Berardinelli-Seip Syndrome

Inherited disorder with hyperinsulinemia caused by insulin resistance combined with lipodystrophy and acromegaloid features.

Berardinelli-Seip-Lawrence Syndrome; Berardinelli Syndrome; Seip Syndrome; Seip-Lawrence Syndrome; Congenital Generalized Lipodystrophy; (Congenital) Lipoatrophic Diabetes; Lipodystrophy-Acromegaloid Gigantism Syndrome.

Estimated prevalence is 0.2-0.3:100,000 in the general population.

Autosomal recessive disorder. Two genetic loci (11q13 and 9q34) are associated with the syndrome.

No unifying pathogenetic mechanism has been identified. The insulin receptor seems to be normal.

Based on the clinical picture, including hyperinsulinemia and in some cases a positive family history. Berardinelli-Seip syndrome commonly refers to the congenital form of generalized lipodystrophy, whereas Seip-Lawrence syndrome usually refers to the acquired form (in which the anabolic syndrome is more variable and immunologic disturbances more common; see also Other Conditions to Be Considered).

Hallmarks of Berardinelli-Seip syndrome are a near-absent adipose tissue present already at birth or in early infancy and a congenital (nonketoacidotic) insulin resistance with variable degrees of glucose intolerance and diabetes mellitus. The insulin resistance with hyperinsulinemia results in an anabolic syndrome resulting in increased growth velocity, advanced bone age, muscular hypertrophy and masculine body build, acromegaloid stigmata, enlarged genitalia in infancy (labial hypertrophy and sexual precocity, polycystic ovaries), abundant scalp hair and hypertrichosis, and organomegaly (often with visceral organs showing twice the normal weight). The anabolic syndrome is further exacerbated by a voracious appetite. Associated features are liver cirrhosis, esophageal varices, and hypertriglyceridemia with risk of pancreatitis. Acanthosis nigricans, which is variable but often marked and extensive, seems to be a constant sign of Berardinelli-Seip syndrome (as seen in other syndromes with pronounced insulin resistance). It is most often located in the extensional areas (elbows, knees) and in places exposed to wear and tear (axilla, neck, waist). Scoliosis and cystic bone lesions are found in some patients. Mental retardation is not a constant feature but is present in approximately 50% of patients. Cardiovascular involvement (arterial hypertension, hypertrophic cardiomegaly, coronary heart disease) is the leading cause of early death. Medical management consists of moderate restriction of caloric intake (preferably with short-chain fatty acids), insulin as indicated, and antihyperlipidemic drug therapy.

No reports describing anesthesia in these patients have been published. However, two features require special attention: diabetes mellitus and cardiovascular involvement. The latter rarely causes problems in childhood, but the risk of coronary ischemia must be considered in young adult patients. If in doubt, at least a chest radiograph and electrocardiogram should be obtained, and chronic cardiac medication must be evaluated. Abrupt discontinuation of angina pectoris medication can precipitate an ischemic episode. Assess hepatic and pancreatic function preoperatively.

Management of the metabolic and cardiovascular derangements follows standard approach. If there are any signs of coronary heart disease, attention should be paid to provide adequate sedation and analgesia. Any increase in myocardial oxygen demand should be avoided (increase in afterload, contractility, or heart rate). Toddlers are at increased risk for developing potentially dangerous hyperplasia of the pharyngeal tonsils and adenoids. Macroglossia has been described in some patients. Maintaining airway patency may be challenging.

In patients with coexisting heart disease, volatile anesthetics are safe in lower concentrations but may cause myocardial depression with worsening left ventricular function at higher concentrations. Benzodiazepines usually are well tolerated, and there is no evidence contraindicating muscle relaxants. In contrast, because of their potential negative inotropic effects, propofol and barbiturates should either be avoided or used in low doses only in patients with significant cardiomyopathy. Ketamine is generally regarded as disadvantageous because of its sympathomimetic effects resulting in increased oxygen requirements. Drugs with predominant hepatic clearance should be avoided in patients with liver failure.

Acquired Generalized Lipodystrophy: Refers to an identical syndrome with later onset, often preceded by a well-defined illness, usually an infection. Acquired generalized lipodystrophy tends to be associated with worse liver disease and a more rapid development of diabetes mellitus.

Partial Lipoatrophy Syndromes: A number of partial lipoatrophy syndromes have been described (Köbberling-Dunnigan Syndrome; Familial Lipodystrophy of Limbs and Lower Trunk; Lipodystrophic Diabetes; and Reverse Partial Lipodystrophy). In some patients, genetic analysis identified an associated locus on chromosome 1q21-22. Loss of subcutaneous adipose tissue usually begins in puberty, sparing chin, neck, axilla, and back, resulting in a cushingoid appearance. Adipose tissue may accumulate intraabdominally. Metabolic abnormalities are similar to those described in Berardinelli-Seip syndrome.

Apolipoprotein C-II Deficiency (Synonym: Familial Hyperlipoproteinemia type IB): An inborn error of metabolism characterized by the deficiency in a necessary cofactor for the activation of lipoprotein lipase. Diabetes mellitus, pancreatitis, or epigastric pain does not exclude the possibility of congestive heart failure and angina in early age.

Hyperlipoproteinemia Type I (Synonyms: Bürger-Grütz Syndrome; Essential Familial Hyperlipemia; Exogenous Hypertriglyceridemia; Fat-Induced Hyperlipemia; Fredrickson Type I Hyperlipoproteinemia; Hyperchylomicronemia; Hyperlipidemia I; Hyperlipoproteinemia Type I; Idiopathic Familial Hyperlipemia; Lipoprotein Lipase Deficiency, Familial Retention Hyperlipemia): Inherited inborn error of metabolism characterized by a massive accumulation of chylomicrons and triglycerides in plasma resulting in recurrent abdominal pain and hepatosplenomegaly.

Hyperlipoproteinemia Type IIA: A 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: (Synonym: Sitosterolemia): A rare inherited disorder characterized by congenital hypercholesterolemia, presenting clinically with tendon xanthomas, premature coronary artery disease and atherosclerosis.