Faculty Bibliography

Background: Contiguous gene deletion of the Wilms tumor gene (WT1) is associated with two well described syndromes; Denys-Drash (DDS) and Frasier (FS). Both are associated with nephropathy and ambiguous genitalia and have overlapping clinical and molecular features (1). The known risk of Wilms tumors in DDS and gonadoblastomas in FS patients requires tumor surveillance.Case report: We evaluated a newborn with ambiguous genitalia, intact Mullerian structures (uterus) and small bilateral perivesicular gonads with a 46,XY (SRY+) karyotype. The physical exam revealed labia with clitoromegaly (1.2 cm in length). There were separate uretheral and vaginal openings with no urogenital sinus. Labs in the early neonatal period (Quest Diagnostics: all male references) revealed 17-OH-Progesterone 96 (<420 ng/dL), testosterone 133 (2-23 ng/dL; tanner 1), DHEAS 441 (73-367 ug/dL), inhibin A <1 (<21 pg/mL; prepubertal), inhibin B 35 (<161 pg/mL; 3-9 years old), and AMH 3.7 (87.3-243 ng/mL; 1-6 years old). After a joint discussion with the family, geneticist, endocrinologist, and psychologist the infant was assigned a female gender. Based on the phenotype (ambiguous genitalia, pre and postnatal hydronephrosis, and genitourinary abnormalities), the exon and exon-intron boundaries were sequenced. A missense mutation leading to the substitution of lysine for glutamine at position 369 of the WT1 protein (Q369K) in exon 8 was found to be consistent with Denys-Drash syndrome. At seven months of age the patient underwent a clitoroplasty and gonadectomy. Bilateral gonadoblastomas were found in an indeterminate left gonad and a right testis. In addition, the patient had bilateral grade 2-3 vesicoureteral reflux and progressed to end stage renal failure at 11 months of age (creatinine 1.4mg/dl). Consequently, the patient has secondary hyperparathyroidism with PTH 691 (12-65 pg/mL), calcium 7.2 (8-10.4 mg/dL), and phosphorus 7 (2.7-4.5 mg/dL). The patient's most recent renal ultrasound does not show evidence of a Wilms tumor (2).Conclusion: This is one of the earliest cases of bilateral gonadoblastoma reported in DDS. This case highlights the importance of early gonadectomy at the time of diagnosis of the WT1 gene mutation as these tumors have potential for malignant transformation

Single nucleotide polymorphism (SNP) based chromosome microarrays provide both a high-density whole genome analysis of copy number and genotype. In the past 21 months we have analyzed over 13,000 samples primarily referred for developmental delay using the Affymetrix SNP/CN 6.0 version array platform. In addition to copy number, we have focused on the relative distribution of allele homozygosity (HZ) throughout the genome to confirm a strong association of uniparental disomy (UPD) with regions of isoallelism found in most confirmed cases of UPD. We sought to determine whether a long contiguous stretch of HZ (LCSH) greater than a threshold value found only in a single chromosome would correlate with UPD of that chromosome. Nine confirmed UPD cases were retrospectively analyzed with the array in the study, each showing the anticipated LCSH with the smallest 13.5 Mb in length. This length is well above the average longest run of HZ in a set of control patients and was then set as the prospective threshold for reporting possible UPD correlation. Ninety-two cases qualified at that threshold, 46 of those had molecular UPD testing and 29 were positive. Including retrospective cases, 16 showed complete HZ across the chromosome, consistent with total isoUPD. The average size LCSH in the 19 cases that were not completely HZ was 46.3 Mb with a range of 13.5-127.8 Mb. Three patients showed only segmental UPD. Both the size and location of the LCSH are relevant to correlation with UPD. Further studies will continue to delineate an optimal threshold for LCSH/UPD correlation

BACKGROUND: Homozygous mutation of the short stature homeobox-containing gene, SHOX, results in Langer mesomelic dysplasia (LMD). Our case presented with severe short stature and skeletal deformities with Turner syndrome (TS) and a SHOX gene abnormality due to a downstream allele deletion in her normal X chromosome. Medical literature review did not reveal similar cases that were treated with GH therapy. METHOD: We present an 11-yr-old with combined TS and LMD with severe short stature and skeletal deformities. She was studied for the effect of GH therapy on stature and skeletal deformities. Karyotype testing showed 45,X/46,X,idic(X). Genetic analysis of SHOX gene testing did not detect any exonic mutations. Interestingly, both alleles of the flanking marker DXYS233, a marker downstream of the 3' end of SHOX coding sequence, were absent with resultant LMD. GH therapy in the mean dose of 0.321 mg/kg/wk was administered for 4 yr (0.287, 0.355, 0.317, and 0.327 mg/kg/week in the first, second, third, and fourth years, respectively). Clinical data were reviewed. RESULT: The growth rates of 3.46, 3.87, 2.3, and 0.7 cm/yr were observed in the first, second, third, and fourth years of the GH therapy, respectively. There was no clinical deterioration of the skeletal deformities. CONCLUSION: There was a failure to achieve growth improvements with GH therapy for 4 years, but there was no worsening of the skeletal deformities. We conclude that GH therapy may not be beneficial in severe short stature due to combined TS and LMD resulting from homozygous SHOX deficiency

BACKGROUND: Ehlers-Danlos syndrome (EDS) is a rare connective tissue disorder characterized by tissue fragility, translucent skin and joint hypermobility. Patients with the vascular type of EDS are prone to spontaneous arterial and visceral rupture. Pregnancy for women with vascular EDS can be life-threatening. Mortality rates are high due to the increased risk for uterine and arterial rupture in the peripartum period. CASE: We describe the counseling, multidisciplinary management, protocol, and successful pregnancy outcome of a 32-year-old woman with vascular EDS. CONCLUSION: There is no consensus in the literature on the timing and mode of delivery for pregnant women with vascular EDS. The management undertaken in our patient may assist others in optimizing the perinatal outcome in other women who elect to continue their pregnancy despite the risks of this severe medical condition

BACKGROUND: Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied. METHODS: Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated. RESULTS AND DISCUSSION: The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB

Von Hippel-Lindau disease (VHL) is a rare genetic disease with a lifetime risk of clear cell renal cell carcinoma in approximately 70% of cases. We present a case of a 63-year-old man with bilateral, multifocal renal masses. Genetic testing results were consistent with a VHL deletion. The patient had no other disease manifestations consistent with VHL. The patient underwent staged bilateral nephron-sparing procedures. Pathology of all renal masses revealed oncocytoma. To our knowledge, we describe the first reported case of multiple renal oncocytomas in a male patient with a germline VHL mutation

Mutations in COL11A2 cause a spectrum of phenotypes affecting chondrogenic tissues. We analyzed this gene by conformation sensitive gel electrophoresis (CSGE) and sequencing in a family with non-ocular Stickler syndrome, and found a heterozygous C --> T mutation in exon 57 + 13 in affected members, resulting in Arg893Stop codon. Since heterozygous nonsense mutations in COL11A2 do not usually lead to any obvious phenotype, all exons and exon boundaries of COL11A2 in the sample of the propositus were sequenced. Because no disease-associated alterations were found, we performed RT-PCR analysis on the RNA. Analysis showed skipping of exon 57 in one allele, resulting in an inframe deletion of 54 bp or 18 amino acids, which would explain the phenotype observed in the family. Thus, the exon skipping resulted from a nonsense-associated altered splicing (NAS). This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html