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

Abstract

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.

Cutis laxa: A comprehensive overview of clinical characteristics and pathophysiology

“…In ARCL type 2 and 3 syndromes associated with impaired vesicular trafficking, severe elastic fiber abnormalities with sparse and disintegrated cores have been reported, 20,22 whereas entities related to cellular metabolism show thin elastic fibers with minimal peripheral fragmentation and an excessive microfibrillar mantle 55,56 . Of note, rather similar elastic fiber abnormalities were reported in X‐linked CL 29 …”

“…OHS usually shows absent to mild mental involvement and has a better prognosis ad vitam 28 . However, significant mortality can be present, especially in young adults, and related to gastrointestinal, respiratory, and bleeding complications 29 . The main clinical abnormalities include CL, urogenital tract diverticula, and skeletal exostoses.…”

“…As in Menkes disease, dysautonomia symptoms can be disabling and consist of chronic diarrhea, hypothermia and orthostatic hypotension 28,30 . Finally, tortuosity of the intracranial arteries, and to lesser extend the cervical, splenic mesenteric arteries, completes the clinical tableau and imposes a risk for aneurysm rupture and bleeding 29 …”

Arterial Tortuosity Syndrome: An Ascorbate Compartmentalization Disorder?

“…Occipital horn syndrome, an X-linked disorder caused by mutations in ATPase copper-transporting alpha (ATP7A), presents not only with intracranial vascular tortuosity but also with distinctive skeletal and urogenital features (10). Loose skin may be reminiscent of different types of cutis laxa, including ARCL type 1A, type 1B, type 1C, and ARCL type 2.…”

ATP7A Clinical Genetics Resource – A comprehensive clinically annotated database and resource for genetic variants in ATP7A gene

“…Similar to MD, OHS is also a rare disorder occurring due to impaired copper absorption. OHS patients are characterized by “occipital horns” which are downward pointing exostosis arising from the occipital bone and certain connective tissue deformities comprising cutis laxa, hernias, joint laxity and bladder diverticula [7] . X-linked distal spinal muscular atrophy type 3 is a rare distal hereditary motor neuropathy.…”