Köbberling-Dunnigan Syndrome

An inherited metabolic disorder mainly affecting young female adults characterized by insulin resistance with glucose intolerance, hypertriglyceridemia, and partial lipodystrophy. Slow onset initially presenting with progressive loss of subcutaneous adipose tissue. Other features include hypocomplementemia, glomerulonephritis, and autoimmune disorders.

Familial Partial Lipodystrophy (FPLD).

Familial Partial Lipodystrophy Type I (Köbberling Type): Characterized by loss of adipose tissue confined to the extremities, with normal or increased amounts of fat on the face, neck, and trunk. So far, this type has been reported only in females.

Familial Partial Lipodystrophy Type II (Dunnigan Type; Familial Lipodystrophy of Limbs and Lower Trunk; Reverse Partial Lipodystrophy; Lipoatrophic Diabetes): Characterized by partial lipodystrophy with onset around puberty after a normal fat distribution in early childhood. The subcutaneous adipose tissue gradually disappears from the upper and lower extremities and the gluteal and truncal regions. Clinical features include a muscular appearance with prominent superficial veins, a double chin, fat neck, or cushingoid appearance. Adipose tissue may accumulate in the axillae, back, labia majora, and intraabdominal region. Acanthosis nigricans, hirsutism, and menstrual abnormalities (polycystic ovary syndrome) occur occasionally. Affected patients are insulin resistant and may develop glucose intolerance and diabetes mellitus after age 20 years.

Familial Partial Lipodystrophy Type III (Familial Partial Lipodystrophy Associated with PPARG Mutations): Characterized by frank type II diabetes requiring insulin treatment and severe sustained hypertension.

Approximately 20 patients with FPLD I have been reported in the literature. More than 200 cases of FPLD II have been described. Females are approximately 5 times more often affected than men. Both types, but particularly FPLD I, are most likely far more common than previously thought.

All forms of FPLD (type I-III) are autosomal dominant inherited, although for some cases of FPLD II X-linked dominant transmission has been discussed. The genetic defects map to 1q21.2 and 3p25 for FPLD II, to 7q11.23-q21 and 3p25 for FPLD III, while for type I the locus has not been determined, yet.

A missense mutation in the gene encoding lamins A and C (LMNA). Lamins provide structural integrity of the nuclear envelope and are associated with chromatins and other nuclear proteins. The exact mechanism by which lamins affect the fat distribution remains to be elucidated.

Phenotype is characteristic, although it has been confused with Cushing syndrome. MRI studies verify virtual absence of subcutaneous fat in extremities with or without trunk involvement with excessive collection of adipose tissue in the head and neck region. Hypertriglyceridemia and hyperinsulinemia.

Type I is characterized by the gradual disappearance of most subcutaneous adipose tissue from the lower extremities and gluteal areas at puberty. Muscles and superficial veins become prominent in these areas. In type II, there is also disappearance of adipose tissue from the upper extremities and trunk, with simultaneous accumulation of adipose tissue on the face and neck, giving a cushingoid appearance. Adipose tissue may accumulate in the axillae, back, labia majora, and intraabdominal region. Acanthosis nigricans and hirsutism occur infrequently in both types. Females may have menstrual abnormalities as a result of polycystic ovaries. After the age of 20 years, affected patients become insulin resistant and may develop glucose intolerance or type II diabetes mellitus. Lipid abnormalities include hypertriglycideridemia and low levels of high-density lipoprotein (HDL) cholesterol. Hypertriglyceridemia may result in acute pancreatitis. Affected patients have a higher incidence of atherosclerosis leading to hypertension and coronary artery disease. Women have a higher incidence of atherosclerosis and diabetes mellitus than men. Females are more likely to be diagnosed because of the relative muscularity and reduced body fat in normal males. Characterization of affected or unaffected status is not possible in prepubertal children. In type III, insulin-dependent diabetes mellitus and severe hypertension have been reported.

Assess for potential difficult airway caused by excessive subcutaneous adipose tissue and for symptoms and signs of obstructive sleep apnea, coronary artery disease, peripheral arterial disease, and cerebrovascular disease. Obtain an electrocardiogram to look for signs of right and left ventricular hypertrophy and ischemic changes suggestive of coronary artery disease. An echocardiogram may help to evaluate cardiac function and estimate pulmonary artery pressure. A cardiology consult may be indicated to optimize management of myocardial ischemia and hypertension prior to anesthesia. Assess management and stability of diabetes mellitus. Consult with endocrinology about perioperative management of blood glucose levels.

Potentially difficult airway management. Patients with obstructive sleep apnea may be very sensitive to sedatives, especially opioids. They may require supplemental oxygen therapy or noninvasive airway support postoperatively (continuous positive airway pressure or bilevel positive airway pressure) to prevent desaturation. Patients with coronary artery disease benefit from slower heart rates, reduced contractility, and reduced afterload. Monitor for myocardial ischemia with five-lead electrocardiogram. Continue cardiac medications perioperatively. Intraoperative management of diabetes mellitus requires serial blood glucose measurements to avoid hyperor hypoglycemia, especially if an insulin infusion is used. The lack of subcutaneous tissue in the extremities may increase the risk of hypothermia, nerve compression, and pressure sores, necessitating careful positioning and padding of all pressure points. Difficult placement of neck and subclavian central venous catheters should be expected.

No specific contraindications.

Other lipodystrophies, especially the following:

Barraquer-Simons Syndrome (Acquired Partial Lipodystrophy; Cephalothoracic Lipodystrophy): Begins in childhood, affects females predominantly, and is not genetically transmitted.

Progressive Lipodystrophy: Progressive disappearance of subcutaneous fat in the upper part of the body with low C3 serum complement levels, presence of C3 nephritic factor, glomerulonephritis, and other autoimmune disorders.

Apolipoprotein C-II Deficiency: Inborn error of metabolism characterized by the deficiency in a cofactor necessary for activation of lipoprotein lipase. Diabetes mellitus, pancreatitis, and epigastric pain do not exclude the possibility of angina in early age and congestive heart failure.

Berardinelli-Seip Syndrome: Inherited disorder with hyperinsulinemia resulting from insulin resistance combined with lipodystrophy and acromegaloid features.

Familial Hyperlipoproteinemia Type I: Inherited inborn error of metabolism characterized by massive accumulation of chylomicrons and triglycerides in plasma resulting in recurrent abdominal pain and hepatosplenomegaly.

Familial Hyperlipidemia Type IIA: Genetic disorder of lipid metabolism causing accumulation of cholesterol and thus increasing the risk of cardiovascular diseases. Hypercholesterolemia, Low Density Lipoprotein-LDL-Receptor Disorder.

Phytosterolemia: Rare inherited disorder characterized by congenital hypercholesterolemia, presenting clinically with tendon xanthomas, premature coronary artery disease, and atherosclerosis.