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Occipital horn syndrome
A rare congenital disorder of copper metabolism that is principally characterized by bony exostoses (including the pathognomonic occipital horns), and connective tissue manifestations with cutis laxa and bladder diverticula. Central nervous system involvement is variable.
ORPHA:198Classification level: Disorder
Occipital horn syndrome (OHS) is a very rare X-linked disease and the exact prevalence is unknown. To date approximately 35 cases have been reported and all but one were male.
Age of onset ranges from infancy to childhood. Observations at birth may include cephalhematoma (12% of cases), loose and wrinkled skin, and umbilical or inguinal hernias. About one third of all patients primarily present with central nervous system involvement (hypotonia, developmental delay and/or seizures). Initial clinical presentation may occur later with bladder diverticula or skeletal manifestations. Bladder diverticula affects the majority of patients (>80%) and may manifest through recurrent urinary tract infections or pollakisuria. The most typical skeletal manifestation (present in 96% of all patients) is an exostosis on the occiput at the insertion of the trapezoid muscle (occipital horn), but exostoses may also occur on the tibia and radius. Other, more variable, skeletal features are hammer-shaped claviculae, scoliosis, pectus deformity, coxa valga, genua valga as well as dislocations of the radial head. Less frequently reported skeletal manifestations include bowing of the long bones, mid-diaphyseal broadening, metaphyseal spurring, rounding of the iliac wings and, rarely, osteopenia. Facial features become distinctive with age and includes a long face (46%), large ears (38%), sagging cheeks (45%) and coarse hair (74%). Trichoscopy may show pili torti. The skin is often hyperextensible and soft with fine wrinkling on the hands and feet. Skin redundancy is remarkable on the belly. Vascular tortuosity is common in the intracranial arteries (65%), but may also affect the cervical, splenic and splanchnic circulation and imposes a risk for aneurysm formation. Aortic root dilatation and dissection may rarely occur. Dysautonomia with postural orthostatic hypotension, temperature instability and chronic diarrhea is present in most patients (>90%). About half of all patients show a delayed motor development due to muscle hypotonia and joint hypermobility, and may report unusual clumsiness. Distal motor neuropathy has been recorded in at least one patient. About half of all patients have intellectual disability (ID) which is usually mild, but moderate to severe impairment may occur.
OHS is due to pathogenic variants (missense, frameshift and splice variants) in the ATP7A gene (Xq21.1) encoding the copper-transport ATPase 1. OHS is allelic with Menkes disease; there are no clear genotype-phenotype correlations, nor a correlation between the type or location of the variant and serum copper levels. However, certain variants may lead to a partially functional protein or reduced amounts of an otherwise normal protein.
Diagnosis is based on clinical features. Radiography shows the characteristic occipital horns. Diagnosis is confirmed by identification of a pathogenic variant.
Menkes disease is the main differential diagnosis and allelic to OHS. Other conditions to be considered include other forms of cutis laxa, including autosomal dominant cutis laxa, and autosomal recessive cutis laxa type 1a and 1c, Ehlers-Danlos syndrome, dermatosparaxis type, and hereditary multiple exostoses.
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Transmission is X-linked recessive. Genetic counseling should be offered to couples where the mother is a carrier of a pathogenic variant, informing them that the risk for a male fetus to be affected is 50% at each pregnancy. The possibility of germ-line mosaicism should be discussed when counselling non-carrier mothers of singleton cases; although not yet described for OHS it has been described for Menkes disease.
Management and treatment
Treatment is symptomatic. No data exist on early parenteral copper-histidine supplementation. Notably, individuals with OHS are at increased risk for post-surgery apnea, and should benefit from prolonged post-surgery monitoring.
Prognosis is variable in OHS. Most patients reach adulthood. Risks for early demise include seizures, bladder rupture, vascular ruptures and postsurgical apnea. Inguinal hernia often recur after surgery.