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IMAGe, a New Clinical Association of Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, and Genital Anomalies

Departments of Human Genetics (E.V.) and Pediatrics (E.V., E.R.B.M.), University of California School of Medicine, Los Angeles, California 90095; Service de Pédiatrie, Hôpital Charles Nicolle (C.L.), Rouen, France; Service de Biologie, Hôpital Val-de-Grâce (F.D.), Paris, France; the Department of Pediatrics and Genetics, Stanford University Medical School (M.A.K.), Stanford, California; and Service de Génétique Médicale, Hôpital Necker-Enfants Malades (M.L.M., P.M.), Paris, France

Address all correspondence and requests for reprints to: Eric Vilain, M.D., Ph.D., Department of Human Genetics, University of California School of Medicine, Gonda Center, Room 6357, 695 Charles E. Young Drive, Los Angeles, California 90095-7088. E-mail: evilain{at}ucla.edu

We report three boys with adrenal hypoplasia congenita (AHC) and additional findings that represent a new syndrome, IMAGe: Intrauterine growth retardation, Metaphyseal dysplasia, AHC, and Genital anomalies. Each presented shortly after birth with growth retardation and severe adrenal insufficiency. Each of the three patients had mild dysmorphic features, bilateral cryptorchidism, a small penis, and hypogonadotropic hypogonadism. Skeletal surveys revealed metaphyseal dysplasia in all three and epiphyseal dysplasia in two. The patients had documented or suspected hypercalciuria and/or hypercalcemia, resulting in nephrocalcinosis in one and in prenatal liver and spleen calcifications in another. AHC presents most often either as an isolated abnormality, caused by mutations in the DAX1 gene, or as part of an Xp21 contiguous gene syndrome, caused by a deletion of the Duchenne muscular dystrophy, glycerol kinase, and DAX1 genes. All three patients with the IMAGe association had normal creatine kinase levels and no evidence of glycerol kinase deficiency. Sequence analysis of DNA from these patients revealed no mutation in the DAX1- or steroidogenic factor-1-coding sequences, nor was a deletion of DAX1 detected. Identification of the molecular basis of the IMAGe association will give new insight into the pathogenesis of this syndromic relationship involving bone, adrenal cortical, and pituitary development.

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