Mandibular Hypoplasia, Deafness, Progeroid Features, And Lipodystrophy Syndrome

A number sign (#) is used with this entry because mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is caused by de novo heterozygous mutation in the POLD1 gene (174761) on chromosome 19q13.

Description

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 including insulin resistance and diabetes mellitus. Sensorineural deafness occurs late in the first or second decades of life (summary by Weedon et al., 2013).

Clinical Features

Shastry et al. (2010) reported 7 unrelated patients with a novel syndrome characterized by mandibular hypoplasia, deafness, progeroid features, and lipodystrophy. The patients presented in early childhood with poor growth and thin limbs due to loss of subcutaneous adipose tissue. Sensorineural deafness occurred between 6 and 18 years of age. Facial features included beaked nose, prominent eyes, crowded teeth, small mouth and uvula, and long eyelashes in some. Some patients had more generalized loss of subcutaneous fat, including in the face and neck, which tended to increase with age. Three patients had joint contractures and 3 had radiographic skeletal anomalies, including hypoplastic metatarsals, fusion of the carpal bones, and slipped epiphyses. All had metabolic abnormalities, such as insulin resistance and hypertriglyceridemia. Males showed hypogonadism and cryptorchidism; the 2 females had poor breast development, although the only postpubertal female had normal menstrual periods. More variable features included hepatomegaly, telangiectasia, skin atrophy, and cataracts. The features were reminiscent of, but distinct from, mandibuloacral dysplasia (see, e.g., MADA, 248370); Shastry et al. (2010) emphasized that their patients did not have acroosteolysis, clavicular hypoplasia, or sparse hair, but did have deafness. Mutations in the LMNA (150330) and ZMPSTE24 (606480) genes were excluded. None of the patients had a family history of a similar disorder, suggesting de novo occurrence.

Weedon et al. (2013) reported 4 unrelated patients with MDPL, including 2 previously reported patients (patients 300.4 and 500.4 in Shastry et al., 2010). The most prominent clinical feature was lack of subcutaneous fat that was first noted in early childhood, although all patients had a normal birthweight. The marked decrease in subcutaneous fat contrasted with a marked increase in visceral adipose tissue as demonstrated by MRI. All affected individuals had clinical and biochemical evidence of insulin resistance, despite having low body mass index (BMI) values. Facial features included mandibular hypoplasia and dental overcrowding, and all had a high-pitched voice. Other common clinical features included skin scleroderma and telangiectasia, ligament contractures, osteoporosis, kyphosis/scoliosis, reduced mass of limb muscles, hypogonadism and undescended testes in males, and sensorineural deafness. All had high educational achievement. Subcutaneous abdominal adipose tissue from 1 patient showed abundant fibrosis, but no inflammatory cell infiltrates. The tissue sample had increased expression of key extracellular matrix genes, such as TGFB1 (190180) and fibronectin (FN1; 135600).

Molecular Genetics

In 4 unrelated patients with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome, Weedon et al. (2013) identified a de novo heterozygous in-frame deletion of residue ser605 in the polymerase active site of the POLD1 gene (174761.0003). The mutation, which was initially found by exome sequencing and confirmed by Sanger sequencing in 2 of the patients, was not found in any of the parents or in several large control databases. In vitro functional expression studies in E. coli showed that the mutant enzyme had lost its DNA polymerase ability, whereas its exonuclease activity, although decreased compared to wildtype, was still present. The studies demonstrated decoupling of the mutant enzyme's activities and suggested that the mutant protein could bind DNA, but was unable to interact with and incorporate dNTPs. The inability to catalyze polymerization likely leads to an increase in stalled replication forks, cell senescence, and death. The findings implicated POLD1 in adipose tissue homeostasis.