Social media was buzzing this week with the sensational announcement that a study of Hitler's DNA revealed he suffered from a rare genetic sexual disorder called Kallmann Syndrome. Kallmann syndrome is a disorder of the hypothalamic–pituitary–gonadal (HPG) axis, the hormonal system that governs puberty, fertility, and sex hormone production. Sufferers have an impaired ability to produce GnRH, the brain hormone that triggers puberty, resulting in symptoms like delayed sexual development, low testosterone, infertility, and in some cases undescended testicles and a reduced sense of smell.
A striking claim, and predictably it has spread like wildfire online. Headlines framed it as a scientific breakthrough that “explains” Hitler’s personality or alleged sexual pathology. The mainstream media stoked this sensationalism to a great degree, running with headlines about a study supposedly “proving” Hitler had a micropenis, despite that trait only belonging to a minority of Kallmann patients anyway.
Firstly, I am not among the chorus of deniers who say this DNA does not belong to Hitler. Researchers studied DNA from a blood spatter taken from the couch Hitler shot himself on, later cut out of the couch and stored by a U.S. Army Officer. Though we do not yet have a peer-reviewed, documented chain of custody or authentication, the DNA has been matched to the unique familial E1b haplogroup of Hitler’s male relatives. Hitler shooting himself in that room is well-attested to by the people there, so while not yet definitive I am pretty satisfied they really were studying Hitler’s DNA.
But the genetics behind Kallmann syndrome are far more complex than the coverage suggests — and once you examine the actual research on the relevant genes, the sensational interpretation falls apart almost immediately.
The study lead, Jean King, gave away a grave error in an interview on her study, which you can watch here. At about the 9:33 point, it is noted that “there are five genes… noted to be associated with Kallmann’s, and we’ve got a deletion in one… in that PROK2 gene.”
The problem is that this statement reflects a fundamental misunderstanding of how PROK2 actually functions in Kallmann syndrome. King speaks as if Kallmann is a straightforward “one gene, one mutation” disorder—implying that a single deletion in any one of the five associated genes is enough to produce the disease. But this simply isn’t true, and all the scientific literature I have found on Kallmann’s is explicit on this point.
A 2007 PNAS study examined a family in which several siblings had Kallmann syndrome and were found to carry a homozygous loss-of-function mutation (meaning both copies of the gene were broken) in the PROK2 gene. Crucially, another brother who was completely healthy had only one broken copy of the gene, and the parents also carried just one broken copy — yet neither of them showed any symptoms. This pattern showed that a single PROK2 mutation is typically not sufficient to cause the disorder. The authors concluded that the disease phenotype appeared either when both PROK2 alleles were mutated or when one mutated allele interacted with defects in other genes involved in GnRH neuronal development:
Combined with our data, it appears that two mutated PROK2 alleles are needed to cause nIHH/KS. Alternatively, additional gene defect(s) could synergize with one mutated PROK2 allele to cause nIHH/KS.1
A 2008 study in the European Journal of Human Genetics expanded on these findings by examining a large group of patients with Kallmann syndrome. The researchers found that the people who clearly had the disorder were those who carried two damaged copies of the PROK2 gene, while individuals with only one damaged copy (like Hitler) were usually completely healthy. In fact, many of these single-copy carriers inherited their PROK2 variant from their fertile parents who had no symptoms at all — strong evidence that a lone mutation does not reliably cause the condition.
The authors conclude with the prediction that:
patients carrying monoallelic mutations in PROK2 have another disease-causing mutation, presumably in still undiscovered Kallmann syndrome genes.2
Finally, a recent 2023 study looked at patients with various pituitary hormonal problems and screened them for mutations in the PROK2 genes. What they found fits perfectly with the other two studies: people with only one damaged copy of PROKR2 often showed no symptoms at all, while others showed mild or highly variable hormonal issues that did not match full Kallmann syndrome.
The argument of the researchers is that PROKR2 variants have a more complex inheritance pattern beyond Kallmann’s, many single-copy mutations simply “lower the threshold” for hormonal dysfunction (perhaps there is a link here to Hitler’s reported undescended testicle, but it certainly does not point to Kallmann’s.) Crucially though, PROKR2 mutations frequently appear in completely healthy individuals, and mouse models only show clear disease when both copies are disrupted:
For instance, heterozygous PROKR2 mutations have been reported in patients with IHH, and in many of these patients, the variants were inherited from an asymptomatic parent. An alternative possibility for this variable phenotype of PROKR2 may be the dominant negative effect of some variants on the normal allele but this mechanism is unlikely to account for the deleterious effect of all missense alterations, as many of them have also been found in healthy individuals.3
So every serious study we have on PROK2 and PROKR2 shows that one mutation isn’t enough to give someone Kallmann Syndrome. You need two defective copies, or other defective genes related to pubertal development, before Kallmann syndrome reliably appears. And many perfectly normal, fertile people walk around with the same kind of single-copy mutations reported in Hitler. Given that this finding came from professional geneticists, it seems like a stunning misinterpretation of their own findings, which have now been inflated even more by the media.
There may be many other interesting findings from the study of Hitler’s DNA, like his reported high tendency toward disorders like autism and schizophrenia, but the author studies have undermined all of this with the fundamental misinterpretation at the heart of their most sensational claim.
Abreu, Ana Paula, Ericka Barbosa Trarbach, Margaret de Castro, Elaine Maria Frade Costa, Beatriz Versiani, Maria Tereza Matias Baptista, Heraldo Mendes Garmes, Berenice Bilharinho Mendonca, and Ana Claudia Latronico. “Loss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndrome.” The Journal of Clinical Endocrinology & Metabolism 93, no. 10 (2008): 4113-4118.
Leroy, Chrystel, Corinne Fouveaut, Sandrine Leclercq, Sébastien Jacquemont, Hélène Du Boullay, James Lespinasse, Marc Delpech, Jean-Michel Dupont, Jean-Pierre Hardelin, and Catherine Dodé. “Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome.” European Journal of Human Genetics 16, no. 7 (2008): 865-868.
Kardelen, Aslı Derya, Adam Najaflı, Firdevs Baş, Birsen Karaman, Güven Toksoy, Şükran Poyrazoğlu, Şahin Avcı et al. “PROKR2 mutations in patients with short stature who have isolated growth hormone deficiency and multiple pituitary hormone deficiency.” Journal of Clinical Research in Pediatric Endocrinology 15, no. 4 (2023): 338.
Hey this is my job
Why is this even important?