BDV Syndrome: An Emerging Syndrome With Profound Obesity and Neurodevelopmental Delay Resembling Prader-Willi Syndrome

J Clin Endocrinol Metab. 2021 Nov 19;106(12):3413-3427. doi: 10.1210/clinem/dgab592.


Context: CPE encodes carboxypeptidase E, an enzyme that converts proneuropeptides and propeptide hormones to bioactive forms. It is widely expressed in the endocrine and central nervous system. To date, 4 individuals from 2 families with core clinical features including morbid obesity, neurodevelopmental delay, and hypogonadotropic hypogonadism, harboring biallelic loss-of-function (LoF) CPE variants, have been reported.

Objective: We describe 4 affected individuals from 3 unrelated consanguineous families, 2 siblings of Syrian, 1 of Egyptian, and 1 of Pakistani descent, all harboring novel homozygous CPE LoF variants.

Methods: After excluding Prader-Willi syndrome (PWS), exome sequencing was performed in both Syrian siblings. The variants identified in the other 2 individuals were reported as research variants in a large-scale exome study and in the ClinVar database. Computational modeling of all possible missense alterations allowed assessing CPE tolerance to missense variants.

Results: All affected individuals were severely obese with neurodevelopmental delay and other endocrine anomalies. Three individuals from 2 families shared the same CPE homozygous truncating variant c.361C > T, p.(Arg121*), while the fourth carried the c.994del, p.(Ser333Alafs*22) variant. Comparison of clinical features with previously described cases and standardization according to the Human Phenotype Ontology terms indicated a recognizable clinical phenotype, which we termed Blakemore-Durmaz-Vasileiou (BDV) syndrome. Computational analysis indicated high conservation of CPE domains and intolerance to missense changes.

Conclusion: Biallelic truncating CPE variants are associated with BDV syndrome, a clinically recognizable monogenic recessive syndrome with childhood-onset obesity, neurodevelopmental delay, hypogonadotropic hypogonadism, and hypothyroidism. BDV syndrome resembles PWS. Our findings suggest missense variants may also be clinically relevant.

Keywords: BDV syndrome; CPE; carboxypeptidase E; hypogonadotropic hypogonadism; neurodevelopmental disorder; obesity.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alleles
  • Carboxypeptidase H / genetics*
  • Child
  • Female
  • Humans
  • Hypogonadism / genetics
  • Hypogonadism / pathology*
  • Hypothyroidism / genetics
  • Hypothyroidism / pathology*
  • Infant, Newborn
  • Loss of Function Mutation*
  • Male
  • Neurodevelopmental Disorders / genetics
  • Neurodevelopmental Disorders / pathology*
  • Obesity / genetics
  • Obesity / pathology*
  • Pedigree
  • Prader-Willi Syndrome / diagnosis*
  • Prognosis
  • Syndrome


  • Carboxypeptidase H