Alternative titles; symbols
SNOMEDCT: 404063007, 766888002; ORPHA: 199276; DO: 0070518;
Familial multiple lipomatosis (FML) is a rare autosomal dominant disorder characterized by numerous encapsulated lipomas on the trunk and extremities (Keskin et al., 2002).
Stephens and Isaacson (1959) observed 17 cases in 3 generations. Usually the condition did not become evident until the age of about 35 years, although in 1 case lipomas were present at age 9. The gastrointestinal tract may be involved (Ling et al., 1959).
Keskin et al. (2002) reported a large family in which 8 members of 3 generations had multiple lipomatosis. In 1 patient, the lipomas occurred only on the neck, but in others they occurred on the trunk, the upper extremities, and the thighs. The lipomas arose in the third or fourth decade in all but 1, who had onset at age 14 years.
Mejia Granados et al. (2020) studied 6 female and 1 male patient from 5 Brazilian families (A to E) segregating autosomal dominant lipomatosis. Onset of symptoms was in the third or fourth decade of life. Two patients were obese, 3 were overweight, and 2 were of normal weight. Affected females reported a peak incidence of nodules after their pregnancies. The skin lesions were soft nodules, highly variable in number and size, located on the trunk and proximal limbs. Of the 5 patients who underwent biopsy, the histopathologic diagnosis was angiolipoma in 4 and lipoma in 1. Comorbidities involving the gastrointestinal tract were present in 3 unrelated patients, including colonic diverticulitis and rectal polyps, colorectal mucinous adenocarcinoma, and severe constipation with hematochezia. The proband in family A (patient A) had generalized nodular angiolipomas with intense pain on the surface of the fatty tissue and around the lipomas. The authors noted that she also experienced daily weakness, fatigue, and chronic depression and anxiety, symptoms that are strongly associated with Dercum disease (adiposis dolorosa; 103200).
Keskin et al. (2002) reported multiple lipomas in 8 members of 3 generations of a family with male-to-male transmission.
Dal Cin et al. (1988) reported on the cytogenetic analysis of 3 different lipomas from a patient with multiple subcutaneous lipomas. Two distinct reciprocal translocations were observed, both with breakpoints at 12q14. The reciprocal translocation t(3;12)(q28;q14) was found in 2 lipomas from this patient; t(1;12)(q34.2;q14) was seen in the third. The authors noted that 2 previously described translocations involving chromosome 12q14 also had breakpoints in the region of 3q27-q28.
Heim et al. (1988) concluded, on the basis of cytogenetic analysis of tumor cells from 50 lipomas, that 4 main cytogenetic subtypes can be recognized: (1) tumors with normal karyotype (18 cases); (2) tumors with rearrangements of 12q13-q14 (18 cases); (3) tumors with ring chromosomes (6 cases); and (4) tumors with other clonal changes (8 cases). All 6 tumors with ring marker chromosomes were histopathologically classified as atypical lipomas. All 7 multiple lipomas were karyotypically normal.
Sreekantaiah et al. (1991) found abnormalities of chromosome 12 in 34 of 92 patients with lipomas.
The distinctness of benign lipomas, including multiple lipomatosis, from myxoid liposarcoma (613488) was indicated by the findings of Mrozek et al. (1993) that the chromosome 12 breakpoint in myxoid liposarcoma is at 12q13.3, as reported by many others, but that the breakpoint in benign lipoma, including multiple lipomatosis, is more distally situated, at 12q15. They suggested that the more distal location is identical to that found in other benign tumors such as uterine leiomyoma (150699) and pleomorphic adenoma of the salivary gland (181030).
In a note added in proof to their report of the HMGIC gene (600698) on chromosome 12 involved in soft tissue tumors with translocations of 12q15, Schoenmakers et al. (1995) referred to the isolation and sequencing of the lipoma-preferred-partner gene (LPP; 600700). Chromosome 3 is the preferred partner in lipomas resulting from translocation involving 12q15. Other translocation partners of 12q15 include chromosomes 1, 2, 4, 5, 6, 7, 10, 11, 13, 15, 17, 21, and X (Sreekantaiah et al., 1991).
Ligon et al. (2005) reported an 8-year-old boy who had a de novo pericentric inversion of chromosome 12, with breakpoints at p11.22 and q14.3, and a phenotype that included extreme somatic overgrowth, advanced endochondral bone and dental ages, a cerebellar tumor, and multiple lipomas. At 27 months of age the patient showed macrocephaly, bilateral bowing and multiple lipomas of the lower extremities, and megaepiphyseal flaring of the femur and tibia at the knee joint. At the age of 4 years, the patient showed disorganized and advanced dental age of both erupted and unerupted teeth. Bone age was estimated at 13.5 years on a wrist radiograph taken at 8 years of age. The chromosomal inversion was found to truncate HMGA2 (600698), 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 mouse Hmga2 in transgenic mice result in somatic overgrowth and, in particular, increased abundance of fat and lipomas (Arlotta et al., 2000), features strikingly similar to those observed in the child.
Prontera et al. (2009) described a 5-year-old girl with encephalocutaneous lipomatosis (ECCL; 613001) and a family history of multiple lipomatosis. The patient had lipomas on the face, alopecia areata, coloboma of iris, chorioretinitis, bilateral epibulbar dermoid, complex partial crises, moderate tricuspid valve insufficiency, increased pulmonary pressure, intracranial lipomas, leptomeningeal angiomatosis, intracranial calcification, hypoplastic corpus callosum, arachnoid cyst of the right temporal lobe, enlargement of the right ventricle, microgyria of the temporal and occipital right lobes, osteolytic lesion in the right jaw, including irregular zones of calcification, ossification and dental elements (odontogenic jaw tumor), moderate speech delay, and macrocephaly. Her father and her paternal grandmother had multiple benign lipomas affecting limbs and trunk that appeared during the second and third decade of life. Prontera et al. (2009) suggested that HMGA2 may be a good candidate for both FML and ECCL. They proposed that a germline mutation in the HMGA2 gene may be responsible for dominant FML and that a somatic mutation in this gene may be responsible for ECCL.
Associations Pending Confirmation
In 7 patients from 5 Brazilian families (A to E) segregating autosomal dominant lipomatosis, Mejia Granados et al. (2020) sequenced the HMGA2 gene and in 2 unrelated patients (A and B1) identified heterozygosity for 2 variants in exon 5: a c.327C-T transition, resulting in a synonymous substitution (D109D) that was believed to be benign; and a c.328T-C transition, predicted to abrogate the stop codon with extension of the protein (Ter110Glnext16). In family B, the proband's affected daughter (B2) did not carry either variant, indicating that they did not segregate with disease. In family A, other family members were not available for segregation analysis. Functional studies were not reported. The authors also screened a panel of 5 syndromic lipomatosis-associated genes in the patients but did not detect any deleterious changes.
Arlotta, P., Tai, A. K.-F., Manfioletti, G., Clifford, C., Jay, G., Ono, S. J. Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas. J. Biol. Chem. 275: 14394-14400, 2000. [PubMed: 10747931] [Full Text: https://doi.org/10.1074/jbc.m000564200]
Dal Cin, P., Turc-Carel, C., Sandberg, A. A. Consistent involvement of band 12q14 in two different translocations in three lipomas from the same patient. Cancer Genet. Cytogenet. 31: 237-240, 1988. [PubMed: 3349440] [Full Text: https://doi.org/10.1016/0165-4608(88)90222-1]
Heim, S., Mandahl, N., Kristoffersson, U., Mitelman, F., Roser, B., Rydholm, A., Willen, H. Reciprocal translocation t(3;12)(q27;q13) in lipoma. Cancer Genet. Cytogenet. 23: 301-304, 1986. [PubMed: 3779626] [Full Text: https://doi.org/10.1016/0165-4608(86)90012-9]
Heim, S., Mandahl, N., Rydholm, A., Willen, H., Mitelman, F. Different karyotypic features characterize different clinicopathologic subgroups of benign lipogenic tumors. Int. J. Cancer 42: 863-867, 1988. [PubMed: 3192332] [Full Text: https://doi.org/10.1002/ijc.2910420612]
Humphrey, A. A., Kingsley, P. C. Familial multiple lipomas: report of a family. Arch. Derm. Syph. 37: 30-34, 1938.
Keskin, D., Ezirmik, N., Celik, H. Familial multiple lipomatosis. Isr. Med. Assoc. J. 4: 1121-1123, 2002. [PubMed: 12516905]
Krabble, K. H., Bartels, E. D. La lipomatose circonscripte multiple. Copenhagen: Munksgaard (pub.) 1944.
Kurzweg, F. T., Spencer, R. Familial multiple lipomatosis. Am. J. Surg. 82: 762-765, 1951. [PubMed: 14903312] [Full Text: https://doi.org/10.1016/0002-9610(51)90405-9]
Ligon, A. H., Moore, S. D. P., Parisi, M. A., Mealiffe, M. E., Harris, D. J., Ferguson, H. L., Quade, B. J., Morton, C. C. Constitutional rearrangement of the architectural factor HMGA2: a novel human phenotype including overgrowth and lipomas. Am. J. Hum. Genet. 76: 340-348, 2005. [PubMed: 15593017] [Full Text: https://doi.org/10.1086/427565]
Limon, J., Turc-Carel, C., Dal Cin, P., Rao, U., Sandberg, A. A. Recurrent chromosome translocations in liposarcoma. (Letter) Cancer Genet. Cytogenet. 22: 93-94, 1986. [PubMed: 3955533] [Full Text: https://doi.org/10.1016/0165-4608(86)90143-3]
Ling, C. S., Leagus, C., Stahlgren, L. H. Intestinal lipomatosis. Surgery 46: 1054-1059, 1959. [PubMed: 14417241]
Mejia Granados, D. M., de Baptista, M. B., Bonadia, L. C., Bertuzzo, C. S., Steiner, C. E. Clinical and molecular investigation of familial multiple lipomatosis: variants in the HMGA2 gene. Clin. Cosmet. Investig. Derm. 13: 1-10, 2020. [PubMed: 32021365] [Full Text: https://doi.org/10.2147/CCID.S213139]
Mrozek, K., Karakousis, C. P., Bloomfield, C. D. Chromosome 12 breakpoints are cytogenetically different in benign and malignant lipogenic tumors: localization of breakpoints in lipoma to 12q15 and in myxoid liposarcoma to 12q13.3. Cancer Res. 53: 1670-1675, 1993. [PubMed: 8453640]
Prontera, P., Stangoni, G., Manes, I., Mencarelli, A., Donti, E. Encephalocraniocutaneous lipomatosis (ECCL) in a patient with history of familial multiple lipomatosis (FML). (Letter) Am. J. Med. Genet. 149A: 543-545, 2009. [PubMed: 19215040] [Full Text: https://doi.org/10.1002/ajmg.a.32692]
Rabbiosi, G., Borroni, G., Scuderi, N. Familial multiple lipomatosis. Acta Derm. Venerol. 57: 265-267, 1977. [PubMed: 71835]
Schoenmakers, E. P. P. M., Wanschura, S., Mols, R., Bullerdiek, J., Van den Berghe, H., Van de Ven, W. J. M. Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours. Nature Genet. 10: 436-444, 1995. [PubMed: 7670494] [Full Text: https://doi.org/10.1038/ng0895-436]
Shanks, J. A., Paranchych, W., Tuba, J. Familial multiple lipomatosis. Canad. Med. Assoc. J. 77: 881-884, 1957. [PubMed: 13472574]
Sreekantaiah, C., Leong, S. P. L., Karakousis, C. P., McGee, D. L., Rappaport, W. D., Villar, H. V., Neal, D., Fleming, S., Wankel, A., Herrington, P. N., Carmona, R., Sandberg, A. A. Cytogenetic profile of 109 lipomas. Cancer Res. 51: 422-433, 1991. [PubMed: 1988102]
Stephens, F. E., Isaacson, A. Hereditary multiple lipomatosis. J. Hered. 50: 51-53, 1959.
Turc-Carel, C., Dal Cin, P., Boghosian, L., Leong, S. P. L., Sandberg, A. A. Breakpoints in benign lipoma may be at 12q13 or 12q14. Cancer Genet. Cytogenet. 36: 131-135, 1988. [PubMed: 3203294] [Full Text: https://doi.org/10.1016/0165-4608(88)90083-0]
Turc-Carel, C., Dal Cin, P., Rao, U., Karakousis, C., Sandberg, A. A. Cytogenetic studies of adipose tissue tumors. I. A benign lipoma with reciprocal translocation t(3;12)(q28;q14). Cancer Genet. Cytogenet. 23: 283-289, 1986. [PubMed: 3779624] [Full Text: https://doi.org/10.1016/0165-4608(86)90010-5]
Weinberg, J. B., Hasstedt, S. J., Skolnick, M. H., Kimberling, W. J., Baty, B. Analysis of a large pedigree with elliptocytosis, multiple lipomatosis, and biological false-positive serological tests for syphilis. Am. J. Med. Genet. 5: 57-67, 1980. [PubMed: 7395901] [Full Text: https://doi.org/10.1002/ajmg.1320050108]