Endocrine Abstracts

JOINT1620

Background: Uniparental disomy presents two primary developmental risks: inheriting a recessive trait or occurrence of an imprinting disorder. Occasionally, these risks may coexist in a single patient, leading to a rare comorbidity. Managing comorbidities associated with rare diseases presents unique clinical challenges. The aim of this study is to present the case of a boy who was ultimately diagnosed with two rare diseases: Prader-Willi syndrome associated with maternal UPD15 and autosomal recessive Lodder-Merl syndrome associated with a new pathogenic variant of the GNB5 gene.

Case report: A fourteen-month-old boy of young, healthy parents, born by cesarean section in the 38th week of pregnancy with a birth weight of 2110 g, Apgar 7 - 10 points. Bilateral cryptorchidism, hypotonia, weak sucking reflex, apneas, congenital pneumonia, and respiratory failure were found. Treated in the Neonatal Intensive Care Unit, fed through a nasogastric tube. In the fourth month of life, semiological seizures consistent with infantile spasms appeared. The attacks occurred daily in 4-6 series lasting approximately 3 minutes. Neurological examination at the age of 4 months revealed microcephaly (OFC 38.5 cm, below the 3rd percentile), bilateral ptosis, open mouth, poor facial expressions, bilateral horizontal nystagmus, without fixation, profound global hypotonia, poor motor skills. The EEG recording was abnormal and drug-resistant epilepsy was diagnosed. During further follow-up, the patient showed no developmental progress. Genetic testing identified an abnormal DNA methylation pattern in the critical PWS 15q11-q13 region. Microsatellite polymorphism analysis in the 15q region in the proband and both parents confirmed maternal uniparental disomy of chromosome 15. Due to the patient’s clinical picture, trio-WES and mitochondrial genome analysis were performed. A homozygous variant of the GNB5 gene was detected in the isodisomy region on chromosome 15. WES analysis of the mother’s sample showed that she was a heterozygous carrier.

Conclusions: Co-occurence of PWS and some unexpected or severe phenotype should always raise suspicion of comorbid genetic disease attributed to genes located in Prader-Willi syndrome-associated critical region of chromosome 15q. Epileptic encephalophaty with cardiac arrythmia should implicate prompt cardiologist and genetic care. Presented case provides further support for uniparental disomy as an unexpected cause of Lodder-Merla syndrome. This implicates the importance of comprehensive genetic testing including parental testing and familial cascade testing to learn about recurrence risk.