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Familial Occurrence of the IMAGe Association: Additional Clinical Variants and a Proposed Mode of Inheritance

Centro de Investigaciones Endocrinológicas (I.B., G.d.R., C.B., S.C.), Hospital de Niños "Ricardo Gutiérrez," 1425 Buenos Aires, Argentina; Servicio de Genética (P.L.), Hospital La Paz, 28046 Madrid, Spain; Human Genetics (M.F.), Institut National de la Santé et de la Recherche Médicale U361, E0021, Hôpital Cochin, 75014 Paris, France; and Laboratorio de Biología Molecular (S.C.), Departamento de Ciencias Biológicas, Universidad CAECE, 1918 Buenos Aires, Argentina

Address all correspondence and requests for reprints to: Ignacio Bergadá, M.D., Hospital de Niños "R. Gutiérrez," División de Endocrinología, Gallo 1330, Buenos Aires (1425), Argentina. E-mail: ibergada{at}cedie.org.ar.

The IMAGe (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies) association (online inheritance in man 300290) is a recently reported disorder comprising intrauterine growth retardation (IUGR), metaphyseal dysplasia, adrenal hypoplasia, and genital anomalies. Four children (three males, one female) from a large pedigree (five generations) were studied. Additional members (n = 10), who died during the neonatal period, were born with IUGR and/or hyperpigmentation and are presumed to have been affected, too. All patients in this series were diagnosed during the newborn period. Minimal clinical features and laboratory findings differ with previously reported patients, suggesting variants in their clinical expression. Adrenal insufficiency was variable within patients. All had severe IUGR and marked postnatal growth failure. Sequence analysis of DNA using an automated cycle from two patients revealed no mutation in the dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1. Analysis of the pedigree showed that the disease is inherited via the maternal line, even in the dead children with suspicion of the disease. Hence, the pattern of inheritance in this family of this unusual disorder might be explained in terms of the genomic imprinting hypothesis with expression through maternal transmission involving an autosomal gene. This transmission may have considerable implications for genetic counseling. Furthermore, pediatric endocrinologists must be aware of the possible occurrence of this life-threatening condition in the offspring of nonaffected women when related to a family member with the association of IUGR, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies.

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