A Novel Syndrome of Mandibular Hypoplasia, Deafness, and Progeroid Features Associated with Lipodystrophy, Undescended Testes, and Male Hypogonadism

Division of Nutrition and Metabolic Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-8537, USA.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 10/2010; 95(10):E192-7. DOI: 10.1210/jc.2010-0419
Source: PubMed


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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    • "It was recently shown that heterozygous germline mutations in the exonuclease domain of POLD1 predispose to colorectal [Palles et al., 2013] and endometrial [Church et al., 2013] cancers. Moreover, an in-frame single amino-acid deletion at the polymerase-active site of POLD1 (c.1812 1814delCTC, p.Ser605del) was shown [Weedon et al., 2013] to cause mandibular hypoplasia, deafness, and progeroid features (MDP) syndrome [Shastry et al., 2010]. Additionally, a recent report identified a missense mutation (c.1519C>T, p.Arg507Cys) as a further cause of MDP [Pelosini et al., 2014]. "
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    ABSTRACT: Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner Syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few non-classical cases of WS, another 10-15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: Mandibular hypoplasia, Deafness, Progeroid features (MDP) syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with Werner Syndrome. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably under-diagnosed segmental progeroid syndrome. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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    • "The most widely studied infantile premature aging syndrome is Hutchinson–Gilford progeria syndrome (HGPS) [Merideth et al., 2008]. However, numerous childhoodonset progeroid syndromes have been reported [Agarwal et al., 2003; Arboleda et al., 2007; Kraemer et al., 2007; Kivuva et al., 2008; Braddock et al., 2010; Friedrich et al., 2010; Shastry et al., 2010]. "
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