Orofacial Manifestations of Stickler Syndrome: An Analysis of Speech Outcome and Facial Growth After Cleft Palate Repair.

PURPOSE: The purpose of this study was to characterize airway problems, speech outcomes, and facial growth in patients with Stickler syndrome undergoing cleft palate repair. METHODS: A retrospective, longitudinal study was performed at the Children's Hospital of Philadelphia on 25 patients with Stickler syndrome and 53 nonsyndromic patients with clefts of the secondary palate repaired between 1977 and 2000. Airway problems were characterized by the incidence of Pierre Robin Sequence (PRS) and the necessity for surgical airway management. Speech was analyzed using the Pittsburgh weighted values for speech symptoms associated with velopharyngeal incompetence (VPI). Longitudinal anthropometric measurements represented up to 12 years of longitudinal cephalofacial growth. RESULTS: Seventy-two percent of patients with Stickler syndrome were diagnosed with PRS, 55.6% of whom required surgical airway management. Conversely, 20.8% of nonsyndromic patients were diagnosed with PRS (P < 0.0001), 18% of whom required surgical intervention (P < 0.05). Speech outcomes were poorer in patients with Stickler syndrome with 40% demonstrating borderline VPI and 13.3% demonstrating VPI, compared with 21.8% and 9.1%, respectively, in the nonsyndromic group. Both groups exhibited significantly shallower upper and mid facial depths and wider upper facial breadths when compared with normal standards of facial growth. Although there was a tendency toward decreased facial depths in patients with Stickler syndrome relative to nonsyndromic patients, the differences were nonsignificant. CONCLUSIONS: Patients with Stickler syndrome show significant potential for early airway compromise and a poorer prognosis for speech outcome after cleft palate repair. Their cephalofacial growth does not differ significantly from that of nonsyndromic cleft palate patients.

Hox11 genes establish synovial joint organization and phylogenetic characteristics in developing mouse zeugopod skeletal elements.

Hox11 genes are essential for zeugopod skeletal element development but their roles in synovial joint formation remain largely unknown. Here, we show that the elbow and knee joints of mouse embryos lacking all Hox11 paralogous genes are specifically remodeled and reorganized. The proximal ends of developing mutant ulna and radius elements became morphologically similar and formed an anatomically distinct elbow joint. The mutant ulna lacked the olecranon that normally attaches to the triceps brachii muscle tendon and connects the humerus to the ulna. In its place, an ulnar patella-like element developed that expressed lubricin on its ventral side facing the joint and was connected to the triceps muscle tendon. In mutant knees, both tibia and fibula fully articulated with an enlarged femoral epiphyseal end that accommodated both elements, and the neo-tripartite knee joint was enclosed in a single synovial cavity and displayed an additional anterior ligament. The mutant joints also exhibited a different organization of the superficial zone of articular cartilage that normally exerts an anti-friction function. In conclusion, Hox11 genes co-regulate and coordinate the development of zeugopod skeletal elements and adjacent elbow and knee joints, and dictate joint identity, morphogenesis and anatomical and functional organization. Notably, the ulnar patella and tripartite knee joints in the mouse mutants actually characterize several lower vertebrates, including certain reptiles and amphibians. The re-emergence of such anatomical structures suggests that their genetic blueprint is still present in the mouse genome but is normally modified to the needs of the mammalian joint-formation program by distinct Hox11 function.

Tongue dysmorphology in craniofacial microsomia.

BACKGROUND: Craniofacial microsomia is one of the most common and well-characterized craniofacial anomalies. Tongue dysmorphism, however, has been neither thoroughly investigated nor reported in the context of this disease. This review focuses on the true prevalence of tongue dysmorphology in craniofacial microsomia and its relation to the deformities seen in this condition. METHODS: A 20-year retrospective study was performed to determine the number of patients who had a documented tongue anomaly and any relation to the development of abnormal speech. In recognition of the limitations of this approach, a 1-year prospective study was also performed to see the true prevalence of tongue dysmorphology in these patients. RESULTS: Eight of 167 patients (4.8 percent) in the retrospective study were found to have tongue dysmorphologies, as opposed to 24 of 55 (43.6 percent) in the prospective study. The majority of tongue anomalies were mild. Of the eight retrospective patients, seven currently have intelligible speech with a combination of intensive speech therapy and/or surgical correction. The eighth patient is without intelligible speech. Tongue dysmorphology was positively correlated with the degree of hard- and soft-tissue deformity. CONCLUSIONS: Tongue dysmorphologies in craniofacial microsomia, although usually mild, are frequently overlooked. The correlation of the tongue, soft tissue, and mandible anomalies may point to a common error early in gestation or an interdependence of adjacent growth centers.

Indian and sonic hedgehogs regulate synchondrosis growth plate and cranial base development and function.

The synchondroses consist of mirror-image growth plates and are critical for cranial base elongation, but relatively little is known about their formation and regulation. Here we show that synchondrosis development is abnormal in Indian hedgehog-null mice. The Ihh(-/-) cranial bases displayed reduced growth and chondrocyte proliferation, but chondrocyte hypertrophy was widespread. Rather than forming a typical narrow zone, Ihh(-/-) hypertrophic chondrocytes occupied an elongated central portion of each growth plate and were flanked by immature collagen II-expressing chondrocytes facing perichondrial tissues. Endochondral ossification was delayed in much of the Ihh(-/-) cranial bases but, surprisingly, was unaffected most posteriorly. Searching for an explanation, we found that notochord remnants near incipient spheno-occipital synchondroses at E13.5 expressed Sonic hedgehog and local chondrocytes expressed Patched, suggesting that Shh had sustained chondrocyte maturation and occipital ossification. Equally unexpected, Ihh(-/-) growth plates stained poorly with Alcian blue and contained low aggrecan transcript levels. A comparable difference was seen in cultured wild-type versus Ihh(-/-) synchondrosis chondrocytes. Treatment with exogenous Ihh did not fully restore normal proteoglycan levels in mutant cultures, but a combination of Ihh and BMP-2 did. In summary, Ihh is required for multiple processes during synchondrosis and cranial base development, including growth plate zone organization, chondrocyte orientation, and proteoglycan production. The cranial base appears to be a skeletal structure in which growth and ossification patterns along its antero-posterior axis are orchestrated by both Ihh and Shh.

The 22q11.2 deletion in African-American patients: an underdiagnosed population?

Findings associated with the 22q11.2 deletion often include congenital heart malformations, palatal anomalies, immunodeficiency, hypocalcemia, and developmental delay or learning disabilities. Often the clinical suspicion of the diagnosis in a patient with one or more of these findings is heightened based on the presence of a characteristic facial appearance. In our large cohort of 370 patients with the 22q11.2 deletion, we report the under-representation of African-Americans in our group, as well as, the paucity of craniofacial dysmorphism in these patients. We note that the absence of the typical facial features may result in decreased ascertainment in this population and, furthermore, may delay the implementation of palliative care, cognitive remediation, and recurrence risk counseling. We, therefore, suggest that the clinician's threshold of suspicion should be lower in African-American patients.

The Children's Hospital of Philadelphia modification of the Furlow double-opposing z-palatoplasty: long-term speech and growth results.

Of the 261 nonsyndromic patients we studied, over 90% had minimal or absent hypernasality, almost 86% had inconsistent or no nasal emission, and 95% had no articulation errors related to velar function. The patients with a Pittsburgh score indicating an incompetent velopharyngeal mechanism comprised only about 6% of the group. Ninety-four percent had a socially functional speech quality. Secondary surgery was done in 6.5% of patients and was done or was recommended in about 8% of patients. Patients with isolated cleft palate seemed to do less well, although their outcomes were not statistically different from those with complete unilateral and bilateral clefts. Relaxing incisions have kept our fistula rate to an acceptably low rate of 6.8%. No major soft palate dehiscences or hard palate flap losses have occurred. The speech outcomes we are achieving are improved over our historical results and compared with published reports using nondouble reversing z-palatoplasty techniques. Similar outcomes with the Furlow repair have been confirmed. Maxillary growth, occlusion, and the need for orthognathic surgery do not seem to be influenced by the CHOP modification of the Furlow double-opposing z-palatoplasty. These modifications facilitate a tension free-closure and a low fistula rate.

Myosin gene mutation correlates with anatomical changes in the human lineage.

Powerful masticatory muscles are found in most primates, including chimpanzees and gorillas, and were part of a prominent adaptation of Australopithecus and Paranthropus, extinct genera of the family Hominidae. In contrast, masticatory muscles are considerably smaller in both modern and fossil members of Homo. The evolving hominid masticatory apparatus--traceable to a Late Miocene, chimpanzee-like morphology--shifted towards a pattern of gracilization nearly simultaneously with accelerated encephalization in early Homo. Here, we show that the gene encoding the predominant myosin heavy chain (MYH) expressed in these muscles was inactivated by a frameshifting mutation after the lineages leading to humans and chimpanzees diverged. Loss of this protein isoform is associated with marked size reductions in individual muscle fibres and entire masticatory muscles. Using the coding sequence for the myosin rod domains as a molecular clock, we estimate that this mutation appeared approximately 2.4 million years ago, predating the appearance of modern human body size and emigration of Homo from Africa. This represents the first proteomic distinction between humans and chimpanzees that can be correlated with a traceable anatomic imprint in the fossil record.