Phenocopy of Wolf–Hirschhorn syndrome in a patient with duplication 12q13.3q14.1

Although most chromosome imbalances share a number of quite nonspecific clinical features, including mental and growth retardation, dysmorphisms and a few major malformations (e.g., congenital heart defects), several aneuploidies, duplications, and deletions, either detected using conventional analysis or molecular cytogenetic techniques, manifest distinct phenotypes. Among the clinically identifiable chromosome disorders, Wolf–Hirschhorn syndrome (WHS) has been recognized more than 40 years ago [Cooper and Hirschhorn, 1961; Hirschhorn et al., 1965; Wolf et al., 1965]. The WHS phenotype is defined by the presence of characteristic facial appearance (microcephaly, ‘‘Greek helmet’’ facies, closure defects), mental retardation, growth delay, congenital hypotonia, and seizures [Battaglia et al., 1999; Zollino et al., 2000]. Wright et al. [1997] have characterized the 165 kb WHS critical region (WHSCR), included between D4S166 and D4S3327 loci, within the 4p16.3 sub-band, and described the transcript map of this region. Zollino et al. [2003] mapped the specific clinical manifestations of WHS phenotype by fine analysis of patients with 4p16.3 terminal microdeletions, spanning 1.9–3.5 Mb. It was shown that the previously defined 165 kb critical WHS interval was fully preserved in a patient hemizygous for a 1.9 Mb deletion, in spite of a typical WHS phenotype. In this latter patient, the deletion spanned from D4S3327 to the telomere. Thus, the basic WHS phenotype, defined by typical face, mental and growth retardation, hypotonia and seizures, was mapped distal to the critical region accepted at that time. These results suggested also the existence of a WHSCR2 included in an interval of 300–600 kb on 4p16.3, between loci D4S3327 and D4S98–D4S168, contiguous distally with the WHSCR defined by Wright et al. [1997]. Van Buggewnhout et al. [2004] provided further refinement of this region and concluded that hemizygosity of WHSC1 (WHS Candidate 1) was the cause of the typical WHS facial appearance. In addition, they considered additional key features likely due to haploinsufficiency of other genes in the region, representing true contiguous gene syndrome phenotypes. Support to the existence of the WHSCR2 was presented by Rodriguez et al. [2005]. Thus, WHS appears as a distinct disorder characterized by a recognizable facial gestalt and clinical manifestations in which the phenotype is highly related to both the size and the location of deletions. We report on a girl with a clinical diagnosis of WHS, who turned out to be heterozygous for a chromosome imbalance not involving the 4p critical region. This girl was evaluated by us at the age of 6 years. She was the only child of healthy Caucasian nonconsanguineous parents. Two previous pregnancies ended in spontaneous abortions. The pregnancy was characterized by growth retardation and breech presentation at delivery at the 39th gestational week. Birth weight was 2,640 g (3rd–10th centile), length 47 cm (3rd–10th centile), and OFC 34 cm (10th–25th centile). Hypotonia and weak cry were recorded at birth. Zellweger syndrome was suspected in the first weeks of life and then excluded based on clinical evolution and genetic testing. Developmental milestones were severely retarded. She did not sit until 12 months of age and started walking at 20 months. The first monosyllables were pronounced in the 2nd year of life. Based on clinical characteristics and in particular on facial features, three independent evaluations by expert clinical geneticists at different ages agreed with the diagnosis of WHS.