Craniofacial Dyssynostosis With Short Stature

Clinical Features

In 2 sisters and 5 unrelated patients, Neuhauser et al. (1976) described a 'new' type of craniosynostosis-craniofacial dysostosis with short stature. Premature closure of the lambdoid and posterior part of the sagittal sutures caused a posteriorly narrow, dolichocephalic skull with small, flat, or bulging occiput and protuberance of the forehead. The disturbance of growth of basal skull structures led to craniofacial dysostosis and secondarily to facial anomalies. The sisters and 2 of the others patients were of Spanish, Mexican, or Puerto Rican ancestry. Mental retardation occurred when surgery was not done. In 3 cases, craniosynostectomy permitted normal development.

Al-Torki et al. (1998) described an Arab boy with craniofacial dyssynostosis. They suggested that cryptorchidism may be part of the syndrome and that the presence of normal stature does not preclude the diagnosis.

Morton (1998) described an English boy thought to have the same disorder. He had lambdoid craniosynostosis, severe global developmental delay, epilepsy, oculomotor dyspraxia, very thin corpus callosum, and minor anomalies. MRI scan showed thinning of the gray matter on the right side and nodular gray matter heterotopia in both cerebral hemispheres consistent with a neuronal migration defect.

Grosso et al. (2004) described a patient who, in addition to having craniofacial dyssynostosis, had hydronephrosis and partially empty sella turcica. Brain MRI showed agenesis of the splenium and posterior portion of the corpus callosum.

Bermejo et al. (2005) described 4 unrelated Spanish patients with craniofacial dyssynostosis and reviewed previously reported cases. Because of phenotypic variability of reported cases, they recommended that additional studies (ophthalmologic, cardiologic, and renal) be performed to rule out associated anomalies.

Hing et al. (2009) described 11 patients (3 female; 8 male) with bilateral lambdoid and sagittal synostosis (BLSS); 5 of the patients were Hispanic/Latino. None of the patients reported a family history of craniosynostosis or consanguinity. All patients had brachyturricephaly, frontal bossing, sagittal/lambdoid sutural ridging, and inferior displacement of the ears. Development was normal in 8 patients (73%), only 1 patient was noted to have an associated malformation (a ventricular septal defect), and all demonstrated normal linear growth. Characteristic CT findings included posterior displacement of the coronal sutures, brachycephaly with a narrow pointed occiput, lambdoid, sagittal suture fusion, and the concave occipital bone deformity.

Cytogenetics

Shiihara et al. (2004) described a 2-year-old girl with craniosynostosis with early closure of the sagittal and lambdoid sutures, atrial septal defect, patent ductus arteriosus, and a karyotype showing 46,XX,der(13)t(5;13)(q33.3;q34). FISH analysis demonstrated 3 copies of the MSX2 gene. Shiihara et al. (2004) suggested that the patient's clinical findings were explained by either partial 13q deletion or partial 5q trisomy, or both, and that the overdose of MSX2 is related to her craniosynostosis through the MSX2-mediated pathway of calvarial osteogenic differentiation.

Tagariello et al. (2006) described a male infant presenting with brachycephaly, proptosis, midfacial hypoplasia, and low-set ears. Three-dimensional cranial computer tomography showed fusion of the lambdoid sutures and distal part of the sagittal suture with a gaping anterior fontanel. Mutations in the coding sequence of FGFR2 and FGFR3 were excluded, and the P252R mutation in FGFR1 (136350.0001) was also excluded. Standard chromosome analysis revealed a de novo balanced translocation t(9;11)(q33;p15). The breakpoint on chromosome 11p15 disrupted SOX6. The breakpoint on chromosome 9 was located in a region with no known or predicted genes. Tagariello et al. (2006) suggested that the translocation may lead to dysregulation of flanking genes on chromosome 9 or 11 involved in skull vault development and the possible function of SOX6, TLR4, and CALCA in cranial suture biology.

Hing et al. (2009) performed chromosome analysis in 5 patients with BLSS and found that 1 had an Xp11.22 deletion. Because of the significant number of unique chromosomal aberrations that have been detected in this disorder, Hing et al. (2009) suggested that the disorder is heterogeneous.

Inheritance

Although autosomal recessive inheritance had been suggested based on the 2 sisters reported by Neuhauser et al. (1976), Bermejo et al. (2005) noted that parental consanguinity was not present in any of the cases.

Clinical Management

Bermejo et al. (2005) recommended early neurologic evaluation to plan early interventions to avoid the consequences of craniosynostosis.

Molecular Genetics

After identifying a translocation disrupting the SOX6 gene in a patient with craniofacial dyssynostosis, Tagariello et al. (2006) performed a mutation screen of the gene in 104 craniosynostosis patients. They identified 1 missense mutation leading to the exchange of a highly conserved amino acid (D68N) in a single patient with complex craniosynostosis involving the coronal and sagittal sutures; however, the same mutation was found in his healthy mother.

Hing et al. (2009) performed molecular analysis in 8 patients with BLSS; no mutations were identified at the FGFR1 P252 (136350.0001) or FGFR3 P250R (134934.0014) sites, in FGFR2 exons 7 and 9, or in TWIST1, MSX2, or SOX6 coding regions.