Nevoid basal cell carcinoma syndrome with medulloblastoma in an African-American boy: A rare case illustrating gene-environment interaction

We present an 8-year-old African-American boy with medulloblastoma and nevoid basal cell carcinoma syndrome (NBCCS) who exhibited the radiosensitive response of basal cell carcinoma (BCC) formation in the area irradiated for medulloblastoma. Such a response is well-documented in Caucasian NBCCS patients with medulloblastoma. The propositus was diagnosed with medulloblastoma at the age of 2 years and underwent surgery, chemotherapy, and craniospinal irradiation. At the age of 6 years, he was diagnosed with NBCCS following his presentation with a large odontogenic keratocyst of the mandible, pits of the palms and soles and numerous BCCs in the area of the back and neck that had been irradiated previously for medulloblastoma. Examination of other relatives showed that the propositus' mother also had NBCCS but was more mildly affected; in particular, she had no BCCs. This case illustrates complex gene-environment interaction, in that increased skin pigmentation in African-Americans is presumably protective against ultraviolet, but not ionizing, radiation. This case and other similar cases in the literature show the importance of considering NBCCS in the differential diagnosis of any patient who presents with a medulloblastoma, especially before the age of 5 years, and of examining other close relatives for signs of NBCCS to determine the patient's at-risk status. Finally, for individuals who are radiosensitive, protocols that utilize chemotherapy in lieu of radiotherapy should be considered. Am. J. Med. Genet. 69:309-314, 1997. © 1997 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

KVLQT1 mutations in three families with familial or sporadic long QT syndrome

Congenital long QT syndrome (LQTS) is a heterogeneous group of heritable disorders characterized by prolongation of the QT interval on the electrocardiogram, ventricular arrhythmias and sudden death. At least four genes can, when mutated, produce this phenotype. Of these genes, the recently identified KVLQT1 potassium channel is thought to be the one most commonly responsible. In this study, we used single strand conformational polymorphism (SSCP) analysis to screen two large and nine small LQTS families for mutations of the KVLQT1 potassium channel gene. We identified a novel missense mutation in two unrelated families which substitutes a serine for a conserved glycine in the putative pore region of the KVLQT1 channel. In a third family, a new alanine to valine mutation at a CpG dinucleotide resulted in the spontaneous occurrence of the long QT syndrome in monozygotic twin offspring of unaffected parents. Mutations at this same nucleotide have been observed in eight of the 19 LQTS families determined to have KVLQT1 mutations, suggesting this is a mutational hot spot. Both of these mutations alter the amino acid sequence in, or adjacent to, the pore of the channel and many diminish the channel's ability to conduct a repolarizing potassium current. To date, all KVLQT1 mutations determined to cause the LQTS are missense mutations. These data confirm the role of KVLQT1 in the LQTS and suggest that mutant KVLQT1 proteins may exert a dominant negative effect on repolarizing potassium currents by forming multimers with normal potassium channel protein subunits, dramatically reducing the number of fully-functional KVLQT1 channels.      

Heterozygous tandem duplication within the PTCH1 gene results in nevoid basal cell carcinoma syndrome

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1. Using multiplex ligation-dependent probe amplification, we identified a heterozygous tandem duplication within the PTCH1 gene in a 14-year-old girl with typical NBCCS. We have sequenced the chromosomal breakpoint and determined the duplication as tandem in orientation and 18,814 bp in size. The fusion occurred between non-repetitive elements with an overlap of three nucleotides. The duplicated segment began at exon 10 and ended at intron 17. Subsequent analysis of cDNA from the patient showed the expression of mutant mRNA species containing a duplicated segment spanning exons 11-17, resulting in a frameshift and premature stop codon. This is the first reported case of NBCCS due to a tandem multiexon duplication of PTCH1 representing a novel mechanism leading to the NBCCS phenotype, and highlights the importance of copy number analysis as an adjunct to exon sequencing in identifying infrequent mutational events in PTCH1.     

Patched homologue 1 mutations in four Japanese families with basal cell nevus syndrome

AIM: To search for patched homologue 1 (PTCH1) mutations in four families with basal cell nevus syndrome (BCNS). METHODS: Mutation analysis of PTCH1 in unrelated Japanese families affected with BCNS was carried out by direct sequencing. RESULTS: Six novel PTCH1 mutations, 833G-->A in exon 6, 1415C-->A and 1451G-->T in exon 10, 2798delC in exon 17, 2918-2925dupAGTTCCCT in exon 18 and 3956C-->A in exon 23, were identified. CONCLUSIONS: Among the six PTCH1 mutations, two frameshift mutations (2798delC and 2918-2925dupAGTTCCCT) and one nonsense mutation (833G-->A) are predicted to lead to premature termination of PTCH1 protein translation. Three simultaneous mutations, 1415C-->A (A472D) and 1451G-->T (G484V) in exon 10, and 3956G-->A (R1319H) in exon 23, were found on one allele in only affected members in one family and none of them were found among 90 unrelated healthy Japanese. The three mutations on one chromosome may have resulted from errors in the recombinational repair process and this is the first report on the PTCH1 mutations due to such a mechanism.     

BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension

Primary pulmonary hypertension (PPH) is a potentially lethal disorder, in which heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR2) gene (BMPR2) have been identified. We conducted a molecular study of BMPR2 mutations in 4 Japanese families with familial PPH and 30 Japanese patients with sporadic PPH, and found 13 different mutations, of which 10 were novel, including missense (n=2), nonsense (n=4), frameshift (n=3), and splice-donor site (n=1) mutations. In total, BMPR2 mutations were found in all 4 familial PPH cases and 12 (40%) of the sporadic PPH cases. Further, a majority of the mutations found were predicted to cause premature termination, as previously reported. In the 9 mutations found in the sporadic cases, 2 were shown to be de novo, 2 were shared in multiple cases, 1 was shared with an FPPH case, and 1 was the same as previously reported in Caucasian FPPH. These results indicate that a substantial portion of Japanese PPH patients carry BMPR2 mutations with considerable heterogeneity.     

Erratum: BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension

During the rendering of the .pdf version of this article, the °C units were replaced with question marks in Table 1. Please find the proper Table 1 published in the online version of this erratum.     

Novel germline mutations in the APC gene of Cypriot patients with familial and sporadic adenomatous polyposis

Familial adenomatous polyposis (FAP) is one of the two commonest familial syndromes that predispose to colorectal cancer. FAP is caused by mutations in the adenomatous polyposis coli (APC) tumour suppressor gene that has a high penetrance. The disease is characterized by the occurrence of hundreds to thousands of colorectal polyps, which if left untreated give rise to colorectal cancer. In Cyprus, there are no molecular data available as yet on families with FAP. This work presents the results of APC analysis in our population for the first time. The APC gene was analyzed in 33 DNA samples from 20 individuals belonging to four FAP families and 13 patients with sporadic polyposis. We identified three truncating mutations, four missense mutations and 11 polymorphisms. It is of interest that two of the three truncating mutations, 2307delA and Q1242X, are novel, which supports the existence of a unique genetic pool in the Cypriot population. This ethnic molecular study in addition to highlighting population heterogeneity also contributes to phenotype-genotype associations that are essential for the clinical management of FAP families in Cyprus.     

Novel mutations in the PATCHED gene in basal cell nevus syndrome

Basal cell nevus syndrome (BCNS) is an autosomal dominant disease characterized by the presence of multiple basal cell carcinomas, odontogenic keratocysts, palmoplantar pits, and calcification in the falx cerebri caused by mutational inactivation of the PTCH gene. To investigate the molecular basis of BCNS in Chinese, we did a mutational analysis of the PTCH gene by performing denaturing high-performance liquid chromatography in three BCNS families. In this study, three novel mutations, two 1-bp frameshift insertions, i.e., 1468insA and 2392insC, and one 8-bp deletion, i.e., IVS5 + 1delGTAAGTGT, affecting a donor splice site, were identified. All the mutations cause a shift of the open reading frames and lead to premature termination of PTCH protein translation. Our results showed that mutational inactivation of the PTCH gene causes BCNS in Chinese.     

Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region

Townes-Brocks syndrome (TBS) is an autosomal dominant malformation syndrome characterized by renal, anal, ear, and thumb anomalies caused by SALL1 mutations. To date, 36 SALL1 mutations have been described in TBS patients. All but three of those, namely p.R276X, p.S372X, and c.1404dupG, have been found only in single families thereby preventing phenotype-genotype correlations. Here we present 20 novel mutations (12 short deletions, five short duplications, three nonsense mutations) in 20 unrelated families. We delineate the phenotypes and report previously unknown ocular manifestations, i.e. congenital cataracts with unilateral microphthalmia. We show that 46 out of the now 56 SALL1 mutations are located between the coding regions for the glutamine-rich domain mediating SALL protein interactions and 65 bp 3' of the coding region for the first double zinc finger domain, narrowing the SALL1 mutational hotspot region to a stretch of 802 bp within exon 2. Of note, only two SALL1 mutations would result in truncated proteins without the glutamine-rich domain, one of which is reported here. The latter is associated with anal, ear, hand, and renal manifestations, indicating that the glutamine-rich domain is not required for typical TBS.     

Microdeletion of 22q11.1 is associated with two cases of familial nonsyndromic basal cell carcinoma

Multiple basal cell carcinomas (BCCs) are a hallmark of Gorlin syndrome (nevoid basal cell carcinoma syndrome), which is caused by mutation in the PTCH1 gene on 9q22.3. However, there are several reports of familial cases with multiple BCCs without the associated defects of Gorlin syndrome. The possibility of underlying genetic abnormalities in these familial BCCs has not been explored previously. The present study investigated a possible genetic abnormality in two members of a family with multiple nonsyndromic BCCs. The possibility of Gorlin syndrome in this family was excluded by both the absence of any clinical and radiological features and the lack of mutation in PTCH1. Notably, whole-genome comparative genomic hybridization (CGH) identified a microdeletion in chromosome 22q11.1 in both of the studied cases. A tiling path CGH array of the 22q11.1 region confirmed this microdeletion and mapped it between 14.46 and 14.5 Mb on chromosome 22q. The 34-kb region of this microdeletion includes three annotated genes: LOC644525, LOC100132389, and LOC729057. Although future studies of other families with the hereditary nonsyndromic BCCs are still warranted, this study identified an association between a microdeletion of 22q11.1 and two familial cases of BCC.     

Undifferentiated sinonasal carcinoma in a patient with nevoid basal cell carcinoma syndrome

Nevoid basal cell carcinoma syndrome is an autosomal dominant multisystem disorder characterized by developmental anomalies and occurrence of multiple basal cell carcinomas and other tumors in early childhood. In this article, the authors report a case of a 19-year-old African American male with nevoid basal cell carcinoma syndrome and a history of medulloblastoma at age 2, meningioma at age 14, thyroid follicular adenomas with papillary carcinoma at age 15, and 2 basal cell carcinomas at ages 16 and 18. Recently, he developed sinonasal undifferentiated carcinoma (SNUC). The radiology and pathology of the sinonasal carcinoma are presented in this report. Review of the literature reveals that this is the first case of SNUC occurring in a patient with nevoid basal cell carcinoma syndrome.     

Cytologic features of metastatic sebaceous carcinoma: report of two cases with comparison to three cases of basal cell carcinoma.

The cytologic findings of two cases of metastatic sebaceous carcinoma are described and compared to three cases of locally recurrent basal cell carcinoma. Morphological findings for sebaceous carcinoma in fine-needle aspiration biopsy (FNAB) smears included cellular, loosely cohesive cell clusters with central necrosis, squamous pearl formation, and adjacent keratin debris. The tumor cells had moderate amounts of vacuolated cytoplasm, round to oval vesicular nuclei with clumped chromatin, nucleoli, some nuclear overlap, and numerous mitotic figures. An interesting finding was the presence of numerous multinucleated giant cells, probably responding to extravasated lipid or keratin material. In contrast, the FNAB smears of basal cell carcinoma typically were less cellular, with more tightly cohesive and smaller clusters of uniform hyperchromatic basaloid cells with high nuclear to cytoplasmic ratios, and a narrow rim of cytoplasm without vacuolization. The morphologic features of sebaceous carcinoma in FNAB smears appear to be distinct from those of basal cell carcinoma. FNAB can be a useful preoperative diagnostic technique to distinguish these two cutaneous malignancies.     

Spectrum of PTCH mutations in Italian nevoid basal cell-carcinoma syndrome patients: identification of thirteen novel alleles

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disease characterized by numerous basal cell carcinomas, odontogenic keratocysts of the jaws, palmar and plantal pits, skeletal abnormalities, and calcification of the falx cerebri. The gene responsible for this syndrome is the PTCH tumor suppressor gene encoding for the sonic hedgehog receptor. In this paper, we report thirteen novel mutations identified in the first screening of NBCCS patients in Italy. Except for p.T230P and p.F505_L506delinsLR, all the other mutations are predicted to determine a premature truncation of the protein.     

DHPLC analysis of patients with Nevoid Basal Cell Carcinoma Syndrome reveals novel PTCH missense mutations in the sterol-sensing domain

Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is an autosomal dominant disorder characterised by multiple basal cell carcinomas, palmar and plantar pitting, odontogenic keratocysts of the jaws and bilamellar calcification of the falx. Mutations in the PTCH gene are responsible for NBCCS but most studies have found mutations in less than half of the cases tested. We used denaturing high performance liquid chromatography (DHPLC) to screen for PTCH mutations in 28 NBCCS cases, most of whom had been previously evaluated by single stranded conformation polymorphism analysis but found to be negative. Protein truncating (n = 10) and missense or indel (n = 4) mutations were found in 14/28 (50%) cases and one additional case carried an unclassified variant, c.2777G>C. Thirteen of the variants were novel. The mutation frequency was similar in inherited and de novo cases. Three of the missense and indel mutations were in the sterol-sensing domain, and one was in the sixth transmembrane domain.     

Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome

Kallmann syndrome is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Putative loss-of-function mutations in PROKR2 or PROK2, encoding prokineticin receptor-2 (a G protein-coupled receptor), and one of its ligands, prokineticin-2, respectively, have recently been reported in approximately 10% of Kallmann syndrome affected individuals. Notably, given PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state in patients, thus raising the question of a possible digenic inheritance of the disease in heterozygous patients. Indeed, one of these patients was also carrying a missense mutation in KAL1, the gene responsible for the X chromosome-linked form of Kallmann syndrome. Mutations in PROK2, however, have so far been found only in the heterozygous state. Here, we report on the identification of PROK2 biallelic mutations, that is, a missense mutation, p.R73C, and a frameshift mutation, c.163delA, in two out of 273 patients presenting as sporadic cases. We conclude that PROK2 mutations in the homozygous state account for a few cases of Kallmann syndrome. Moreover, since the same R73C mutation was previously reported in the heterozygous state, and because Prok2 knockout mice exhibit an abnormal phenotype only in the homozygous condition, we predict that patients carrying monoallelic mutations in PROK2 have another disease-causing mutation, presumably in still undiscovered Kallmann syndrome genes.     

Twenty-six novel EFNB1 mutations in familial and sporadic craniofrontonasal syndrome (CFNS)

Craniofrontonasal syndrome (CFNS) is an X-linked disorder characterized by a more severe manifestation in heterozygous females than in hemizygous males. Heterozygous females have craniofrontonasal dysplasia (CFND) and occasionally extracranial manifestations including midline defects and skeletal abnormalities, whereas hemizygous males show no or only mild features such as hypertelorism and rarely show cleft lip or palate. Mutations in the EFNB1 gene in Xq12 are responsible for familial and sporadic CFNS. The EFNB1 gene encodes ephrin-B1, a transmembrane ligand that also exhibits receptor-like effects. We performed mutation analysis in nine unrelated families and 29 sporadic patients with CFNS. DNA sequencing revealed mutations in 33 (86.8%) cases including 26 distinct novel mutations. A recurrent nonsense mutation, c.196C>T/R66X, was detected in one family and four sporadic patients. The majority of mutations (26/33) were located in exons 2 and 3 of the EFNB1 gene encoding the extracellular ephrin domain. The mutation spectrum includes frameshift, nonsense, missense, and splice site mutations, with a predominance of frameshift and nonsense mutations resulting in premature truncation codons. For the first time we describe mutations in exons 4 and 5 of EFNB1. Of particular interest are the frameshift mutations located in the last 25 codons of EFNB1 encoding the carboxyterminal end of ephrin-B1. They result in an extension by 44 residues. These mutations disrupt the intracellular binding sites for Grb4 and PDZ-effector proteins involved in reverse signaling. We conclude that the major causes of familial as well as sporadic CFNS are loss of function mutations in the EFNB1 gene that comprise premature termination or abrogate receptor-ligand interaction, oligomerization, and ephrin-B1 reverse signaling.