An Autosomal Recessive Syndrome of Joint Contractures, Muscular Atrophy, Microcytic Anemia, and Panniculitis-Associated Lipodystrophy

Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 09/2010; 95(9):E58-63. DOI: 10.1210/jc.2010-0488
Source: PubMed


Genetic lipodystrophies are rare disorders characterized by partial or complete loss of adipose tissue and predisposition to insulin resistance and its complications such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, and polycystic ovarian syndrome.
The objective of the study was to report a novel autosomal recessive lipodystrophy syndrome.
We report the detailed phenotype of two males and one female patient, 26-34 yr old, belonging to two pedigrees with an autosomal recessive syndrome presenting with childhood-onset lipodystrophy, muscle atrophy, severe joint contractures, erythematous skin lesions, and microcytic anemia. Other variable clinical features include hypergammaglobulinemia, hepatosplenomegaly, generalized seizures, and basal ganglia calcification. None of the patients had diabetes mellitus or acanthosis nigricans. Two had mild hypertriglyceridemia and all had low levels of high-density lipoprotein cholesterol. Skin biopsy of an erythematous nodular skin lesion from one of the patients revealed evidence of panniculitis. The lipodystrophy initially affected the upper body but later became generalized involving abdomen and lower extremities as well.
We conclude that these patients represent a novel autoinflammatory syndrome resulting in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy. The molecular genetic basis of this disorder remains to be elucidated.

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    • "Lipo-muscular atrophy of the lower body is NNS prominent manifestation [87]. High-dose corticosteroids can be used to treat skin lesions, but are ineffective on lipodystrophy, while anti-TNFα and anti-IL-1β agents may be a valid therapeutic choice [88]. A last autoinflammatory disorder with skin involvement is CARD14- mediated pustular psoriasis, related to autosomal dominant mutations in the caspase recruitment domain-containing protein 14 (CARD14), a well-known regulator of the NF-kB pathway, recently discovered in patients with pityriasis rubra pilaris and pustular psoriasis [89] [90]. "
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    ABSTRACT: There is a thriving interest in the field of hereditary autoinflammatory disorders (HAID), a gamut of heterogeneous conditions deriving from an aberrant orchestration of innate immunity, unified by the common feature of seemingly unprovoked inflammation, which might be systemic or occur in localized niches of the organism. Recurrent fever and episodic inflammation in the joints, serosal membranes, skin, gut, and other organs are the common denominator of HAID. Mutations in the inflammasome-related genes have been associated with different HAID, showing the intimate link existing between interleukin-1 (IL-1)-structured inflammasome and their pathogenesis. Differential diagnosis of HAID can be challenging, as there are no universally accepted diagnostic protocols, and near half of patients may remain without any genetic abnormality identified. The use of IL-1-antagonists has been associated with beneficial effects in a large number of HAID associated with excessive IL-1 signalling, such as cryopyrin-associated periodic syndromes, familial Mediterranean fever, and deficiency of IL-1 receptor antagonist. This review will discuss about the key-clues of HAID which might guide for an early recognition and drive decisions for treatment.
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    • "The use of corticosteroids has no effect, however, on lipodystrophy, and even worsens central obesity, while biological agents, such as anti-TNF-α and anti-IL-1β, might be working alternatives [109]. Although NNS has been assumed to be found exclusively in Japan, a similar syndrome related to PSMB8 mutations has been reported from foreign countries and named JMP [103, 110]. "
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    ABSTRACT: The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment.
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