Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome: Clinical and Molecular Analysis of a Case Francesca Mari, MD, a Daniela Giachino, MD, a Lucia Russo, MD, b Giuseppe Pilia, MD, c Francesca Ariani, BS, a Elisa Scala, BS, a Francesca Chiappe, BS, c Katia Sampieri, BS, a Aldo Caporossi, MD, b Alessandra Renieri, MD, PhD, a and Giacomo Lasorella, MD b Blepharophimosis–ptosis– epicanthus inversus syn- drome (OMIM #110100) is a rare autosomal-domi- nant disorder in which an eyelid malformation is as- sociated (type I) or not (type II) with premature ovar- ian failure in the affected female. It is invariably characterized by 4 major features: (1) bilaterally short- ened horizontal palpebral fissure (blepharophimosis); (2) severe impairment of the superior palpebral leva- tor (ptosis); (3) a vertical skin fold arising from the lower eyelid, which inserts medially in the upper lid (epicanthus inversus) and (4) an increased inner can- thal distance with a normal outer canthal distance (telecanthus). The mutations causing this disorder are found in the FOXL2 gene, a forkhead transcription factor, located in 3q23. Although many patients with blepharophimosis–ptosis– epicanthus inversus syn- drome have an affected parent, a conspicuous number of sporadic cases also have been reported. We describe here a sporadic case with a mutation in the FOXL2 gene that was well characterized both clinically and molecularly. CASE REPORT The proband was the second child of nonconsanguineous and healthy parents. No similar cases or cases of premature ovarian failure or infertility were described in the family. The mother and father’s ages at the birth of the proband were 25 and 46, respectively. The older sister, now 11 years old, was born with a congenital cardiac defect: atrial septal defect associated with persistent ductus arteriosus of Botallo, which resolved spontaneously. The proband was 3 years old at the time of the first examination (Figure 1). The mother had a normal pregnancy and delivery. Birth weight was 3200 g (50° percentile), length 50 cm (50-75° percentile), head circumference 34.5 cm (50-75° percen- tile) and thoracic circumference 34 cm (+1SD/+2SD). Blepharophimosis, ptosis, and epicanthus inversus were immediately noticed at birth. The occurrence of 5 febrile convulsive episodes and frequent regurgitation were de- scribed by the parents. The proband achieved normal developmental milestones. At the time of the first investi- gation, a compensatory chin-up position was present. No additional ocular or systemic malformations were detected except for a mild syndactyly between the 2° and 3° toe bilaterally, a broad and flat nasal bridge, high vaulted and narrow palate, and an asymmetry in the maxillary region. None of these minor malformations were present in either parent, except for the facial asymmetry in the mother. The proband’s abilities and behavior were adequate for his age. No cognitive tests were performed because the parents did not consent to them. Echocardiography, electroencepha- logram, brain magnetic resonance imaging, and abdominal and pelvic echography were normal except for the identi- fication of 1 polar cyst in the right kidney. A chromosome analysis at 400 banding resolution revealed a normal 46,XY karyotype. The patient underwent surgery in 2 steps: canthal sur- gery was performed at the age of 3.5 years and ptosis surgery later on at the age of 4.5 years. Peripheral blood samples were obtained from proband and parents after informed consent for genomic DNA isolation. DNA se- quence analysis of all the coding exons of the FOXL2 gene showed the mutation c.909_938dup (p.A224_A234dup), in heterozygous state, in the proband and not in the parents. We demonstrated that the mutation was derived pater- From the a Medical Genetics, Molecular Biology Department, University of Siena, Siena, Italy b Ophtalmologic Clinic, Policlinico “S. Maria alle Scotte,” Siena, Italy c Istituto di Neurogenetica e Neurofarmacologia, CNR, University of Cagliari, Cagliari, Italy. Submitted January 4, 2005. Revision accepted October 25, 2005. Reprint requests: Alessandra Renieri, MD, PhD, Associate Professor, Medical Genetics- University of Siena, Policlinico S. Mariaalle Scotte, viale Bracci 2, 53100, Siena, Italy (e-mail: renieri@unisi.it). J AAPOS 2006;10:279-280. Copyright © 2006 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2006/$35.00 + 0 doi:10.1016/j.jaapos.2006.01.002 FIG 1. Detail of the eyes of the proband before surgery. Journal of AAPOS June 2006 279