Cornelia de Lange Syndrome Presenting as Hydrops Fetalis due to Intestinal Atresia

 

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Introduction

Cornelia de Lange Syndrome (CdLS) is characterized by growth retardation, severe mental retardation, short stature, a low-pitched growling cry, brachycephaly, low-set and/or posteriorly rotated ears, webbed neck, carp mouth, depressed nasal bridge, hirsute forehead, bushy eyebrows meeting at the midline, hirsutism, malformations of the hands, and structural malformations that mainly involve the genitourinary, cardiac, gastrointestinal, and central nervous systems [Qiao et al., Front Genet 2021; 12: 628890; Mutlu et al., Clin Dysmorphol 2010; 19: 161–163; Li et al., Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021; 38: 1132–1135]. The first description of CdLS was by a Dutch pediatrician, who observed it in two children in 1933 [De Lange, Arch Med Enfants 1933; 36: 713–719]. CdLS is a rare, clinically and genetically heterogeneous, multisystem developmental disorder, diagnosed on the basis of clinical observations. Although almost any organ system can be affected, the neurodevelopmental, craniofacial, gastrointestinal, and musculoskeletal systems are the most commonly involved [Holthusen et al., Tidsskr Nor Laegeforen 1998; 118: 1559–1560; Yuan et al., J Clin Invest 2015; 125: 636–651; Li et al., Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2021; 38: 1132–1135; Peng et al., Front Genet 2021; 12: 699894]. The mutations in the SMC1A, SMC3, NIPBL, RAD21 and HDAC8 genes have been identified as responsible for CdLS in some of the cases [Krantz et al., Nat Genet 2004; 36: 631–635; Tonkin et al., Nat Genet 2004; 36: 636–641; Musio et al., Nat Genet 2004; 38: 528–530; Deardorff et al., Am J Hum Genet 2007; 80: 485–494; Deardorff et al., Am J Hum Genet 2012; 90: 1014–1027; Deardorff et al., Nature 2012; 489: 313–317]. The genetic cause underlying is unknown in approximately 30% of CdLS cases. The diagnosis of CdLS is usually made according to the clinical signs after birth. Prenatal diagnosis of CdLS can be made if there are abnormalities such as congenital diaphragmatic hernia, characteristic extremity abnormalities, and facial profile detected by fetal ultrasound. However, routine prenatal ultrasonography is diagnostically unsuccessful in more than two-thirds of CdLS cases with major malformations [Peng et al., Front Genet 2021; 12: 699894; Selicorni et al., Genes (Basel) 2021; 12: 1075]. We present a CdLS case who had non-immune hydrops fetalis (NIHF), which has not been ever reported in the literature.

Case

A 1335 g male newborn who was followed as hydrops fetalis (HF) during pregnancy, was delivered by cesarean section to a 21-year-old mother, at 32^5/7 weeks gestation due to absent umbilical arterial end diastolic flow. After successful resuscitation, 20 cc/kg of paracentesis was performed in order to handle severe abdominal ascites. Intrauterine growth retardation, excessive hair growth, hirsute forehead, depressed nasal bridge, low-set and abnormal rotation of ears, long philtrum, syndactylia on right hand and abdominal distension were detected on physical examination ([Fig. 1a–b]).

The patient was the first child to consanguineous marriage from a mother with gravidity 2 and parity 1, who had preeclampsia and healthy father without any familiar diseases or genetic defects. Antenatal ultrasonographic examination at 32 weeks of gestation demonstrated HF. The mother’s blood group was A Rh (+) and indirect coombs was negative, therefore, Rh and ABO incompatibility were eliminated as the cause of HF. IgM antibody against syphilis and TORCH serology were all negative. Fetal echocardiographic examination showed muscular ventricular septal defect (VSD) and minimal pericardial effusion. The patient subsequently underwent amniocentesis and the karyotype revealed 46 XY. Molecular genetic analysis was performed in the identified CdLS genes and SMC1A mutation was detected. We have figured out a heterozygous mutation of c.1951G>A in Exon part 14 during genetic sequence analysis. We could not analyze the parents’ sequence because they were out of reach. But we have not found any similar cases in the family due to patient’s history.

The patient was diagnosed as CdLS according to clinical presentation. He needed mechanical ventilation support for 8 days. Upright radiograph of the abdomen due to abdominal distension demonstrated many dilated loops of bowel together with air-fluid levels. The contrast enema study demonstrated micro-colon with abrupt cut-off of contrast material filling of the ileum. The patient was diagnosed as ileal atresia and ileostomy was performed on the fourth day of life. The infant tolerated full oral feeding on postnatal 33^th day. The patient’s ileostomy was closed on the postnatal day 96. No complications occurred after ileostomy. The feeding was continued with breast milk. Postnatal growth of the patient occurred in accordance with its own growth curve.

Publication History

Article published online:
21 July 2023

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