Lipomatosis, Multiple Symmetric

Description

Multiple symmetric lipomatosis (MSL) is a rare disorder characterized by the growth of uncapsulated masses of adipose tissue. It is associated with high ethanol intake and may be complicated by somatic and autonomic neuropathy and by the infiltration of the adipose tissue at the mediastinal level (summary by Enzi et al., 2002).

Clinical Features

McKusick (1962) described 3 brothers with a collar of fat around the neck in the submandibular area and involving the nape of the neck. The age of onset was said to be 45, 39, and 29 years in the 3 patients. The mother was said to be definitely unaffected, having died at age 61, but 2 sisters and a maternal aunt were also affected. In advanced stages the process extended into the upper mediastinum. In 3 of those affected, lipomata of conventional type were present (e.g., in the epitrochlear area, back, axillae, and internal aspect of forearm).

Lyon (1910) reported a striking case which was familial. Michon and Rose (1935) observed familial cases.

Cervical lipomatosis was associated with gout and hyperlipoproteinemia type IV in the sisters reported by Greene et al. (1970). Oligomenorrhea, muscle cramps, pes cavus, and extensor plantar reflexes were also described.

Because fat cells are smaller than normal in this disorder, Enzi et al. (1977) concluded that lipomata are attributable to neoformation of adipocytes. In their studies of 10 affected males, reduced glucose tolerance and hyperlipoproteinemia were no more frequent than in controls. In lipomatous tissue but not in normal fat tissue from these subjects, in vitro insensitivity to the lipolytic effect of catecholamines was demonstrated. The block appeared to be proximal to cyclic AMP formation because theophylline induced a prompt and significant decrease in intracellular ATP in lipomatous tissue.

Enzi et al. (1985) documented the high frequency of somatic and autonomic neuropathies. In 28 of 33 male patients changes varying from vibratory sensory loss to incapacitating trophic ulcers or Charcot arthropathy were found. High density lipoprotein was increased, consistent with the diagnosis of hyperalphalipoproteinemia, and low density lipoprotein fractions were reduced with a marked enhancement of lipoprotein lipase activity in adipose tissue.

Pollock et al. (1988) pointed out that, with increasing age, peripheral neuropathy becomes more common in multiple symmetric lipomatosis and is a principal cause of severe disability. The peripheral neuropathy is often attributed to alcoholism, but the pathologic findings of Pollock et al. (1988) led them to conclude that the neuropathy is in fact an integral part of the syndrome. Biochemical observations suggested a defect in catecholamine-stimulated lipolysis at the level of cell membranes. Chalk et al. (1990) also thought that alcoholism could be excluded. Sural nerve biopsy in 1 patient showed nerve fiber loss, predominantly affecting large myelinated fibers. The relationship between myelin sheath thickness and axon diameter was normal, arguing that this neuropathy is not due to primary axonal atrophy.

Zancanaro et al. (1990) presented studies suggesting that multiple symmetric lipomatosis may be a neoplastic disease that originates in brown fat.

Williams et al. (1993) described the findings on magnetic resonance imaging in 2 unrelated women, aged 27 and 48 years. Tizian et al. (1983) had described malignant degeneration within the lipomatosis tissue. This must be very rare inasmuch as Williams et al. (1993) could find no other report of this complication.

Klopstock et al. (1994) pointed out that ragged-red fibers are occasionally found in muscle of patients with multiple symmetric lipomatosis, suggesting a mitochondrial abnormality. They studied 11 unrelated patients with this disorder by means of neurophysiology, muscle morphology, muscle biochemistry, Southern blot, and PCR analysis of mitochondrial DNA. All patients were men, aged 41 to 63 years. Clinical or electrophysiologic signs of sensorimotor polyneuropathy were present in 9 patients, 8 of whom had a history of alcoholism. In muscle biopsy specimens, the most prominent feature was pathologic subsarcolemmal accumulations of mitochondria. Biochemical analysis of respiratory chain enzymes revealed a moderate but significant decrease of cytochrome c oxidase activity as compared with age-matched controls. In 1 patient, Southern blot analysis showed multiple deletions of mitochondrial DNA.

In a longitudinal study of 31 patients with MLS (mean follow-up of 14.5 +/- 5.0 years), Enzi et al. (2002) confirmed the association of the disorder with high ethanol intake. Onset was usually in the fourth or fifth decade. Eight patients (25.8%) died during follow-up, none of whom had signs or symptoms of coronary heart disease. In addition to this high fatality rate, a substantial morbidity related to the occupation of the mediastinal space by the lipomatous tissue and to somatic neuropathy was observed.

Inheritance

Enzi (1984) studied 34 patients with MLS, 3 of whom had other affected family members: a brother in 2 instances and a father and son in the third. The other patients declared that none of their sibs (34 brothers, 28 sisters) or parents was affected.

Chalk et al. (1990) described coexisting peripheral neuropathy and multiple symmetric lipomatosis in 4 of 7 sibs, 3 female and 1 male. They favored autosomal recessive inheritance because of absence of either condition in 3 other generations of this family.

Population Genetics

Enzi et al. (1985) suggested that MSL is not unusual in Mediterranean areas and that the frequency in Italy is about 1 per 25,000 males.

Clinical Management

Taylor et al. (1961) described surgical procedures adopted in a case similar to those reported by McKusick (1962).

Williams et al. (1993) commented that the standard treatment is surgical debulking, but prognosis is guarded because of frequent recurrences.

In a longitudinal follow-up of patients with MLS, Enzi et al. (2002) found that alcohol discontinuation was associated with a slight regression of lipomatous depots and that an increase in ethanol consumption seemed to accelerate the lipomatous growth.

Molecular Genetics

Holme et al. (1993) reported a woman with multiple symmetric lipomas in the neck and shoulder area associated with a heteroplasmic c.8344A-G mutation in the MTTK gene (590060.0001). Her son, who also carried the mutation, had MERRF syndrome (545000); the mother had no signs of MERRF syndrome. The fraction of mutant mtDNA in the woman varied between 62% and 80% in cultured skin fibroblasts, lymphocytes, normal adipose tissue, and muscle, whereas the fraction of mutant mtDNA in the lipomas ranged from 90 to 94%. Ultrastructural examination of the lipomas revealed numerous mitochondria and electron-dense inclusions in some adipocytes. Holme et al. (1993) concluded that the mutation may either directly or indirectly perturb the maturation process of the adipocytes, increasing the risk of lipoma formation.

Gamez et al. (1998) identified a heteroplasmic c.8344A-G mutation in the MTTK gene in 6 members of a family with multiple symmetric lipomatosis. The 36-year-old female proband had a history of progressive muscle weakness associated with peripheral polyneuropathy, neurosensory hypoacusis, and symmetric confluent large lipomas over the neck and upper trunk. She developed dysarthria, dysphagia, and ptosis, suggestive of a stroke, and subsequently had lactic acidosis with multiorgan failure; some of these features are found in MERRF syndrome. Muscle biopsy of the proband showed both ragged-red and COX-negative fibers. The proportion of mutated mtDNA was higher in lipomas than in muscle and blood. Five maternal relatives had multiple symmetric lipomatosis but no neuromuscular involvement; only the proband's affected mother had hearing loss.

History

Brodie (1846) is said to have first described diffuse symmetrical lipomatosis with predilection for the neck. It was called 'Fetthals" (fat neck) by Madelung (1888).