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Asphyxiating thoracic dysplasia: Clinical and molecular review of 39 families
Abstract
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.
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.
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%).
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.
... 10,12 Apart from distinctive skeletal changes, these diseases often give rise to the involvement of extraskeletal organs, and cause extraskeletal phenotypes including polycystic kidney disease, retinal degeneration, and cardiac, liver, and brain anomalies. 6,10,14,24 The causative link between JATD and variants in several genes involved in the assembly and transport of cilia has been well established. 13,15,16 The association of the WDR60 gene, also known as DYNC2I1, with ciliopathies was recognized for the first time in 2013. ...
... High-throughput sequencing was used to analyze all the exon regions and adjacent intronic regions of JATD/ SRPS-associated genes that have been reported previously, including CEP120, DYNC2H1, EVC, EVC2, IFT43, IFT80, IFT122, IFT140, IFT172, NEK1, TTC21B, WDR19, WDR34, WDR35, and WDR60. 14,15,17,[21][22][23] After raw data processing, reads that passed were then mapped to the human reference genome (UCSC hg19) using the Burrows Wheeler Aligner (University of California, Santa Cruz, CA, USA). The variant call file (VCF) containing the detected variants was annotated with Variant Effect Predictor v83 and the dbNSFP (Database for Nonsynonymous SNPs' Functional Predictions) v3.1. ...
... A total of 30% of the surviving JATD patients developed end-stage renal disease, and 50% of the JATD cases presented retinal alterations similar to the proband in this report; however, the age of onset of extraosseous manifestations is still unevaluated to date. 14,25 To make a definite diagnosis and find the pathogenic gene, a JATD/SRPS panel including fifteen genes was screened by high-throughput sequencing, a novel homozygous variant c.2789C>T (p.S930L) in exon 24 of the WDR60 gene was found, and multiple sequence alignment indicated the evolutionary conservation of the p.S930L among different species (Figure 4). In silico analysis by four software programs highly suggested that the variant was a pathogenic form. ...
We report a Chinese patient with JATD presenting a mild skeletal phenotype and with renal insufficiency as the initial symptom of the disease. A novel homozygous c.2789C>T (p.S930L) variant in the WDR60 gene was identified. Our report will help to improve awareness and diagnosability for this disease.
... In addition to JATD, skeletal ciliopathies also encompass shortrib polydactyly syndromes (SRPS; MIM 611263, MIM613091, MIM 263520, MIM 269860, MIM 614091), Mainzer-Saldino syndrome (MZSDS; MIM 266920) [11], Sensenbrenner syndrome or cranio-ectodermal dysplasia (CED; MIM 218330) [12], oral-facial-digital syndrome 4 (OFD4; MIM 258860) and Ellis-van Creveld syndrome (EVC; MIM 225500) [10,12,13]. Apart from distinctive skeletal changes, these diseases often give rise to the involvement of extraskeletal organs, and cause extraskeletal phenotypes including polycystic kidney disease, retinal degeneration, and cardiac, liver, and brain anomalies [6,14]. ...
... Genomic DNA was extracted from the peripheral blood leucocytes using Blood genome DNA Extraction kit (Promega, USA). High-throughput sequencing was used to analyze all the exon regions and adjacent intronic regions of JATD/SRPS associated genes that have been reported previously including CEP120, DYNC2H1, EVC, EVC2, IFT43, IFT80, IFT122, IFT140, IFT172, NEK1, TTC21B, WDR19, WDR34, WDR35, and WDR60 [14,15,17,21,22,23]. After raw data processing, reads that passed were then mapped to the human reference genome (UCSC hg19) using the Burrows Wheeler Aligner (University of California, Santa Cruz, CA, USA). ...
... Notably, the proband's only sibling died of respiratory failure at infancy stage without definite diagnosis. It is estimated that 60% of JATD cases accompanied with lethal respiratory distress after birth [14]. Once overcome the respiratory dysfunction through a careful nursing at early stage after birth and the survival rate of infants will be improved. ...
We reported a delayed diagnosised Chinese JATD case with mild skeletal phenotype, and presented with renal insufficiency as the initial symptom of disease onset. Novel bilateral c.2789C>T (p.S930L) mutations in WDR60 gene were identified. Our report will help to improve our awareness and diagnosibility for this disease in China.
... No human patients with biallelic null variants in DYNC2H1 or WDR34 have been identified to date, likely because of embryonic lethality; all reported cases carry at least one presumably hypomorphic missense allele [58,60,[129][130][131][132][133]. In humans, impaired retrograde IFT motor dysfunction results in a complex developmental, often lethal, phenotype in humans summarized under the term short-rib thoracic dysplasia, with or without polydactyly (OMIM #611263, #613091, #263520, # 269860, # 614091, and #208500). ...
... WDR34 mutations can also cause non-syndromic rod−cone dystrophy (a single case reported) [141]. In contrast with JATD patients with IFT-gene mutation related ciliopathies, patients with dynein gene mutations show a more severe rib and lung phenotypes, often leading to neonatal death [129,135,136,142]. However, the surviving patients usually do not seem to develop clinically relevant eye or kidney disease until mid-adulthood; however, because of the low number of adult patients reported, it is unclear if this may occur later in life [129,135]. ...
... In contrast with JATD patients with IFT-gene mutation related ciliopathies, patients with dynein gene mutations show a more severe rib and lung phenotypes, often leading to neonatal death [129,135,136,142]. However, the surviving patients usually do not seem to develop clinically relevant eye or kidney disease until mid-adulthood; however, because of the low number of adult patients reported, it is unclear if this may occur later in life [129,135]. In contrast, IFT gene mutations seem to cause a mild rib phenotype, but nearly all JATD patients with IFT gene variants develop renal and retinal degeneration during childhood or adolescence [129,142]. ...
Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel developments in the field.
... Compared with that of other SRPs with high mortality caused by cardiopulmonary failure, the survival rate of JATD is 40%-80% [139,140]. JATD and SRP types I-IV have typical phenotypes of the skeletal system, such as shortened ribs and bell-shaped thorax, but patients with JATD have a lower probability of having respiratory insufficiency [141]. Other manifestations are short bones, polydactyly, irregular spurs on the acetabular bone and metaphysis, and cone-shaped epiphyses [141][142][143][144]. Surviving patients occasionally present retinal degeneration, polycystic kidneys, and hepatopathy [145]. ...
... The IFT140 mutation has also been detected in patients with JATD [129,153]. At least 6 other genes are related to JATD, namely, DYNC2H1, IFT80, IFT139, IFT140, WDR19, and WDR34 [129][130][131][139][140][141]144,149,154,155], indicating a complex correspondence between genotype and phenotype. Schmidts et al. concluded that the IFT140 mutation is a rare cause of JATD in general but is a frequent cause of JATD with renal involvement [141]. ...
Bone and teeth are hard tissues. Hard tissue diseases have a serious effect on human survival and quality of life. Primary cilia are protrusions on the surfaces of cells. As antennas, they are distributed on the membrane surfaces of almost all mammalian cell types and participate in the development of organs and the maintenance of homeostasis. Mutations in cilium-related genes result in a variety of developmental and even lethal diseases. Patients with multiple ciliary gene mutations present overt changes in the skeletal system, suggesting that primary cilia are involved in hard tissue development and reconstruction. Furthermore, primary cilia act as sensors of external stimuli and regulate bone homeostasis. Specifically, substances are trafficked through primary cilia by intraflagellar transport, which affects key signaling pathways during hard tissue development. In this review, we summarize the roles of primary cilia in long bone development and remodeling from two perspectives: primary cilia signaling and sensory mechanisms. In addition, the cilium-related diseases of hard tissue and the manifestations of mutant cilia in the skeleton and teeth are described. We believe that all the findings will help with the intervention and treatment of related hard tissue genetic diseases.
... Синдром Жёна -генетически гетерогенное расстройство, являющееся представителем цилиопатий, или расстройств, связанных с дисфункциями первичных ресничек [3,4,5]. В 2013 г. ...
... Все они кодируют белки, принадлежащие семейству IFT (Intraflagellar transport), имеющие большое значение для цилиогенеза, которые управляют целым рядом важных клеточных событий в нормальном развитии человека. Учитывая разнообразие вовлеченных в мутации генов и различные формы мутаций (сдвиг рамки считывания, делеции, сайт-сплайсинг), количество вариаций мутантных генов может достигать более семидесяти [4]. ...
... DYNC2H1 gene, with both parents being heterozygous carriers. This variant was previously reported in three patients with asphyxiating thoracic dysplasia (ATD) or short rib-polydactyly syndrome (SRPS) (Baujat et al., 2013;Dagoneau et al., 2009;Zhang et al., 2018). Particularly, only one 16-month-old patient (Baujat et al., 2013) had this variant in homozygosity; he showed clinical signs consistent with ATD as short ribs with narrow thorax, trident acetabular roof, long bones shortening, respiratory neonatal distress, long-term respirator complications, and short stature, so the DYNC2H1 variant was considered as disease causing by the authors. ...
... This variant was previously reported in three patients with asphyxiating thoracic dysplasia (ATD) or short rib-polydactyly syndrome (SRPS) (Baujat et al., 2013;Dagoneau et al., 2009;Zhang et al., 2018). Particularly, only one 16-month-old patient (Baujat et al., 2013) had this variant in homozygosity; he showed clinical signs consistent with ATD as short ribs with narrow thorax, trident acetabular roof, long bones shortening, respiratory neonatal distress, long-term respirator complications, and short stature, so the DYNC2H1 variant was considered as disease causing by the authors. ...
Background:
In the last few years trio-whole exome sequencing (WES) analysis has demonstrated its potential in obtaining genetic diagnoses even in nonspecific clinical pictures and in atypical presentations of known diseases. Moreover WES allows the detection of variants in multiple genes causing different genetic conditions in a single patient, in about 5% of cases. The resulting phenotype may be clinically discerned as variability in the expression of a known phenotype, or as a new unreported syndromic condition.
Methods:
Trio-WES was performed on a 4-month-old baby with a complex clinical presentation characterized by skeletal anomalies, congenital heart malformation, congenital hypothyroidism, generalized venous and arterial hypoplasia, and recurrent infections.
Results:
WES detected two different homozygous variants, one in CEP57, the gene responsible for mosaic variegated aneuploidy syndrome 2, the other in DYNC2H1, the main gene associated with short-rib thoracic dysplasia.
Conclusion:
The contribution of these two different genetic causes in determining the phenotype of our patient is discussed, including some clinical signs not explained by the detected variants. The report then highlights the role of WES in providing complete and fast diagnosis in patients with complex presentations of rare genetic syndromes, with important implications in the assessment of recurrence risk.
... On the molecular level, ATD represents a heterogeneous group of genetic disorders with mutations in several genes including IFT80, DYNC2H1, TTC21B and WDR19 (Baujat et al., 2013). On the clinical level, ATD is characterized by short ribs resulting in narrow chest and reduced thoracic capacity, short long bones, inconstant polydactyly, and trident acetabular roof sometimes accompanied by renal, liver and retinal disease (Dagoneau et al., 2009). ...
... Especially mutations in DYNC2H1 seem to be the major gene responsible for ATD. For example, in the group of 53 patients with ATD including 23 patients and 30 foetuses from 39 families, mutations in DYNC2H1 was found in 59% of cases (Baujat et al., 2013). Also in one of our patients, mutations in DYNC2H1 was found including a frame-shift mutation c.4458delT resulting in premature stopcodon p.Phe1486Leufs*11 (Zhang et al., 2018) and a missense mutation c.9044A>G (p.Asp3015Gly) (Dagoneau et al., 2009;Schmidts et al., 2013a). ...
Asphyxiating thoracic dysplasia (ATD) represents a heterogeneous group of skeletal dysplasias with short ribs, narrow chest and reduced thoracic capacity. Mutations in several genes including IFT80 , DYNC2H1 , TTC21B and WDR19 have been found in patients with ATD. Both severe and milder course of the disease were described in correlation with secondary involvement of lung’s function. Two children with attenuated form of ATD are described. Their anthropometric parameters for birth weight, length and head circumference were normal but narrow thorax was observed in both of them in early infancy with chest circumference < –3 SD (standard deviation) in comparison to age related controls. The postnatal adaptation and development of both children was uneventful except for mild tachypnoea in one of them which persisted till the age of 6 months. In both children, radiographs revealed narrow upper half of the chest with shorter ribs and atypical configuration of pelvis with horizontally running acetabula and coarse internal edges typical for ATD. Molecular analyses using whole exome sequencing in one family revealed that the patient is compound heterozygote in DYNC2H1 gene for a frame-shift mutation c.4458delT resulting in premature stop-codon p.Phe1486Leufs*11 and a missense mutation c.9044A>G (p.Asp3015Gly). The second family refused the DNA analysis. Regular monitoring of anthropometric parameters during childhood is of big importance both in health and disease. In addition, measurement of the chest circumference should be included, at least at birth and during infancy.
... A subset of these disorders have profound abnormalities of the skeleton and present with a characteristic set of phenotypic features that include long narrow chests with markedly short ribs, short limbs and polydactyly. The skeletal ciliopathies are clinically, radiographically, and genetically heterogeneous diseases that include the non-lethal phenotypes Ellis-van Creveld syndrome (EVC, MIM# 225500) and cranioectodermal dysplasia (CED, also known as Sensenbrenner syndrome, MIM# 218330), the more severe asphyxiating thoracic dystrophy (ATD, also known as Jeune syndrome, MIM# 208500) phenotype that is lethal in a up to half of the cases, especially those with dynein-2 complex mutations (Baujat et al., 2013;Tuysuz et al., 2009), and the perinatal lethal short-rib polydactyly syndromes (SRPS) . Based on distinctive radiographic findings, the SRPS have been classified into four subtypes: SRPS type I (Saldino-Noonan Syndrome, MIM# 263530), SRPS type II (Majewski Syndrome, MIM# 263520), SRPS type III (Verma-Naumoff Syndrome, MIM# 263510), and SRPS type IV (Beemer-Langer Syndrome, MIM# 269860). ...
... DYNC2H1 mutations were by far the most frequent overall cause of the skeletal ciliopathies studied, accounting for 48% of the families screened and with wide clinical variability ranging from ATD to SRPS types I, II, and III (but not SRPS type IV). DYNC2H1 mutations have been previously reported in five SRPS type II, eight SRPS type III, and 48 ATD cases, and the gene has been recognized as the major locus for ATD (Baujat et al., 2013;Schmidts et al., 2013a). We identified mutations in DYNC2H1 in 30 out of 66 ATD cases. ...
... Retinal abnormalities are reported in 15-50%, but it may represent under-ascertainment [14,15,16]. All of our patients had documented retinal pigmented dystrophy by fundoscopy and/or electroretinography, but only half of them suffered of night blindness, usually manifested after the age of 2 years. ...
... Recently, five genes causing JATD have been reported, all encoding proteins involved in IFT (DYNC2H1, IFT80/WDR56, IFT139/TTC21B, IFT144/WDR19, IFT140) [4,10,15,[27][28][29][30][31][32][33]. ...
Introduction/Objective. Jeune syndrome (JS) is a rare hereditary ciliopathy characterized by asphyxiating thoracic dystrophy, shortened limbs and brachydactyly. Extraskeletal anomalies such as chronic renal failure (CRF), hepatic fibrosis, and retinitis pigmentosa may be a part of the JATD phenotype. The aim of this study is to present long-term follow-up of JS patients with early progressive kidney disease. Methods. This is a retrospective study of pediatric patients with JS and CRF who were treated at the University Children’s Hospital between January 1980 and December 2014. The patients’ data were retrospectively reviewed from the medical records. Results. There were thirteen patients from 11 families, five girls and eight boys mean aged 4.3 years at the time of diagnosis. All of the patients had characteristic skeletal findings, retinal degeneration and an early onset of CRF at age range from 1.5 to 7 years. Five patients had neonatal respiratory distress and congenital liver fibrosis was diagnosed in five patients. One patient died due to complications of CRF, while others survived during follow-up of mean 11 years. IFT140 mutations were found in four genetically tested patients. Conclusion. The average incidence rate of JS with renal phenotype in Serbia was about 0.2 per one million of child population. Long-term survival of JS patients depends on renal replacement therapy, while skeletal dysplasia, growth failure, respiratory and eyes problems have impact on the patients’ quality of life.
... DYNC2H1 is essential for ciliogenesis and plays an important role in Hedgehog signaling events which are critical to human skeletal development (Krakow et al., 2000;Pazour et al., 2006). DYNC2H1 encodes a subunit of cytoplasmic dynein complex, a component of IFTA involved in the retrograde transport from the ciliary tip to the basal body of the ciliary axoneme and plays a role in the generation and maintenance of mammalian cilia (Baujat et al., 2013). Variants in DYNC2H1 have been associated with a heterogeneous spectrum of conditions related to altered primary cilium function that often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys (Chen et al., 2016). ...
Background and aims: Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3) represents a type of severe fetal skeletal dysplasia (SD) characterized by shortened limbs, narrow thorax with or without polydactyly, which is caused by the homozygous or compound heterozygous mutations in the DYNC2H1 gene. SRTD3 is a recessive disorder, identification of the responsible genetic variation would be beneficial to an accurate prenatal diagnosis and well-grounded counseling for the affected families.
Material and methods: Two families having experienced recurrent fetal SDs were recruited and submitted to a multiplatform genetic investigation. Whole-exome sequencing (WES) was performed with samples collected from the probands. Sanger sequencing and fluorescent quantitative PCR (qPCR) were conducted as validation assays for suspected variations.
Results: WES identified two compound heterozygous variations in the DYNC2H1(NM_001080463.2) gene, namely c.2386C>T (p.Arg796Trp) and c.7289T>C (p.Ile2430Thr) for one; and exon (64–83)del and c.8190G>T (p.Leu2730Phe) for the other, respectively. One variant in them, exon (64–83)del, was novelly identified.
Conclusion: The study detected two compound heterozygous variation in DYNC2H1 including one novel deletion: exon (64–83) del. Our findings clarified the cause of fetal skeletal dysplasia in the subject families, provided guidance for their future pregnancies, and highlighted the value of WES in diagnosis of skeletal dysplasia with unclear prenatal indications.
... Renal changes in fetuses with Joubert syndrome (enlarged, hyperechogenic, cystic kidneys with reduced or absent CMD) are found in approximately 25-30% [2,8,15] and dependent on the underlying mutations [16]. In Jeune syndrome, renal abnormalities were present in approximately 1/3 of cases and mainly include cysts or hydronephrosis [8,17]. ...
Purpose
Report on the diagnosis of prenatally detected fetal kidneys with bilateral polycystic appearance in a single center between 1999 and 2020 with special focus on renal morphology and biometry, amniotic fluid and extrarenal findings and proposal for an diagnostic algorithm.
Methods
Retrospective observational study including pregnancies with prenatally detected kidneys with bilateral polycystic appearance (n = 98). Cases and outcomes were compared according to prenatal findings with special focus on renal morphology, amount of amniotic fluid, and presence of extrarenal abnormalities.
Results
Most frequent diagnoses were autosomal recessive polycystic kidney disease (ARPKD, 53.1%), Meckel–Gruber syndrome (MKS, 17.3%) and autosomal dominant polycystic kidney disease (ADPKD, 8.2%). Other diagnoses included: Joubert-, Jeune-, McKusick–Kaufman- and Bardet–Biedl syndrome, overgrowth syndromes, Mainzer–Saldino syndrome and renal tubular dysgenesis.
Renal abnormalities most frequently observed were hyperechogenic parenchyma, kidney enlargement, changes of corticomedullary differentiation and cystic changes of various degree. Oligo- and anhydramnios were mainly seen in ARPKD, RTD and second-trimester MKS. Extrarenal findings included skeletal (35.7%) and cardiac (34.7%) abnormalities as well as abnormalities of the central nervous system (27.6%).
Conclusion
Gestational age at manifestation, kidney size, visibility of cysts, echogenicity, amniotic fluid volume, and the presence of associated extrarenal malformations allow to differentiate between the most frequent underlying diseases presenting with bilateral polycystic kidneys on prenatal ultrasound by following a diagnostic algorithm.
... Among all the cases of reported SRTD, Okamoto et al. once reported a Japanese patient carrying a c.5682_5683 delAA and c.9010C > T mutations who showed an extremely severe phenotype, including rib and long bone shortness, severe thoracic hypoplasia, polydactyly, ventriculomegaly, macrocephaly, polyhydramnios, visceral heterotaxia, a congenital heart defect and hypoplasia of the iliac bones [16]. Baujat et al. reported a baby in Turkey aged 9 months who was diagnosed with SRTD3 with situs inversus [17]. As evidenced by this study of SRTD3 with situs inversus totalis and mirror-image dextrocardia at the prenatal stage, we added one more detailed piece of the situs inversus phenotype with SRTD3 in a Chinese foetus. ...
Background
Short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3, OMIM: 613091) is an autosomal recessive disorder. SRTD3 presents clinically with a narrow thorax, short ribs, shortened tubular bones, and acetabular roof abnormalities. Clinical signs of SRTD3 vary among individuals. Pathogenic variants of DYNC2H1 (OMIM: 603297) have been reported to cause SRTD3.
Methods
We performed a detailed clinical prenatal sonographic characterization of a foetus with SRTD3. Trio whole-exome sequencing was used to identify causative variants in the family. The identified variants in the families were validated by Sanger sequencing and mass spectrometry. Multiple computational tools were used to predict the harmfulness of the two variants. A minigene splicing assay was carried out to evaluate the impact of the splice-site variant.
Results
We evaluated prenatal sonographic images of the foetus with SRTD3, including abnormal rib curvature, narrow thorax, bilateral hypoplastic lungs, bilateral polydactyly, syndactyly, and foetal visceral situs inversus with mirror-image dextrocardia. We revealed novel compound variants of DYNC2H1 (NM_001377.3:c.11483T > G (p.Ile3828Arg) and c.2106 + 3A > T). Various statistical methods predicted that the variants would cause harmful effects on genes or gene products. The minigene assay findings suggested that c.2106 + 3A > T caused the skipping over exon 14, producing an exon 14 loss in the protein.
Conclusion
This study identified a foetus with SRTD3 with situs inversus totalis with mirror-image dextrocardia in a Chinese family, revealing two novel compound heterozygous dynein cytoplasmic 2 heavy chain 1 ( DYNC2H1 ) variants, expanding the phenotypic spectrum of SRTD3. The minigene study of c.2106 + 3A > T was predicted to cause an inframe exclusion of exon 14, which was predicted to have important molecular functions. Our findings strongly supported the use of WES in prenatal diagnosis and helped to understand the correlation of genotype and phenotypes of DYNC2H1 . The specific sonographic findings and the molecular diagnosis helped add experience to further our expertise in prenatal counselling for SRTD3.
... SRPS is inherited in an autosomal recessive manner and several genes involving the basal body and intraflagellar transport (IFT) have been associated with this condition. Most of these cases result from mutation in genes encoding dynein-2 components, such as the heavy chain DYNC2H1 gene (Baujat et al., 2013) and the intermediate chain DYNC212 gene (previously known as WDR34) (Antony et al., 2021). Interestingly, biallelic loss of function mutations in DYNC2H1 have been reported in individuals with isolated retinal degeneration (Vig et al., 2020). ...
The primary cilium is a highly specialized and evolutionary conserved organelle in eukaryotes that plays a significant role in cell signaling and trafficking. Over the past few decades tremendous progress has been made in understanding the physiology of cilia and the underlying pathomechanisms of various ciliopathies. Syndromic ciliopathies consist of a group of disorders caused by ciliary dysfunction or abnormal ciliogenesis. These disorders have multiorgan involvement in addition to retinal degeneration underscoring the ubiquitous distribution of primary cilia in different cell types. Genotype-phenotype correlation is often challenging due to the allelic heterogeneity and pleiotropy of these disorders. In this review, we discuss the clinical and genetic features of syndromic ciliopathies with a focus on Bardet-Biedl syndrome (BBS) as a representative disorder. We discuss the structure and function of primary cilia and their role in retinal photoreceptors. We describe the progress made thus far in understanding the functional and genetic characterization including expression quantitative trait locus (eQTL) analysis of BBS genes. In the future directions section, we discuss the emerging technologies, such as gene therapy, as well as anticipated challenges and their implications in therapeutic development for ciliopathies.
... In this case, the patient was secondarily diagnosis with NSHPT at 11 months of age after further review of the radiographs revealed signs of metabolic bone disease (diffuse osteopenia, short ribs with irregular rib ends, and metaphyseal sclerosis at the ends of multiple long bones) and a biochemical evaluation indicated PTH-dependent hypercalcemia (Fisher et al., 2015). Jeune syndrome (MIM#208500) is an autosomal recessive skeletal ciliopathy in which a narrowed/bell-shaped thorax is associated with short ribs and irregular rib ends, short long bones with an irregular metaphysis, renal abnormalities, and less frequently, polydactyly, and hepatic, retinal, or pancreatic abnormalities (Baujat et al., 2013). Short ribs are noted if chest-to-abdominal circumference ratio is below 0.8, and a ratio below 0.6 is strongly suggestive of lethality (Yoshimura et al., 1996;Krakow et al., 2009). ...
Background
Loss-of-function variants in the calcium-sensing receptor (CASR) gene are known to be involved in a clinical spectrum ranging from asymptomatic familial hypocalciuric hypercalcemia (FHH) to neonatal severe hyperparathyroidism (NSHPT). Homozygous or compound heterozygous variants are usually responsible for severe neonatal forms, whereas heterozygous variants cause benign forms. One recurrent pathogenic variant, p.Arg185Gln, has been reported in both forms, in a heterozygous state. This variant can be a de novo occurrence or can be inherited from a father with FHH.
NSHPT leads to global hypotonia, failure to thrive, typical X-ray anomalies (diffuse demineralization, fractures, metaphyseal irregularities), and acute respiratory distress which can be fatal. Phosphocalcic markers show severe hypercalcemia, abnormal urinary calcium resorption, and hyperparathyroidism as major signs.
Classical treatment involves calcium restriction, hyperhydration, and bisphosphonates. Unfortunately, the disease often leads to parathyroidectomy. Recently, calcimimetics have been used with variable efficacy. Efficacy in NSHPT seems to be particularly dependent on CASR genotype.
Case presentation
We describe the antenatal presentation of a male with short ribs, initially suspected having skeletal ciliopathy. At birth, he presented with NSHPT linked to the pathogenic heterozygous CASR variant, Arg185Gln, inherited from his father who had FHH. Postnatal therapy with cinacalcet was successful.
Discussion
An exhaustive literature review permits a comparison with all reported cases of Arg185Gln and to hypothesize that cinacalcet efficacy depends on CASR genotype. This confirms the importance of pedigree and parental history in antenatal short rib presentation and questions the feasibility of phosphocalcic exploration during pregnancy or prenatal CASR gene sequencing in the presence of specific clinical signs. It could in fact enable early calcimimetic treatment which might be effective in the CASR variant Arg185Gln.
... Skeletal features that are observed in almost all patients with a skeletal ciliopathy are a narrow thorax, shortening of the ribs, and abnormal limbs and digits. These features are most severe in SRPS patients, resulting in embryonic or neonatal lethality [1][2][3]. A close resemblance of this phenotype, but to a milder degree, is seen in patients with ATD and MZSDS. ...
Skeletal ciliopathies are a group of disorders caused by dysfunction of the cilium, a small signaling organelle present on nearly every vertebrate cell. This group of disorders is marked by genetic and clinical heterogeneity, which complicates accurate diagnosis. In this study, we developed a robust, standardized immunofluorescence approach to accurately diagnose a subset of these disorders. Hereto we determined and compared the cilium phenotype of healthy individuals to patients from three different ciliopathy subgroups, using skin-derived fibroblasts. The cilium phenotype assay consists of three parameters; (1) ciliogenesis, based on the presence or absence of cilium markers, (2) cilium length, measured by the combined signal of an axonemal and a cilium membrane marker, and (3) retrograde intraflagellar transport (IFT), quantified by the area of the ciliary tip. Analysis of the cilium phenotypic data yielded comparable and reproducible results and in addition, displayed identifiable clusters for healthy individuals and two ciliopathy subgroups, i.e. ATD and CED. Our results illustrate that standardized analysis of the cilium phenotype can be used to discriminate between ciliopathy subgroups. Therefore, we believe that standardization of functional assays analyzing cilium phenotypic data can provide additional proof for conclusive diagnosis of ciliopathies, which is essential for routine diagnostic care.
... Additionally, the narrow thorax phenotype in ATD is usually severe compared to the relatively milder one in CED; leading to respiratory distress and subsequent neonatal or infantile death in 60 to 80% of cases. 23 Our patient died at 10 months of age with respiratory distress and infection as a result of lung hypoplasia secondary to the small thoracic cage. ...
Protein disulfide isomerase A6 (PDIA6) is an unfolded protein response (UPR)‐regulating protein. PDIA6 regulates the UPR sensing proteins, IRE1 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. WES 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.
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... Schmidt et al. in their article described comprehensively the similar findings [6]. Baujat et al. reviewed 53 cases of ATD in 39 families both clinically and at molecular level and concluded DYNC2CH1 as the major gene responsible [7]. Badiner et al. reported three cases with gene sequencing and revealed compound heterozygosity for mutations in DYNC2H1 [8]. ...
Jeune syndrome, also known as asphyxiating thoracic dystrophy, is a rare multisystem potentially lethal skeletal dysplasia. It has an estimated incidence of 1/100,000–130,000 live births. A term outborn female neonate born by vaginal delivery to a primigravida mother, presented to our neonatal intensive care unit with severe respiratory distress since birth. The baby was noticed to have multiple characteristic skeletal anomalies including small bell-shaped thorax and short limbs leading to the clinical diagnosis of Jeune syndrome. Whole genome sequencing was done which confirmed the diagnosis. A correct clinical and genetic diagnosis in index cases of Jeune syndrome should be established to facilitate prenatal diagnosis and genetic counseling.
... Le syndrome de Jeune est une maladie rare autosomique récessive, appartenant au groupe des ciliopathies, et pouvant impliquer différents gènes codant chacun pour une protéine du transport intraflagellaire [1,2]. Appelé aussi dysplasie pulmonaire asphyxiante, il se manifeste par une ostéochondrodysplasie responsable d'un syndrome dysmorphique associant une hypoplasie thoracique, un nanisme à prédominance rhizomyélique avec des membres courts et plus rarement une polydactylie [3,4]. ...
... Short-rib thoracic dysplasia-3 with or without polydactyly (SRTD3; 613091) is a rare skeletal dysplasia disease caused by homozygous or compound heterozygous mutations in the DYNC2H1 gene (603297) (Baujat et al., 2013). Generation of the human iPSC lines from a SRTD3 patient will provide a useful cellular model for investigating the pathogenic mechanism of SRTD3 related to DYNC2H1 mutations. ...
An induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells from a 27-month-old boy with short rib-thoracic dysplasia syndrome type III carrying compound heterozygous mutations (c.940T>C(p.W314R) and c.10163C>T(p.P3388L)) in DYNC2H1. The iPSCs have a normal karyotype, and express pluripotency markers and bear differentiation potential in vitro.
... Extra-renal manifestations occur in approximately 10%-20% of patients, including retinitis pigmentosa (7) , skeletal defects (8) , hepatic fibrosis (9) , neurologic abnormalities (10) , and cardiac defects (11) . NPHP is also a major clinical finding in several syndromes, including Senior-Loken, Joubert, Meckel-Gruber, Cogan, and Sensenbrenner syndromes, and asphyxiating thoracic dystrophy (ATD, also known as Jeune syndrome). ...
Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end‐stage renal disease in children. Nephronophthisis is a genetically heterogenous disorder with more than 25 identified genes. In 10%–20% of cases, there are additional features of a ciliopathy syndrome, such as retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. This review provides an update of the recent advances in the clinical features and related gene mutations of nephronophthisis, and novel approaches for therapy in nephronophthisis patients may be needed.
... The hexameric IFT-B2 complex was recently identified in several studies 8,25,26 . Missense mutations in IFT80, which encodes an IFT-B2 subunit, have been identified in individuals with the skeletal ciliopathies Jeune asphyxiating thoracic dystrophy (JATD) as well as Verma-Naumoff syndrome [27][28][29] , but it is still unclear how these alterations affect protein function. ...
Oligomeric assemblies of intraflagellar transport (IFT) particles build cilia through sequential recruitment and transport of ciliary cargo proteins within cilia. Here we present the 1.8Å resolution crystal structure of the Chlamydomonas IFT-B protein IFT80, which reveals the architecture of two N-terminal b-propellers followed by an a-helical extension. The N-terminal b-propeller tethers IFT80 to the IFT-B complex via IFT38 whereas the second b-propeller and the C-terminal a-helical extension result in IFT80 homo-dimerization. Using CRISPR/Cas to create biallelic Ift80 frameshift mutations in IMCD3 mouse cells, we demonstrate that IFT80 is absolutely required for ciliogenesis. Structural mapping and rescue experiments reveal that human disease-causing missense mutations do not cluster within IFT80 and form functional IFT particles. Unlike missense mutant forms of IFT80, deletion of the C-terminal dimerization domain prevented rescue of ciliogenesis. Taken together our results may provide a first insight into higher order IFT complex formation likely required for IFT train formation.
... Recently, our group and others have shown that ciliary chondrodysplasias are associated with mutations in genes encoding IFT-A complex subunits and associated dynein motor proteins (30,34,35). Specifically, mutations in WDR19, which encodes the IFT-A subunit IFT144, result in a large spectrum of ciliopathies including either isolated NPH, Senior-Løken (SLS: NPH and RD), NPH and liver involvement (Caroli disease or syndrome) as well as CED or JATD, depending on the severity of the mutations (29,(36)(37)(38)(39)(40)(41). Despite the fact that proteins encoded by primary ciliopathy genes are present in all types of cilia, clinical symptoms classically associated with PCD (e.g. ...
A child presenting with Mainzer-Saldino syndrome (MZSDS), characterized by renal, retinal and skeletal involvements, was also diagnosed with lung infections and airway ciliary dyskinesia. These manifestations suggested dysfunction of both primary and motile cilia, respectively. Targeted exome sequencing identified biallelic mutations in WDR19, encoding an IFT-A subunit previously associated with MZSDS-related chondrodysplasia, Jeune asphyxiating thoracic dysplasia and cranioectodermal dysplasia, linked to primary cilia dysfunction, and in TEKT1 which encodes tektin-1 an uncharacterized member of the tektin family, mutations of which may cause ciliary dyskinesia. Tektin-1 localizes at the centrosome in cycling cells, at basal bodies of both primary and motile cilia and to the axoneme of motile cilia in airway cells. The identified mutations impaired these localizations. In addition, airway cells from the affected individual showed severe motility defects without major ultrastructural changes. Knockdown of tekt1 in zebrafish resulted in phenotypes consistent with a function for tektin-1 in ciliary motility which was confirmed by live imaging. Finally, experiments in the zebrafish also revealed a synergistic effect of tekt1 and wdr19. Altogether, our data show genetic interactions between WDR19 and TEKT1 likely contributing to the overall clinical phenotype observed in the affected individual and provide strong evidence for TEKT1 as a new candidate gene for primary ciliary dyskinesia.
Skeletal ciliopathies constitute a subgroup of ciliopathies characterized by various skeletal anomalies arising from mutations in genes impacting cilia, ciliogenesis, intraflagellar transport process, or various signaling pathways. Short‐rib thoracic dysplasias, previously known as Jeune asphyxiating thoracic dysplasia (ATD), stand out as the most prevalent and prototypical form of skeletal ciliopathies, often associated with semilethality. Recently, pathogenic variants in GRK2 , a subfamily of mammalian G protein‐coupled receptor kinases, have been identified as one of the underlying causes of Jeune ATD. In this study, we report a new patient with Jeune ATD, in whom exome sequencing revealed a novel homozygous GRK2 variant, and we review the clinical features and radiographic findings. In addition, our findings introduce Morgagni hernia and an organoaxial‐type rotation anomaly of the stomach and midgut malrotation for the first time in the context of this recently characterized GRK2 ‐related skeletal ciliopathy.
Renal ciliopathies are a group of genetic disorders that affect the function of the primary cilium in the kidney, as well as other organs. Since primary cilia are important for regulation of cell signaling pathways, ciliary dysfunction results in a range of clinical manifestations, including renal failure, cyst formation, and hypertension. We summarize the current understanding of the pathophysiological and pathological features of renal ciliopathies in childhood, including autosomal dominant and recessive polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome, as well as skeletal dysplasia associated renal ciliopathies. The genetic basis of these disorders is now well-established in many cases, with mutations in a large number of cilia-related genes such as PKD1, PKD2, BBS, MKS, and NPHP being responsible for the majority of cases. Renal ciliopathies are broadly characterized by development of interstitial fibrosis and formation of multiple renal cysts which gradually enlarge and replace normal renal tissue, with each condition demonstrating subtle differences in the degree, location, and age-related development of cysts and fibrosis. Presentation varies from prenatal diagnosis of congenital multisystem syndromes to an asymptomatic childhood with development of complications in later adulthood and therefore clinicopathological correlation is important, including increasing use of targeted genetic testing or whole genome sequencing, allowing greater understanding of genetic pathophysiological mechanisms.
Intraflagellar transport (IFT) proteins have been reported to regulate cell growth and differentiation as the essential functional component of primary cilia. The effects of IFT80 on early bone healing of extraction sockets have not been well studied. To investigate whether deletion of Ift80 in alveolar bone‐derived mesenchymal stem cells (aBMSCs) affected socket bone healing, we generated a mouse model of specific knockout of Ift80 in Prx1 mesenchymal lineage cells (Prx1 Cre ;IFT80 f/f ). Our results demonstrated that deletion of IFT80 in Prx1 lineage cells decreased the trabecular bone volume, ALP‐positive osteoblastic activity, TRAP‐positive osteoclastic activity, and OSX‐/COL I‐/OCN‐positive areas in tooth extraction sockets of Prx1 Cre ; IFT80 f/f mice compared with IFT80 f/f littermates. Furthermore, aBMSCs from Prx1 Cre ; IFT80 f/f mice showed significantly decreased osteogenic markers and downregulated migration and proliferation capacity. Importantly, the overexpression of TAZ recovered significantly the expressions of osteogenic markers and migration capacity of aBMSCs. Lastly, the local administration of lentivirus for TAZ enhanced the expression of RUNX2 and OSX and promoted early bone healing of extraction sockets from Prx1 Cre ; IFT80 f/f mice. Thus, IFT80 promotes osteogenesis and early bone healing of tooth sockets through the activation of TAZ/RUNX2 pathway.
b> Introduction: Ciliopathies with major skeletal involvement embrace a group of heterogeneous disorders caused by pathogenic variants in a group of diverse genes. A narrow thorax with shortening of long bones inspires a clinical entity underlined by dysfunction of primary cilia. Currently, more than 23 genes are listed in the OMIM database corresponding to this clinical entity: WDR19/34/35/60, IFT43/52/80/81/140/172, DYNC2LI1, TTC21B, DYNLT2B, EVC2, EVC, INTU, NEK1, CEP120, DYNC2H1, KIAA0586, SRTD1, KIAA0753, and SRTD12. Recently, individuals with biallelic loss-of-function variants in GRK2 are shown to demonstrate a phenotype compatible with Jeune syndrome. Experimental evidence has shown that impaired function of GRK2 compromises cilia-based signaling of Hedgehog pathway as well as Wnt signaling, while cilia morphology remains intact. Hence, GRK2 is now considered an essential protein in regulation of the skeletogenesis. Case Presentation: We presented a female infant born to a consanguineous marriage who was found to have a biallelic p.R474* alteration in GRK2 in reanalysis of the whole-exome sequencing (WES) data. The patient was exhibiting major clinical features of Jeune syndrome, such as shortened long bones, ribs, and narrow thorax. Discussion: Our reanalysis of WES data revealed a likely pathogenic biallelic variant in the GRK2 which is probably responsible for the Jeune syndrome phenotype in the patient. Hence, our report supports the recently discovered association of GRK2 loss-of-function variants with Jeune syndrome phenotype and emphasizes the significance of reanalysis of WES data, notably in patients with phenotypes suggestive of a such discernible Mendelian disorder.
Renal ciliopathies are a common cause of kidney failure in children and adults, and this study reviewed their ocular associations. Genes affected in renal ciliopathies were identified from the Genomics England Panels. Ocular associations were identified from Medline and OMIM, and the genes additionally examined for expression in the human retina ( https://www.proteinatlas.org/humanproteome/tissue ) and for an ocular phenotype in mouse models ( http://www.informatics.jax.org/ ). Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have an ocular phenotype, including inherited retinal degeneration, oculomotor disorders, and coloboma. Diseases associated with pathogenic variants in ANK6, MAPKBP1, NEK8, and TCTN1 have no reported ocular manifestations, as well as low retinal expression and no ocular features in mouse models. Ocular abnormalities are not associated with the most common adult-onset "cystic" kidney diseases, namely, autosomal dominant (AD) polycystic kidney disease and the AD tubulointerstitial kidney diseases (ADTKD). However, other kidney syndromes with cysts have ocular features including papillorenal syndrome (optic disc dysplasia), Hereditary Angiopathy Nephropathy, Aneurysms and muscle Cramps (HANAC) (tortuous retinal vessels), tuberous sclerosis (retinal hamartomas), von Hippel-Lindau syndrome (retinal hemangiomas), and Alport syndrome (lenticonus, fleck retinopathy). Ocular abnormalities are associated with many pediatric-onset renal ciliopathies but are uncommon in adult-onset cystic kidney disease. However the demonstration of ocular manifestations may be helpful diagnostically and the features may require monitoring or treatment.
Cilia are evolutionarily extremely well conserved, microtubule based structures. Over the past two decades, their essential role during development and for tissue homeostasis, especially for the mammalian kidney, has come to light and with the development of Next Generation Sequencing techniques, an ever increasing number of ciliary genes has been identified as causative for human hereditary renal diseases. Most of these conditions manifest themselves at birth, in childhood or during adolescence and the vast majority causes complex phenotypes affecting multiple organ systems. While cilia and ciliary dysfunction have been linked to multiple cellular signalling pathways, the molecular pathomechanism underlying renal ciliopathies is still poorly understood. This chapter will focus on what is known to date about ciliary structure and their involvement in cell signalling pathways, summarize ciliopathies with renal involvement, especially conditions resulting from dysfunction of Intraflagellar Transport (IFT) and discuss their underlying pathobiology.KeywordsNephronophthisisCiliopathyIntraflagellar transportHedgehog signalingWnt signalingBardet-Biedl syndrome (BBS)Ciliary chondrodysplasia
Antenatal ultrasound examination has become a routine component for the care of pregnant women. Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most frequent organ malformations and constitute the most common cause of chronic renal failure in children. In this chapter we introduce the tools of assessment, describe the spectrum of fetal phenotypes and discuss the various approaches taken in the clinical management of prenatally diagnosed disorders of the kidneys and urinary tract. Based on this,, we outline rational antenatal and postnatal investigation strategies.KeywordsFetusCAKUTHydronephrosisAntenatalUltrasoundRenal cysts
The article shows the genetic causes of recurrent fetal malformations on the example of a clinical case of hereditary short-rib thoracic dysplasia type 3. Congenital malformations of the fetus are most often sporadic; however, in rare cases, this pathology can recur in one married couple, and the formation of congenital anomalies during subsequent pregnancy can both have general syndromes and affect various systems and organs. Short-rib thoracic dysplasia type 3 is a rare genetic disorder with autosomal recessive inheritance. Patients for whom the carriage of pathogenic alleles in genes associated with congenital skeletal anomalies has been confirmed require a detailed clinical examination. Such married couples want expert-level medical genetic counseling with performing additional genetic tests, if necessary. This may clarify the diagnosis, which will determine further tactics for preparing the couple for the next pregnancy on their own or using assisted reproductive technology programs and / or surrogate motherhood.
Background:
The 100 000 Genomes Project (100K) recruited National Health Service patients with eligible rare diseases and cancer between 2016 and 2018. PanelApp virtual gene panels were applied to whole genome sequencing data according to Human Phenotyping Ontology (HPO) terms entered by recruiting clinicians to guide focused analysis.
Methods:
We developed a reverse phenotyping strategy to identify 100K participants with pathogenic variants in nine prioritised disease genes (BBS1, BBS10, ALMS1, OFD1, DYNC2H1, WDR34, NPHP1, TMEM67, CEP290), representative of the full phenotypic spectrum of multisystemic primary ciliopathies. We mapped genotype data 'backwards' onto available clinical data to assess potential matches against phenotypes. Participants with novel molecular diagnoses and key clinical features compatible with the identified disease gene were reported to recruiting clinicians.
Results:
We identified 62 reportable molecular diagnoses with variants in these nine ciliopathy genes. Forty-four have been reported by 100K, 5 were previously unreported and 13 are new diagnoses. We identified 11 participants with unreportable, novel molecular diagnoses, who lacked key clinical features to justify reporting to recruiting clinicians. Two participants had likely pathogenic structural variants and one a deep intronic predicted splice variant. These variants would not be prioritised for review by standard 100K diagnostic pipelines.
Conclusion:
Reverse phenotyping improves the rate of successful molecular diagnosis for unsolved 100K participants with primary ciliopathies. Previous analyses likely missed these diagnoses because incomplete HPO term entry led to incorrect gene panel choice, meaning that pathogenic variants were not prioritised. Better phenotyping data are therefore essential for accurate variant interpretation and improved patient benefit.
BACKGROUND: Ciliopathies include the large group of hereditary diseases caused by mutations in the genes encoding primary cilia components. The largest type of skeletal ciliopathies is short-rib thoracic dysplasia. AIM: This study describes the clinical and genetic characteristics of Russian patients with STRD with or without polydactyly caused by mutations in the genes DYNC2H1, DYNC2I2, IFT80, and IFT140. MATERIALS AND METHODS: A comprehensive examination of 10 unrelated children aged from 9 days to 9 years, with phenotypic signs of short-rib thoracic dysplasia with or without polydactyly, was conducted. The diagnosis was confirmed using genealogical analysis, clinical examination, neurological examination, radiography, and targeted sequencing of a panel consisting of 166 genes responsible for the development of inherited skeletal pathology. RESULTS: As a result of the molecular genetic analysis, four short-rib thoracic dysplasia genetic variants were identified. Seven patients were diagnosed with short-rib thoracic dysplasia type 3, and three unique patients were diagnosed with types 11, 2, and 9 due to mutations in the DYNC2H1 and DYNC2I2, IFT80, and IFT140 genes, respectively. From the 14 detected variants, six were identified for the first time. As in the previously described patient samples, in the analyzed sample, more than half of the cases were due to a mutation in the DYNC2H1 gene, which is responsible for the SRTD type 3. The differences in the severity of clinical manifestations and the disease course in patients with mutations in certain regions of the gene, which have a different effect on its protein product function, have been shown. CONCLUSIONS: The results of this molecular genetic study broaden the spectrum of mutations in the DYNC2H1, DYNC212, and IFT140 genes causing short-rib thoracic dysplasia and confirm the usefulness of the whole-exome sequencing as the most informative method for identifying mutations of the genetically heterogeneous short-rib thoracic dysplasia group.
Cytoplasmic Dynein-2 or IFT-dynein is the only known retrograde motor for intraflagellar transport, enabling protein trafficking from the ciliary tip to the base. Dysfunction of WDR34 and WDR60, the two intermediate chains of this complex, causes Short Rib Thoracic Dystrophy (SRTD), human skeletal chondrodysplasias with high lethality. Complete loss of function of WDR34 or WDR60 is lethal in vertebrates and individuals with SRTD carry at least one putative hypomorphic missense allele. Gene knockout is therefore not suitable to study the effect of these human missense disease alleles.
Using CRISPR single base editors, we recreated three different patient missense alleles in cilia-APEX-IMCD3 cells. Consistent with previous findings in dynein-2 full loss of function models and patient fibroblasts, mutant cell lines showed hedgehog signaling defects as well as disturbed retrograde IFT. Transcriptomics analysis revealed differentially regulated expression of genes associated with various biological processes, including G-protein-coupled receptor signaling as well extracellular matrix composition, endochondral bone growth and chondrocyte development. Further, we also observed differential regulation of genes associated with Golgi intracellular transport, including downregulation of Rab6b , a GTPase involved in Golgi-ER retrograde protein trafficking and interacting with components of cytoplasmic dynein-1, in mutant ciliated and non-ciliated clones compared to controls. In addition to providing cellular model systems enabling investigations of the effect of human SRTD disease alleles, our findings indicate non-ciliary functions for WDR34 and WDR60 in addition to the established roles as components of the retrograde IFT motor complex in cilia.
The development of the kidney and the urinary tract is directed by a highly complex cellular dialogue between the ureteric bud and metanephric mesenchyme. Developmental defects are the result of disruptions in this reciprocal signaling. The complexity of signaling pathways in nephrogenesis explains the locus heterogeneity of congenital anomalies of the kidney and urinary tract (CAKUT). However, under this single label acronym lie different phenotypes, which present an incomplete penetrance and variable clinical presentation during the fetal period, making uniform and extended data collections difficult and introducing potential selection bias. There is not only clinical but also genetic support to the use of CAKUT, because it is well known that mutations in a single gene have pleiotropic effects on the development of the urogenital tract. The precise analysis of phenotypes with the establishment of genotype/phenotype correlations remains a gold standard for taking in turn full advantage from genomics. The standard definitions of patients’ phenotypes are mandatory for the data exchange: Semantic standards ensure that the terms used correlate with described patients’ characteristics consistently.
Less common types of chest wall malformations include sternal defects such as sternal cleft (SC), Poland Syndrome (PS) and Jeune syndrome (JS). SC is a congenital malformation characterized by the failure of sternal fusion during early embryonic life. PS comprises a spectrum of abnormalities of one side of the chest such as pectoralis muscle agenesia, defect of breast development and costal malformations. JS is a congenital dwarfism determining chest wall deformity. This chapter aims to provide an overview of the most common clinical findings, best diagnostic strategy and correct surgical treatments of these rarer anomalies.
Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD).
Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay).
Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2–4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD).
The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD.
Mutations in subunits of the cilia-specific cytoplasmic dynein-2 (CD2) complex cause short-rib thoracic dystrophy syndromes (SRTDs), characterized by impaired bone growth and life-threatening perinatal respiratory complications. Different SRTD mutations result in varying disease severities. It remains unresolved whether this reflects the extent of retained hypomorphic protein functions or relative importance of the affected subunits for the activity of the CD2 holoenzyme. To define the contribution of the LC8-type dynein light chain subunit to the CD2 complex, we have generated Dynll1-deficient mouse strains, including the first-ever conditional knockout (KO) mutant for any CD2 subunit. Germline Dynll1 KO mice exhibit a severe ciliopathy-like phenotype similar to mice lacking another CD2 subunit, Dync2li1. Limb mesoderm-specific loss of Dynll1 results in severe bone shortening similar to human SRTD patients. Mechanistically, loss of Dynll1 leads to a partial depletion of other SRTD-related CD2 subunits, severely impaired retrograde intra-flagellar transport, significant thickening of primary cilia and cilia signaling defects. Interestingly, phenotypes of Dynll1-deficient mice are very similar to entirely cilia-deficient Kif3a/Ift88-null mice, except that they never present with polydactyly and retain relatively higher signaling outputs in parts of the hedgehog pathway. Compared to complete loss of Dynll1, maintaining very low DYNLL1 levels in mice lacking the Dynll1-transcription factor ASCIZ (ATMIN) results in significantly attenuated phenotypes and improved CD2 protein levels. The results suggest that primary cilia can maintain some functionality in the absence of intact CD2 complexes and provide a viable animal model for the analysis of the underlying bone development defects of SRTDs. © 2019 The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Objective:
Intensive genetic analysis was performed to reveal comprehensive molecular insights into hypothalamic hamartoma (HH).
Methods:
Thirty-eight individuals with HH were investigated by whole exome sequencing, target capture-based deep sequencing, or single nucleotide polymorphism (SNP) array using DNA extracted from blood leukocytes or HH samples.
Results:
We identified a germline variant of KIAA0556, which encodes a ciliary protein, and 2 somatic variants of PTPN11, which forms part of the RAS/mitogen-activated protein kinase (MAPK) pathway, as well as variants in known genes associated with HH. An SNP array identified (among 3 patients) one germline copy-neutral loss of heterozygosity (cnLOH) at 6p22.3-p21.31 and 2 somatic cnLOH; one at 11q12.2-q25 that included DYNC2H1, which encodes a ciliary motor protein, and the other at 17p13.3-p11.2. A germline heterozygous variant and an identical somatic variant of DYNC2H1 arising from cnLOH at 11q12.2-q25 were confirmed in one patient (whose HH tissue, therefore, contains biallelic variants of DYNC2H1). Furthermore, a combination of a germline and a somatic DYNC2H1 variant was detected in another patient.
Conclusions:
Overall, our cohort identified germline/somatic alterations in 34% (13/38) of patients with HH. Disruption of the Shh signaling pathway associated with cilia or the RAS/MAPK pathway may lead to the development of HH.
We report novel causative mutations in the IFT80 gene identified in four fetuses from two unrelated families with Beemer‐Langer syndrome (BLS) or BLS‐like phenotypes. We discuss the implication of the IFT80 gene in ciliopathies, and its diagnostic value for BLS among other SRPS.
Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult‐onset disorders. Pathogenic variants in more than 100 ciliary protein‐encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT‐A) and anterograde transport (IFT‐B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c.118_125del, p.(Thr40Glyfs*11) and a c.352 +1G > T in IFT27, which encodes a small GTPase component of the IFT‐B complex. We conclude that bilateral renal agenesis is a rare feature of this severe ciliopathy and this report highlights the phenotypic overlap of Pallister–Hall syndrome and ciliopathies. The phenotype in patients with IFT27 gene variants is wide ranging from Bardet–Biedl syndrome to a lethal phenotype.
Human "ciliopathies," congenital developmental defects arising from cilia dysfunction, are thought to affect more than 1 per 2000 people. A subset of ciliopathies are skeletal syndromes marked by a narrowed thorax with shortened ribs, polydactyly and variable extraskeletal findings including renal and retinal involvement. These are usually caused by gene mutations affecting ciliary intraflagellar transport (IFT). Most mutations affect the IFT retrograde motor, cytoplasmic IFT dynein-2, most commonly its heavy chain dynein, DYNC2H1. Mutations are also found in its dynein intermediate chains, WDR60 and WDR34; light-intermediate chain, DYNC2LI1; and one light chain, TCTEX1D2. These retrograde motor dynein mutations can cause both lethal short-rib polydactyly syndromes and Jeune asphyxiating thoracic dysplasia with high (∼80%) survival, without any clear phenotype-genotype correlations. Mutations affecting motor-associated IFT complex A and B proteins (IFT140, IFT172, IFT80, and more rarely IFT144, IFT139/TTC21B) and several proteins localizing to the ciliary base can also cause skeletal ciliopathies. Here we describe clinical aspects of dynein biology focusing on the spectrum of IFT-associated skeletal abnormalities.
The short-rib polydactyly syndromes (SRPS) are a group of autosomal recessively inherited skeletal disorders termed skeletal ciliopathies. Ultrasound abnormalities include small, long, narrow chests; shortened appendicular long bones; and frequently seen polydactyly. Visceral abnormalities are commonly seen and occur in the neurologic, cardiac, gastrointestinal, and genitourinary systems, further complicating outcomes. The short-rib polydactyly syndromes, including asphyxiating thoracic dystrophy, are highly associated with lethality because of pulmonary hypoplasia and respiratory compromise.
This chapter focuses upon the impact of musculoskeletal disorders in the eye. A comprehensive review of Marfan Syndrome, Ehlers Danlos Syndrome, Osteogenesis Imperfecta, Stickler Syndrome, Fibrous Dysplasia, Osteopetrosis, Kneist Dystrophy, Spondyloepiphyseal Dysplasia, Sclerosteosis and Jeune Thoracic Dystrophy is presented. The chapter will examine the important features of these rare conditions and how they may presented to an ophthalmologist. Management of these disorders is discussed with a thorough literature review highlighting any developments in treatment.
In 1955, Jeune et al. described familial asphyxiating thoracic dystrophy (ATD) in a pair of siblings with severely narrow thoraxes. This condition is also known as Jeune syndrome. Incidence is estimated at 1 per 100,000–130,000 live births (den Hollander et al. 2001).
We previously reported exome sequencing in a short-rib thoracic dystrophy (SRTD) cohort, in whom recessive mutations were identified in SRTD-associated genes in 10 of 11 cases. A heterozygous stop mutation in the known SRTD gene WDR60 was identified in the remaining case; no novel candidate gene/s were suggested by homozygous/compound heterozygous analysis. This case was thus considered unsolved. Re-analysis following an analysis pipeline update identified a homozygous mutation in C21orf2 (c.218G > C; p.Arg73Pro). This homozygous variant was previously removed at the quality control stage by the default GATK parameter "in-breeding co-efficient." C21orf2 was recently associated with both Jeune asphyxiating thoracic dystrophy (JATD) and axial spondylometaphyseal dysplasia (axial SMD); this particular mutation was reported in homozygous and compound heterozygous state in both conditions. Our case has phenotypic features of both JATD and axial SMD; and the extent of thoracic involvement appears more severe than in other C21orf2-positive cases. Identification of a homozygous C21orf2 mutation in this case emphasizes the value of exome sequencing for simultaneously screening known genes and identifying novel genes. Additionally, it highlights the importance of re-interrogating data both as novel gene associations are identified and as analysis pipelines are refined. Finally, the severity of thoracic restriction in this case adds to the phenotypic spectrum attributable to C21orf2 mutations.
Asphyxiating thoracic dystrophy, also known as Jeune syndrome, is included in a group of syndromic skeletal ciliopathies associated with mutations in genes encoding proteins involved in the formation or function of motile cilia. Herein, we report a 6-mo-old male admitted to hospital with recurrent lung infections, thoracic dystrophy, and respiratory distress that was diagnosed as Jeune syndrome; DYNC2H1 mutation was detected via genetic analysis and ciliary dysfunction was noted via high-speed video microscopy.
Cilia are evolutionarily extremely well conserved, microtubule based structures. Over the past two decades, their essential role during development and for tissue homeostasis, especially for the mammalian kidney, has come to light and with the development of Next Generation Sequencing techniques, an ever increasing number of ciliary genes has been identified as causative for human hereditary renal diseases. Most of these conditions manifest themselves at birth, in childhood or during adolescence and the vast majority causes complex phenotypes affecting multiple organ systems. While cilia and ciliary dysfunction have been linked to multiple cellular signalling pathways, the molecular pathomechanism underlying renal ciliopathies is still poorly understood. This chapter will focus on what is known to date about ciliary structure and their involvement in cell signalling pathways, summarize ciliopathies with renal involvement, especially conditions resulting from dysfunction of Intraflagellar Transport (IFT) and discuss their underlying pathobiology.
The issue of antenatal ultrasound examination has become a routine component for the care of a pregnant woman. Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most frequent organ malformations and constitute the most common cause of chronic renal failure in children. In this chapter we introduce the tools of assessment, describe the spectrum of fetal phenotypes and discuss the various approaches taken in the clinical management of prenatally diagnosed disorders of the kidneys and urinary tract. Based on this body of information, we outline rational antenatal and postnatal investigation strategies.
Jeune syndrome, originally described as asphyxiating thoracic dystrophy by Jeune et al. [Jeune et al. (1955); Arch Fr Pediatr 12:886-891], is an autosomal recessive osteochondrodysplasia with characteristic skeletal abnormalities, and variable renal, hepatic, pancreatic, and retinal complications. We present eight patients, including two brothers with Jeune syndrome, and an extensive review of 118 cases in the published literature with the purposes of: (1) defining the clinical and radiological diagnostic criteria for Jeune syndrome; (2) comparing our cases to those in the literature meeting the documented clinical and radiological findings of Jeune syndrome, in order to: (3) provide an accurate clinical characterization of Jeune syndrome with frequency of associated complications and outcome data. In order to estimate the frequency of phenotypic abnormalities in Jeune syndrome as precisely as possible, we did not include reports in the literature with incomplete descriptions of the radiologic and clinical findings, nor those reports having additional findings overlapping with other syndromes. We found that the occurrence of renal, hepatic, and ophthalmologic complications is variable; does not correlate with severity of the skeletal phenotype; nor is it predictable even with the presence of a well-defined skeletal phenotype, as in this study. Based upon these cases with Jeune syndrome, renal and hepatic abnormalities occur in approximately 30% of cases, with renal failure occurring in 38% of those with kidney involvement. Eye abnormalities are reported in 15%, but it is unclear whether this represents under-ascertainment. There is a 1.2:1 ratio between living and deceased patients; a respiratory cause of death is most common, occurring almost exclusively in those less than 2 years of age, and a renal etiology accounts for all deaths between the ages of 3-10 years of age. There is a paucity of affected individuals reported in the literature greater than age 20 years, and a lack of longitudinal data to obtain accurate data on morbidity and mortality of Jeune syndrome at older ages. This study provides a well-defined group of patients with Jeune syndrome with delineation of the frequency of associated findings, which may form a basis for current and future genotype-phenotype studies.
Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ∼5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders.
Asphyxiating thoracic dystrophy-Jeune syndrome (JS) is a rare autosomal recessive disease characterized by small thorax and short limb dwarfism. Besides the clinical variability, prognosis also differs greatly among patients. Pulmonary involvement is predominant in some cases whereas renal involvement is much more evident in others. We aimed to investigate the clinical variability and prognosis in 13 patients with JS from 11 families. Two of them, who had been diagnosed in the prenatal period were assessed by autopsy findings. All patients had a bell-shaped or long narrow short thorax and brachydactyly at varying degrees from mild to severe. Short stature was common feature emerging in the postnatal period. One patient had atlantoaxial instability and spinal cord compression which have not been reported in JS before. In the postnatal follow up of 11 patients, respiratory distress was observed in eight patients and proved lethal in six, one patient died of chronic renal failure, and the remaining four patients were still alive at the end of the study. Patients were classified into three groups consisting of severe pulmonary involvement, renal involvement, and mild form in terms of prognosis. Patients with severe pulmonary involvement had bell-shaped thorax and mild brachydactyly, the one patient with renal involvement had long narrow thorax and severe brachydactyly, and patients with mild involvement presented with polydactyly and moderate to severe brachydactyly. It is important to establish a correct diagnosis both in severe and mild forms since JS might recur within the same family.
Jeune syndrome (asphyxiating thoracic dystrophy, ATD) is a rare autosomal recessive skeletal dysplasia characterized by a small, narrow chest and variable limb shortness with a considerable neonatal mortality as a result of respiratory distress. Renal, hepatic, pancreatic and ocular complications may occur later in life. We describe 13 cases with ages ranging from 9 months to 22 years. Most patients experienced respiratory problems in the first years of their life, three died, one experienced renal complications, and one had hepatic problems. With age, the thoracic malformation tends to become less pronounced and the respiratory problems decrease. The prognosis of ATD seems better than described in literature and in our opinion this justifies long term intensive treatment in the first years. We also propose a follow-up protocol for patients with ATD.
Jeune asphyxiating thoracic dystrophy, an autosomal recessive chondrodysplasia, often leads to death in infancy because of a severely constricted thoracic cage and respiratory insufficiency; retinal degeneration, cystic renal disease and polydactyly may be complicating features. We show that IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease. Knockdown of ift80 in zebrafish resulted in cystic kidneys, and knockdown in Tetrahymena thermophila produced shortened or absent cilia.
Three children with Jeune syndrome (asphyxiating thoracic dystrophy) had clinical and laboratory evidence of liver disease. In two patients the disease evolved to biliary cirrhosis, whereas in the third it was recognized when extensive fibrosis was developing. In the three patients, treatment with ursodeoxycholic acid appeared to control the progression of the hepatic dysfunction. Am. J. Med. Genet. 87:324–328, 1999. © 1999 Wiley-Liss, Inc.
A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy. Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis. WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport. We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis. Our results suggest that isolated nephronophthisis, Jeune, and Sensenbrenner syndromes are clinically overlapping disorders that can result from a similar molecular cause.
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.
The short-rib polydactyly (SRP) syndromes are a heterogeneous group of perinatal lethal skeletal disorders with polydactyly and multisystem organ abnormalities. Homozygosity by descent mapping in a consanguineous SRP family identified a genomic region that contained DYNC2H1, a cytoplasmic dynein involved in retrograde transport in the cilium. Affected individuals in the family were homozygous for an exon 12 missense mutation that predicted the amino acid substitution R587C. Compound heterozygosity for one missense and one null mutation was identified in two additional nonconsanguineous SRP families. Cultured chondrocytes from affected individuals showed morphologically abnormal, shortened cilia. In addition, the chondrocytes showed abnormal cytoskeletal microtubule architecture, implicating an altered microtubule network as part of the disease process. These findings establish SRP as a cilia disorder and demonstrate that DYNC2H1 is essential for skeletogenesis and growth.
Thoracic pelvic phalangeal dystrophy (TPPD) is an unusual, recessively inherited chondrodystrophy that was originally described by Jeune et al. They described two siblings with extreme constriction of the thoracic cage, which led to death in early infancy. Subsequent reports have detailed additional clinical and radiologic features of the TPPD syndrome. These include a constricted, narrow, bell shaped chest; short ribs and high clavicles; short flared iliac crests; cone shaped epiphyses; brachydactyly; and recessive inheritance. Because of the chest abnormalities, many of these children die at birth and some die in early childhood of respiratory embarrassment that is due to pneumonia. A progressive interstitial nephritis often develops in those who survive early childhood and they eventually die of renal failure. 2 unrelated patients with thoracic pelvic phalangeal dystrophy syndrome and retinal degeneration are presented. A pathologic study of both eyes from one of the patients showed severe degeneration of the peripheral retina, with predominantly cone type cells remaining.
A patient with typical TPPD is presented who has survived to age 11 years with no pulmonary problem except a single episode of pneumonia at age 5 years. She has no evidence of renal disease. An associated ocular lesion is described which resembles Leber congenital amaurosis. The patient demonstrated poor vision and nystagmus from birth. Visual acuity is approximately 20/300 with a small myopic astigmatic correction. There is a large exotropia. The ocular fundi show a striking picture of pigment epithelial atrophy in an unusual distribution. The electroretinogram shows depressed responses. The variable clinical picture now evolving, several suggestive family histories, and the death of consanguineous parents suggest that autosomal dominant inheritance may fit the genetics of this disease in some families better than the generally accepted autosomal recessive pattern.
Three children with Jeune syndrome (asphyxiating thoracic dystrophy) had clinical and laboratory evidence of liver disease. In two patients the disease evolved to biliary cirrhosis, whereas in the third it was recognized when extensive fibrosis was developing. In the three patients, treatment with ursodeoxycholic acid appeared to control the progression of the hepatic dysfunction.
Jeune syndrome (JS) and short-rib polydactyly syndrome type III (SRP type III) are autosomal recessive disorders characterized by short ribs and polydactyly. They are distinguished from each other by the more severe radiological and histological bone findings as well as the occurrence of facial anomalies, ambiguous genitalia, and occasionally, cloacal abnormalities in SRP type III. We present a family in which two children have mild JS and one has SRP type III as evidence that JS and SRP type III are variants of the same disorder. The intrafamilial variability may reflect the effects of modifying loci on gene expression.
http://www.ncbi.nlm.nih.gov/ Omim/; University of California Ocular findings in thoracic-pelvic-phalangeal dystrophy
- Genome Server
Ensembl Human Genome Server, http://ensembl.org/; Primer3, http://frodo.wi.mit. edu/; Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/ Omim/; University of California, Santa Cruz (UCSC) Genome Browser, http://genome. ucsc.edu/; The Human Gene Mutation Database, http://www.hgmd.org/. REFERENCES 1 Allen AW Jr, Moon JB, Hovland KR, Minckler DS. Ocular findings in thoracic-pelvic-phalangeal dystrophy. Arch Ophthalmol 1979;97:489–92.