American Journal of Medical Genetics 130A:315–316 (2004) Clinical Report Assisted Reproductive Technology and Congenital Overgrowth: Some Speculations on a Case of Pallister–Killian Syndrome P. Chiurazzi, J. Bajer, E. Tabolacci, M.G. Pomponi, R. Lecce, M. Zollino, and G. Neri* Istituto di Genetica Medica, Facolta ` di Medicina ‘‘A. Gemelli,’’ Universita ` Cattolica del S. Cuore, Roma, Italy We report on a boy with Pallister–Killian syn- drome (PKS) who was conceived by assisted re- productive technology (ART), specifically in vitro fertilization (IVF) with parents’ gametes. A pre- natal diagnosis performed elsewhere by CVS failed to detect the presence of the isochromosome 12p that was demonstrated postnatally in ap- proximately 50% of cultured skin fibroblasts. Given that the patient did not show the congenital overgrowth typical of PKS, we speculate that ART might have restricted overgrowth in this parti- cular case. More broadly, we hypothesize that overgrowth might protect from early demise fetuses conceived by ART, a technology known to cause low and very low birth weight. ß 2004 Wiley-Liss, Inc. KEY WORDS: assisted reproductive technology; in vitro fertilization; intra- cytoplasmic sperm injection; imprinting defects; overgrowth syndromes; Pallister–Killian syn- drome INTRODUCTION A quarter century after the introduction of assisted repro- ductive technology (ART) and the birth of more than one million babies conceived by ART, there has been a sudden surge of concern about the possibility of an increased rate of birth defects among these infants. In March of 2002, two reports were published in the New England Journal of Medi- cine, one from Australia on a series of 301 infants conceived by intracytoplasmic sperm injection (ICSI) and 837 conceived by in vitro fertilization (IVF), and one from the United States on a series of 42,463 infants conceived by ART. The first of these reports, by Hansen et al. [2002], concluded that there is twice as high a risk of major birth defects among infants conceived by ICSI or IVF compared to naturally conceived controls. The other report by Schieve et al. [2002] concluded that ART accounts for an excess of low- and very-low-birth-weight in- fants. These two papers were followed in short order by four reports describing imprinting disorders, specifically Angelman syndrome (AS) and Beckwith–Wiedemann syndrome (BWS), in children who had been conceived by ART, including ICSI. Cox et al. [2002] described anecdotally one boy and one girl with AS, both conceived by ICSI. In a more systematic study, DeBaun et al. [2003] reported a case series of children with BWS and found that a disproportionately high number had been conceived by ART, concluding, therefore, that there may be an association between BWS and ART. It is worthy of note that of a total of seven cases, five had been conceived by ICSI. Similar results were obtained by Maher et al. [2003] and by Gicquel et al. [2003]. These observations were recently re- viewed in The Lancet by Gosden et al. [2003] who, among other things, point to the analogies between the overgrowth of BWS infants and that of cloned animals, the latter being likely due to loss of imprinting of the Igf2r gene [Young et al., 2001]. Neonatal overgrowth is also present in the so-called Pallister – Killian syndrome (PKS) (OMIM 601803), a multiple congenital anomalies/mental retardation syndrome, caused by mosaic tetrasomy of chromosome 12p. Nine of 11 cases reported by Reynolds et al. [1987] had a birthweight between the 75th and 90th centile. The authors note that this finding, although not obligatory, is nonetheless significant, given that most ane- uploidies are associated with growth retardation. The mech- anism leading to congenital macrosomia in PKS is unknown [Reynolds et al., 1987], although probably related to the chromosome imbalance rather than to an imprinting defect. We report on a boy with PKS who was conceived by IVF, with the intention of drawing attention to the possibility that there may be a relationship, resulting from various mechanisms, between overgrowth and ART. CLINICAL REPORT Our patient, a boy, was conceived by IVF with gametes obtained from the biological parents, because of maternal tubal obstruction. The 38-year-old father and 33-year-old mother were healthy and nonconsanguineous. Their chromosomes were normal. Four previous pregnancies, two of which were tubal, aborted spontaneously. The child was born at term after a pregnancy complicated by abruptio placentae of limited ex- tension. Prenatal cytogenetic diagnosis by CVS was reported normal. Delivery was by C-section. Birthweight was 3,780 g (75th centile), length 50 cm (25th centile), head circumference 37 cm (75th centile), and Apgar scores were 6 and 8 at 1 and 5 min, respectively. The infant was hypotonic and had a distanctive face, a small atrial septal defect and evidence of cerebral atrophy with dilatation of the ventricles and of the subdural spaces on CT scan. These findings prompted the repetition of a chromosome test on peripheral blood lympho- cytes. The result was again normal (46,XY). When we saw the child at 10 months, his physical growth was along the same centiles observed at birth, but psychomotor development was clearly delayed, with marked muscular hypotonia. The face was typical of PKS with high forehead, frontal bossing, hypoplasia of the supraorbital ridges and of the nasal root, hypertelorism (inner canthal distance 2.9 cm, 97th centile), epicanthic folds, malar hypoplasia, anteverted nares, invert- ed V shape of the mouth with pouting lower lip, highly arched *Correspondence to: G. Neri, M.D., Istituto di Genetica Medica, Universita ` Cattolica del S. Cuore, Largo F. Vito 1, 00168 Roma, Italy. E-mail: gneri@rm.unicatt.it Received 12 February 2004; Accepted 26 May 2004 DOI 10.1002/ajmg.a.30300 ß 2004 Wiley-Liss, Inc.