Endocrine Abstracts

JOINT2277

Background: POLD1 gene encodes the catalytic subunit of the DNA polymerase delta, an enzyme essential for genome replication and repair. Pathogenic mutations in the POLD1 gene are responsible for Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy (MDPL) syndrome, a rare autosomal dominant disorder. The key clinical features are reflected in its name, with additional manifestations including joint contractures, prominent eyes, crowded teeth, small mouth, beaked nose, poor breast development in females, insulin resistance, diabetes mellitus, abnormal liver function, and hypertriglyceridemia. Here, we describe a new paediatric case of MDPL syndrome, focusing on her clinical features.

Clinical Case: A 5-year-old girl was referred to our Endocrinology Unit for growth delay. Her medical history revealed consistently normal but below-average growth, with a deceleration over the past year. At the first evaluation, height was below the genetic target (-2.26 SDS), with a BMI indicative of severe underweight (-5.21 SDS). She exhibited distinctive phenotypic features, including hypoplastic earlobes, thin nasal bridge, short philtrum, deep bite, clinodactyly of the fifth toes, bilateral ankle joint stiffness and reduced subcutaneous adipose tissue. Blood tests performed to investigate the growth failure resulted within normal ranges, with adequate IGF-1 levels. The Bone age X-ray findings were consistent with the patient’s chronological age. During follow-up, she exhibited a further decline in BMI, increased joint stiffness and reported early signs of hearing impairment, confirmed by an audiological evaluation revealing bilateral sensorineural hearing loss. Given the clinical suspicion of a lipodystrophy syndrome, whole-exome sequencing was performed, identifying a de novo POLD1 mutation and confirming the diagnosis of MDPL syndrome. The mutation consists of an in-frame deletion (c.1812_1814delCTC) of the serine residue at position 605 of the polypeptide chain, resulting in the complete loss of DNA polymerase activity. Metabolic blood tests revealed normal serum levels of leptin, cholesterol, triglycerides and transaminases. An oral glucose tolerance test ruled out insulin resistance.

Conclusions: Our case confirms that MDPL syndrome belongs to the highly heterogeneous group of lipodystrophy disorders. Moreover, this condition should be considered in the differential diagnosis of patients with growth delay, and early-onset hearing impairment. Progressive loss of subcutaneous fat, gradually occurring in late childhood, must be a mandatory criterion for diagnostic suspicion. Early identification of the genetic mutation allows for better management of symptoms and long-term potential complications. Additionally, this case highlights the value of whole-exome sequencing in diagnosing rare genetic disorders.