Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, And Genital Anomalies

A number sign (#) is used with this entry because of evidence that intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGE) is caused by heterozygous mutation in the CDKN1C gene (600856) on chromosome 11p15.

A recessive form of IMAGE with immunodeficiency (IMAGEI; 618336) is caused by mutation in the POLE gene (174762) on chromosome 12q24.

Description

IMAGE is a rare multisystem disorder characterized by intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital anomalies. Patients with this condition may present shortly after birth with severe adrenal insufficiency, which can be life-threatening if not recognized early and steroid replacement therapy commenced. Other reported features in this condition include hypercalciuria and/or hypocalcemia, craniosynostosis, cleft palate, and scoliosis (summary by Balasubramanian et al., 2010).

Clinical Features

Vilain et al. (1999) reported 3 boys with adrenal hypoplasia congenita (AHC; see 300200) and additional findings representing a novel syndrome that they designated IMAGE: intrauterine growth retardation, metaphyseal dysplasia, AHC, and genital anomalies. The patients presented shortly after birth with growth retardation and severe adrenal insufficiency, and each had mild dysmorphic features, bilateral cryptorchidism, a small penis, and hypogonadotropic hypogonadism. Skeletal surveys revealed metaphyseal dysplasia in all 3 patients and epiphyseal dysplasia in 2. 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 (NR0B1; 300473), or as part of an Xp21 contiguous gene syndrome caused by a deletion of the Duchenne muscular dystrophy (DMD; 300377), glycerol kinase (GK; 300474), and DAX1 genes. All 3 patients with the IMAGE association had normal creatine kinase levels and no evidence of GK deficiency (307030). Sequence analysis revealed no mutation in the DAX1- or steroidogenic factor-1 (SF1; 184757)-coding sequences and no deletion of DAX1.

Bergada et al. (2005) studied 4 children with IMAGE association (3 males, 1 female) from a large 5-generation pedigree. Ten additional members who died during the neonatal period who were born with intrauterine growth retardation (IUGR) and/or hyperpigmentation were presumed to have been affected as well. All patients in this series were diagnosed during the newborn period. Adrenal insufficiency was variable within patients. All had severe IUGR and marked postnatal growth failure. Sequence analysis from 2 patients revealed no mutation in DAX1. Analysis of the pedigree revealed a pattern consistent with inheritance via the maternal line. 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.

Balasubramanian et al. (2010) reported a 4-year-old boy who had typical features of IMAGE syndrome as well as bilateral sensorineural hearing loss, a feature not previously reported in this syndrome. The authors reviewed previously reported cases, noting that epiphyseal dysplasia had consistently been reported as a feature; they suggested that it should be considered as a diagnostic feature in the absence of clear evidence of metaphyseal dysplasia because the metaphyseal changes may be variable and confined to the short tubular bones or relatively mild.

Mapping

In a large 5-generation Argentinian family with IMAGE syndrome, originally reported by Bergada et al. (2005), Arboleda et al. (2012) detected a 17.2-Mb identical-by-descent region on chromosome 11 that was shared by 7 affected family members but not an unaffected sib, with a lod score of 5.4. No contiguous gene deletion or duplication was identified in the affected individuals.

Molecular Genetics

In 2 patients from the 5-generation Argentinian family with IMAGE syndrome originally reported by Bergada et al. (2005) and 3 additional unrelated patients, Arboleda et al. (2012) performed targeted high-throughput genomic sequencing of all exons within a conservative identical-by-descent region and identified 4 different heterozygous missense mutations in a single gene, CDKN1C (600856.0007-600856.0010). Analysis of CDKN1C in an additional patient with IMAGE syndrome identified another heterozygous mutation (600856.0011); all 5 mutations clustered in a highly conserved region within 6 amino acids of the PCNA (176740)-binding domain of CDKN1C and disrupted PCNA binding. Targeted expression of IMAGE-associated CDKN1C mutations in Drosophila caused restricted eye and wing growth, suggesting a gain-of-function mechanism. Familial analysis showed an imprinted mode of inheritance in the Argentinian family, in which only maternal transmission of the mutation resulted in IMAGE syndrome.