Perinasal Osteotomy With Distraction Osteogenesis for a Mild Syndromic Craniosynostosis.

Le Fort II and III procedures have generally been performed for syndromic craniosynostosis with midfacial hypoplasia and skeletal class III malocclusion. However, some patients have midfacial hypoplasia without malocclusion. Perinasal osteotomy was performed with distraction osteogenesis to move the midface forward in 2 patients (a 17-year old female patient with Crouzon-like disease and a 15-year-old female patient with Antely-Bixler syndrome) with mild midface hypoplasia without malocclusion. The success of the procedure was assured by 3 features: the intermaxillary sutures were fixed by a mini metal plate to prevent separation during distraction; the distraction wires were fixed through the bone of the piriform aperture with the mini metal plates to prevent the wires from coming off; and the osteotomy line was designed in front of the palatomaxillary suture to avoid suture damage. These were expected to secure the procedure. Perinasal osteotomy with distraction osteogenesis is considered one of the recommended procedures for mild midfacial hypoplasia as seen in mild syndromic craniosynostosis without malocclusion.

P450 oxidoreductase deficiency with maternal virilization during pregnancy.

PURPOSE: The authors report on a rare case of maternal virilization during pregnancy caused by autosomal recessive P450 oxidore- ductase (POR) deficiency. MATERIALS AND METHODS: A 24-year-old primigravida developed a deepening voice and hirsutism in the second trimester. Prenatal ultrasonography failed to detect any fetal abnormality and fetal growth was normal. POR deficiency was suspected, but the mother declined fetal genetic testing. A female neonate was delivered by cesarean section at 41 weeks' gestation. RESULTS: The neonate had skeletal abnormalities. Mutational analysis of the POR gene demonstrated homozygosity for c.1370 G>A and p.R457H in the patient and heterozygosity in her parents. POR deficiency was confirmed in the neonate. CONCLUSION: POR deficiency should be suspected in cases of maternal virilization. Maternal urinary estriol, fetal magnetic resonance imaging, and parental genetic testing should be performed. Parental consent for fetal genetic testing should be sought to ensure prompt diagnosis and early treatment.

Disorder of sex development as a diagnostic clue in the first Spanish known newborn with P450 oxidoreductase deficiency.

We report the first known case of p450 oxidoreductase deficiency (PORD) in a Spanish boy who presented ambiguous genitalia at birth as a unique feature. He had palpable gonads in the inguinal canal and a normal 46,XY karyotype. Blood tests showed increased lanosterol and androgen precursors (17-OH-pregnenolone and 17-OH-progesterone) and low adrenal androgens (dehydroepiandrosterone and its sulfate). Blood pressure and serum electrolytes were normal. As he had low-testosterone response to human chorionic gonadotropin stimulation but responded to exogenous testosterone with phallic growth, male sex was assigned. Testosterone/dihydrotestosterone ratio and inhibin B were normal. Adrenal insufficiency was detected by corticotropin test. Hydrocortisone replacement treatment was administered. Congenital adrenal hyperplasia was ruled out and molecular analysis of POR gene showed the missense mutation p.Gly539Arg in compound heterozygosity located at splice acceptor site of intron 2 and the coding variant p.Gly80Arg. Surgery for cryptorchidism and hypospadias was performed.

Anesthetic risks associated with Antley-Bixler syndrome.

Antley-Bixler syndrome is an autosomal recessive disorder characterized by multiple bone and cartilaginous abnormalities. The main features of this syndrome include brachycephaly, midface hypoplasia, dysplasia of ears and nose, radiohumeral synostosis, choanal stenosis, or atresia. Distinctive features are based on craniofacial deformity and humeroradial synostosis. In this report, we describe the anesthesia management of a 20-year-old Antley-Bixler syndrome patient who underwent maxillary advancement via Le Fort I osteotomy. During surgical management of craniofacial syndrome patients, particularly Antley-Bixler syndrome, the whole surgical team should be aware of possible deformities involving the airway, which may be underestimated or nondetected prior to surgery. These deformities including choanal atresia/stenosis may lead to failure of nasotracheal intubation and mask ventilation, therefore jeopardizing the surgical procedure and/or patient safety. Accurate preoperative preparation and being aware of the components of this syndrome is vital to eliminate respiratory complications and enable uneventful anesthetic and surgical management.

Clinical and biochemical consequences of p450 oxidoreductase deficiency.

Patients with P450 oxidoreductase (POR) deficiency typically present with adrenal insufficiency, genital anomalies and bony malformations resembling the Antley-Bixler craniosynostosis syndrome. Since our first report in 2004, more than 40 POR mutations have been identified in over 65 patients. POR is the obligate electron donor to all microsomal P450 enzymes, including the steroidogenic enzymes CYP17A1, CYP21A2 and CYP19A1. POR deficiency may cause disordered sexual development manifested as genital undervirilization in 46, XY newborns as well as overvirilization in those who are 46, XX. This may be explained by impaired aromatization of fetal androgens that may cause maternal virilization and low urinary estriol levels during pregnancy. In addition, the alternate 'backdoor' pathway of androgen biosynthesis, which leads to dihydrotestosterone production bypassing androstenedione and testosterone, may also play a role. Functional assays studying the effects of POR mutations on steroidogenesis showed that several POR variants impaired CYP17A1, CYP21A2 and CYP19A1 activities to different degrees, indicating that each POR variant must be studied separately for each potential target P450 enzyme. POR variants may also affect skeletal development and drug metabolism. As most drugs are metabolized by hepatic microsomal P450 enzymes, studies of the impact of POR mutations on drug-metabolizing P450s are particularly important.

Cytochrome P450 oxidoreductase deficiency with Antley-Bixler syndrome: steroidogenic capacities.

For patients with cytochrome P450 oxidoreductase deficiency (PORD), steroid replacement is recommended at times of stress. However, it is unknown how hormones respond to actual physical stress in these patients. We report a female infant with PORD accompanied by the Antley-Bixler syndrome phenotype. Her urinary steroid profile revealed defective CYP17A1 and CYP21A2 activities, and an adrenocorticotropin (ACTH) stimulation test showed potential adrenal insufficiency. Hormonal responses to actual physical stress were as follows: Vigorous crying during blood sampling rarely affected the serum cortisol level. Acute viral gastroenteritis led to marked increases in blood ACTH and 17alpha-hydroxyprogesterone levels in proportion to the severity of the illness. The serum cortisol level also responded to this stress, but the response might have been blunted. Regarding peri-operative steroid replacement, intravenous hydrocortisone administration even at a dose of 6 mg/kg, which is lower than that recommended for congenital adrenal hyperplasia in Japan, proved to be excessive.