American Journal of Medical Genetics 127A:197–200 (2004) Clinical Report Mild Wolf–Hirschhorn Phenotype and Partial GH Deficiency in a Patient With a 4p Terminal Deletion L. Titomanlio, 1 A. Romano, 1 A. Conti, 2 R. Genesio, 3 M. Salerno, 1 D. De Brasi, 1 L. Nitsch, 2,3 and E. Del Giudice 1 * 1 Department of Pediatrics, Federico II University, Naples, Italy 2 Department of Cellular and Molecular Biology and Pathology, Federico II University, Naples, Italy 3 Biotechnology and Molecular Genetics in Southern Italy (BioGeM), Italy Wolf–Hirschhorn syndrome (WHS) is caused by a variably-sized deletion of chromosome 4 invol- ving band 4p16 whose typical craniofacial fea- tures are ‘‘Greek warrior helmet appearance’’ of the nose, microcephaly, and prominent glabella. Almost all patients show mental retardation and pre- and post-natal growth delay. Patient was born at term, after a pregnancy characterized by intra-uterine growth retardation (IUGR). Deliv- ery was uneventful. Developmental delay was evident since the first months of life. At 2 years, he developed generalized tonic-clonic seizures. Because of short stature, low growth velocity and delayed bone age, at 4 years he underwent growth hormone (GH) evaluation. Peak GH after two provocative tests revealed a partial GH defi- ciency. Clinical observation at 7 years disclosed a distinctive facial appearance, with microce- phaly, prominent eyes, and beaked nose. Brain MRI showed left temporal mesial sclerosis. GTG banded karyotype was normal. Because of mental retardation, subtelomeric fluorescence in situ hybridization (FISH) analysis was performed, disclosing a relatively large deletion involving 4p16.2 ! pter (about 4.5 Mb), in the proband, not present in the parents. The smallest deletion detected in a WHS patient thus far includes two candidate genes, WHSC1 and WHSC2. Interest- ingly, that patient did not show shortness of stature, and that could be due to the haploinsuffi- ciency of other genes localized in the flanking regions. Contribution of GH alterations and pos- sible GH therapy should be further considered in WHS patients. ß 2004 Wiley-Liss, Inc. KEY WORDS: GH; 4p deletion; Wolf–Hirschhorn INTRODUCTION Variably-sized deletion of the distal portion of the short arm of chromosome 4 usually results in Wolf–Hirschhorn syndrome (WHS). WHS is characterized by typical craniofacial features consisting of ‘‘Greek warrior helmet appearance’’ of the nose, microcephaly, prominent glabella, ocular hypertelorism, epi- canthus, micrognathia, and poorly formed ears [Wilson et al., 1981; Battaglia et al., 2000]. Mental retardation of variable degree is always present [Battaglia et al., 2001]. Seizures occur in the majority of children and are either unilateral clonic or tonic, or generalized, frequently triggered by fever and usually associated with distinctive electroencephalographic abnormal- ities [Battaglia et al., 2001]. Structural central nervous system defects are also reported [Lazjuk et al., 1980; Battaglia et al., 2000]. Skeletal anomalies, hearing loss, heart defects, and urinary tract malformations have been reported only in a part of the patients, but all patients present with pre- and post-natal growth deficiency, despite adequate energy and protein intake [Estabrooks et al., 1995; Battaglia et al., 2001]. WHS could be clinically misdiagnosed because it partially overlaps with other disorders, including CHARGE association, and Smith–Lemli– Opitz [Battaglia et al., 2001]. The similarity in the size of the critical regions between Pitt–Rogers–Danks (PRD) syndrome and WHS in combination with the phenotypic similarities of the two syndromes suggested that they represent the clinical spectrum of the same condition [Wright et al., 1998]. A critical region, namely WHS critical region (WHSCR), has been considered responsible for the WHS phenotype. Recently, a new critical region (WHSCR-2, more terminal than WHSCR) has been identified and suggested to contribute to the basic WHS phenotype, consisting of typical facial appearance, mental retardation, seizures, congenital hypotonia, and growth delay [Zollino et al., 2003]. Diagnosis of WHS by conventional cyto- genetic analysis (routine and high-resolution) is successful in only 60–70% of patients whereas fluorescence in situ hybridiza- tion (FISH) using a WHSCR probe detects more than 95% of deletions in WHS [Battaglia et al., 2001]. We report on a patient carrying a 4p terminal deletion presenting with a mild WHS phenotype and partial GH deficiency. CLINICAL REPORT The patient, B.G., is a male, born at term, after a pregnancy characterized by intra-uterine growth retardation (IUGR). Delivery was uneventful. Developmental delay was evident since the first months of life. He sat at 13 months and walked alone at 22 months. Parents reported beginning of language at about 3 years and 6/12. At 2 years, he developed generalized tonic-clonic seizures. At the age of 4 years, height was 91.3 cm (less than 5th centile), weight was 10.900 g (less than 5th centile), head circumference was 46 cm (less than 5th centile). Because of short stature quite below his target height (175  5 cm), delayed bone age (corresponding to 2 years), and impaired growth velocity (4.8 cm/year, at the 3rd centile for age), an endocrine evaluation was performed. Growth hormone (GH) reserve was investigated by both arginine and clonidine GH provocative tests. Both tests showed partial GH deficiency, GH Grant sponsor: BioGeM (Biotechnology and Molecular Genetics in Southern Italy). *Correspondence to: Ennio Del Giudice, M.D., Department of Pediatrics, Child Neuropsychiatry Unit, Federico II University, Via S. Pansini, 5, 80131 Naples, Italy. E-mail: endelgiu@unina.it Received 4 May 2003; Accepted 7 September 2003 DOI 10.1002/ajmg.a.20667 ß 2004 Wiley-Liss, Inc.