ß 2007 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 143A:1371–1378 (2007) Clinical Report Expanding Spectrum of Congenital Disorder of Glycosylation Ig (CDG-Ig): Sibs With a Unique Skeletal Dysplasia, Hypogammaglobulinemia, Cardiomyopathy, Genital Malformations, and Early Lethality Christian Kranz, 1 Alice A. Basinger, 2 * Mu ¨ge Gu ¨c ¸savas ¸-C ¸ alıkog ˘lu, 2 Liangwu Sun, 1 Cynthia M. Powell, 2 Frederick W. Henderson, 3 Arthur S. Aylsworth, 2 and Hudson H. Freeze 1 1 Burnham Institute for Medical Research, La Jolla, California 2 Departments of Pediatrics and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 3 Department of Pediatrics, Division of Infectious Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Received 9 June 2006; Accepted 25 February 2007 In this report, we describe a brother and sister who presented at birth with short-limb skeletal dysplasia, poly- hydramnios, prematurity, and generalized edema. Dys- morphic features included broad nose, thick ears, thin lips, micrognathia, inverted nipples, ulnar deviation at the wrists, spatulate fingers, fifth finger camptodactyly, nail hypoplasia, and talipes equinovarus. Other features included short stature, microcephaly, psychomotor retardation, B-cell lym- phopenic hypogammaglobulinemia, sensorineural deafness, retinal detachment and blindness, intestinal malrotation with poor gastrointestinal motility, persistent hyponatremia, intermittent hypoglycemia, and thrombocytopenia. Cardiac anomalies included PDA, VSD, hypertrophic cardiomyopa- thy, and arrhythmias. The brother had a small penis with hypospadias, hypoplastic scrotum, and non-palpable testes. Skeletal findings included absent ossification of cervical vertebral bodies, pubic bones, knee epiphyses, and tali. Both sibs died before age 2 years, one of overwhelming sepsis and the other of cardiorespiratory failure associated with her cardiomyopathy. Metabolic studies showed a type 1 pattern of abnormal serum transferrin glycosylation. Fibroblasts synthesized truncated LLOs, primarily Man 7 GlcNAc 2 , sug- gestive of CDG-Ig. Both sibs were compound heterozygotes for a novel 301 G > A (G101R) mutation and a previously described 437 G > A (R146Q) mutation in ALG12. Congenital disorders of glycosylation should be considered for children with undiagnosed multi-system disease including neurode- velopmental delay, skeletal dysplasia, immune deficiency, male genital hypoplasia, and cardiomyopathy. ß 2007 Wiley-Liss, Inc. Key words: congenital disorders of glycosylation; CDG-Ig; carbohydrate-deficient glycoprotein syndrome; skeletal dys- plasia; genital hypoplasia; immunodeficiency; cardiomyo- pathy How to cite this article: Kranz C, Basinger AA, Gu ¨c ¸savas ¸-C ¸ alkog ˘lu M, Sun L, Powell CM, Henderson FW, Aylsworth AS, Freeze HH. 2007. Expanding spectrum of congenital disorder of glycosylation Ig (CDG-Ig): Sibs with a unique skeletal dysplasia, hypogammaglobulinemia, cardiomyopathy, genital malformations, and early lethality. Am J Med Genet Part A 143A:1371 –1378. INTRODUCTION Congenital disorders of glycosylation type I (CDG- I) are hereditary, multisystemic disorders that are caused by disruption in production of lipid-linked oligosaccharides (LLOs) [Freeze, 2006]. LLOs contain short sugar chains that are sequentially assembled on a lipid carrier and transferred to nascent proteins in the endoplasmic reticulum. Initially, a specific glycan, Glc 3 Man 9 GlcNAc 2 , is Christian Kranz and Alice A. Basinger contributed equally to this study. Grant sponsor: National Institute of Digestive and Kidney Diseases; Grant number: DK55695; Grant sponsor: NIDDK; Grant number: F32DK 072890. *Correspondence to: Alice A. Basinger, M.D., Ph.D., Department of Genetics, Cook Children’s Physician Network, 1300 W. Lancaster, #204 Fort Worth, TX. E-mail: a-basinger@cookchildrens.org DOI 10.1002/ajmg.a.31791