Novel mutation in cytochrome P450c17 causes complete combined 17alpha-hydroxylase/17,20-lyase deficiency.

BACKGROUND: Cytochrome P450c17 (CYP17) has two principal enzyme activities, 17alpha-hydroxylase and 17,20-lyase, which are required for cortisol and androgen biosynthesis, respectively. Mutations in the gene encoding for CYP17 result in 17alpha-hydroxylase deficiency (17OHD), a rare form of congenital adrenal hyperplasia, a disorder characterized by adrenal insufficiency, hypertension, primary amenorrhea and sexual infantilism. We describe a case of complete combined 17OHD caused by mutations in the CYP17 gene. PATIENT: This study evaluates a 19 year-old Korean female born from a non-consanguineous relationship who presented with primary amenorrhea, hypertension, hyperpigmentation, absent axillary hair and pubic hair, and Tanner I breasts. Laboratory evaluation showed markedly elevated adrenocorticotropin and 11-deoxycorticosterone with suppressed plasma renin, aldosterone, and cortisol, consistent with 17OHD. METHODS: Genomic DNA was isolated from peripheral blood leukocytes. The eight exons of the human CYP17 gene were amplified in four segments by polymerase chain reaction. Amplicons were gel-purified and directly sequenced. RESULTS: The patient was found to be compound heterozygous for mutations in exon 6: a novel mutation R358X (CGA--TGA) and Y329 del/ sub (TAC-->AA). Both alterations introduce premature stop codons prior to the hemebinding cysteine and are predicted to completely inactivate the encoded P450c17 proteins. CONCLUSION: This patient is a compound heterozygote for nonsense mutations in the CYP17 gene, which confirms the diagnosis of 17OHD.

Exclusion of APC and VHL gene deletions by array-based comparative hybridization in two patients with microscopically visible chromosomal aberrations.

Karyotyping is a major component of the genetic work-up of patients with dysmorphism. Cytogenetic aberrations close to a known tumor suppressor gene raise important clinical issues because deletion of that tumor suppressor gene can cause genetic predisposition to cancer. We present two cancer-free dysmorphic patients with karyotypes of 46,XX,del(5)(q15q22.3) and 46,XX,del(3)(p25.2~pter). These deletions are close to the APC and VHL genes that confer susceptibility to familial Adenomatous polyposis (OMIM #17510) and von-Hippel-Lindau syndrome (OMIM #193300), respectively. The array-based comparative genomic hybridization (array-CGH) analysis using a custom Agilent 44K oligonucleotide array demonstrated an interstitial 20.7-megabase (Mb) deletion on 5q (chr5: 89,725,638-110,491,345) and a terminal 9.45-Mb deletion on 3p (chr3:pter-9,450,984). According to the March 2006 human reference sequence, the APC gene is located at chr5: 112,101,483-112,209,835 and the VHL gene is located at chr3: 10,158,319-10,168,746. These results indicate that the APC gene is 2,300 kilobases (kb) and the VHL gene is 700 kb away from deleted regions. Southern blot analysis for APC and VHL genes were negative, consistent with array-CGH findings. These results demonstrate the power of array-CCH to assess potential tumor suppressor gene involvement and cancer risk in patients with microscopically visible deletions in areas near tumor suppressors.

Familial congenital bilateral vocal fold paralysis: a novel gene translocation.

OBJECTIVES: True vocal fold (TVF) paralysis is a common cause of neonatal stridor and airway obstruction, though bilateral TVF paralysis is seen less frequently. Rare cases of familial congenital TVF paralysis have been described with implied genetic origin, but few genetic abnormalities have been discovered to date. The purpose of this study is to describe a novel chromosomal translocation responsible for congenital bilateral TVF immobility. METHODS: The charts of three patients were retrospectively reviewed: a 35 year-old woman and her two children. The mother had bilateral TVF paralysis at birth requiring tracheotomy. Her oldest child had a similar presentation at birth and also required tracheotomy, while the younger child had laryngomalacia without TVF paralysis. Standard karyotype analysis was done using samples from all three patients and the parents of the mother, to assess whether a chromosomal abnormality was responsible. RESULTS: Karyotype analysis revealed the same balanced translocation between chromosomes 5 and 14, t(5;14) (p15.3, q11.2) in the mother and her two daughters. No other genetic abnormalities were identified. Neither maternal grandparent had the translocation, which appeared to be a spontaneous mutation in the mother with autosomal dominant inheritance and variable penetrance. CONCLUSIONS: A novel chromosomal translocation was identified that appears to be responsible for familial congenital bilateral TVF paralysis. While there are other reports of genetic abnormalities responsible for this condition, we believe this is the first describing this particular translocation.

Pregnancy outcome in a woman with prune belly syndrome.

Prune belly syndrome is a rare congenital syndrome that primarily affects male fetuses. Affected men are universally infertile; however, there is a paucity of information published on the reproductive potential of affected women. Pregnancy outcomes in affected women have not been described in the literature. We describe the case of pregnancy in an affected woman. Her pregnancy progressed without complication. Her fetus had no stigmata of the syndrome. Her labour and delivery were, however, complicated by a prolonged second stage of labour and need for vacuum-assisted vaginal delivery.

Prenatal Diagnosis of Cystic Hygroma related to a Deletion of 16q24.1 with Haploinsufficiency of FOXF1 and FOXC2 Genes.

We report the prenatal diagnosis of cystic hygroma that was subsequently identified to have haploinsufficiency of the FOXF1 and FOXC2 genes via array comparative genomic hybridization (aCGH). Deletion o f these genes has previously neither been associated with cystic hygroma nor prenatally diagnosed. The FOX gene cluster is involved in cardiopulmonary development. This case expands the phenotypic spectrum o f abnormalities of the FOXF1 and FOXC2 genes, as it seems within the spectrum of function that disruption of the FOX gene cluster would lead to include abnormalities of prenatal onset. Identification of this association would not be possible with conventional karyotype or targeted aCGH. This case highlights the power of whole genomic aCGH to further delineate the etiology of birth defects.

Chromosome deletion of 14q32.33 detected by array comparative genomic hybridization in a patient with features of dubowitz syndrome.

We report a 4-year-old girl of Mexican origins with a clinical diagnosis of Dubowitz syndrome who carries a de novo terminal deletion at the 14q32.33 locus identified by array comparative genomic hybridization (aCGH). Dubowitz syndrome is a rare condition characterized by a constellation of features including growth retardation, short stature, microcephaly, micrognathia, eczema, telecanthus, blepharophimosis, ptosis, epicanthal folds, broad nasal bridge, round-tipped nose, mild to moderate developmental delay, and high-pitched hoarse voice. This syndrome is thought to be autosomal recessive; however, the etiology has not been determined. This is the first report of this deletion in association with this phenotype; it is possible that this deletion may be causal for a Dubowitz phenocopy.