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

A number sign (#) is used with this entry because of evidence that intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (IMAGEI) is caused by compound heterozygous mutation in the POLE gene (174762) on chromosome 12q24.

Description

IMAGEI is an autosomal recessive disorder characterized by intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency. Patients exhibit distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency (Logan et al., 2018).

An autosomal dominant form of the disorder, without immunodeficiency (IMAGE; 614732), is caused by mutation in the CDKN1C gene (600856) on chromosome 11p15.

Clinical Features

Pedreira et al. (2004) reported a 5-year-old Australian boy who had adrenal hypoplasia congenita (AHC) in association with intrauterine growth retardation (IUGR) and dysmorphic features, including small low-set ears, micrognathia, bilateral cryptorchidism, and micropenis. AHC manifested at age 4.5 years, when he was noted to have increased generalized skin pigmentation and limited energy; intravenous adrenocorticotropic hormone (ACTH) stimulation confirmed primary adrenal insufficiency. In addition, he exhibited skeletal abnormalities, including gracile long bones with widening and sclerosis of the metaphyseal margins, especially at the knees and ankles. Hand x-rays were distinctive, with metaphyseal cupping of the short tubular bones and dense 'ivory' epiphyses at the distal interphalangeal joints.

Tan et al. (2006) described 2 Australian sisters with IUGR, AHC, and dysmorphic facial features, including frontal bossing and small low-set ears. Both girls had normal genitalia. The older girl died suddenly at age 3 months after developing a respiratory tract infection. Radiologic examination of the younger girl at age 6 months found widened rib metaphyses, metaphyseal cupping of the metacarpals and proximal phalanges, and absence of the femoral capital epiphyses. Two older brothers in this family had normal growth and development.

Logan et al. (2018) studied 15 patients from 12 families with IMAGEI, including the patients reported by Pedreira et al. (2004) and Tan et al. (2006). All patients had IUGR, with significant short stature postnatally (range, -5.5 to -11.27 SD). Head circumference was also significantly reduced (-2.7 to -8.03 SD), but was less severe, resulting in relative macrocephaly. Affected individuals exhibited a common facial appearance, with long thin nose, small low-set posteriorly rotated ears, crowded dentition, micrognathia, and short wide neck. Adrenal insufficiency was present in 12 of the 15 patients, and all affected males had genitourinary abnormalities, including bilateral cryptorchidism and/or hypospadias. Skeletal anomalies included osteopenia, metaphyseal dysplasia, and developmental dysplasia of the hip. In addition, 11 patients had immunodeficiency, consisting of lymphocyte subset deficiencies and/or IgM hypogammaglobulinemia in most, as well as deficiency of natural killer cells in 3 patients. Two patients and the affected sister of a proband died of respiratory infections.

Molecular Genetics

From a cohort of 48 patients diagnosed with microcephalic primordial dwarfism, Logan et al. (2018) identified 3 patients who were compound heterozygous for mutations in the POLE gene. Targeted sequencing of POLE in additional cases of primordial dwarfism yielded 5 more patients with biallelic mutations. Because a diagnosis of IMAGE syndrome (614732) had been considered in 2 of those patients and adrenal failure had been reported in another 3, the authors examined whole-genome sequencing data from patients diagnosed with IMAGE who were negative for mutation in the CDKN1C gene (600856), and identified 6 more individuals with compound heterozygous mutations in POLE, including the patients reported by Pedreira et al. (2004) and Tan et al. (2006). All affected individuals shared the same intronic variant (c.1686+32C-G; 174762.0003) as part of a common haplotype, in combination with different presumed loss-of-function mutations (see, e.g., 174762.0004-174762.0007).