Childs Nerv Syst. 2011 Oct 29;
Rivero-Garvía M, Marquez-Rivas J, Rueda-Torres AB, Ollero-Ortiz A

AIMS: Endoscopy-assisted treatment of craniosynostosis constitutes a novel modality for management of complex craniosynostoses. In this work, the authors aimed to assess the safety and advantages of performing these techniques in patients under 4 months of age. PATIENTS AND METHODS: Our study group comprised patients aged 4 months or younger with multiple-suture craniosynostosis undergoing endoscopy-assisted cranial remodeling. RESULTS: Between March 2007 and June 2011, we treated seven patients with combined affected sutures, five with unclassified nonsyndromic craniosynostosis, one with Muenke's and another with Crouzon's syndromes. One child with a cloverleaf skull had a family history of craniosynostosis. Mean age at diagnosis was 35.3 days (1-90 days). The most frequent combinations of involved sutures were sagittal and bicoronal suture (n = 3) and bilateral coronal suture (n = 3). Mean age at treatment was 62.8 days (13-109 days). Blood transfusion was required in only two patients. The mean length of hospital stay was 2.3 days (2-4 days). Mean follow-up period was 20.14 months (7-46 months). No patient presented ventriculomegaly or Chiari I malformation in follow-up studies, and only one showed a vertical disposition of the posterior fossa. No patient presented complications related to the procedures. A good result (Barlett I) was observed at 3- and 6-month follow-up visits. Four patients followed up for more than 1 year did not develop craniolacunae. CONCLUSION: Endoscopy-assisted surgery for correction of craniosynostosis in children under 4 months represents a valid and safe management option. Early treatment may contribute to prevent the development of associated ventriculomegaly and Chiari I malformation.

S D Med. 2011 Apr; 64(4): 125-7
Moes JA, Boyle JG, Flanagan JD, Mroch AR, Stein QP

Standard two-dimensional ultrasound has been used to aid prenatal visualization and detection of anomalies for the past 60 years. Three-dimensional ultrasound, introduced in the 1980s, provides the additional capability of examining the in utero environment from a variety of different angles. Use of this technology in conjunction with standard two-dimensional ultrasound can lead to a more thorough evaluation of structural defects and a greater patient understanding of genetic conditions.

Hum Mutat. 2011 Apr; 32(4): E2069-78
Jenkins D, Baynam G, De Catte L, Elcioglu N, Gabbett MT, Hudgins L, Hurst JA, Jehee FS, Oley C, Wilkie AO

Carpenter syndrome, a rare autosomal recessive disorder characterized by a combination of craniosynostosis, polysyndactyly, obesity, and other congenital malformations, is caused by mutations in RAB23, encoding a member of the Rab-family of small GTPases. In 15 out of 16 families previously reported, the disease was caused by homozygosity for truncating mutations, and currently only a single missense mutation has been identified in a compound heterozygote. Here, we describe a further 8 independent families comprising 10 affected individuals with Carpenter syndrome, who were positive for mutations in RAB23. We report the first homozygous missense mutation and in-frame deletion, highlighting key residues for RAB23 function, as well as the first splice-site mutation. Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys. High birth weight was not evident in the current group of patients, but further evidence for laterality defects is reported. No genotype-phenotype correlations are apparent. We provide experimental evidence that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in the pathogenesis of many RAB23 mutations. These observations refine the phenotypic spectrum of Carpenter syndrome and offer new insights into molecular pathogenesis.

J Craniofac Surg. 2011 Mar; 22(2): 571-5
de Jong T, Mathijssen IM, Hoogeboom AJ

In about 30% of the patients with syndromal craniosynostosis, a genetic mutation can be traced. For the purpose of adequate genetic counseling and treatment of these patients, the full spectrum of clinical findings for each specific mutation needs to be appreciated. The Pro250Arg mutation in the FGFR3 gene is found in patients with Muenke syndrome and is one of the most frequently encountered mutations in craniosynostosis syndromes. A number of studies on the relationship between genotype and phenotype concerning this specific mutation have been published. Two Dutch families with Muenke syndrome were screened for the reported characteristics of this syndrome and for additional features. New phenotypical findings were hypoplasia of the frontal sinus, ptosis of the upper eyelids, dysplastic elbow joints with restricted elbow motion, and mild cutaneous syndactyly. Incidentally, polydactyly, severe ankylosis of the elbow, fusion of cervical vertebrae, and epilepsy were found. Upper eyelid ptosis is thought to be pathognomonic for Saethre-Chotzen syndrome but was also observed in our series of patients with Muenke syndrome. Because Muenke and Saethre-Chotzen syndrome can have similar phenotypes, DNA analysis is needed to distinguish between these syndromes, even when a syndrome diagnosis is already made in a family member.

Gan To Kagaku Ryoho. 2010 Dec; 37 Suppl 2: 215-7
Ogasawara Y

A home pediatric patient with artificial respirator has little chance to go out. The primary reasons are as follows: (1) Lack of experience in controlling the situation by the family when artificial respirator related troubles occur. (2) Whenever the patient wants to go out, no caregiver is available for assistance. (3) Going-out is just a psychological burden for the patient and family. (4) Availability of receiving institutions for a patient who needs an emergency care. Hence, a caregiver should improve not only the patient's ADL but also establishes a system that provides a satisfactory care for the patient and family. In doing so, the caregiver's role is important more than ever.

Plast Reconstr Surg. 2011 Mar; 127(3): 1163-72
Cray J, Burrows AM, Vecchione L, Caccamese JF, Losee JE, Moursi AM, Siegel MI, Cooper GM, Mooney MP

Craniosynostosis is defined as the premature fusion of one or more cranial sutures. Bone morphogenetic proteins (BMPs), regulators of ossification, have been implicated in premature suture fusion. Noggin, an extracellular BMP inhibitor, has been shown experimentally to inhibit resynostosis following surgery. The present study was designed to test the hypothesis that BMP inhibition using noggin therapy may rescue sutures destined to fuse by inhibiting initial ossification.Twenty-six, 10-day old rabbits with familial, delayed-onset, coronal suture synostosis were randomly divided into three groups: (1) the sham surgical control group, (2) the bovine serum albumin-treated group [10 μg/suture (protein/vehicle controls)], and (3) the noggin therapy group (10 μg/suture; experimental group). Sutural growth was monitored by radiopaque markers implanted at 10 days of age. At 25 days, the bovine serum albumin or noggin was combined with a slow-resorbing collagen vehicle and injected subperiosteally above the coronal suture. Somatic and sutural growth data were collected at 10, 25, 42, and 84 days of age. Coronal sutures were harvested at 84 days to histologically assess fusion.Results showed no significant (p > 0.05) differences in suture separation at any age. Suture fusion assessed by histomorphology did not differ among the three groups. Although previous data showed noggin to inhibit postoperative resynostosis in this craniosynostotic rabbit model, here there was no effect on initial suture fusion.These results suggest that in this rabbit model of craniosynostosis, BMPs do not play a role in the pathogenesis of craniosynostosis and only play a role in postoperative bony wound healing.

Eur J Hum Genet. 2011 Jul; 19(7): 757-62
Hurst JA, Jenkins D, Vasudevan PC, Kirchhoff M, Skovby F, Rieubland C, Gallati S, Rittinger O, Kroisel PM, Johnson D, Biesecker LG, Wilkie AO

Greig cephalopolysyndactyly syndrome (GCPS) is a multiple congenital malformation characterised by limb and craniofacial anomalies, caused by heterozygous mutation or deletion of GLI3. We report four boys and a girl who were presented with trigonocephaly due to metopic synostosis, in association with pre- and post-axial polydactyly and cutaneous syndactyly of hands and feet. Two cases had additional sagittal synostosis. None had a family history of similar features. In all five children, the diagnosis of GCPS was confirmed by molecular analysis of GLI3 (two had intragenic mutations and three had complete gene deletions detected on array comparative genomic hybridisation), thus highlighting the importance of trigonocephaly or overt metopic or sagittal synostosis as a distinct presenting feature of GCPS. These observations confirm and extend a recently proposed association of intragenic GLI3 mutations with metopic synostosis; moreover, the three individuals with complete deletion of GLI3 were previously considered to have Carpenter syndrome, highlighting an important source of diagnostic confusion.

J Med Assoc Thai. 2010 Oct; 93 Suppl 4: S24-33
Thanapaisal C, Chowchuen B, Chowchuen P

Craniofacial surgery for craniosynostosis is one of the most challenging reconstructive procedures. Restoration of particular functional and anatomic requirements is important for development from infancy to adulthood. The purpose of this study is to present the authors' experience of craniofacial surgery for management of patients with craniosynostosis in Srinagarind Hospital, Khon Kaen, Thailand, addressing the challenges of diagnosis, management and outcomes, which may be adapted in other developing countries.This paper presents the cranial and associated deformities, diagnosis, radiologic findings, preoperative evaluation, craniofacial and maxillary surgeries and outcome(s) of patients with craniosynostosis. The care team, made up of neurosurgeons, plastic surgeons, radiologists, ophthalmologists and pediatricians, established the Tawanchai Center's protocol for craniosynostosis, to manage the timing of craniofacial procedures from infancy to adulthood.The physical examination and radiologic findings of three patients, two with sagittal synostosis and one with plagiocephaly are reported. The clinical, craniofacial and maxillofacial surgeries and long-term outcomes of another three patients were studied one with Apert syndrome and two with Crouzon syndrome. All the latter three patients were lost to follow-up after the initial post-surgical visit. At that time, there were appropriate surgical results vis-a-vis appearance and satisfaction from the perspective of the two patients with Crouzon syndrome and their families. One of the patients with Crouzon syndrome received normal education supported by a successful family, while the other was still continuing her studies at school with good progress. The patient with Apert syndrome continued to live with his parents. Additional reconstructive surgery is recommended for all three patients. Economic problems and lack of adequate information were the main reasons for their discontinuing follow-up appointments.Systematic physical examination and radiologic assessments by the craniofacial team are critically important for diagnosis, evaluation, planning of management and outcome assessment of the patients with craniosynostosis. In Thailand and other developing countries, the challenges in management of these patients are the development of standard craniofacial surgery, craniofacial team management and well-coordinated care, planned surgeries and outcome assessments from infancy to adolescence. A supportive government health system and establishment of a craniofacial center and foundation is needed in order to support and provide proper care for these groups of patients.

J Craniofac Surg. 2011 Jan; 22(1): 187-90
Ranger A, Chaudhary N, Rau J, Matir D, Goobie S

Muenke syndrome is a fibroblast growth factor receptor 3 (FGFR-3)-associated coronal craniosynostosis syndrome, which was first described in 1997.We report an infant girl who was born to a 29-year-old primapara at 38 weeks' gestation. When evaluated at 3 days old, physical examination revealed a high forehead with frontal bossing, upturned nose, arched palate, shallow midface structures, and heavily ridged coronal sutures bilaterally. Clinically, the infant seemed to be neurologically normal. Skull radiographs and computed tomography confirmed the presence of bilateral coronal synostosis, with patency of all other sutures. Family history was remarkable, in that the infant's father, paternal grandmother, and a paternal cousin demonstrated subtle craniofacial features, which had not been previously identified. Mutation analysis of FGFR-3 revealed a missense mutation in exon 6, c.749 C>G, with a resultant amino acid change from proline to arginine at codon 250 (P250R), in keeping with Muenke syndrome (Am J Hum Genet 1997;60:555-564). The mutation was subsequently identified in her father, suggesting variable expression in this family, as he had only mild midfacial flattening. At 9 months of age, our patient underwent anterior cranial expansion, correction of orbital hypertelorism, intracranial orbital osteotomies, and advancement of the frontal bandeau. She tolerated the procedure well and has done well postoperatively.We report the case of an infant with Muenke syndrome, with evidence of variable expressivity within the paternal family. The pertinent literature, in which only 2 prior Canadian cases were identified, is reviewed.

Am J Hum Genet. 2011 Jan 7; 88(1): 70-5
Klopocki E, Lohan S, Brancati F, Koll R, Brehm A, Seemann P, Dathe K, Stricker S, Hecht J, Bosse K, Betz RC, Garaci FG, Dallapiccola B, Jain M, Muenke M, Ng VC, Chan W, Chan D, Mundlos S

Indian hedgehog (IHH) is a secreted signaling molecule of the hedgehog family known to play important roles in the regulation of chondrocyte differentiation, cortical bone formation, and the development of joints. Here, we describe that copy-number variations of the IHH locus involving conserved noncoding elements (CNEs) are associated with syndactyly and craniosynostosis. These CNEs are able to drive reporter gene expression in a pattern highly similar to wild-type Ihh expression. We postulate that the observed duplications lead to a misexpression and/or overexpression of IHH and by this affect the complex regulatory signaling network during digit and skull development.

Am J Med Genet A. 2010 Dec; 152A(12): 3007-15
Melville H, Wang Y, Taub PJ, Jabs EW

Craniosynostosis, the premature fusion of one or more cranial sutures, is a common malformation of the skull that can result in facial deformity and increased intracranial pressure. Syndromic craniosynostosis is present in ∼15% of craniosynostosis patients and often is clinically diagnosed by neurocranial phenotype as well as various other skeletal abnormalities. The most common genetic mutations identified in syndromic craniosynostosis involve the fibroblast growth factor receptor (FGFR) family with other mutations occurring in genes for transcription factors TWIST, MSX2, and GLI3, and other proteins EFNB1, RAB23, RECQL4, and POR, presumed to be involved either upstream or downstream of the FGFR signaling pathway. Both syndromic and nonsyndromic craniosynostosis patients require early diagnosis and intervention. The premature suture fusion can impose pressure on the growing brain and cause continued abnormal postnatal craniofacial development. Currently, treatment options for craniosynostosis are almost exclusively surgical. Serious complications can occur in infants requiring either open or endoscopic repair and therefore the development of nonsurgical techniques is highly desirable although arguably difficult to design and implement. Genetic studies of aberrant signaling caused by mutations underlying craniosynostosis in in vitro calvarial culture and in vivo animal model systems have provided promising targets in designing genetic and pharmacologic strategies for systemic or adjuvant nonsurgical treatment. Here we will review the current literature and provide insights to future possibilities and limitations of therapeutic applications.

Cell Mol Life Sci. 2011 Mar; 68(6): 951-64
Trueb B

FGFRL1 (fibroblast growth factor receptor like 1) is the most recently discovered member of the FGFR family. It contains three extracellular Ig-like domains similar to the classical FGFRs, but it lacks the protein tyrosine kinase domain and instead contains a short intracellular tail with a peculiar histidine-rich motif. The gene for FGFRL1 is found in all metazoans from sea anemone to mammals. FGFRL1 binds to FGF ligands and heparin with high affinity. It exerts a negative effect on cell proliferation, but a positive effect on cell differentiation. Mice with a targeted deletion of the Fgfrl1 gene die perinatally due to alterations in their diaphragm. These mice also show bilateral kidney agenesis, suggesting an essential role for Fgfrl1 in kidney development. A human patient with a frameshift mutation exhibits craniosynostosis, arguing for an additional role of FGFRL1 during bone formation. FGFRL1 contributes to the complexity of the FGF signaling system.