@article {1848, title = {A mosaic sperm donor fathers a large group of half sibs with NF1. Rapid Response Re: Danish sperm donor passed neurofibromatosis on to five children }, journal = {BMJ}, volume = {345}, year = {2012}, chapter = {e6570}, abstract = {

A Danish sperm donor was earlier in BMJ reported to have passed neurofibromatosis on to five children (1). The sperm donor no 7042 from Nordic Cryobank ApS, has fathered several offspring with neurofibromatosis type 1 (2), NF1, worldwide. In 2009 the first offspring diagnosed with NF1 based on clinical findings was reported from Belgium. This case was considered a de novo mutation and not until reports of another two offspring from the US the sperm bank occurred the distribution of specimen from the donor was discontinued. Thorough genetic analysis of the donor sperm demonstrated an intragenic deletion spanning exon 11-23.1 in the NF1 gene and revealed a germ line mosaicism of approximately 20\% (3). In a letter to the involved Danish fertility clinics Nordic Cryobank ApS informed of an expected risk of 10-20 \% for NF1 inheritance among the donor offspring. This estimate was maintained in their recent update letter to the fertility clinics (4).

After Danish donor recipients contacted several Danish public medias this unfortunate, very unusual and controversial case has from May 2011 been given much attention in both the Danish (5, 6) and international media (7, 8) regarding the clinical, ethical, commercial and political aspects. The scientific society yet remains to become fully engaged to qualify the given information, to facilitate knowledge necessary for renewal of relevant national and international legislation on donation of germ cells, and not least in importance to sample and report whatever new information on genetics and neurofibromatosis the study of this rare half sib ship may generate.

The total number worldwide of donor 7042 offspring is still unknown. Nordic Cryobank ApS has not published the figures. In September 2012 based on information from the Danish National Board of Health, the Danish Broadcasting Corporation, DR TV, reported of 43 children conceived in Danish fertility clinics of which 25 are Danish citizens and 18 are citizens in Norway and Sweden. It was stated that nine of the Danish children are known to have inherited NF1. Furthermore the donor specimens have been used in USA, Canada, Belgium, Island, Georgia, Greece, Spain and Thailand. According to the world\’s largest sperm bank, Cryos International \– Denmark ApS, who exports to more than 70 countries, one single donor could possibly father more than 200 children globally (5, 6).

At Centre for Rare Diseases, Aarhus University Hospital, one of the two Danish reference centres for NF1 patients we have since 2010 examined 17 offspring of donor no 7042 of whom eight have NF1. Moreover we know of another three Danish affected offspring. Our data strongly suggest an inheritance risk of 50 \% equal to the general risk for all autosomal dominant disorders. Our findings are in accordance with two previous reports where germ line mosaicisms of 10 \% and 10-17 \% have lead to sib ships of 3:6 and 2:3 diagnosed with NF1 respectively (9, 10). Therefore, in future genetic counselling we highly recommend to inform of an up to 50 \% risk of NF1 affected offspring in the present case of donor no 7042. Also the same risk applies to autosomal dominant disorders in general.

Autosomal dominant diseases have previously been diagnosed in offspring of sperm donors e.g. hypertrophic cardiomyopathy, Marfan syndrome, and polycystic kidney disease (11,12). Similar cases are likely to occur in the future since the nature of germ line mosaicism remains, and since the concept of sperm donation has evolved into a large worldwide profitable industry. After the Danish law regarding artificial conception, recently underwent revision, the Danish Board of Health now recommend to restrict the earlier permitted number of 25 to 12 pregnancies per sperm donor (13). The present case underlines an instant need for international legislation and regulation. The primary goal must be to avoid a greater number of affected offspring from a disease gene carrying sperm donor than could have occurred from natural conception. Moreover the politicians should aim at preventing an artificial excessive spread of the same set of human genes leading to an increased risk of inbreeding, an overall hazard to genetic health in any species.

To secure possible future scientific follow up we initiate The 7042 Donor NF1 Sibling Register. The register will facilitate the study of phenotypic variability in the genotype identical NF1 patients. This may reveal important new knowledge of other genes modifying the NF1 gene and thereby possibly contribute to future individualised targeted clinical follow up and treatment.

}, keywords = {Child, Denmark, Humans, Male, Neurofibromatoses, Norway, Spermatozoa, Sweden, Tissue Donors}, issn = {1756-1833}, author = {Haagerup, A.} }