Prenatal diagnosis of cleft lip: what the sonologist needs to tell the surgeon.
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Cleft Lip↗
Biomedical subjects
J B Mulliken
Publications and source records attributed to J B Mulliken.
No evidence supporting MTHFR as a risk factor in the development of familial NSCLP.
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Alleles↗
KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation.
Hyperkeratotic capillary-venous malformations (HCCVMs) are rare cutaneous lesions that occur in a small subgroup of patients with cerebral capillary malformation (CCM). CCMs cause neurological problems that range from headaches to life-threatening intracranial bleeding. CCMs and HCCVMs have a similar histopathological appearance of dilated capillary-venous channels. Genetic linkage of inherited CCMs has been established to three chromosomal loci, 3q25. 2-27, 7p13-15 and 7q21-22. The first mutations were identified in the CCM1 gene (located on 7q21-22), which encodes KRIT1 protein (KREV1 interaction trapped 1), presumably a membrane-bound protein with signalling activity. Although KRIT1 is known to interact with KREV1/RAP1A, a Ras-family GTPase, the exact function of KRIT1 in the formation of cerebral capillaries and veins is poorly understood. In this study, we screened five families with CCM for mutations in the KRIT1 gene. In one of the families, CCMs co-segregated with HCCVMs. We identified a KRIT1Delta(G103)mutation in this family, suggesting that this rare form of the condition is also caused by mutations in the CCM1 gene and that KRIT1 is probably important for cutaneous vasculature. Interestingly, this deletion introduces the earliest stop codon among identified mutations, suggesting a possible correlation between the molecular alteration and the cutaneous phenotype. Another novel mutation, KRIT1(IVS2+2(T-->C)), was found in a family with only cerebral capillary-venous malformations.
Brain↗
Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis.
Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR), two hamartoma-tumour syndromes, and somatic PTEN alterations have been shown to participate, to a greater or lesser extent, in a wide variety of sporadic neoplasia. PTEN is a tumour suppressor and dual-specificity phosphatase which affects apoptosis via its lipid phosphatase activity in the phosphoinositol-3-kinase and AKT pathway as well as inhibiting cell spreading via the focal adhesion kinase pathway. CS and BRR share some features, such as hamartomas and lipomatosis. To determine whether other syndromes characterized by overgrowth and lipomas are part of the PTEN syndrome spectrum, we ascertained six individuals with overgrowth and lipomas but who did not meet the diagnostic criteria for CS or BRR. Five had Proteus syndrome and one, a Proteus-like syndrome. When germline DNA and DNA from at least one involved tissue per case were examined for PTEN mutations, only the Proteus-like patient was found to harbour a germline R335X mutation. Interestingly, a lipomatous mass, an epidermoid naevus and arteriovenous malformation tissue, all of which were sampled from physically distinct sites, were all found to carry a second hit R130X mutation on the allele opposite the germline R335X. Both mutations have been described in CS and BRR. We postulate that the second hit, R130X, occurred early in embryonic development and may even represent germline mosaicism. Thus, PTEN may be involved in Proteus-like syndrome with its implications for cancer development in the future.
Arteriovenous Malformations↗
Residual lesions after Kasabach-Merritt phenomenon in 41 patients.
BACKGROUND: Kasabach-Merritt phenomenon (KMP) is the association of a vascular tumor and thrombocytopenic coagulopathy. Vascular tumors are either kaposiform hemangioendothelioma or tufted angioma but not "true" common hemangioma of infancy. There is a conspicuous absence in the literature regarding the late outcome and possible residual lesions after apparent clinical cure of KMP. OBJECTIVE: The purpose of the study was to analyze these residua in a large number of patients. METHODS: Clinical data on 41 patients who had KMP were accrued in an international cooperative study. The emphasis was on the residual lesions after resolution of the thrombocytopenia and other coagulation abnormalities. Imaging studies (follow-up magnetic resonance imaging studies available for 10 patients) and histologic specimens (30 specimens available for 26 patients, 18 biopsies done during the KMP and 12 concerning the sequelae) were reviewed. RESULTS: Residual lesions after "cure" of KMP were common. They exhibited 3 clinical patterns: type I lesions (n = 28) showed a cutaneous red stain, with or without associated red papules. The stain might overlap a minor fibrotic infiltration or a significant poorly delineated diffuse fibrotic infiltration. These cutaneous vascular lesions varied in size and appearance over time and were occasionally painful. Type II lesions were telangiectatic streaks and swelling (n = 5), and type III lesions showed a minor, firm, irregular, subcutaneous mass assessed by palpation or deep infiltration evidenced by computed tomography or magnetic resonance imaging (n = 8). A fourth feature was sequelae in muscles and/or joints. Histologically, tufted angioma was more common in the specimens from residual lesions, whereas kaposiform hemangioendothelioma was more common during the active phase of KMP. Imaging findings were remarkably reproducible and revealed a persistent vascular tumor. CONCLUSION: Residua of tumors associated with KMP are common after the resolution of thrombocytopenia and coagulopathy. They are (more or less) prominent dormant vascular tumors, not "scars" and, clinically as well as histologically, they differ markedly from involuted hemangioma.
Adolescent↗
VEGF and its receptors are expressed in a pediatric angiosarcoma in a patient with Aicardi's syndrome.
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Abnormalities, Multiple↗
Tc-99m red blood cell imaging of blue rubber bleb nevus syndrome.
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Adult↗
Progression of facial asymmetry in hemifacial microsomia.
Hemifacial microsomia is a common craniofacial anomaly, variably affecting structures derived from the first and second pharyngeal arches. Correction of the skeletal deformity in children has been advocated to improve growth potential and reduce secondary deformity. However, contrary reports have suggested that facial asymmetry in hemifacial microsomia does not increase with growth; therefore, skeletal correction can be postponed, even until adolescence. The purpose of this study was to test the hypothesis that facial asymmetry in hemifacial microsomia is progressive. This is a retrospective evaluation of 67 patients with untreated hemifacial microsomia. The patients were categorized as: group I (mandible type I, IIa), n = 38, and group II (mandible type IIb, III), n = 29. Pretreatment posterior-anterior cephalometric radiographs were used to analyze asymmetry by measuring the angle between the true horizontal and the following planes: piriform rim, maxillary occlusal plane, and intergonial angle. Angular measurements were averaged for patients in the deciduous (<6 years), mixed (> or =6<13 years), and permanent dentition (> or =13 years). In group I, angle piriform rim, maxillary occlusal plane, and intergonial angle increased from 7.0, 4.3, and 4.4 to 8.4, 6.6, and 6.1 degrees, respectively [mean age, 4.1 (deciduous) to 8.6 (mixed) to 21.0 (permanent) years]. In group II, angle piriform rim, maxillary occlusal plane, and intergonial angle increased from 9.5, 6.2, and 5.3 to 11.7, 7.6, and 8.0 degrees, respectively [mean age, 3.4 (deciduous) to 8.0 (mixed) years]. These data demonstrate that hemifacial microsomia is progressive and underscores the importance of early surgical correction of mandibular asymmetry in this disorder.
Adolescent↗
Analysis of fronto-orbital advancement for Apert, Crouzon, Pfeiffer, and Saethre-Chotzen syndromes.
The purposes of this study were (1) to document outcome after primary fronto-orbital advancement for the four major eponymous craniosynostotic syndromes (Apert, Crouzon, Pfeiffer, and Saethre-Chotzen) and (2) to identify factors that might influence need for primary and secondary fronto-orbital advancement or foreheadplasty. Also tested was the hypothesis that coincident sagittal synostosis could modulate brachycephaly and affect whether a primary or secondary frontal operation was necessary. Data were collected on age and indications for initial operation, type of primary and secondary frontal procedures, and concomitant sagittal synostosis. Patients initially managed by subcranial Le Fort III were included in the study group but excluded from analysis of fronto-orbital advancement. Patients treated by monobloc advancement or Le Fort III osteotomies with frontal grafting or Anderl modification were assessed as having had primary fronto-orbital advancement. Minimum time to follow-up was 5 years. A total of 126 patients met inclusion criteria. Lateral photographs were examined to assess preoperative and postoperative sagittal position of supraorbital rims-to-globes. Frontal re-advancement was indicated if the corneal apex was anterior to the supraorbital rim. Foreheadplasty was indicated for unacceptable frontal contour and normal supraorbital rim-to-globe relationship. Primary correction for frontal retrusion was not required in 4 percent of Apert (1 of 25), 16 percent of Crouzon (7 of 44), 6 percent of Pfeiffer (2 of 31), and 19 percent of Saethre-Chotzen (5 of 26) patients. Of those infants who had a primary fronto-orbital advancement, reoperation for either supraorbital retrusion or frontal deformity was necessary in all 16 Apert patients and in 5 of 19 Crouzon (26 percent), 10 of 26 Pfeiffer (38 percent), and 13 of 20 Saethre-Chotzen (65 percent) patients (p < 0.001). Age at initial fronto-orbital advancement did not influence reoperative rate. No correlation was found between concomitant sagittal synostosis and necessity for primary or secondary frontal correction (p = 0.22). In summary, phenotypic diagnosis was determinant for outcome as defined by need for secondary fronto-orbital advancement, foreheadplasty, or both. Apert patients had the highest incidence of reoperation for frontal retrusion or forehead contour. Crouzon and Saethre-Chotzen patients were most likely to express a minor phenotype and not require fronto-orbital correction. Coincident sagittal synostosis did not influence frontal projection, as reflected in need for either primary or secondary frontal advancement.
Acrocephalosyndactylia↗
Soft-tissue vascular anomalies: utility of US for diagnosis.
PURPOSE: To determine the ultrasonographic (US) features that distinguish soft-tissue hemangioma from vascular malformation and one type of malformation from another. MATERIALS AND METHODS: Eighty-seven vascular anomalies were evaluated by means of US. Lesions were assessed for the presence of solid tissue and abnormal arteries, veins, or cysts. Vessel density, peak flow velocities, and resistive indexes were compared. RESULTS: There were 49 hemangiomas and 38 vascular malformations. A significantly greater proportion of hemangiomas (48 of 49) compared with vascular malformations (zero of 38) consisted of a solid-tissue mass (P < .001). Vessel density was comparable for hemangioma and arteriovenous malformation (AVM) but significantly greater compared with the other vascular malformations (P < .001 in each case). No differences in mean arterial peak velocity were detected between hemangiomas and malformations. Mean venous peak velocity was significantly higher for AVM than for other vascular malformations and hemangioma. Mean resistive index was greater for lymphatic malformation than for hemangioma or AVM. Abnormal veins, arteries and veins, or cysts were univariate predictors for distinguishing between venous, arteriovenous, and lymphatic malformations (P < .001 in all cases). Solid-tissue mass was the only multivariate predictor for differentiating hemangioma from vascular malformation (likelihood ratio test = 109.8, P < .001). CONCLUSION: US can be used to distinguish hemangioma from vascular malformation and detect arterial flow. These distinctions are critical for subsequent management and assessing prognosis.
Adolescent↗
Repair of bilateral complete cleft lip and nasal deformity--state of the art.
OBJECTIVE: Dissatisfaction with the stigmata of repaired bilateral cleft lip has stimulated surgeons to change conventional operative strategies. The old staged labial repairs, one side and later the other, have been replaced by simultaneous closure. For nasal correction, most surgeons no longer believe that the columella is deficient, and thus there is no need to recruit tissue from the lip or nostril sills as a secondary procedure. The columella is concealed in the nose. The new strategy is to construct the columella and nasal tip by anatomic positioning of the alar cartilages and sculpting the investing skin. Furthermore, nasal correction is done at the time of bilateral labial repair and, whenever possible, the alveolar clefts are closed as well. The goal is primary repair of the primary palate. CONCLUSION: Although the principles of synchronous repair of the bilateral complete cleft lip and nasal deformity are established, the techniques continue to evolve. Bilateral nasolabial repair requires continual study of three-dimensional form and fourth-dimensional changes that are normal and altered by the deformity. Every surgeon who lifts a knife to care for these children has an obligation to periodically assess outcome.
Alveolar Process↗
Prominent basal emissary foramina in syndromic craniosynostosis: correlation with phenotypic and molecular diagnoses.
BACKGROUND AND PURPOSE: Jugular foraminal stenosis (JFS) or atresia (JFA) with collateral emissary veins (EV) has been documented in syndromic craniosynostosis. Disruption of EV during surgery can produce massive hemorrhage. Our purpose was to describe the prevalence of prominent basal emissary foramina (EF), which transmit enlarged EV, in syndromic craniosynostosis. Our findings were correlated with phenotypic and molecular diagnoses. METHODS: We reviewed the medical records and imaging examinations of 33 patients with syndromic craniosynostosis and known fibroblast growth factor receptor (FGFR) mutations. All patients underwent CT and 14 MR imaging. The cranial base was assessed for size of occipitomastoid EF and jugular foramina (JF). Vascular imaging studies were available from 12 patients. A control group (n = 76) was used to establish normal size criteria for JF and EF. RESULTS: Phenotypic classification included Crouzon syndrome (n = 10), crouzonoid features with acanthosis nigricans (n = 3), Apert syndrome (n = 10), Pfeiffer syndrome (n = 4), and clinically unclassifiable bilateral coronal synostosis (n = 6). EF > or = 3 mm in diameter and JFS or JFA were identified in 23 patients with various molecular diagnoses. Vascular imaging in patients with JFS or JFA and enlarged EF revealed atresia or stenosis of the jugular veins and enlarged basal EV. JFA was seen in all patients with the FGFR3 mutation with crouzonoid features and acanthosis nigricans. Four patients had prominent EF without JFS. Six patients had normal JF and lacked enlarged EF. CONCLUSION: Enlarged basal EF are common in syndromic craniosynostosis and are usually associated with JFS or JFA. Bilateral basilar venous atresia is most common in patients with the FGFR3 ala391glu mutation and crouzonoid features with acanthosis nigricans, but may be found in patients with FGFR2 mutations. Skull base vascular imaging should be obtained in patients with syndromic craniosynostosis with enlarged EF.
Acrocephalosyndactylia↗
Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation.
Proteus syndrome is a complex disorder comprising malformations and overgrowth of multiple tissues. The disorder is highly variable and appears to affect patients in a mosaic manner. This intrinsic variability has led to diagnostic confusion associated with a dearth of longitudinal data on the natural history of Proteus syndrome. To clarify some of these issues, a workshop on Proteus syndrome was held in March 1998 at the National Institutes of Health, and participants developed recommendations for diagnostic criteria, differential diagnosis, and guidelines for the evaluation of patients. This is a review of those recommendations.
Diagnosis, Differential↗
The infant with a vascular tumor.
Vascular birthmarks look alike in various tints of blue, pink, or red. These anomalies are either vascular tumors or vascular malformations. Hemangioma is the most common vascular tumor of infancy, typically appearing in the neonatal period. Hemangiomas grow rapidly during the first year of life and regress slowly during childhood. Treatment is indicated for problematic or endangering hemangiomas, usually the administration of corticosteroids or interferon-alfa, and in some instances, embolization or surgical resection. The more aggressive and rare vascular tumors, kaposiform hemangioendothelioma and tufted angioma, are often associated with thrombocytopenia and coagulopathy (Kasabach-Merritt phenomenon) and less responsive to pharmacological therapy. Vascular tumors, particularly hemangioma, are often confused with vascular malformations; although etiology, histology, and clinical behavior are quite different. Vascular lesions should be biopsied if there is any suspicion of malignancy.
Blood Vessels↗
Hemifacial microsomia: anatomical prediction of difficult intubation.
Hemifacial microsomia (HFM) is associated with a difficult airway. We hypothesized that a difficult intubation would be predicted by radiographic evaluation of the severity of mandibular hypoplasia. A retrospective review of anaesthetic and surgical records of 102 children with HFM from 1986 to 1996 was conducted for radiographic classification of mandibular hypoplasia and degree of difficulty with intubation. Intubation was classified as Grade A-easy, Grade B-difficult, or Grade C-very difficult. The mandibular anatomy was categorized as Type I-'mini-mandible', Type II-abnormal condylar size and shape, or Type III-absent ramus, condyle, and temporomandibular joint. In the 82 patients with HFM, 70% were classified as Grade A, 21% had Grade B and 9% had Grade C airways. No patients with Type I mandible had Grade C airway, while 25% of the patients with Type III mandible had Grade C airway. The correlation of the degree of airway difficulty with mandibular type was significant (P=0.001). In 20 patients with bilateral mandibular hypoplasia, 30% had Grade A, 35% had Grade B, and 35% had Grade C airways. We conclude that radiographic classification of mandibular deformity is a useful adjunct for preoperative prediction of airway difficulty in the management of children with unilateral HFM.
Adolescent↗
Vascular malformations of the upper limb: a review of 270 patients.
Vascular malformations of the upper limb were once thought to be impossible to properly diagnose and treat. We reviewed our experience with these malformations of the upper limb in 270 patients seen over a 28-year period. These anomalies were slightly more common in females than males (ratio, 1.5:1.0). The malformations were categorized as either slow flow (venous, n = 125; lymphatic, n = 47; capillary, n = 32; combined, n = 33) or fast flow (arterial, n = 33). Three categories of fast-flow malformations were identified and designated as types A, B, and C. Over 90% of these lesions could be properly diagnosed by their appearance and growth pattern within the first 2 years of life. Additional radiographic studies were used to confirm this diagnosis and to define specific characteristics. Magnetic resonance imaging with and without contrast best demonstrated site, size, flow characteristics, and involvement of contiguous structures for all types of malformations. Algorithms for treatment of both slow-flow and fast-flow anomalies are presented. Two hundred sixty surgical resections were performed in 141 patients, including 24 of 33 fast-flow anomalies. Preoperative angiographic assessment, with magnified views, was an important preoperative adjunct before any well-planned resection of fast-flow arteriovenous malformations. The surgical strategy in all groups was to thoroughly extirpate the malformation, with preservation of nerves, tendons, joints, and uninvolved muscle, and microvascular revascularization and skin replacement as required. Resections were always restricted to well-defined regions and often completed in stages. Symptomatic slow-flow malformations and types A and B fast-flow anomalies were resected without major sequelae. Type C arterial anomalies, diffuse, pulsating lesions with distal vascular steal, and involvement of all tissues, including bone, progressed clinically and resulted in amputation in 10 of 14 patients. The complication rate was 22% for slow-flow lesions and 28% for fast-flow lesions.
Adolescent↗
A gene for inherited cutaneous venous anomalies ("glomangiomas") localizes to chromosome 1p21-22.
Venous malformations (VMs) are localized defects of vascular morphogenesis. They can occur in every organ system, most commonly in skin and muscle. They can cause pain and bleeding, and in some critical locations they can be life threatening. Usually venous anomalies occur sporadically, but families with dominant inheritance have been identified. Using linkage analysis, we have established in earlier reports that some families with inherited VMs show linkage to chromosome 9p21; the mutation causes ligand-independent activation of an endothelial cell-specific receptor tyrosine kinase, TIE-2. Here we show that VMs with glomus cells (known as "glomangiomas"), inherited as an autosomal dominant trait in five families, are not linked to 9p21 but, instead, link to a new locus, on 1p21-p22, called "VMGLOM" (LOD score 12.70 at recombination fraction.00). We exclude three known positional candidate genes, DR1 (depressor of transcription 1), TGFBR3 (transforming growth factor-beta receptor, type 3), and TFA (tissue factor). We hypothesize that cutaneous venous anomalies (i.e., glomangiomas) are caused by mutations in a novel gene that may act to regulate angiogenesis, in concert with the TIE-2 signaling pathway.
Chromosomes, Human, Pair 1↗