Thanatophoric Dysplasia Research Articles (Page 1)

To study genotype-phenotype correlations in children with FGFR3 variants and to improve clinical recognition of related disorders. Clinical data of 95 patients aged 0-18 years harboring FGFR3 variants, confirmed by whole‑exome sequencing at Shanghai Children's Medical Center from January 2012 to December 2023, were retrospectively reviewed. Detailed phenotypic characterization was performed for 22 patients with achondroplasia (ACH) and 10 with hypochondroplasia (HCH). Among the 95 patients, 52 (55%) had ACH, 24 (25%) had HCH, 9 (9%) had thanatophoric dysplasia, 3 (3%) had syndromic skeletal dysplasia, 2 (2%) had severe achondroplasia with developmental delay and acanthosis nigricans, and 5 (5%) remained unclassified. A previously unreported FGFR3 variant, c.1663G>T, was identified. All 22 ACH patients presented with disproportionate short stature accompanied by limb dysplasia, commonly with macrocephaly, a depressed nasal bridge, bowed legs, and frontal bossing; complications were present in 17 (77%). The 10 HCH patients predominantly exhibited disproportionate short stature with limb dysplasia and depressed nasal bridge. ACH is the most frequent phenotype associated with FGFR3 variants, and missense variants constitute the predominant variant type. The degree of FGFR3 activation appears to correlate with the clinical severity of skeletal dysplasia.

Thanatophoric Dysplasia (TD) is a rare, lethal skeletal dysplasia caused by FGFR3 gene mutations, leading to severe bone and cartilage abnormalities. TD is classified into two subtypes: Type 1, characterized by bowed femurs and a normal skull, and Type 2, with straight femurs and a cloverleaf skull deformity. Common features include micromelia, macrocephaly, a narrow thorax, and respiratory insufficiency. We report a case of 32-year-old primigravida presented at 28 weeks gestation with reduced fetal movements and no prior antenatal visits. Ultrasound revealed breech presentation, limb shortening, and macrocephaly. Labor was induced, resulting in a preterm vaginal delivery. Postnatal examination showed bowed femurs, short ribs, and a narrow thorax. Despite intensive care, the infant developed respiratory distress and died on the fourth day. Radiological findings, including macrocephaly and telephone receiver deformity of the femurs, confirmed Type 1 TD. Key Words: Thanatophoric Dysplasia, Macrocephaly, Craniosynostosis, Chorioamnionitis,Achondroplasia

P354: Vosoritide as a targeted therapy for FGFR3-related thanatophoric dysplasia

Prenatal Diagnosis and Management of Thanatophoric Dysplasia Type 1: A Case Report and Literature Review

Thanatophoric dysplasia type 2: prenatal diagnosis through fetal ultrasound and next-generation sequencing

A Single Multiplex PCR and Single-Nucleotide Extension Assay for the Detection of Common Thanatophoric Dysplasia I and II Mutations

The article aims to report a rare case of a patient diagnosed with Thanatophoric Dysplasia admitted to the Neonatal Intensive Care Unit of a tertiary hospital in a city in the inner state of São Paulo. The female infant has been hospitalized since birth, with history, physical, and radiological examination suggestive of Thanatophoric Dysplasia and an unaltered karyotype test, whose evolution and severity made it necessary to institute minimally invasive care. She remained in the Neonatal Intensive Care Unit for five months and 23 days requiring invasivemechanical ventilation through a tracheostomy and gastrostomy feeding, until the irreversible nature of the condition was determined. The purpose of this case report aims to promote reflection on the importance of a multidisciplinary approach to patient care, providing quality of life, orthothanasia, and the importance of family-centered care practices.

Abstract Congenital skeletal disorders are a heterogeneous group of anomalies that become evident during gestation. They are expressed in the shape and growth of the bones during development because of a defective genetic background. With the follow‐up of pregnant women and the advances in prenatal ultrasonographic examination and molecular genetic tests, nowadays, congenital skeletal disorders are identified at an early gestational age. If they are considered lethal, the termination of pregnancy is advised. This work unveils an exceptional instance of a rare pathological condition identified in a perinate (birth ± 2 weeks) from the 17th to 19th centuries, recovered during an excavation at the cloister of the São Domingos Convent in Lisbon, Portugal. The skeleton presents with exuberant modifications that include, among others, severe shortening (micromelia) and bowing of the long bones of the upper and lower limbs. The main skeletal findings indicated a presumptive general diagnosis of skeletal dysplasia, while the differential diagnosis includes hypophosphatasia, campomelic dysplasia, achondrogenesis, thanatophoric dysplasia, and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) as the most plausible causes for the observed skeletal changes. Even though an exact diagnosis is unattainable based only on the macroscopic analysis of the bones, the phenotypic features observed in this perinate are more consistent with thanatophoric dysplasia type 1.

Tanatophoric dysplasia is a usually lethal genetic syndrome in the perinatal period, which has a significant psychological impact on the pregnant woman and family. It necessitates careful monitoring by the health professionals involved in the care. The objective of this work is to present an experience report on the psychological and multidisciplinary monitoring of a pregnant woman diagnosed with type 2 tanatophoric dysplasia during prenatal screening. The methodology of the present study involves presenting a clinical case with a description of the clinical and psychological conditions of the pregnant woman, along with the interventions carried out by the health professionals involved in the case. The pregnant woman sought psychological care after receiving the diagnosis of type 2 tanatophoric dysplasia. Subsequently, the psychologist coordinated with other health professionals involved in the case and the institution where the delivery would take place, leading to the development of a collaborative planning and management approach. Upon discussion, the pregnant woman and her family opted for palliative care for the newborn. The team of professionals aligned their approach to meet the family’s wishes and needs. The newborn received supportive measures but survived for only a few hours before passing away. The integrated performance of the health team professionals and the flexibility of the hospital institution allowed the adequate planning of care actions and facilitated a positive reception experience for the family. This case highlights the importance of psychological support, individualized planning, and the relevance of teamwork in providing comprehensive care during such challenging circumstances.

Introduction: Foetal autopsy is one of the primary modalities for establishing the underlying causative aetiology in congenitally anomalous foetuses. Genetic aetiology is the cause in at least half of the foetuses. A correlative approach including dysmorphological evaluation, histopathology, imaging studies, and genetic testing plays a significant role in establishing the final diagnosis and management of such cases. Aim: To investigate the cause of perinatal death through a correlative approach involving Ultrasonography (USG), cytogenetic analysis, and autopsy in congenitally malformed neonates. Materials and Methods: This cross-sectional study was conducted in the Department of Pathology and Obstetrics and Gynaecology at SCB Medical College, Cuttack, Odisha, India, from June 2018 to June 2020. The study included 19 congenitally malformed foetuses/aborted foetuses/neonates not compatible with life, born in the labour room. Written informed consent was obtained, and cord/cardiac blood/soft tissue samples from congenitally anomalous foetuses were collected in a heparinised vial/sterile container during delivery and sent for cytogenetic testing. The deceased foetuses were weighed, external abnormalities and anthropometry were recorded, and then they were preserved in 10% formalin. Autopsies were performed using Virchow’s method. All internal abnormalities were recorded, and sections were sent for Histopathological (HP) study. All the data was analysed using the Statistical Package for Social Sciences (SPSS) software version 20.0. Results: The study included a total of 19 cases, including 11 (57.8%) cases of Intrauterine Deaths (IUD). The majority were males 8 (42%), in the gestational age group of 20-25 weeks (36.7%). Maternal age ranged from 21 to 30 years, with the majority being nine cases (47.3%), and 13 cases (68.3%) without antenatal check-ups. The study comprised 6 cases (31.57%) of genetic syndromes, including Trisomy 21, 13, 18, and Monosomy X, 5 cases (26.3%) of musculoskeletal defects such as Meckel Gruber syndrome, Heterotaxy syndrome, and Thanatophoric dysplasia, and 5 cases (26.3%) of neural tube defects. Conclusion: Autopsy determined the cause of death in 90% of the cases and, when combined with genetic analysis, established the syndromic diagnosis. Autopsy findings can complement or modify the ultrasonographic findings. Therefore, perinatal autopsy should always be included in the management of deaths due to congenital anomalies.

Thanatophoric dysplasia is a lethal skeletal dysplasia characterized by marked underdevelopment of the skeleton and short-limbed dwarfism [1]. The child will present with a short neck, narrow chest, and prominent abdomen. Other anatomical features include a relatively enlarged head with frontal prominence, prominent eyes, hypertelorism, and a depressed nasal bridge. Diagnosis is typically established by ultrasound in the second trimester of pregnancy. In this study, we report a case of this rare entity, emphasizing its anatomical characteristics, anomalies, and clinical profile, along with a relevant literature review.

Thanatophoric dysplasia (TD) is a rare and lethal skeletal dysplasia caused by a de novo mutation in the fibroblast growth factor receptor 3 gene (FGFR3), with a frequency range of 1 in 20,000 to 50,000. We report a case of a 19-year-old primigravida from rural Nepal who presented with ultrasonographic findings suggestive of TD at 26 weeks and three days of gestation. The pregnancy was terminated due to the lethal nature of the condition. Accurate prenatal diagnosis and comprehensive counselling are paramount for families affected by this condition. This case has been reported due to its rarity, with the aim of raising awareness among healthcare professionals about this devastating condition.

Thanatophoric dysplasia type 1 is a form of lethal skeletal dysplasia, characterized by axial-appendicular skeletal disproportions as well as short stature, frontal bossing, cloverleaf skull, narrow chest, femoral bowing, and micromelia. These phenotypic characteristics are the result of pathogenic variants in the fibroblast growth factor receptor 3 (FGFR-3) gene, located on chromosome 4p16.3 For its study, obstetric ultrasound, physical examination and radiographic findings are important. However, the diagnosis must be confirmed by genetic study in order to discover new variants or associations, as well as to reveal its actual casuistry in a certain region.

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. 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. 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. The authors reported this case due to the rarity of this condition and the need for a systematic and multidisciplinary approach.

Background: Noninvasive prenatal tests for monogenic diseases (NIPT-SGG) have recently been reported as helpful in early-stage antenatal screening. Ourstudy describes the clinical and genetic features of cases identified by NIPT-SGG. Materials & methods: In a cohort pregnancy with abnormal sonograms, affected cases were confirmed by invasive diagnostic testsconcurrently, with NIPT-SGG targeting 25 common dominant single-gene diseases. Results: A total of 13single-gene fetuses were confirmed, including Noonan and Costello syndromes, thanatophoric dysplasia, achondroplasia, osteogenesis imperfectaand Apert syndrome. Two novel variants seenwere tuberous sclerosis complex (TSC2 c.4154G>A) and Alagille syndrome (JAG1 c.3452del). Conclusion: NIPT-SGG and standard tests agreeon the results for 13 fetuses with monogenic disorders. This panel method ofscreening can benefit high-risk Vietnamese pregnancies, butfurther research is encouraged to expand on the causative gene panel.

Bone dysplasias are a broad, heterogeneous group of diseases. Thanatophoric dysplasia is a rare bone dysplasia, but it is the most common lethal skeletal dysplasias. The major role in diagnostics plays a high-quality ultrasound examination in the 2nd trimester and the latest methods of genetic testing, including clinical exome testing. Knowing the correct diagnosis is crucial for the future of the fetus and the couple.

Thanatophoric dysplasia, TD (OMIM: 187600, 87601) belongs to the group of FGFR3 chondrodysplasias and is divided intotypes I and II. The incidence of TD is approximately 1:20,000-50,000 newborns. TD is usually caused by pathogenic variantsin the FGFR3 gene, which provides instructions for making a protein involved in the development and maintenance of bone andbrain tissue. Mutations in the gene result in excessive protein activity. TD is inherited as an autosomal dominant trait, althoughcases of autosomal recessive inheritance have been described.According to the radiologic changes of the bones and skull, there are 2 clinical types of TD: type I (TD1, MIM 187600) andtype II (TD2, MIM 187601) with some overlap between them. Type I TD is characterized by micromelia with curved femurs,marked platyspondylia with or without a cloverleaf skull. TD type II is characterized by micromelia with straight femurs andthe uniform presence of moderate to severe craniosynostosis with a leaf-shaped skull deformity due to premature closure of the coronal and lambdoid sutures..The diagnosis of TD is made syndromologically and/or radiologically and/or by detection of a heterozygous pathogenicFGFR3 variant identifi ed by molecular genetic testing.The article presents a rare clinical case of TD in monochorionic dizygotic twins with a fatal outcome. During prenatalultrasound examination at 26-27 and 35-36 weeks of gestation, signs of skeletal dysplasia were diagnosed in both fetuses against the background of pronounced polyhydramnios. It should be noted that the father of the children is over 60 years old.The diagnosis of both children was made syndromologically and radiologically based on the detection of phenotypic signs of TD(predominance of the skull over the face, short upper and lower limbs, altered shape of the chest, infl amed nasal bridge) and radiological signs of TD (short ribs, narrow chest, relative macrocephaly, micromelia of all limbs). Genetic testing for TD was not performed.The clinical case was published with the consent of the parents in accordance with the principles of bioethics.

This paper presents a rare case of fetal hydrops detected at just 23 weeks of gestation in a 22-year-old woman’s first pregnancy. The fetal ultrasound revealed severe skeletal anomalies, craniofacial deformities, and thoracic abnormalities, suggesting a complex and severe skeletal dysplasia, potentially type IA Achondrogenesis—a lethal autosomal recessive condition marked by ossification delay. This case highlights the significance of advanced genetic testing, such as next-generation sequencing (NGS) and whole-genome sequencing (WGS), in diagnosing and understanding skeletal dysplasias. Skeletal dysplasias represent a group of genetic disorders that affect osteogenesis. The prevalence of this condition is 1 in 4000 births. Sadly, 25% of affected infants are stillborn, and around 30% do not survive the neonatal period. There is a wide range of rare skeletal dysplasias, each with its own specific recurrence risk, dysmorphic expression, and implications for neonatal survival and quality of life. When skeletal dysplasia is incidentally discovered during routine ultrasound screening in a pregnancy not known to be at risk of a specific syndrome, a systematic examination of the limbs, head, thorax, and spine is necessary to reach the correct diagnosis. Prenatal diagnosis of skeletal dysplasia is crucial for providing accurate counselling to future parents and facilitating the proper management of affected pregnancies. An accurate diagnosis can be a real challenge due to the wide spectrum of clinical presentations of skeletal dysplasia but advances in imaging technologies and molecular genetics have improved accuracy. Additionally, some of these skeletal dysplasias may present clinical overlap, making it especially difficult to distinguish. After the 11th revision of genetic skeletal disorder nosology, there are 771 entities associated with 552 gene mutations. The most common types of skeletal dysplasia are thanatophoric dysplasia, osteogenesis imperfect, achondroplasia, achondrogenesis, and asphyxiating thoracic dystrophy.

The fibroblast growth factor receptor 3 (FGFR3) gene mutations were identified to be involved in the pathogenesis of most chondropathies. The FGFR3 gene encodes the FGFR3 receptor and is involved in the regulation of bone growth by limiting the ossification of long bones. Mutations of the FGFR3 gene result in abnormal cell proliferation and improper cartilage development. We aim to provide an overview of the roles of FGFR3 in skeletal dysplasia by highlighting the pathogenesis, clinical variants of skeletal dysplasia, diagnosis, and their management.
 Achondroplasia is the most common form of chondropathies, occurring in approximately 1 in 20,000-30,000 live births, and it is the most common form of genetic dwarfism. In over 80% of cases of achondroplasia, the mutation is sporadic, and only 20% are inherited autosomal dominant. Achondroplasia results from a point mutation in the gene encoding the transmembrane portion of FGFR3. Two viable base substitutions are identified in achondroplasia, including a point mutation of guanine substituted for adenine (c.1138G>A); this is identified in approximately 98% of the affected individuals, and transversion of guanine to cytosine (c.1138G>C).
 Hypochondroplasia is a milder form of chondropathies with an incidence between 1 in 33,000 and 1 in 47,000 live births. Missense mutations of FGFR3 (p.Asn540Lys) are isolated in tyrosine kinase domain I occurring in approximately 60% of cases, and missense mutation of FGFR3 (p.Lys650Asn) identified in the tyrosine kinase domain II of FGFR3. Thanatophoric dysplasia is the most lethal form of chondropathies, with neonatal fetal death secondary to pulmonary hypoplasia. In thanatophoric dysplasia, there is Lys650Met substitution in FGFR3 (Type I) with impairment of endochondral bone growth and a pathogenic variant of p.Lys650Glu substitution in FGFR3 (Type II). In addition, specific amino acid substitution in the FGFR3 gene (G380R) was identified to be associated with severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN).
 The diagnosis of achondroplasias is routinely made from clinical presentations and radiological findings. FGFR3 molecular genetic testing is performed in children with atypical presentations. In addition, a pre-implantation genetic diagnosis should be available for parents pursuing in-vitro fertilization and embryo implantation procedures. Management of chondropathies includes symptomatic treatment with drugs, surgical intervention, and lifelong follow-up care. Different pharmacological options have been used, including those that directly block FGFR3 activation or regulate signalling pathways controlling chondrocyte proliferation and differentiation.

Background: 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. Methods: 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 de novo variants were validated by Sanger sequencing. Results: 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%; p = 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%, p = 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%; p < 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. Conclusion: 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.