SAT-705 - Blakemore-Durmaz-Vasileiou Syndrome: Multiple Endocrine Disorders, Obesity and Neurodevelopmental Disability

Blakemore Durmaz Vasileiou syndrome (BDVS) is a rare neuroendocrine disorder caused by loss-of-function variants in the CPE gene. This gene encodes carboxypeptidase E, a key enzyme in prohormone processing. Reported manifestations include obesity, intellectual disability, diabetes mellitus, hypogonadism, and variable pituitary hormone deficiencies. Due to its rarity, BDVS remains unrecognized in clinical practice.

A 22-year-old male with intellectual disability, morbid obesity with BMI 40.15 and gastroesophageal reflux disease presented to establish care and for work up of obesity and hyperphagia. Patient has a family history of obesity, neurodevelopmental delay and endocrine disorders. Routine laboratory evaluation revealed hemoglobin A1c of 12.5% (4–6), AST 62 U/L ( < 41), and ALT 121 U/L ( < 41). Thyroid studies showed normal TSH 1.04 µIU/mL (0.270 - 4.200), with low free T4 0.69 ng/dL (0.93–1.70), suggestive of central hypothyroidism. Further endocrine evaluation showed hypogonadism with a morning total testosterone of 62 ng/dL (264–916) and inappropriately normal gonadotropins LH 7.5 mIU/mL (1.3–9.6), FSH 6.4 mIU/mL ( < 12.4), consistent with central hypogonadism. ACTH was 65 pg/mL (7.2–63.3) with an adequate cosyntropin-stimulated cortisol of 20.5 µg/dL (>17.9) at 60 minutes. IGF-1, growth hormone, and prolactin were within reference ranges. MRI of the pituitary demonstrated a normal hypothalamus and pituitary system. Genetic testing was done which identified a pathogenic variant in the CPE gene confirming the diagnosis of BDVS. The patient was treated with levothyroxine, tirzepatide and is being evaluated for testosterone replacement therapy.

BDVS is an extremely rare neuroendocrine disorder with an estimated prevalence < 1 in 1,000,000 individuals worldwide. To date, only a small number of affected individuals have been described in the medical literature consisting of eight individuals from five unrelated consanguineous families. These families have documented biallelic CPE loss-of-function variants and a recognizable BDVS clinical phenotype of obesity, neurodevelopmental delay, and endocrine dysfunction. The patient in this case is related to one of the five families described in literature. This condition is characterized by early onset weight gain, truncal obesity and hyperphagia. This phenotype closely resembles Prader-Willi syndrome which must be excluded as part of the diagnostic workup. CPE gene, which encodes carboxypeptidase E, is a crucial enzyme in converting prohormones to their bioactive forms. A loss of function results in hormonal deficiencies and their clinical manifestations.

BDVS is a genetic condition that leads to several hormonal deficiencies. Therefore, timely diagnosis can lead to prompt management, metabolic optimization, and genetic counseling.

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