Acrania is a rare congenital disorder that occurs in the human fetus in which the flat bones in the cranial vault are either completely or partially absent. The cerebral hemispheres develop completely but abnormally. The condition is frequently, though not always, associated with anencephaly. The fetus is said to have acrania if it meets the following criteria: the fetus should have a perfectly normal facial bone, a normal cervical column but without the fetal skull and a volume of brain tissue equivalent to at least one-third of the normal brain size. Causes
Genetics
There are no known family ties in acrania and recurrence rates are extremely low. Not much is known about the exact mechanism involved in acrania. It is hypothesized that, like other developmental malformations, there are multiple origins for acrania.Recent work has identified mutations in the hedgehog acyltransferase (HHAT) gene that have caused acrania along with holoprosencephaly and agnathia. The mutation in HHAT which causes this disease is a loss-of-function mutation. Before this discovery in 2010, HHAT was known to play a role in the sonic hedgehog pathway. When HHAT contains a loss-of-function mutation, less HHAT protein is produced. HHAT is necessary for the production of Hedgehog (Hh) proteins post-transcriptionally. As HHAT production decreases, production of long-range Hh proteins decreases proportionally. Decreases in Hh| production disturb the production of extracellular signal-regulated kinases, bone morphogenetic proteins, and fibroblast growth factors, all of which play important roles in craniofacial patterning.
These are major components of bone development, and the low function of each leads to the weak bones that characterize HCS. Diagnosis
One of the main methods of pinpointing a NOTCH2 mutation that leads to HCS is through whole genome sequencing. This is then followed by exome capture by means of in-solution hybridization. The exome part of the genome consists of exons. Parallel sequencing follows the hybridization, which results in about 3.5 Gb of sequence data. These sequence data are then analyzed. Through sequence analysis and symptom presentation in HCS patients, this proves to be the most definitive method of diagnosis. Types
Laboratory testing reveals multiple mutations of HCS. Two genetic variants result in sporadic HCS symptoms, which are HCS-02 and HCS-03. These mutations produce symptoms that come and go, but have been present de novo. HCS-03 was identified as the variant that is passed through affected family members and presents symptoms throughout the lifetime of the individual. All variants of HCS lead to the same premature termination of PEST sequences which compromise normal function of NOTCH2. NOTCH has four different receptors, which have an affinity for similar ligands. They are classified as single-pass transmembrane receptors. Treatment
Since about 2002, some patients with this disorder have been offered drug therapy with bisphosphonates (a class of osteoporosis drugs) to treat problems with bone resorption associated with the bone breakdown and skeletal malformations that characterize this disorder. Brand names include Actonel (risedronate/alendronate), made by Merck Pharmaceuticals. Other drugs include Pamidronate, made by Novartis and Strontium Ranelate, made by Eli Lilly.