As innate as admiring a new baby and congratulating the parents when we enter the room, our tendency as pediatricians to palpate the anterior fontanel when we meet an infant, the “pediatrician’s handshake,” is universal. Why do we do this?

Craniofacial microsomia (CFM) is a complex condition associated with microtia, mandibular hypoplasia, and preauricular tags. It is the second most common congenital facial condition treated in many craniofacial centers and requires longitudinal multidisciplinary patient care. The purpose of this article is to summarize current recommendations for clinical management and discuss opportunities to advance clinical research in CFM. © 2013 Wiley Periodicals, Inc.

Osteopathia striata congenita with cranial sclerosis (OSCS) is a skeletal dysplasia caused by germline deletions of or truncating point mutations in the X‐linked gene WTX (FAM123B, AMER1). Females present with longitudinal striations of sclerotic bone along the long axis of long bones and cranial sclerosis, with a high prevalence of cleft palate and hearing loss. Intellectual disability or neurodevelopmental delay is not observed in females with point mutations in WTX leading to OSCS. One female has been described with a deletion spanning multiple neighbouring genes suggesting that deletion of some neighbouring loci may result in abnormal neurodevelopment. In this cohort of 13 females with OSCS resulting from deletions of WTX, a relationship is observed where deletion of ARHGEF9 and/or MTMR8 in conjunction with WTX results in an additional neurodevelopmental phenotype whereas deletion of ASB12 along with WTX is associated with a good neurodevelopmental prognosis.

The syndromic craniosynostoses, usually involving multiple sutures, are hereditary forms of craniosynostosis associated with extracranial phenotypes such as limb, cardiac, CNS and tracheal malformations. The genetic etiology of syndromic craniosynostosis in humans is only partially understood. Syndromic synostosis has been found to be associated with mutations of the fibroblast growth factor receptor family (FGFR1, -R2, -R3), TWIST1, MSX2, and EFNB1. Apert, Pfeiffer, Crouzon, and Jackson-Weiss syndromes are due to gain-of-function mutations of FGFR2 in either the Ig II-III linker region (Apert) or Ig III domain. Loss of function mutations of TWIST1 and gain-of-function mutations of MSX2 lead to Saethre-Chotzen and Boston-type syndromes, respectively. The mutations in Pfeiffer (FGFR1), Muenke (FGFR3), and Apert syndrome (FGFR2) are caused by the same amino acid substitution in a highly conserved region of the Ig II-III linker region of these proteins, which suggests that these receptor tyrosine kinases have an overlapping function in suture biology. In this review we will discuss the historical descriptions, current phenotypes and molecular causes of the more common forms of syndromic craniosynostosis.

BACKGROUND Cleidocranial dysplasia (CCD) is an autosomal-dominant skeletal dysplasia syndrome that is characterized by widely patent calvarial sutures, clavicular hypoplasia, supernumerary teeth, and short stature. CCD is caused by mutations in the transcription factor RUNX2, which is known to function as a major regulator of bone differentiation. Despite the characterization of 67 unique mutations in 97 individual cases, and the availability of animal models, no obvious genotype-phenotype correlation has emerged. METHODS We describe 3 new cases that were ascertained on the basis of a severe calvarial phenotype, that were associated with 3 novel mutations in the C-terminal region of RUNX2 distal to the DNA-binding runt domain. In addition, a review of all previously described cases was undertaken in an effort to standardize mutation nomenclature, characterize the position of known mutations relative to the runt domain, and explore the hypothesis that C-terminal mutations that preserve the runt domain may lead to more-severe craniofacial phenotypes. RESULTS Upon mutational analysis of RUNX2, we identified either frameshift or splice-site mutations that affect the C-terminal region of the resultant protein distal to the runt domain. CONCLUSIONS In the context of previously described mutations, these cases suggest that C-terminal mutations that preserve the DNA-binding runt domain while disrupting the SMAD 1,2,3,5 binding domain and the nuclear matrix targeting signal may be responsible for the severe phenotype observed.

We describe a novel autosomal recessive malformation syndrome in four related individuals from a geographically isolated Native Alaskan community, who have facial defects similar to those of individuals with Treacher Collins (TCS) and Miller syndrome. Distinctive findings include malar and mandibular hypoplasia, lower eyelid coloboma, choanal atresia, orofacial clefting, and external ear malformation with preauricular tags. Intellect is normal and profound mixed hearing loss has been observed in affected adults. Variable extracranial findings include atrioseptal defect, renal dysplasia, and imperforate anus, however, no limb defects have been observed. Cranial imaging studies demonstrate relative prominence of the zygoma, inferior orbital maxillary hypoplasia, and lateral orbital wall defects with an accessory superior bony projection off the zygoma lateral to the orbital rim. We propose that these individuals have inherited a novel autosomal recessive condition we have termed oculo-oto-facial dysplasia (OOFD) with unique radiographic findings. © 2006 Wiley-Liss, Inc.

OBJECTIVE:To describe a novel set of scaphocephaly severity indices (SSIs) for predicting and quantifying head- and skull-shape deformity in children diagnosed with isolated sagittal synostosis (ISS) and compare their sensitivity and specificity with those of the traditional cranial index (CI).METHODS:Computed tomography head scans were obtained from 60 patients diagnosed with ISS and 41 age-matched control patients. Volumetric reformations of the skull and overlying skin were used to trace two-dimensional planes defined in terms of skull-base plane and internal or surface landmarks. For each patient, novel SSIs were computed as the ratio of head width and length as measured on each of these planes. A traditional CI was also calculated and a receiver operating characteristic curve analysis was applied to compare the sensitivity and specificity of the proposed indices with those of CI.RESULTS:Although the CI is a sensitive measure of scaphocephaly, it is not specific and therefore not a suitable predictor of ISS in many practical applications. The SSI-A provides a specificity of 95% at a sensitivity level of 98%, in contrast with the 68% of CI. On average, the sensitivity and specificity of all proposed indices are superior to those of CI.CONCLUSIONS:Measurements of cranial width and length derived from planes that are defined in terms of internal or surface landmarks and skull-base plane produce SSIs that outperform traditional CI measurements.

Duplications of organs and/or tissues are rare in morphogenesis and have frequently been attributed to incomplete twinning. To further elucidate the phenotypes associated with organ duplications, we present three infants with duplication of the pituitary gland (DPG). A review of previously reported cases with DPG showed that the commonest additional findings were hypothalamic enlargement, a broad or duplicated sella, cleft palate, hypertelorism, oropharyngeal tumors, agenesis or hypoplasia of the corpus callosum, and abnormalities of vertebrae. DPG and additional malformations constitute a distinct and recognizable pattern of anomalies, which may constitute a polytopic field defect due to splitting of the notochord. However, the precise inductive mechanism resulting in DPG remains unknown. © 2005 Wiley‐Liss, Inc.

OBJECTIVE:In this article, we review the normal anatomy and development of the posterior skull base and describe distinguishing imaging features of the two most common causes of posterior plagiocephaly: posterior deformational plagiocephaly and unilateral lambdoid synostosis. We also describe three unusual cases of posterior plagiocephaly, including asymmetric premature fusion of the anterior and posterior intraoccipital synchondroses, with diagnoses enabled by volume-reformatted MDCT.CONCLUSION:Three-dimensional reformatted MDCT enables accurate diagnosis of common and rare causes of posterior plagiocephaly in children.

Acromelic frontonasal dysostosis (AFND) represents a subgroup of patients with frontonasal malformation with limb abnormalities including preaxial polydactyly and tibial hypoplasia. Previous case reports have suggested autosomal recessive inheritance, given parental consanguinity. However, no affected siblings have been described. Longitudinal clinical history is limited as many do not survive the first years of life. The molecular basis of AFND is not known. Previous investigators have proposed that AFND may result from a perturbation in the Sonic Hedgehog pathway. We present clinical and radiographic findings in two unrelated boys, ages 8 and 9 years, with AFND, one of whom has a family history suggesting dominant inheritance. A focused study of genetic marker data and candidate gene mutation analysis in this family is presented. © 2004 Wiley‐Liss, Inc.

Neuroectodermal melanolysosomal disease, also known as Elejalde syndrome, is a rare syndrome characterized by silvery hair, pigment abnormalities, and profound central nervous system dysfunction. It is similar to the Chediak-Higashi and Griscelli syndromes, although these syndromes are associated with severe immunologic dysfunction. We report on a 12-year-old male with Elejalde syndrome and compare the Elejalde, Chediak-Higashi, and Griscelli syndromes.