A novel syndrome of mandibular hypoplasia, deafness, and progeroid features associated with lipodystrophy, undescended testes, and male hypogonadism.
ABSTRACT Mandibuloacral dysplasia (MAD) is an autosomal recessive progeroid disorder associated with type A (partial) or B (generalized) lipodystrophy and is due to mutations in lamin A/C (LMNA) or zinc metalloproteinase (ZMPSTE24) genes.
The objective of the study was to report a novel syndrome with some overlapping features with MAD.
We report seven patients with mandibular hypoplasia, deafness, progeroid features (MDP), and associated lipodystrophy. These patients have similar features to MAD patients such as hypoplastic mandible, beaked nose, stiff joints, and sclerodermatous skin. However, the patients did not harbor any disease causing variants in LMNA or ZMPSTE24 and showed distinct characteristics such as sensorineural hearing loss and absence of clavicular hypoplasia and acroosteolysis. All males with MDP had undescended testes and were hypogonadal. One adult female showed lack of breast development. Skinfold thickness, dual-energy X-ray absorptiometry and whole-body magnetic resonance imaging for body fat distribution revealed a lack of lipodystrophy in a prepubertal female but a progressive loss of sc fat presenting with partial lipodystrophy in young adults and generalized lipodystrophy in older patients.
Patients with MDP syndrome have a few overlapping but some distinct clinical features as compared with MAD, suggesting that it is a novel syndrome. The molecular basis of MDP syndrome remains to be elucidated.
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ABSTRACT: The LINC complex spans the nuclear envelope and plays critical roles in coordinating nuclear and cytoplasmic activities and in organizing nuclear and cytoskeletal features. LINC complexes are assembled from KASH and SUN-domain proteins, which interact in the nuclear envelope and form a physical link between the cytoskeleton and the nuclear interior. A number of diseases have been associated with mutations in genes coding for LINC complex proteins. Mouse models of LINC complex protein have provided valuable insight into LINC complex functions and into how these proteins contribute to the various diseases with which they have been associated.Current Topics in Developmental Biology 01/2014; 109:287-321. · 4.21 Impact Factor
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ABSTRACT: Objective Progressive lipodystrophy is one of the major features of the rare MDPL syndrome. Until now, 9 patients affected by this syndrome have been described and a recent study identified in 4 of them an in-frame deletion (Ser605del) of a single codon in the POLD1 gene. Sequence alterations of the POLD1 gene at different sites have been previously reported in human colorectal and endometrial carcinomas. Materials/Methods A 48-year-old woman was admitted to our Department for the assessment of a previously diagnosed lipodystrophy. She did not report a family history of diabetes or other metabolic disorders. Hypertriglyceridemia was diagnosed incidentally when she was 25 years old. At that time she was also diagnosed with sensorineural bilateral hearing loss. At physical examination she presented lipoatrophy affecting nearly the entire body, mandibular hypoplasia, bird-like face, beaked nose, progeroid facial features, with crowded teeth, small mouth and uvula. Abdominal ultrasound showed hepatomegaly and hepatosteatosis. Fat Mass Index measured with DXA was 4.59 Kg/m2, indicating a fat deficit; the oral glucose tolerance test showed an impaired glucose tolerance. Results Sequence analysis of the entire coding region of the POLD1 gene, disclosed a novel heterozygous mutation in exon 13 (R507C). Conclusion The MDPL patient herein described harbors a novel mutation in the exonuclease domain of POLD1. This new variant provides further evidence for a role of POLD1 in the pathogenesis of MDPL. The mechanisms that link changes at various sites of the protein with different diseases remain to be clarified.Metabolism 11/2014; · 3.61 Impact Factor
Article: [Uncommon lipodystrophic syndromes.]Medicina Clínica 04/2014; · 1.25 Impact Factor