Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme paucity of adipose tissue from birth, and early onset of metabolic complications related to
insulin resistance. Mutations in three genes, 1-acylglycerol 3-phosphate-O-acyltransferase 2 (AGPAT2),
Berardinelli Seip Congenital Lipodystrophy 2 (BSCL2), and
Caveolin-1 (CAV1) are associated with the three subtypes of this disorder, CGL1, CGL2 and
CGL3, respectively. We report two siblings of Hispanic origin who displayed characteristic features of CGL such as generalized loss of subcutaneous fat from birth,
acanthosis nigricans, acromegaloid habitus, umbilical prominence, hepatosplenomegaly, hypoleptinemia,
dyslipidemia, and
insulin resistance. However, no disease causing variants were detected in the DNA sequence of AGPAT2, BSCL2 or CAV1 genes. Further, whole body magnetic resonance imaging (MRI) in the two siblings revealed marked loss of subcutaneous, intraabdominal and intrathoracic fat like in other patients with CGL, but preservation of bone marrow fat which is invariably lost in all patients with CGL1 and CGL2, but not in the patient reported with
CGL3. They also had generalized
muscle weakness during infancy and early childhood associated with a nearly fivefold increase in serum
creatine kinase (CK) levels, but with normal muscle biopsy and electrophysiologic studies. Both patients were also found to have atlantoaxial dislocation requiring surgical intervention. Thus, this pedigree represents a novel subtype of CGL characterized by generalized loss of body fat but with preservation of bone marrow fat, congenital
muscular weakness and cervical spine instability. The genetic basis of this novel subtype remains to be determined.