ß 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:1120–1125 (2007) Clinical Report Otopalatodigital Syndrome Type 2 in Two Siblings With a Novel Filamin A 629G>T Mutation: Clinical, Pathological, and Molecular Findings Adria ´n Marin ˜o-Enrı ´quez, 1 Pablo Lapunzina, 2 Stephen P. Robertson, 3 and Jose ´ I. Rodrı ´guez 1 * 1 Department of Pathology, La Paz University Hospital, Madrid, Spain 2 Department of Medical Genetics, La Paz University Hospital, Madrid, Spain 3 Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University, Dunedin, New Zealand Received 2 November 2006; Accepted 24 December 2006 Otopalatodigital syndrome type 2 (OPD2) is an uncommon X-linked condition characterized by dysmorphic facies, a skeletal dysplasia affecting the axial and appendicular skeleton and extraskeletal anomalies including malforma- tions of the brain, heart, genitourinary system, and intestines. Missense mutations of the FLNA gene, which encodes for the protein filamin A, have recently been shown to cause OPD2 and the allelic syndromes otopalatodigital type 1, Melnick- Needles, and frontometaphyseal dysplasia. Collectively these conditions constitute the otopalatodigital spectrum disor- ders. We report on two sibs affected by OPD2. The diagnosis was achieved at autopsy of a macerated male stillborn with typical external and skeletal findings of OPD2. A subsequent pregnancy was terminated due to ultrasonographic findings resembling those observed in the previous sibling. Histo- pathological studies revealed osseus sclerosis and do not support the previously reported membranous ossification defect observed in this condition. Mutation analysis demon- strated a novel mutation, 629G>T, in FLNA that had arisen de novo in the mother. This missense mutation predicts the substitution C210F within the second calponin homology domain of the actin-binding domain of filamin A. The identical substitution has been recently identified in an analogous amino-acid position within the actin binding domain of b-spectrin leading to hereditary spherocytosis. The observation that phenylalanine is normally present in the same position in other proteins (utrophin, dystrophin) but leads to disease when present in filamin A implies that the function and/or structure of these actin binding domains are not entirely equivalent. ß 2007 Wiley-Liss, Inc. Key words: otopalatodigital syndrome type 2; autopsy; neonatal autopsy; FLNA gene; novel mutation; pathology; histopathology; prenatal diagnosis How to cite this article: Marin ˜o-Enrı ´quez A, Lapunzina P, Robertson SP, Rodrı ´guez JI. 2007. Otopalatodigital syndrome type 2 in two siblings with a novel filamin A 629G>T mutation: Clinical, pathological, and molecular findings. Am J Med Genet Part A 143A:1120 – 1125. INTRODUCTION Otopalatodigital syndrome type 2 (OPD2: MIM 304120) is a rare and severe X-linked disorder characterized primarily by a skeletal dysplasia. Muta- tions in FLNA, the gene encoding the cytoskeletal protein filamin A, were shown to underlie OPD2 and other three clinically similar disorders already sus- pected to be allelic by some authors [Superti-Furga and Gimelli, 1987; Nishimura et al., 1997; Superti-Furga, 2000; Verloes et al., 2000]: OPD1, Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD) [Robertson et al., 2001, 2003]. Consequently all four conditions have been subsumed under the term otopalatodigital spectrum disorders. We here present two male siblings with OPD2 diagnosed on autopsy by pathological examination. Molecular analysis of FLNA in the second fetus and his mildly affected carrier mother established a novel mutation, 629G >T, as the underlying cause of the condition in this family. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www. interscience.wiley.com/jpages/1552-4825/suppmat/index.html. *Correspondence to: Dr. Jose ´ I. Rodrı ´guez, Departamento de Anatomı ´a Patolo ´ gica, Hospital Universitario La Paz, P8 de la Castellana, 261, 28046, Madrid Spain. E-mail: jirodriguez.hulp@salud.madrid.org DOI 10.1002/ajmg.a.31696