Diagnosis of Menke-Hennekam syndrome by prenatal whole exome sequencing and review of prenatal signs

Mol Genet Genomic Med. 2023 Sep;11(9):e2219. doi: 10.1002/mgg3.2219. Epub 2023 Jun 23.


Introduction: CREBBP truncating mutations and deletions are responsible for the well-known Rubinstein-Taybi syndrome. Recently, a new, distinct CREBBP-linked syndrome has been described: missense mutations located at the 3' end of exon 30 and the 5' portion of exon 31 induce Menke-Hennekam syndrome. Patients with this syndrome present a recognizable facial dysmorphism, intellectual disability of variable severity, microcephaly, short stature, autism, epilepsy, visual and hearing impairments, feeding problems, upper airway infections, scoliosis, and/or kyphosis. To date, all diagnoses were made postnatally.

Method and case report: Trio-whole exome sequencing (WES) was performed in a fetus showing increased nuchal translucency persistence and aorta abnormalities at 28 weeks of gestation (WG).

Results: WES revealed a CREBBP de novo missense mutation (c.5602C>T; p.Arg1868Trp) in exon 31, previously reported as the cause of Menke-Hennekam syndrome. Termination of pregnancy was performed at 32 WG. We further reviewed the prenatal signs of Menke-Hennekam syndrome already reported. Among the 35 patients reported and diagnosed postnatally up to this day, 15 presented recognizable prenatal signs, the most frequent being intra-uterine growth retardation, brain, and cardiovascular anomalies.

Conclusion: Menke-Hennekam is a rare syndrome with unspecific, heterogeneous, and inconstant prenatal symptoms occurring most frequently with the c.5602C>T, p.(Arg1868Trp) mutation. Therefore, the prenatal diagnosis of Menke-Hennekam syndrome is only possible by molecular investigation. Moreover, this case report and review reinforce the importance of performing prenatal WES when unspecific signs are present on imaging.

Keywords: CREBBP; Menke-Hennekam syndrome; fetal anomalies; molecular genetics.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Exome Sequencing
  • Female
  • Humans
  • Menkes Kinky Hair Syndrome*
  • Mutation
  • Mutation, Missense
  • Phenotype
  • Pregnancy
  • Rubinstein-Taybi Syndrome* / genetics