In response to the article on the sperm donor who passed along a serious heart defect, Donor Sibling Registry Board member, Dr. Kirk Maxey, sent this letter to the editors at JAMA:
Dear Sirs;
It is admirable to note that Dr. Maron and his coauthors recognize that unintended transmission of genetic illness through sperm donation is inadequately addressed by current US FDA guidelines. I was rather stunned by their naivety, however, on their subsequent admission that they were aware of only one documented instance of such a medical outcome.[1] In addition to the 2008 case of Fragile X to which they refer, there are numerous others. Severe Congenital Neutropenia (SCN) due to ELA2 mutation was transmitted to 5 offspring by Michigan Cryogenics donor F827 as reported by Boxer et. al in 2006.[2]. In 2004, Dutch law regulating sperm donation was reformed to outlaw anonymity, establish a central donor registry, and limit donors to 10 offspring, stimulated in part by the disclosure in 2002 that a donor in the city of Den Bosch had conceived 18 children in 13 families before being diagnosed with autosomal dominant cerebellar ataxia (ADCA), when his diagnosis had been known to physicians but kept secret since 1997. [3] In May of 1995 in California, Brittany Johnson was diagnosed with Autosomal Dominant Polycystic Kidney Disease (ADPKA) inherited through her donor parent, California Cryobank donor 276, despite a clear history of kidney disease supplied on the donor family history questionnaire. ( See Johnson vs The Superior Court of Los Angeles, and references therein.)
There are no accurate records of the number of donor conceived children born each year in the US, but estimates range between 30,000 and 100,000. It should surprise no one that genetic illness is present in any population of this size. But in a tragic twist of fate, the procurement and supply of human gametes is an unregulated, profit-centered business, unlike the charitable and altruistic system used for blood products, kidneys, and virtually all other living tissue. The cloak of secrecy enacted by most sperm banks and the absence of federal regulations conspire together to insure that questions about the prevalence of inherited illness in this population cannot be answered, because the population cannot even be identified. Substantial numbers of reproductive services providers continue to counsel their patients to withhold from their offspring even the knowledge that they are donor conceived. The US donor conceived community today is a mixture children and adults who unwittingly harbor false personal genetic and family histories, and others who have gained in later life (at the cost of variable but real psychological trauma) the knowledge that their biological parent was a donor. It is unusual for these persons to have any information about this donor at all.
In 2000, Wendy Kramer and her donor-conceived son established an internet site called the Donor Sibling Registry, (DSR), a private, voluntary ad hoc substitute in the US for the government mandated donor registries required by Australia, England, and many other western nations. In the case of Pacific Reproductive Service donor 203, whose transmission of HCM is described by Dr. Maron et. al., 5 of the 13 recipient families (38%) were DSR members, indicating that the 27,000 registrants on the DSR site represent a substantial fraction of the donor conceived community. Theoretically, the incidence of genetic illness among this population should be less than the population at large, since sperm banks could easily take steps to disqualify donors who carry known mutations or other risk factors, and in fact most sperm banks stridently assert that they do so.
A simple survey of the medically documented cases of inherited disease among DSR members confounds this idea. Some defects are well defined, such as the balanced translocation of chromosome 10 in NECC donor D-250, a defect visible upon simple karyotype, which resulted in severe disability and the institutionalization of a donor conceived daughter, and the conception of a number of balanced translocation carriers. Several donors have fathered cohorts of offspring having an incidence of autism/Aspergerâ€
s syndrome exceeding 60%. A different Pacific Reproductive Services donor carries the gene for OCA1A albinism, while a Fairfax donor is associated with familial Hemophagocytic lymphohistiocytosis (HLH) and pre-adolescent mortality and morbidity among his progeny. Another Fairfax donor carries a cystic fibrosis (CF) mutation. There is congenital hypothyroidism, Williams-Beuren syndrome, PKU, and many more. The percentage of all congenital and developmental disorders among DSR offspring actually seems to exceed the population average. This deserves further study, as it is logical that a strong selection bias predisposes parents with sick donor conceived children to search for the DSR and pay its subscription fees in the hope of filling the void of paternal medical information that is the legacy of anonymous sperm donation.
The assertion by the authors that such genetic illness cannot be prevented is only true in the narrow sense that no one could be expected to screen a donor for this novel MYH7 mutation in the early 1990s. However, most of the cases of HCM revealed by Maron and his colleagues could have been prevented, if a simple protocol of periodic donor quarantine and detailed pediatric examinations had been instituted in combination with a mandatory central register of all donor conceptions. The graded protocol of donor quarantines that we have proposed many times, generally known as “5 & 2”, would have averted the conception and subsequent death of the 2.5 year old patient.
“5 & 2” prescribes that after thorough and complete medical qualification of naive donors, they are permitted no more than 5 pregnancies, and they are then quarantined until the youngest in this cohort reaches age 2 and completes an extensive pediatric evaluation, along with all of the other 4 half-sibs. If all are healthy and without detectable abnormality, the donor is re-permitted and can now be used for 2 times his prior number of conceptions – in this case, 10. Upon reaching that milestone, he is again quarantined, while his ten new two and three year offspring undergo their physicals, along with the now seven to eight-year old first set of sibs. Had this system been followed by Pacific Reproductive Services, the first cohort, which included the proband, would have contained four carriers of the mutation, two of whom have hypertrophy easily detected on cardiology exam, and the donor would have been retired ten years before conceiving the unfortunate patient IV-11, who died of his condition at age two and a half.
It is my sincere hope that the positive outcome of this new knowledge will be the meaningful reform of a seriously flawed system of donor gamete acquisition and quality surveillance.
.
Sincerely,
Kirk M. Maxey, MD
President and CEO, Cayman Chemical Company
Member of the Board of Directors, Donor Sibling Registry
Ann Arbor Reproductive Services Donor #A013
1. Am J Med Genet A. 2008; 146(7) p 888-892
2. J Pediatrics 2006; 148(5) p 633-636
3. J Med Ethics 2002; 28 p 213-214