Short-rib Polydactyly Syndrome Type Research Articles

VP16.14: Diagnosis of short rib polydactyly syndrome type IV (Beemer‐Langer syndrome): a case report

Short rib-polydactyly syndrome (SRPS) is a rare congenital autosomal recessive inherited disease classified in four subtypes. Prenatal ultrasonography findings and postnatal examinations may help classify in one of four subtypes. We present a case of an infant who presented multiple congenital anomalies and the postnatal radiography helped to classify the SRPS as type IV (Beemer-Langer). A 23-year-old was referred for prenatal ultrasound which showed cystic hygroma, small omphalocele and choledocal cyst. Chromosomal analysis revealed a normal male karyotype. Morphological scan revealed small thorax, short ribs, micromelic shortening of limbs with the tibia slightly longer than the fibula, unilateral clubfoot, hidrocephalus and renal hiperechogenicity. Magnetic Resonance performed at 35 weeks revealed micrognathia and mesenteric lymphangioma. The infant delivered at 38 weeks of gestation and died within 60 minutes due to respiratory failure. Postmortem radiography showed marked shortening of all long bones, strikingly narrow thorax with short and horizontal ribs, highly placed clavicles, small scapulae, small ilia and the tibia was longer then the fibula. Identification of the SRPS subtype can be difficult due to overlap of clinical and pathologic findings. This case may help understanding Beemer-Langer type's phenotypic features such as micrognathia, cleft lip, hydrops, hydrocephalus and omphalocele. The most common radiological findings include narrow thorax with short ribs, short tubular bones, highly placed clavicle, small scapulae and ilia and bowing of radius and ulna with the tibia being longer than the fibula. The prognosis of Beemer-Langer syndrome is poor as infants usually die shortly after birth because of respiratory failure secondary to marked pulmonary hypoplasia.

Case Report Of Short Rib Polydactyly Syndrome

Short rib polydactyly syndrome (SRPS) is a group of skeletal dysplasias manifested by short-limb dwarfism, short ribs with thoracic dysplasia and polydactyly. SRPS is an inherited autosomal-recessive disorder with dif-ferent prenatal sonographic and postnatal clinical, histological and radiologic findings. In this report, we pre-sent a case of SRPS type 3 (Verma-Naumoff) with thoracic hypoplasia, short limbs and postaxial polydactyly in a 30-week fetus. Keywords: Short rib polydactyly syndrome, Verma-Naumoff, Ultrasonography, Narrow thoracic cage

Exome sequencing for the differential diagnosis of ciliary chondrodysplasias: Example of a WDR35 mutation case and review of the literature

Exome sequencing is becoming widely popular and affordable, making it one of the most desirable methods for the identification of rare genetic variants for clinical diagnosis. Here, we report the clinical application of whole exome sequencing for the ultimate diagnosis of a ciliary chondrodysplasia case presented with an initial clinical diagnosis of Asphyxiating Thoracic Dystrophy (ATD, Jeune Syndrome). We have identified a novel homozygous missense mutation in WDR35 (c.206G > A), a gene previously associated with Sensenbrenner Syndrome, Ellis-van Creveld syndrome and Short-rib polydactyly syndrome type V. The genetic findings in this family led to the re-evaluation of the initial diagnosis and a differential diagnosis of Sensenbrenner Syndrome was made after cautious re-examination of the patient. Cell culture studies revealed normal subcellular localization of the mutant WDR35 protein in comparison to wildtype protein, pointing towards impaired protein-protein interaction and/or altered cell signaling pathways as a consequence of the mutated allele. This research study highlights the importance of including pathogenic variant identification in the diagnosis pipeline of ciliary chondrodysplasias, especially for clinically not fully defined phenotypes.

A relatively mild skeletal ciliopathy phenotype consistent with cranioectodermal dysplasia is associated with a homozygous nonsynonymous mutation in WDR35.

Ciliopathies are a class of clinically and genetically heterogeneous disorders characterized by deficits of the primary cilium, an important organelle for cellular signaling and development. Here we report on a patient from a consanguineous family presenting with renal cysts, short stature, distinctive facial features, missing teeth, brachydactyly, narrow chest, and abnormal ribs. His phenotype resembled a skeletal ciliopathy and the initial clinical differential diagnosis included Jeune thoracic dystrophy and cranioectodermal dysplasia. Due to the presence of parental consanguinity, a homozygous recessive mutation was the suspected cause and homozygosity mapping was used to direct candidate gene sequencing. WDR35, an intraflagellar transport protein previously associated with cranioectodermal dysplasia, the more severe short rib polydactyly syndrome type V and recently Ellis van Creveld syndrome, is present within a region of homozygosity and sequencing of all coding exons identified a novel homozygous nonsynonymous variant, p.Trp1153Cys. This variant affects a highly conserved tryptophan residue, is predicted to be deleterious, and is the most distal mutation yet reported in WDR35. This case expands the spectrum of phenotypes caused by WDR35 mutations, which we review herein.

Deletion of IFT80 Impairs Epiphyseal and Articular Cartilage Formation Due to Disruption of Chondrocyte Differentiation.

Intraflagellar transport proteins (IFT) play important roles in cilia formation and organ development. Partial loss of IFT80 function leads Jeune asphyxiating thoracic dystrophy (JATD) or short-rib polydactyly (SRP) syndrome type III, displaying narrow thoracic cavity and multiple cartilage anomalies. However, it is unknown how IFT80 regulates cartilage formation. To define the role and mechanism of IFT80 in chondrocyte function and cartilage formation, we generated a Col2α1; IFT80f/f mouse model by crossing IFT80f/f mice with inducible Col2α1-CreER mice, and deleted IFT80 in chondrocyte lineage by injection of tamoxifen into the mice in embryonic or postnatal stage. Loss of IFT80 in the embryonic stage resulted in short limbs at birth. Histological studies showed that IFT80-deficient mice have shortened cartilage with marked changes in cellular morphology and organization in the resting, proliferative, pre-hypertrophic, and hypertrophic zones. Moreover, deletion of IFT80 in the postnatal stage led to mouse stunted growth with shortened growth plate but thickened articular cartilage. Defects of ciliogenesis were found in the cartilage of IFT80-deficient mice and primary IFT80-deficient chondrocytes. Further study showed that chondrogenic differentiation was significantly inhibited in IFT80-deficient mice due to reduced hedgehog (Hh) signaling and increased Wnt signaling activities. These findings demonstrate that loss of IFT80 blocks chondrocyte differentiation by disruption of ciliogenesis and alteration of Hh and Wnt signaling transduction, which in turn alters epiphyseal and articular cartilage formation.

Majewski Syndrome, Short Rib Polydactyly Syndrome (SRPS) Type II - A Rare Case Report, with Review of Literature

Short Rib Polydactyly Syndrome (SRPS) type II also known as Majewski syndrome, is the rarest of the four subtypes of SRPS which is a rare inherited skeletal dysplasia. We report a case of Majewski syndrome in a neonate with brief review of literature. A 24 years old primigravida, with history of second degree consanguineous marriage underwent a Prenatal USG which revealed anhydramnios, bilateral enlarged kidneys, extremely narrow thorax and bilateral short limbs with polydactyly. Based on these findings a probable diagnosis of lethal skeletal dysplasia was made and termination of pregnancy advised. Refusing termination the mother delivered a male foetus at 30 weeks with severe respiratory distress and gross anomalies. The foetus succumbed to respiratory failure inspite of resuscitation. Gross findings were a male Case Study Andola et al.; BJMMR, 9(12): 1-8, 2015; Article no.BJMMR.18367 2 foetus with enlarged head, hydropic face, hypertelorism, short nose, depressed nasal bridge, pseudo cleft lip, cleft palate, low set posterior rotated ears, cystic hygroma, micrognathia, short and narrow chest, all the limbs showed mesomelic limb shortening, postaxial polydactyly, syndactyly and brachydactyly. Postnatal X-ray, CT scan and USG confirmed the above mentioned features and additional findings were extremely short horizontal ribs and disproportionately shortened ovoid tibia. Autopsy revealed a bell shaped thorax, small hypoplastic lungs, bilateral enlarged kidneys, atrial septal defect, hypoplastic epiglottis and larynx and short small intestine. Microscopic findings of pulmonary hypoplasia, renal cystic dysplasia, hepatic fibrosis and markedly retarded endochondral ossification correlate with the clinical, radiological and pathological findings of Short Rib Polydactyly Syndrome Type II -Majewski Syndrome.

WDR34 Mutations that Cause Short-Rib Polydactyly Syndrome Type III/Severe Asphyxiating Thoracic Dysplasia Reveal a Role for the NF-κB Pathway in Cilia

Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period. Presently, mutations in two genes, IFT80 and DYNC2H1, have been identified as being responsible for SRP type III. Via homozygosity mapping in three affected siblings, a locus for the disease was identified on chromosome 9q34.11, and homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family. WDR34 encodes a member of the WD repeat protein family with five WD40 domains, which acts as a TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-κB activation pathway. We showed, through structural modeling, that two of the three mutations altered specific structural domains of WDR34. We found that primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip. This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-κB activation pathway is involved in the pathogenesis of the skeletal ciliopathies.

IFT80 is essential for chondrocyte differentiation by regulating Hedgehog and Wnt signaling pathways

Partial mutation of intraflagellar transport 80 (IFT80) in humans causes Jeune asphyxiating thoracic dystrophy (JATD) and short-rib polydactyly (SRP) syndrome type III. These diseases are autosomal recessive chondrodysplasias that share clinical similarities, including shortened long bones and constricted thoracic cage. However, the role and mechanism of IFT80 in the regulation of chondrocyte differentiation and function remain largely unknown. We hypothesize that IFT80 is required for the formation and function of cilia and plays a critical role in chondrogenic differentiation by regulating Hedgehog (Hh) and Wingless (Wnt) signaling pathways. To test this hypothesis, we first analyzed the IFT80 expression pattern and found that IFT80 was predominantly expressed in growth plate chondrocytes and during chondrogenic differentiation. Silencing IFT80 impaired cilia formation and chondrogenic differentiation in mouse bone marrow derived stromal cells (BMSCs), and decreased the expression of chondrocyte marker genes—collagen II and aggrecan. Additionally, silencing IFT80 down-regulated Hh signaling activity whereas up-regulated Wnt signaling activity. The overexpression of Gli2 in IFT80-silenced cells promoted chondrogenesis and recovered the chondrogenic deficiency from IFT80 silencing. Overall, our results demonstrate that IFT80 is essential for chondrocyte differentiation by regulating the Hh and Wnt signaling pathways.

Prenatal diagnosis and molecular genetic analysis of short rib-polydactyly syndrome type III (Verma-Naumoff) in a second-trimester fetus with a homozygous splice site mutation in intron 4 in the NEK1 gene

ObjectiveTo demonstrate perinatal imaging findings and to investigate the mutation in the NEK1 gene in a fetus with type III short rib-polydactyly syndrome (SRPS) (Verma-Naumoff). Case ReportA 34-year-old woman with no past history of fetal SRPS was referred to the hospital at 21 weeks of gestation because of sonographic diagnosis of short limbs in the fetus. Fetal ultrasound revealed a narrow thorax, short ribs, short limbs with marginal spurs, and postaxial hexadactyly in both the hands and feet. A diagnosis of SRPS III (Verma-Naumoff) was made. Amniocentesis was performed. The karyotype was 46,XY. Molecular genetic analysis of the amniotic fluid cells identified a homozygous splice site mutation in intron 4 (c.331-1 A > G) or IVS4-1 A > G in the NEK1 gene. The parents were heterozygous for the mutation. The pregnancy was subsequently terminated and a malformed fetus was delivered with prominent forehead, a flattened nasal bridge, a narrow and short trunk, a protuberant abdomen, bilateral postaxial polydactyly and syndactyly of the hands and feet, and micromelic limbs. No facial cleft or genital abnormality was noted. The radiograph was consistent with SRPS III. ConclusionPolydactyly, micromelia, metaphyseal spurs, widened humeral metaphyses, and shortened ribs can be prominent prenatal ultrasound findings of SRPS III. The present case provides evidence for a correlation of a mutation in the NEK1 gene with SRPS III.

Short rib-polydactyly syndrome type II (Majewski): Prenatal diagnosis, perinatal imaging findings and molecular analysis of the NEK1 gene

ObjectiveTo demonstrate perinatal imaging findings and to investigate the mutation in the NEK1 gene in a fetus with type II short rib-polydactyly syndrome (SRPS) (Majewski). Case ReportA 34-year-old woman with a past history of fetal SRPS was referred to the hospital at 16 weeks of gestation because of sonographic diagnosis of short limbs in the fetus. Fetal ultrasound revealed short ribs, short limbs, absence of tibiae, polydactyly, syndactyly and choroid plexus cysts. At 21 weeks of gestation, polycystic kidneys were found. The pregnancy was terminated, and a fetus was delivered with facial dysmorphism, a median cleft lip, a narrow chest, micromelia, aplasia of tibiae, hypoplastic nails, syndactyly and postaxial polydactyly. The karyotype was 46,XX. Molecular analysis of fetal tissues showed a paternal-origin heterozygous splice site mutation in intron 7 (c.465-1 G>A) in the NEK1 gene, but no mutations in the genes of WDR35, DYNC2H1, IFT80, EVC and EVC2. The NEK1 mutation causes an alteration of the splice acceptor site of intron 7 (IVS7-1 G>A). No second mutation was identified. ConclusionTibial aplasia, choroid plexus cysts and polycystic kidneys can be prominent prenatal ultrasound findings of type II SRPS. The present case provides evidence for a correlation of NEK1 mutation with type II SRPS.

Prenatal diagnosis of Jeune‐like syndromes with two‐dimensional and three‐dimensional sonography

The purpose of this article is to describe the use of three-dimensional sonography as an adjuvant to two-dimensional sonography facilitating an earlier and more definitive diagnosis of Jeune and Jeune-like syndromes in the second trimester. We report two cases in which three-dimensional sonography facilitated the diagnosis of these malformations. A diagnosis of Jeune syndrome was made in our first case. Our second case was found to be short-rib polydactyly syndrome Type IV. Three-dimensional skeletal survey visualized short ribs, short limbs, the presence of normal scapulae, and the absence of polydactyly in both cases. Three-dimensional sonography can assist two-dimensional sonography in providing a more accurate display of skeletal anomalies, limb abnormalities, and facial features.

Prenatal diagnosis of short-rib polydactyly syndrome type 3 (Verma-Naumoff type) by three-dimensional helical computed tomography

We present a case of short-rib polydactyly syndrome (SRPs) type 3 in which accurate prenatal diagnosis was feasible using both ultrasonography and 3D-CT. SRP encompass a heterogeneous group of lethal skeletal dysplasias. However, the phenotypes overlap with those of nonlethal skeletal dysplasias (i.e. Ellis-van Creveld syndrome and Jeune syndrome). As accurate prenatal diagnosis of SRP is helpful for parents, we used 3D-CT in the early third trimester to examine a fetus suggested to have phenotypes of 'short-rib dysplasia group' on ultrasonography. 3D-CT showed mild modification of the vertebral bodies, small ilia with horizontal acetabula and triangular partial ossification defects, and subtle metaphyseal irregularities of the femora. These CT findings and an extensive literature search regarding the phenotypes of various diseases categorized as short-rib dysplasia group led to a correct prenatal diagnosis of SRP type 3. This case exemplified the usefulness of 3D-CT for the precise prenatal diagnosis of skeletal dysplasias.

Diagnosis of short rib polydactyly syndrome type IV (Beemer–Langer syndrome) with cystic hygroma: A case report

Short rib polydactyly syndrome (SRPS) is a very rare congenital autosomal recessive inherited disease, classified into four subtypes. It has distinct imaging findings on prenatal sonography (US) and ancillary findings on both pre- and postnatal examinations may help classify individual cases into one of four subtypes. We report the US findings in a case of SRPS type IV (Beemer-Langer dysplasia) in a male fetus with multiple congenital anomalies, including cystic hygroma. The postnatal ultrasound, radiographic, and postmortem examinations helped to classify the SRPS as type IV. We believe this is the first documented case associating cystic hygroma and polydactyly.

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

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

Ciliary Abnormalities Due to Defects in the Retrograde Transport Protein DYNC2H1 in Short-Rib Polydactyly Syndrome

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.

Orofaciodigital Syndrome Type IV (Mohr-Majewski Syndrome): Report of a Family with Two Affected Siblings

We report on sibling fetuses with orofaciodigital syndrome (OFDS) type IV (Mohr-Majewski syndrome). The 1st was a 13-week-old fetus with hypertelorism; a median cleft defect of the upper lip, soft palate, and uvula; a polypoid lower lip and multiple frenula of the tongue adherent to the mandible; a congenital heart defect; pre- and postaxial polydactyly of the upper and preaxial polydactyly of the lower limbs; and an intersex genitalia. However, the shortening of both arms and forearms was particularly striking, with shortening of the ulna and ulnar deviation of both hands. The 2nd fetus was of the same parents, was 11 weeks old, and presented with a similar spectrum of malformations. The features of both fetuses showed a transitional phenotype between the OFDS type II (Mohr syndrome) and the short rib-polydactyly syndrome type II (Majewski syndrome), thus extending the known spectrum of the OFDS type IV.

Recurrence of short rib polydactyly syndrome – a rare skeletal dysplasia

A case of short rib polydactyly syndrome type I-Saldino Noonan was diagnosed in three successive pregnancies from a non consanguineous couple. Short limbs, short ribs, polydactyly, with visceral anomalies were noted and confirmed on autopsy.

Additional Evidence of a Continuous Phenotypic Spectrum in the Short Rib-Polydactyly Syndromes

We report a stillborn female with most of the clinical, histologic, and radiographic characteristics of the short rib-polydactyly syndrome (SRPS) type IV (Beemer-Langer) but also presenting prominent metaphyseal and scapular irregularities and spiking, a feature not previously described in this disease but considered typical of types I (Saldino-Noonan) and III (Verma-Naumoff) SRPS. These data support the suggested hypothesis that the SRPS alternative manifestations of a single genetic entity. In addition, we found histologic features not previously documented in the Beemer-Langer syndrome illustrating the histopathologic variability of the condition.

Cardiac malformation in two infants with hypochondrogenesis

Autopsy records from the Women and Infants' Hospital from January 1974 through January 1994 were reviewed to identify cardiac malformations in the presence of skeletal dysplasia. Of 24 cases of lethal fetal or neonatal osteochondrodysplasias, 4 were given diagnoses in which disorders of type II collagen are regarded as causative. These 4 were categorized in the spondyloepiphyseal dysplasia (SED) spectrum of disorders; specifically two patients with hypochondrogenesis and two with spondyloepiphyseal dysplasia congenita were identified. Defects in cardiac septation were noted in the 2 patients with hypochondrogenesis. No cardiovascular abnormalities were present in the remaining cases, which included thanatophoric dysplasia, osteogenesis imperfecta, and asphyxiating thoracic dystrophy. Although cardiovascular malformations have been described in other types of osteochondrodysplasias, e.g., short rib polydactyly syndrome type II and chondroectodermal (Ellis-van Creveld) dysplasia, congenital heart disease has not been described in hypochondrogenesis. Type II collagen, which has been found to be abnormal in some patients with hypochondrogenesis, is considered to have a limited tissue distribution, and has not been detected as yet in human myocardium. The findings presented here suggest that type II collagen may function in human cardiogenesis.

Short‐rib polydactyly syndrome (SRPS) type III diagnosed during routine prenatal ultrasonographic screening. A case report

The prenatal diagnosis of skeletal dysplasias is often initiated by the finding of a shortened extremity during a routine sonographic examination. Second-trimester diagnosis of these anomalies allows the couple to consider the option of terminating a pregnancy when a lethal anomaly is detected. A 21-year-old Bedouin woman underwent routine ultrasonographic screening at 20 weeks' gestation. Severe micromelia, a narrow thorax with shortened ribs, and postaxial polydactyly were detected. The patient delivered a male dwarf at 20 weeks' gestation following prostaglandin induction of labour for a diagnosis of short-rib polydactyly syndrome type III. The prenatal ultrasonographic diagnosis of short-rib polydactyly syndrome type III was made at 20 weeks' gestation, allowing termination of the pregnancy. A proper sonographic approach to skeletal dysplasias allows both early detection and differentiation between lethal and non-lethal anomalies.