A Chinese Girl with Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy (MDPL) Diagnosed via POLD1 Mutation Detection
Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome is an extremely rare genetic disorder characterized by a constellation of clinical features, including mandibular hypoplasia, sensorineural deafness, progressive lipodystrophy, and progeroid appearance. This case report describes a 15-year-old Chinese girl from Chengdu, Sichuan province, who was diagnosed with MDPL syndrome based on clinical manifestations and genetic testing, which revealed a de novo mutation in the POLD1 gene.
The patient presented to the hospital in December 2019 with a history of tinnitus and hearing loss that had developed over the previous five months. Her mother reported that the girl had been thin since the age of three, but no other abnormalities were noted at that time. Upon admission, the patient exhibited low subcutaneous fat and distinctive facial features, including a small jaw, thin lips, mandibular dysplasia, and crowded teeth. Her height was 1.50 meters, and her body mass index (BMI) was 13.3 kg/m², indicating significant underweight status. A dual-energy X-ray absorptiometry (DXA) scan revealed a total fat mass of 6.65 kg, with a calculated fat mass index (FMI) of 2.96 kg/m², confirming a fat deficit.
Laboratory investigations showed a triglyceride level of 1.40 mmol/L, cholesterol level of 3.08 mmol/L, and uric acid level of 476 mmol/L. Abdominal ultrasound indicated the presence of a fatty liver. Hormonal assessments revealed a human growth hormone level of 0.1 mg/L and an estradiol level of 64 pg/mL. An oral glucose tolerance test demonstrated normal glucose tolerance but increased insulin resistance. Fasting serum glucose levels were 4.64 mmol/L, with postprandial levels at 1 hour and 2 hours being 7.75 mmol/L and 7.12 mmol/L, respectively. Fasting serum insulin levels were 25.7 mU/mL, with postprandial levels at 1 hour and 2 hours being 253.6 mU/mL and 257.4 mU/mL, respectively. Similarly, fasting serum C-peptide levels were 25.7 nmol/L, with postprandial levels at 1 hour and 2 hours being 253.6 nmol/L and 257.4 nmol/L, respectively.
Imaging studies included a plain magnetic resonance imaging (MRI) scan of the internal auditory canal, which showed no obvious abnormalities bilaterally. However, otolaryngologic examination confirmed sensorineural hearing loss. A craniocerebral MRI plain scan did not detect clear abnormalities, but bone density examination revealed osteoporosis. Given the patient’s unique clinical presentation, an underlying genetic disorder was suspected, prompting trio whole-exome sequencing for the patient and her parents. The genetic analysis identified a de novo variation in the DNA polymerase delta 1 catalytic subunit (POLD1) gene [NM_002691.3: c.1812_1814del, p.(Ser605del)] in the patient, while no abnormalities were found in either parent.
The diagnosis of MDPL syndrome was established based on the combination of clinical features and the genetic finding. MDPL syndrome is an autosomal dominant disorder first reported by Shastry et al. in 2010. The syndrome is characterized by mandibular hypoplasia, sensorineural deafness, progressive lipodystrophy, skin scleroderma, telangiectasia, ligament contractures, reduced limb muscle mass, hypogonadism, and diabetes. To date, 24 cases of MDPL syndrome have been reported worldwide, with 19 cases involving the deletion of the highly conserved serine residue in POLD1 p.(Ser605del), which is the most common genetic variation associated with the disorder.
The POLD1 gene encodes the DNA polymerase delta 1 (Pol δ1) protein, which belongs to the family of human DNA polymerases. This protein is involved in the synthesis of the lagging DNA strand during replication and possesses both polymerase and 3’ to 5’ exonuclease activity. POLD1 functionally interacts with Werner helicase during DNA replication and repair, and it has been implicated in human aging processes. The clinical manifestations of MDPL syndrome overlap with those of other lipodystrophy syndromes, making clinical diagnosis challenging. Currently, there are no specific diagnostic guidelines for MDPL, and molecular genetic testing is essential for accurate diagnosis and differentiation from other similar conditions, such as mandibuloacral dysplasia-associated lipodystrophy and Werner syndrome.
There is no effective treatment for MDPL syndrome, and management is primarily focused on symptom prevention and amelioration. Early diagnosis is crucial for implementing supportive therapies and monitoring for potential complications. In this case, the patient’s clinical presentation and genetic testing results were consistent with MDPL syndrome, highlighting the importance of molecular genetics in confirming the diagnosis of rare genetic disorders.
The patient’s special facial features, including a small jaw, thin lips, and crowded teeth, are illustrated in Figure 1A (front view) and Figure 1B (side view). The reduced subcutaneous fat in the forearms and lower limbs is shown in Figure 1C and Figure 1D, respectively. The de novo variation in the POLD1 gene (c.1812_1814del) is depicted in Figure 1E.
In conclusion, MDPL syndrome is a rare genetic disorder with a distinct clinical presentation and a known association with mutations in the POLD1 gene. This case underscores the importance of molecular genetic testing in the accurate diagnosis of rare diseases and the need for further research to develop effective treatments for MDPL syndrome. The patient’s clinical and genetic findings contribute to the growing body of knowledge on this rare condition and emphasize the role of genetic testing in the diagnosis and management of genetic disorders.
doi.org/10.1097/CM9.0000000000000986
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