Faculty Bibliography

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for approximately 5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

A 7-year-old white girl presented with left hemiparesis and ischemic stroke secondary to moyamoya syndrome, a progressive cerebrovascular occlusive disorder of uncertain but likely multifactorial etiology. Past medical history revealed hearing loss and developmental delay/intellectual disability. Routine karyotype demonstrated extra chromosomal material on 6p. Single nucleotide polymorphism microarray revealed a previously unreported complex de novo genetic rearrangement involving subtelomeric segments on chromosomes 6p and 12q. The duplicated/deleted regions included several known OMIM-annotated genes. This novel phenotype and genotype provides information about a possible association of genomic copy number variation and moyamoya syndrome. Dosage-sensitive genes in the deleted and duplicated segments may be involved in aberrant vascular proliferation. Our case also emphasizes the importance of comprehensive evaluation of both developmental delay and congenital anomalies such as moyamoya.

Abstract Mutation of the Wilms tumor gene (WT1) is associated with two well-described syndromes called Denys-Drash (DDS) and Frasier (FS). Both are associated with nephropathy and ambiguous genitalia and have overlapping clinical and molecular features. The known risk of Wilms tumor in DDS and gonadoblastoma (GB) in FS patients requires tumor surveillance. The literature reports the occurrence of GB in DDS as lower than FS. This case highlights a very early presentation of bilateral GB in DDS and the consideration of early prophylactic gonadectomy at the time of diagnosis with DDS.

Neuroendocrine tumors of the pancreas are rare in children. They usually occur in the setting of genetic syndromes such as multiple endocrine neoplasia type 1, von Hippel-Lindau disease, and neurofibromatosis 1. These tumors have also been reported in the tuberous sclerosis complex (TSC), but the incidence is low in comparison with other syndromes. Only 9 cases have been described to date, and it is not yet well understood if any connection exists between TSC and pancreatic endocrine tumors. TSC is characterized by mutations in TSC1 and TSC2 genes, which activate the AKT-mTOR oncogenic cascade. Recent molecular studies in pancreatic endocrine tumors showed activation of the same pathway, which points toward a common molecular pathway between these two entities. We present a case of well-differentiated neuroendocrine carcinoma of the pancreas in a child with TSC and discuss the genetic aspects of this disease

A 5-year-old girl with Noonan-neurofibromatosis syndrome was diagnosed with bilateral superior oblique palsy. At surgery, the right superior oblique tendon was absent, and further exploration revealed abnormal tissue inserting into Tenon's capsule. Orbital imaging was not performed. Congenital absence of the superior oblique tendon was diagnosed. Although Noonan syndrome is known to have many ocular manifestations, absence of the superior oblique tendon has not been previously reported.

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