Apert syndrome with congenital diaphragmatic hernia

78 Short case report Apert syndrome with congenital diaphragmatic hernia: another case report and review of the literature Ravneet Kaura, Puneeta Mishraa, Surjeet Kumarb, Mari J. Sankarb, Madhulika Kabraa and Neerja Guptaa Clinical Dysmorphology 2019, 28:78–80 a b Department of Pediatrics, Division of Genetics and Department of Pediatrics, Division of Neonatology, All India Institute of Medical Sciences, New Delhi, India Tel: + 91 999 999 5630 / + 91 112 659 4585 ×106; fax: + 91 112 658 8663 /+ 91 112 658 8641; e-mail: [email protected] Received 12 September 2018 Accepted 3 January 2019 Correspondence to Neerja Gupta, MD, DM, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India, Room 6, Genetics Unit, Ansari Nagar, New Delhi 110029, India List of key features Widely open metopic suture Down-slanting palpaberal fissures Midface hypoplasia Depressed nasal bridge Anteverted nares Syndactyly Introduction Apert syndrome (MIM 101200), first described by a French physician Eugene Apert in 1906 (DeGiovanni et al., 2007), is a rare autosomal dominant acrocephalosyndactyly syndrome type 1 with a birth prevalence of one in 64 500 live births, with males and females being affected equally (Cohen and Kreiborg, 1992). It is characterized by craniosynostosis, midface hypoplasia, and complex syndactyly of the hands and feet. It is linked to mutations in fibroblast growth factor receptor 2 (FGFR2) on chromosome 10q26 (Wilkie et al., 1995). There are several associated malformations in Apert syndrome such as fusion of C5–C6 cervical vertebrae (Thompson et al., 1996), hydrocephalus (Cohen and Kreiborg, 1990), occasional cardiac and gastrointestinal defects (Cohen and Kreiborg, 1993), and ovarian dysgerminoma (Rouzier et al., 2008). Congenital diaphragmatic hernia has been reported in four cases previously. We describe a fifth case of Apert syndrome and review the literature. Clinical report A term female baby was born to a 27-year-old primigravida. Antenatal ultrasound at 18 weeks of gestation indicated diaphragmatic hernia with dextrocardia without any other associated craniofacial or limb abnormality. Both the parents were normal and there was no significant family history. The baby was conceived spontaneously after 5 years of primary infertility. In view of fetal bradycardia and congenital diaphragmatic hernia (CDH), the baby was delivered by Cesarean section and weighed 2222 g (< 10th centile) at birth, with APGAR scores of 1 and 3 at 1 and 5 min, respectively. The baby 0962-8827 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. was admitted to NICU in view of severe birth asphyxia and respiratory distress, and was intubated and mechanically ventilated. Clinical examination showed dysmorphic facial features, with widely open metopic suture, frontal bossing, down-slanting palpebral fissures, midface hypoplasia, depressed nasal bridge, and anteverted nares (Fig. 1a). There was severe syndactyly (type II) of the hands and feet. The thumbs of both the hands were broad and radially deviated. There was syndactyly of the second, third, and fourth digits with partial syndactyly of the fourth and fifth digits, and fusion of the nails of the second to fourth digits (Fig. 1b and c). Both the great toes were short and broad, with complete syndactyly of the second, third, fourth, and fifth toes, and skin webbing between great toes and second toe bilaterally (Fig. 1d). Radiological examination indicated left-sided CDH with the presence of bowel loops in the left hemithorax and shifting of the heart to the right side (Fig. 1e). The baby required high ventilator settings, and developed shock after a few hours. Despite the inotropic support and respiratory support, the baby died after 14 h of birth. On autopsy, the left hemithorax was observed to be occupied by the small and large intestine, the heart was pushed to the right side, and the left lung was severely hypoplastic. The diagnosis of Apert syndrome was confirmed by sequencing of the FGFR2 gene, which indicated heterozygous c.755C > G (p.S252W) (Fig. 1f), the most common variant in exon 7. As most of the cases are sporadic, the family was counseled on the low recurrence risk; however, as the germline mosaicism cannot be ruled out, prenatal diagnostic options for the next pregnancy were explained. Discussion Apert syndrome is one of the most common forms of the craniosynostosis syndromes, accounting for 4.5% of all cases (Hehr and Muenke, 1999). Most of the cases are sporadic, and are diagnosed postnatally or late in gestation, as the specific ultrasound findings of Apert syndrome such as syndactyly, midface hypoplasia, and craniosynostosis can be usually detected reliably, either DOI: 10.1097/MCD.0000000000000261 Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved. Apert syndrome with CDH Kaur et al. 79 Fig. 1 (a) Facial features. Widely open metopic suture with anteverted nares. (b) Syndactyly of the second to fifth digits with partial syndactyly of the fourth and fifth digit, and fusion of the nails of the second to fourth digits. (c) Right thumb broad and radially deviated. (d) Short and broad great toes, complete syndactyly of the second to fifth toes. (e) Left-sided diaphragmatic hernia with bowel loops and nasogastric tube in the left hemithorax. (f) ECG of the patient showing a heterozygous c.755C > T variant. in the third trimester or sometimes in the late second trimester (Filkins et al., 1997; Skidmore et al., 2003). Early prenatal diagnosis has been reported in familial cases, where a high index of suspicion leads to better interpretation of ultrasound abnormalities in the fetus (Narayan and Scott, 1991). In sporadic cases, it is usually the presence of some nonspecific ultrasonographic abnormalities that leads to a more detailed evaluation and serial ultrasound for the appearance of more specific signs (Skidmore et al., 2003). The nonspecific ultrasound markers reported previously include thickened nuchal folds (Chenoweth-Mitchell and Cohen, 1994), polyhydramnios (Kaufmann et al., 1997), arthrogryposis (Mahieu-Caputo et al., 2001), and congenital heart disease (Skidmore et al., 2003). CDH has been described in association with Apert syndrome in four cases previously (Witters et al., 2000; Bulfamante et al., 2011; Sobaih and AlAli, 2015; Kosiński et al., 2016), and in three of these (Witters et al., 2000; Bulfamante et al., 2011; Kosiński et al., 2016), CDH was the predominant prenatal ultrasonographic sign, whereas in one of these, diaphragmatic hernia and Apert syndrome were diagnosed in the postnatal period as the mother had not sought any antenatal care. In the prenatally reported CDH cases, the prenatal ultrasound showed craniofacial dysmorphism with brachycephaly, frontal bossing, hypertelorism, syndactyly of the hands and feet, and mild ventriculomegaly at 22 weeks of gestation (Witters et al., 2000). In the second reported case, the additional findings were an unusually high forehead, micrognathia, bilateral hypoplasia of the middle phalanx of the fifth finger, bilateral syndactyly, corpus callosum agenesis, and mild hydronephrosis at 20 weeks of gestation (Bulfamante et al., 2011). In the third case, there was mild ventriculomegaly and an abnormal shape of the cavum septum pellucidum at 22 weeks of gestation, whereas the follow-up scan at 31–32 weeks indicated a broad forehead, midface hypoplasia, hypertelorism, exophthalmos, and mitten-like hands (Kosiński et al., 2016). In our case, CDH was the only abnormality detected in the prenatal sonography at 18 weeks of gestation. Werner et al. (2018) used three-dimensional physical and virtual models to evaluate fetal skull shape and extremities for syndromic craniosynostosis (Werner et al., 2018). Three-dimensional ultrasound enables better delineation of the fetal craniofacial and extremity abnormalities in cases where these fetal anatomical structures are not clearly visible in two-dimensional ultrasound. Fetal MRI can also be used as a diagnostic adjunct in cases where the ultrasound yields equivocal results and in cases with suspicious associated central nervous system abnormalities. Although the prenatal diagnosis in this study was made in the late third trimester, this evaluation might be useful at early gestation for a timely diagnosis. Copyright r 2019 Wolters Kluwer Health, Inc. All rights reserved. 80 Clinical Dysmorphology 2019, Vol 28 No 2 Table 1 Some syndromes with congenital diaphragmatic hernia and additional abnormalities Syndromes Additional key features Edwards syndrome Patau syndrome Pallister–Killian syndrome Cornelia de Lange syndrome Fryns syndrome Simpson–Golabi–Behmel syndrome Kabuki syndrome Donnai-Barrow syndrome Meacham syndrome Lethal multiple pterygium syndrome Matthew-Wood syndrome IUGR, clenched fists, congenital heart defect, renal anomalies IUGR, holoprosencephaly, scalp defects, cleft lip/palate, omphalocele, cardiac, and renal malformations Increased nuchal translucency, polyhydramnios, rhizomelic shortening, fetal overgrowth, abnormal facial profile Limb anomalies (short forearms, limb reduction defects), distinctive craniofacial features (microbrachycephaly, synophrys, depressed nasal bridge, long smooth philtrum), IUGR, congenital heart defect Brachytelephalyngy, polyhydramnios, orofacial clefting, craniofacial dysmorphism, distal digital hypoplasia, CNS anomalies Macrosomia, structural brain anomalies, vertebral fusion, polydactyly, heart defects IUGR, facial dysmorphism, congenital heart disease, gastrointestinal and genitourinary abnormalities Typical craniofacial features (large anterior fontanel, wide metopic suture, hypertelorism), agenesis of corpus callosum Cardiac and pulmonary malformations with sex reversal in karyotypic males Fetal akinesia, cystic hygroma, joint contractures and webbing, IUGR, heart defects Pulmonary hypoplasia, cardiac defects, anophthalmia Genomic abnormalities Trisomy 18 Trisomy 13 Tetrasomy 12p (mosaic) NIPBL, RAD21, SMC3 Unknown GPC3, GPC4 KMT2D, KDM6A LRP2 WT1 CHRNG STRA6 CNS, central nervous system; IUGR, intrauterine growth restriction. The definitive mechanism for this association of diaphragmatic hernia with Apert syndrome has not been proven, although it was hypothesized that the fibroblast growth factor (FGF) pathway (particularly, mesenchymal FGF-10 and its epithelial receptor FGFR2) is an important pathway for limb and diaphragm development. Therefore, loss of function and haploinsufficiency for FGFR2 might be a predisposing factor for CDH in Apert syndrome (van Dooren et al., 2003). Conclusion CDH might be considered an early ultrasonographic sign of Apert syndrome. Its presence should raise the suspicion to actively search for craniofacial abnormalities, facial dysmorphism, and syndactyly in the fetus as most of the cases are of sporadic occurrence. Postnatal detection of these abnormalities poses a serious mental impact on the families because of the multiple surgeries and multidisciplinary approach and lifelong follow-up required for the management of children with Apert syndrome. In the families opting for termination of pregnancy for CDH, or other nonspecific signs, a detailed fetal examination and autopsy is important to make a syndromic diagnosis, along with proper counseling, as there are a number of other syndromes where CDH is commonly encountered. Table 1 describes the syndromes where CDH is commonly seen and other common features that should be actively looked for in a case with a prenatal diagnosis of CDH (Wynn et al., 2014). Acknowledgements Conflicts of interest There are no conflicts of interest. References Bulfamante G, Gana S, Avagliano L, Fabietti I, Gentilin B, Lalatta F (2011). Congenital diaphragmatic hernia as prenatal presentation of Apert syndrome. Prenat Diagn 31:910–911. Chenoweth-Mitchell C, Cohen GR (1994). Prenatal sonographic findings of Apert syndrome. J Clin Ultrasound 22:510–514. Cohen MM Jr, Kreiborg S (1990). The central nervous system in the Apert syndrome. Am J Med Genet 35:36–45. Cohen MM Jr, Kreiborg S (1992). 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