Occipital horn syndrome (OHS), formerly considered a variant of Ehlers–Danlos syndrome, is an

X-linked recessive X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...

mitochondrial and

connective tissue disorder A connective tissue disease (collagenosis) is any disease that has the connective tissues of the body as a target of pathology. Connective tissue is any type of biological tissue with an extensive extracellular matrix that supports, binds togeth ...

. It is caused by a deficiency in the transport of the essential mineral

copper Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...

, associated with mutations in the ATP7A gene. Only about 2/3 of children with OHS are thought to have genetically inherited the disorder; the other 1/3 do not have the disease in their family history. Since the disorder is X-linked recessive the disease affects more males. This is because they do not have a second X chromosome, unlike females, so essentially are lacking the 'backup' copy with proper function. Females are much more likely to be carriers only. For a female to be affected they must carry two defective X chromosomes, not just one.Horn Syndrome
, 9 August 2004. The disorder is considered a milder variant of

Menkes disease Menkes disease (MNK), also known as Menkes syndrome, is an X-linked recessive disorder caused by mutations in genes coding for the copper-transport protein ATP7A, leading to copper deficiency. Characteristic findings include kinky hair, growth ...

Signs and symptoms

It is characterized by a deficiency in biliary

excretion that causes deformations in the skeleton. These include projections on the back of the

skull The skull is a bone protective cavity for the brain. The skull is composed of four types of bone i.e., cranial bones, facial bones, ear ossicles and hyoid bone. However two parts are more prominent: the cranium and the mandible. In humans, th ...

(parasagittal bone exostoses arising from the occipital bone—the so-called "occipital horns") as well as deformities of the

elbow The elbow is the region between the arm and the forearm that surrounds the elbow joint. The elbow includes prominent landmarks such as the olecranon, the cubital fossa (also called the chelidon, or the elbow pit), and the lateral and the me ...

, radial head dislocation, hammer-shaped lateral ends of the

clavicle The clavicle, or collarbone, is a slender, S-shaped long bone approximately 6 inches (15 cm) long that serves as a strut between the shoulder blade and the sternum (breastbone). There are two clavicles, one on the left and one on the r ...

s, and abnormalities of the hips and pelvis. OHS presents in early to middle childhood. Children may present with features such as:

Causes

OHS is a milder allelic variant of Menkes disease, having a later age of onset and being associated with far less severe central neurodegeneration. The milder nature of OHS is often attributable to ‘leaky’ splice junction mutations that allow 20–30% of ATP7A messenger RNA (mRNA) transcripts to be correctly processed. As in cases of Menkes disease, individuals with OHS manifest connective tissue abnormalities resulting from deficient activity of lysyl oxidase, a copper-requiring enzyme that normally deaminates lysine and hydroxylysine in the first step of collagen crosslink formation. Such individuals also often endure inconvenient dysautonomic signs and symptoms related to a partial deficiency in dopamine-β-hydroxylase (DBH) activity. DBH, another copper-dependent enzyme, normally converts dopamine to norepinephrine, a crucial neurotransmitter in norepinephrinergic neurons. A natural mouse model of OHS, the so-called mottled blotchy model, recapitulates the connective tissue abnormalities, DBH deficiency and mild CNS damage seen in humans.

Diagnosis

The initial diagnosis of Menkes disease (MD) and its milder variants such as Occipital Horn Syndrome is based on the clinical symptoms. Low serum copper and ceruloplasmin levels support the clinical suspicion of OHS, but biochemical confirmation in tissue culture is needed. The ultimate diagnostic proof is the demonstration of a molecular defect in ATP7A. Demonstration of the bony protuberances on the occiput will clinch the diagnosis, and these can be palpated in some patients.

Treatment

Courses of treatment for children with OHS is dependent upon the severity of their case. Children with OHS often receive physical and occupational therapy. They may require a feeding tube to supplement nourishment if they are not growing enough. In an attempt to improve the neurological condition (seizures) copper histidine or copper chloride injections can be given early in the child's life. However, copper histidine injections have been shown ineffective for treating the connective tissue manifestations of OHS.

Prognosis

The long term natural history of OHS is not known. Some patients have died suddenly as young as 17 years of age, whereas one patient has survived to age 57. Causes of death include respiratory failure, aortic aneurysm, and intracranial hemorrhage.

Research

The NIH and Cyprium Therapeutics are coordinating the joint-development of an Adeno-Associated virus gene therapy named AAV-ATP7A, for Menkes disease and its milder variants such as Occipital Horn Syndrome. In March 2017, Cyprium Therapeutics acquired the World-Wide development and commercial rights to the Menkes program at NIH/NICHD through CRADA and licensing agreements with NICHD. AAV-ATP7A is still in pre-clinical stage, although it has received orphan drug designation from the FDA.

References

External links

GeneReviews/NCBI/NIH/UW entry on ATP7A-Related Copper Transport Disorders
* {{Inborn errors of metal metabolism X-linked recessive disorders Rare syndromes Copper in health Inborn errors of metal metabolism Abnormalities of dermal fibrous and elastic tissue