Rhizomelic Limb Research Articles

Prenatal diagnosis of a skeletal disorder characterized by rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene: Case report and literature review.

The protein kinase domain containing cytoplasmic (PKDCC) gene (OMIM#618821) is associated with bone development. Biallelic variants in the PKDCC gene can cause rhizomelic limb shortening with dysmorphic features. A fetus was found to be rhizomelic limb shortening at 16 weeks of gestation and amniocentesis was performed at 19 weeks of gestation. Genomic DNA extracted from the amniotic fluid was subjected to chromosomal microarray analysis (CMA), and Trio-total whole-exome sequencing (Trio-WES). Sanger sequencing was used to verify the candidate pathogenic variants. CMA was normal, while Trio-WES identified two compound heterozygous variants in the PKDCC gene, namely c.417_c.423delCGGCGCG insTCATGGGCTCAGTACAC(p.G140fs*35) and c.345G>A (p.W115*,379). Then the fetus was aborted and the development of its bone cells were compared with that of a normal fetus of similar gestational age by histopathological examination. Clinical findings of the fetus were shortening humerus and femur, synophrys, much hair on the side face, simian line on the right palm, etc. Histopathological examination showed that the affected fetus had increased proliferative chondrocytes, widened proliferative bands, and delayed bone mineralization. We reported a prenatal case of rhizomelic shortening of limbs caused by compound heterozygous variants in the PKDCC gene, which emphasized the important role of Trio-WES for diagnosis of skeletal dysplasia in fetuses.

Prenatal diagnosis to identify compound heterozygous variants in PKDCC that causes rhizomelic limb shortening with dysmorphic features in a fetus from China

BackgroundRhizomelic limb shortening with dysmorphic features (RLSDF) has already been a disorder of the rare autosomal recessive skeletal dysplasia, just having a few reported cases. RLSDF is caused by protein kinase domain containing, cytoplasmic(PKDCC)gene variants. In this study, we describe the clinical features and potential RLSDF molecular etiology in a fetus from China.MethodsGenomic DNA (gDNA) extracted from the fetal muscle tissue and parents’ peripheral blood was subjected to chromosomal microarray analysis (CMA) and trio-based whole exome sequencing (Trio-WES). The candidate pathogenic variants were verified by using Sanger sequencing.ResultsTrio-WES identified two compound heterozygous variants in PKDCC, c.346delC (p.Pro117Argfs*113) and c.994G > T (p.Glu332Ter), inherited from the father and mother, respectively. Both variants are classified as pathogenic according to American College of Medical Genetics and Genomics guidelines.ConclusionsWe reported the first prenatal case of RLSDF caused by PKDCC in the Chinese population. Our findings extended the variation spectrum of PKDCC and emphasized the necessity of WES for the early diagnosis of skeletal dysplasia and other ultrasound structural abnormalities in fetuses.

Athena Specialty Certificate Examination case for Paediatrics and Genetics.

This is an Athena Specialty Certificate Examination case of a child who presented with marked ichthyosis at birth, alongside clinical features including rhizomelic limb shortening, bilateral cataracts and conductive hearing loss. We discuss the diagnosis, along with potential causes of congenital ichthyoses, highlighting distinguishing features among them.

Prenatal Diagnosis of Costello Syndrome Using Noninvasive Prenatal Single Gene Testing With Maternal Blood

Introduction Costello syndrome (CS) is a rare disorder that affects multiple organ systems, which is usually diagnosed postnatally, except for 2 cases diagnosed prenatally from chromosome analysis by amniocentesis. We present the first case of prenatally diagnosed CS via maternal blood testing. Case Description A 38-year-old woman was referred for genetic screening at 28 weeks of gestational age (GA) due to polyhydramnios and shortened limbs seen on prenatal ultrasound. Cell-free DNA, noninvasive prenatal single gene screening was positive for G12S HRAS mutation, which is indicative of CS. The infant was delivered via elective repeat cesarean section at 36 weeks and 6 days GA, was admitted to the neonatal intensive care unit for respiratory distress. Physical examination was significant for macrocephaly, wide depressed nasal bridge, short neck, rhizomelic limb shortening, micropenis, and bilateral equinovarus deformity of the feet. Echocardiography on the first day showed severe pulmonary hypertension. Brain MRI showed a possible cavernous mass lesion and small arachnoid cyst over the left cerebellar hemisphere. Postnatal gene-targeted testing confirmed CS diagnosis with pathogenic variants. The infant was managed for respiratory distress, hypoglycemia, jaundice, and feet deformities. He was subsequently transferred to another hospital at 45 weeks of age for gastrostomy tube placement due to persistent difficulty with oral feeding. Discussion CS affects multiple organ systems. Clinical presentations includes short stature; macrocephaly; coarse facial features, loose and soft skin; hypotonia and joint laxity; cardiac involvement with congenital heart defect, feeding difficulty, and developmental delay. The phenotypic spectrum is wide and can range from mild features to early lethal complications mostly as a result of severe progressive Hypertrophic Cardiomyopathy (HCM) and respiratory compromise. CS is an autosomal dominant genetic disorder caused by mutations in the HRAS gene, but almost all cases have new mutations with no family history. Disease course depends on cardiac and predisposition to benign and malignant tumor complications. Treatment requires a multidisciplinary team directed toward the specific clinical findings. Conclusion To our knowledge, this is the first reported case of prenatally diagnosed CS via maternal blood testing. Molecular diagnosis in the prenatal period allows neonatal care providers to prepare for potential complications in the postnatal period.

Heterozygous variant in FGFR3 underlying severe phenotypes in the second trimester: a case report

BackgroundAchondroplasia is a congenital skeletal system malformation caused by missense variant of FGFR3 gene with an incidence of 1 per 20,000–30,000 newborns, which is an autosomal dominant inheritance disease. Despite similar imaging features, the homozygous achondroplasia is absolutely lethal due to thoracic stenosis, whereas heterozygous achondroplasia does not lead to fetal death.Case presentationA fetus with progressive rhizomelic short limbs and overt narrow chest was detected by prenatal ultrasound in the second trimester. Gene sequencing results of amniotic fluid sample indicated a rare missense variant NM_000142.4: c.1123G > T(p.Gly375Cys), leading to a glycine to cysteine substitution. Re-sequencing confirmed that it was a heterozygous variant, and thoracic stenosis was then confirmed in the corpse by radiological examination.ConclusionsWe identified a heterozygous variant of the FGFR3 gene as the rare pathogenic variant of severe achondroplasia in a fetus. Heterozygous variants of p.Gly375Cys may have a severe phenotype similar to homozygote. It’s crucial to combine prenatal ultrasound with genetic examination to differentiate heterozygous from homozygous achondroplasia. The p.Gly375Cys variant of FGFR3 gene may serve as a vital target for the diagnosis of severe achondroplasia.

A novel variant in GNPNAT1 gene causing a spondylo-epi-metaphyseal dysplasia resembling PGM3-Desbuquois like dysplasia.

Spondylo-epi-metaphyseal dysplasias (SEMDs) are a clinically and genetically heterogeneous group of skeletal dysplasias characterized by short stature and abnormal modeling of the spine and long bones. A novel form of rhizomelic skeletal dysplasia, Ain-Naz type, associated with a homozygous variant in GNPNAT1 was recently identified. Herein, we report an Egyptian patient, offspring of consanguineous parents, who presented with a severe form of unclassified SEMD. Whole exome sequencing identified a novel homozygous variant in exon 3, c.77T>G, (p.Phe26Cys) in GNPNAT1, that was confirmed by Sanger sequencing and both parents were found to be heterozygous for the identified variant. Main features included severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings expanding the clinical phenotype described in the previously reported family. We conclude that variants in the GNPNAT1 gene cause an autosomal recessive form of SEMD resembling Desbuquois like dysplasia caused by PGM3, which is involved in the same pathway as GNPNAT1.

Morquio syndrome or something cryptic: think!

<p class="abstract">Morquio syndrome (MS) or mucopolysaccharidosis type IV A is an autosomal recessive lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase. The disorder is marked by characteristic physical features, skeletal abnormalities and normal intellect. We report a nine year old boy who presented with coarse facial features, barrel shaped chest, rhizomelic limb shortening and intellectual disability. Along with facial features, the initial radiological survey pointed to the diagnosis of MS. However when the urinary glycosaminoglycans came to be negative, the radiographs and clinical features were reviewed which led us to a rare syndrome with significantly different treatment and prognosis. A pediatrician should keep a high index of suspicion to pick up mimics of mucopolysaccharidosis as the variable prognosis and management protocol might be life saving in some cases. </p>

Rhizomelic limb shortness and abnormal facies: short stature syndrome sharing some manifestations with robinow syndrome

In children, short stature and disproportionate skeletal growth are associated with many syndromes and these syndromes have characteristic radiological changes which help in their diagnosis. However, many of them have no well-defined diagnostic criteria, and thus overlap between apparently distinct syndromes is common. Here, we report a child with characteristic features seen distinct from any other dwarfing syndrome known to us with some of the features similar to Robinow syndrome. Newborn had a broad and prominent forehead, mid-face hypoplasia, hypertelorism, flat nasal bridge, upturned nose, elongated philtrum, protruding tongue, single crease in the left hand, widely spaced nipple, brachydactyly in lower limbs, and disproportionately short rhizomelic upper and lower limbs. Based on these features, a diagnosis of Robinow syndrome was made. The case was the first of his kind admitted to our institute. The diagnosis was made clinically after follow-up.

Prenatal diagnosis of Pallister-Killian syndrome using cord blood samples

BackgroundPallister-Killian syndrome (PKS) (OMIM:#601803) is a rare sporadic genetic disorder characterized by multi-malformations which is caused by the presence of the extra isochromosome 12p. PKS is featured by the tissue-limited mosaicism of the isochromosome 12p [i(12p)]. There were a wide spectrum of prenatal ultrasound findings of PKS, which made it difficult to be found in first or second trimester. Polyhydramnios, diaphragmatic hernia, and rhizomelic limb shortening were the most common prenatal ultrasound abnormalities in PKS. This study retrospectively analyzed the ultrasound findings and molecular cytogenetic results of four PKS fetuses diagnosed by using cord blood samples.ResultsThe ultrasound anomalies of four PKS fetuses are described as follows: fetal macrosomia, cerebral ventriculomegaly, increased NT thickness, rhizomelic limbs shortening, polyhydramnios. Biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL) measurements were above the mean in three fetuses,while one fetus showed rhizomelic limbs shortening. Combined with this study and previous literature, polyhydramnios was the most frequent anomaly observed in prenatal ultrasound examination of PKS, which accounted for 48% (94/194). Fetal macrosomia was present in 15% (29/194), cerebral ventriculomegaly in 13% (25/194), thickened nuchal fold in 9% (18/194), rhizomelic limbs shortening in 26% (51/194). I(12p) was found in the karyotype analysis of cultured cord blood lymphocytes and the mosaic ratios ranged from 2 to 5%. Single nucleotide polymorphisms array (SNP-array) results suggested that the whole short arm of chromosome 12 was duplicated with 2~3 copies. Fluorescence in situ hybridization (FISH) was performed to confirm the results of karyotype and SNP-array.ConclusionsIn case non-specific indicators such as fetal macrosomia, polyhydramnios and rhizomelic limbs shortening are observed meanwhile in prenatal ultrasound, targeted detection of PKS should be considered. In the prenatal diagnosis of PKS, the combination of SNP-array and FISH with conventional karyotype are the key to seek i(12p) and for precise diagnosis.

SA25 - AN INHERITED DISTAL 16P11.2 DELETION DEMONSTRATES VARIABLE EXPRESSIVITY AND INCOMPLETE PENETRANCE FOR PSYCHIATRIC ILLNESS AS WELL AS ASSOCIATION WITH RHIZOMELIC SHORTENING: A CASE REPORT

Background The most commonly reported 16p Copy Number Variant (CNV) - 16p11.2 deletion syndrome (16pDS) (~600 kb; 29.5 -30.1 Mb) – has been robustly associated with schizophrenia (SZ), as well as Intellectual Disabilities (ID)/Developmental Delays (DD), congenital anomalies, dysmorphic features and obesity. Non-overlapping “distal” 16p11.2 deletions (~200 kb; 28.7 -28.9 Mb) are less commonly reported, but have a variable phenotype similar to that of 16pDS, including emerging data suggesting a psychiatric phenotype. We report here on a parent/child dyad who share a distal 16p11.2 deletion. Methods Patient 1 (index) was assessed (for indications including seizures, DD, and short limbs) at ages 2, 17, and 36, when she had clinical Chromosomal Microarray (CMA) (Affymetrix Cytoscan HD array, clinical thresholds: 200 kb (deletions), 400 kb (duplications), Chromosome Analysis suite (v2.0.0 195)). Fluorescence in Situ Hybridization (FISH) was used to confirm the deletion and determine origin. Results Patient 1 was born at term to non-consanguineous parents. A 46XX karyotype was confirmed at age 2 and 17 (testing indications: myoclonic seizures, DD, rhizomelic shortening of upper limbs). At age 17, she was also noted to have small hands ( Discussion While distal 16p11.2 deletions have been shown to increase risk for schizophrenia, this report contributes to the emerging evidence that this CNV is also associated with broader psychiatric phenotypes, such as bipolar disorder. The father's milder cognitive and metabolic phenotype supports variable expressivity of distal 16p11.2 deletions, even when inherited; his negative psychiatric history reinforces the incomplete penetrance of this CNV for psychiatric disorders. This report also contributes to the generation of a more thorough clinical description of the phenotypic range of distal 16p11.2 deletion, which we suggest, includes rhizomelic limb shortening.

Prenatal profile of Pallister-Killian syndrome: Retrospective analysis of 114 pregnancies, literature review and approach to prenatal diagnosis.

Pallister-Killian syndrome (PKS) is a tissue limited mosaic disorder, characterized by variable degrees of neurodevelopmental delay and intellectual disability, typical craniofacial findings, skin pigmentation anomalies and multiple congenital malformations. The wide phenotypic spectrum of PKS in conjunction with the mosaic distribution of the i(12p) makes PKS an underdiagnosed disorder. Recognition of prenatal findings that should raise a suspicion of PKS is complicated by the fragmentation of data currently available in the literature and challenges in diagnosing a mosaic diagnosis on prenatal testing. Ultrasound anomalies, especially congenital diaphragmatic hernia, congenital heart defects, and rhizomelic limb shortening, have been related to PKS, but they are singularly not specific and are not present in all affected fetuses. We have combined prenatal data from 86 previously published reports and from our cohort of 114 PKS probands (retrospectively reviewed). Summarizing this data we have defined a prenatal growth profile and identified markers of perinatal outcome which collectively provide guidelines for early recognition of the distinctive prenatal profile and consideration of a diagnosis of PKS as well as for management and genetic counseling.

How to Integrate Cell-Free DNA Screening With Sonographic Markers for Aneuploidy: An Update.

The sonologist detects a so-called "soft marker" during approximately 10% of routine second-trimester anatomy examinations and is often uncertain about what further management is appropriate. This article will specifically address the management of patients with sonographic markers for six common entities: choroid plexus cysts (CPCs), ventriculomegaly (VM), echogenic intracardiac focus (EIF), urinary tract dilation (UTD), fetal echogenic bowel (FEB), and femoral and humeral shortening. The use of cell-free DNA screening and its relationship to these sonographic findings will be reviewed. The era of ultrasound markers as a screen for fetal aneuploidy is coming to a close. The detection of these markers on an ultrasound examination should simply serve as a reminder to ensure that the patient was offered cell-free DNA screening or conventional analyte screening. Cell-free DNA testing is revolutionizing screening. With normal results on a cell-free DNA test, many isolated soft markers-including CPCs, EIF, mild rhizomelic limb shortening, and mild pyelectasis-are irrelevant from a genetic standpoint. However, further counseling and workup are indicated for VM, true FEB, femur or humerus length measurement that is less than 2.5-percentile value, and pyelectasis to evaluate for the nongenetic associations with these findings. Finally, cell-free DNA testing is currently a screening test; positive results require definitive diagnostic testing with amniocentesis or chorionic villus sampling.

Imaging of Skeletal Disorders Caused by Fibroblast Growth Factor Receptor Gene Mutations.

Fibroblast growth factors and fibroblast growth factor receptors (FGFRs) play important roles in human axial and craniofacial skeletal development. FGFR1, FGFR2, and FGFR3 are crucial for both chondrogenesis and osteogenesis. Mutations in the genes encoding FGFRs, types 1-3, are responsible for various skeletal dysplasias and craniosynostosis syndromes. Many of these disorders are relatively common in the pediatric population, and diagnosis is often challenging. These skeletal disorders can be classified based on which FGFR is affected. Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia, and disorders caused by type 2 mutations include Crouzon syndrome (CS), Apert syndrome (AS), and PS. Disorders caused by type 3 mutations include achondroplasia, hypochondroplasia, thanatophoric dysplasia (TD), severe achondroplasia with developmental delay and acanthosis nigricans, Crouzonodermoskeletal syndrome, and Muenke syndrome. Most of these mutations are inherited in an autosomal dominant fashion and are gain-of-function-type mutations. Imaging plays a key role in the evaluation of these skeletal disorders. Knowledge of the characteristic imaging and clinical findings can help confirm the correct diagnosis and guide the appropriate molecular genetic tests. Some characteristics and clinical findings include premature fusion of cranial sutures and deviated broad thumbs and toes in PS; premature fusion of cranial sutures and syndactyly of the hands and feet in AS; craniosynostosis, ocular proptosis, and absence of hand and foot abnormalities in CS; rhizomelic limb shortening, caudal narrowing of the lumbar interpediculate distance, small and square iliac wings, and trident hands in achondroplasia; and micromelia, bowing of the femora, and platyspondyly in TD. ©RSNA, 2017.

Targeted prenatal diagnosis of Pallister-Killian syndrome.

To present five new cases of prenatally diagnosed Pallister-Killian syndrome (PKS) and to propose an approach for a targeted diagnosis. We retrospectively analyzed ultrasound findings and cytogenetic results in PKS. We also searched through dysmorphology databases for features occurring in PKS that could potentially be seen in prenatal ultrasound examination. On the basis of collected data, frequent and distinctive features in fetuses with PKS were established. The most appropriate material and method of testing were proposed. Rhizomelic limb shortening, diaphragmatic hernia, thickened nuchal fold, increased prenasal thickness, polydactyly and polyhydramnios were frequent and distinctive findings in fetuses with PKS. Amniocentesis was the most frequent prenatal procedure for material collection. Percentage of aneuploid cells was higher in amniotic fluid than in cord blood. Cytomolecular tests were useful as confirmation as well as preliminary tests. Cytogenetic identification of the isochromosome was done in all cases except one. In case of ultrasound evaluation of features frequent and distinctive for PKS in second and third trimesters of pregnancy, targeted diagnosis should be considered. Amniotic fluid instead of cord blood collection is preferable. Communication with the laboratory is important because modification of routine procedures enhances a chance for correct diagnosis. © 2017 John Wiley & Sons, Ltd.

Conradi-Hünermann-Happle Syndrome With Cervical Stenosis

A Taiwanese girl was born to a short statured mother (140 cm) and exhibited features of generalized ichthyosis (Fig 1), bilateral cataracts, narrow chest, and rhizomelic limbs with widespread stippled calcifications. During early childhood, she suffered from esotropia, craniofacial-limb asymmetry, later cicatricial alopecia, frequent infection, wry neck, and growth retardation. Magnetic resonance imaging of the cervical spine revealed cervical spinal stenosis and a small cervical syrinx (Fig 2).

Prenatal Diagnosis of Achondroplasia with Ultrasound, Three-Dimensional Computed Tomography and Molecular Methods

A 29-year-old female was transferred to our clinic because of short femurs (<2 percentile) on ultrasound scan. She had nonspecific medical and obstetrical history. The ultrasound scan at 32 weeks of gestational age revealed rhizomelic shortening of the extremities, frontal bossing and the over rounded metaphyseal - epiphyseal interface at the femur ends while connecting to diaphysis, also called “collar hoop” sign. A 3D helical computed tomography (3D-HCT) scan reported rhizomelic limbs, narrowing of the interpediculate distance of the lumbosacral spine, rounded iliac wings and bilateral “collar hoop” sign of the proximal femurs. All these findings led to diagnosis of achondroplasia, which was confirmed by DNA testing. A well, active male baby was born. Postnatal x-ray also confirmed antenatal findings of ultrasound and 3D-HCT.

New lethal skeletal dysplasia with Dandy–Walker malformation, congenital heart defects, abnormal thumbs, hypoplastic genitalia, and distinctive facies

We report on two sibs with a lethal form of bone dysplasia with distinctive skeletal findings including rhizomelic and mesomelic limb shortening, hooked clavicles, dumbbell femurs, and absence of talus and calcaneus ossification. Other clinical features include Dandy-Walker malformation, congenital heart defects, joint contractures, genital hypoplasia, and distinctive facial features. These sibs appear to have a previously undescribed skeletal dysplasia, which is most likely inherited in an autosomal recessive fashion.

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVCgene

BackgroundEllis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.MethodsBecause of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the EVC/EVC2 locus. The results did not exclude linkage, so samples were sequenced for mutations.ResultsWe identified a c.1868T>C mutation in EVC, which predicts p.L623P, and was homozygous in affected individuals.ConclusionWe conclude that this EVC mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. EVC mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.

Prenatal diagnosis of a rare skeletal dysplasia by ultrasound and scan tomography: Atelosteogenesis III (AO III). Correlation with autopsy

We present the case of a 28-year-old woman, gravida1 para 0, who was referred at 22 weeks of gestation(WG) to our center to explore abnormalities revealedby second-trimester routine ultrasound examination. Thepatient’s medical and obstetrical history was unremark-able. The couple was not consanguineous. The firstscreening ultrasound scan, at 13 weeks, showed a 70-mm crown-rump length and a 2.4-mm nuchal translu-cency thickness. The levels for serum markers for Downsyndrome at 15 weeks were normal, and she was atlow risk for chromosomal abnormalities. The second-trimester ultrasound revealed a polymalformative syn-drome. The fetus was characterized, in two-dimensional(2D) and 3D ultrasound scan, by rhizomelic limb short-ness, with a single leg bone, strain spine, macrocra-nium, flattened temporal bones, retrognatism, unusualface with hypoplastic nose and widely spaced eyes,broad hands and digits, and club feet. The study ofthorax and abdomen was considered normal. Three-dimensional helical computed tomography was per-formed at 24 weeks to improve accuracy of the prenataldiagnosis of this skeletal dysplasia. It revealed a dou-ble curve configuration of the cervical spine, shorts ribs,vertebral hypoplasia with platyspondyly, thoraco-lumbarcoronal clefting and hypoplastic iliac wings with verticalblock-like ischia (Figure 1). The face was flattened andnarrow, associated with hypoplastic maxillary and thinmedian cleft palate, hypoplastic mandible, and pointedchin. The femurs were short, curved, and proximallyflared, the tibiae were slightly dumbbell-shaped andbowed, and the fibulae were absent. The humeri weremarkedly short with rounding and flaring of the proximal

Congenital lobar emphysema and increased nuchal translucency

Congenital lobar emphysema and increased nuchal translucency