John G. Pappas, M.D.

Well-differentiated Pancreatic Neuroendocrine Carcinoma in Tuberous Sclerosis-Case Report and Review of the Literature
Arva, Nicoleta C; Pappas, John G; Bhatla, Teena; Raetz, Elizabeth A; Macari, Michael; Ginsburg, Howard B; Hajdu, Cristina H
2012 Jan;36(1):149-153, American journal of surgical pathology
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
— id: 147697, year: 2012, vol: 36, page: 149, stat: Journal Article,

UPD detection using homozygosity profiling with a SNP genotyping microarray
Papenhausen, Peter; Schwartz, Stuart; Risheg, Hiba; Keitges, Elisabeth; Gadi, Inder; Burnside, Rachel D; Jaswaney, Vikram; Pappas, John; Pasion, Romela; Friedman, Kenneth; Tepperberg, James
2011 Apr;155A(4):757-768, American journal of medical genetics. Pt A
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
— id: 135202, year: 2011, vol: 155A, page: 757, stat: Journal Article,

Congenital absence of the superior oblique tendon in Noonan-neurofibromatosis syndrome
Sugumaran, Hema K.; Pappas, John G.; Kodsi, Sylvia R.
2011 DEC ;15(6):593-594, Journal of AAPOS: American Association for Pediatric Ophthalmology & Strabismus
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
— id: 149886, year: 2011, vol: 15, page: 593, stat: Journal Article,

Successful pregnancy outcome in Ehlers-Danlos syndrome, vascular type
Palmquist, Maria; Pappas, John G; Petrikovsky, Boris; Blakemore, Karin; Roshan, Daniel
2009 Oct;22(10):924-927, Journal of maternal-fetal & neonatal medicine
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
— id: 145548, year: 2009, vol: 22, page: 924, stat: Journal Article,

Effect of growth hormone therapy on severe short stature and skeletal deformities in a patient with combined Turner syndrome and Langer mesomelic dysplasia
Shah, Bina C; Moran, Ellen S; Zinn, Andrew R; Pappas, John G
2009 Dec;94(12):5028-5033, Journal of clinical endocrinology & metabolism
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
— id: 105647, year: 2009, vol: 94, page: 5028, stat: Journal Article,

Greig cephalopolysyndactyly syndrome: diagnosis based on prenatal sonographic features coupled with comparative genomic hybridization
Timor-Tritsch, Ilan E; Kapp, Sarah; Berg, Robert; Bejjani, Bassem A; Adams, Sara Anne; Monteagudo, Ana; Divon, Michael; Pappas, John G
2009 Dec;28(12):1735-1742, Journal of ultrasound in medicine
— id: 105513, year: 2009, vol: 28, page: 1735, stat: Journal Article,

A molecular and clinical study of Larsen syndrome caused by mutations in FLNB
Bicknell, Louise S; Farrington-Rock, Claire; Shafeghati, Yousef; Rump, Patrick; Alanay, Yasemin; Alembik, Yves; Al-Madani, Navid; Firth, Helen; Karimi-Nejad, Mohammad Hassan; Kim, Chong Ae; Leask, Kathryn; Maisenbacher, Melissa; Moran, Ellen; Pappas, John G; Prontera, Paolo; de Ravel, Thomy; Fryns, Jean-Pierre; Sweeney, Elizabeth; Fryer, Alan; Unger, Sheila; Wilson, L C; Lachman, Ralph S; Rimoin, David L; Cohn, Daniel H; Krakow, Deborah; Robertson, Stephen P
2007 Feb;44(2):89-98, Journal of medical genetics
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
— id: 96974, year: 2007, vol: 44, page: 89, stat: Journal Article,

Multifocal renal oncocytoma in a patient with Von Hippel-Lindau mutation
Fiske, Joshua; Patel, Rupa; Kau, Eric; Pappas, John G; Garcia, Roberto A; Taneja, Samir S
2005 Dec;66(6):1320-1320, Urology
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
— id: 61863, year: 2005, vol: 66, page: 1320, stat: Journal Article,

Langer mesomelic dysplasia in a patient with 45, X/46, X, idic(X)
Moran, E; Hovanes, K; Perle, M; Kaffe, S; Pappas, J
2004 JUL-AUG ;6(4):304-304, Genetics in medicine
— id: 48693, year: 2004, vol: 6, page: 304, stat: Journal Article,

A stop codon mutation in COL11A2 induces exon skipping and leads to non-ocular Stickler syndrome
Vuoristo, Mirka Marjanna; Pappas, John Georgios; Jansen, Valerie; Ala-Kokko, Leena
2004 Oct 1;130(2):160-164, American journal of medical genetics. Pt A
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
— id: 48980, year: 2004, vol: 130, page: 160, stat: Journal Article,

Missense mutation in the PANK2 gene in a patient with atypical Pantothenate kinase associated neurodegeneration
Pappas, J; Borsuk, J; Das, S; Bennett, H
2003 NOV ;73(5):276-276, American journal of human genetics
— id: 55448, year: 2003, vol: 73, page: 276, stat: Journal Article,

Phenotypic and molecular cytogenetic characterization of a girl with mosaicism for terminal deletions of Chromosome 5p
Allan KM; Perle M; Pappas JG
2002 ;71(4 Suppl):293-294 Oct abstract #707, American journal of human genetics
— id: 48983, year: 2002, vol: 71, page: 293, stat: Journal Article,

A Puerto Rican boy with dislocated hips and radial heads and carpal coalition: a new case of syndrome described only in Puerto Rican children
Moran ES; Vepa S; Pappas JG
2002 ;71(4 Suppl):274-274 Oct abstract #599, American journal of human genetics
— id: 48982, year: 2002, vol: 71, page: 274, stat: Journal Article,

Deletion 3p25 in a mother and child
Pappas JG; Duncan C; Genovese M; Gu H; Jenkins EC
2002 ;71(4 Suppl):301-301 Oct absrract #755, American journal of human genetics
— id: 48984, year: 2002, vol: 71, page: 301, stat: Journal Article,

Phenotypic and molecular cytogenetic characterization of a child with a terminal deletion of 7q [Del(7) (Q36.2)]
Pappas JG; Reich E; Allan K; McMorrow ELE; Perle M; Wyandt HE; Milunski JM
2002 ;71(4 Suppl):298-298 Oct abstract #739, American journal of human genetics
— id: 48985, year: 2002, vol: 71, page: 298, stat: Journal Article,

Huntington's disease with childhood onset of mental retardation and possible late onset disease in the father
Pappas JG; Punales-Morejon D; Penchaszadeh VB
2000 ;67(4 Suppl):113-113 Dec abstract #566, American journal of human genetics
— id: 48992, year: 2000, vol: 67, page: 113, stat: Journal Article,

Possible mother-daughter transmission of Wildrervank syndrome
Pappas JG; Rimar E; Penchaszadeh VB
1999 ;65(4 Suppl):A337-A337 Oct abstract #1901, American journal of human genetics
— id: 48991, year: 1999, vol: 65, page: A337, stat: Journal Article,

De novo terminal deletion of 11q [del(11)(q24.2)]
Pappas JG; Sadiq A; Bhatt J; Babu A; Penchaszadeh VB
1998 ;63(4 Suppl):A146-A146 Oct abstract #826, American journal of human genetics
— id: 48990, year: 1998, vol: 63, page: A146, stat: Journal Article,

DAX1 mutations map to putative structural domains in a deduced three-dimensional model
Zhang YH; Guo W; Wagner RL; Huang BL; McCabe L; Vilain E; Burris TP; Anyane-Yeboa K; Burghes AH; Chitayat D; Chudley AE; Genel M; Gertner JM; Klingensmith GJ; Levine SN; Nakamoto J; New MI; Pagon RA; Pappas JG; Quigley CA; Rosenthal IM; Baxter JD; Fletterick RJ; McCabe ER
1998 Apr;62(4):855-864, American journal of human genetics
The DAX1 protein is an orphan nuclear hormone receptor based on sequence similarity in the putative ligand-binding domain (LBD). DAX1 mutations result in X-linked adrenal hypoplasia congenita (AHC). Our objective was to identify DAX1 mutations in a series of families, to determine the types of mutations resulting in AHC and to locate single-amino-acid changes in a DAX1 structural model. The 14 new mutations identified among our 17 families with AHC brought the total number of families with AHC to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. These mutations included 23 frameshift, 12 nonsense, and six missense mutations and one single-codon deletion. We mapped the seven single-amino-acid changes to a homology model constructed by use of the three-dimensional crystal structures of the thyroid-hormone receptor and retinoid X receptor alpha. All single-amino-acid changes mapped to the C-terminal half of the DAX1 protein, in the conserved hydrophobic core of the putative LBD, and none affected residues expected to interact directly with a ligand. We conclude that most genetic alterations in DAX1 are frameshift or nonsense mutations and speculate that the codon deletion and missense mutations give insight into the structure and function of DAX1
— id: 48981, year: 1998, vol: 62, page: 855, stat: Journal Article,

De novo duplication of distal 10q[dup(10)(q25.3q26.2]
Pappas JG; Hina SL; Bogosian V; Bhatt J; Babu A; Penchaszadeh VB
1997 ;61(4 Suppl):A137-A137 Oct abstract #777, American journal of human genetics
— id: 48989, year: 1997, vol: 61, page: A137, stat: Journal Article,

Mutations in DAX1 identified by sequencing of genomic DNA from patients with Adrenal Hypoplasia Congenita (AHC)
Zhang Y-H; Huang BL; Guo W; Vilain E; McCabe L; Buris TP; Anyane-Yeboa K; Burghes A; Chitayat D; Chudley AE; Gerner JM; Klingensmith G; Nakamoto J; New M; Pappas JG; Quigley CA; Rosenthal JM; Salisbury S; McCabe ERB
1996 ;59(4 Suppl):A296-A296 Oct abstract #1719, American journal of human genetics
— id: 48988, year: 1996, vol: 59, page: A296, stat: Journal Article,

Trisomy 2 mosaicism
Pappas JG; Havens G; Bogosian V; Batt J; Paka K; Babu A; Penchaszadeh VB
1995 ;57(4 Suppl):A286-A286 Oct abstract #1666, American journal of human genetics
— id: 48986, year: 1995, vol: 57, page: A286, stat: Journal Article,

Variants of alpha 1-antitrypsin in Puerto Rican children with asthma
Colp C; Pappas J; Moran D; Lieberman J
1993 Mar;103(3):812-815, Chest
A survey of 393 Puerto Rican and 354 non-Hispanic pediatric patients at Beth Israel Hospital, New York, revealed a significantly larger percentage of asthmatic subjects among Puerto Ricans, confirming findings of a study of Puerto Rican adults in New York. Assays of alpha 1-antitrypsin (AAT) concentration and phenotypes in 61 Puerto Rican asthmatic children revealed a significantly larger number with an S or Z variant in AAT phenotype. The AAT concentration was not a significant variable in this relationship, since four of five subjects with intermediate deficient AAT concentrations and a PiM phenotype were among control nonasthmatic Puerto Rican subjects. A family history of asthma was more common among asthmatic than control subjects and was most common for variant AAT phenotypes in either asthmatic or control subjects. We speculate that the S or Z variant of AAT affects the inflammatory response in such a way as to predispose to asthma
— id: 48979, year: 1993, vol: 103, page: 812, stat: Journal Article,