American Journal of Medical Genetics 130A:406–409 (2004) Clinical Report Is SHORT Syndrome Another Phenotypic Variation of PITX2? Nadide Nilu ¨ fer Karadeniz, 1 * Inci Kocak-Midillioglu, 2 Derya Erdogan, 3 and Isık Bo ¨ kesoy 4 1 Dr. Zekai Tahir Burak Women Hospital, Department of Medical Genetics, Ankara, Tu ¨ rkiye 2 Ankara Training and Research Hospital, Department of Ophthalmology, Ankara, Tu ¨ rkiye 3 Dr. Sami Ulus Children Hospital, Department of Pediatric Surgery, Ankara, Tu ¨ rkiye 4 Ankara University, Faculty of Medicine, Medical Biology Department, Ankara, Tu ¨ rkiye Even though responsible genetic loci and mode of inheritance for the Rieger syndrome have been well established, the mode of inheritance and the genetic basis for SHORT syndrome are still uncertain. The purpose of this paper is to docu- ment a familial translocation of t(1;4)(q31.2;q25), in a mother and her son manifesting Rieger syndrome with polycystic ovaries and SHORT syndrome, respectively. It is suggested that these two syndromes may be different expressions of the same gene, PITX2, localized at 4q25. Our pa- tient is the second with the association of Rieger syndrome and polycystic ovaries, and thus this may not be coincidental, moreover insulin resis- tance-related phenotypes, such as lipodystrophy and polycystic ovaries, can be major component of syndromes with Rieger eye malformation. ß 2004 Wiley-Liss, Inc. KEY WORDS: Rieger eye malformation; Rieger syndrome; SHORT syndrome; translocation; PITX2 gene; insu- line resistance INTRODUCTION The Rieger eye malformation includes anterior segment defects, which consist of prominent and anterior displaced Schwalbe’s line attached by iris strands, and iris stromal changes such as corectopia and atrophy malformation. The Rieger eye malformation is present in both Rieger syndrome and SHORT syndrome together with nonocular developmental defects [Gorlin et al., 1975; Fitch and Kabacak, 1978; Koenig et al., 2003]. We describe here for the first time, both Rieger syndrome and SHORT syndrome with familial segregated translocation between chromosome 1 and 4, t(1;4)(q31.2;q25), and associa- tion of Rieger eye malformation with polycystic ovaries as a second observation. CLINICAL REPORT The male infant was born at the eighth month of unfollowed pregnancy by caesarean section as the first baby of a non- consangineous parents. At the time of birth, the mother and the father were 30 and 35 years old, respectively. His birth weight was 1,350 g (<3rd centile) and length was 45 cm (<3rd centile). He was operated at sixth day of age due to omphalomesenteric canal defect. At the age of 8 months, his weight was 4,200 g (<3rd centile), length was 57 cm (<3rd centile), occipitofrontal circumference (OFC) was 40.5 cm (<3rd centile). His features include microphthalmia, deep set eyes, narrow and down slanted palpebral fissures, broad nasal bridge, long-smooth philtrum, downcurved mouth with thin lips, low-set and pos- teriorly- angulated malformed ears, narrow and highly arch- ed palate, short neck, generalized hypotrichosis, diminished subcutaneous fat (lipoatrophy), ventricular septal defect (VSD), micropenis with coronal hypospadias, bilateral undes- cended testicles, left ingiunal hernia, redundant periumblical skin, slender fingers, and hyperextensibility of joints (Fig. 1). VSD closed spontaneously at age 16 months. Psychomotor development was within the normal range: he sat at 6 months, stood at 10 months, walked at 14 months, and spoke at 17 months. Hearing was normal. He had no teeth till the age of 18 months, and his weight was 6.5 kg (<3rd centile), length was 65 cm (<3rd centile), OFC was 44.5 cm (<3rd centile) at age of 18 months. His neurological examination was normal. Frequent illness during his follow-up was also observed. His ophthalmic examination under general anesthesia showed intraocular pressure (IOP) of 24 mmHg in the right eye (RE) and 10 mmHg in the left eye (LE), and microcornea (8 mm in both eyes). He had a prominent Schwalbe line with attached iris, stromal hypoplasia of iris, and corectopia. Ultrasonogra- phy also demonstrated microophthalmia bilaterally (axial length of 19.21 mm in RE and 19.84 mm in LE) (Fig. 2). Patient underwent trabeculectomy in RE due to high IOP. The last IOP measurements were 13 and 12 mmHg for the right and left eyes, respectively. Results of routine blood biochemical tests, growth hormone level, and thyroid function studies were normal. While both IgM and IgG were negative for Toxoplasma gondii, Rubella, CMV, HSV type 1 and 2; IgM was negative and IgG was positive for EBV. In the medical history of the mother, glaucoma operations were noted for both eyes 9 years ago due to Axenfeld–Rieger syndrome. On her physical examination, there was right ptosis, umblical hernia, teeth abnormalities including mis- shapen teeth with hypodontia, and mid-facial hypoplasia. Polycystic ovaries were detected by ultrasonography. She also had oligomenorrhoea, facial hirsutism, and she was constantly gaining weight. Her ophthalmologic examination revealed bilateral microcornea (10 mm), broad bands and membranous iridocorneal adhesions, corectopia, and atropic iris stroma in RE, thread like iris structures extending to Schwalbe line in LE (Fig. 3). She had normal fundus appearence except cup/disk ratio of 0.7 and 0.8 in RE and LE, respectively. Her recent IOP measurements were 14 mmHg bilaterally. Results of biochem- ical studies for polycystic ovaries total testesterone, free testes- terone, 17-OH progesterone, dehidroepiandesterone, LH, FSH *Correspondence to: Nadide Nilu ¨ fer Karadeniz, Sevil Sokak 16/ 3 06590, Cebeci-Ankara, Tu ¨ rkiye. E-mail: trkaradeniz@hotmail.com Received 8 August 2003; Accepted 3 March 2004 DOI 10.1002/ajmg.a.30206 ß 2004 Wiley-Liss, Inc.