Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients.

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis.

Analysis of the cephalometric changes in the first 3 months after spring-assisted cranioplasty for scaphocephaly.

BACKGROUND: Spring-assisted cranioplasty (SAC) has become an accepted treatment for patients with sagittal craniosynostosis; however, the early effects of springs on skull dimensions have never been assessed with objective measurements in the literature. The present study evaluated the changes in skull dimensions and intracranial volume (ICV) during the first 3 months after SAC for sagittal synostosis. METHODS: Sixteen patients with sagittal synostosis underwent SAC. The cephalic index (CI) and the distance between the spring foot plates were chronologically measured until spring removal at 3 months. Pre- and post-treatment CT scans available for 6 patients were used to assess changes in head shape. Thirteen patients underwent objective aesthetic assessment using pre- and post-operative photographs. Statistical analysis was performed using the linear mixed model for chronological data, t-test statistics for normative data comparisons and Wilcoxon's signed rank test for non-parametric data. RESULTS: For scaphocephalic patients, pre-operative and post-operative CIs were 0.70 and 0.74 (p = 0.001), respectively. Cranial widening towards normative values was observed (p = 0.0005). A continuous expansion in the distance between the spring foot plates was observed over the treatment period. Frontal and occipital angles were not affected by SAC despite apparent clinical improvements in frontal bossing and occipital prominence. CT analysis demonstrated relative reduction in the anterior cranial volume (p = 0.01) and relative expansion of the superior occipital volume (p = 0.03). CONCLUSIONS: Spring expansion was most marked in the hours following spring insertion. The expansion rate reduced to the minimum by day 1 post-operatively. Clinical benefits of SAC resulted from an increase in the bi-temporal width that camouflaged the frontal bossing. Improvement in occipital prominence was due to superior occipital volume expansion, allowing the occiput to remodel to a more rounded shape.

The latissimus dorsi added fat flap for natural tissue breast reconstruction: report of 15 cases.

The latissimus dorsi added fat flap is an alternative method of natural tissue breast reconstruction. A significant volume of additional subcutaneous back fat is left attached to a traditional latissimus dorsi flap, avoiding the need for an additional implant. The surgical technique and results in 15 patients are discussed.

The neurovascular territories of the skin and muscles: anatomic study and clinical implications.

In 1987, the results of a series of total-body investigations of the arterial system of the skin and underlying deep tissues were published. This resulted in the angiosome concept. In 1990, a similar series of studies of the venous network was published. In both investigations, it was noted that "vessels hitchhike with nerves." This anatomic study analyzes these neurovascular relationships in the skin and in the underlying muscles. Seven fresh human cadavers and nine animals were studied over a 2-year period. The entire integument of each and a total of 538 human and 72 animal muscles were removed and analyzed. Either the arterial or the venous system was injected with a radiopaque lead oxide mixture, and the dissected nerves were labeled with fine wires, being segregated later by a subtraction radiography technique. The results of these investigations are presented, with special emphasis placed on the design of long axial skin flaps placed along neurovascular systems and their relationship with the current design of skin flaps. The muscles are classified according to their extrinsic and intrinsic neurovascular supplies, and suggestions are made as to how they may or may not be subdivided into functional units for local and distant transfer. The cutaneous nerves, as well as the motor nerves of the muscles, were invariably accompanied by a longitudinal system of arteries and veins that often was the dominant supply to the region. Whether the nerves appeared together with the vessels, whether the nerves crossed them at an angle, or whether they approached the vessels from opposite directions, in each case the main trunk of the vessel or some of its branches soon "peeled off" to course parallel to the nerve. This information provides the basis for the design of long skin flaps placed along neurovascular systems. Indeed, it reveals that many of the current "axial" or "fasciocutaneous" skin flaps used in clinical practice are in fact neurovascular flaps. The muscles are classified into four types according to their extrinsic and intrinsic neurovascular supplies. Type I muscles are supplied by a single unbranched nerve. In type II muscles, the nerve branches before entering the muscle. Type III muscles receive multiple motor nerves from the same nerve trunk, and type IV muscles are supplied from multiple nerve trunks. Suggestions are made as to how muscles of each type may or may not be subdivided into functional neurovascular units for local and distant transfer.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of distraction rate on biomechanical, mineralization, and histologic properties of an ovine mandible model.

Craniofacial microsomia is a common congenital malformation. Ilizarov's method of distraction osteogenesis applied to the mandible has yielded promising results both experimentally and clinically. Because the technique is used predominantly in a pediatric population, length of treatment and compliance may be problematic. To date, the limits of distraction rate in the craniofacial skeleton have not been defined. This study was designed to investigate the effects of distraction rate, in a large animal model, on the mineralization, biomechanical, and histologic properties of lengthened mandibles. Clinically faster distraction rates would decrease the overall treatment time. Twenty-four animals were divided into four groups, with varying rates of distraction (1, 2, 3, and 4 mm/day). A uniaxial distractor at the angle of the mandible was used. The mandibles were lengthened to 24 mm and fixed for a period of 5 weeks, when the animals were killed. The specimens were analyzed with respect to mineralization using dual energy x-ray absorptiometry, biomechanical strength, through a modified three-point bending test, and histologic properties with hematoxylin and eosin stains. Biomechanical, mineralization, and histologic analyses of the samples indicated that group 1 (1 mm/day) samples were significantly superior (p<0.05) to those of group 4 (4 mm/day). Although bone formation was achieved in all groups, group 1 (1 mm/day) demonstrated the strongest biomechanical and histologic properties. Bone mineral density obtained using dual energy x-ray absorptiometry may be clinically useful as a reliable, noninvasive, and relatively cheap predictor for removal time of the fixator.

The cephalic vein: an aid in free TRAM flap breast reconstruction. Report of 12 cases.

The harvesting of the cephalic vein is a simple and effective technique for providing or augmenting venous drainage in free TRAM flap breast reconstruction. It may be divided distally and rotated about the infraclavicular fossa as a cephalic vein transfer or used as a source of free vein grafts. It is easily harvested with minimal morbidity. Its anatomy, surgical technique, indications, and results of use are discussed. In some circumstances, a cephalic vein transfer may allow greater areas of the free TRAM flap to be used more safely. This is discussed.

Oral premedication for local anesthesia in plastic surgery: prospective, randomized, blind comparison of lorazepam and temazepam.

Patients undergoing plastic surgical procedures under local anesthesia as inpatients were entered into a phase III randomized, blind trial designed to compare two commonly used oral premedications, lorazepam and temazepam. The effects of the drugs on each patient's memory, pain, sedation, and anxiety were assessed by questions asked of the patient, the nurse, and the surgeon. Analysis was based on 100 randomized patients. Lorazepam had a significantly greater amnesic effect (p < 0.0001), resulted in less pain with the local anesthetic injection (p = 0.006), and had a greater sedative effect than temazepam (p < 0.0001, patient's assessment; p = 0.005, observers' assessments). There was no significant difference in anxiolysis between the two premedications (p = 0.20). If premedication is indicated, we advocate the use of lorazepam rather than temazepam as premedication for plastic surgical procedures to be performed under local anesthesia, provided there is adequate postoperative supervision.

Plating of metacarpal fractures: unicortical or bicortical screws?

Mid-shaft transverse osteotomies were performed in 18 cadaveric metacarpals and randomly divided into two groups. Using dorsally applied plates for repair, one group was secured using 6mm unicortical screws, while bicortical screws were used in the second group. The metacarpals were tested to failure with a four-point bending protocol using a servo-hydraulic testing machine and a 1kN load cell. The mean load to failure was 596N (SD=142) for the unicortical and 541N (SD=171) for the bicortical group. The stiffness was 333N/mm (SD=116) for the unicortical and 458N/mm (SD=158) for the bicortical group. Both load to failure and stiffness were not statistically significant between the two groups. Failure occurred by fracture at the screw-bone interface in all specimens: no screw pull-out was observed. No biomechanical advantage was found when using bicortical screws in metacarpal fracture plating.

Performance of a knotless four-strand flexor tendon repair with a unidirectional barbed suture device: a dynamic ex vivo comparison.

With increased numbers of reports using barbed sutures for tendon repairs we felt the need to design a specific tendon repair method to draw the best utility from these materials. We split 30 sheep deep flexor tendons in two groups of 15 tendons. One group was repaired with a new four-strand barbed suture repair method without knot. The other group was repaired with a conventional four-strand cross-locked cruciate repair method (Adelaide repair) with knot. Dynamic testing (3-30 N for 250 cycles) and additional static pull to failure was performed to investigate gap formation and final failure forces. The barbed suture repair group showed higher resistance to gap formation throughout the test. Additionally final failure force was higher for the barbed suture group compared with the conventional repair group. When used appropriately, barbed suture materials could be beneficial to use in tendon surgery, especially with regard to early loading of the repair site and gap formation.

Isolated limb perfusion for melanoma: effectiveness and toxicity of cisplatin compared with that of melphalan and other drugs.

In patients with advanced or recurrent melanoma confined to a limb, hyperthermic isolated limb perfusion (ILP) with melphalan produces complete remission in 35-40% of cases and partial remission in a further 35-40%. Mild or moderate limb toxicity is usual, but severe toxic reactions in the limb sometimes occur. After preliminary reports suggested that cisplatin administered by ILP was even more effective than melphalan yet less toxic, a study was undertaken to further assess the value of hyperthermic ILP with cisplatin in the management of limb melanoma. Ten patients were treated. The procedure failed to eliminate melanoma in the limb in 5 of the 6 who received therapeutic ILPs for recurrent disease, and recurrence developed in 2 of the 4 patients who received prophylactic ILPs. Toxicity in the perfused limbs was unacceptably high, with 2 of the 10 patients having severe reactions, one necessitating amputation. We conclude from the results of this study and from a review of literature that neither cisplatin nor any other drug or drug combination so far used for ILP in melanoma patients achieves results which are clearly superior to those achieved with melphalan. Studies are currently in progress investigating double perfusion protocols, new strategies with regional hyperthermia, and the administration by ILP of biological response modifiers such as tumor necrosis factor and interferon. However, for the present, hyperthermic ILP with melphalan remains the treatment most likely to be successful in eliminating or controlling advanced or recurrent melanoma in a limb.

Delayed hypersensitivity reaction to subcutaneous heparin.

Two women developed well-demarcated eczematous and erythematous plaques localized to the injection sites of subcutaneous preservative-free heparin 72-96 h after heparin administration. The plaques resolved within a week of discontinuing the therapy. Neither epicutaneous testing with preservative-free heparin nor in vitro proliferation assays to heparin and two low molecular weight glycosaminoglycans could elicit a response in either patient. In contrast, both patients developed localized eczematous plaques 48-96 h after re-challenge with intradermal and/or subcutaneous heparin. Delayed hypersensitivity reactions to subcutaneous heparin are uncommon and have not been reported in the Australasian medical literature. Given the frequency with which heparin preparations are used, it is important for physicians and surgeons to be aware of this potential adverse reaction.

Mazabraud's syndrome: intramuscular myxoma associated with fibrous dysplasia of bone.

A 53 year old male with a large swelling on the medial aspect of his right thigh was referred with a presumptive diagnosis of soft tissue sarcoma. However, biopsy revealed intramuscular myxoma and X-rays and CT scans suggested fibrous dysplasia of adjacent bone. Angiography had shown an expanded, hypervascular, intramedullary lesion in the femur, and a large avascular soft tissue mass lying medially in the distal thigh. Fibrous dysplasia of the femur was confirmed on bone biopsy. Subsequently one large and two smaller intramuscular myxomata were excised, with an uneventful postoperative course. This case illustrates Mazabraud's syndrome: the rare association between benign intramuscular myxoma and fibrous dysplasia of bone.

Ulnar adamantinoma: en bloc excision and fibular osteoseptocutaneous free flap reconstruction.

Adamantinoma is a rare tumor of the appendicular skeleton, and only six cases of ulnar involvement have been reported. We present the case of a 58-year-old man who sustained a pathologic fracture of the proximal third of this right ulna. Biopsy at the time of intramedullary fixation revealed adamantinoma, and he was referred for treatment. There was no evidence of metastatic disease. At operation, the proximal 22 cm of ulna was excised en bloc and the defect reconstructed using a vascularized fibular osteoseptocutaneous flap. The postoperative course was uneventful, and the patient has remained free of disease with very good function 3 years later.

Neck dissection for cutaneous malignant melanoma.

This retrospective study examines the experience of the Sydney Melanoma Unit in the management of cervical lymph nodes among patients with cutaneous melanoma of the head and neck. From 1960 to 1990, 397 patients had neck dissections for cutaneous malignant melanoma of the head and neck. This number represents 40% of all patients treated for head and neck melanoma at the Sydney Melanoma Unit during this period. Neck dissections were therapeutic in 152 patients, elective in 234 patients and for an unknown indication in 11 patients. Lymph nodes were histologically positive in 39% of operations overall and in 7% of elective neck dissections. The incidence of recurrence in the neck after dissection was 24% overall, 28% when nodes were histologically positive and 13% when nodes were histologically negative. Patients who developed recurrent neck disease after neck dissection had a worse prognosis than those with positive nodes who did not recur, but the difference in survival was not statistically significant. Patients with histologically positive nodes had a significantly worse survival than those with negative nodes, 34% vs 67% respectively at 10 years (p less than 0.001). Elective neck dissection was associated with a significant improvement in survival for patients with melanomas 1.5-3.9 mm thick, using univariate analysis. This apparent benefit was lost when multivariate analysis was carried out. Patients having elective neck dissection currently have selective modified radical dissections depending upon the anatomic site of the primary melanoma. Postoperative radiotherapy is used for multiple positive nodes or extracapsular spread.

The rational use of homologous blood in elective surgery.

The supply of homologous blood in Australia is limited, but the demand for blood and blood products is steadily increasing. Elective surgery is a major part of this demand. In many institutions the blood ordering practices for elective surgery have been haphazard. This study was undertaken to document current patterns of blood use in a major city teaching hospital. A retrospective analysis of blood ordering and transfusion for elective surgical procedures was carried out over a 12 month period. As in several previous studies, an inefficient use of blood was demonstrated. Possible strategies to rationalize the use of blood in elective surgery have been proposed. These include the use of a 'group and screen' procedure instead of a full cross-match when transfusion is unlikely to be necessary, and ordering according to a 'maximum blood order schedule' when transfusion is usually required for a procedure.

The role of transforming growth factor-beta, insulin-like growth factor I, and basic fibroblast growth factor in distraction osteogenesis of the mandible.

Distraction osteogenesis is a viable method for regenerating large amounts of bone. In contrast to fracture healing, the mode of bone formation in distraction osteogenesis is primarily intramembranous ossification. The basic biology of the process is still not well understood. The growth factor cascade is likely to play an important role in distraction. This study examines the growth factor cascade in a lengthened ovine mandible model. Twenty-four animals were divided into four groups with varying rates of distraction (1, 2, 3, and 4 mm/day). A unilateral distractor at the angle of the mandible was used. The mandibles were lengthened to 24 mm and fixed for a period of 5 weeks, after which the animals were killed. The sections were probed for transforming growth factor-beta, basic fibroblast growth factor, and insulin-like growth factor I. The growth factors studied were present in all four groups. Transforming growth factor-beta, basic fibroblast growth factor, and insulin-like growth factor I were present in both the bony matrix of the sections and the cytoplasm of the cells, osteoblasts, and a small number of mesenchymal cells. The sections obtained from groups distracted at faster rates showed stronger presence of the growth factors examined by more intense staining. In fracture healing, the localization of transforming growth factor-beta in stage I of healing corresponded with the precise region of intramembranous ossification in stage II. Diffuse presence of transforming growth factor-beta throughout the lengthened region corresponded with the process of intramembranous ossification observed in distraction. In fracture healing, insulin-like growth factor I and basic fibroblast growth factor have been shown to promote proliferation and differentiation of osteoblasts from precursor cells. The intense presence of insulin-like growth factor I and basic fibroblast growth factor in the distracted region may account for osteoblast proliferation and formation from precursor mesenchymal cells. Mechanical strain has been shown to increase the expression of transforming growth factor-beta and insulin-like growth factor I. Distraction may serve as a source of mechanical strain, which may explain, in part, the expression of these growth factors, particularly in the faster groups.

Movement detection at the human big toe.

1. To be detected, movements of the interphalangeal joint of the big toe must be greater than at other joints. This poor acuity may arise because the anatomy of the foot and ankle results in poor coupling between the toe and the muscles that operate it. To vary this coupling, the effect of ankle position on proprioceptive acuity at the toe was measured. 2. We measured proprioceptive acuity at the toe with the ankle in different positions and found that ankle plantarflexion did improve acuity. This implies that, with the ankle at mid-range or dorsiflexed, toe movement is inadequately transferred to muscle fascicles. 3. To determine actual changes in fascicle length of the toe extensor, movements of extensor hallucis longus near the toe and at the muscle-tendon junction were measured during surgical exposure in one subject. Ankle position greatly affected movement transfer from toe to muscle-tendon junction: no tendon movement was transferred with the ankle dorsiflexed, but all movement was transferred with the ankle plantarflexed. 4. When the relationship between joint rotation and muscle fascicle length measured in vivo was used to express the smallest detectable movements of the toe as proportional changes in muscle fascicle length, these detectable changes were similar to those at all other limb joints. This suggests that change in muscle fascicle length is of major interest to the nervous system.

Reduced need for alveolar bone grafting by presurgical orthopedics and primary gingivoperiosteoplasty.

OBJECTIVE: The purpose of this study was to evaluate if narrowing and approximation of the alveolar cleft through presurgical alveolar molding followed by gingivoperiosteoplasty (GPP) at the time of lip repair reduces the need for a bone-grafting procedure. DESIGN: This was a retrospective blind study of patients with unilateral or bilateral alveolar clefts who underwent presurgical infant alveolar molding and GPP by a single surgeon. Alveolar bone formation was assessed prior to the eruption of the maxillary lateral incisor or canine by clinical examination, panoramic and periapical radiographs, and/or a dental CT scan. The criterion for bone grafting was inadequate bone stock to permit the eruption and maintenance of the permanent dentition. SETTING: This study was performed at the Institute of Reconstructive Plastic Surgery by the members of the Cleft Palate Team. PATIENTS: All patients with unilateral (n = 16) or bilateral (n = 2) alveolar clefts who underwent presurgical infant alveolar molding and GPP by a single surgeon from 1985 to 1988 were studied. The control population consisted of all alveolar cleft patients (n = 14) who did not undergo alveolar modeling or GPP during the same time period. INTERVENTIONS: Presurgical alveolar modeling was performed with an intraoral acrylic molding plate. This plate was modified on a weekly basis to align the alveolar segments and close the alveolar gap. The surgical intervention consisted of a modified Millard GPP. MAIN OUTCOME MEASURES: The primary study outcome measure was the elimination of the need for a secondary bone graft in patients who underwent presurgical alveolar molding and GPP. RESULTS: Of the 20 sites in the 18 patients who underwent GPP, 12 sites did not require an alveolar bone graft. Of the 8 sites requiring a bone graft, 4 presented minimal bony defects. All 14 patients in the control group required bone grafts. CONCLUSIONS: In this series of 20 alveolar cleft sites treated with presurgical orthopedics and GPP, 60% did not need a secondary alveolar bone graft in the mixed dentition.

Malignant melanoma in childhood: a clinicopathologic study of 13 cases and comparison with Spitz nevi.

The clinical and histological features of 13 malignant melanomas in children less than 13 years of age in New South Wales, Australia, were compared with those in a control group of children with 15 Spitz nevi, 4 of which were considered atypical, and 2 unusual compound nevocellular nevi. Six of the controls had been previously diagnosed histologically as malignant melanoma. The objective observations made by one or more histopathologists experienced in reporting melanocytic lesions, and the clinical details, mainly from the Sydney Melanoma Unit files, were entered on a detailed protocol. Evaluation was assisted by the use of SPSS-X software on a mainframe VAX computer. Six of the 13 children with malignant melanoma died with their disease. The most frequent clinical features found in the malignant melanomas were bleeding, ulceration, itching, and black or variegated color. Recent enlargement and darkening were noted in the majority of both the malignant melanomas and the Spitz nevi. Histological features favoring malignancy in this series were mitoses within 0.25 mm of the dermal margin of the melanoma, a dermal mitotic rate exceeding 2/mm2, ulceration, surface exudate, large pigment granules, and clear-cell differentiation. The median thickness of the malignant melanomas was 1.3 mm but in the 4 children who died with melanoma the median thickness was 2.9 mm. Absence of mitoses, predominance of spindle cells, and diffuse maturation favored Spitz nevus. The median thickness of the Spitz nevi was 0.7 mm.

Topical negative pressure in wound management.

OBJECTIVE: To investigate the role of topical negative pressure (TNP) therapy in the management of difficult wounds. DESIGN: Prospective consecutive patient series. PATIENTS AND SETTING: 30 patients referred to our tertiary plastic and reconstructive surgical service with wounds deemed unsuitable for reconstructive surgery were treated between November 1997 and the end of December 1998. The mean pretreatment duration of the wounds was 418 days (range, 8-1650 days). All wounds were at least Grade III pressure sores. INTERVENTION: Topical negative pressure therapy (TNP) using the VAC device (KCI Medical, San Antonio, USA). Suction (75-125 mmHg) was continuous for the first 48 hours, then intermittent (2 min on, 5 min off). MAIN OUTCOME MEASURES: Achievement of wound healing endpoints: (1) complete healing of the wound; (2) obliteration of the wound cavity to allow surface dressings; or (3) closure of the wound by suture or skin graft. RESULTS: TNP was successful in 26 out of 30 patients with mean therapy time of 35 days (range, 3-124 days). Healing was more rapid in acute (less than six weeks old) wounds. A reduction in the number of bacterial species and colonies was also observed during therapy. CONCLUSION: TNP can, in some circumstances, promote rapid secondary wound healing. A further randomised trial of TNP versus more traditional wound management modalities is justified.