Defining the Clinical, Molecular and Ultrastructural Characteristics in Occipital Horn Syndrome: Two New Cases and Review of the Literature

Genes (Basel). 2019 Jul 12;10(7):528. doi: 10.3390/genes10070528.


Occipital horn syndrome (OHS) is a rare connective tissue disorder caused by pathogenic variants in ATP7A, encoding a copper transporter. The main clinical features, including cutis laxa, bony exostoses, and bladder diverticula are attributed to a decreased activity of lysyl oxidase (LOX), a cupro-enzyme involved in collagen crosslinking. The absence of large case series and natural history studies precludes efficient diagnosis and management of OHS patients. This study describes the clinical and molecular characteristics of two new patients and 32 patients previously reported in the literature. We report on the need for long-term specialized care and follow-up, in which MR angiography, echocardiography and spirometry should be incorporated into standard follow-up guidelines for OHS patients, next to neurodevelopmental, orthopedic and urological follow-up. Furthermore, we report on ultrastructural abnormalities including increased collagen diameter, mild elastic fiber abnormalities and multiple autophagolysosomes reflecting the role of lysyl oxidase and defective ATP7A trafficking as pathomechanisms of OHS.

Keywords: ATP7A; Ehlers–Danlos syndrome type IX; Menkes syndrome; collagen; copper transport; elastic fiber; occipital horn syndrome; review.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Collagen / metabolism
  • Copper-Transporting ATPases / genetics
  • Cutis Laxa / enzymology
  • Cutis Laxa / genetics
  • Cutis Laxa / pathology*
  • Diverticulum / pathology
  • Ehlers-Danlos Syndrome / enzymology
  • Ehlers-Danlos Syndrome / genetics
  • Ehlers-Danlos Syndrome / pathology*
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Protein-Lysine 6-Oxidase / metabolism
  • Urinary Bladder / abnormalities
  • Urinary Bladder / pathology
  • Young Adult


  • Collagen
  • Protein-Lysine 6-Oxidase
  • ATP7A protein, human
  • Copper-Transporting ATPases

Supplementary concepts

  • Bladder Diverticulum
  • Occipital horn syndrome