Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).

BACKGROUND: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance and metabolic abnormalities. This syndrome is caused by heterozygous de novo mutations in the POLD1 gene. To date, 19 patients with MDPL have been reported in the literature and among them 14 patients have been characterized at the molecular level. Twelve unrelated patients carried a recurrent in-frame deletion of a single codon (p.Ser605del) and two other patients carried a novel heterozygous mutation in exon 13 (p.Arg507Cys). Additionally and interestingly, germline mutations of the same gene have been involved in familial polyposis and colorectal cancer (CRC) predisposition. PATIENTS AND METHODS: We describe a male and a female patient with MDPL respectively affected with mild and severe phenotypes. Both of them showed mandibular hypoplasia, a beaked nose with bird-like facies, prominent eyes, a small mouth, growth retardation, muscle and skin atrophy, but the female patient showed such a severe and early phenotype that a first working diagnosis of Hutchinson-Gilford Progeria was made. The exploration was performed by direct sequencing of POLD1 gene exon 15 in the male patient with a classical MDPL phenotype and by whole exome sequencing in the female patient and her unaffected parents. RESULTS: Exome sequencing identified in the latter patient a de novo heterozygous undescribed mutation in the POLD1 gene (NM_002691.3: c.3209T>A), predicted to cause the missense change p.Ile1070Asn in the ZnF2 (Zinc Finger 2) domain of the protein. This mutation was not reported in the 1000 Genome Project, dbSNP and Exome sequencing databases. Furthermore, the Isoleucine1070 residue of POLD1 is highly conserved among various species, suggesting that this substitution may cause a major impairment of POLD1 activity. For the second patient, affected with a typical MDPL phenotype, direct sequencing of POLD1 exon 15 revealed the recurrent in-frame deletion (c.1812_1814del, p.S605del). CONCLUSION: Our work highlights that mutations in different POLD1 domains can lead to phenotypic variability, ranging from dominantly inherited cancer predisposition syndromes, to mild MDPL phenotypes without lifespan reduction, to very severe MDPL syndromes with major premature aging features. These results also suggest that POLD1 gene testing should be considered in patients presenting with severe progeroid features.

The eleventh reported case of Mulvihill-Smith syndrome in the literature.

BACKGROUND: The Mulvihill-Smith Syndrome was first recognized in 1975. After the recognition of the Mulvihill-Smith Syndrome, ten cases have been described. CASE PRESENTATION: This article describes the eleventh case of this syndrome in a male patient, 24 years-old with short stature and microcephaly with mild cognitive impairment, deafness and allergic conjunctivitis. The patient was hospitalized several times for repeated infections, and the presence of multiple melanocytic nevi on his skin was noticed. CONCLUSIONS: Based on the entire set of signs and symptoms presented in our study, it was diagnosed the patient with Mulvihill-Smith Syndrome.

Hutchinson-Gilford progeria syndrome: clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature.

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature ageing disorder that belongs to a group of conditions called laminopathies which affect nuclear lamins. Classical and atypical forms of HGPS have been reported and there are clinical overlaps with mandibulo-acral dysplasia and restrictive dermopathy. To date, mutations in two genes, LMNA and ZMPSTE24, have been found in patients with HGPS. The p.G608G LMNA mutation is the most commonly reported mutation. Correlations between genotype and phenotype in children with progeroid syndromes are beginning to emerge. OBJECTIVES: To establish whether the LMNA p.G608G mutation is associated with a particular phenotype of HGPS. METHODS: We reviewed the clinical features and skin histology of three children with HGPS associated with the p.G608G LMNA mutation, and compared our findings with those reported in the literature. RESULTS: Our patients shared a very similar presentation and clinical course. Skin changes were the earliest finding in all three. Skin histology showed nonspecific changes only. CONCLUSIONS: The LMNA p.G608G mutation results in a uniform phenotype through early to mid-childhood, in keeping with that described in classical HGPS. Skin changes are the earliest distinctive clinical finding and should prompt careful physical and radiological examination for other features of HGPS. Skin biopsy for histology is not a useful investigation when a diagnosis of HGPS is suspected.

The accelerated occurrence of age-related changes of organism in Chernobyl workers: a radiation-induced progeroid syndrome?

The rate of aging was studied in 306 persons working at Chernobyl Atomic Power Station after the accident by means of integral and partial biological age assessment. An accelerated rate of aging was found in 81% of men and in 77% of women in comparison with a control random population sample of Kiev. Persons younger than 45 years appeared to be more vulnerable to radiation. The biological age of persons who worked in the contaminated zone immediately after the disaster exceeded the biological age in those who arrived in Chernobyl 4 months later. The biological age in the investigated persons exceeded its average populational value for 5 years (the integral biological and partial cardiopulmonary age) and for 11 years for the partial psychological age. These data may underlie the concept of radiation progeroid syndrome as the form of accelerated aging.

Progeria: medical aspects, psychosocial perspectives, and intervention guidelines.

This article discusses progeria, a rare genetic childhood disorder that invariably results in the individual's death during early adolescence. The article begins by describing the major medical aspects of progeria. This is followed by a discussion of the psychosocial implications of the disorder with particular emphasis upon grief-triggered reactions. The article concludes with an overview of psychosocial intervention guidelines for caregivers who work with families of dying children and adolescents.

Premature aging in female alcoholics. A neuropsychological study.

The hypothesis of premature aging in middle-aged female alcoholics was tested by comparing their level pattern of neuropsychological test performance with age-equated nonalcoholic females and elderly nonalcoholic women. Alcoholics had significantly poorer performance on the tests than nonalcoholic peers but performed significantly better than the elderly. A subsample of more severe alcoholics was not significantly different from the elderly in level of performance although they were approximately 20 years younger. However, there were no differences among the groups in pattern of test performance. The data on level of performance partially support the hypothesis of premature aging in alcoholics. Stronger support would be attained if it were demonstrated that the alcoholics and elderly have a similar impairment in the neuropsychological processes eventuating in lowered performance.