized by early prenatal expression and lethality and variable malformations. We first excluded IFT80 in a series of 26 fetuses and children belonging to 14 families diagnosed with either ATD or SRP type III. Studying a consanguineous family from Morocco, we mapped an ATD gene to chromosome 11q14.3-q23.1 in a 20.4 Mb region and identified homozygous mutations in the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene in the affected children. Compound heterozygosity for DYNC2H1 mutations was also identified in four additional families. Among the five families, 3/5 were diagnosed with ATD and 2/5 included pregnancies terminated for SRP type III. DYNC2H1 is a component of a cytoplasmic dynein complex and is directly involved in the generation and maintenance of cilia. From this study, we conclude that ATD and SRP type III are variants of a single disorder belonging to the ciliopathy group.

Jeune's syndrome (asphyxiating thoracic dystrophy): congenital and acquired

Familial asphyxiating thoracic dystrophy (ATD), also known as Jeune's syndrome, is a rare autosomal recessive disorder with variable severity and multiple musculo-skeletal manifestations. Respiratory distress may be severe, resulting in death during infancy. Surgical repair techniques have typically involved median sternotomy (with graft interposition), resulting in poor outcomes. Acquired ATD may rarely result from impairment of chest wall growth following "open" (Ravitch-type) repair of pectus excavatum or carinatum deformities. Symptomatic patients may have profound restriction of pulmonary function. Repair techniques typically involve re-do Ravitch-type procedures or median sternotomy with rib graft interposition. Mild to moderate improvements in pulmonary function tests have been documented.

Asphyxiating thoracic dystrophy with facial dysmorphism

Here it is reported a male newborn baby with features of asphyxiating thoracic dystrophy (ATD) with facial dysmorphism. The disproportionate rhizomelic short stature, narrow thorax, long fibulae, wide metaphysis and trident acetabule are consistent with diagnosis of ATD. In addition the baby had facial dysmorphism and broad thumbs and great toes similar to Oto-palato-digital syndrome type II (OPD II). The association of these features with ATD is not reported till date.

Further experience with the operative management of asphyxiating thoracic dystrophy after pectus repair

Background/Purpose Asphyxiating thoracic dystrophy (ATD) can occur years after a Ravitch-type repair of pectus excavatum, resulting in debilitating alteration in pulmonary function (PFT). An operation was devised to attempt repair of this deformity. Methods After institutional review board approval, the records of 10 children (ages 9-18 years) with ATD that developed 4 to 12 years postpectus operation who underwent attempted repair of ATD were reviewed. Data obtained before ATD operation and at 6, 12, and 24 months afterward included chest computed tomography, pulmonary functions (PFT), and a quality of life questionnaire. The operation consisted of sternal split with rib graft placement to permanently hold the sternum apart. Results All children survived and the bone grafts healed solidly. Computed tomography showed a change from a flat to a round chest contour on cross section, with increased anteroposterior dimension. Two patients had no change in PFT at 24 months whereas the other 8 had 21% to 30% improvement in PFT parameters. All patients reported improved exercise tolerance, and 3 began sports activities who were previously unable to do so. Two patients on oxygen, essentially bedridden, are now active, breathing only room air. Seven of 10 patients continue to have cosmetic concerns. Conclusions A small population of patients who had postoperative pectus repair developed severe, debilitating ATD. The repair described improves most patients, some dramatically, but does not significantly improve cosmetic appearance. The operation is undergoing further refinement to address these issues.

Exclusion of the Ellis-van Creveld region on chromosome 4p16 in some families with asphyxiating thoracic dystrophy and short-rib polydactyly syndromes.

Ellis-van Creveld syndrome (EVC) is a relatively rare, usually non-lethal, autosomal recessive skeletal dysplasia characterized by short stature, polydactyly, cardiac and renal anomalies. Linkage analysis has localized the disease gene to chromosome 4p16, with the markers at loci D4S827 and D4S3135 defining the centromeric and telomeric limits of the linked interval, respectively. There has been long-term speculation that asphyxiating thoracic dystrophy (ATD) and the short-rib polydactyly syndromes (SRP) represent the severe end of the EVC disease spectrum. We performed linkage analysis using markers from the EVC region in seven families manifesting either ATD or SRP type III. In two of the families, one segregating ATD and one SRP kindred, linkage of the phenotype to the EVC region was excluded. In the other five families linkage of the phenotype to the EVC region could not be excluded, but the families were too small for linkage to the region to be established. The exclusion of the EVC region in ATD and SRP III families suggests that locus heterogeneity exists within the short-rib dysplasia (with and without polydactyly) group of disorders.

ASPHYXIATING THORACIC DYSTROPHY

ASPHYXIATING THORACIC DYSTROPHY

Del(12)(p11.21p12.2) associated with an asphyxiating thoracic dystrophy or chondroectodermal dysplasia‐like syndrome

We describe a 5-year-old Japanese boy who has some radiographic findings characteristic of asphyxiating thoracic dystrophy (ATD)-chondroectodermal dysplasia with a de novo chromosome abnormality. He also has mild mental retardation, short stature, hypoplastic hair and skin, oligodontia, small thoracic cage, hypoplastic pelvis and cone-shaped epiphyses of hands. On cytogenetic studies he was found to have a de novo del(12)(p11.21p12.2). These results suggest that the locus of the gene associated with ATD-chondroectodermal dysplasia may be situated at 12p11.21p12.2.

A Case of Jeune Syndrome (Asphyxiating Thoracic Dystrophy)

A Case of Jeune Syndrome (Asphyxiating Thoracic Dystrophy)

624 Prenatal Ultrasound Findings in Asphyxiating Thoracic Dystrophy (ATD)

624 Prenatal Ultrasound Findings in Asphyxiating Thoracic Dystrophy (ATD)

Ａｓｐｈｙｘｉａｔｉｎｇ Ｔｈｏｒａｃｉｃ Ｄｙｓｔｒｏｐｈｙの１例

Asphyxiating thoracic dystrophy (ATD) was first described by Jeune et al in 1954. The main features are a narrow, constricted rib cage and generalized chondrodystrophy with shortlimbed dwarfism. A case of ATD is reported. A boy was 4years 9month old. He had a episode of cardiorespiratory arrest in infancy. He was first seen at our hospital with spastic quadriplegia caused by intracranial hemorrhage. He was admitted in order to have an operation for dislocation of rt-hip joint.

Thoracic-pelvic dysostosis: a 'new' autosomal dominant form.

A form of thoracic and pelvic dysostosis is reported in a mother and her son. The short ribs caused respiratory distress in the baby and raised the possibility of asphyxiating thoracic dystrophy (ATD). The radiological features, however, distinguish this benign condition from ATD and other described skeletal dysplasias.