Occipital Horn Syndrome

A number sign (#) is used with this entry because occipital horn syndrome (OHS) is caused by mutation in the gene encoding Cu(2+)-transporting ATPase, alpha polypeptide (ATP7A; 300011). Menkes syndrome (309400) is caused by mutation in the same gene.

Description

Occipital horn syndrome is a rare connective tissue disorder characterized by hyperelastic and bruisable skin, hernias, bladder diverticula, hyperextensible joints, varicosities, and multiple skeletal abnormalities. The disorder is sometimes accompanied by mild neurologic impairment, and bony abnormalities of the occiput are a common feature, giving rise to the name (summary by Das et al., 1995).

Clinical Features

Lazoff et al. (1975) described an unusual syndrome in an 11-year-old male and 2 maternal uncles. Bony 'horns,' symmetrically situated on each side of the foramen magnum and pointing caudad, were demonstrable radiographically. A lifelong history of frequent loose stools, obstructive uropathy requiring in 1 uncle ileal loop diversion, and mild mental retardation were other features. Some suspicion that a relative through the maternal grandfather had the same condition (which could not be confirmed because of lack of cooperation) meant that autosomal dominant inheritance with reduced penetrance could not be excluded.

Byers et al. (1976) found deficiency of lysyl oxidase in affected males in a family with apparent X-linked cutis laxa. Three affected males were observed, each in a different sibship connected through females who as children showed joint laxity but outgrew it. Hooked nose and long philtrum typical of cutis laxa were described. In 1 case, pectus excavatum and carinatum were sufficiently severe to require surgical repair shortly after birth. Two cousins were brought to medical attention because of recurrent urinary tract infection due to multiple large diverticula of the bladder.

MacFarlane et al. (1980) described 2 kindreds with an X-linked disorder that in general appeared to fall into the Ehlers-Danlos category but had some unusual features such as bladder diverticula, bladder neck obstruction, marked varicosities, and, by x-ray, occipital horns, short broad clavicles, and fused carpal bones. Hall (1980) found that the children studied with Byers et al. (1976) also had occipital horns, and diarrhea, a feature found in MacFarlane's families, was also present. Thus, these are probably the same disorder. The age at which the affected persons were studied may have been a factor in determining whether the disorder was labeled cutis laxa or EDS. Low levels of ceruloplasmin (117700) and serum copper were found in these cases, suggesting that, like Menkes syndrome, it may be a disorder of copper metabolism rather than a primary defect of lysyl oxidase.

Hollister (1981) pointed out that the patients show hypermobility of the finger joints but limitation of extension of the elbows.

Kuivaniemi et al. (1982) studied 2 brothers with bladder diverticula, inguinal hernias, slight skin laxity and hyperextensibility, and skeletal abnormalities, including occipital exostoses. Lysyl oxidase activity was low in the medium of cultured skin fibroblasts, and conversion of newly synthesized collagen into the insoluble form was reduced. Copper concentrations were markedly elevated in cultured skin fibroblasts but decreased in serum and hair. Serum ceruloplasmin levels were low.

Kaitila et al. (1982) suggested that this disorder may be allelic to Menkes disease.

Peltonen et al. (1983) found many similar abnormalities of copper and collagen metabolism in the cultured fibroblasts of 13 patients with Menkes syndrome and 2 patients with OHS (then called EDS IX). In both disorders, fibroblasts had markedly increased copper content and rate of incorporation of (64)Cu, and accumulation was in metallothionein or a metallothionein-like protein as previously established for Menkes cells. Histochemical staining showed that copper was distributed uniformly throughout the cytoplasm in both cell types, this location being consistent with accumulation in metallothionein. Both fibroblast types showed very low lysyl oxidase activity and increased extractability of newly synthesized collagen, but no abnormality in cell viability, duplication rate, prolyl 4-hydroxylase activity, or collagen synthesis rate. Skin biopsy specimens from one EDS IX patient showed the same abnormalities in lysyl oxidase activity and collagen extractability. Fibroblasts of the mother of EDS IX patients showed increased (64)Cu incorporation.

Allelism of occipital horn syndrome and Menkes syndrome was demonstrated in a definitive way by Das et al. (1995) who identified hemizygosity for a mutation in the copper-transporting ATPase that is mutant in Menkes syndrome. One of the mild mottled mutants in the mouse, 'blotchy,' symbolized Mo-blo, exhibits connective tissue abnormalities reminiscent of those seen in OHS patients, including weak skin and bone abnormalities. In blotchy males, hindlegs are occasionally deformed, vibrissae are kinked at birth, crosslinking of skin collagen and aortic elastin is defective, and death frequently results from aortic rupture. Das et al. (1995) identified similar splicing mutations in both the blotchy mouse and cases of the occipital horn syndrome. Das et al. (1995) reported 2 OHS patients in each of whom there was a deletion of 1 exon in the ATP7A gene; one deletion was caused by an A-to-G transition at the -4 position of the splice acceptor site 5-prime of the skipped exon, and the other deletion was caused by a G-to-A transition at the +5 splice donor site following the skipped exon. The first patient had presented to a genetics clinic at the age of 14 years for evaluation of musculoskeletal abnormalities and recurrent bladder rupture. In the neonatal period, mild hypotonia and, on radiographs, cranial contour abnormalities and wormian bones had been observed. There had been numerous orthopedic interventions, including osteotomies for leg straightening and treatment for multiple compression fractures of the vertebrae. Recurrent bladder rupture, bladder diverticula, vesicular calcium stones, and atonic bladder required intermittent catheterization. Examination showed dolichocephaly, prominent and simple ears, downslanting palpebral fissures with bilateral ptosis, dental crowding, pectus carinatum, cutis laxa, and muscle wasting. Neurologic status, including cognition, was normal. Serum ceruloplasmin was slightly low. Radiographs demonstrated osteopenia, dislocated radial heads, and characteristic occipital horns. Radiocopper accumulation in fibroblasts was elevated. The second patient presented to a medical genetics clinic at the age of 15 years, at which time he was wheelchair-bound because of genu valgum and coxa vara deformities. He was mentally retarded. The skin had a cobblestone appearance with hyperelasticity at the elbows and without skin friability. There was laxity of the interphalangeal joints with contractures at the elbows and knees. Serum ceruloplasmin and copper determinations were normal. Radiographs showed bilateral occipital horns. The large diverticula of the bladder were demonstrated. X-rays of the skeleton showed osteoporosis, fusion anomalies in the wrist, and dysplasia of the radius and ulna, with dislocation of the radius at the elbow.

That the occipital horn syndrome has ramifications beyond connective tissue is suggested by peculiarities of personality. Unlike patients with Menkes disease, most patients with OHS have mild mental retardation. Wakai et al. (1993) described the first Japanese case in a 34-year-old man who had psychomotor retardation and seizures since early childhood. At the time of study, he had severe mental retardation and generalized muscular atrophy, in addition to characteristic facial features, hyperelasticity of the skin, and joint subluxation. Laboratory studies demonstrated low serum copper and ceruloplasmin levels as well as intestinal nonabsorption of copper. Radiographic studies showed occipital exostoses, bladder diverticula, tortuosity of peripheral veins, and osteoporosis. Lysyl oxidase activity was decreased in skin.

Tsukahara et al. (1994) described OHS in an 18-year-old Japanese boy. In addition to bilateral occipital exostosis, radiologic features were prominent mandibular angles, short and broad clavicles with 'hammer-shaped' distal ends, long bones with thin and undercalcified cortices, coalescence between the hamate and capitate bones and between the greater and lesser multiangular bones, and coxa valga. Since birth the patient had had chronic diarrhea (5-10 times/day) that did not respond to antidiarrheal drugs. Tsukahara et al. (1994) found reports of a total of 21 patients, all male. Mild manifestations were described in some of the mothers or aunts of patients (Herman et al., 1992).

In a study of cultured cells from patients with EDS IX, Kuivaniemi et al. (1985) could not demonstrate that there was secreted into the medium or contained in the cell any significant amounts of copper-deficient, catalytically inactive lysyl oxidase protein. Although the rapid degradation of a mutant protein could not be excluded, the authors favored the idea that synthesis of the lysyl oxidase protein is impaired. Levinson et al. (1993) found a marked reduction in expression of a copper-transporting ATPase gene, which Vulpe et al. (1993) had designated Mc1 and proposed as a candidate gene for Menkes disease, in Northern blots of RNA extracted from fibroblasts of 2 unrelated males with X-linked cutis laxa.

Blackston et al. (1987) studied copper storage and copper retention in females at risk of being heterozygous. In the mother of an affected male, they found in skin fibroblasts a level of total copper and a value for retention of copper that were outside the normal. The findings in a sister of the proband indicated that she was homozygous normal.

Khakoo et al. (1997) reported 2 phenotypically similar patients with primary cutis laxa associated with deficiency of lysyl oxidase. Previous reports of congenital cutis laxa had concerned mainly the X-linked form of the disorder, which is characterized by typical occipital osseous projections and an abnormality of copper metabolism. The 2 patients reported by Khakoo et al. (1997) showed no occipital projections and had normal copper metabolism. Furthermore, they showed wormian bones, and the family pattern of inheritance was thought to be consistent with an autosomal recessive disorder. The first boy, 15 years old at the time of report, was born with unusually translucent wrinkled skin with prominent veins, generalized joint laxity, and a hooked nose. A large umbilical hernia was repaired at 3 months of age. Lysyl oxidase deficiency was demonstrated by study of cultured fibroblasts. Lax skin, generalized joint laxity, and blue sclerae were consistently noted. The ears were large with prominent lobes. At the age of 10, the skin had become thicker without residual translucency. Wormian bones were demonstrated in the lambdoid sutures and osteoporosis of the lumbar spine was found. The mother's lysyl oxidase levels were approximately half normal. The second boy was born to first-cousin parents of Pakistani origin. Again the skin was lax at birth and the nose hooked, the joints of the hands and feet were hypermobile, and wormian bones were demonstrated in the lambdoid sutures. There was an irreducible, translocated left hip. Lysyl oxidase activity was measured at 20% of normal. At 2 years of age, the patient developed acute renal failure, owing to a vesicoureteric obstruction causing gross bilateral hydroureters and hydronephrosis. Bladder atonicity was also present. The ears were large, and radiographs of the lumbar spine showed osteoporosis. Bilateral dislocatable shoulders were also present in this boy, who was 5 years old at the time of the report.

Tang et al. (2006) described 2 brothers with occipital horn syndrome. The proband had occipital horns bilaterally at age 4 years, short broad clavicles, broad and flat ilia, and dislocated radial heads. Both brothers had genu valgum; the proband required bilateral tibial osteotomies. Both brothers had coarse hair and hyperelastic skin but no dysmorphic facial features. The mother, who carried the mutation present in her sons, had had clubfoot requiring multiple surgeries as a young child. She had coarse hair and mild hyperextensibility of the metacarpophalangeal and interphalangeal joints, which was marked in her sons.

Molecular Genetics

Kaler et al. (1994) reported a 15-year-old male with OHS who had an A-to-G change at base 2642 of the MNK locus, predicting a neutral glycine for serine substitution at nucleotide 833. Actually, this mutation at the -2 exonic position of a splice donor site caused exon skipping and activation of a cryptic splice acceptor site (300011.0002). The authors suggested that maintenance of some normal splicing could explain the relatively mild phenotype of this patient.

In a patient with OHS, Levinson et al. (1996) identified a 98-bp deletion involving an upstream regulatory element of the MNK gene; see 300011.

Tang et al. (2006) described 2 brothers with occipital horn syndrome who had a missense mutation (N1304S; 300011.0013) that had 33% residual copper transport activity. Serum copper level was low, and ceruloplasmin was at the low end of normal.

Nomenclature

MacFarlane et al. (1980) suggested the designation Ehlers-Danlos syndrome type IX. It was suggested at a workshop convened in Berlin by Beighton (1986) that this disorder be removed from the Ehlers-Danlos category (with the EDS IX number retired, as with MPS V and clotting factor IV) and instead be placed in a category of disorders with secondary changes in connective tissue due to a defect in copper metabolism.