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Heterogeneity for congenital generalized lipodystrophy in seventeen patients from Oman
Anna Rajab1, Kirsten Heathcote, Surendra Joshi
1Genetic Unit, DGHA, Ministry of Health, Muscat, Sultanate of Oman. drarajab@omantel.net.om
Insights
This study observed 17 children with Berardinelli-Seip Congenital Lipodystrophy (BSCL) in Oman, identifying two distinct clinical groups. Genetic analysis linked one group to the BSCL2 locus, suggesting a new lipodystrophy syndrome in the other.
Area of Science:
- Genetics
- Endocrinology
- Pediatrics
Background:
- Congenital generalized lipodystrophy, or Berardinelli-Seip Congenital Lipodystrophy (BSCL), is a rare disorder characterized by widespread absence of adipose tissue.
- Previous research has identified genetic loci associated with BSCL, but variations in presentation suggest potential for further classification.
Purpose of the Study:
- To investigate the clinical and genetic heterogeneity of Berardinelli-Seip Congenital Lipodystrophy (BSCL) in Omani children.
- To subclassify BSCL cases based on distinct clinical features and explore potential genetic underpinnings.
Main Methods:
- Clinical observation and assessment of 17 children with BSCL from 12 consanguineous sibships.
- Subclassification of patients into two distinct groups based on phenotypic presentation.
- Molecular genetic analysis, including homozygosity testing at the BSCL2 locus.
Main Results:
- Two distinct groups of BSCL were identified: Group 1 (7 cases) exhibited features consistent with known BSCL, including acanthosis nigricans, hyperinsulinemia, and insulin resistance, with four cases showing homozygosity at the BSCL2 locus.
- Group 2 (10 cases) presented with significant skeletal and nonskeletal muscle abnormalities, such as reduced exercise tolerance, myoxedema, and cardiac issues, with genetic evidence against homozygosity at known BSCL loci.
- A correlation between acanthosis nigricans severity and disorder severity was noted in Group 1.
Conclusions:
- BSCL in Omani children presents with significant heterogeneity, necessitating subclassification into distinct clinical entities.
- The findings suggest that Group 1 is associated with the BSCL2 locus, while Group 2 may represent a novel genetic syndrome with lipodystrophy.
- Further genetic investigation is warranted for the second group to identify the underlying genetic cause of this distinct lipodystrophy phenotype.
Abstract:
Seventeen children with congenital generalized lipodystrophy or Berardinelli-Seip Congenital Lipodystrophy (BSCL) from 12 consanguineous sibships were observed in Oman. All children had widespread absence of adipose tissue from infancy together with apparent muscle hypertrophy and hepatomegaly. They did not appear to represent a single homogenous entity, and it was possible to subclassify the cases into two distinct groups. In the first group of seven cases, the features were similar to other published cases with acanthosis nigricans, raised insulin levels, and insulin resistance. In this group, there was an association between the degree of acanthosis nigricans and the severity of the disorder. Molecular analysis of these cases showed homozygosity at the BSCL2 locus on chromosome 11q13 in four of the seven cases. In the second group of ten cases, there were striking abnormalities in both skeletal and nonskeletal muscle. Reduced exercise tolerance and percussion myoxedema were observed in skeletal muscle, while infantile hypertrophic pyloric stenosis, prominent veins (phlebomegaly), disturbance of cardiac rhythm, and cardiomyopathy were observed in nonskeletal muscle. There was evidence against homozygosity in some cases for the known loci for BSCL, and this group may represent a new clinical syndrome with lipodystrophy at a different genetic location.