Editor—Neurofibromatosis type 1 (NF1) is a common human disorder (1/3500 live births) with neuroectodermal involvement primarily resulting in dermatological manifestations of café au lait spots, cutaneous/subcutaneous neurofibromas, and freckling of major skin folds.1 Owing to diagnostic uncertainties, especially in young patients, an international scoring system has been discussed and agreed upon.2 Half of the cases result from new mutations, while others show an autosomal dominant mode of inheritance. The encoded product, referred to as neurofibromin, is a member of the so called GTPase activating proteins (GAPs), and is an upstream downregulator of the RAS(p21)/RAF/MAPkinase3 and RAS/RAL4 signalling pathways. Although locus homogeneity is a hallmark of this condition, phenotypic heterogeneity has been exemplified by a wide spectrum of diversity ranging from malformation or malignant variants to virtually benign dermatological changes.1 In particular, and among the many causes of gastrointestinal involvement in NF1 patients, the association with intrinsic intestinal dysmotility, resulting from intestinal neuronal dysplasia type B (IND B)5 6 or aganglionic megacolon (Hirschsprung's disease, HSCR),7 has been documented and is now well established.

Interestingly, a substantial fraction of the phenotypic variability seen in NF1 patients might be governed by non-allelic, trait specific, “modifying” loci.8 Although the action of such modifying loci has been primarily shown in the number of café au lait spots or the number of cutaneous/subcutaneous neurofibromas, it can be speculated that such a genetic phenomenon might also be operative in other phenotypic traits, especially in individual or familial cases with an enteric phenotype.

The female proband from the family analysed here (fig 1A) had minor cutaneous manifestations of NF1, dysmorphic facial features (midface hypoplasia), congenital heart disease (ventricular septal defect, coarctation of the aorta), and congenital megacolon. She subsequently underwent a Duhamel abdominoperineal pull through and pathological …