A Case of Thanatophoric Dysplasia Type ɪ With a Missense Mutation in the FGFR3 Gene in a Preterm NeonateMohamed Ghamry 1,2Pediatrics Department, BronxCare Health System, Bronx, NYMount Sinai Health System, NY, USACorresponding Author: Mohamed Ghamry, MDEmail: mghamry1991@gmail.comKeywordsThanatophoric dysplasia, FGFR3 mutation, skeletal dysplasia, preterm neonate, micromelia, case reportAuthor ContributionsDr. Mohamed Ghamry contributed to patient management, data collection, literature review, manuscript writing, and final editing. He approves the final version and agrees to be accountable for all aspects of the work.Patient Consent StatementWritten informed consent was obtained from the patient’s legal guardian for publication of this case report and accompanying images.Key Clinical MessageThanatophoric dysplasia is a rare, often fatal skeletal disorder diagnosed by prenatal imaging and confirmed genetically. Awareness of its hallmark radiological features allows for timely counseling and decision-making during pregnancy.IntroductionThanatophoric dysplasia (TD) is a congenital, rare, sporadic short-limb skeletal dysplasia that is usually lethal in the perinatal period caused by a new dominant mutation in the fibroblast growth factor receptor-3 (FGFR3) gene which is located on the short arm of chromosome 4 [1]. The most common mutations in TD are p.R248C, p.S249C, and p.Y373C where a cysteine residue is created within the extracellular domain [1]. TD is divided into two clinically defined subtypes: type I and II with some clinical overlap between the two subtypes [2]. They can be differentiated by the skull shape and femur morphology [2].Case History/examinationA 25-year-old healthy woman in her 1st pregnancy with an uncomplicated preconception and no prior antenatal visits admitted to the Emergency Room (ER) with continuous painless leaking of fluid out of vagina and inability to feel infant movements. Ultrasound scan revealed a female fetus of 34 weeks of gestation with features of deformed shorten limbs, narrow thorax with short ribs, protuberant abdomen, and oligohydramnios. A Caesarian section was performed, and Mother had uneventful recovery. A preterm female baby weighed 1.9 Kg was delivered which had a delayed first cry, cyanosis, and respiratory distress. Her length is 34 cm which was below 3rd percentile for her gestational age according to Fenton growth charts for preterm girls while her weight was 1900 gm which was about 26th percentile for her gestational age according to Fenton growth charts for preterm girls. Baby showed dysmorphic features, macrocephaly (head circumference 36 cm which is above 97th percentile for her gestational age according to Fenton growth charts for preterm girls), edematous face with mid facial hypoplasia, macroglossia, micrognathia, depressed nasal bridge, short neck, and shortened upper and lower limbs with short fingers and deep skin creases (Figure 1).She also had a narrow chest and a protuberant abdomen with chest-to-abdominal circumference ratio <0.6 (Figure 2).Differential Diagnosis, Investigations, and TreatmentWe considered several differentials for the severe skeletal dysplasia, including Jeune syndrome, achondrogenesis, and osteogenesis imperfecta.Full-body x-ray (Infantogram) showed macrocephaly, small proximal long bones of limbs giving a rhizomelic character (Figure 3), narrow chest with short horizontal ribs (Figure 4), and markedly curved femurs with metaphyseal flaring with telephone receiver like configuration (Figure 5).Echocardiography showed ASD 2mm with left to right shunt, PDA 2 mm with left to right shunt and mild pulmonary hypertension 25-30mmHg. Transcranial and abdominopelvic ultrasound showed no remarkable abnormalities. She was intubated, admitted to Neonatal Intensive Care Unit (NICU), and mechanically ventilated.Conclusion and Results (Outcome and follow-up)At age of 15 days, the neonate died due to respiratory failure. Postmortem DNA analysis confirmed the diagnosis of TD type 1 by the detection of a missense mutation at position 373 on short arm of chromosome 4 where tyrosine has been replaced by cysteine (p.Y373C). Both parents were debriefed and counselled.DiscussionThanatophoric dysplasia (TD) is a rare congenital lethal sporadic skeletal dysplasia [1].. The name ”thanatophoric” derives from the Greek “thanatophoros” meaning ”death bearing” or ”death bringing” [3]. Its prevalence in USA ranged from 0.21 to 0.30 per 10,000 livebirths [4].It results from a new autosomal dominant mutation affecting FGFR3 gene [5]. The FGFR3 gene is located on the short (p) arm of chromosome 4 at position 16.3 from base pair 1,793,299 to base pair 1,808,872 [5]. Type I thanatophoric dysplasia is caused by at least 10 FGFR3 gene mutations [5]. The most frequent mutations (p.R248C, p.S249C, p.Y373C) create a cysteine residue within the extracellular domain, whereas the others eliminate the termination codon (p.X807R, p.X807C, p.X807G, p.X807S, p.X807W) [6]. Type 2 thanatophoric dysplasia is caused by replacement of the amino acid lysine with the amino acid glutamic acid at position 650 of the FGFR3 protein [5]. These mutations lead to over activation in FGFR3 gene which causes severe problems with bone growth that occur in both types of thanatophoric dysplasia [5].There are two subtypes with relative incidence: Type I-80% and Type II-20% [2]. The two subtypes can be differentiated by the skull shape and femur morphology [2].Type 1 characterized particularly by the femur shape which is in a telephone receiver like configuration, while, the femur is straight in type 2 TD and the clover-leaf skull deformity (trilobed skull) is significant [5].Both types of TD may have any of the following characteristics: large anterior fontanel, macrocephaly, a small foramen magnum, characteristic facial features (frontal bossing, low nasal bridge, mid face hypoplasia), small narrow thorax with horizontally short ribs which may falsely appear asymmetric in antenatal fetal ultrasound, protuberant abdomen, severe platyspondyly, marked shortening of long bones, brachydactyly (short broad fingers and toes) etc. [7].Neonates with this condition are usually stillborn or die shortly after birth and the main cause of death is respiratory failure. However, a small number of individuals have survived into childhood and a very few beyond, requiring respiratory support. The oldest known living TD survivor as of 2013 was a 29-year-old woman [8].Diagnosis of a lethal skeletal dysplasia by two dimensional ultrasound in the second trimester is often straight forward, however determining its specific diagnosis can be difficult so a three-dimensional ultrasound may be used to detect facial features and other soft tissue findings such as very short extremities, trilobed skull (cloverleaf skull), small narrow thorax with short ribs, and splayed digits which are suggestive of TD [9]. To confirm the diagnosis molecular genetic analysis from either cultured amniotic fluid cells, cord blood or fetal tissue can be done [10]. Postnatal gross, radiological (Infantogram) or histological is usually done to make a diagnosis. In addition, Postnatal tissue sample or autopsy may be used to confirm the diagnosis by histopathology or genetic analysis [6].Palliative care is often in the management plan for those who are born with TD. Studies have shown that C-type natriuretic peptide (CNP) plasma levels are altered in FGFR3-opathies so CNP analogues carry the possibility of being helpful to children with TD in the future [11].Differential diagnosis of TD includes perinatal lethal short rib-polydactyly syndromes, Jeune asphyxiating thoracic dystrophy (polydactyly and multisystem features are common; may involve cardiac, renal, liver, pancreatic, intestinal, genital, retinal, and ectodermal tissues [12]), achondrogenesis (Minimal or absent ossification of vertebral bodies, iliac, and ischial bones), osteogenesis imperfect type ɪɪ (generalized hypo mineralization of bones with multiple bone fractures and blue sclera) , homozygous achondroplasia(one or both parents are affected and has no telephone receiver femur or cloverleaf skull deformity), rhizomelic chondrodysplasia punctata (stippled epiphyses on radiography which indicate Punctate epiphyseal dysplasia, coronal vertebral clefts , and prominent rhizomelia), campomelic dwarfism (bowing and angulation of long bones, longer femurs compared to TD, immature ossification, and Profound hypoplasia of the body of the scapulae) [13].Presence of telephone receiver appearance of humerus and femur with platyspondyly, small narrow thorax with short horizontal ribs, protuberant abdomen, and facial features (mid facial hypoplasia, macrocephaly, depressed nasal bridge and macroglossia) differentiates TD type ɪ from the other causes of severe short stature with micromelia. Confirmation was done by DNA analysis.ConclusionsThis case of Thanatophoric dysplasia type ɪ is being reported for its fatality, rarity and the high importance of detecting its features during prenatal ultrasound because early prenatal diagnosis is important as it gives alternative options of termination of pregnancy when an affected fetus is detected. Most fetuses with this case die in utero and those who survive suffer from respiratory insufficiency and are dependent on a ventilator. Health professionals should be aware of radiological and morphological features of TD and its differential diagnosis.ReferencesWarman ML, Cormier-Daire V, Hall C, et al.: Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A. 2011, 155:943-968. 10.1002/ajmg.a.33909Samsudeen MF, Maggonage CG, Wedisha IG, Thuvaratheepan R, Kaluarachchi A: Fetal thanatophoric dysplasia. 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