As already mentioned, Charles II, the last king of the Spanish Habsburg dynasty, presented important physical and mental disabilities suffering from a number of different diseases during his life [4]–[5], [17], hence being known in Spanish history as El Hechizado (“The Hexed”). According to contemporary writings, he was often described as “big headed” and “weak breast-fed baby”. He was unable to speak until the age of 4, and could not walk until the age of 8. He was short, weak and quite lean and thin. He was described as a person showing very little interest on his surroundings (abulic personality). He first marries at 18 and later at 29, leaving no descendency. His first wife talks of his premature ejaculation, while his second spouse complaints about his impotency. He suffers from sporadic hematuria and intestinal problems (frequent diarrhea and vomits). He looked like an old person when he was only 30 years old, suffering from edemas on his feet, legs, abdomen and face. During the last years of his life he barely can stand up, and suffers from hallucinations and convulsive episodes. His health worsens until his premature death when he was 39, after an episode of fever, abdominal pain, hard breathing and comma. In the light of the knowledge of the current clinical genetics and on information gathered by the historians on the health of Charles II we might speculate on the origin of his illness. Although we recognize that it is highly speculative, some of the health problems suffered by Charles II could have been caused by the action of detrimental recessive genes given his high inbreeding coefficient (F = 0.254) with 25.4% of his autosomal genome expected to be homozygous. In this sense, the simultaneous occurrence in Charles II of two genetic disorders determined by recessive alleles, combined pituitary hormone deficiency (CPHD, OMIM 26260) and distal renal tubular acidosis (dRTA, OMIM 602722), could explain an important part of his complex clinical profile. The most frequent genetic cause of hereditary CPHD is mutations in PROP1 (5q) that cause a multiple endocrine deficit of pituitary hormones [22]–[24]. This anomalous hormonal phenotype would lead to development of short stature, hypotonia and muscular weakness and abulic personality as well as infertility/impotence and gastrointestinal symptoms which characterize much of the clinical profile of Charles II. Any additional physical stress will exacerbate these clinical manifestations, often resulting in intense abdominal pain, fever and lethargy followed by hypovolemic vascular collapse [25]–[26]. dRTA is a rare renal disease associated with alterations of the urine acidification mechanisms and may be caused by recessive mutations in ATP6V0A4 (7q) or ATP6V1B1 (2q) genes [27]–[28]. In Charles II, his muscular weakness at a young age, rickets, hematuria and his big head relative to his body size could be attributed to this genetic disorder. In this way, we may speculate that most of the symptomatology showed by Charles II could be explained by two different genetic disorders produced by detrimental recessive alleles at two unlinked loci. Evidently, the probability of an affected individual suffering from two very rare recessive traits must be very low but it must be taken into account that inbreeding may cause the association of two recessive traits even for unlinked loci [29]. In addition, recent studies with SNPs and microsatellite markers have shown that the amount of genomic homozygosity of consanguineous individuals is often greater than expected from pedigree information [30], suggesting that the genomic homozygosity of Charles II could have been higher than the inferred 25.4%.
http://plosone.org/article/info:doi/10.1371/journal.pone.0005174#article1.body1.sec3.p3

Dear Sirs,

We read with interest the recent paper concerning consanguinity in the Hapsburg dynasty [1]. Although we realise that the attribution of Charles II’s ill-health partly to autosomal recessive distal renal tubular acidosis (dRTA) was highly speculative, we must point out that there is no evidence from his complex clinical phenotype to implicate this disorder.

Firstly, the haematuria reported by contemporaries must have been macroscopic, a finding highly unusual in recessive dRTA. Charles II was more likely to have had an infective or haematological cause for haematuria. Secondly the muscular weakness and rickets from which he suffered are classic features of vitamin D deficiency, common among Western European children during the 17th century [2]. Furthermore, the dRTA phenotype cannot account for his “big head relative to his body size”, nor is it associated with impotence.

Recessive dRTA arises from mutations in genes encoding subunits of the proton pump, responsible in the kidney for distal tubular urinary acidification, and in the inner ear for maintenance of normal endolymph pH [3,4]. The majority of patients with recessive dRTA thus also develop severe bilateral sensorineural hearing loss [5], not noted to be a feature of Charles II’s condition (but which would surely have been commented on by contemporary sources).

From the available information, we cannot agree that recessive dRTA is a likely contributor to Charles II’s diagnosis. If the authors have access to his DNA we would be very happy to investigate this further!

Fry AC, Norgett EE, Hiemstra TF, Karet FE
Departments of Nephrology and Medical Genetics
University of Cambridge
United Kingdom


1. Alvarez G, Ceballos FC, Quinteiro C (2009). The role of inbreeding in the extinction of a European royal dynasty. PLoS ONE 4(4): e5174. Doi:10.1371/journal.pone.0005174
2. Glisson F (1651). A treatise of the rickets: being a disease common to children. Translated and edited by N. Culpeper. London: P. Cole.
3. Karet FE et al (1999). Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet 21: 84-90.
4. Stover, EH et al (2002). Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. J Med Genet 39: 796-803.
5. Rodriguez Soriano J (2002). Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 13: 2160-2170.