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A De Novo POLD1 Mutation Associated With Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome in a Family With Werner Syndrome.

ABSTRACT: Background. Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome is a recently recognized genetic disorder comprised of mandibular hypoplasia, deafness, progeroid features, and lipodystrophy. It is caused by an autosomal dominant mutation in the POLD1 gene, with <20 genetically confirmed cases to date. Clinical overlap with other progeroid syndromes including Werner syndrome (WS) can present diagnostic challenges. Case. The proband is a 36-year-old male of Sicilian ancestry who was phenotypically normal at birth. Onset of lipodystrophic and progeroid features began at 18 months, with progressive loss of subcutaneous fat, prominent eyes, and pinched nose. Over the next 2 decades, he developed hearing loss, small fingers, joint contractures, hypogonadism, osteoporosis, and hypertriglyceridemia. Three of his 4 siblings had premature hair graying and loss, severe bilateral cataracts, skin changes, and varying degrees of age-related metabolic conditions, raising suspicion for a genetic progeroid syndrome. Genetic Analysis. A targeted sequencing panel identified a heterozygous WRN mutation in the proband's genomic DNA. Sanger sequencing further revealed his parents and an asymptomatic brother to be carriers of this mutation, and in his 3 brothers affected with classic WS the mutation was identified in the homozygous state. Whole exome sequencing ultimately revealed the proband harbored the causative de novo in-frame deletion in POLD1 (p.Ser605del), which is the most common mutation in MDPL patients. Conclusion. We report the unusual convergence of 2 rare progeroid disorders in the same family: the proband displayed sporadic MDPL syndrome, while 3 brothers had classical autosomal recessive WS. Whole exome sequencing was invaluable in clarifying the molecular diagnoses in this family.

SUBMITTER: Wang LR

PROVIDER: S-EPMC6047234 | biostudies-literature | 2018 Jan-Dec

REPOSITORIES: biostudies-literature

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A De Novo POLD1 Mutation Associated With Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome in a Family With Werner Syndrome.

Wang Linda R LR Radonjic Aleksandar A Dilliott Allison A AA McIntyre Adam D AD Hegele Robert A RA

Journal of investigative medicine high impact case reports 20180101

Background. Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome is a recently recognized genetic disorder comprised of mandibular hypoplasia, deafness, progeroid features, and lipodystrophy. It is caused by an autosomal dominant mutation in the POLD1 gene, with <20 genetically confirmed cases to date. Clinical overlap with other progeroid syndromes including Werner syndrome (WS) can present diagnostic challenges. Case. The proband is a 36-y ...[more]

PMID: 30023403

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Project description:Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase.We analysed the clinical and biological features of two women, aged 32 and 36, referred for partial lipodystrophic syndrome which led to the molecular diagnosis of Werner syndrome. Cultured skin fibroblasts from one patient were studied.Two normal-weighted women presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis. One of them had also diabetes. Both patients showed a peculiar, striking lipodystrophic phenotype with subcutaneous lipoatrophy of the four limbs contrasting with truncal and abdominal fat accumulation. Their oral glucose tolerance tests showed extremely high levels of insulinemia, revealing major insulin resistance. Low serum levels of sex-hormone binding globulin and adiponectin suggested a post-receptor insulin signalling defect. Other clinical features included bilateral cataracts, greying hair and distal skin atrophy. We observed biallelic WRN null mutations in both women (p.Q748X homozygous, and compound heterozygous p.Q1257X/p.M1329fs). Their fertility was decreased, with preserved menstrual cycles and normal follicle-stimulating hormone levels ruling out premature ovarian failure. However undetectable anti-müllerian hormone and inhibin B indicated diminished follicular ovarian reserve. Insulin-resistance linked ovarian hyperandrogenism could also contribute to decreased fertility, and the two patients became pregnant after initiation of insulin-sensitizers (metformin). Both pregnancies were complicated by severe cervical incompetence, leading to the preterm birth of a healthy newborn in one case, but to a second trimester-abortion in the other. WRN-mutated fibroblasts showed oxidative stress, increased lamin B1 expression, nuclear dysmorphies and premature senescence.We show here for the first time that partial lipodystrophy with severe insulin resistance can reveal WRN-linked premature aging syndrome. Increased expression of lamin B1 with altered lamina architecture observed in WRN-mutated fibroblasts could contribute to premature cellular senescence. Primary alterations in DNA replication and/or repair should be considered as possible causes of lipodystrophic syndromes.

Project description:Background:Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods:We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results:Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions:Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.

Dataset Information

A De Novo POLD1 Mutation Associated With Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome in a Family With Werner Syndrome.

Publications

A De Novo <i>POLD1</i> Mutation Associated With Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome in a Family With Werner Syndrome.

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