Background Despite major advances in understanding the molecular basis of various genetic lipodystrophy syndromes, some rare patients still remain unexplained.
Cases We report a novel autosomal recessive lipodystrophy affecting two sisters aged 17 and 19 years and characterised by early onset intellectual disability, and subsequent development of near-generalised loss of subcutaneous fat with diabetes mellitus, extreme hypertriglyceridemia, hepatic steatosis, short stature, clinodactyly, joint contractures, leiomyoma of uterus and cataracts in childhood. The lipodystrophy was more pronounced in the upper and lower extremities, and there was no associated muscular hypertrophy. Using whole exome sequencing in this consanguineous Hispanic pedigree, we report disease-causing homozygous p.Arg545His LMNA variant in the affected subjects, and confirm the lack of pathogenic variants in other known lipodystrophy genes. The mother and a younger brother were both heterozygous for p.Arg545His LMNA variant and were overweight with acanthosis nigricans without any evidence of lipodystrophy. Our patients are distinct from previously reported autosomal recessive lipodystrophy syndromes and have no overlap with other autosomal recessive laminopathies, including mandibuloacral dysplasia, Emery-Dreifuss muscular dystrophy and Charcot-Marie-Tooth neuropathy.
Conclusion Our report of this unusual familial generalised lipodystrophy syndrome adds to the pleiotropy associated with biallelic autosomal recessive LMNA variants.
- diabetes mellitus
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Contributors Conception and design: NP, CX, AG. Acquisition, analysis or interpretation of data: NP, SH, CX, ZZ, CQ, AG. Drafting and revising the manuscript for important intellectual content: NP, SH, CX, ZZ, CQ, AG. All authors have approved the final version and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. None of the authors has conflicts of interest to declare. All of the authors have seen and approved the submission and take full responsibility for the manuscript.
Funding This work was supported by grants from the National Institutes of Health, R01-DK105448, and Southwestern Medical Foundation.
Competing interests None declared.
Patient consent for publication Parental/guardian consent obtained.
Ethics approval The protocol was approved by Institutional Review Board of UT Southwestern, Dallas, Texas, USA.
Provenance and peer review Not commissioned; externally peer reviewed.