Constitutional rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas

Abstract

Although somatic mutations in a number of genes have been associated with development of human tumors, such as lipomas, relatively few examples exist of germline mutations in these genes. Here we describe an 8-year-old boy who has a de novo pericentric inversion of chromosome 12, with breakpoints at p11.22 and q14.3, and a phenotype including extreme somatic overgrowth, advanced endochondral bone and dental ages, a cerebellar tumor, and multiple lipomas. His chromosomal inversion was found to truncate HMGA2, a gene that encodes an architectural factor involved in the etiology of many benign mesenchymal tumors and that maps to the 12q14.3 breakpoint. Similar truncations of murine Hmga2 in transgenic mice result in somatic overgrowth and, in particular, increased abundance of fat and lipomas, features strikingly similar to those observed in the child. This represents the first report of a constitutional rearrangement affecting HMGA2 and demonstrates the role of this gene in human growth and development. Systematic genetic analysis and clinical studies of this child may offer unique insights into the role of HMGA2 in adipogenesis, osteogenesis, and general growth control.

Figure 1

Clinical features of DGAP103. A, Facial features at age 27 mo, showing macrocephaly, flat supraorbital ridges, widely spaced eyes, and prominent alveolar ridges. B, Bilateral bowing and multiple lipomas on lower extremities at age 27 mo. C, Hematoxylin- and eosin-stained tissue sections of right lateral leg subcutaneous soft-tissue mass (biopsied at age 14 mo) confirms a benign lipoma comprised of mature adipocytes and paucicellular collagen. D, Megaepiphyseal flaring of the femur and tibia at the knee joint at 1 year of age. E, Broad distal ulna and radius with enlarged epiphyses (arrows) at 4 years of age. Advanced bone age is indicated by initial ossification of the trochlea of the ulna (arrowhead) which occurs, on average, at ∼7 years of age). F, Cerebellar mass in the right cerebellar hemisphere (arrow). G, Disorganization and advanced dental age evident both for erupted and unerupted teeth on panoramic dental X-ray taken at 4 years of age. H, Facial features with more severe flattening of supraorbital ridges, narrow eye openings, prominent ears with protruding antihelix, and significant gum hypertrophy with recessed mandible at 8 years of age. I, Brachydactyly and enlarged interphalangeal joints with joint restriction at 8 years of age. J, Advanced bone age of 13.5 years, without evidence of epiphyseal closure, on wrist radiograph taken at 8 years of age.

Figure 2

FISH mapping of chromosome 12 breakpoints. A, Idiograms for normal chromosome 12 (left) and inverted homolog (right) showing inv(12)(p11.22q14.3). B, Representative hybridization pattern following FISH with BAC clone RP11-677M24, which maps to band q14.3 on chromosome 12 and spans the long (q) arm breakpoint. One green signal is present on the normal chromosome 12, whereas two green signals can be seen on the inverted homolog (arrow indicates signal translocated to the short arm by the inversion). C, 12q14.3 breakpoint mapping. Initial FISH mapping of the 12q14.3 breakpoint showed that cosmids 142H1 and 27E12 flank the breakpoint, placing it between exons 2 and 4 of HMGA2. BAC RP11-677M24 was split in the inverted chromosome 12, narrowing the breakpoint region to an ∼19.5-kb interval. D, 12p11.22 breakpoint mapping. BAC CTD-2308H7 is split by the inversion. No genes are known to be disrupted by this breakpoint. Potential candidate genes and their respective distances from the 12p11.22 breakpoint are indicated.

Figure 3

Molecular analyses. A, Southern blot analysis refines the 12q14.3 breakpoint within HMGA2 to a 2,115-bp interval that maps within intron 3. This intron is a frequent target of disruption in mesenchymal tumors. B, Northern blot analysis performed using a cDNA probe against the entire HMGA2 coding sequence identifies a wild-type 4.1-kb transcript in total RNA from lymphoblastoid cells established from DGAP103 (right) and control (left) peripheral blood specimens.