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.

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

Figure 1

Clinical characteristics in subjects F1:II-1 and F2:II-1. Subject F1:II-1 displays mild facial dysmorphism with a flat face, deep-set eyes, a long and narrow nose, large ears and mild webbing of the neck. Craniofacial features in patient F2:II-1 are more pronounced and include dolichocephaly, a high forehead, biparietal narrowing, downslanting eyes, a convex nasal ridge, midfacial hypoplasia, micrognathia and low-set ears. No hair abnormalities were observed. Both have lax and hyperextensible skin, marked joint hypermobility and deformities of the proximal radius.

Figure 2

Total skeletal radiography and MRI/MRA studies in subject F1:II-1 showing severe skeletal dysplasia with occipital horns, undertubulation of bony structures and broadening of the ventral end of the first left rib, both claviculae and scapular neck, bowing of the long bones with mid-diaphyseal broadening, bilateral luxation of the radial heads, bilateral overgrowth of the ulnar coronoid processes, prominent trochanter minor of both femurs, short fibula, bilateral coxa valga with rounded iliac wings and broad metatarsals. Brain MRI and angiography showed tortuous intracranial arteries and normal brain structure.

Figure 3

ATP7A pathogenic variants reported in this study. ATP7A consists of six amino terminal metal binding domains (MBD1-MBD6), a transmembrane domain containing eight transmembrane helices (TM1-TM8) and an N-, P- and A- soluble catalytic domain. The pathogenic variants identified in subjects F1:II-1 and F2:II-1 are indicated in bold and outlined.

Figure 4

Transmission electron microscopy findings in occipital horn syndrome. Transmission electron microscopy (TEM) findings in skin samples of patients F1:II-1 and F2:II-1 and a matched control showing collagen (column 1), elastic fibers (column 2) and a fibroblast (column 3). col = collagen; ef = elastic fiber; fb = fibroblast. Magnification for column 1: ×15,000, column 2: ×8000 and column 3: ×4000.