Fetus with interstitial del(5)(p13.1p14.2) diagnosed postnatally with Cornelia de Lange syndrome

Cornelia de Lange (CdLS), also known as Brachmann de Lange, is a complex disorder that includes characteristic facial features, hirsutism, limb abnormalities, diaphragmatic hernia, pre- and postnatal growth retardation, and mental retardation. It is estimated to occur in 1 in 10,000 live births [Opitz, 1985]. CdLS is usually diagnosed by postnatal clinical findings; however, prenatal diagnosis has been made by the presence of congenital diaphragmatic hernia, characteristic limb abnormalities, and facial profile, as detected by fetal ultrasound [Urban and Hartung, 2001; Marino et al., 2002]. The gene responsible for CdLS, NIPBL, was recently identified, due in part to the clinical report of this case [Hulinsky et al., 2003] as well as an infant with a balanced de novo translocation (5;13)(p13.1;q12.1) [Krantz et al., 2004]. The proposita was the second child born to a nonconsanguineous Caucasian couple. The mother was referred at 20-week gestation to evaluate abnormal sonographic findings. Targeted ultrasound revealed multiple anomalies including diaphragmatic hernia, single umbilical artery, nuchal thickening, and abnormal upper extremities. Maternal serum screening was normal. The patient had one previous normal pregnancy with delivery at term of a healthy female. The family history was noncontributory. Due to the multiple congenital abnormalities, karyotype analysis by amniocentesis was performed at 20-week gestation. The karyotype was 46,XY,del(5)(p13.1p14.2) at 425 band level, and was confirmed by postnatal chromosome analysis (Fig. 1). Fluorescence in situ hybridization (FISH) analyses using whole-chromosome 5 paint and the cri-du-chat syndrome probe at 5p15.2 demonstrated a simple, interstitial deletion centromeric to the cri-du-chat syndrome deletion breakpoint. Parental karyotypes were normal. G-banded chromosome 5 ideogram. Band level 425. Del(5)(p13.1p14.2) Partial karyotype of the proband showing the abnormal chromosome 5, which is indicated by del(5). Arrow points to the diagram of abnormal chromosome indicating deletion. The couple was counseled extensively regarding poor prognosis, specifically in the context of a chromosome deletion, oligohydramnios, and diaphragmatic hernia. Follow-up ultrasounds at 26-, 30-, and 34-week gestation showed progressive reduction of amniotic fluid (there was no evidence of premature rupture of membranes) and progressive IUGR. Fetal echocardiogram at 26-week gestation was apparently normal. Precipitous delivery at 36-week gestation resulted in an infant born at home. The parents reported no movement or respiratory effort after delivery. Autopsy demonstrated a male infant with manifestations of Cornelia de Lange and the karyotype was confirmed by tissue biopsy. The facial features were consistent with CdLS, including low hairline, characteristic “penciled in” eyebrows without synophrys, long philtrum, thin lips, upturned nasal tip, and posteriorly rotated and abnormal ears (Fig. 2). Limb abnormalities were also consistent with a diagnosis of CdLS, which included micromelia and oligodactyly of the upper limbs with single forearm bones and short feet. Other external abnormalities consistent with a diagnosis of CdLS included cleft of the soft palate, hirsutism, and hypospadias. Internal abnormalities consistent with a diagnosis of CdLS included left-sided diaphragmatic hernia, and ventricular septal defect. Internal findings of unclear significance included hypoplastic kidneys, fused and hypoplastic adrenals, and multiple thin-walled cysts arising from the esophagus, stomach, and lungs. Facial characteristics and oligodactyly of upper extremities demonstrate characteristic manifestations of CdLS. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] The external and internal postmortem findings confirmed the phenotype of CdLS. Furthermore, both pre- and postmortem cytogenetic studies excluded other chromosomal abnormalities such as trisomy 18, trisomy 9, and tetrasomy 12p, which have been associated with congenital diaphragmatic hernia [Tibboel and Gaag, 1996; Jones, 1997; Bianchi et al., 2000]. Several cases of CdLS have been diagnosed prenatally based on the presence of diaphragmatic hernia, upper limb abnormalities, and facial features [Urban and Hartung, 2001; Marino et al., 2002]. While studies had indicated an association of CdLS with partial trisomy 3q [Ireland et al., 1991], none had reported an association with deletion 5p. The majority of terminal deletions in chromosome 5p are associated with Cri-du-chat syndrome. The deletion can range from the entire short arm to only encompass 5p15.3. Children with deletions, excluding the cri-du-chat syndrome critical region (5p15.2), may still have characteristics of the condition including mental retardation and facial gestalt. Cri-du-chat syndrome is characterized by microcephaly, mental retardation, cat-like cry, and distinctive face. Limb defects and diaphragmatic hernia are not associated with cri-du-chat syndrome. Interstitial deletions of band 5p14 have been reported in individuals with no abnormalities [Overhauser et al., 1986], in individuals with microcephaly and developmental delay [Johnson et al., 2000], and in an individual with a peroxisomal disorder [Hand et al., 2000]. A report of a three-generation family with del(5)(p14.3p13.3) showed various malformations including microcephaly, hypertonia, micrognathia, and mental retardation, the authors suggest the phenotype is associated with the deletion of 5p13 [Keppen et al., 1992]. None of these cases demonstrated manifestations of CdLS. A female infant reported with terminal deletion 5p13 was reported to have cardiac lesions, thymic dysplasia, and oligosyndactyly [Taylor and Josifek, 1981]. While the child was not reported as having CdLS, facial features combined with characteristic upper extremities support this diagnosis. After birth, the recognition of CdLS in this infant led to the realization that haploinsufficient genes in the deletion could contribute to CdLS. This was the first reported case of CdLS in association with partial monosomy 5p [Hulinsky et al., 2003], and contributed to the identification of NIBPL as the CdLS gene [Krantz et al., 2004; Tonkin et al., 2004]. Further delineation of the syndrome has been possible by evaluation of gene mutations in individuals with CdLS, and a milder phenotype is seen in individuals with missense mutations than in those with other types of mutations [Gillis et al., 2004]. In retrospect, it is apparent that the complete deletion of NIBPL caused the severe phenotype seen in this individual. The hypoplastic kidneys, fused and hypoplastic adrenals, and thin-walled cysts in the esophagus, lungs, and stomach, in this case, may be related to the hemizygosity of contiguous genes to the NIPBL locus. The overlap of fused adrenals between this case and the infant with terminal deletion of 5p13 [Taylor and Josifek, 1981] is suggestive of a gene associated with adrenal development located in the region of 5p13. Special thanks to Heather Winesette, M.D. for autopsy photographs and Zhong Chen, M.D. for cytogenetics. Also, thanks to Karin Dent, M.S., the Clinical Genetics Research Program (supported by the PCMC Foundation), and the Huntsman General Clinical Research Center (MO1RR00064) for family study enrollment and phenotype collection.