Historical Review

Horm Res Paediatr 2022;95:579–592 Received: August 8, 2022

Accepted: August 10, 2022
DOI: 10.1159/000527011 Published online: November 29, 2022

Rickets, Vitamin D, and Ca/P Metabolism

Walter L. Miller a Erik A. Imel b, c
aDepartment
of Pediatrics, Center for Reproductive Sciences and Institute for Human Genetics, University of
California, San Francisco, San Francisco, CA, USA; bDepartment of Medicine, Indiana University School of Medicine,
Indianapolis, IN, USA; cDepartment of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

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Keywords
Bone · Calcitriol · FGF23 · Parathyroid · Parathyroid hormone ·
Phosphorus · Rickets
Abstract
Rickets was a major public health problem dating from Ro-
man times, and medical descriptions of rickets date from the
17th century. Sniadecki first advocated treatment by expo-
sure to sunshine in 1822; contemporaneously, several British
physicians advocated use of cod liver oil. Both approaches
were successful. Work in 1924 showed that exposure to UV
light endowed fats and other foods with antirachitic proper-
ties. Vitamins D2 and D3, the antirachitic agent in cod liver oil,
were, respectively, produced by UV radiation of ergosterol
and 7-dehydrocholesterol. Calcitriol (1,25[OH]2D3) was iden-
tified as the biologically active form of vitamin D in the early
1970s. The vitamin D 25-hydroxylase, 24-hydroxylase, and
1α-hydroxylase were cloned in the 1990s and their genetic
defects were soon delineated. The vitamin D receptor was
also cloned and its mutations identified in vitamin D-resis-
tant rickets. Work with parathyroid hormone (PTH) began
much later, as the parathyroids were not identified until the
late 19th century. In 1925, James B. Collip (of insulin fame)
identified PTH by its ability to correct tetany in parathyroid-
ectomized dogs, but only in the 1970s was it clear that only
a small fragment of PTH conveyed its activity. Congenital hy-
poparathyroidism with immune defects was described in
1968, eventually linked to microdeletions in chromosome
22q11.2. X-linked hypophosphatemic rickets was reported
in 1957, and genetic linkage analysis identified the causative
PHEX gene in 1997. Autosomal dominant hypophospha-
temic rickets similarly led to the discovery of FGF23, a phos-
phate-wasting humoral factor made in bone, in 2000, revo-
lutionizing our understanding of phosphorus metabolism.
© 2022 S. Karger AG, Basel
Early History of Vitamin D-Deficient (Nutritional)
Rickets
Several recent histories of rickets and vitamin D are
available [1–4]. Nutritional rickets has affected children
since antiquity. Soranus of Ephesus, a Roman physician
during the reigns of Trajan and Hadrian, left a remark-
ably complete text on gynecology, midwifery, and new-
born care, stating:
“When the infant attempts to sit and to stand, one should help
in its movements. For if it is eager to sit up too early and for too
long a period it usually becomes hunchbacked (the spine bending
because the little body has as yet no strength). If, moreover, it is too
prone to stand up and desirous of walking, the legs may become
distorted in the region of the thighs. This is observed to happen
particularly in Rome as some people assume, because cold waters
flow beneath the city. (Now) if nobody looks after the movements

Karger@karger.com © 2022 S. Karger AG, Basel Correspondence to:

www.karger.com/hrp Walter L. Miller, wlmlab @ ucsf.edu
Erik A. Imel, eimel @ iu.edu
of the infant the limbs of the majority become distorted, as the
whole weight of the body rests on the legs … then of necessity the
limbs give in a little, since the bones have not yet become strong.”
[Soranus. Gynecology, Book II, 48. Translated by O. Temkin.
The Johns Hopkins Press, Baltimore, 1956]
As detailed by Bagley [5], the descriptions provided by
both Soranus and soon thereafter by Galen provide evi-
dence that rickets was commonplace, perhaps even typi-
cal, among Roman children due to breastfeeding up to a
year of age and the common practice of swaddling new-
borns for the first few months of life, preventing exposure
to sunlight. O’Riordan and Bijvoet [6] cite other early,
imprecise reports from Theodosius of Bologna (in 1554),
and Bartholomaeus Reusner (in 1582), and state that “lat-
er texts, from Holland in 1614, might be referring to rick-
ets under the titles of ‘Ailment of Saint Willibrod’ in
which children had knobs on their ribs and ‘Ailment of
Saint Machutus’ in which children had deformed legs,”
thus the classic “rachitic rosary” was known at least 400
years ago. The 1634 Annual Bill of Mortality of the City
of London listed 10,900 deaths, ascribing 14 of them to
“rickets,” and by 1659, 441 deaths were ascribed to rickets
[6]. Most authors date the medical understanding of rick-
ets from 1645, when Daniel Whistler described rickets
and osteomalacia in his MD thesis [7], soon followed by
Francis Glisson’s extensive text, first in Latin in 1650 [8],
then in English in 1668 [9]. In 1772, Levacher de la Feutrie
published a French text on rickets, including descriptions
of devices to straighten deformed bones [10].
Vitamin D – Sunshine and Fish Oil
The first person to implicate deficient sunlight in the
etiology of rickets and its use as a cure may have been the
Polish physician/chemist Jedrzej Sniadecki (1768–1838).
As reported by Wlodzimierz Mozolowski [11], in volume
1 of his “Dziela,” written in 1822, but published in 1840,
Sniadecki stated:
“If the parents’ financial status permits, it is best to take the
children out into the country and keep them as much as possible
in the dry, open and pure air. If not, at least they should be carried
about in the open air especially in the sun, the direct action of
which on our bodies must be regarded as one of the most efficient
methods for the prevention and the cure of this disease… Thus
strong and obvious is the influence of the sun on the cure of the
English disease, and the frequent occurrence of the disease in
densely populated towns, where the streets are narrow and the
dwellings of the working-class people low and very poorly lit.”
Mozolowski concluded: “From the passages quoted
above it is quite clear that J. Sniadecki fully realized the
580 Horm Res Paediatr 2022;95:579–592
DOI: 10.1159/000527011
Color version available online
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Fig. 1. … and Prof. Huldschinsky said, “Let there be light”, and
there was light – UVB quartz-mercury-vapor light (with appropri-
ate protection). From Chesney [14].
significance of the sun both in prevention and cure of
rickets.” Thomas Percival reported the use of cod liver oil
for “rheumatisms” in adults, and quotes a letter from a
physician, Robert Darbey, the last paragraph of which re-
ports its salutary effect in two children with apparent
rickets, but without using that term [12]. Both D. Schütte
in 1824 [13] and others (reported by ref. [6]) showed that
cod-liver oil was effective in treating rickets. As reported
by Chesney in 2012, 60–90% of urban British children
had rickets in the late 19th century, but its cause and treat-
ment were controversial [14]. Theobold Palm, a medical
missionary, noted the absence of rickets in Asian coun-
tries, but a high incidence in Britain, with a much higher
incidence in crowded urban areas; he recommended sun-
baths and relocating rachitic children from urban to rural
areas [15]; Bucholz reported curing rachitic children with
incandescent light in 1904 [16].
The science of the etiology and treatment of rickets
advanced rapidly after World War I. Mellanby rendered
puppies rachitic, then supplemented their diets with var-
ious additives, noting that fats, notably cod liver oil, re-
paired the bony defects, concluding that “fat-soluble A”
was responsible for the antirachitic action [17]. In 1922,
McCollum et al. [18] showed that heat and oxygen inac-
tivated the fat-soluble vitamin A in cod liver oil, but not
the fat-soluble “calcium-depositing vitamin” (i.e., vita-
min D), showing that vitamin A was not responsible for
the salutary action of cod liver oil. Also at this time, UV
light was successfully used to treat rickets [19, 20] (Fig. 1);
Miller/Imel
 Table 1. Brief history of calcium, phosphorus, and vitamin D research

∼120 Soranus of Ephesus appears to describe rickets

1645 Daniel Whistler describes rickets and osteomalacia
1650 Glisson’s De Rachitide Sive Morbo Puerili Quoi Vulgo
1789 Thomas Percival and Robert Darbey advocate oral cod liver oil for rickets
1840 Jedrzej Sniadecki advocates sunlight to treat rickets
1852 Richard Owen describes the parathyroid glands in the rhinoceros
1880 Ivar Sandstrom describes human, dog, cat, horse, cow, and rabbit parathyroids
1890 Theobold Palm: rickets more common in urban industrialized areas
1904 Bucholz treats rickets with incandescent light
1909 Berkeley and Beebe ameliorate human tetany with a parathyroid extract
1919 Huldschinsky treats rickets with light from quartz-mercury lamp
1922 McCollum shows cod liver oil contains an antirachitic factor that is not vitamin A
1922 AM Hanson prepares a bovine PTH extract
1924 Hess & Weinstock and Steenbock & Black: UVB light renders foods antirachitic
1925 James B. Collip prepares a better bovine PTH extract (“Parathormone”)
1926 Martha May Eliot shows that either cod liver oil or sunlight can cure rickets

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1930 Askew prepares and characterizes ergocalciferol from irradiated ergosterol
1936 Windaus & Bock prepare cholecalciferol from irradiated 7-dehydrocholesterol
1937 Albright describes “vitamin D-resistant rickets” (hypophosphatemic rickets)
1957 Winters describes X-linked dominant hypophosphatemic rickets
1960 Rasmussen shows PTH activity in small PTH peptide
1961 Prader describes “vitamin D-dependent rickets” (VDDR)
1968 DiGeorge syndrome
1970 Egon Kodicek identifies 1,25(OH)2D3 (calcitriol) as the active form of vitamin D
1970 Complete amino acid sequence of PTH
1973 Fraser shows that VDDR is 1α-hydroxylase deficiency
1974 Mark Haussler discovers vitamin D receptor bound to chromatin
1978 Reports of vitamin D-resistant rickets by Brooks et al. and Marks et al.
1987 PTHrP cloned
1988 Baker et al. clone the human gene for the vitamin D receptor
1988 Hughes et al. report first mutations in the vitamin D receptor
1993 Cloning of the calcium-sensing receptor
1995 Cloning of PHEX by the HYP Consortium as the cause of XLH
1997 Groups at McGill, University of Tokyo, and Showa University clone rat and mouse 1α-hydroxylase
1997 Fu et al. at UCSF clone human 1α-hydroxylase and show its mutations in VDDR
1997 Klotho identified
1998 Wang et al. discover the most common 1α-hydroxylase mutations
2000 FGF23 discovered: the long-sought “phosphatonin”
2004 Cheng et al. show that CYP2R1 mutations cause 25-hydroxylase deficiency
2006 Kurosu et al. link klotho activity to FGF23 signaling
2011 Schlingmann et al. describe CYP24 mutations causing infantile hypercalcemia
2018 Burosumab (anti-FGF23 antibody) approved for treatment of XLH

Hess noted that rickets had a seasonal variation, being
most prevalent in late March, after children had been in-
doors during the winter [21] and that such “heliotherapy”
increased circulating phosphate levels [22].
The link between sunlight and dietary supplementa-
tion with a “vitamin” came in 1924, when Hess and
Weinstock at Columbia University [23] and Steenbock
& Black at the University of Wisconsin [24] showed that
UV radiation of either certain fats or plants endowed
them with antirachitic properties; the use of filters es-
tablished that “UVB” radiation (∼280–320 nm) was the
active form of sunshine [25]. The carefully controlled
work of Martha May Eliot led to the acceptance of both
cod liver oil and sunlight in the prevention and cure of
rickets [26]. Cod liver oil is unpalatable, but milk and
other foods were soon irradiated with UV light, nearly
eliminating rickets. The material activated by UV light
was traced to the “sterol” fraction of both animal and
vegetable foods, suggesting that light acted on a choles-
terol-like molecule (now known to be 7-dehydrocho-

Rickets, Vitamin D, and Ca/P Metabolism Horm Res Paediatr 2022;95:579–592 581
DOI: 10.1159/000527011
lesterol) in skin. In 1931, Askew et al. [27] reported the
isolation and structural characterization of ergocalcif-
erol (vitamin D2) from irradiated ergosterol. Desmond
Bernal was first to use X-ray crystallography to study
biological molecules, showing that cholesterol is a pla-
nar, 4-ring structure, and determining the structure of
vitamin D [28]. In Göttingen, Adolph Windaus, recipi-
ent of the 1928 Nobel Prize in Chemistry for his work
with sterols, showed that D2 was produced by UV ra-
diation of ergosterol [29] and that D3 is similarly pro-
duced from 7-dehydrocholesterol [30]. The antirachitic
component of cod liver oil was found to be identical to
vitamin D3, thus closing the loop between fish oil and
sunshine. An outline of research discoveries concern-
ing calcium metabolism is presented in Table 1.
Vitamin D Biosynthesis and Its Disorders
Early clinical descriptions of two severe, infantile ra-
chitic disorders presaged the elucidation of the path-
ways of vitamin D synthesis and action. Resistance to
the action of vitamin D, even when administered in
huge doses, was reported by Fuller Albright in 1937 and
was logically termed “vitamin D-resistant rickets” [31];
in 1961, Andrea Prader described a clinical phenocopy
of this disorder that was sensitive to high-dose vitamin
D therapy [32], and became known as “vitamin D-de-
pendent rickets.” Such observations raised the question
of what chemical forms of vitamin D were biologically
active. Using tritiated vitamin D3 revealed polar me-
tabolites; substantial biochemical effort (silica gel chro-
matography, reversed-phase chromatography, mass
spectrometry, and NMR spectrometry) identified the
principal form in human circulation as 25OHD3, which
was more potent than D3 [33]. From 1969 to 1971, sev-
eral groups, notably that of Egon Kodicek in Britain,
identified 1,25(OH)2D3 (calcitriol) from the kidney as
the truly active metabolite of vitamin D [34–37]. The
corresponding forms of vitamin D2 were soon identi-
fied, as were other metabolites hydroxylated at C24,
C26, and the various combinations of these hydroxyl-
ations [1, 4]. This work established that both vitamins
D2 and D3 are 25-hydroxylated in the liver, that 25OHD
is the predominant metabolite in the circulation, and
that the kidney then 1α-hydroxylates 25OHD to bio-
logically active 1,25(OH)2D2 or 1,25(OH)2D3. The dis-
ease identified by Prader in 1961 was a defect in renal
1α-hydroxylation [38]. With the dawn of the era of mo-
lecular biology, most steroidogenic enzymes were
582 Horm Res Paediatr 2022;95:579–592
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cloned between 1984 and 1990, and the identification
of the genes and enzymes participating in vitamin D
metabolism followed (reviewed in [39]).
Vitamin D 25-Hydroxylases
Study of hepatic vitamin D 25-hydroxylation was
complicated by the presence of multiple enzymes that
could catalyze this reaction (at least in vitro), and by the
lack of obvious regulation of this step, so that circulating
25OHD concentrations are mainly determined by dietary
intake and exposure to UV light. In 1990, two groups re-
ported 25-hydroxylase activity in both mitochondria and
microsomes and cloned cDNA for an enzyme initially
called P450c25 [40, 41], but that enzyme mainly hydrox-
ylates C26 and C27 in bile acid synthesis; it is now termed
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CYP27A1 [42], and its mutations cause cerebrotendinous
xanthomatosis without disordered calcium metabolism
[43], and hence it is not a significant vitamin D 25-hy-
droxylase. Several hepatic microsomal P450 enzymes can
also catalyze some 25-hydroxylase activity, but are clearly
minor players [39].
In 1994, Samuel Casella et al. [44] reported two broth-
ers of Nigerian parentage who had hormonal findings
suggesting 25-hydroxylase deficiency, but subsequent
studies found no mutations in CYP27A1. In 2003, David
Russell’s laboratory reported that microsomal CYP2R1
was a potent vitamin D 25-hydroxylase [45]; in collabora-
tion with Michael A. Levine, they used DNA from an
EBV-transformed cell line established from one of Ca-
sella’s patients to identify a homozygous mutation of
CYP2R1 that impaired 25-hydroxylase [46]. Follow-up
studies found no CYP2R1 mutations in 27 Nigerian chil-
dren with sporadic rickets, but missense mutations were
identified in affected members in 2 of 12 families [47].
These genetic findings confirm that CYP2R1 is the prin-
cipal human hepatic enzyme catalyzing 25-hydroxylation
of vitamin D; 25-hydroxylase deficiency is very rare,
probably because other enzymes contribute to vitamin D
25-hydroxylation in vivo. Polymorphisms in or near the
CYP2R1 gene differ in their worldwide distribution and
affect vitamin D homeostasis [48].
Vitamin D 24-Hydroxylase
Most vitamin D is inactivated is by its 23- and 24-hy-
droxylation by mitochondrial CYP24A1 in the kidney
and intestine, initiating the inactivation pathway leading
to calcitroic acid. Ohyama et al. [49] first cloned CYP24
by purifying the protein from rat renal mitochondria,
raising an antiserum, and screening a rat kidney cDNA
expression library; the human cDNA was reported 2 years
Miller/Imel
later [50]. Homozygous or compound heterozygous mu-
tations in CYP24A1 causing hypercalcemia were reported
in 2011 [51, 52]. Most patients were infants with weight
loss, failure-to-thrive, hypercalcemia, hypercalciuria,
and/or nephrocalcinosis, with normal 25OHD levels,
normal to moderately elevated 1,25(OH)2D levels, low
24,25(OH)2D levels, and low levels of parathyroid hor-
mone (PTH). Once known causes of infantile hypercalce-
mia are eliminated, the diagnosis is usually “idiopathic
infantile hypercalcemia”; however, such infants may have
CYP24A1 mutations. In addition, heterozygous
CYP24A1 mutations may lead to clinically apparent hy-
percalcemia in individuals ingesting very large amounts
of vitamin D [53, 54]. In the 1950s, there was a dramatic
rise in the incidence of “idiopathic infantile hypercalce-
mia” in Britain shortly after the introduction of excessive
fortification of milk and cereal with vitamin D [55]. Brit-
ain and most of the world then banned fortification of
milk with vitamin D, and the incidence of hypercalcemia
decreased, but the USA and Canada, which added much
less vitamin D to milk and other foods, continued their
successful policy of milk fortification; this history was re-
viewed in detail in 1967 [56]. Contemporary data show
little correlation of serum calcium levels and vitamin D
intake in normal adults [57].
Vitamin D 1α-Hydroxylase
1α-Hydroxylation has been of long-standing interest
because of its importance in normal physiology and be-
cause synthesis of 1,25(OH)2D is impaired in several clin-
ical disorders. Classic approaches for protein purification
failed because of the very low abundance of 1α-hydroxylase
in renal mitochondria. However, in 1997, four groups (St-
Arnaud & Glorieux [McGill U. Montreal], Takeyama and
Kato [U. Tokyo], Miller & Portale [UCSF] and Shinki &
Suda [Showa U., Tokyo]) using different approaches re-
ported the cloning of the human, rat, and mouse cDNAs
[58–62] and the human gene [62, 63] for the mitochon-
drial vitamin D-1α-hydroxylase, subsequently termed
CYP27B1. Kato’s group used mice lacking the vitamin D
receptor (VDR), which thus overproduced the
1α-hydroxylase enzyme, and then screened a cDNA ex-
pression library for activation of a VDR construct [59].
The Glorieux and Shinki groups increased rat renal
1α-hydroxylase mRNA by feeding the animals a diet de-
ficient in calcium and phosphorus, then used probes cor-
responding to the conserved P450 heme-binding site to
identify candidate sequences [58, 61].
At UCSF, Walter L. Miller’s laboratory, collaborating
with Anthony A. Portale in pediatric nephrology, ob-
Rickets, Vitamin D, and Ca/P Metabolism
tained the first human clone [60]. Human keratinocytes
have robust 1α-hydroxylase activity when grown in se-
rum-free, low-calcium medium; they made a keratino-
cyte cDNA library and screened it with oligonucleotides
having sequences corresponding to the ferredoxin-bind-
ing and heme-binding sites of other P450s, identifying a
putative 1α-hydroxylase cDNA. Multiple experiments in-
dicated that the CYP27B1 encoded by the keratinocyte
cDNA was the same as the renal enzyme; most notably,
keratinocyte cDNA from a patient with 1α-hydroxylase
deficiency carried the same mutations found in the pa-
tient’s genomic DNA. Thus, “vitamin D-dependent rick-
ets type I” was vitamin D 1α-hydroxylase deficiency, as
expected based on Prader’s report in 1961 [32]. The hu-
man CYP27B1 gene was cloned and localized to chromo-
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some 12 [63]; at the same time, St-Arnaud and Glorieux
cloned the rat cDNA and used it to map the human gene
to 12q13.1-13.3 [58]. This was the predicted location, be-
cause in 1991, taking advantage of the very high incidence
of 1α-hydroxylase deficiency among the French Canadi-
an population of the Charlevoix-Saguenay-Lac Saint Jean
region of Quebec, that laboratory had mapped
1α-hydroxylase deficiency to chromosome 12q13-q14 by
linkage analysis [64].
“Vitamin D 1α-hydroxylase deficiency” is a mecha-
nistically descriptive term designating “hereditary pseu-
do-vitamin D deficiency rickets”, “vitamin D dependent
rickets,” or “vitamin D-dependent rickets type I.” Be-
cause 1α-hydroxylase deficiency is rare, most studies
have reported only a few individuals. However, in 1998,
Wang et al. identified the mutations in 19 patients from
17 families in multiple ethnic groups [56]. DNA sequenc-
ing and microsatellite haplotyping showed that French-
Canadian patients carried a single haplotype and the
same CYP27B1 frameshift mutation (958ΔG in codon
88) that ablates enzyme activity. This study also found
that multiple families carried a third copy of the 7-base
sequence CCCACCC that is normally duplicated in
CYP27B1 exon 8, causing an inactivating frameshift mu-
tation. This 7-bp insertion was associated with several
different microsatellite haplotypes and was found in sev-
eral unrelated ethnic groups, indicating that the 7-bp in-
sertion arose recurrently de novo [65]; the recurrent na-
ture of this mutation has been confirmed in other studies
[66, 67]. Some rare missense mutations retain partial ac-
tivity [68, 69], but most patients with classic findings
have nonsense mutations [70].
Horm Res Paediatr 2022;95:579–592 583
DOI: 10.1159/000527011

Fig. 2. The two sisters, aged 7 years (left) and 3 years (right), with
rickets, alopecia, and vitamin D resistance who were reported by
Rosen et al. [75].
The Vitamin D Receptor
Albright’s paper in 1937 [31] is generally credited as
the first description of vitamin D resistance, but he lacked
the assays now used to define that disorder clinically; and
based on the prominence of renal phosphate wasting and
hypophosphatemia in this description, his patient may
instead have had X-linked hypophosphatemia. In 1969,
Mark Haussler at the University of Arizona provided the
first evidence for a VDR that bound to chromatin [71],
and in 1974, he reported that a specific cytosolic receptor
bound calcitriol and associated with chromatin in chick-
en intestinal cells [72]. He coauthored a 1978 report de-
scribed a young woman with hypocalcemia, hyperpara-
thyroidism, osteomalacia, and osteitis fibrosa in whom
584 Horm Res Paediatr 2022;95:579–592
DOI: 10.1159/000527011
serum concentrations of 25OHD were normal but those
of 1,25(OH)2D were very high [73]. That report proposed
the patient had end-organ resistance to the action of
1,25(OH)2D and proposed the name “vitamin D-depen-
dent rickets type II” (VDDR-II) to distinguish it from
VDDR-I (1α-hydroxylase deficiency). Marx et al. [74] de-
scribed a brother and sister who developed infantile rick-
ets with similar clinical and laboratory findings, but
whose hypocalcemia responded to doses of calcitriol
about 20 times higher than those needed to treat
1α-hydroxylase deficiency; this suggested a disorder in
the unknown molecule(s) that mediated the action of vi-
tamin D. Rickets with alopecia, now recognized as a clas-
sic presentation of vitamin D-resistant rickets, was re-
ported in 1979 with clinical/metabolic characterization
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[75] (Fig. 2), and a study in 1982 showed absent binding
of 1,25(OH)2D in cells from a similar patient [76]. The
human VDR was cloned in 1988 [77], and mutations
causing vitamin D-resistant rickets were identified soon
thereafter. The human VDR is a typical zinc-finger pro-
tein nuclear receptor, encoded by a gene on chromosome
12q13-14, very near the CYP27B1 gene for the vitamin D
1α-hydroxylase. The first mutations in the VDR gene
were reported in 1988 [78], and mutations were soon
found in all exons and all functional domains of the VDR
[79].
Parathyroids, Their Function, and Their Hormone
The assiduous efforts of Renaissance anatomists failed
to reveal the parathyroid glands, which escaped notice
until the 19th century. Both Remak in 1851 and Virchow
in 1864 apparently mentioned parathyroids briefly [80].
Richard Owen (1809–1882), describing his 1852 autopsy
of an Indian rhinoceros that died at the London Zoo, re-
ported “a small, compact, yellow glandular body attached
to the thyroid at the point where the veins emerge” [81].
In 1877, Ivar Sandström (1852–1889), then a medical stu-
dent in Uppsala, described the parathyroids in detail by
dissections and histology of dogs, cats, cattle, horses, and
rabbits and then confirmed his results in 50 human ca-
davers. His manuscript was apparently rejected by prom-
inent German journals [82, 83] and finally appeared in a
local Swedish language journal in 1880 [84, 85]. Experi-
mental parathyroidectomy (sparing the thyroid) caused
tetany and seizures, which had previously been noted in
experimental thyroidectomy (which did not spare the
parathyroids) [86, 87]. Despite this, most early investiga-
tors believed that the parathyroids were functionally, as
Miller/Imel
well as anatomically, associated with the thyroid. In 1899,
Gustave Moussu reported that an equine parathyroid ex-
tract worsened myxedema in dogs but benefited hyper-
thyroidism, and suggested that the action of the parathy-
roids was to restrain the thyroid [88].
The roles of the thyroid and parathyroids were distin-
guished in 1909 when Berkeley and Beebe ameliorated
human tetany with a parathyroid extract [89], and
MacCallum and Vogetlin noted that parathyroid destruc-
tion caused tetany responsive to intravenous calcium
chloride [90]; these studies connected the parathyroids to
calcium metabolism. An alternative hypothesis was that
the parathyroids were detoxifying organs, as parathyroid-
ectomized animals excreted methyl guanidine [91], and
its administration caused tetany [92]. PTH was identified

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independently by Adolph M. Hanson (1880–1959), a pri-
vate practitioner working in his garage in Faribault, MN
[93–95], and by James B. Collip (1892–1965), chair of
biochemistry at the University of Alberta, who was fa-
mous for preparing the insulin used by Banting, Best, and
MacLeod in Toronto. Hanson lacked Collip’s resources
and influence; McCullagh’s 1928 review [96] does not
even mention him. Hanson patented his preparation, but
was unable to market it, and eventually assigned his pat-
ent rights to the Smithsonian Institution [82]. Collip may
have been inspired to work on the parathyroids by his
1919 meeting with Noel Paton, the principal proponent
of the “methyl guanidine school” [97]. Collip’s prepara-
tion was superior to Hanson’s, corrected the tetany of Fig. 3. Captain Charles Martel: before his hyperparathyroidism
parathyroidectomized dogs [98], and caused hypercalce- (left) and after 6 years of bone loss (right). From Bauer and Feder-
mia in normal animals [99]; in an era when every little mann [104].
observation could be published, these two papers are sur-
prisingly modern in their thoroughness and scope. Col-
lip’s preparation was then marketed by Eli Lilly with the
brand name “Parathormone.” A history of this work, PTH Action and Vitamin D
based on personal notes and files as well as the published
literature, is provided by Alison Li [97]. Over the next 20 years, clinical disorders of hypo- and
The harsh HCl extraction procedure used by Collip hyperparathyroidism were reported, most famously the
resulted in the partial degradation of PTH into multiple case of Capt. Charles Martel with hyperparathyroidism
peptides; Rasmussen showed that one of these peptides of due to a mediastinal tumor (Fig. 3) [104]. Studies of hy-
only about 33 amino acids was active in raising Ca levels perparathyroidism did not reveal the site of PTH action,
in rats [100]. The 84 amino acid sequence of bovine PTH leading to a vigorous debate: J.B. Collip said it acted on
was reported in 1970 [101], the sequence of the bioactive bone, while Fuller Albright said it was on the kidney; both
N-terminal 34 amino acids of human PTH was reported were right, but they fought over this issue for 17 years
in 1972 [102], and the full-length protein in 1978 [103]. [105]. Albright described “pseudohypoparathyroidism”
Teriparatide, the N-terminal 34 amino acids of human as an example of the “Seabright-Bantam” (sic) syndrome,
PTH, is marketed by several firms for treatment of osteo- referring to the male Sebright bantam chicken and its fe-
porosis. Several reports describe its use in children, but it male feathering pattern; this is now known to be due to
has not been approved for children because of animal an aromatase defect [106], but these animals were long
data suggesting a possible risk for osteosarcoma. thought to represent “end-organ resistance” to the action

Rickets, Vitamin D, and Ca/P Metabolism Horm Res Paediatr 2022;95:579–592 585
DOI: 10.1159/000527011
of a hormone [107]. In fact, patients with pseudohypo-
parathyroidism do not have mutations of the PTH recep-
tor, but are a heterogeneous population with different
GNAS mutations (for review see [108]). Thus, Albright is
generally credited for describing hormone resistance as a
mechanism of disease.
In 1968, Angelo DiGeorge (1921–2009), a founding
member and past president of the (LW)PES, described
congenital hypoparathyroidism in conjunction with thy-
mic aplasia and immune defects [109]. The syndrome was
broadened to include multiple congenital anomalies and
became known as a developmental field defect of the third
and fourth pharyngeal pouches; thus, “DiGeorge Syn-
drome” became known as “velo-cardio-facial syndrome.”
The majority of these patients had a deletion on the long
arm of chromosome 22 (chromosome 22q11.2 deletion
syndrome) [110]. The acronym CATCH22 (cardiac ab-
normality/abnormal facies, T-cell deficit due to thymic
hypoplasia, cleft palate, and hypocalcemia due to hypo-
parathyroidism resulting from 22q11 deletion) is also
widely used [111]. Botto et al. [112] found an incidence
of about 1:6,000 births, making it is one of the most com-
mon chromosomal disorders.
It was known from the 1920s that deficiency of either
vitamin D or PTH caused hypocalcemia, but through the
1960s, the connection was unclear, despite complex,
well-executed experiments [113, 114]. Children with
1α-hydroxylase deficiency (formerly termed “VDDR-I”
or pseudo-vitamin D-deficiency rickets) typically have
hypocalcemia and secondary hyperparathyroidism [38,
115], and patients with CYP27B1 gene mutations causing
1α-hydroxylase deficiency have elevated PTH values
[65], even in those where there is partial retention of
function [68]. When the genes for rodent and human
1α-hydroxylase were cloned in 1997 (described above), it
was soon shown that PTH activates expression of the
mouse Cyp27B1 gene [116], closing the loop between
PTH and vitamin D.
Parathyroid Hormone-Related Protein
Hypercalcemia without elevated circulating PTH was
long noted as a paraneoplastic syndrome in some adult
patients with malignancies. A long search led to the iden-
tification of a parathyroid hormone-related protein
(PTHrP) by groups in Melbourne, Australia [117, 118],
and in San Francisco [119]. The physiological roles of
PTHrP remain under investigation; it is a widely ex-
pressed autocrine/paracrine factor, rather than a classic
586 Horm Res Paediatr 2022;95:579–592
DOI: 10.1159/000527011
hormone; a major role in fetoplacental calcium transport
was suggested by its abundant expression in fetal mem-
branes [120], and an active role in maternofetal calcium
transport was shown in 1996 [121]. Thus, PTHrP, dis-
covered in adult cancer, appears to be mainly a fetal hor-
mone with multiple roles in calcium and bone metabo-
lism.
Phosphate Disorders and FGF23
Discoveries about the physiology of phosphate metab-
olism were facilitated by the existence of several disorders
caused by abnormalities related to fibroblast growth fac-
tor 23 (FGF23), especially the genetic forms of hypophos-
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phatemic rickets caused by renal phosphate wasting.
While not a complete assessment of every discovery, we
provide a general overview of the journey highlighting
several important milestones and advances in phosphate
disorders in the last century, leading to the discovery of
FGF23 and directed treatment of patients with these dis-
orders.
Although earlier authors had described case reports of
rickets that was difficult to treat, in 1937 Fuller Albright
provided the first detailed investigation of a child with
hypophosphatemic rickets due to renal phosphate wast-
ing and without other evidence of renal tubulopathy. He
characterized this disorder as being a “vitamin D-resis-
tant rickets,” based on the inability to effectively heal the
rickets with doses of vitamin D usually used for nutri-
tional rickets, and the ability to demonstrate some skele-
tal improvements with higher vitamin D doses than usu-
al [31]. In 1957, Winters et al. [122] then highlighted sev-
eral published cases of different forms of rickets to which
“vitamin D resistance” was attributed, but noted especial-
ly the X-linked dominant familial form of hypophospha-
temic rickets as a “vitamin D-resistant” form of rickets.
Shortly thereafter, Prader et al. [123] described a patient
with hypophosphatemic tumor-induced osteomalacia.
Early efforts to treat patients with hypophosphatemic
rickets and osteomalacia focused on the application of
high doses of vitamin D, which carried a risk for vitamin
D toxicity. Frame and Smith noted that adult patients
with acquired hypophosphatemic osteomalacia could
improve using phosphate salts [124]; in children, the rick-
ets could also be refractory to oral phosphate salts [125].
Given the limited response to vitamin D, Stickler et al.
[126] tried to treat familial hypophosphatemic rickets by
increasing the calcium-phosphate product through in-
creasing intake of phosphate and calcium (on alternating
Miller/Imel
days to ensure absorption), without vitamin D. However,
this approach also proved unsuccessful, and they con-
cluded that, at least to some degree, gastrointestinal ab-
sorption was also impaired. However, based on later un-
derstanding of the underlying physiology of X-linked hy-
pophosphatemia, true “vitamin D resistance” at the level
of the receptor is not actually part of the pathophysiology.
Thus, the term “vitamin D resistant rickets” is misleading
and in the modern setting should be abandoned in pa-
tients with X-linked hypophosphatemic rickets (XLH)
and applied only when the VDR gene is mutated (see
above).
In 1978, Charles Scriver provided an important link to
the apparent abnormalities in vitamin D responsiveness.
He and his coauthors used a competitive binding assay to
demonstrate that 1,25-dihydroxyvitamin D (1,25[OH]2D
or calcitriol) levels were impaired in children with hypo-
phosphatemic rickets [115]. With the combination of hy-
pophosphatemia and low or low-normal calcitriol levels
being key components of this renal phosphate-wasting
disease, studies were then conducted to confirm that ad-
dition of calcitriol was critical to healing the osteomalacia
and rickets [127–129]. Combining phosphate salts with
high doses of calcitriol (or other active vitamin D ana-
logues) became the standard of care for children with
XLH. Both the effects of XLH on phosphorus and on cal-
citriol are mediated through the kidney, but neither ad-
ministration of phosphate nor calcitriol corrected the re-
nal phosphate leak [127]. The underlying cause of the
phenotype in XLH remained elusive.
A key step in further understanding of XLH was the
generation of the hyp mouse model, published in 1976 by
Eicher et al. [130]. This mouse model recapitulated the
X-linked dominant inheritance pattern and the biochem-
ical and skeletal phenotype of XLH. Even though the ge-
netic defect had not yet been discovered, this model en-
abled studies that eventually demonstrated clearly that a
hormonal factor was responsible for the renal phosphate
wasting, rather than a kidney factor. Through parabiosis
experiments, Meyer et al. [131] were able to demonstrate
that the wild-type mouse developed phosphaturia when
parabiosed to the hyp mouse, indicating that crossing of
a humoral factor was causative [131]. Further confirma-
tion of a humoral factor came when Nesbitt et al. [132]
conducted crossed renal transplant experiments between
hyp and wild-type mice. The hyp mouse kidney did not
develop phosphaturia when transplanted in the wild-type
mouse, but the wild-type kidney did develop phosphatu-
ria when transplanted in the hyp mouse.
Rickets, Vitamin D, and Ca/P Metabolism
A consortium of investigators was convened to find
the genetic cause of XLH, through linkage studies in kin-
dreds. Eventually this led to the discovery of the phos-
phate-regulating gene with homologies to endopeptidas-
es on the X-chromosome or PHEX (originally published
in 1997 as PEX and later changed) [133]. However, the
protein PHEX is expressed in bones and teeth and is not
a humoral factor.
A kindred with an autosomal dominant form of hypo-
phosphatemic rickets had been described in 1971 by
Bianchine et al. [134], having similarities to XLH. Mi-
chael Econs later studied another kindred with this in-
heritance pattern, which was described as autosomal
dominant hypophosphatemic rickets (ADHR) [135].
Persons with ADHR presented with a similar biochemical
Downloaded from http://karger.com/hrp/article-pdf/95/6/579/3751569/000527011.pdf by guest on 24 October 2023
phenotype to XLH: hypophosphatemia, impaired tubular
reabsorption of phosphate, and low or inappropriately
normal calcitriol levels. However, it was clear from this
kindred that not everyone developed “rickets.” This fam-
ily demonstrated incomplete penetrance. Additionally,
some children presented similarly to XLH and then nor-
malized their biochemistry over time. Others were con-
firmed as normal during childhood and developed new
onset severe hypophosphatemia and osteomalacia as ado-
lescents or adults. Genetic linkage studies in this and oth-
er ADHR kindreds led to the discovery of FGF23 in 2000
[136]. The name FGF23 derives from its structural rela-
tionship to other FGF (fibroblast growth factor) mole-
cules and does not imply an action on fibroblasts. FGF23
was also cloned from tumors causing tumor-induced os-
teomalacia [137]. FGF23 proved to be a humoral factor
normally expressed in bone, and the mutation causing
ADHR occurred in a cleavage motif, leading to impaired
proteolytic cleavage preserving intact, active FGF23 [138,
139]. FGF23 appears to fulfill all the characteristics that
had been expected of the hypothetical hormone “phos-
phatonin” [140].
Multiple causes of autosomal recessive hypophospha-
temic rickets or ARHR were also discovered starting in
2006, through studies of clinically affected patients. These
linked abnormalities of 3 additional genes, DMP1, ENPP1,
and FAM20C, to increased gene expression of FGF23
[141–144]. Thus, the common feature of each of these
genetic diseases (XLH, ADHR, and the forms of ARHR)
is high FGF23 expression, along with the resulting bio-
chemical consequences of excess FGF23.
Klotho had been discovered in 1997 in a mouse model
that had multiple aging-related phenotypes [145]. While
klotho had been thought to be a gene conferring an anti-
aging phenotype, several of the features of klotho defi-
Horm Res Paediatr 2022;95:579–592 587
DOI: 10.1159/000527011
ciency actually recapitulated mineral metabolism disor- as chronic kidney disease. Future studies will expand our
ders, including hyperphosphatemia and high calcitriol. understanding of mechanisms and the consequences of
The deficiency of klotho in mouse models was strikingly too much and too little FGF23, phosphorus, and their in-
similar to that of FGF23 deficiency [146]. In 2006, Ku- fluence on overall mineral metabolism.
roso et al. [147] made the critical connection when klotho
was found to be a crucial cofactor in the signaling of
FGF23 through FGF receptors. Alpha klotho enables sig- Statement of Ethics
naling of FGF23 through the FGF receptors, FGFR1, 3,
Not applicable.
and 4, and provides tissue specificity of FGF23 activity,
primarily in the kidney. Ichikawa et al. [148] demonstrat-
ed the first pathogenic variant in klotho causing human Conflict of Interest Statement
disease. This patient had hyperphosphatemic tumoral
calcinosis along with extreme elevation of intact FGF23 Dr. Erik A. Imel receives research funding and consulting from
consistent with a response to FGF23 resistance [148]. Ultragenyx Pharmaceuticals and consulting fees from Kyowa Ki-
rin Pharmaceuticals.
It is important to note that treatment with calcitriol

Downloaded from http://karger.com/hrp/article-pdf/95/6/579/3751569/000527011.pdf by guest on 24 October 2023

and phosphate does not lower FGF23, but rather stimu-
lates FGF23 levels as demonstrated by multiple studies in Funding Sources
normal humans and in patients with XLH [149–151].
Since FGF23 mediates the hypophosphatemia seen in The authors have not received any funding or financial support
for this work.
XLH, it is logical to target FGF23 itself to improve the
phenotype of XLH. A placebo-controlled trial of anti-
FGF23 antibody (burosumab) in adults with XLH dem- Author Contributions
onstrated increased phosphorus levels, fracture healing,
and other salutary patient-reported outcomes [152], and Walter L. Miller wrote the material concerning the early his-
tory of rickets, vitamin D, and PTH; Erik A. Imel wrote the mate-
in children burosumab improved rickets more than con-
rial concerning phosphorus and FGF23; both authors reviewed
ventional therapy. and approved the entire manuscript.
Much has been learned regarding phosphorus metab-
olism since the first description of children and adults
with hypophosphatemic rickets. FGF23 has become crit- Data Availability Statement
ically important in our understanding of these disorders
No new data were generated for this report.
and also has relevance to more common conditions such

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