Clinical features and genetic analysis of a case series of skeletal ciliopathies in a prenatal setting.

BACKGROUND: Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias. METHODS: Systemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues. RESULTS: The major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively. CONCLUSION: Our findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.

Ellis van creveld syndrome: Cardiac anomalies and anesthetic implications.

Ellis-Van Creveld syndrome (EVC), also known as mesoectodermal dysplasia, is a rare autosomal recessive disorder with a tetrad of clinical features, comprising dwarfism, polydactyly, ectodermal dysplasia with sparse hair, hypoplastic nails and enamel, hypodontia and conical teeth and congenital heart disease (CHD). We report an 18-year-old girl with short stature and polydactyly, who got admitted to our hospital with shortness of breath on exertion for the last 2 years. On echocardiography, a partial atrioventricular canal (AV canal) defect was diagnosed, which was repaired surgically. The patient had an uneventful perioperative period.

RETINAL DYSTROPHY IN JEUNE SYNDROME: A MULTIMODAL IMAGING CHARACTERIZATION.

PURPOSE: To report multimodal imaging findings in a patient affected by Jeune syndrome-associated retinal dystrophy. METHODS: Observational case report. RESULTS: An 18-year-old girl affected by Jeune syndrome was referred to our low vision unit. She presented with bilateral high myopia, reduced visual acuity, exotropia, and nystagmus. Fundus examination detected posterior myopic staphyloma and diffuse retinal dystrophy confirmed using a full-field electroretinogram as a cone-rod dystrophy. Spectral domain optical coherence tomography detected a thick anomalous hyperreflective band located beneath an irregular and disrupted external limiting membrane, showing the primary involvement of the photoreceptors outer segment with relative sparing of the retinal pigment epithelium, as confirmed by fundus autofluorescence. CONCLUSION: This is a case of Jeune syndrome with retinal abnormalities studied with fundus autofluorescence and optical coherence tomography. Retinal noninvasive multimodal imaging could provide significant insight in the retinal involvement of patients affected by Jeune syndrome and should have an essential role in the multidisciplinary diagnostic approach and follow-up.

Displasia torácica asfixiante / Suffocating thoracic dysplasia

El síndrome de Jeune o displasia torácica asfixiante es una enfermedad genética de herencia autosómica recesiva, que se caracteriza por presentar un fenotipo característico. El diagnóstico es clínico y radiológico. Se han descrito mutaciones en genes (IFT80, DYNC2H1, WDR19, IFT140 y TTC21B) que codifican proteínas de transporte intraflagelares responsables de la enfermedad

Jeune syndrome or suffocating thoracic dysplasia is a genetic disease with autosomal recessive inheritance, characterized by presenting a quirky phenotype. The diagnosis is clinical-radiological. Mutations in genes IFT80, DYNC2H1, WDR19, IFT140 and TTC21B that encode intraflagellar transport proteins responsible for the disease have been described

Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal-onset diabetes.

Protein disulfide isomerase A6 (PDIA6) is an unfolded protein response (UPR)-regulating protein. PDIA6 regulates the UPR sensing proteins, Inositol requiring enzyme 1, and EIF2AK3. Biallelic inactivation of the two genes in mice and humans resulted in embryonic lethality, diabetes, skeletal defects, and renal insufficiency. We recently showed that PDIA6 inactivation in mice caused embryonic and early lethality, diabetes and immunodeficiency. Here, we present a case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile-onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage-dependent manner, supporting a loss-of-function effect of this variant. Phenotypic correlation with the mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. In general, the phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans. This is the first study to associate ATD to the UPR gene, PDIA6. We recommend screening ATD cases with or without insulin-dependent diabetes for variants in PDIA6.

Common atrium/atrioventricular canal defect and postaxial polydactyly: A mild clinical subtype of Ellis-van Creveld syndrome caused by hypomorphic mutations in the EVC gene.

Clinical expression of Ellis-van Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein, we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium, and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1, and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a noncanonical splice-site in-frame change (c.1316-7A>G) in the daughter. Complementary DNA sequencing, immunoblot, and immunofluorescence experiments using patient-derived fibroblasts and Evc-/- mouse embryonic fibroblasts showed that p.Arg622Ter is a loss-of-function mutation, whereas p.Arg663Pro and the splice-site change c.1316-7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as "common atrium/AVCD with postaxial polydactyly" is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotype-phenotype correlations in this syndrome.

Skeletal ciliopathies: a pattern recognition approach.

Ciliopathy encompasses a diverse group of autosomal recessive genetic disorders caused by mutations in genes coding for components of the primary cilia. Skeletal ciliopathy forms a subset of ciliopathies characterized by distinctive skeletal changes. Common skeletal ciliopathies include Jeune asphyxiating thoracic dysplasia, Ellis-van Creveld syndrome, Sensenbrenner syndrome, and short-rib polydactyly syndromes. These disorders share common clinical and radiological features. The clinical hallmarks comprise thoracic hypoplasia with respiratory failure, body disproportion with a normal trunk length and short limbs, and severely short digits occasionally accompanied by polydactyly. Reflecting the clinical features, the radiological hallmarks consist of a narrow thorax caused by extremely short ribs, normal or only mildly affected spine, shortening of the tubular bones, and severe brachydactyly with or without polydactyly. Other radiological clues include trident ilia/pelvis and cone-shaped epiphysis. Skeletal ciliopathies are commonly associated with extraskeletal anomalies, such as progressive renal degeneration, liver disease, retinopathy, cardiac anomalies, and cerebellar abnormalities. In this article, we discuss the radiological pattern recognition approach to skeletal ciliopathies. We also describe the clinical and genetic features of skeletal ciliopathies that the radiologists should know for them to play an appropriate role in multidisciplinary care and scientific advancement of these complicated disorders.

The Role of Ellis-Van Creveld 2(EVC2) in Mice During Cranial Bone Development.

EvC syndrome is a type of autosomal-recessive chondrodysplasia. Previous case studies in patients suggest abnormal craniofacial development, in addition to dwarfism and tooth abnormalities. To investigate how craniofacial development is affected in EvC patients, surface models were generated from micro-CT scans of control mice, Evc2 global mutant mice and Evc2 neural crest-specific mutant mice. The anatomic landmarks were placed on the surface model to assess the morphological abnormalities in the Evc2 mutants. Through analyzing the linear and angular measurements between landmarks, we identified a smaller overall skull, shorter nasal bone, shorter frontal bone, and shorter cranial base in the Evc2 global mutants. By comparing neural crest-specific Evc2 mutants with control mice, we demonstrated that the abnormalities within the mid-facial regions are not accounted for by the Evc2 mutation within these regions. Additionally, we also identified disproportionate length to width ratios in the Evc2 mutants at all levels from anterior to posterior of the skull. Overall, this study demonstrates a more comprehensive analysis on the craniofacial morphological abnormalities in EvC syndrome and provides the developmental insight to appreciate the impact of Evc2 mutation within the neural crest cells on multiple aspects of skull deformities. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 301:46-55, 2018. © 2017 Wiley Periodicals, Inc.

Anesthetic Management of a Child With Jeune Syndrome for Tracheotomy: A Case Report.

Jeune syndrome is a rare autosomal-recessive skeletal disorder. Anesthetic management of these patients is often difficult because of thoracic and lung hypoplasia. A 5-month-old boy with Jeune syndrome was scheduled to undergo a tracheotomy. Despite 5-minute preoxygenation with continuous positive airway pressure, the patient's oxygen saturation rapidly dropped during the induction of anesthesia. The continuous positive airway pressure should have been titrated to effective tidal volume during preoxygenation to recruit the patient's functional residual capacity and to prevent desaturation. During tracheotomy, volume-controlled ventilation with a high respiratory rate and sufficient inspiratory time effectively improved the patient's respiratory status.

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.

[Clinical, radiological and auxologic long-term evolution of 8 children with asphyxiating thoracic dysplasia]. / Evolución clínica, radiológica y auxológica a largo plazo de 8 niños con displasia torácica asfixiante.

UNLABELLED: Asphyxiating thoracic dysplasia is an uncommon condition with multiple organ affectation and high neonatal mortality. It presents with short stature, short extremities, narrow thorax. With growth, there is respiratory improvement, but emergence of renal, hepatic, pancreatic and/or retinal impairment. OBJECTIVE: to describe the long-term evolution of 8 patients of a pediatric hospital. METHODS: we retrospectively evaluated age at diagnosis, sex, anthropometric variables, complications and radiology. RESULTS: male/female 6/2. Median age at diagnosis: 2.54 years. EVOLUTION: 8/8 respiratory compromise, 3/8 kidney, liver 2/8, 1/8 ophthalmologic, cardiac 1/8. Median height at diagnosis -1.76 DS, normal postnatal growth and body proportions. Radiology: 8/8 narrow chest and brachyphalangia in hands. 5/8 acetabular abnormalities. DISCUSSION: for surveillance it is recommended to monitor renal, liver and eye function. The pediatrician should suspect this entity in a newborn with narrow thorax and respiratory distress.

[Clinical case of Jeune syndrome].

The paper reports a clinical case of Jeune syndrome in a baby, in whom the diagnosis was established immediately after his birth. He was also diagnosed as having multiple congenital malformations, such as Dandy-Walker anomaly, hexadactyly of the left hand, cleft palate, choroidal colobomas in both eyes, and atrial septal defect and he also had interstitial nephritis and hepatitis.

One-stage sequential bilateral thoracic expansion for asphyxiating thoracic dystrophy (Jeune syndrome).

OBJECTIVES: Jeune syndrome (asphyxiating thoracic dystrophy) is a rare disorder characterized by skeletal dysplasia, reduced diameter of the thoracic cage and extrathoracic organ involvement. Fatal, early respiratory insufficiency may occur. Two-stage lateral thoracic expansion has been reported, addressing each side sequentially over 3-12 months. While staged repair theoretically provides less invasive surgery in a small child with respiratory distress, we utilized a single stage, bilateral procedure aiming to rapidly maximize lung development. Combined bilateral surgery also offered the chance of rapid recovery, and reduced hospital stay. We present our early experience of this modification of existing surgical treatment for an extremely rare condition, thought to be generally fatal in early childhood. METHODS: Nine children (6 males, 3 females; median age 30 months [3.5-75]) underwent thoracic expansion for Jeune syndrome in our centre. All patients required preoperative respiratory support (5 with tracheostomy, 8 requiring positive pressure ventilation regularly within each day/night cycle). Two children underwent sequential unilateral (2-month interval between stages) and 7 children bilateral thoracic expansion by means of staggered osteotomies of third to eighth ribs and plate fixation of fourth to fifth rib and sixth to seventh rib, leaving the remaining ribs floating. RESULTS: There was no operative mortality. There were 2 deaths within 3 months of surgery, due to pulmonary hypertension (1 following two-stage and 1 following single-stage thoracic expansion). At the median follow-up of 11 months (1-15), 3 children have been discharged home from their referring unit and 2 have significantly reduced respiratory support. One child remains on non-invasive ventilation and another is still ventilated with a high oxygen requirement. CONCLUSION: Jeune syndrome is a difficult condition to manage, but bilateral thoracic expansion offers an effective reduction in ventilator requirements in these children. While two-stage repair has been described previously, this is the first report of single-stage bilateral thoracic expansion. Single-stage repair is feasible and may offer better resource management and significant cost savings by potentially reducing theatre usage and overall length of stay (intensive care and hospital) without compromising clinical outcomes.

Short-rib polydactyly and Jeune syndromes are caused by mutations in WDR60.

Short-rib polydactyly syndromes (SRPS I-V) are a group of lethal congenital disorders characterized by shortening of the ribs and long bones, polydactyly, and a range of extraskeletal phenotypes. A number of other disorders in this grouping, including Jeune and Ellis-van Creveld syndromes, have an overlapping but generally milder phenotype. Collectively, these short-rib dysplasias (with or without polydactyly) share a common underlying defect in primary cilium function and form a subset of the ciliopathy disease spectrum. By using whole-exome capture and massive parallel sequencing of DNA from an affected Australian individual with SRPS type III, we detected two novel heterozygous mutations in WDR60, a relatively uncharacterized gene. These mutations segregated appropriately in the unaffected parents and another affected family member, confirming compound heterozygosity, and both were predicted to have a damaging effect on the protein. Analysis of an additional 54 skeletal ciliopathy exomes identified compound heterozygous mutations in WDR60 in a Spanish individual with Jeune syndrome of relatively mild presentation. Of note, these two families share one novel WDR60 missense mutation, although haplotype analysis suggested no shared ancestry. We further show that WDR60 localizes at the base of the primary cilium in wild-type human chondrocytes, and analysis of fibroblasts from affected individuals revealed a defect in ciliogenesis and aberrant accumulation of the GLI2 transcription factor at the centrosome or basal body in the absence of an obvious axoneme. These findings show that WDR60 mutations can cause skeletal ciliopathies and suggest a role for WDR60 in ciliogenesis.

Ultrasound diagnosis of recurring Jeune's syndrome: a case report.

Jeune's Syndrome or asphyxiating thoracic dystrophy (ATD) is a rare autosomal recessive skeletal dysplasia syndrome characterized by a small and narrow chest, short extremities, and often polydactyly associated with multiple organ manifestations. The severity of complications ranges from mild to lethal. This is a report of two cases of ATD diagnosed in successive pregnancies of a nonconsanguineous couple. The contribution of sonography in prenatal diagnosis of the syndrome is highlighted.

Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families.

BACKGROUND: Asphyxiating Thoracic Dysplasia (ATD) belongs to the short rib polydactyly group and is characterized by a narrow thorax, short long bones and trident acetabular roof. Other reported features include polydactyly, renal, liver and retinal involvement. To date, mutations in IFT80, DYNC2H1, TTC21B and WDR19 have been reported in ATD. The clinical and molecular heterogeneity leads to difficulties in the evaluation of the long-term prognosis. METHODS: We investigated 53 ATD cases (23 living cases and 30 fetuses) from 39 families. They benefited from a combined approach of deep phenotyping and IFT80 and DYNC2H1 molecular screening. RESULTS: Among the 23 postnatal cases, pulmonary insufficiency was noted in 60% of cases, with tracheotomy requirement in five cases. Renal and liver diseases occurred respectively in 17% and 22% of cases, whereas retinal alteration was present in 50% of cases aged more than 5 years. We identified DYNC2H1 mutations in 23 families (59%) and IFT80 mutations in two families (5%). However, in six families, only one heterozygote mutation in either IFT80 or DYNC2H1 was identified. Finally, the two genes were excluded in 14 families (36%). CONCLUSIONS: We conclude that DYNC2H1 is a major gene responsible for ATD, while IFT80 is rarely involved. The presence of only one mutation in six families and the exclusion of the two genes in 14 families support the involvement of other causal cilia genes. The long-term follow up emphasizes that the pulmonary prognosis is probably less pejorative and retinal involvement more frequent than previously thought.

Late survival in Ellis-van Creveld syndrome - a case report.

Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by chondrodystrophy, polydactyly, ectodermal dysplasia, and cardiac anomalies. Acromelic shortening of upper and lower limbs, genu valgum, multiple frenula, deformed teeth, short ribs and narrow thorax and congenital heart diseases complete the picture. The patients with the syndrome rarely survive into adulthood. Here, we report a lady with EVC presenting for the first time in middle age.

A novel chondroectodermal dysplasia mapped to chromosome 2q24.1-q31.1.

Chondroectodermal dysplasias are genetically heterogeneous group of disorders involving defects in one or more ectodermal appendages (hair, nail, teeth and sweat glands) in association with anomalies of the cartilage. In the present study a novel form of chondroectodermal dysplasia, segregating in an autosomal recessive pattern in a Pakistani family, was investigated. The clinical features including proportionate short stature, osteopenia with fracturing and breaking of bones, hypodontia, hypertrophic and convex shaped nails, night blindness, watering eyes and infection of ears were observed in affected individuals of the family. Genetic linkage study mapped the novel autosomal recessive form of chondroectodermal dysplasia on human chromosome 2q24.1-q31.1. Linkage to the region was established by scanning human genome using Human Mapping 250K Nsp array. Linkage interval for chondroectodermal dysplasia on human chromosome 2q24.1-q31.1 spans 13.76 cM, which corresponds to 15.72 Mb according to the sequence-based physical map (Build 36.2). The maximum multipoint LOD score of 3.37 was obtained with several markers along the disease interval. Sequence analysis of three candidate genes (TANK, ITGB6, TBR1) located in the candidate interval did not discover potentially causal variants.

First-trimester prenatal diagnosis of Ellis-van Creveld syndrome.

OBJECTIVE: To present the perinatal findings and first-trimester molecular and transabdominal ultrasound diagnosis of a fetus with Ellis-van Creveld (EvC) syndrome. CASE REPORT: A 35-year-old woman was referred for genetic counseling at 13 weeks of gestation because of a family history of skeletal dysplasia. She had experienced one spontaneous abortion, and delivered one male fetus and one female fetus with EvC syndrome. During this pregnancy, a prenatal transabdominal ultrasound at 13(+4) weeks of gestation revealed a nuchal translucency (NT) thickness of 2.0 mm, an endocardial cushion defect, postaxial polydactyly of bilateral hands, and mesomelic dysplasia of the long bones. Amniocentesis was performed at 13(+5) weeks of gestation. Results of a cytogenetic analysis revealed a karyotype of 46,XX and that of a molecular analysis revealed compound heterozygous mutations of c.1195C>T and c.871-2_894del26 in the EVC2 gene. Prenatal ultrasound at 16 weeks of gestation showed a fetus with short limbs, an endocardial cushion defect, and postaxial polydactyly of bilateral hands. The parents decided to terminate the pregnancy, and a 116-g female fetus was delivered with a narrow thorax, shortening limbs, and postaxial polydactyly of the hands. CONCLUSION: Prenatal diagnosis of an endocardial cushion defect with postaxial polydactyly should include a differential diagnosis of EvC syndrome in addition to short rib-polydactyly syndrome, Bardet-Biedl syndrome, orofaciodigital syndrome, Smith-Lemli-Opitz syndrome, and hydrolethalus syndrome.