ß 2008 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 146A:2005–2007 (2008) Research Letter Be Careful With Familial Unbalanced Chromosome Abnormalities! L. Rodrı ´guez, 1,2 * E. Niebuhr, 3 A. Garcı ´a, 4 M.L. Martı ´nez-Ferna ´ndez, 1 and J.L. Pen ˜a Segura 4 1 Estudio Colaborativo Espan ˜ol de Malformaciones Conge ´nitas (ECEMC) del Centro de Investigacio ´n sobre Anomalı ´as Conge ´nitas (CIAC), Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Madrid, Spain 2 Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain 3 Department of Medical Biochemistry and Genetics, The Panum Institute, Copenhagen, Denmark 4 Departamento de Pediatrı ´a del Hospital de Guadalajara de la Seguridad Social, Guadalajara, Spain Received 29 October 2007; Accepted 9 March 2008 How to cite this article: Rodrı ´guez L, Niebuhr E, Garcı ´a A, Martı ´nez-Ferna ´ndez ML, Pen ˜a Segura JL. 2008. Be careful with familial unbalanced chromosome abnormalities!. Am J Med Genet Part A 146A:2005 – 2007. To the Editor: In the last few years, the detection of chromosomal alterations not associated with congenital malforma- tions, is generating the development of new chro- mosome concepts such as inherited unbalanced chromosome abnormalities (UCA), euchromatic var- iants (EV) and/or chromosome heteromorphisms (CH) [Wyandt and Tonk, 2004; Barber, 2005; Balikova et al., 2007; Kowalczyk et al., 2007; Rodrı ´guez et al., 2007]. In those cases, a chromosome alteration is found in a newborn with malformations and in healthy members of the same family. In such families, the chromosome abnormality is not considered respon- sible for the malformations observed in the newborn, and therefore they are considered to be a carrier of an UCA or an EV or a CH. Consequently, the real cause of the newborn malformations, as well as risk for future pregnancies, remains unknown. Never- theless, we would like to call the attention to those cases, since we would propose that a meticulous molecular study should be done before coming to any final conclusion. In this sense we would like to illustrate this by reporting a family where a male patient was born as a product of the second pregnancy of a non- consanguineous couple, age 31 and 28 years old. The patient was born at 40 weeks of gestation with a birth weight of 3,340 g (25 < c < 50), a length of 50 cm (50 < c < 75), and an OFC of 34 cm (c 50). He had triangular face with hypertelorism, broad and flat nasal bridge, epicanthus, blepharophimosis, abnormal ears, brachycephaly, flat forehead, and microretrognathia. He was hypotonic and had a distinctive cry. Figure 1 shows the baby when he was 23 months old. Now the baby is 10 years and has mental retardation. When the baby was 5 months old, the high- resolution G-band karyotype performed on a periph- eral blood sample, showed an abnormal pattern of bands on the short arm of a chromosome 5 (5p) (Fig. 2a). Thus, fluorescence in situ hybridization (FISH) techniques were applied with the subtelomeric 5p/5q specific region probes, and with the cri-du-chat syndrome specific probe, at 5p15.2 (CDCR), showing the pattern of hybridization with no chromosome deletion on any of those regions (Fig. 2b,c). Finally, a FISH with a whole chromosome painting probe from chromosome 5 (WCP5), showed both chromo- somes 5 totally painted from end to end, with no other signal in any other chromosome, rejecting any other chromosome rearrangement at least with a sufficient size to be detected (Fig. 2d). Consequently, we concluded that the child had an interstitial deletion of the short arm of a chromosome 5 [del (5)(p14.3 p15.2)], as the cause of his malformations. Parental high-resolution G-band karyotypes were done and the mother had a normal karyotype; the same abnormal pattern of bands was observed in a paternal chromosome 5, who presumably then had the same 5p interstitial deletion (Fig. 3a), although he was healthy and clinically normal. Three other family members had the same interstitial chromosome 5 deletion [del (5)(p14.3p15.2)] (Fig. 4). Grant sponsor: Fondo de Investigaciones Sanitarias; Grant number: PI020028; Grant sponsor: Instituto de Salud Carlos III. Ministerio de Sanidad y Consumo, Spain. *Correspondence to: L. Rodrı ´guez, CIAC, Instituto de Salud Carlos III, Sinesio Delgado 6, Pabello ´n 6, 28029 Madrid, Spain. E-mail: laura@isciii.es DOI 10.1002/ajmg.a.32383