Autosomal dominant inheritance of a heterozygous mutation in <i>SAMHD1</i> causing familial chilblain lupus

Abstract

Chilblain lupus is considered a dermatological subtype of systemic lupus erythematosus (SLE), and is typically characterized by tender, bluish red swellings and nodules on the hands, feet, ears, and nose, with histological changes of lupus [Crowson and Magro, 1997]. The phenotype is induced by cold so that patients frequently report a worsening of lesions in the winter months. A cold dependency likely explains the peripheral distribution of the cutaneous lesions seen. Chilblain lupus usually occurs sporadically in middle-aged women, and the pathology of the disorder remains poorly understood. However, a familial form of the disease, inherited as an autosomal dominant trait, has been described in two families segregating distinct mutations in TREX1 [Lee-Kirsch et al., 2007a; Rice et al., 2007a]. TREX1 mutations also cause some cases of the genetic encephalopathy Aicardi–Goutières syndrome (AGS) [Crow et al., 2006]. Interestingly, approximately 40% of patients with AGS experience chilblains, so that familial chilblain lupus (FCL) might usefully be considered as a forme fruste of AGS [Rice et al., 2007b]. Of further note, heterozygous mutations in TREX1 represent the single most common cause of SLE identified to date [Lee-Kirsch et al., 2007b]. In 2009, we reported biallelic SAMHD1 mutations in patients with AGS [Rice et al., 2009]. More recently, we have described mutations in SAMHD1 to cause a relatively nonspecific inflammatory phenotype including a progressive arthropathy with distal joint contractures, painful mouth ulcers, and chilblains [Dale et al., 2010]. Here, we present a mother and son with typical features of FCL, segregating a heterozygous mutation in SAMHD1. The proposita is a 46-year-old white woman who was initially seen at the age of 13 years because of chilblains. Since the age of 4 years she experienced recurrent lesions, particularly prominent over the winter months, affecting her hands, feet, buttocks, and thighs (Fig. 1). Additionally, she complained of sensitivity to the sun, with a tendency to the development of a sunburn-like reaction on minimal sun exposure. Her parents were nonconsanguineous and there was no antecedent family history of note. Clinical appearance and biopsy findings of observed chilblains. Chilblains on the dorsal (A) and ventral surfaces (B), of the hands of Patient 1, and the feet of Patient 2 (C). Fixed angiomatous lesions are illustrated on the dorsal surface of the fingers of Patient 2 (D). E: demonstrates lesions above the knees in Patient 1. A biopsy taken from acral skin of Patient 1 at age 13 years shows a florid perivascular lymphocytic vasculitis, papillary dermal edema, and an interface dermatitis with keratinocyte necrosis (F). All blood investigations were normal, including an extensive autoantibody panel, complement levels, cryoglobulins, cold agglutinins, and a porphyria screen. In addition to the chilblain lesions on the hands, she developed angiomatous lesions on the fingers which became persistent. Biopsy of chilblain lesional skin demonstrated a florid lymphocytic vasculitis, with papillary dermal edema, interface dermatitis, and keratinocyte necrosis, consistent with lupus. Management has been with nifedepine over the winter months, and hydroxychloroquine plus sun block in the summer. The second patient is a 15-year-old male, son of the proposita. His parents are nonconsanguineous. He was seen initially at age 9 months with chilblains on the feet, fingers and ears. These lesions had been present from 3 months of age. Subsequently, during the summer, he also experienced photosensitivity with a sunburn like reaction to sunlight, and he has developed fixed angiomatous lesions on the fingers. Physical signs were very similar to the proposita. He underwent the same battery of tests as his mother, with normal results. Biopsy was declined. Treatment with nifedepine during the winter and hydroxychloroquine during the summer was commenced in infancy with some benefit. Recently, he has chosen to manage with no treatment except sun block in the summer months. Appropriate written informed consent was obtained for inclusion in this study, which was approved by the Leeds (East) Multi-Centre Research Ethics Committee. Genomic DNA was extracted from peripheral blood leucocytes using standard techniques. Primers were designed to amplify the coding exons of SAMHD1 as described previously [Rice et al., 2009]. Mutation description is based on the reference cDNA sequence NM_015474, numbering relative to 1 = A of the initiator codon. Both patients were shown to be heterozygous for a T > A transversion at position 602 in exon 5 of SAMHD1, leading to the substitution of an asparagine for an isoleucine at amino acid 201 (I201N). The isoleucine residue at this position is conserved to the sea anemone Nematostella vectensis. This mutation, which has been seen in four AGS families, was not present in 450 non-AGS/FCL control alleles. No mutations were identified in TREX1, RNaseH2A, RNaseH2B, or RNaseH2C. Here, we describe a mother and son with a history of early onset chilblains conforming to the clinical and histological characteristics of FCL. Both patients, who were otherwise in good health, carry the same heterozygous mutation in SAMHD1. Considering that this molecular lesion is not annotated as a polymorphism on the available databases, was not present on more than 450 control alleles, shows high evolutionary conservation, and has been identified in four families segregating an AGS phenotype, we are confident that it is pathogenic. The lack of phenotypic expression for the same mutation in three parents, of children with AGS, shown to harbor the I201N mutation in the heterozygous state is of note. Although the possibility of variants at other loci remains, we speculate that such phenotypic variability relates to stochastic differences in enzyme activity. An analogous situation has been observed in relation to TREX1. Thus, Lee-Kirsch et al. [2007a] reported a D18N heterozygous mutation in TREX1 to segregate with an FCL phenotype in a large dominant family. Interestingly, we have recently observed the exact same heterozygous D18N mutation, occurring as a de novo event, in a female with both chilblains and neurological involvement typical of AGS [Haaxma et al., 2010]. Although the function of the 626 amino-acid protein SAMHD1 remains unknown, evidence suggests that, like TREX1, it has an important role in innate immunity and inflammation [Crow and Rehwinkel, 2009]. Following on from our recent description of progressive arthropathy with distal joint contractures and painful mouth ulcers in association with bialleic SAMHD1 mutations [Dale et al., 2010], and of a large vessel intracerebral vasculitis in patients with SAMHD1-associated AGS [Ramesh et al., 2010], this current report further highlights the variable inflammatory phenotypes which can arise due to mutations in SAMHD1. Moreover, by analogy with TREX1, our findings suggest a possible role for SAMHD1 in the pathogenesis of SLE. We would like to thank the family for their cooperation in this study. YJC acknowledges the Manchester NIHR Biomedical Research Centre. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 241779.