Alternative titles; symbols
SNOMEDCT: 238902007; ORPHA: 2398; DO: 14116;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.22 | Lipomatosis, multiple symmetric, with or without peripheral neuropathy | 151800 | Autosomal recessive | 3 | MFN2 | 608507 |
A number sign (#) is used with this entry because of evidence that multiple symmetric lipomatosis (MSL) with or without axonal peripheral neuropathy is caused by homozygous or compound heterozygous mutation in the MFN2 gene (608507) on chromosome 1p36.
Biallelic mutation in the MFN2 gene causes autosomal recessive axonal Charcot-Marie-Tooth disease type 2A2B (CMT2A2B; 617087) without lipomatosis.
Multiple symmetric lipomatosis (MSL) is an autosomal recessive metabolic disorder characterized by the growth of unencapsulated masses of adipose tissue with predilection for the cervical and thoracic regions. The lipoma growth is striking and disfiguring, and growth around the neck may cause difficulty swallowing or breathing. The age at onset ranges from childhood to young adulthood. Most, but not all, patients develop axonal peripheral neuropathy, which can appear at any age and varies in severity. Laboratory studies in MSL show low leptin (164160), low adiponectin (605441), variably increased lactate, and increased FGF21 (609436). Some patients may have insulin resistance. The disorder is exclusively associated with a particular MFN2 mutation (R707W; 608507.0013), usually in the homozygous state, but sometimes in the compound heterozygous state (Rocha et al., 2017; Capel et al., 2018).
Nicholson et al. (2008) reported a 33-year-old woman (CMT40) with onset of severe axonal peripheral neuropathy at 2 years of age. Other features included hearing loss and kyphosis. She was also noted to have 'lipodystrophy'. Sawyer et al. (2015) reported follow-up of this patient, noting that she developed pronounced cervical and thoracic lipomatosis in her late twenties, as well as fatty nodules on her forearms and chest. MRI showed accumulation of subcutaneous unencapsulated fat, and laboratory studies showed increased lactate. Features of the neuropathy included club foot at birth and progressive muscle weakness, muscle atrophy, areflexia, and distal sensory impairment of the lower limbs during childhood. At age 48, she walked with a cane and needed a wheelchair for longer distances; she was diagnosed with autosomal recessive axonal Charcot-Marie-Tooth disease (see 617087). Her parents and 2 daughters had minor signs and symptoms of a peripheral neuropathy, but neurophysiology was normal and they were not diagnosed with Charcot-Marie-Tooth disease.
Sawyer et al. (2015) reported 2 brothers, born of consanguineous Irish parents, who developed progressive cervical and thoracic lipomatosis as adults. P1 had onset in his twenties and P2 in his mid-forties. P1 had striking unencapsulated lipomas and progressive tongue hypertrophy, resulting in swallowing difficulties. He underwent multiple liposuction surgeries with recurrence of the lesions. P1 developed diabetes mellitus in his early fifties that was controlled with oral hypoglycemic medication. Laboratory studies showed elevated lactate and decreased leptin and adiponectin. P2 developed multiple encapsulated cervical and thoracic lipomas with frequent surgical interventions. Both patients developed axonal peripheral neuropathy as adults, which was more severe in P1.
Carr et al. (2015) reported a 44-year-old man (family 4) with multiple lipomata and facial lipodystrophy associated with early-onset axonal peripheral neuropathy. He presented with foot drop and pes cavus at 24 months of age. Although there was weakness of the upper and lower limbs, he remained ambulatory.
Rocha et al. (2017) reported 4 patients from 3 families of European ancestry with onset of MSL in the first or second decades (range 5 to 13 years). They had striking upper body adipose overgrowth affecting the upper back, head, and neck with concomitant paucity of adipose tissue in the limbs and lower body. P1 was an 18-year-old girl who also had peripheral neuropathy and primary amenorrhea with evidence of partial hypogonadotropic hypogonadism. P2 and P3, a 17-year-old female (P2) and a 16-year-old male (P3), were sibs from a large consanguineous Irish family. They had normal progression through puberty and did not have signs or symptoms of peripheral neuropathy. There was a family history of lipomatosis affecting the upper back, chest, and head and neck across 3 generations, although these family members were not available for study. Some of the affected family members reportedly had severe airway occlusion due to overgrown neck adipose tissue; 1 of these patients had a severe sensorimotor axonal neuropathy. P4 was a 37-year-old woman who developed signs of MSL around 13 years of age. She also had male pattern hair growth, irregular menstrual cycle, and acanthosis nigricans, suggesting insulin resistance, as well as mild symptoms of a peripheral neuropathy. Laboratory studies of all 4 patients showed decreased adiponectin. Two showed increased lactate and decreased leptin. All had moderate to severe insulin resistance, and 2 had fasting hyperglycemia. Two patients had elevated triglycerides associated with hepatic steatosis.
Capel et al. (2018) reported 6 patients from 5 families of French or Portuguese origin with MSL due to a homozygous R707W mutation in the MFN2 gene. The patients, who ranged from 31 to 76 years of age, showed phenotypic heterogeneity in the chronology of onset of disease manifestations and the severity. In 2 patients, neurologic signs of a peripheral neuropathy occurred first during childhood, followed by development of lipomatous masses at 25 and 30 years of age. In 3 patients, lipoma-like masses appeared between 2 and 11 years of age, and mild neurologic signs began in adulthood. One of these individuals presented with acanthosis nigricans, hyperglycemia, and severe insulin resistance at age 10, followed by adipose overgrowth at age 11. In another patient, lipomatous signs appeared at age 35 and neurologic signs at age 65. Fat accumulation variably occurred at the neck, upper back, thorax, proximal upper limbs, chin, and abdomen, whereas the lower limbs and forearms showed lipoatrophy. The lipomatous masses were unencapsulated and difficult to delineate on imaging. Laboratory findings included low serum leptin (164160) and low adiponectin (605441). Two patients studied had increased serum FGF21 (609436). Other abnormalities included increased triglycerides and insulin resistance; 1 patient had diabetes that was treated with diet. All 5 patients studied showed hepatic steatosis. Neurologic findings of a peripheral neuropathy included pes cavus or foot deformities, distal weakness and atrophy of the lower and upper limbs, distal sensory impairment, and hyporeflexia. Electrophysiologic studies were consistent with an axonal sensorimotor polyneuropathy. Bone imaging of 3 patients showed centromedullary cystic lesions of the tibial, peroneal, and femoral epiphyses, metaphyses, and diaphyses. Additional more variable clinical features included deafness, precocious puberty, constipation with diarrhea, and hypothyroidism. None had a history of alcohol abuse. Histologic studies of lipomatous tissue showed white fat with unilocular normal sized adipocytes and rare multilocular adipocytes. Adipose tissue was highly vascularized.
Early Reports
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.
Golsch and Worret (1995) described a family with 9 cases of familial multiple lipomatosis in 3 generations. The oldest living member of the family suffered from a nonalcoholic peripheral neuropathy. Polyneuropathy has been described in association with multiple symmetric lipomatosis and may be an intrinsic part of the disorder.
In a longitudinal study of 31 patients with MSL (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.
The transmission pattern of MSL in the families reported by Rocha et al. (2017) was consistent with autosomal recessive inheritance.
Enzi (1984) studied 34 patients with MSL, 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.
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 MSL, 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.
In a 33-year-old woman (CMT40) with MSL and early-onset peripheral axonal neuropathy, Nicholson et al. (2008) identified a homozygous missense mutation in the MFN2 gene (R707W; 608507.0013). Her parents, who were heterozygous for the mutation, showed mild features of a peripheral neuropathy, but were not diagnosed with Charcot-Marie-Tooth disease.
In 2 brothers, born of consanguineous Irish parents, with MSL, Sawyer et al. (2015) identified a homozygous R707W mutation in the MFN2 gene. The mutation, which was found by whole-exome sequencing, was not present in their unaffected sibs. In vitro expression studies in MFN2-null cells showed that the R707W mutant had a reduced capacity to tubulate mitochondria. In addition, mitochondria in mutant cells were prone to aggregation, were defective in forming homooligomers, and formed smaller oligomeric complexes compared to wildtype MFN2.
In a 44-year-old man (family 4) with MSL and early-onset axonal peripheral neuropathy, Carr et al. (2015) identified compound heterozygous mutations in the MFN2 gene: an ex7-8 deletion (608507.0018) and R707W. His carrier parents were unaffected.
In 3 patients (P2, P3, and P4) from 2 unrelated European families with MSL, Rocha et al. (2017) identified a homozygous R707W mutation in the MFN2 gene. Another patient with the disorder (P1) was compound heterozygous for R707W and arg343del (608507.0023). The mutations, which were found by exome sequencing or direct Sanger sequencing, segregated with the disorder in the families from whom parental DNA was available for study. Studies of abnormal adipose tissue showed hyperplasia of UCP1 (113730)-negative unilocular adipocytes and proliferation of round, enlarged mitochondria with fragmented cristae. Transcriptome analysis of adipose tissue showed perturbation of gene expression related to mitochondrial dysfunction and oxidative phosphorylation. There was also alteration of genes related to cellular stress response pathways, including oxidative stress and unfolded protein response pathways, and upregulation of signatures related to tissue proliferation and survival. Examination of gene expression patterns identified the overgrown adipose tissue as white adipose tissue. In contrast, patient fibroblasts showed normal MFN2 expression and appropriate mitochondrial localization with normal mitochondria. These findings suggested that the abnormalities resulting from MFN2 mutations are tissue-specific.
In 6 patients from 5 families of French or Portuguese descent with MSL, Capel et al. (2018) identified a homozygous R707W mutation in the MFN2 gene. The patients were ascertained from a cohort of 66 individuals with altered fat distribution and lipomas who underwent sequencing of the MFN2 gene. Patient-derived lipomatous adipose tissue showed weak expression of the brown fat marker UCP1, and increased expression of thermogenic markers CITED1 (300149) and FGF21 (609436). Ultrastructural studies showed enlargement of the cytoplasmic ring of adipocytes and increased numbers of enlarged mitochondria with disorganized cristae or double membrane structures, suggestive of mitophagy. Gene expression studies of lipomatous tissue showed normal MFN2 expression and decreased expression of leptin and adiponectin.
Associations Pending Confirmation
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.
Lindner et al. (2019) studied a 4-generation family with MSL in which a woman, her son, and her paternal grandmother were affected; the proband's father, an obligate carrier, was not affected. None of the family members were reported to have signs of myopathy or neuropathy. Whole-exome sequencing revealed heterozygosity for an R9X mutation in the CAPSL gene (618799) in the 3 affected individuals and the obligate carrier; there was no evidence for involvement of known lipodystrophy- or overgrowth syndrome-associated genes. Analysis of the CAPSL gene in 21 unrelated MSL patients did not reveal any mutations. Adipose tissue from the proband and from 10 patients with sporadic MSL, from both affected and unaffected regions of the body, showed markedly reduced or absent expression of CASL compared to control adipocytes. The authors suggested an association between CAPSL deficiency and the MSL phenotype.
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.
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).
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