Strengthening molecular genetics and training in craniosynostosis: The need of the hour

Investigations

(1) Skull radiograph, (2) 3D CAT SCAN, (3) funduscopy examination, (4) psychological tests, (5) molecular tests, (6) clinical photographs, (7) family history, (8) essential additional information from second degree relatives of father and mother, (9) measurement of skull diagram, (10) anthropometric analysis, (11) dental evaluation, (12) IQ test, and (13) coginitive, speech test and (14) behavioral analysis should be done.

Antenatal diagnosis

Prenatal testing is available for high risk pregnancies if a molecular defect has been identified in the family (such as an earlier affected child or an affected parent). Fetal DNA obtained through chorionic villous sampling (CVS) at about 10-12 weeks of gestation (preferably) or amniocentesis at 16-18 weeks of gestation can be analyzed for the known disease causing mutation. In a pregnancy not previously identified to be at risk for CS in which an abnormal skull shape is detected on prenatal ultrasound examination, prenatal testing is often not possible, unless other findings indicate a well-known syndrome form such as the limb anomalies in Apert syndrome.

Low risk craniosynostosis

A vast majority of patients do not have neurologic complications or mental retardation. Most patients present with either cosmetic deformity or sociopsychological problems.[7]

Intermediate risk craniosynostosis

This group of CS may be treated surgically by removing the affected sutures. These are complex procedures that require extensive planning and CT scan with three-dimensional reconstruction and a team of physicians including neurosurgeons and anesthesiologists. Correction is usually performed in the first year of life for intermediate risk CS patients.[8]

High risk craniosynostosis

Untreated CS at time of diagnosis usually require extensive investigation including are X-ray skull, funduscopy, size of skull, SPECT/CT or the cognitive and language development and IQ tests. There may be a greater developmental risk for infants with a single suture CS then? Those secondary to (1) Primary microcephaly, (2) hydrocephalus, (3) postural plagiocephaly. Recently we observed that advanced paternal age and higher parental education level are also associated with CS.[9]

Surgical therapy

No medical treatment exists to stop early ossification of a cranial suture. Reasons to perform surgical interventions can be increased intracranial pressure (ICP), decrease of skull growth below third centile, facial deformity (which can give cosmetic reasons for interventions), and (rarely) progressive exophthalmoses threatening the eyes. Not all children with a CS need surgical interventions. The results are best when surgery is performed between the age of 4 and 8 months at an early stage of although there may be reasons to postpone surgery till a later age.[10] Infants with a CS may require a series of surgical procedures.[1112] Procedures for correction of CS are performed in young infants with a small blood volume (SBV) yet represent major surgery with extensive blood loss (EBL).[1314]

Induction therapy

Pre-treatment with erythropoietin and iron combined with acute preoperative normovolaemic hemodilution (APNH) could decrease homologous blood transfusion during surgery in CS patients.[15] Ringers lactate (RL) solutions and normal (0.9%) saline (NS) are also useful because the surgery requires large amount of intravenous fluid replacement, which alter the ionic composition of body compartments.[16]

Molecular therapy

Bone morphometric proteins (BMP) are part of the transforming growth factor β (TGF-β) super family and are originally found to induce bone and cartilage formation.[17] This large group of proteins, comprising nearly one third of the TGF-β superfamily, has also been found to be involved in mesoderm induction, skeletal patterning, and limb development.[18] Immunohistological analysis of embryonic mouse sagittal sutures revealed expression of BMP-2 and BMP-4 at the osteogenic fronts, and BMP-4 in suture mesenchyme and osteogenic fronts of both fusing and patent sutures.[19] Novel tissue engineering techniques may allow the design of targeted complementary therapies to decrease the complications inherent in high-risk surgical procedures. Recent development in this filed include identifying genetic mutations, formulating etiopathogenesis of various craniosynostotic conditions, understanding cranial suture biology and molecular biochemical pathways involved in suture fusion and the design, development and application of various vehicles and tissue engineered constructs to deliver cytokines and genes to cranial sutures. (Many of genes involved in syndromic forms of (CS are shown in Table 1).

Table 1 Mutation detected in craniosynostosis patients

We find out novel and innovative mutation including with non-syndromic craniosynostosis (NSC), FGFR2iiia, FGFR2iiib, FGFRiiic has been given 80% (120). However, FGFR1, FGFR3 has observed lesser correlation with NSC. Hence, we found that FGFR2 gene and its isomers FGFR2iiia, FGFR2iiic genes are helpful for prognostic marker and 99m Tc ECD SPECT/CT test as a diagnostic marker as the gold standard for CS. Hence, biologically based therapies maybe used as surgical adjuncts to rescue fusing sutures or help to manage postoperative resynostosis.[20]

Genetic counseling

For adequate genetic counseling, it is important to make a distinction between isolated and syndromic forms of CS. Adequate evaluation for additional symptoms has to be performed in each child with CS. Autosomal dominant inheritance is the most common inheritance pattern of most syndromic forms of CS.[1920] The percentage of patients showing spontaneous new mutation is high. However, germ line mosaicism is also known to occur and should be discussed with the family. Human genetics is now at a critical juncture. The molecular methods used successfully to identify the genes underlying rare Mendelian principle are failing to find the numerous genes causing more common, familial non-Mendelian disease. The human genome project opened new avenues to identify unknown biological process in human disease like CS. This massive and multifactorial data generated by the present high-through put omics assays and explore the utility of system biology approaches in this subject.[21] New opportunities are being presented for unraveling the complex genetic basis at non-Mendelian disorders based on large-scale genome-wide studies.[22] Usually non-Mendelian pattern of inheritance can be identified in non-syndromic forms of CS, although rarely the isolated CS is familial, following an autosomal dominant pattern of inheritance with reduced penetrance. The recurrence risk in such cases is dependent on the nature of the suture involved.