Pheochromocytomas are neural crest–derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1α. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1α activity in tumors.

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Desmopressin was able to stimulate the pituitary-adrenal axis in patients with Cushing's disease and, like corticotrophin releasing hormone, it may prove useful in the differential diagnosis of Cushing's syndrome.

Phaeochromocytomas may occur sporadically, or as part of the inherited cancer syndromes multiple endocrine neoplasia (MEN) type 2, von Hippel-Lindau disease (VHL), and, rarely, in type 1 neurofibromatosis. In MEN 2, germline missense mutations have been found in one of eight codons within exons 10, 11, 13, 14, and 16 of the RET proto-oncogene. In VHL, germline mutations within one ofthe three exons are responsible for the majority of cases. To determine if somatic mutations similar to those seen in the germline in MEN 2 or VHL disease play a role in the pathogenesis ofsporadic or familial phaeochromocytomas, we analysed 48 sporadic tumours and tumours from 17 MEN 2 and five VHL patients for mutations in RET exons 9, 10, 11, 13, 14, 15, and 16, and the entire coding sequence of VHL. Five of 48 sporadic phaeochromocytomas had RET mutations within exons 10, 11, and 16. Of these, one was proven to be germline and two were proven to be somatic mutations. Four of 48 had VHL mutations; these included both the bilateral cases in the series (one was proven to be a germline mutation) and two others, of which one was proven somatic. (J Med Genet 1995;32:934-937) The susceptibility genes for VHL and MEN 2 have been identified using positional cloning techniques. Germline deletions and intragenic mutations have been detected along the length of the VHL tumour suppressor gene, which encodes a protein of unknown function, in approximately 70% of VHL kindreds.'01' In the majority of families with the three MEN 2 syndromes, germline missense mutations have been found in one of eight codons of the RET proto-oncogene, which codes for a receptor tyrosine kinase.12-20 Mutation in one of codons 609, 611, 618, 620 (exon 10), 634 (exon 11), 768 (exon 13), or 804 (exon 14) is responsible for the majority of MEN 2A and FMTC families, while a missense mutation in methionine codon 918 (exon 16) is responsible for >93% of MEN 2B cases.20To determine if somatic RET and VHL mutations play a role in tumour progression in sporadic or familial phaeochromocytomas, mutation analyses of the VHL gene and those exons of the RET proto-oncogene which have been shown previously to be involved in MEN 2 or MTC were performed in phaeochromocytomas from sporadic cases and from MEN 2 and VHL patients.

Acheiropodia is an autosomal recessive developmental disorder presenting with bilateral congenital amputations of the upper and lower extremities and aplasia of the hands and feet. This severely handicapping condition appears to affect only the extremities, with no other systemic manifestations reported. Recently, a locus for acheiropodia was mapped on chromosome 7q36. Herein we report the narrowing of the critical region for the acheiropodia gene and the subsequent identification of a common mutation in C7orf2-the human orthologue of the mouse Lmbr1 gene-that is responsible for the disease. Analysis of five families with acheiropodia, by means of 15 polymorphic markers, narrowed the critical region to 1.3 cM, on the basis of identity by descent, and to <0.5 Mb, on the basis of physical mapping. Analysis of C7orf2, the human orthologue of the mouse Lmbr1 gene, identified a deletion in all five families, thus identifying a common acheiropodia mutation. The deletion was identified at both the genomic-DNA and mRNA level. It leads to the production of a C7orf2 transcript lacking exon 4 and introduces a premature stop codon downstream of exon 3. Given the nature of the acheiropodia phenotype, it appears likely that the Lmbr1 gene plays an important role in limb development.