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1: Indian J Dermatol Venereol Leprol. 2002 Mar-Apr;68(2):67-72.
Acanthosis nigricans: a dermatologic marker of metabolic disease.
Varthakavi PK, Waingankar A, Patel KL, Wadhwa SL, Khopkar U, Sengupta RA,
Merchant PC, Mehtalia SD, Nihalani KD.
Dept of Endocrinology, TN Medical College & BYL Nair Ch. Hospito, Mumbai-400 008,
India.
Most patients with acanthosis nigricans have either clinical or subclinical insulin resistance. We undertook a study to estimate the insulin sensitivity of a
group of patients referred from the dermatologist with biopsy proven acanthosis
nigricans. Thirty-six patients were evaluated in the Endocrinology clinic. Plasma
glucose and serum Insulin levels were estimated after a 75 gms oral glucose load
(OGTT). An intravenous Insulin Tolerance Test (ITT) was performed with measurement of Glucose Disposal Rate (GDR). There were 28 females and 8 males
(M:F--3.5:1; mean age 26.3+/-1.7 years) in the study. 25/36 patients were
morbidly obese (BMI--36.0 +/- 1.2 Kg/m2) with an abnormal body fat distribution
(WH ratio--0.9 +/ - 0.02). One patient had generalized lipoatrophy. 16/36
patients with acanthosis nigricans had IGT or overt diabetes and all had highly
significant hyperinsulinemia (AUCI = 20825 +/ 1287.7 vs. 6340.0 +/- 984.2
mIU/ml/hr in controls, p < 0.0005). The GDR in patients with acanthosis nigricans
was reduced (-0.66 +/- 0.07) compared to controls (-0.39 +/- 0.08; p < 0.01).
There was a significant positive correlation between indices of adiposity and
insulin resistance in subjects with impaired tolerance.
2: Clin Endocrinol (Oxf). 2007 Oct;67(4):479-84. Epub 2007 Jun 11.
Inherited lipodystrophies and the metabolic syndrome.
Monajemi H, Stroes E, Hegele RA, Fliers E.
Department of Vascular Medicine, Academic Medical Center, University of
Amsterdam, The Netherlands. h.monajemi@amc.nl
Lipodystrophies represent a heterogeneous group of diseases characterized by an
abnormal subcutaneous fat distribution, the extent of which can vary from
localized, to partial, to generalized lipoatrophy. Whereas partial and
generalized lipodystrophies are each associated with metabolic abnormalities, the
localized form is not. These metabolic changes include insulin resistance with
type 2 diabetes, acanthosis nigricans, dyslipidaemia predominantly consisting of
hypertriglyceridaemia (associated with the onset of pancreatitis) and depressed
HDL cholesterol, liver steatosis and hypertension. Affected women are often
hirsute and this can be associated with the presence of polycystic ovarian
syndrome (PCOS). Most of these clinical features are present to some extent in
patients with the common metabolic syndrome. As the prevalence of metabolic
syndrome far outweighs that of lipodystrophy, the diagnosis of this rare disorder
may often be overlooked with the affected patient diagnosed as merely being 'yet'
another case of metabolic syndrome. In this article, we draw attention to the
importance of recognizing patients with lipodystrophy who present with metabolic
abnormalities, as both the diagnostic as well as the therapeutic approach of
these patients differ profoundly from patients with the metabolic syndrome.
3: Ann Endocrinol (Paris). 2007 Feb;68(1):10-20. Epub 2007 Feb 21.
[Primary lipodystrophies]
Capeau J, Magré J, Lascols O, Caron M, Béréziat V, Vigouroux C.
Inserm, U680, 75012 Paris, France. Jacqueline.Capeau@st-antoine.inserm.fr
Primary lipodystrophies represent a heterogeneous group of very rare diseases
with a prevalence of less than 1 case for 100.000, inherited or acquired,
caracterized by a loss of body fat either generalized or localized (lipoatrophy).
In some forms, lipoatrophy is associated with a selective hypertrophy of other
fat depots. Clinical signs of insulin resistance are often present: acanthosis
nigricans, signs of hyperandrogenism. All lipodystrophies are associated with
dysmetabolic alterations with insulin resistance, altered glucose tolerance or
diabetes and hypertriglyceridemia leading to a risk of acute pancreatitis.
Chronic complications are those resulting from diabetes involving the retina,
kidney and nerves, cardiovascular complications and steatotic liver lesions that
could result in cirrhosis. Genetic forms of generalized lipodystrophy (or
Berardinelli-Seip syndrome) result, in most cases, from recessive mutations in
one of two genes: either BSCL2 coding seipin or BSCL1 coding AGPAT2, an
acyl-transferase involved in triglyceride synthesis. Acquired generalized
lipodystrophy (Lawrence syndrome) is of unknown origin but is sometimes
associated with signs of autoimmunity. Partial lipodystrophies can be familial
with dominant transmission. Heterozygous mutations have been identified in the
LMNA gene encoding nuclear lamin A/C belonging to the nuclear lamina, or in PPARG
encoding the adipogenic transcription factor PPARgamma. Some less typical
lipodystrophies, associated with signs of premature aging, have been linked to
mutations in LMNA or in the ZMPSTE24 gene encoding the protease responsible for
the maturation of prelamin A into lamin A. Acquired partial lipodystrophy
(Barraquer-Simons syndrome) is characterized by cephalothoracic fat loss. Its
aetiology is unknown but mutations in LMNB2, encoding the lamina protein lamin
B2, could represent susceptibility factors. Highly active antiretroviral
treatments for HIV infection are currently the most frequent cause of acquired
secondary lipodystrophic syndromes. The genetic diagnosis is performed in
specialized laboratories and, in the most severe forms, antenatal diagnosis could
be proposed. Treatment of diabetes, dyslipidemia and complications involves the
classical intervention strategies. Insulino-sensitizing drugs are useful.
Therapeutic trials with recombinant human leptin in patients with very low leptin
levels reported good results with respect to the metabolic and liver alterations.
The prognosis is linked to the precocity and severity of the diabetic,
cardiovascular and liver complications.
4: J Pediatr Endocrinol Metab. 2006 Oct;19(10):1257-61.
Some effect of metformin on insulin resistance in an infant with leprechaunism.
Atabek ME, Pirgon O.
Department of Pediatric Endocrinology and Diabetes, Faculty of Medicine, Selcuk
University, Konya, Turkey. meatabek@hotmail.com
Leprechaunism was first recognized in 1954 and is characterized by severe
intrauterine and postnatal growth retardation, failure to thrive, lipoatrophy,
dysmorphic features (globular eyes, large ears, and micrognathia), hirsutism and
acanthosis nigricans. The presented infant, a 30 day-old boy, had multiple
phenotypic anomalies, including low-set ears, prominent eyes, decreased
subcutaneous fat, hirsutism, breast hyperplasia, and penile enlargement. We found
persistent hyperglycemia with remarkably high immunoreactive insulin levels. His
phenotypic and laboratory features were consistent with a diagnosis of
leprechaunism. We observed some effect of treatment with metformin but not with
insulin glargine.
5: Clin Dermatol. 2006 Jul-Aug;24(4):237-46.
Diabetes mellitus.
Ahmed I, Goldstein B.
Division of Endocrinology, Diabetes and Metabolic Diseases, Department of
Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia,
PA 19107, USA. intekhab.ahmed@jefferson.edu
Dermatologic problems are common in diabetes, with approximately 30% of patients
experiencing some cutaneous involvement during the course of their illness. Skin
manifestations generally appear during the course of the disease in patients
known to have diabetes, but they may also be the first presenting sign of
diabetes or even precede the diagnosis by many years. The skin involvement can be
autoimmune in nature, such as acanthosis nigricans, necrobiosis lipoidica,
diabetic dermopathy, scleredema, and granuloma annulare, or infectious in the
form of erythrasma, necrotizing fasciitis, and mucormycosis. Pharmacologic
management of diabetes, in addition, can also result in skin changes, such as
lipoatrophy and lipohypertrophy, at the site of injection of insulin, and oral
antidiabetic agents can cause multiple skin reactions as adverse effects. The
management of these cutaneous manifestations is tailored according to the
underlying pathophysiology, but a tight control of blood glucose is a
prerequisite in all management strategies.
6: Novartis Found Symp. 2005;264:166-77; discussion 177-82, 227-30.
A-type lamin-linked lipodystrophies.
Vigouroux C, Capeau J.
INSERM U.402, Faculty of Medicine Saint-Antoine and Department of Biochemistry,
Tenon Hospital, Pierre and Marie Curie University, 27 rue Chaligny, 75571 Paris,
France.
Lipodystrophies represent a group of diseases characterized by altered body fat
repartition and major metabolic alterations with insulin resistance. Genetic
forms of partial lipodystrophy are currently recognized as two syndromes with
subcutaneous lipoatrophy but preserved or increased fat at the level of face and
neck (Dunnigan syndrome or FPLD due to LMNA mutations) and/or abdomen
(PPARgamma-linked forms) and are both transmitted as dominant diseases. FPLD is
further characterized by muscular hypertrophy, hyperandrogenism, acanthosis
nigricans, hepatomegaly with steatosis and at the biological level, marked
hypertriglyceridaemia, low HDL cholesterol, insulin resistance and altered
glucose tolerance or diabetes. These signs occur after puberty and their
prevalence and severity are more marked in female than in male patients. At the
genetic level, LMNA mutations concern in most cases the type-A lamin C-terminal
domain and more than 80% are heterozygous substitutions located at position 482
(R482W/Q/L). The other locations are G465D, K486N, R582H and R584H. The presence
of signs evocative of limb-girdle muscular dystrophy has been reported in
patients with typical forms of FPLD. In addition, forms presenting with
lipodystrophy and myopathy have been reported for patients with mutations at
position R28W, R60G, R62G or R527P. In addition, lipodystrophy, either partial or
generalized, can be associated with syndromes of premature ageing like
Hutchinson-Gilford progeria or acromandibular dysplasia, but also with other
phenotypes, as we described in a patient bearing the LMNA R133L heterozygous
substitution.
7: J Pediatr (Rio J). 2004 Jul-Aug;80(4):333-6.
Congenital generalized lipodystrophy
Figueiredo Filho PP, Costa Val A, Diamante R, Cunha CF, Norton RC, Lamounier JA,
Leão E.
Dep. de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais
(UFMG), Belo Horizonte, MG.
OBJECTIVE: To present the major clinical and biochemical characteristics of
congenital generalized lipodystrophy. DESCRIPTION: Eight infants with congenital
generalized lipodystrophy were identified at the Endocrine and Nutritional
Pediatric Disease Outpatient Clinics at Hospital de Clínicas, Universidade
Federal de Minas Gerais (UFMG). Clinical manifestations common to all patients
included muscle hypertrophy, generalized lipoatrophy, and acromegalic physical
appearance. Acanthosis nigricans was identified in five patients,
hepatosplenomegaly in six, hypertriglyceridemia and low levels of HDL cholesterol
in seven, cardiac hypertrophy in one and diabetes mellitus in two patients. All
patients are under dietetic and clinical control. COMMENTS: The phenotypic characteristics of congenital generalized lipodystrophy are well identified,
which, in most cases, favors the clinical diagnosis. The congenital generalized
lipodystrophy is a very unusual syndrome that illustrates the importance of the
adipose tissue for the majority of metabolic processes. A better understanding of
this syndrome may open new horizons in the research of more prevalent diseases
such as diabetes mellitus and obesity.
8: Muscle Nerve. 1996 Jul;19(7):843-7.
Köbberling-Dunnigan syndrome: a rare cause of generalized muscular hypertrophy.
Wildermuth S, Spranger S, Spranger M, Raue F, Meinck HM.
Department of Neurology, University of Heidelberg, Germany.
A 36-year-old woman presented with muscle hypertrophy (particularly of the
calves) since puberty, occasional muscle cramps, a musculine habitus, and a loss
of subcutaneous fat on limbs and trunk sparing her face, neck, and vulva.
Multiple lipomas were found on her trunk, and acanthosis nigricans on her neck.
Laboratory testing revealed hyperlipidemia and pathological glucose tolerance
with hyperinsulinemia. Physical and laboratory findings are consistent with
Köbberling-Dunnigan syndrome, a rare inherited form of lipoatrophy. The patient's
mother had the same body habitus and insulin-dependent diabetes mellitus. These
cases suggest that partial lipodystrophy also affects muscle and is a cause of
genuine muscular hypertrophy.
9: Pediatr Dermatol. 1996 Nov-Dec;13(6):477-82.
Partial lipodystrophy associated with juvenile dermatomyositis: report of two
cases.
Quecedo E, Febrer I, Serrano G, Martinez-Aparicio A, Aliaga A.
Department of Dermatology, Hospital General Universitario, Valencia, Spain.
A 27-year-old woman and a 13-year-old girl diagnosed with juvenile
dermatomyositis in childhood developed clinical findings of partial lipodystrophy
10 years after diagnosis. Exhaustive clinical and laboratory examinations showed
an association with other abnormalities: hypertrichosis, steatohepatitis, and an
abnormal insulin response to the glucose loading test in the first patient.
Hypertrichosis, steatohepatitis, insulin-resistant diabetes mellitus, and
acanthosis nigricans were observed in the second patient. Renal function was
normal in both patients. Although a localized form of lipodystrophy has been
reported associated with connective tissue disease (connective tissue
lipoatrophy), the partial form has been infrequently described in association
with juvenile dermatomyositis.
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