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JNMA; Journal of the Nepal Medical... Mar 2020Thanatophoric skeletal dysplasiais the most lethal, rare, sporadic birth defect due to de novo mutation in the fibroblast growth factor receptor-3. Clinically this is...
Thanatophoric skeletal dysplasiais the most lethal, rare, sporadic birth defect due to de novo mutation in the fibroblast growth factor receptor-3. Clinically this is characterized by shortening of the limbs (micromelia), small conical thorax, flat vertebral bodies and macrocephaly at birth. We encountered a similar case with ultrasonographic findings suggestive of Thanatophoric Skeletal Dysplasia which resulted in the death of the baby within an hour of birth. Almost all cases of this condition have been reported to have died interuterinally or a few days after birth.
Topics: Cesarean Section; Fatal Outcome; Female; Gestational Age; Humans; Infant, Newborn; Male; Pregnancy; Thanatophoric Dysplasia; Young Adult
PubMed: 32347827
DOI: 10.31729/jnma.4488 -
Annals of Medicine and Surgery (2012) Nov 2023Thanatophoric dysplasia is a rare, fatal, and sporadic form of skeletal dysplasia caused by a mutation in fibroblast growth factor receptor 3 (FGFR3). It is...
INTRODUCTION AND IMPORTANCE
Thanatophoric dysplasia is a rare, fatal, and sporadic form of skeletal dysplasia caused by a mutation in fibroblast growth factor receptor 3 (FGFR3). It is characterized by a conical thorax, platyspondyly (flat vertebral bodies), and macrocephaly. This disorder can be diagnosed antenatally as early as 13 weeks of gestation.
CASE PRESENTATION
The authors reported a case of thanatophoric dysplasia on USG in a 19 year old young consanguineous female in her second trimester of pregnancy. Ultrasound examination showed a clover leaf-shaped skull, a widened anterior fontanel, a coarse and edematous face, a flattened nasal bridge, a short neck, a low set of ears, shortening of both upper and lower limbs with short fingers, bowed thighs and legs, and a relatively narrow thorax.
CLINICAL DISCUSSION
Lung hypoplasia, polyhydramnios, and hydrops in affected individuals lead to a poor prognosis. Hence, timely intervention should be done to avoid a poor prognosis. However, a mix of sonographic, genetic, histological, and autopsy studies are applied to make the most accurate diagnosis.
CONCLUSION
The authors reported this case due to the rarity of this condition and the need for a systematic and multidisciplinary approach.
PubMed: 37915702
DOI: 10.1097/MS9.0000000000001356 -
Case Reports in Obstetrics and... 2021Obstetric ultrasonography is routinely used to screen for fetal anomalies. Thanatophoric dysplasia (TD) is one of the common though rare lethal skeletal dysplasia,...
INTRODUCTION
Obstetric ultrasonography is routinely used to screen for fetal anomalies. Thanatophoric dysplasia (TD) is one of the common though rare lethal skeletal dysplasia, detected during routine ultrasound scan. TD is caused by a mutation in FGFR3 gene. Characteristic features include shortening of limbs, macrocephaly and platyspondyly. In our local setting, it is common to miss the diagnosis in the early scans due to lack of expertise of the sonographers. To the best of our knowledge, this is the first publication from Ghana. . We present the case of a 33-year-old woman who was referred to the facility on account of ultrasound scan report suggestive of thanatophoric dysplasia type 1 at 34 weeks of a female baby. The diagnosis was not made despite the mother being a regular antenatal attendant, until a fifth scan done at 34 weeks reported features suggestive of thanatophoric dysplasia. The ultrasound scan features included a biparietal diameter of 37weeks, femur length-24weeks, narrowed thoracic cage with hypoplastic lungs and short ribs. The liquor volume was increased with amniotic fluid index (AFI) of 38.4 cm. The femur, tibia, fibula, humerus, ulna, and radius were shortened (micromelia). The diagnosis of thanatophoric dysplasia type 1 was confirmed on autopsy.
CONCLUSION
This report was aimed to highlight the potential contribution of ultrasound scan in the diagnosis of thanatophoric dysplasia in our setting.
PubMed: 33953997
DOI: 10.1155/2021/9940063 -
Case Reports in Pediatrics 2022Thanatophoric dysplasia (TD) is a rare but uniformly lethal inherited disorder of the skeletal system resulting from defects in the fibroblast growth factor receptor-3...
Thanatophoric dysplasia (TD) is a rare but uniformly lethal inherited disorder of the skeletal system resulting from defects in the fibroblast growth factor receptor-3 gene on the short arm of chromosome ##4. It is characterised by pronounced shortening of the tubular bones resulting in significant short stature, macrocephaly, a funnel-shaped chest, protuberant abdomen, redundant skin in the limbs, and typical facies among others. The two clinical types of TD are differentiated by typical cranial and tubular bone configurations. Antenatal diagnosis is usually made in the last trimester and corroborated at birth. We present 2 cases of TD seen at Barau Dikko Teaching Hospital (BDTH) between January and August 2021 to highlight the potential difficulty with antenatal diagnosis, its diagnostic features, and associated early postnatal fatality. The antenatal diagnosis was missed in both cases in spite of repeated 2 and 3-trimester sonographic examinations. Both babies presented with remarkable micromelic short stature with the telephone-handle appearance of the femoral bones characteristic of type 1 TD, developed progressive respiratory distress at birth, and died within 36 hours of life despite respiratory support with Bubble CPAP. These cases are discussed along with a review of existing relevant literature.
PubMed: 36213390
DOI: 10.1155/2022/3056324 -
International Medical Case Reports... 2022Spontaneous uterine rupture, especially in an unscarred uterus, is a rare pregnancy complication that can cause severe morbidity and mortality in both the mother and...
BACKGROUND AND IMPORTANCE
Spontaneous uterine rupture, especially in an unscarred uterus, is a rare pregnancy complication that can cause severe morbidity and mortality in both the mother and the fetus. The vast majority of uterine ruptures occur in the presence of a previous uterine scar, most commonly from a previous cesarean delivery. To our knowledge, here we reported the first case of spontaneous rupture of unscarred uterus in a term primigravida secondary to lethal skeletal dysplasia fetus (Type 1 Thanatophoric dysplasia) faced by a practicing clinician in an underdeveloped country (Somalia) with a successful outcome.
CASE PRESENTATION
The patient was 24 yrs. Old Primagravida, at 40 weeks gestation by LMP, presented with abdominal pain and active vaginal bleeding; she did not receive antenatal care during pregnancy; after initial abdominal ultrasonography and vaginal examination, laparotomy was performed due to high suspicion of uterine rupture. After dead fresh fetal extraction, the uterine defect was repaired successfully, and the patient was discharged home in good condition after several days.
CONCLUSION
Through this case, we would like to highlight the urgent need to focus on and recognize the importance of receiving antenatal care in the community so that the burden of thousands of lives lost each year can be reduced.
PubMed: 36225974
DOI: 10.2147/IMCRJ.S383195 -
Frontiers in Genetics 2023Prenatal diagnosis of fetal short long bones (SLBs) was reported to be associated with skeletal dysplasias, chromosomal abnormalities, and genetic syndromes. This study...
Prenatal diagnosis of fetal short long bones (SLBs) was reported to be associated with skeletal dysplasias, chromosomal abnormalities, and genetic syndromes. This study aims to identify the genetic causes for fetal short long bones, and retrospectively evaluate the additional diagnostic yield of exome sequencing (ES) for short long bones following the use of conventional genetic testing. A cohort of ninety-four fetuses with sonographically identified short long bones was analyzed by trio-exome sequencing between January 2016 and June 2021. Fetuses with abnormal results of karyotype or chromosomal microarray analysis were excluded. Variants were interpreted based on ACMG/AMP guidelines. All diagnostic variants were validated by Sanger sequencing. Of the 94 fetuses, 38 (40.4%) were found to carry causal genetic variants (pathogenic or likely pathogenic) in sixteen genes with 38 variants. Five fetuses (5.3%) had variant(s) of uncertain significance. Thirty-five cases (37.2%) were diagnosed as genetic skeletal dysplasias including 14 different diseases that were classified into 10 groups according to the Nosology and Classification of Genetic Skeletal Disorders. The most common disease in the cohort was achondroplasia (28.9%), followed by osteogenesis imperfecta (18.4%), thanatophoric dysplasia (10.5%), chondrogenesis (7.9%), and 3-M syndrome (5.3%). The diagnostic yield in fetuses with isolated short long bones was lower than the fetuses with non-isolated short long bones, but not reached statistical significance (27.3% vs. 44.4%; = 0.151). Whereas, the rate in the fetuses with other skeletal abnormalities was significantly higher than those with non-skeletal abnormalities (59.4% vs. 32.5%, = 0.023), and the diagnostic rate was significantly higher in femur length (FL) below -4SDs group compared with FL 2-4SDs below GA group (72.5% vs. 16.7%; < 0.001). A long-term follow-up showed that outcomes for fetuses with FL 2-4SDs below GA were significantly better than those with FL below -4SDs. Additionally, fourteen (36.8%) novel short long bones-related variants were identified in the present study. The findings suggest that in fetuses with short long bones routine genetic tests failed to determine the underlying causes, exome sequencing could add clinically relevant information that could assist the clinical management of pregnancies. Novel pathogenic variants identified may broaden the mutation spectrum for the disorders and contributes to clinical consultation and subsequent pregnancy examination.
PubMed: 36923788
DOI: 10.3389/fgene.2023.1032346 -
Prenatal Diagnosis Mar 2021The aim is to develop a novel noninvasive prenatal testing (NIPT) method that simultaneously performs fetal aneuploidy screening and the detection of de novo and...
OBJECTIVE
The aim is to develop a novel noninvasive prenatal testing (NIPT) method that simultaneously performs fetal aneuploidy screening and the detection of de novo and paternally derived mutations.
METHODS
A total of 68 pregnancies, including 26 normal pregnancies, 7 cases with fetal aneuploidies, 7 cases with fetal achondroplasia or thanatophoric dysplasia, 18 cases with fetal skeletal abnormalities, and 10 cases with β-thalassemia high risk were recruited. Plasma cell-free DNA was amplified by Targeted And Genome-wide simultaneous sequencing (TAGs-seq) to generate around 99% of total reads covering the whole-genome region and around 1% covering the target genes. The reads on the whole-genome region were analyzed for fetal aneuploidy using a binary hypothesis T-score and the reads on target genes were analyzed for point mutations by calculating the minor allelic frequency of loci on FGFR3 and HBB. TAGs-seq results were compared with conventional NIPT and diagnostic results.
RESULTS
In each sample, TAGs-seq generated 44.7-54 million sequencing reads covering the whole-genome region of 0.1-3× and the target genes of >1000×depth. All cases of fetal aneuploidy and de novo mutations of achondroplasia/thanatophoric dysplasia were identified with high sensitivities and specificities except for one false-negative paternal mutation of β-thalassemia.
CONCLUSIONS
TAGs-seq is a novel NIPT method that combines the fetal aneuploidy screening and the detection of de novo FGFR3 mutations and paternal HBB mutations.
Topics: Adult; Aneuploidy; Female; Fetus; Humans; Noninvasive Prenatal Testing; Paternal Inheritance; Pregnancy; Receptor, Fibroblast Growth Factor, Type 3; beta-Thalassemia
PubMed: 33340121
DOI: 10.1002/pd.5879 -
Palliative Medicine Reports 2020Thanatophoric dysplasia (TD) is a rare skeletal dysplasia commonly thought to be lethal. In this case report, we discuss a nine-year-old male with TD and review his...
Thanatophoric dysplasia (TD) is a rare skeletal dysplasia commonly thought to be lethal. In this case report, we discuss a nine-year-old male with TD and review his parents' decision making shortly after their son was born, the technology needed to sustain him, and his parents' perception of his quality of life. We also summarize the clinical course of published long-term survivors with TD. Pediatric Palliative Care teams, especially those conducting perinatal palliative care consultations, are often asked to support families in the face of prognostic uncertainty. Our case report and review of the literature adds to the uncertainty of prognosis in TD and suggests that pediatric palliative care providers should be wary of the label "lethal."
PubMed: 34223453
DOI: 10.1089/pmr.2020.0016 -
Medicine Oct 2022Fetal skeletal anomalies are one of the most common and potentially pathogenic developmental abnormalities detected by ultrasound screening. Any suspected fetal skeletal...
RATIONALE
Fetal skeletal anomalies are one of the most common and potentially pathogenic developmental abnormalities detected by ultrasound screening. Any suspected fetal skeletal dysplasias often require further comprehensive evaluations.
PATIENT CONCERNS
Here 4 families with adverse fetal skeletal system histories were enrolled, including their histories of gestation, childbirth, familial skeletal abnormalities, and pregnancy outcomes. The corresponding diagnosis were done by whole exome sequencing (WES) combined with dynamic examination.
DIAGNOSIS
All of the families were definitively diagnosed through cytogenetics, molecular genetics, ultrasound, combined with multidisciplinary evaluation. Both of the fetuses in case 1 and case 2 were diagnosed with thanatophoric dysplasia type I, while the neonate in case 3 was diagnosed with Apert syndrome and a 3-years-old proband daughter with Crouzon syndrome in case 4.
INTERVENTIONS
We conducted karyotyping, copy number variation sequencing (CNV-seq), combined with WES to evaluate genetic conditions of abnormal fetus, neonate or proband patient. WES was preferred to obtain a relatively definitive diagnosis.
OUTCOMES
In cases 1 and 2, the families decided to choose termination of pregnancy due to fatal dysplasias. The couple in case 3, delivered a female baby diagnosed with Apert syndrome. Fortunately, in case 4, the family, which had a 3-years-old baby with Crouzon syndrome, gave birth to a healthy baby through prenatal diagnosis.
LESSONS SUBSECTIONS
Invasive prenatal diagnosis and dynamic assessments for the management of fetal skeletal dysplasias could contribute to revealing possible causes of fetal skeletal abnormalities and help clinicians conduct further genetic counseling in clinical practice.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Child, Preschool; Exome Sequencing; DNA Copy Number Variations; Acrocephalosyndactylia; Fetus; Prenatal Diagnosis; Osteochondrodysplasias; Musculoskeletal Abnormalities; Craniofacial Dysostosis; Ultrasonography, Prenatal
PubMed: 36316869
DOI: 10.1097/MD.0000000000031321 -
American Journal of Medical Genetics.... Mar 2021We describe an individual in whom clinical and radiographic features are typical for achondroplasia, but in whom the common variants of FGFR3 that result in...
We describe an individual in whom clinical and radiographic features are typical for achondroplasia, but in whom the common variants of FGFR3 that result in achondroplasia are absent. Whole exome sequencing demonstrated a novel, de novo 6 base pair tandem duplication in FGFR3 that results in the insertion of Ser-Phe after position Leu324. in vitro studies showed that this variant results in aberrant dimerization, excessive spontaneous phosphorylation of FGFR3 dimers and excessive, ligand-independent tyrosine kinase activity. Together, these data suggest that this variant leads to constitutive disulfide bond-mediated dimerization, and that this, surprisingly, occurs to an extent similar to the neonatal lethal thanatophoric dysplasia type I Ser249Cys variant.
Topics: Achondroplasia; Adolescent; Adult; Female; Humans; Male; Mutation; Phosphorylation; Prognosis; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction
PubMed: 33368972
DOI: 10.1002/ajmg.a.62043