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Genetic disorders of calcium, phosphorus, and bone homeostasis

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Translational Science of Rare Diseases 3 (2018) 1–36
DOI 10.3233/TRD-180019
IOS Press
1
Review Article
Genetic disorders of calcium, phosphorus,
and bone homeostasis
Allen W. Root
Department of Pediatrics, Johns Hopkins Medicine – All Children’s Hospital, St. Petersburg,
FL, USA
Abstract. Calcium and phosphorus [in the form of phosphate (H2PO4/HPO42)] are the most abundant elements in the body
where they subserve many functions – the most prominent of which is the formation of hydroxyapatite [Ca10(PO4)10(OH)2]–
the mineral portion of bone [1, 2]. Calcium and phosphate are present in every cell in the body and are essential for
normal cellular function. Calcium is indispensable for transmission of neural signals, muscle contractility, intracellular signal
transduction, and secretion of cellular products. Phosphate is required for formation of nuclear and mitochondrial DNA and
RNA, phospholipids for cell membrane formation, glycolysis and generation of high energy bonds (ATP), and intracellular
signaling by guanosine triphosphate (GTP)-bearing proteins (G-proteins) and cyclic adenosine monophosphate (AMP).
Phosphorylation of networks of intracellular proteins by many different kinases propagate the transmission of signals from
the cell’s plasma membrane into the nucleus to regulate gene expression and cellular function. Genetic disorders of calcium,
phosphate, and skeletal homeostasis lead to hypercalcemia, hypocalcemia, rickets or osteomalacia, osteopenia with marked
skeletal fragility, and excessively dense bones.
Keywords: Bone, calcium, hypercalcemia, hypocalcemia, osteopenia, osteosclerosis, phosphorus
Abbreviations
AD Autosomal dominant
ADHR Autosomal dominant hypophosphatemic rickets
AHO Albright’s hereditary osteodystrophy
APECED Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
AR Autosomal recessive
ASARM Acidic serine- and aspartate-rich motif
BMP Bone morphogenetic protein
CASR Calcium sensing receptor
DMP1 Dentin matrix protein-1
FGF Fibroblast growth factor
FGFR FGF receptor
GPCR G-protein coupled receptor
MEPE Matrix extracellular phosphoglycoprotein
NFκB Nuclear factor kappa B
NPT Sodium/phosphate cotransporter
Corresponding author: Allen W. Root, Department of Pediatrics, Johns Hopkins Medicine – All Children’s Hospital,
St. Petersburg, FL, USA. E-mail: aroot3@jhmi.edu.
2214-6490/18/$35.00 © 2018 – IOS Press and the authors. All rights reserved
This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0).
2A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
OI Osteogenesis imperfecta
PHP Pseudohypoparathyroidism
PKA Protein kinase A
PPHP Pseudopseudohypoparathyroidism
PTG Parathyroid gland
PTH Parathyroid hormone
PTHR PTH receptor
PTHrP PTH related protein
RANK Receptor activator of nuclear factor κB
RANKL Rank ligand
RXR Retinoid X receptor
sFRP-4 Secreted frizzled-related protein-4
SIBLINGS Small integrin-binding ligand, N-linked glycoprotein
TF Transcription factor
TGFTransforming growth factor
TIO Tumor induced osteomalacia
VDR Vitamin D receptor
VDRE VDR response element
WSTF Williams syndrome transcription factor
XHR X-linked hypophosphatemic rickets
25OHD3 25-Hydroxyvitamin D3 (calcidiol)
1,25(OH)2D3 1,25-Dihydroxyvitamin D3 (calcitriol)
1. Normal calcium, phosphate, and skeletal homeostasis
1.1. Calcium and phosphate
Ninety-nine percent of body calcium is deposited in bone as hydroxyapatite. Circulating, extracel-
lular and intracellular calcium, and surface bone account for approximately one percent of total body
calcium. Within bone calcium is both deeply deposited where turnover rate is relatively slow (several
weeks) and on the bone surface where it is immediately accessible for homoeostatic needs. In blood,
calcium circulates in the free or ionized state (Ca2+), bound to proteins (primarily albumin), and com-
plexed to citrate, bicarbonate, or lactate. It is the Ca2+concentration that is the biologically active
form of plasma calcium and hence its concentration is closely controlled by the interaction of parathy-
roid hormone (PTH), calcitriol (1,25-dihydroxyvitamin D3), and calcitonin, a product of the thyroid
parafollicular (C) cell, upon the kidney, bone, and intestinal tract [1, 3]. The circulating concentration
of Ca2+is monitored by the calcium sensing receptor (CaSR), a 7 transmembrane G-protein coupled
receptor (GPCR) situated on the cell membranes of the parathyroid gland chief cell and renal tubular
cells [4]. Binding of Ca2+to the CaSR leads to activation of the Gq subunit of the G-protein followed
by increase in phospholipase C activity with ensuing enzymatic conversion of membrane-bound phos-
phatidylinositol 4,5-bisphosphate to cytosolic diacylglycerol and inositol trisphosphate; the latter then
increases intracellular levels of Ca2+by releasing it from storage sites in the endoplasmic reticulum.
In the parathyroid chief cell, increases in intracellular concentrations of Ca2+depress expression of
PTH and decrease synthesis and secretion of its product. In the renal tubule, increased cytoplasmic
Ca2+levels depress reabsorption of filtered calcium and increase its urinary excretion.
PTH is synthesized as a preprohormone of 115 amino acids that is subsequently metabolized to a pro-
hormone (90 amino acids) and then to the mature product (84 amino acids) by the enzyme furin. PTH
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 3
is further metabolized to smaller carboxyl and amino terminal fragments either within the parathyroid
glands (PTGs) themselves prior to secretion, a process dependent on the cytosolic Ca2+concentration,
or in the periphery (primarily the kidney) after secretion. The first 34 amino acids of PTH are essential
for bioactivity as they contain the sites of binding to the PTH receptor (PTHR1). PTHR1 is a G-protein
coupled receptor (GPCR) that mediates the effects of PTH and PTH related protein (PTHrP). PTHR1
is structurally related to the GPCRs for growth hormone releasing hormone, corticotropin releas-
ing hormone, secretin, glucagon, and vasoactive intestinal polypeptide. PTH inhibits renal tubular
reabsorption of phosphate. It enhances renal tubular reabsorption of calcium from glomerular filtrate
and bone (Fig. 1). PTH also amplifies absorption of intestinal calcium by increasing renal tubular
synthesis of calcitriol. In bone, PTH stimulates the stromal cell/osteoblast to synthesize agents that
regulate osteoclastogenesis (Receptor Activator of Nuclear Factor κB ligand = RANKL and its antag-
onist Osteoprotegerin). PTHrP (MIM 168470) is a 144 amino acid peptide with sequence homology to
PTH in its first 13 amino acids; it binds to PTHR1 with affinity equal to that of PTH. PTHrP is active
primarily in the fetus as a regulator of endochondral bone development and the formation of teeth and
breasts; it is frequently a cause of humoral hypercalcemia of malignancy due to its ectopic secretion
by neoplastic tumors.
The bulk of vitamin D3 (cholecalciferol) is synthesized in skin by exposure to ultraviolet light and
heat [5, 6] (Fig. 2). In the liver, cholecalciferol is hydroxylated at carbon-25 to form calcidiol (25-
Fig. 1. Regulation of calcium and phosphate homeostasis by the parathyroid glands, bone, kidney, and intestinal tract.
Increase in serum Ca2+stimulates secretion of PTH that acts upon the renal tubule (increases calcium reabsorption, decreases
phosphate reabsorption, increases synthesis of calcitriol) and bone (stimulates osteoclastogenesis and reabsorption of skeletal
calcium and phosphate. Increases in serum phosphate levels stimulates skeletal production of FGF23 (depresses renal tubular
reabsorption of phosphate and synthesis of calcitriol). (Reproduced with permission from Levine MA. Investigation and
management of hypocalcemia. Meet-the-Professor. Meeting of the Endocrine Society, 2010, p 81-86.)
4A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
Synthesis and
Metabolism
of Vitamin D
Rosen CJ.NEJM
364:248,2011
Fig. 2. Synthesis and metabolism of vitamin D. Precursors of vitamin D synthesized in skin are metabolized to cholecalciferol
in response to ultraviolet light and heat. Cholecalciferol is then successively hydroxylated in the liver and the kidney to
form calcitriol. (Reproduced with permission from Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J Med
364:248-254,2011.)
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 5
hydroxyvitamin D3 =25OHD3); in the kidney, calcidiol is hydroxylated at carbon-1 to form calcitriol
[1,25-dihydroxyvitamin D3 = 1,25(OH)2D3], the biologically most active metabolite of vitamin D.
Intracellularly, calcitriol binds to a nuclear transcription factor – the vitamin D receptor (VDR) – that
then links as a heterodimer with the retinoid-X receptor (RXR) to the vitamin D response element
(VDRE) in the 5’ promoter region of target genes to either stimulate or inhibit their transcription.
Calcitriol is catabolized by renal 1,25(OH2)D3-24 hydroxylase to calcitroic acid and then excreted
[7]. Calcitriol stimulates intestinal absorption of calcium and phosphate and increases reabsorption of
calcium from bone and renal glomerular filtrate.
Calcitonin is a 32 amino acid hypocalcemic peptide encoded by CALCA (MIM 114130, chromosome
11p15.2-15.1) that is synthesized by the parafollicular C cells of the thyroid gland in response to rising
concentrations of Ca2+. It antagonizes the effects of PTH and calcitriol on bone mineral reabsorption
and intestinal calcium absorption, respectively. In the kidney, calcitonin binding to the renal tubule
inhibits reabsorption of phosphate and calcium. CALCA also encodes calcitonin gene-related protein,
a neuromodulatory peptide involved in regulation of the autonomic nervous system, and katacalcin,
a second hypocalcemic factor. Acting through its GPCR – CALCR (CALCR, MIM 114131, chromo-
some 7q21.3) expressed on the plasma membrane of osteoclasts and other responsive cells, calcitonin
stimulates signal transduction through stimulation of adenylyl cyclase activity. Serum concentrations
of calcitonin serve as a marker of C cell hyperplasia and of medullary carcinoma of the thyroid.
Phosphate is present primarily in bone bound to calcium in the hydroxyapatite crystal. In the circu-
lation it is complexed to various cations. Intracellularly, phosphate is a component of the G-proteins,
cyclic AMP, and numerous intermediates in all of the many signal transduction systems that culminate
in gene expression and cellular function. Phosphate is an irreplaceable part of nucleic acids linking
individual nucleic acids to form chains of DNA and RNA. Phosphate is essential for cellular glucose
processing [e.g., glucose-6-phosphate is the first compound formed during intracellular generation of
high energy bonds (i.e., ATP)] and hence for energy utilization and cell metabolism [8]. Approximately
70 percent of phosphate filtered through the renal glomerulus is actively reabsorbed in the proximal
renal tubule through apical membrane situated sodium-phosphate cotransporters – NPT2a and NPT2c
(Fig. 3) [9]. PTH inhibits renal tubular reabsorption of phosphate by stimulating the rapid internal-
ization and degradation of these cotransporters; PTH also down-regulates the expression of the genes
encoding these transporters, mechanisms also promoted by the hypophosphatemic phosphatonins.
Phosphatonins are substances that increase renal tubular excretion of phosphate and depress renal
tubular synthesis of calcitriol – the latter by down regulating expression of the gene encoding
25-hydroxyvitamin D-1-hydroxylase. Four substances with phosphatonin-like activity have been
identified – primarily because they have been produced by mesenchymal tumors associated with
hypophosphatemic osteomalacia: Fibroblast growth factor 23 (FGF23), Matrix extracellular phospho-
glycoprotein (MEPE), Secreted frizzled-related protein-4 (sFRP-4), and Fibroblast growth factor 7.
FGF23 is a 251 amino acid peptide whose full length is required for optimal bioactivity. Its amino
and carboxyl terminal domains are linked at an enzymatic cleavage site located within amino acids
176–180; mutations at this site delay degradation of FGF23 and prolong its biological half-life leading
to autosomal dominant hypophosphatemic rickets (ADHD) [10]. FGF23 is synthesized and secreted
by osteoblasts and osteocytes in response to rising serum concentrations of phosphate and calcitriol.
There is a direct positive relationship between serum levels of phosphate and those of FGF23. In addi-
tion to its inhibitory effects on phosphate reabsorption in the proximal renal tubule and upon synthesis
of calcitriol, FGF23 also impairs expression of PTH in the PTGs thereby decreasing the synthesis and
secretion of PTH [11]. FGF23 is produced in excess in patients with X-linked dominant hypophos-
phatemic rickets (XHR) and autosomal dominant and recessive forms of hypophosphatemic rickets. In
addition, FGF23 is secreted ectopically by neoplasms (tumor-induced osteomalacia = TIO) and non-
ossifying fibrous dysplastic tissue (McCune-Albright syndrome) and by patients with osteoglophonic
6A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
Prie D, Friedlander G.NEJM 362:2399,2010
Disorders of Renal Phosphate Transport-Reabsorption
Fig. 3. Reabsorption of phosphate from the renal tubule is blocked by PTH and FGF23 acting upon their respective receptors
to down regulate the number of sodium phosphate luminal transmembrane channels through which phosphate is reabsorbed
from the glomerular filtrate. (Reproduced with permission from Prie D, Friedlander G. Genetic disorders of renal phosphate
transport. N Engl J Med 362:2399-2409,2010.)
dysplasia, Jansen type metaphyseal chondrodysplasia, and linear nevus sebaceous syndrome; concen-
trations of FGF23 are also increased by the intravenous administration of ferric oxide-maltose – a drug
employed in the treatment of iron deficiency anemia [12]. Loss of function mutations in FGF23 leading
to decreased FGF23 synthesis result in autosomal recessive hyperphosphatemic familial tumoral cal-
cinosis [13]. UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3
(GALNT3) is an enzyme that glycosylates FGF23 amino acid number 178 (threonine) in the ortho
position; O-glycosylation at Thr178 is essential for normal translation of FGF23 and its subsequent
cleavage between amino acids Arg179-Ser180. Loss of function mutations of GALNT3 lead to dis-
ordered post-translational processing of FGF23, decreased secretion of FGF23, and thence also to
autosomal recessive hyperphosphatemic familial tumoral calcinosis with large amounts of calcium
being deposited in skin and subcutaneous tissues, particularly the eyelids. Hyperostosis of the long
bones may also occur in some patients with this syndrome [14].
FGF23 transmits its message through binding to cell membrane fibroblast growth factor receptor
1 (FGFR1). The extracellular domain of the FGFRs contains three immunoglobulin-like sequences,
the third of which may be differentially incorporated into the FGFR protein by alternative splicing
of messenger RNA during translation. A tyrosine kinase domain is present within the intracellular
portion of the FGFRs. FGF23 is recognized specifically by the isoform – FGFR1(IIIc) – in which part
of the third immunoglobulin-like domain is lacking. Klotho (encoded by KL) is a 1012 amino acid
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 7
transmembrane protein that also binds FGF23. (Klotho is the name of the Fate in Greek mythology
who spun the thread of life, so named because Klotho also plays a role in the aging process.) Binding
of Klotho to FGF23 enables FGFR1(IIIc) to recognize FGF23; Klotho and FGFR1(IIIc) acting
in concert constitute the FGF23 receptor. Loss of function mutations in KL lead also to autosomal
recessive hyperphosphatemic familial tumoral calcinosis [15]. Thus, inactivating mutations in three
different but functionally interrelated genes (FGF23, GALNT3, KL) result in the same clinical disease
phenotype of autosomal recessive hyperphosphatemic familial tumoral calcinosis.
1.2. Bone
Bone is composed of a protein matrix of collagen type I [an intertwined heterotrimeric structure
of two molecules of collagen type I subunit 1(I) and one molecule of collagen type I subunit 2(I)
bridged by disulfide bonds] that provides an extracellular platform upon which is deposited the mineral
portion of bone in the form of the hydroxyapatite lattice [Ca8(PO4)10(OH)2]. Approximately 10%
of bone matrix consists of non-collagenous proteins such as osteocalcin and osteonectin. Bone is
composed of a cortex of compact bone braced by internal trabecular (spongy or cancellous) bone [16].
Bone formation is regulated by osteoblast function, while bone reabsorption is mediated by osteoclasts.
Osteoblasts are derived from multipotential mesenchymal cell under the guidance of many transcription
factors including bone morphogenetic proteins (BMP2, BMP7), WNT1,RUNX2, and SP7 [17, 18].
Osteoblasts produce collagen type I – subunits 1 and 2, as they express both COL1A1 and COL1A2.
Each gene encodes a core structure of 1014 amino acids at both the amino and carboxyl terminals
by propeptides that are removed during post-translational processing. Glycine comprises every third
amino acid in collagen; lysine and proline are other commonly present amino acids. In the endoplasmic
reticulum of the osteoblast, procollagen type I subunits 1 and 2 are linked to form type I procollagen
that, in turn, undergoes complex post-translational modifications including 4-prolyl hydroxylation,
lysyl hydroxylation, and glycosylation of hydroxylysine before assuming a stable three-dimensional
configuration. Hydroxylation at carbon-3 of proline residue 986 of collagen type I subunit 1(I) is
essential for optimal stability of the helical form of intact collagen type I [16]. Prolyl-3 hydroxylation is
accomplished by a complex of three proteins; prolyl-3-hydroxylase-1 (LEPRE1), cartilage-associated
protein (CRTAP), and peptidyl-prolyl isomerase B (PPIB). Chaperones (e.g., HSP47, FKBP65) guide
the post-translational modifications of procollagen type I and the folding process that results in the
three dimensional configuration of the protein. After exiting the endoplasmic reticulum, procollagen
type I transits the Golgi apparatus, is entrapped in secretory vesicles, secreted into the extracellular
matrix, and further processed by removal of amino and carboxyl terminal propeptide amino acid
sequences forming mature collagen type I. When embedded within formed bone, osteoblasts become
terminally differentiated osteocytes that are interconnected by cytoplasmic strands within canaliculi
[19]. Osteocytes function as a network sensing mechanical loading and alterations in bone strength;
this network modulates bone remodeling by sending signals to both osteoclasts and osteoblasts; they
also respond to PTH and PTHrP.
In addition to collagen type I, osteoblasts secrete into bone matrix a number of non-collagenous
proteins that aid and abet bone mineralization. SIBLINGS (Small integrin-binding ligand, N-linked
glycoprotein) are matrix proteins such as bone sialoprotein, matrix extracellular glycoprotein (MEPE),
dentin matrix protein-1 (DMP1), and osteopontin that bind avidly to and coat hydroxyapatite. They
share a sequence or motif of acidic serine- and aspartate-rich amino acids (ASARM). ASARM may
be released into the circulation by catalytic proteolysis of its parent protein; phosphorylated ASARM
inhibits bone mineral deposition. Bone contains 99 percent of the total body calcium content in two
functional compartments – newly deposited surface bone that is part of the readily exchangeable
and rapidly available calcium pool as is the calcium in serum and interstitial fluid, and more deeply
8A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
deposited bone that although not inert as it turns over with a half life of approximately six weeks is
not immediately available for maintenance of normal extra- and intracellular calcium levels; deeply
deposited bone preserves the firm structural integrity of the skeleton.
Bone is remodeled by osteoclasts that reabsorb the mineral and protein components of bone. Osteo-
clasts are mutinucleated giant cells derived from mesenchymal mononuclear cells that differentiate
and fuse under the guidance of a number of osteoclast activating and differentiating factors (e.g., PTH,
calcitriol, prostaglandins, interleukins, macrophage-colony stimulating factor) [20, 21] (Fig. 4). Osteo-
clast activating factors stimulate the stromal cell/osteoblast to express on its cell surface and to release
into the circulation RANKL, a protein that enhances osteoclastogenesis. RANKL is recognized by
RANK expressed on the plasma membrane of an osteoclast precursor cell derived from hematopoietic
stem cells. Binding of RANKL to RANK promotes further differentiation of committed pre-osteoclasts
and their fusion to form the mature, multinucleated osteoclast (osteoclastogenesis). Osteoblasts also
secrete osteoprotegerin – a protein that binds to RANKL and prevents its interaction with RANK,
thereby inhibiting osteoclastogenesis (i.e., osteoprotegerin serves as a “decoy” receptor). Remodeling
of bone begins with the attraction of an osteoclast to a site of bone injury summoned by a signal from
Structure & Actions of the Osteoclast
Glowacki J.NEJM 360:1,2009
Fig. 4. Diagrammatic representation of osteoclastic bone reabsorption depicting the osteoclast adherent to bone, subosteo-
clastic lacuna, secretion of acid and proteolytic enzymes into the lacuna and transport of digested products of reabsorption
through the osteoclast. (Reproduced with permission from Glowacki J The deceiving appearances of osteoclasts. N Engl J.
Med 360:80-82,2009.)
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 9
the osteocyte network. The osteoclast adheres or seals to the bone surface at the site of the injured
bone. On its undersurface, the osteoclast forms an irregular (ruffled) border through which it secretes
hydrochloric acid into a sub-osteoclastic lacuna to dissolve the mineral portion of bone and enzymes
(cathepsin K, matrix metalloproteins 9 and 13) to break down collagen and other bone matrix proteins.
Intracellularly, hydrochloric acid is generated by conversion of carbon dioxide to carbonic acid, a
process catalyzed by carbonic anhydrase II (encoded by CA2). Protons (H+) are “pumped” into the
sub-osteoclastic lacuna through a vacuolar H+ATPase-regulated 6-transmembrane protein linked to a
chloride channel (encoded by CLCN7) and chloride-bicarbonate exchanger. From the sub-osteoclast
lacuna, catabolized bone products are absorbed into and transported through the osteoclast and then
released into the circulation. As bone is dissolved, osteoblasts are attracted to the site and begin to
form new bone in a process of continual remodeling. Errors in osteoblast function lead to impaired
bone formation and various forms of osteogenesis imperfecta, while errors in osteoclast differenti-
ation and function compromise bone reabsorption resulting in high bone mass, osteopetrosis, and
osteosclerosis.
Bone mineralization is under extensive genetic regulation – an estimated 60 to 90 percent of indi-
vidual variation in bone mineralization is related to genetic factors with a plethora of involved genes
each accounting for only a small fraction (perhaps 1 percent) of the total genetic variability in bone
mass [22]. Genome wide association studies have identified genes related to bone mineralization that
are essential for bone formation. These include SP7 (MIM 606633) encoding Osterix, a transcription
factor that is indispensable for osteoblast differentiation and WNT1 (MIM 164820) encoding a cir-
culating protein that signals through the 7-transmembrane domain-Frizzled receptor (MIM 603408)
with intracellular signal transduction by stabilization of -catenin (MIM 116806) that leads to differ-
entiation and proliferation of osteoblasts and to transcription of COL1A1 and COL1A2 and formation
of collagen type I [23]. Lipoprotein receptor-related protein 5 (LRP5 – MIM 603506) is a cell sur-
face protein that is expressed on the plasma membrane of the osteoblast and osteocyte. LRP5 has
three domains: the extracellular domain of LRP5 contains four amino acid sequences resembling
those of epidermal growth factor (EGF repeats); there are also single transmembrane and cytoplas-
mic domains. Gain of function mutations in LRP5 are associated with high bone mass, and loss of
function mutations result in low bone mass. In vitro and in vivo studies indicate that LRP5 func-
tions as a co-receptor (with Frizzled) for WNT enabling signal transduction through -catenin. Both
Dickkopf-related protein 1 (MIM 605189) and sclerostin (MIM 605740) antagonize LRP5-mediated
WNT1 signaling in the osteoblast by binding to the extracellular domain of LRP5 and impairing for-
mation of the LRP5-WNT1-Frizzled complex. However, it has also been reported that rather than
acting through the WNT1-Frizzled--catenin pathway in osteoblasts, LRP5 affects bone mineral
accrual through its expression in intestinal enterochromaffin cells. There, LRP5 inhibits expression of
TPH1 (MIM 191060) encoding tryptophan hydroxylase and consequently the synthesis of serotonin
[24–26]. In bone, serotonin inhibits osteoblast proliferation and mineralization. Thus, through this
suggested pathway, upregulated LRP5-mediated inhibition of intestinal serotonin production results
in enhanced osteoblast function and high bone mass and vice versa. Experimentally, support for the
enteral-serotonin mechanism of LRP5 function has been challenged [27]. However, it may be that
depending on extant conditions LRP5 may exert its effects through both mechanisms. Many genes that
normally regulate bone formation have had deleterious effects on mineralization when rendered non-
functional by noxious mutations – e.g.,SP7,SOST,TNFSF11A (RANKL), and TNFRSF11A (RANK)
(Tables 3–5) [22].
Alkaline phosphatase (encoded by ALPL – MIM 171760) is an ectoenzyme produced by and
expressed on the surface of osteoblasts that degrades endogenous inhibitors of mineralization (e.g.,
pyrophosphate, pASARM) while increasing local concentrations of phosphate (natural substrates
pyridoxal-5’-phosphate and phosphoethanolamine) to values that exceed the calcium-phosphate
10 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
solubility product allowing deposition of calcium-phosphate as the hydroxyapatite crystal upon colla-
gen type 1. Inactivating mutations in ALPL lead to hypophosphatasia of variable severity depending
on the site of mutation.
2. Hypocalcemia
Hypocalcemia in children and adolescents is most commonly an acquired abnormality. In preterm
and/or highly stressed neonates, hypocalcemia is the cumulative result of limited secretion of PTH,
hypercalcitonemia, vitamin D deficiency, hypomagnesemia, glucocorticoid inhibition of intestinal
calcium absorption, and limited calcium intake [2]. In older patients, hypocalcemia may be the result
of vitamin D deficiency or an autoimmune destructive process (autoimmune polyglandular syndrome
type 1) or surgical insult to the parathyroid glands. Genetic disorders that cause hypocalcemia include
those due to mutations in genes that control development of the PTGs, PTH synthesis or biologic
effectiveness, vitamin D synthesis or functionality, and the CaSR (Table 1).
Hypoparathyroidism may be transmitted as an autosomal recessive or dominant characteristic or
as an X-linked trait or it may be part of more complex congenital disorders such as the deletion
of chromosome 22q11.2 syndrome [28]. Autosomal recessive familial isolated hypoparathyroidism
due to agenesis of the PTGs has been attributed to loss of function mutations in GCM2, a nuclear
transcription factor expressed only in and essential for formation of these structures. Expression of
GCM2 is regulated by both GATA3 and TBX1; loss of function mutations in these genes result in
hypoparathyroidism in association with other malformations (vide infra) [29]. Mutations in GCM2
may also be transmitted as an autosomal dominant trait when the mutation exerts a dominant-negative
effect on the product of the wt allele [30]. Interestingly, GCM2 mutations transmitted as autosomal
recessive traits occur in the DNA binding domains of GCM2 nearer to the amino terminal of the protein,
while those transmitted as dominant characteristics occur in the second transactivation domain near
the carboxyl terminus of GCM2.
Hemizygous deletions of chromosome 22q11.2 of variable lengths occur in approximate 1 in 4000
births [31]. They are present in patients with the DiGeorge syndrome (DGS – MIM 188400) of
hypoplasia of the thymus and PTGs (leading to mild to moderately severe immune deficiencies and
hypoparathyroidism, respectively) and anatomic malformations of the outflow tract of the heart and in
patients with the velocardiofacial syndrome (MIM 192430) comprised of cleft palate, velopharyngeal
insufficiency, conotruncal cardiac anomalies, atypical face (hypertelorism, short palpebral fissures,
micrognathia), and learning disabilities (III and IV pharyngeal arch syndromes) (Fig. 5) [32–34]. Iso-
lated hypoparathyroidism may also be observed in patients with chromosome 22delq11. Chromosome
22q11 segment is susceptible to deletion because it is bracketed by low copy repeat numbers that make
this region intrinsically unstable during meiotic exchange leading to asynchronous replication [31].
One of the genes lost in deletion 22q11.2 is TBX1, a transcription factor that also interacts with a
histone methyltransferase complex to regulate gene expression [35]. TBX1 is essential for normal car-
diac and PTG differentiation. Monoallelic inactivating mutations in TBX1 alone (haploinsufficiency)
lead to five major abnormalities that occur in patients with the chromosome deletion 22q11 syn-
drome: conotruncal face (nasal segmentation, hypertelorism, short palpebral fissures, small mouth);
velopharyngeal insufficiency with cleft palate; cardiac defects (tetrology of Fallot, atrial and ventricular
septal defects, interrupted aortic arch); thymic hypoplasia; hypoparathyroidism [34]. Manifestations
of the chromosome deletion 22q11.2 syndromes may be influenced by modifier genes (e.g.,VEGF
polymorphism).
The presence of an interstitial deletion-insertion involving chromosomes Xq27.1 near SOX3 and
2p25.3 and the known expression of SOX3 in the developing PTG have suggested that abnormal
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 11
Table 1
Genetic causes of hypocalcemia
Gene
Chromosome
MIM
Pathophysiology Mutation – Clinical manifestations
Hypoparathyroidism
GCM2 – Glial cells missing,
Drosphila, homolog of, 2
6p24.2
603716
TF essential for normal development of
PTGs
Loss of function mutations lead to familial
isolated hypoparathyroidism; AR, AD
TBX1 – T-Box 1
22q11.2
602054
TF that also interacts with transcriptional
co-regulators; regulates expression of
GCM2 – TF essential for differentiation
of the PTGs
Hemizygous deletion of chromosome
22q11.2 (DiGeorge & velocardiofacial
syndromes) – Hypoparathyroidism,
immune dysfunction, cleft palate.
conotruncal congenital heart disease,
AD; monoallelic inactivating mutations
of TBX1 lead to several of the
manifestations of the chromosome
del22q11.2 syndrome
SOX3 – SRY-Box 3
Xq26.3
313430
TF expressed in the developing PTG Abnormal expression of SOX3 may be
related to pathogenesis of X-linked
hypoparathyroidism
GATA3 – GATA-binding
protein3
10p15
131320
TF regulating expression of GCM2 –aTF
requisite for differentiation of the PTGs;
GATA3 also essential for development of
auditory structures & kidneys & immune
regulation
Monoallelic loss of function mutations
result in Barakat (HDR) syndrome:
Hypoparathyroidism, sensorineural
deafness, renal disease, AD
TBCE – Tubulin specific
chaperone E
1q42-43
604934
Encodes a chaperone protein necessary for
proper formation of the cytoskeleton,
protein transport, & secretion
Inactivating mutations lead to –
Sanjad-Sakati (HRD) syndrome:
Hypoparathyroidism-retardation-
dysmorphism syndrome, AR;
Kenny-Caffey syndrome, type 1:
Hypoparathyroidism, medullary stenosis,
osteosclerosis, recurrent bacterial
infections, AR
PTH – Parathyroid hormone
11p15.3-p15.1
168450
Peptide that mobilizes calcium from bone
by stimulating osteoclastogenesis and
increases its reabsorption from
glomerular filtrate; enhances intestinal
absorption of calcium by stimulating
synthesis of calcitriol
Loss of function mutations result in
familial isolated hypoparathyroidism;
AR, AD
CASR – Calcium sensing
receptor
3q13.3-q21
601199
GPCR that monitors ambient Ca2+
concentrations
Gain of function mutations results in
autosomal dominant
hypoparathyroidism, AD
TRPM6 – Transient receptor
potential cation channel,
subfamily M, member 6
9q21
607009
One member of a TRPM6/TRPM7
complex that is essential for epithelial
transport of Mg2+in kidney & intestine
Loss of function mutations lead to familial
hypomagnesemia with secondary
hypocalcemia, AR
(Continued)
12 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
Table 1
(Continued)
Gene
Chromosome
MIM
Pathophysiology Mutation – Clinical manifestations
Resistance to PTH
PTHR1 – PTH receptor 1
3p22-p21.1
156400
GPCR for PTH & PTHrP Loss of function mutations result in
Blomstrand chondrodysplasia &
hypocalcemia despite elevated serum
levels of PTH, AR
GNAS – GNAS complex
locus
20q13.2
139320
Stimulatory alpha subunit of G-protein
(Gs) that responds to ligand binding of
GPCR; activates adenylyl cyclase
generating cyclic AMP resulting in
activation of PKA
Monoallelic inactivating mutations result
in pseudohypoparathyroidism type 1a;
methylation defects in maternal allele
lead to type 1
PRKAR1A – Protein kinase,
cAMP-dependent regulatory,
type 1, alpha
17q23-q24
188830
Component of PKA response to cyclic
AMP that leads to cascade of intracellular
signal transduction signals in response to
Gs that regulate cell division,
differentiation, metabolism, apoptosis
Gain of function mutation leads to
acrodysostosis & peripheral resistance to
the biologic effects of PTHrP, PTH &
TSH; (de novo)
Other
AIRE1 – Autoimmune
regulator
21q22.3
607358
TF expressed in medulla of thymus that
enables this organ to differentiate
self-antigens from foreign antigens
Loss of function mutations result in
autoimmune polyendocrine syndrome
type 1 with autoimmune
hypoparathyroidism & other
endocrinopathies, mucocutaneous
candidiasis, ectodermal dystrophy, AR
expression of this gene may be of etiopathogenic significance in patients with X-linked hypoparathy-
roidism associated with agenesis of the PTGs [36]. The autosomal dominant Barakat syndrome (MIM
146255) of hypoparathyroidism, sensorineural deafness, and renal dysfunction is due to loss of func-
tion mutations in GATA3, a transcription factor that regulates expression of GCM2 and is also involved
in differentiation of the auditory system and kidneys. The Sanjad-Sakati syndrome (MIM 241410)
of hypoparathyroidism, intrauterine and postnatal growth retardation, developmental delay, seizures,
dysmorphic facial features (microcephaly, prominent forehead, deeply set eyes, beaked nose, thin
upper lip, micrognathia, large and droopy external ears), and increased susceptibility to infections
is an autosomal recessive disorder due to inactivating mutations in TBCE encoding tubulin specific
chaperone E; this disorder may be genetically heterogeneous, however [37–39]. The intact product
of TBCE facilitates proper folding of proteins – specifically alpha and beta tubulin heterodimers that
interconnect microtubules (structures essential for normal architecture of the cytoskeleton) and endo-
cytic vesicles and facilitate the intracellular transport and secretion of proteins. Inactivating mutations
in TBCE are also present in patients with the Kenny-Caffey syndrome type 1 (MIM 244460), an
autosomal recessive disorder with many findings similar to those in the Sanjad-Sakati syndrome but
with the additional manifestations of medullary stenosis of the long bones and cranial osteosclerosis.
(Kenny-Caffey syndrome type 2 is transmitted as an autosomal dominant characteristic due to variants
of FAMILIA.)
Inactivating mutations in PTH that obstruct the processing of preproPTH to its bioactive product
(PTH) result in functional hypoparathyroidism that may be transmitted as an autosomal dominant or
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 13
HUMAN DELETION 22q11.2 SYNDROME
Yagi H et al Lancet 362:1366,2003
Fig. 5. Facial characteristics of the deletion chromosome 22.q11 syndrome and/or mutations in TBX1. Panels A and B are
mother and son – arrowheads point to the divide into upper and lower segments. Panel C schematically depicts a – ocular
hypertelorism; b – short palpebral fissures; d – small mouth (a – inner canthal distance; b – outer canthal distance; c –
transverse facial width; d – oral width; e – nasal width). Panel D depicts the face of a patient with conotruncal anomaly face
syndrome, intact chromosome 22q11, mutation in TBX1. Panels E and F display frontal and lateral views of a patient with the
DiGeorge syndrome, intact chromosome 22q11, and mutation in TBX1. (Reproduced with permission from Yagi H, Furutani
Y, Hamada H, et al. Role of TBX1 in human del22q11.2 syndrome. Lancet 362:1366-1373,2003.)
recessive characteristic. Depending on the specificity of the immunoassay for PTH, serum levels of
PTH may be low, normal or even high in these patients. Autosomal dominant hypoparathyroidism is the
result of gain of function mutations in CASR. In this disorder very low levels of Ca2+activate the CaSR
and repress parathyroid chief cell transcription of PTH as well as renal tubular reabsorption of calcium
leading to paradoxical hypercalciuria – the mirror image of familial hypocalciuric hypercalcemia
(vide infra). Magnesium is essential for release of PTH from the PTGs and for normal peripheral
responsiveness to PTH. Familial hypomagnesemia type 1 with secondary hypocalcemia (MIM 602014)
is an autosomal recessive disorder due to inactivating mutations in TRPM6 encoding an essential subunit
of a TRPM6/TRPM7 renal and intestinal epithelial co-transporter for this cation. Mutations in FXYD2
(MIM 601814), CLDN16 (MIM 603959), EGF (MIM 131530), and CLDN19 (MIM 610036) have been
identified in patients with renal hypomagnesemia types 2–5, respectively. In addition, many patients
with Bartter (MIM 241200) or Gitelman (MIM 263800) syndromes may be hypomagnesemic.
Patients with inactivating mutations in PTHR1, encoding the GPCR for PTH and PTHrP, have
functional hypoparathyroidism (hypocalcemia, hyperphosphatemia) although serum concentrations
of PTH are elevated. Additionally, these subjects have an osteochondrodystrophy – Blomstrand
14 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
Table 2
Genetic causes of hypercalcemia
Gene
Chromosome
MIM
Pathophysiology Mutation – Clinical manifestations
Hyperparathyroidism
MEN1 – Menin
11q13
131100
Menin is a nuclear protein that inhibits
transcription activated by JunD, SMAD3
& other transcription factors & serves as
a tumor suppressor
Germline loss of function mutations in
MEN1 and somatic loss of MEN1 sum to
produce multiple endocrine neoplasia
type 1 or familial isolated
hyperparathyroidism; AD
CDKN1B – Cyclin dependent
kinase inhibitor 1B
12p13.1
600778
Inhibitor of cyclin-mediated cell
proliferation; tumor suppressor
Monoallelic loss of function mutations lead
to parathyroid, pituitary, renal, testicular
tumors (MEN type 4), AD
CDC73 – Cell division cycle
protein 73, S. cerevisiae,
homolog of
1q31.2
607393
Also designated HRPT2; encodes
parafibromin, a protein involved in gene
transcription & translation
Germline gain of function mutations result
in hyperparathyroidism type 2 –
hyperparathyroidism-jaw tumor
syndrome (HRPT2) & familial isolated
hyperparathyroidism type 1; AD
PTHR1 – PTH receptor 1
3p22-p21.1
156400
GPCR for PTH & PTHrP Monoallelic activating mutations result in
Murk-Jansen metaphyseal
chondrodysplasia & hypercalcemia with
low serum levels of PTH
CASR – Calcium sensing
receptor
3q13.3-q21
601199
GPCR for Ca2+Monoallelic loss of function mutations
result in clinically occult familial benign
hypocalciuric hypercalcemia; biallelic
mutations lead to neonatal severe
hyperparathyroidism; AD, AR
ELN – Elastin
7q11.23
130160
One of the genes encoded on chromosome
7q11.23 – hemizygous loss likely
account for the vascular malformations
associated with WBS
Williams-Beuren syndrome – infantile
hypercalcemia, supravalvular aortic
stenosis, characteristic face – contiguous
gene deletion syndrome at chromosome
7q11.23; AD
BAZ1B – Bromodomain
adjacent to zinc finger
domain, 1B
7q11.2
605681
Encodes Williams syndrome transcription
factor (WSTF)- haploinsufficiency
interferes with calcitriol-VDR mediated
inhibition of transcription of CYP27B1 &
synthesis of calcitriol
Williams-Beuren syndrome – infantile
hypercalcemia, supravalvular aortic
stenosis, characteristic face – contiguous
gene deletion syndrome at chromosome
7q11.23; AD
CYP24A1 – Cytochrome
P450, family 24, subfamily
A, polypeptide 1
20q13.2-13.3
126065
Encodes renal 1,25(OH2)D3-24
hydroxylase enzyme that initiates
inactivation of 1,25(OH2)D3 and its
excretion as calcitroic acid
Loss of function mutations result in
idiopathic infantile hypercalcemia, AR
chondrodysplasia (MIM 215045) – characterized by advanced skeletal and dental maturation and
very short extremities – abnormalities detectable in utero by fetal ultrasonography. Histological exam-
ination of the growth plates of long bones of these patients reveals that loss of function mutations
in PTHR1 are typified by a narrow zone of proliferating epiphyseal cartilage, erratically distributed
and vacuolated chondrocytes, and few osteoclasts. The disorder is due to defective in utero response
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 15
Table 3
Disorders of mineralization: Rickets and osteomalacia
Gene Chromosome MIM Pathophysiology Mutation – Clinical manifestations
Disorders of vitamin D metabolism
CYP2R1 – Cytochrome P450,
subfamily IIR, polypeptide 1
11p15.2
608713
Hepatic 25-Hydroxylase – enzyme that
converts vitamin D3 to 25OHD3
(calcidiol)
Biallelic loss of function mutation leads to
vitamin D hydroxylation-deficient rickets
type 1B (also termed vitamin D
dependent rickets type 1B), AR
CYP27B1 – Cytochrome
P450, subfamily XXVII,
polypeptide 1
12q13.1-q13.3
609506
25OHD3-1hydroxylase – enzyme that
converts 25OHD3 to 1,25(OH)2D3
(calcitriol)
Biallelic inactivating mutations result in
vitamin D dependent rickets type 1A, AR
VDR – Vitamin D receptor
12q12-q14
601769
Vitamin D receptor – transcription factor
that transduces the effects of calcitriol on
gene activation or repression
Biallelic loss of function mutations lead to
resistance to calcitriol and vitamin D
dependent rickets type 2A, AR
HNRNPC – Heterogeneous
nuclear ribonucleoprotein C
164020
Encodes a ribonucleoprotein that regulates
gene transcription by reciprocally and
transiently occupying the VDRE in the
upstream promoter region of vitamin
D-responsive target genes
Overexpression in vitamin D-responsive
tissues leads to prolonged occupancy of
the VDRE that interferes with interaction
of the VDR/RXR with the VDRE
resulting in vitamin D dependent rickets
type 2B
Disorders of phosphate metabolism
SLC34A1 – (Solute carrier
family 34 (sodium phosphate
cotransporter), member 1
5q35
182309
Encodes NPT2a – sodium/phosphate
cotransporter expressed on the apical
membrane of the proximal renal tubule;
under the inhibitory control of PTH
Loss of function mutations result in
hypophosphatemia with urolithiasis and
osteopenia; AD
SLC34A2 – (Solute carrier
family 34 (sodium phosphate
cotransporter), member 2
2p15.31-p15.2
604217
Encodes NPT2b – sodium/phosphate
cotransporter expressed in the small
intestine, lung, and testes
Loss of function mutations associated with
pulmonary alveolar microlithiasis and
testicular microlithiasis. AR
SLC34A3 – (Solute carrier
family 34 (sodium phosphate
cotransporter), member 3
9q34
609826
Encodes NPT2c – sodium/phosphate
cotransporter expressed on the apical
membrane of the proximal renal tubule
Loss of function mutation results in
hereditary hypophosphatemic rickets
with hypercalciuria, AR
SLC9A3R1 – Solute carrier
family 9, member 3,
regulator 1
17q25.1
604990
Encodes NHERF1 – a renal tubular
sodium/hydrogen exchange regulatory
factor that binds NPT2a anchoring it to
the luminal membrane of the proximal
renal tubule; phosphorylation by PTH
leads to its dissociation from &
endocytosis of NPT2a
Loss of function mutations result in
autosomal recessive hypophosphatemic
rickets & nephrolithiasis, AR
CLCN5 – Chloride channel 5
Xp11.23-p11.22
300008
Encodes a proximal renal tubular
exchanger of chloride & hydrogen ions
Loss of function mutations result in
X-linked recessive hypophosphatemic
rickets, hypercalciuria, nephrocalcinosis,
XLR
(Continued)
16 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
Table 3
(Continued)
Gene Chromosome MIM Pathophysiology Mutation – Clinical manifestations
PHEX
Phosphate-regulating
endopeptidase homolog,
X-linked
Xp22.2-p22.1
300550
Ectoenzyme expressed on the cell membrane
of osteoblasts; its physiological substrate
may be MEPE & pASARM, its
phosphorylated degradation product that
coats hydroxyapatite & hinders mineral
deposition
Loss of function mutation leads to X-linked
hypophosphatemic rickets; associated with
increased expression of FGF23; X-linked
dominant
DMP1 – Dentin matric
acidic phosphoprotein 1
4q21
600980
Non-collagenous, serine-rich, bone matrix
protein; a small integrin-binding ligand,
N-linked glycoprotein (SIBLING)
expressed in osteocytes
Loss of function mutations lead to increased
osteocyte synthesis of FGF23,
hyperphosphaturia, & autosomal recessive
hypophosphatemic rickets, AR
ENPP1 – Ectonucleotide
pyrophosphatase/
phosphodiesterase 1
6q22-q23
173335
Ectoenzyme expressed by chondrocytes,
bone, & plasma cells that hydrolyzes ATP
to pyrophosphate, an inhibitor of bone
mineralization
Loss of function mutations result in
autosomal recessive hypophosphatemic
rickets with increased expression of
FGF23, AR
ANKH – ANK, mouse,
homolog of
5p15.2-141
605145
Transmembrane-spanning cell surface
protein that regulates pyrophosphate
secretion
Inactivating mutations result in mild
hypophosphatemia & joint ankylosis,
developmental delay, deafness, &
dentinogenesis imperfecta; AR
FGF23 – Fibroblast growth
factor 23
12p13.3
605380
Product of osteoblast & osteocyte that
depresses renal tubular reabsorption of
phosphate & inhibits synthesis of calcitriol
Gain of function mutation that decreases the
rate of degradation of FGF23 results in
autosomal dominant hypophosphatemic
rickets, AD; excessive ectopic synthesis by
neoplasms leads to hypophosphatemic
rickets; loss of function mutation leading
to decreased FGF23 synthesis results in
autosomal recessive hyperphosphatemic
familial tumoral calcinosis, AR
GALNT3 – UDP-N-Acetyl-
alpha-D-Galactosamine:
polypeptide
N-acetylglactosaminyl
transferase 3 1q24-q31
601756
Encodes an enzyme that is essential for
O-glycosylation of Thr178 of FGF23
during post-translational processing;
failure of this step leads to degradation of
FGF23 prior to its secretion
Loss of function mutation leads to autosomal
recessive hyperphosphatemic familial
tumoral calcinosis, AR
KL – Klotho
13q12
604824
Co-receptor with FGFR1(IIIc) for FGF23
that converts FGFR1(IIIc) into the specific
FGF23 receptor enabling signal
transduction
Loss of function mutation leads to autosomal
recessive hyperphosphatemic familial
tumoral calcinosis, AR
Hypophosphatasia
ALPL – Alkaline
phosphatase, liver
1p36.12
171760
Tissue non-specific alkaline phosphatase –
ectoenzyme expressed on the cell
membrane of osteoblasts, removes
organically bound phosphate; major
substrates are pyrophosphate,
phosphoethanolamine,
pyridoxal-5’-phosphate
Loss of function mutations lead to
hypophosphatasia & rickets of variable
severity & onset: perinatal, infancy,
childhood, adult, odontohypophosphatasia;
AR, AD
Adapted from Farrow EG, White KE. Recent advances in renal phosphate handling. Nature Rev/Nephrol 6:207-217,2010.
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 17
Table 4
Disorders of mineralization: Low bone mass (Osteogenesis imperfecta Types I XI – see Table 5)
Gene Chromosome MIM Pathophysiology Mutation – Clinical manifestations
LRP5 – Low density
lipoprotein receptor-related
protein 5
11q13.4
603506
Transmembrane receptor expressed on
plasma membrane of osteoblasts,
osteocytes & enterochromaffin cells; in
osteoblasts & osteocytes, LRP5 &
Frizzled are co-receptors for WNT & the
complex stimulates signal transduction
by -catenin; in enterochromaffin cells
activation of LRP5 inhibits synthesis of
tryptophan hydroxylase & serotonin
decreasing serotonin-mediated inhibition
of osteoblast proliferation & function
Inactivating mutations result in
osteoporosis-pseudoglioma, AR
FBN1 – Fibrillin 1
15q21.1
134797
Glycosylated component of the
microfibrillar system of extracellular
matrix elastic fibers that are essential
components of elastic and non-elastic
connective tissue
Inactivating mutations lead to Marfan
syndrome (MIM 154700), AD, AR
CBS – Cystathionine beta
synthase
21.q22.3
613381
Encodes enzyme that conjugates
homocysteine and serine to form
cystathionine
Inactivating mutations lead to
homocystinuria (MIM 236200) –
phenotype similar to that of Marfan
syndrome
TNFRSF11B – Tumor
necrosis factor receptor
superfamily, member 11B
8q24
602643
Encodes osteoprotegerin, decoy receptor
for RANKL
Juvenile Paget disease
COL1A1 – Collagen type I,
alpha-1
17q21.3-q22
120150
Encodes a protein that forms collagen
type I
Inactivating mutations result in
osteogenesis imperfecta types I–IV (see
Table 5), Ehlers-Danlos syndrome type I
(MIM 130000)
to PTHrP, an essential factor for normal fetal cartilage differentiation and maturation. Blomstrand
chondrodysplasia is often lethal in early infancy.
Patients with loss of function mutations in GNAS encoding the stimulatory alpha subunit (Gs) of G-
protein also develop hormone resistance – primarily pseudohypoparathyroidism (PHP) with or without
the phenotype of Albright’s hereditary osteodystrophy (AHO). The clinical manifestations of AHO
include short stature, brachydactyly, obesity, round face, and heterotopic subcutaneous calcifications.
Whether the AHO phenotype is expressed in the patient with PHP depends on which parent has donated
the inactive GNAS allele, because the tissue expression of GNAS in renal tissue is imprinted and
determined by the parent of origin allele. Both GNAS alleles are expressed in most tissues including
bone; however, in the kidney only maternal GNAS is expressed. Hence, the clinical manifestations
of PHP in an individual patient depend on whether the inherited maternal or paternal GNAS allele
is defective. Thus, loss of function mutations of the maternal GNAS allele result in PHP type Ia
with end-organ resistance to many protein hormones including PTH (resulting in hypocalcemia and
hyperphosphatemia) as well as the skeletal defects of AHO. Inactivating mutations of paternal GNAS
result in pseudopseudohypoparathyroidism (PPHP) with intact hormonal responsiveness (including
renal reactivity to PTH) but abnormal skeletal phenotype due to haploinsufficiency of GNAS in bone.
18 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
Table 5
Disorders of mineralization: Osteogenesis imperfecta
Type – MIM:
Disease – Gene
Chromosome
Severity Clinical features Growth
impairment
Blue sclera Inheritance Functional defect
I – 166200 –
COL1A1 – Collagen
type I, alpha-1
17q21.3-q22
1120150
Mild Few fractures, little
deformity, hearing loss
in 50%; rarely
dentinogenesis
imperfecta
Minimal Present –
intense
AD Nonsense & frameshift mutations resulting
in premature STOP codons result in
decreased production of collagen type I
IIA – 166210 –
COL1A1 or
COL1A2 – Collagen
type I, alpha-2
7q22.1
120160
Perinatal lethal –
congenital
Many rib & long bone
fractures in utero &at
birth, severe long bone
deformities,
unmineralized
calvarium
Severe Present AD, parental
mosaicism
A – Glycine substitutions in COL1A1 or
COL1A2 result in structurally abnormal
collagen type I
IIB – 610854 –
CRTAP – Cartilage
associated protein
3p22
605497
Perinatal lethal –
congenital
Many rib & long bone
fractures at birth, severe
long bone deformities,
unmineralized
calvarium
Severe Present AR B – Inactivating mutations of CRTAP
impair 3-prolyl (986) hydroxylation of
procollagen 1(I)
III – 259420 –
COL1A1 or
COL1A2
Severe, progressive,
deforming
Moderate to severe
bowing, multiple
fractures,
dentinogenesis
imperfecta, hearing loss
Severe Present but
lighten with
age
AD Glycine substitutions in COL1A1 or
COL1A2 result in structurally abnormal
collagen type I
IV -166220
COL1A1 or
COL1A2
Moderately
deforming
Mild to moderate bowing,
fractures
Moderate,
variable
Greyish or
absent
AD Glycine substitutions in COL1A1 or
COL1A2 result in structurally abnormal
collagen type I
V – 610967 Moderately
deforming,
clinically similar
to Type IV
Mild to moderate bone
fragility, ossification of
interosseous membranes
of forearm, hypertrophic
callus formation at
fracture sites
Mild to
moderate
Absent AD Unknown
IFITMS-Interferon-
induced
transmembrane protein
V IIP15.5614757
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 19
VI – 610968
FKBP65
FK506-binding protein
10
17q21.2
607062
Moderately to
severely
deforming,
clinically similar
to Type III
Onset of fractures in
infancy, increased
alkaline phosphatase
activity & osteoid,
“fish-scale” pattern of
lamellation
Moderate to
severe
Absent or faint AR Loss of function mutations in a chaperone
protein -FKBP65 – essential for
post-translational processing of
procollagen type I; may co-segregate
with epidermolysis bullosa; also mutated
in Bruck syndrome type 1
VII – 610682
*CRTAP – Cartilage
associated protein
3p22
605497
Moderately
deforming
Fractures present at birth,
rhizomelia, limb
deformities
Moderate Absent or faint AR Inactivating mutations (duplication) of
CRTAP impair hydroxyation of 3-prolyl
(986) of procollagen 1(I)
VIII- 610915
*LEPRE1 – Leucine-
and proline-enriched
proteoglycan 1
1p34
610339
Severely
deforming,
overlaps type II &
III
Phenotype overlaps those
of types II and III
Severe Absent AR Inactivating mutations of LEPRE encoding
prolyl-3-hydroxylase (leprecan) impair
hydroxylation of 3-prolyl (986) of
procollagen 1(I)
IX – 259440 –
*PPIB- Peptidyl-prolyl
isomerase B
15q21-q22
123841
Lethal to severe Shortened, bowed, &
fractured long bones in
mid-gestation
Severe Grey AR Inactivating mutations of PPIB encoding
peptidyl-prolyl isomerase B impair
hydroxylation of 3-prolyl (986) of
procollagen 1(I)
X – 613848 –
SERPINH1 – Serpin
peptidase inhibitor,
clade H, member 1
11q13.5
600943
Severe to lethal Short bowed femora in
utero, multiple fractures
in first month of life
Severe Present AR Loss of function mutations in a chaperone
protein – HSP47 – essential for
post-translational processing of
procollagen type I
(Continued)
20 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
Table 5
(Continued)
Type – MIM:
Disease – Gene
Chromosome
Severity Clinical features Growth
impairment
Blue sclera Inheritance Functional defect
XI – 613849 –
SP7 – Transcription
factor specificity factor
(Sp)7
12q13.13
606633
Severe, resembles
OI type IV
Multiple fractures in early
infancy; bowing of long
bones
Severe Absent AR Inactivating mutations in Osterix, a
transcription factor essential for
osteoblast differentiation
PLOD2
Procollagen-lysine,
2-oxoglutarate
5-dioxygenase 2
3q24
601865
Severe, OI with
congenital joint
contractures –
Bruck syndrome
2 – (MIM
609222)
Fractures in infancy,
pterygia, scoliosis
Severe Absent AR Encodes a lysyl hydroxylase necessary for
formation of collagen type 1 teleopeptide
(Modified from 2 Root AW, Diamond FB Jr. Disorders of bone mineral metabolism in the newborn, infant, child, and adolescent. in Sperling MA (ed). Pediatric Endocrinology,
3rd ed, Saunders/Elsevier, Philadelphia, 2008, p 686-769, with permission.). Form a complex essential for hydroxylation of carbon 3 of proline at position 986 of procollagen
type 1(I).
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 21
In PHP type Ib, lack of maternal GNAS expression is confined to the kidney resulting in selective renal
resistance to PTH; skeletal expression of maternal GNAS and hence skeletal formation are normal. PHP
type Ib is due to a methylation defect in the imprinting region that regulates maternal GNAS expression
in the kidney. Patients with PHP type II have a normal skeletal phenotype but are partially resistant to
the renal effects of PTH; its cause is unknown as yet. [Although not yet described clinically, it may be
anticipated that a loss of function mutation in LRP6 (encoding lipoprotein receptor-related protein 6 –
MIM 603507) will be associated with resistance to the biologic effect of PTH. In addition to its role as
a cell surface protein necessary for receptor-mediated endocytosis of lipoproteins, LRP6 is essential
for the movement of Gs to the plasma membrane and for its coupling to PTHR1 [40]. Experimentally,
in vitro “knock down” or inactivating mutation of Lrp6 decreases the cellular response to PTH.]
The next step in the signal transduction pathway initiated by activation of Gs entails cAMP-
mediated activation of protein kinase A (PKA). A patient with a de novo germline gain-of-function
mutation (Arg368Stop) in PRKAR1A, encoding the cyclic AMP-dependent regulatory subunit of PKA
leading to hormone resistance (specifically PTH and TSH) and to acrodysostosis, a chondrodysplasia
with many features of AHO (MIM 101800 – short stature, obesity, brachydactyly, abnormal face with
nasal and maxillary hypoplasia, advanced skeletal maturation) has been identified [41]. Translation
of the mutant messenger RNA of PRKAR1A resulted in a shortened protein product with enhanced
function, because the mutated regulatory subunit lacked one of its two cyclic AMP binding domains
and was catabolized very slowly. Consequently, the mutated regulatory subunit was unresponsive to
normal levels of cyclic AMP; it bound tightly to the catalytic subunit of PKA preventing its release
and thus maintaining the inactive state as evidenced experimentally by the reduced bioactivity of the
resultant PKA in response to cyclic AMP in vitro.
Children and adolescents with inactivating mutations in AIRE develop hypoparathyroidism (usually
between infancy and 10 years of age) together with other autoimmune endocrinopathies (adrenalitis,
primary hypogonadism, insulin-dependent diabetes mellitus, thyroiditis), mucocutaneous candidiasis,
and ectodermal dystrophy (APECED) resulting in autoimmune polyendocrine syndrome type 1 (APS1
– MIM 240300) [42, 43]. The cytoplasmic PTG autoantigen against which many APS1 patients with
hypoparathyroidism develop antibodies is NLRP5 (Nacht domain-, leucine-rich repeat-, and Pyd-
containing protein 5, MIM 609658), a peptide that is one component of a multi-protein inflammasome
[44]. Other autoimmune disorders associated with APS1 are chronic active hepatitis, juvenile-onset
pernicious anemia, vitiligo, and alopecia. AIRE encodes a zinc-finger transcription activating factor
that regulates thymic function enabling it to differentiate between self and foreign proteins (antigens).
In order to do so, AIRE interacts with thymic proteins involved with nuclear transport, chromatin
binding, transcription, and pre-mRNA processing [45].
Hypocalcemia occurs in infants with inactivating mutations in CYP27B1, the gene that encodes
25-hydroxyvitamin D-1-hydroxylase, the enzyme essential for synthesis of calcitriol, and in VDR
encoding the vitamin D receptor (Table 3). Hypocalcemia may also be found in patients with mitochon-
drial fatty acid oxidation disorders due to mutations in mitochondrial DNA in association with other
distinguishing characteristics [Kearns-Sayre (MIM 530000 – ophthalmoplegia, pigmentary degen-
eration of the retina, cardiomyopathy), MELAS (MIM 540000 – myopathy, encephalopathy, lactic
acidosis, diabetes mellitus)].
3. Hypercalcemia
In children and adolescents, hypercalcemia is most commonly an acquired abnormality due to immo-
bilization, excessive vitamin D or vitamin A intake, increased synthesis of calcitriol by inflammatory
monocytes (e.g., subcutaneous fat necrosis, sarcoidosis), or medication ingestion (e.g., thiazide diuret-
ics, lithium, alkali-containing antacids) [46, 47]. Familial isolated primary hyperparathyroidism may
22 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
be due to hyperplasia, adenoma, or carcinoma of the PTGs. Familial isolated hyperparathyroidism
types 1 (MIM 145000) and 2 (MIM 145001 – associated with functional cystic adenomas and carcino-
mas of the PTGs as well as ossifying fibromas of the maxilla and/or mandible) are due to heterozygous
germline activating mutations in CDC73 (Table 2). This gene encodes parafibromin, a member of
a protein complex that associates with both a RNA polymerase II and a histone methyltransferase
complex and plays roles in both gene transcription and translation. Parafibromin is also a component
of the WNT/-catenin intracellular signal transduction pathway. Familial isolated primary hyper-
parathyroidism type 3 (MIM 610071) has been linked to chromosome 2p14-p13.3, but no specific
gene has as yet been identified in this region as its cause. In addition to the syndrome of multiple
endocrine neoplasia type I, mutations in MEN1 have been associated with familial isolated primary
hyperparathyroidism. Monoallelic inactivating germline mutations in CDKN1B, encoding a tumor
suppressor gene, are of etiopathogenic significance in patients with MEN type 4 (MIM 610755)
which is associated with adenomas of the parathyroid and pituitary glands and tumors of the kidneys
and testes.
Among the more frequent (albeit still unusual) genetic causes of hypercalcemia due to hyperparathy-
roidism are loss of function mutations in CASR, encoding the calcium sensing receptor, that result in
decreased sensitivity to the PTH-suppressing effects of Ca2+. Consequently, higher serum concentra-
tions of Ca2+are required to suppress synthesis and secretion of PTH. In most instances, familial benign
hypocalciuric hypercalcemia (type I) (MIM 145980) is an autosomal dominant trait due to monoallelic
loss of function mutations in CASR [48]. These patients have asymptomatic hypercalcemia (total cal-
cium level 11-12 mg/dL), relative hypocalciuria (calcium/creatinine ratio <0.1), and normal or slightly
elevated serum concentrations of PTH and are usually identified during routine chemical screening
or during family surveys when another family member is found to be hypercalcemic. Biallelic inacti-
vating mutations in CASR are associated with neonatal severe hyperparathyroidism (NSHPT) (MIM
239200), at times a life threatening disorder as serum calcium concentrations are markedly elevated
(total calcium >15 mg/dL) as are levels of PTH. Newborns bearing a monoallelic mutation in CASR
may develop NSHPT if the offspring is born to a normal mother and affected father because of the
fetal need to increase secretion of PTH in utero in order to maintain the high levels of calcium present
in the fetus. Occasionally, NSHPT is transmitted as an autosomal recessive disorder by parents whose
clinical and biochemical phenotypes are normal [49, 50]. Other forms of familial benign hypocalciuric
hypercalcemia have been linked to chromosome 19p13.3 (type II) and to chromosome 19q13 (type
III), but no gene mutations at these loci have as yet been identified.
Activating mutations of PTHR1 result in Murk-Jansen metaphyseal chondrodysplasia in associ-
ation with hypercalcemia (MIM 156400). Patients with this disorder are very short (adult height
100 cm); the metaphyses of the long bones are long and extremely disorganized and skeletal mat-
uration is quite delayed; in adults the cranial bones are sclerotic. Biochemically, serum and urine
analyte values are comparable to those in patients with primary hyperparathyroidism except that PTH
concentrations are extremely low (hypercalcemia and hypercalciuria, hypophosphatemia but hyper-
phosphaturia, increased urinary excretion of cyclic AMP, elevated serum concentrations of calcitriol).
The chondrodysplasias of Blomstrand due to inactivating mutations in PTHR1 (vide supra) and Murk-
Jansen are mirror images of one another. [Eiken syndrome (MIM 60002) is associated with multiple
epiphyseal dysplasias and markedly delayed skeletal maturation but normal serum concentrations of
calcium, phosphate, and PTH. It has ben associated with biallelic mutations in that portion of PTHR1
encoding the carboxyl terminal cytoplasmic tail of the receptor [51].]
Williams-Beuren syndrome (WBS – MIM 194050) is a hemizygous contiguous gene deletion syn-
drome (involving 26 to 28 genes on chromosome 7q11.23) affecting multiple systems that occurs in
approximately 1:10,000 individuals and is transmitted as an autosomal dominant disorder [52]. WBS is
characterized by a distinctive pixie-like face (flat nasal bridge, upturned nose, full lips), congenital heart
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 23
Infant Child Adult 12 y 83 y
Williams-Beuren Syndrome
Pober BR. NEJM 362:239,2010
Fig. 6. Facial characteristics (pixie-like face with flat nasal bridge, upturned nose, full lips) of a patient with the Williams-
Beuren syndrome from infancy to elderly. (Reproduced with permission from Pober BR. Williams-Beuren syndrome. N Engl
J Med 362:239-252,2010.)
disease (supravalvular aortic stenosis, peripheral pulmonary arterial stenoses, mitral valve prolapse),
developmental delay (mean IQ 58, range 20–106) and weak visuospatial skills but enhanced language
skills, vocabulary, and musical ability (Fig. 6) [47, 52]. When present, infantile hypercalcemia usually
resolves by two years of age but occasionally persists into childhood and adulthood. The pathogenesis
of hypercalcemia in WBS subjects may relate to loss of the Williams syndrome transcription factor
(WSTF) encoded by BAZ1B. This nuclear protein is part of a very large multimeric, ATP-dependent,
chromatin remodeling complex termed WINAC (WSTF including nucleoside assembly complex) [53].
Independently of ligand-binding, the VDR interacts with WINAC; normally, when calcitriol binds to
the VDR-WINAC complex, it represses renal tubular transcription of CYP27B1, the gene encoding
25-hydroxyvitamin D-1-hydroxylase, and stimulates transcription of CYP24A1, the gene encoding
25-hydroxyvitamin D-24-hydroxylase. Hence, haploinsufficiency of WSTF permits increased and
relatively unregulated synthesis of calcitriol and at the same time slows its rate of degradation; con-
sequently, the intestinal absorption of calcium increases and hypercalcemia ensues. Other findings in
patients with WBS include short stature, hypertension, narrowing of the thoracic and abdominal aortae
and renal and cerebral arteries, hyperacusis in childhood leading to nerve deafness, and somewhat early
onset of puberty in girls. Other endocrinopathies associated with WBS include glucose intolerance and
hypothyroidism. Deletion chromosome 7q11.23 is the result of unequal crossover of genes between
chromosome 7 homologs during meiosis (unequal meiotic recombination) and occurs with equal fre-
quency in the gametes of both parents. Among the 26 to 28 genes deleted in chromosome 7q11.23,
hemizygous loss of ELN encoding elastin is the likely cause of the cardiovascular malformations and
hypertension observed in WBS. Hemizygosity for LIMK1 (MIM 601329) may be a partial cause of
visuospatial and cognitive difficulties in WBS. Hemizygous loss of STX1A (MIM 186590) may be
pathogenetically related to development of glucose intolerance in WBS subjects [52].
Idiopathic infantile hypercalcemia (MIM 143880) is manifested by failure to thrive, hypercalcemia,
hypercalciuria, and nephrocalcinosis. It has been attributed to ingestion of excessive amounts of vitamin
D in fortified formulas and milk, although the amounts of vitamin D (500 to 4000 IU/day) consumed
by affected infants are far less than those known to be associated with toxicity in the general population
[5]. Although hypercalcemic, these patients usually have normal serum concentrations of calcidiol and
normal or slightly increased values of serum calcitriol, factors that differentiate these patients from those
with vitamin D poisoning. Thus, patients with idiopathic infantile hypercalcemia have been considered
to be extremely “sensitive” to vitamin D. Biallelic loss of function mutations in CYP24A1, encoding
the mitochondrial enzyme that inactivates 1,25(OH2)D3 by converting it to 1,24,25(OH)3D3 and then
to calcitroic acid and by converting 25OHD3 to 24,25(OH)2D3, have been identified in patients with
24 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
this disorder [7]. Thus, hypercalcemia in these subjects is likely due to ingestion of relatively high
amounts of vitamin D3 and the associated prolonged increases in serum levels of calcitriol due to its
slow rate of catabolism. Patients with hypophosphatasia (MIM 171760) are also “hypersensitive” to
calcitriol and may develop hypercalcemia when consuming usual amounts of cholecalciferol, although
the mechanism of this phenomenon is as yet unidentified.
Hypercalcemia, hypercalciuria, and nephrocalcinosis of undetermined pathogenesis are found in
patients with the blue diaper syndrome (MIM 211000) associated with a defect in intestinal transport
of tryptophan, lactase deficiency, and disaccharide intolerance. Bartter syndrome (MIM 601678) is
the designation of a group of diseases that collectively is due to attenuated reabsorption of sodium
chloride in the renal tubular thick ascending loop of Henle. These autosomal recessive disorders are
characterized by hypokalemic alkalosis, salt wasting, and hypercalciuria. Hypercalcemia may occur
in some infants with antenatal Bartter syndrome due to loss of function mutations in SCL12A1 (type 1
– MIM 600839) encoding the furosemide-sensitive NaK-2Cl-cotransporter or KCNJ1 (type2–MIM
600359) encoding the renal outer-medullary potassium channel (ROMK) – an inwardly rectifying
potassium channel [47].
4. Disorders of bone mineralization
4.1. Rickets
Clinically, rickets is a disorder of bone formation and remodeling in the growing infant, child, and
adolescent in which defective bone mineralization due to impairment of hydroxyapatite deposition onto
collagen type I in bone matrix results in skeletal deformations (genu valgum, genu varum, metaphyseal
flaring). Hypocalcemia may be a presenting manifestation of vitamin D deficiency in the neonate
or infant. In the adult, osteomalacia leading to increased fracture risk is the outcome of a similar
process. Rickets is due to inadequate supplies of calcium or phosphate (dietary deficiencies, lack
of vitamin D, malabsorption syndromes) or to excessive urinary loss of calcium or phosphate or to
abnormalities in the synthesis or function of alkaline phosphatase [2]. Osteoporosis is the result of
decreased synthesis or excessively rapid degradation of bone matrix proteins, particularly collagen
type I, that leads to osteopenia because of decreased collagen scaffolding upon which to deposit
hydroxyapatite. In children and adolescents, decreased bone mineralization has been defined as bone
mineral content or concentration that is two standard deviations below the mean normal for similar
gender and chronologic age by the method employed for its determination. Osteopenia has been
defined as bone mineralization between –1 and –2 standard deviations for similar gender and age.
Bone mineralization is considered increased if it is more than two standard deviations above the mean
normal for similar gender and chronologic age. However, when evaluating bone mineralization data it
is imperative to consider not only the gender and chronologic age of the patient but also his/her race,
ethnicity, height, weight, and stage(s) of sexual maturation.
Deficiency of vitamin D due to either limited dietary intake or insufficient exposure to sunlight
impairing endogenous synthesis of cholecalciferol is the most common cause of rickets. Genetically
restricted synthesis of endogenous calcitriol or functional responsiveness to calcitriol are uncommon
causes of rickets (Table 3). Defective hepatic 25-hydroxylation of vitamin D3 (cholecalciferol) due
to an inactivating mutation in CYP2R1 results in vitamin D hydroxylation-deficient rickets type 1 B
(MIM 600081). Loss of function mutations in CYPB27B1 encoding renal 25-hydroxyvitamin D3-1-
hydroxylase result in decreased synthesis of calcitriol and vitamin D dependent rickets type 1A (MIM
264700). Inactivating mutations in VDR impair tissue responsiveness to calcitriol and lead to vitamin
D dependent rickets type 2A (MIM 277440). In the latter patients, alopecia and hypocalcemia are often
present. HNRNPC encodes a ribonucleoprotein that transiently occupies hormone response elements
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 25
within the 5’ upstream promoter region of target genes; when overexpressed, HNRNPC interferes with
interaction of the VDR/RXR heterodimer with the VDRE resulting in a secondary form of vitamin D
resistance termed vitamin D dependent rickets type 2B (MIM 600785) in which clinical manifestations
are similar to those recorded in patients with mutations in VDR [54]. The mechanism by which
HNRNPC is overexpressed in patients with vitamin D dependent rickets type 2B is unknown as yet.
Hypophosphatemic rickets may be due to abnormalities of intestinal phosphate absorption or its
reabsorption in the proximal renal tubule (Table 3). SLC34A1 encodes a sodium/phosphate cotrans-
porter (NPT) expressed in the proximal renal tubule; loss of function mutations in SLC34A1 result in
hypophosphatemia due to hyperphosphaturia, renal calculi, and osteopenia. Inactivating mutations in
SLC9A3R1 encoding NHERF1, a renal tubular protein that binds NPT2a thereby anchoring it to the
luminal membrane of the proximal renal tubule, lead to autosomal recessive hypophosphatemic rickets
with urolithiasis; mutations in SLC9A3R1 potentiate PTH-induced generation of cyclic AMP and inhi-
bition of proximal renal tubular reabsorption of phosphate. Inactivating mutations of SLC34A3, a gene
encoding a second proximal renal tubular sodium/phosphate cotransporter, lead to autosomal reces-
sive hereditary hypophosphatemic rickets with hypercalciuria, the latter due to excessive synthesis of
calcitriol in response to systemic hypophosphatemia [55].
The most common form of hypophosphatemic rickets encountered is X-linked (XHR) due to inac-
tivating mutations in PHEX. This gene encodes a zinc-metalloendopeptidase situated on the surface
of osteoblasts and osteocytes whose physiologic substrate has proven difficult to identify with cer-
tainty. Unexpectedly, FGF23 is not a physiologic substrate of PHEX. Rather, current data indicate
that a phosphorylated peptide derived from MEPE is the primary substrate for PHEX action [56–58].
MEPE is a 525 amino acid non-collagenous protein secreted by osteoblasts that is present in extra-
cellular bone matrix; it is also found in teeth and in brain. MEPE inhibits renal tubular phosphate
uptake and, thus, is a phosphatonin. It is also one of the SIBLING group of non-collagenous matrix
proteins. MEPE contains an ASARM in its carboxyl terminal region that can be released by cathepsin
B. Normally, PHEX and MEPE bind to one another in a non-proteolytic manner as a result of which
MEPE is not degraded by cathepsin B and ASARM is not released. In the absence of normal PHEX
activity, ASARM is released from MEPE by cathepsin B. Indeed, serum ASARM levels are increased
in patients with XHR. Serine-phosphorylated ASARM binds directly to hydroxyapatite by interac-
tion with calcium atoms and prevents further deposition of calcium and phosphate thereby inhibiting
mineralization. Additionally, PHEX proteolytically cleaves pASARM between serine-glutamate and
serine-aspartate residues, thereby destroying pASARM and further preventing pASARM-mediated
inhibition of bone mineralization. The role of non-phosphorylated ASARM in the mineralization pro-
cess is as yet incompletely understood; ASARM can also bind to hydroxyapatite, albeit weakly, and
inhibit mineralization; ASARM too is enzymatically cleaved by PHEX. Thus, in XHR the primary
pathophysiologic abnormalities appear to be failure of mutated and bioinactive PHEX 1) to prevent
proteolytic cleavage of MEPE and release of ASARM and 2) to degrade pASARM derived from MEPE
thereby extending pASARM-mediated inhibition of mineralization. It is of interest that in XHR, two
phosphatonins – FGF23 and MEPE – are present in excess further exacerbating the mineralization
defect by increasing renal phosphate excretion and lowering still more the supply of phosphate ions
necessary for construction of hydroxyapatite. Interestingly, pASARM increases expression of FGF23
in bone cells [58]. pASARM catalytically released from osteopontin also binds to hydroxyapatite and
inhibits mineralization; osteopontin-derived pASARM is a PHEX substrate but non-phosphorylated
ASARM is not [57]. The pathophysiologic role of osteopontin and its pASARM in XHR is uncertain
at present. Mutations in DMP1,ENPP1, and ANKH result in autosomal recessive forms of hypophos-
phatemic rickets. X-linked recessive hypophosphatemic rickets (MIM 300554) is due to inactivating
mutations in CLCN5 (MIM 30008) encoding a proximal renal tubular exchanger of chloride and hydro-
gen ions [59]. This disorder is characterized clinically by failure of proximal renal tubular reabsorptive
26 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
function, hypophosphatemic rickets, hypercalciuria, nephrocalcinosis, and proteinuria progressing to
renal failure (Dent disease).
Fibroblast growth factor 23 is synthesized by osteoblasts and osteocytes; it depresses renal tubular
reabsorption of phosphate and inhibits synthesis of calcitriol. Gain of function mutations in FGF23
decrease the rate of degradation of FGF23 and result in autosomal dominant hypophosphatemic rickets.
Excessive ectopic synthesis of FGF23 by neoplasms and by the fibrodysplastic lesions of the McCune-
Albright syndrome and neurofibromatosis type 1 also leads to hypophosphatemic rickets. Loss of
function mutations in FGF23 lead to decreased FGF23 synthesis resulting in autosomal recessive
hyperphosphatemic familial tumoral calcinosis. This disorder that may also be due to inactivating
mutations in GALNT3 (MIM 601756) encoding an enzyme that is essential for O-glycosylation of
FGF23 during post-translational processing and whose failure leads to degradation of FGF23 prior to
its secretion and KL (MIM 604824), encoding Klotho – a co-receptor with FGFR1(IIIc) for FGF23 –
whose loss results in renal tubular unresponsiveness to FGF23.
The clinical and biochemical manifestations of rickets due to hypophosphatasia are due to loss of
function in ALPL (MIM 171760) encoding alkaline phosphatase, the osteoblast enzyme essential for
degradation of inhibitors of bone mineralization such as pyrophosphate and pASARM and for increas-
ing local concentrations of phosphate enabling deposition of hydroxyapatite onto collagen type I. Peri-
natal/infantile (MIM 241500), childhood (MIM 241510), and adult/odontohypophosphatasia (prema-
ture shedding of deciduous and/or secondary teeth, dental caries) (MIM 146300) forms of this disorder
have been described. In all subjects with hypophosphatasia, serum bone alkaline phosphatase activity
is inappropriately low. The severity of the disorder depends on the site of the mutation and residual
enzymatic activity and whether the affected subject has a biallelic or a monoallelic mutation in ALPL.
4.2. Low bone mass
Decreased nutritional intake, limited physical activity, chronic diseases, and hormonal deficiencies
are the most common factors leading to low bone mass in children and adolescents. In addition, several
deleterious gene mutations lead to osteopenia in children (Table 4). Mutations in genes controlling
normal collagen synthesis are the major causes of osteogenesis imperfecta or “brittle bone disease,” a
disorder characterized by low bone mass and increased osseous fragility (Table 5). Loss of function
mutations in LRP5 result in the osteoporosis-pseudoglioma syndrome (MIM 259770), an autosomal
recessive disorder associated with marked osteopenia leading to skeletal fractures, deformities, and
short stature and pseudotumors of the retina – at times mistaken for retinoblastoma; monoallelic
carriers of these mutations may have reduced bone mass of variable severity. Marfan syndrome (MIM
154700) is a connective tissue disorder characterized by abnormalities of the skeleton (tall stature,
long limbs, arachnodactyly, joint laxity, osteopenia, scoliosis/lordosis, highly arched palate, dental
crowding), eye (myopia, lenticular subluxation), and cardiovascular system (mitral valve prolapse and
regurgitation, dilatation of the aortic root, aortic valve regurgitation, aortic aneurysm and dissection).
Marfan syndrome is due to inactivating mutations in fibrillin-1 encoded by FBN1, a glycosylated
component of the microfibrillar system of extracellular matrix elastic fibers to which transforming
growth factor (TGF)binds and within which it is sequestered. Loss of function mutations in FBN1
permit TGFto mount an inflammatory state that leads to degradation of elastin fibers and weakening
of connective tissue [60]. Patients with homocystinuria (MIM 236200) have a phenotype similar to that
of Marfan syndrome and are also osteopenic. The Ehlers-Danlos syndromes are a group of connective
tissue disorders whose clinical manifestations include hyperextensibility of the skin, hypermobility
of the joints, tissue fragility, and in many patients substantially decreased bone mineralization; in
some subjects, this disorder is related to monoallelic inactivating mutations in COL1A1. Mutations in
COL3A1,COL5A1,COL5A2, and PLOD1 have also resulted in clinical Ehlers-Danlos syndromes.
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 27
4.3. Osteogenesis imperfecta
The predominant clinical characteristic of osteogenesis imperfecta (OI) is bone fragility due to low
bone mass leading to bone deformation and fracture [16]. Loss-of function mutations in the genes
encoding the two subunits of collagen type I (COL1A1,COL1A2) predominate in children with OI,
although there is substantial genetic heterogeneity of this disease as we learn more about the factors
that regulate and assist normal collagen formation (Table 5) [61, 62]. Traditionally, the forms (types)
of OI have been classified by their clinical manifestations as initially described by Sillence. Depending
on the site, mutations in COLIA1 or COL1A2 impair either synthesis or structure of the subunits of
collagen type I, may vary from lethal to mild in severity, and may be transmitted as either autosomal
dominant or autosomal recessive traits (OI types I–IV). A number of harmful sequence variations have
also been identified in genes that control the post-translational processing of both subunits of collagen
type I and whose disease phenotypes often overlap those of other types of OI, making a molecular
diagnosis increasingly important in the evaluation and management of children with OI. The mildest
clinical form of OI (type I) is that due to mutations in COL1A1 that reduce its rate of production.
Mutations in COL1A1 or COL1A2 that alter the structure of collagen type I and interfere with the
function of the collagen fiber result in more severe clinical disorders (types II–IV).
OI type V due to variants of IFITMS is characterized by radiographically dense metaphyseal bands
adjacent to the cartilage growth plate, calcification of the interosseous membrane between the radius
and ulna, exuberant callus formation at the site of fractures, and distinct and irregular “mesh-like”
appearance of the iliac lamellae microscopically. In OI type VI, the microscopic appearance of bone
is that of an array of “fish scales.” OI type VI is due to inactivating mutations in FKBP65, a gene that
encodes a chaperone that is essential for normal post-translational processing of procollagen type I. In
several Turkish families, OI type VI co-segregated with epidermolysis bullosa due to an inactivating
mutation in KRT14 encoding keratin 14, also situated on chromosome 17q21 [61]. Osteogenesis
imperfecta type X is a severe form of OI due to a loss of function mutation in SERPINH1, encoding
collagen binding protein 2 (CPB2) or heat shock protein 47 (HSP47), another chaperone [63]. HSP47 is
essential for normal localization of procollagen type I within the osteoblast; in its absence procollagen
type I accumulates in the Golgi apparatus. HSP47 is also necessary for formation and stabilization of
the collagen triple helix configuration.
In the endoplasmic reticulum, a proline residue at position 986 within procollagen type IA must
be specifically hydroxylated by a tripartite complex of prolyl 3-hydroxylase 1 (encoded by LEPRE),
cartilage associated protein (encoded by CRTAP), and peptidyl-prolyl isomerase B (encoded by PPIB).
The third member of the prolyl 3-hydroxylase complex, peptidyl-prolyl isomerase B, is also termed
cyclophilin B. Loss of function mutations in CRTAP,LEPRE,orPPIB result in moderate to severe and
often lethal forms of osteogenesis imperfecta (designated types IIB, VII, VIII, and IX, respectively).
One child has been described with autosomal recessive OI (type XI) due to a loss-of-function mutation
in SP7 encoding osterix, a transcription factor essential for osteoblast differentiation and activation of
COL1A1 [64].
Increased bone fragility is found in children with Bruck syndromes 1 and 2 (MIM 259450; 609220)
characterized by congenital joint contractures, pterygia, fractures beginning in infancy or early child-
hood, short stature, and scoliosis. In patients with Bruck syndrome type 1, mutations in FKBP10, (also
known as FKBP65 – see osteogenesis imperfecta type VI) encoding a collagen chaperone, have been
identified [65]. In Bruck syndrome type 2, biallelic mutations in PLOD2 (MIM 601865) encoding a
lysyl hydroxylase necessary for normal formation of collagen type 1 teleopeptide have been found [66,
67]. The Cole-Carpenter syndrome (MIM 112240) is manifested by multiple fractures developing in
the first year of life, craniosynostosis, progressive ocular proptosis, hydrocephalus, and an unusual face
(frontal bossing, mid-face hypoplasia, micrognathia), it is due to variants of P4HB or SEC24D [68].
28 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
4.4. Increased bone mass/Osteopetrosis
Increased bone mineralization may be the result of an excessive rate of bone formation or of a
decreased rate of reabsorption of already formed bone (Table 6). Sequence variations (e.g., Gly171Val,
Arg214Val) in LRP5 are associated with high bone mass and resistance to fractures in otherwise normal
subjects. These clinically benign sequence variants impair the binding to and thus the inhibitory effects
of Dickkopf-1 (encoded by DKK1) and sclerostin (encoded by SOST) upon LRP5. More significant
activating mutations in LRP5 lead to autosomal dominant osteopetrosis type 1 (607634) whose pheno-
type closely resembles that of high bone mass patients with endosteal osteosclerosis (MIM 144750) or
van Buchem disease type 2 (MIM 607636). Inactivating mutations in SOST (expressed in osteoblasts
and osteocytes and secreted by osteoclasts) that are unable to modulate LRP5-WNT-Frizzled stimula-
tion of bone formation result in pathologic forms of high bone mass including sclerosteosis (cortical
hyperostosis with cutaneous syndactyly – MIM 269500) and van Buchem disease (osteosclerosis of
skull, long bones, clavicle, ribs – MIM 239100).
Disorders of bone dissolution result in several forms of osteopetrosis that are characterized
histologically by either abundant or scarce osteoclasts (Table 6). Osteopetrosis in which bone
biopsy reveals a paucity of osteoclasts include those associated with loss of function mutations in
TNFSF11,TNFRSF11A, and IKBKG. Type 2 autosomal recessive osteopetrosis (MIM 259710) is
a disorder of variable severity characterized by progressive blindness, anemia, thrombocytopenia,
hepatosplenomegaly, skeletal and dental deformities, mandibular osteomyelitis, and increased frac-
ture risk; it is due to loss of function mutations in TNFSF11 encoding RANKL, a member of the
tumor necrosis factor ligand superfamily, thereby decreasing the stimulus to osteoclastogenesis [69].
Loss of function mutations in TNFRSF11A encoding RANK result in impaired osteoclastogenesis
and immune dysfunction (autosomal recessive osteopetrosis type 7 – MIM 612301). Some mutations
in TNFSF11 reduce binding of RANKL to RANK [70]. Inactivation of the NFκB essential modula-
tor (NEMO – the cytosolic regulatory subunit of IkappaB kinase essential for NFκB signaling that is
encoded by IKBKG) impairs NFκB-mediated immune responsiveness and osteoclastogenesis resulting
in a complex of immunodeficiency, lymphedema, anhidrotic ectodermal dysplasia, and osteopetrosis
transmitted as an X-linked trait (MIM 300301) [71].
Forms of osteopetrosis in which bone biopsy reveals abundant but poorly or non-functional osteo-
clasts are those associated with loss of function mutations in CA2,TCIRG1,CLCN7,OSTM1, and
PLEKHM1. Autosomal recessive osteopetrosis type 6 (MIM 611497) is a relatively mild form of
osteopetrosis characterized by high bone mass and slight deformities of long bones that is due to loss
of function mutations in PLEKHM1. This gene encodes a protein that enables the osteoclast to form
ruffled borders; thus its loss prevents sealing of osteoclasts to bone and initiation of the reabsorption
process. PLEKHM1 may also assist the transport of vesicles. Inability of the osteoclast to synthe-
size carbonic acid prevents formation of H+and dissolution of bone mineral resulting in autosomal
recessive osteopetrosis type 3 (MIM 259730); it is due to inactivating mutations in CA2 encoding
carbonic anhydrase II. Patients with this moderately severe form of osteopetrosis are characterized
by fractures in early childhood, short stature, visual impairment, and developmental challenges. Loss
of function mutations in TCIRG1 impair transport of H+into the subosteoclastic lacuna preventing
dissolution of hydroxyapatite resulting in autosomal recessive infantile malignant/lethal osteopetrosis
type 1 (MIM 259700). This disorder has also been termed Albers-Schonberg or marble bone dis-
ease. Beginning in utero and progressing rapidly postnatally, affected patients manifest macrocephaly,
progressive blindness and deafness, severe anemia, and hepatosplenomegaly. The clinically severe
infantile form of osteopetrosis may also be due to mutations in CLCN7 (autosomal recessive osteopet-
rosis type 4 – MIM 611490) and OSTM1 (autosomal recessive osteopetrosis type 5 – MIM 259720)
(vide infra). The phenotypic spectrum of osteopetrosis due to inactivating mutations in CLCN7 is
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 29
Table 6
Disorders of mineralization: Increased bone mass
Gene
Chromosome
MIM
Pathophysiology Mutation – Clinical manifestations
LRP5 – Low density
lipoprotein receptor-related
protein 5
11q13.4
603506
Transmembrane receptor expressed on
plasma membrane of osteoblasts,
osteocytes & enterochromaffin cells; in
osteoblasts & osteocytes, LRP5 &
Frizzled are co-receptors for WNT & the
complex stimulates signal transduction
by -catenin; in enterochromaffin cells
activation of LRP5 inhibits synthesis of
tryptophan hydroxylase & serotonin
decreasing serotonin-mediated inhibition
of osteoblast proliferation & function
Gain of function mutations lead to
autosomal dominant osteopetrosis type I,
endosteal hyperostosis, osteosclerosis,
van Buchem disease type 2, AD
SOST – Sclerostin
17q11.2
605740
Antagonist of WNT signaling of osteoblast
function, inhibitor of bone
morphogenetic protein-stimulated
differentiation of osteoblasts – secreted
by osteoclasts
Sclerosteosis, van Buchem disease, AR
TNFSF11 – Tumor necrosis
factor ligand superfamily,
member 11
13q14
602642
Encodes RANKL – activates RANK on the
membrane of the pre-osteoclast
enhancing osteoclastogenesis through
signaling to NFκB
Osteopetrosis, autosomal recessive type 2 –
relatively less severe form of
osteopetrosis than type 1
TNFRSF11A – Tumor
necrosis factor receptor
superfamily, member 11A
18q21.1
603499
Encodes RANK – activation results in
NFκB-mediated osteoclastogenesis &
osteoclast function
Osteopetrosis, autosomal recessive type 7 –
with hypogammaglobulinemia
IKBKG – Inhibitor of kappa
light polypeptide gene
enhancer in B cells, kinase of,
gamma
Xq28
300248
Also termed NEMO (NFκB essential
modulator) – component of IkappaB
kinase complex that is essential for
NFκB signaling
Inactivating mutations lead to a syndrome
complex of immunodeficiency,
lymphedema, anhidrotic ectodermal
dysplasia, osteopetrosis; X-linked
PLEKHM1 – Pleckstrin
homology domain-containing
protein, family M, member 1
17q21.31
611466
Encodes a protein that may affect vesicular
transport within the osteoclast & the
attachment of the osteoclast to bone.
Osteopetrosis, autosomal recessive type 6 –
intermediate phenotype, Erlenmeyer
flask deformity of long bone
CA2 – Carbonic anhydrase II
8q22
611492
Carbonic anhydrase – osteoclast enzyme
that generates protons (H+) from
carbonic acid
Osteopetrosis, autosomal recessive type 3 –
associated with renal tubular acidosis
TCIRG1 – T cell immune
regulator type 1
11q13.2
604592
Subunit of vacuolar proton pump that
transports H+into the sub-osteoclastic
lacunae to dissolve hydroxyapatite
Osteopetrosis, autosomal recessive type 1 –
infantile malignant osteopetrosis
(Continued)
30 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
Table 6
(Continued)
Gene
Chromosome
MIM
Pathophysiology Mutation – Clinical manifestations
CLCN7 – Chloride channel 7
16p13
602727
Chloride channel that transports Clinto
the sub-osteoclastic lacunae to dissolve
hydroxyapatite
Osteopetrosis, autosomal recessive type 4;
monoallelic mutations lead to autosomal
dominant osteopetrosis type II – of
intermediate severity
OSTM1
Osteopetrosis-associated
transmembrane protein 1
6q21
607649
CLCN7 & OSTM1 form a molecular
complex that cooperatively enable the
transport of Clfrom the osteoclast into
the sub-osteoclastic lacuna permitting
dissolution of hydroxyapatite
Osteopetrosis, autosomal recessive type 5 –
associated with retinal and neural
dysplasia
CTSK – Cathepsin K
1q21
601105
Cysteine endoproteinase essential for
degradation of bone extracellular organic
matrix
Pycnodysostosis, AR
LEMD3 – LEM
domain-containing protein 3
12q14
607844
Nuclear membrane protein that modulates
signal transduction by bone
morphogenetic proteins
Osteopoikilosis, AD
COL1A1 – Collagen type I,
alpha-1
17q21.3-q22
1120150
COL1A1 & COL1A2 form the triple helix
of collagen type 1
Infantile cortical hyperostosis (Caffey
disease), AD with variable penetrance
SAMD9 – Sterile alpha motif
domain-containing protein 9
7q21.2
610455
Encodes a protein expressed in skin
endothelial cells and fibroblasts
Homozygous mutation results in familial
normophosphatemic tumoral calcinosis,
AR
ACVR1 – Activin A receptor,
type I
2q24.1
102576
Transmembrane receptor for BMP type 1
(& activin), members of the TGFsuper
family
Heterozygous gain of function mutations
lead to fibrodysplasia ossificans
progressiva, AD
wide [72]. Clinically, biallelic mutations in CLCN7 encoding the osteoclast chloride channel are asso-
ciated with autosomal recessive infantile malignant osteopetrosis, while monoallelic mutations lead
to a much less severe form of autosomal dominant osteopetrosis type II (MIM 166600). Loss of
function mutations in OSTM1 encoding a protein that forms a complex with CLCN7 that enables
the transport of Clinto the sub-osteoclastic lacuna and the reabsorption of hydroxyapatite also
result in early onset form of often lethal osteopetrosis paired with neuroaxonal and retinal dystrophies
[73, 74].
Clinically, pycnodysostosis (MIM 265800) is manifested by short stature, osteosclerosis, cranial
deformities, and osseous fragility. It is due to biallelic inactivating mutations in CTSK, encoding a cys-
teine endoproteinase necessary for degradation of components of skeletal extracellular organic matrix.
The process of bone demineralization is normal in patients with pycnodysotosis. LEMD3 encodes a
nuclear membrane protein that antagonizes intracellular signal transduction by bone morphogenetic
proteins. Heterozygous loss of function mutations in LEMD3 result in osteopoikilosis (MIM 166700)
characterized by bone “spots” composed of discrete sclerotic areas present in epiphyses and metaphyses
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 31
Table 7
Osteochondrodystrophies
Gene Chromosome MIM Pathophysiology Clinical disorder (MIM)
TRIP11 – Thyroid hormone
interactor 11
14q31-q32
604505
Co-activator of the nuclear
triiodothyronine receptor;
interacts with microtubules &
Golgi apparatus
Achondrogenesis, type IA (200600), AR
SLC26A2 – Solute carrier
family 26 (sulfate transporter)
5q31-q34
606718
Encodes sulfate transporter essential
for normal collagen synthesis
Achondrogenesis, type IB (600972),
AR; Atelosteogenesis II (256050), AR;
Diastrophic dysplasia (222600), AR
COL2A1 – Collagen, type II,
alpha 1
12q13.11
120140
Subunit of collagen type II, the
major collagen of cartilage
comprised of three 3-alpha 1(II)
chains
Achondrogenesis, type II, (200610), AD;
Spondyloepiphyseal dysplasia congenita
(183900), AD; Spondylometaphyseal
dysplasia (184252), AD
FLNB – Filamin B
3p14.3
603381
Protein that influences vertebral
segmentation, endochondral
ossification, joint formation
Atelosteogenesis I (108720),
AR; Atelosteogenesis III (108721), AR
FGFR1 – Fibroblast growth
factor receptor 1
8p11.2-p11.1
136350
Transmembrane tyrosine kinase
receptor for FGFs
Pfeiffer (101600), AD
FGFR2 – Fibroblast growth
factor receptor 2
10q25.3-q26
176943
Transmembrane tyrosine kinase
receptor for FGFs
Apert (101200), AD
Crouzon (123500), AD
Jackson-Weiss (123150), AD;
Antley-Bixler with normal
steroidogenesis(207410), AD
FGFR3 – Fibroblast growth
factor receptor 3
4p16.3
134934
Transmembrane tyrosine kinase
receptor for FGFs
Achondroplasia (100800), AD
Hypochondroplasia (146100), AD
Thanatophoric dysplasia types I (187600) &
II (187601), AD
COMP – Cartilage
oligomeric matrix protein
19p13.1
600310
Chondrocyte protein that binds
calcium & collagen types I, II, &
IX
Pseudoachondroplasia (177170), AD
Multiple epiphyseal dysplasia (132400), AD
SHOX – Short stature
homeobox
Xpter-p22.32
312865
Homeobox gene transcription factor
located on the pseudoautosomal
region of Yp
Leri-Weill dyschondrosteosis (127300),
X-linked dominant; Langer dysplasia
(249700), biallelic
SOX9 – SRY-box 9
17q23
608160
Transcription factor essential for
chondrogenesis & testicular
differentiation
Campomelic dysplasia (114290), AD
RUNX2 – Runt-related
transcription factor 2
6p21
600211
Osteoblast specific transcription
factor
Cleidocranial dysostosis (119600), AD
(Continued)
32 A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis
Table 7
(Continued)
Gene Chromosome MIM Pathophysiology Clinical disorder (MIM)
PTHR1 – PTH receptor 1
3p22-p21.1
168468
GPCR recognizing PTH & PTHrP
with equal affinity
Inactivating mutations lead to Blomstrand
osteochondrodysplasia & hypocalcemia
(215045), AR; activating mutations result in
hypercalcemia & Murk-Jansen metaphyseal
chondrodysplasia (156400); Eiken
syndrome (600002); AD
PRKAR1A – Protein kinase,
cAMP-dependent regulatory,
type 1, alpha
17q23-q24
188830
Component of PKA response to
cyclic AMP that leads to cascade
of intracellular signal transduction
signals in response to Gs that
regulate cell division,
differentiation, metabolism,
apoptosis
Gain of function mutation leads to
Acrodysostosis & peripheral resistance to
the biologic effects of PTHrP, PTH & TSH;
(de novo)
HSPG2 – Heparan sulfate
proteoglycan of basement
membrane
1p36.1-p34
142461
Stabilizes basement membranes &
influences permeability;
co-receptor for FGFR2
Inactivating mutations result in
Schwartz-Jampel type 1 myotonic
chondrodystrophy (255800), AR
POR – Cytochrome P450
oxidoreductase
7q11.2
124015
Flavoprotein co-factor that donates
electrons to microsomal
17-hydroxylase, 21-hydroxylase,
& aromatase
Inactivating mutations lead to congenital
adrenal hyperplasia usually with genital
ambiguity in both 46XX & 46XY subjects
& at times in association with skeletal
abnormalities (Antley-Bixler syndrome –
craniosynostosis, mid-face hypoplasia,
choanal stenosis, femoral bowing,
radioulnar synostosis – 201750); AR
PAPSS2
3-Prime-phosphoadenosine
5-prime-phosphosulfate
synthase2
10q24
603005
Enzyme that synthesizes the sulfate
donor (3’-phosphoadenosine
5’-phosphosulfate) from ATP &
sulfate that is the co-factor for
adrenocortical sulfotransferase
Spondyloepimetaphyseal dysplasia (Pakistani
type) (612847)
PTPN11 – Protein tyrosine
phosphatase, non-receptor,
type 11
12q24.1
176876
Encodes SHP2 – a non-receptor
protein tyrosine phosphatase that
acts upstream of RAS
Monoallelic loss of function mutations lead to
metachondromatosis (MIM 156250) or
Noonan syndrome with multiple lentigenes;
monoallelic gain of function mutations
result in Noonan syndrome;
cranio-facio-cutaneous syndrome
of long bones, pelvis, and scapulae, often in association with distinct skin lesions; it is a relatively
benign disorder. Infantile cortical hyperostosis (Caffey disease – MIM 114000) is manifested by acute
onset of tenderness and warmth of the skull or ribs that is self limited; it has been associated with a
specific heterozygous mutation (Arg836Cys) in COL1A1 [75].
Hyperphosphatemic familial tumoral calcinosis is an autosomal recessive disorder characterized by
subcutaneous calcifications that may be due to inactivating mutations in FGF23,GALNT3,orKL as
discussed in section IV.A (Table 3). Normophosphatemic familial tumoral calcinosis (MIM 610455) is
A.W. Root / Genetic disorders of calcium, phosphorus, and bone homeostasis 33
an autosomal recessive disease in which subcutaneous calcified nodules develop over the limbs during
infancy and early childhood. Calcification is preceded by cutaneous inflammation. It is due to biallelic
loss of function mutations in SAMD9, a protein that is regulated by interferon-and of pathogenic
importance in suppression of inflammation [76]. Fibrous dysplasia ossificans progressiva (also termed
myositis ossificans progressiva – MIM 135100) is characterized by heterotopic development of mature
endochondral bone within extraskeletal sites (muscle, tendons, ligaments) and is usually associated
with congenital anomalies of the big toes (monophalangic) and fingers (short thumbs, clinodactyly) [77,
78]. This disorder is due to gain of function mutations in ACVR1 encoding a receptor for both activin
(a stimulus to the secretion of pituitary follicle stimulating hormone) and BMP type 1, members of the
transforming growth factor (TGF) super family [79]. One heterozygous mutation (Arg206His) has
been identified most frequently (but not exclusively) in patients with familial disease and in sporadically
affected subjects.
4.5. Osteochondrodysplasia
Dysplasias of cartilage and bone are manifested by widely variable clinically characteristics and
heterogeneous genetic mutations involving the vertebrae and epiphyses and metaphyses of the long
bone [80]. Selected dysplasias of bone and cartilage development, many of them with a metabolic
basis, are listed in Table 7.
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... Serum levels of calcium are tightly controlled and monitored by calcium sensing receptors (CaSR) [4]. The CaSRs are G-protein coupled receptors found in the kidneys and parathyroid glands. ...
... The CaSRs are G-protein coupled receptors found in the kidneys and parathyroid glands. In excess, calcium binds to CaSRs resulting in decreased parathyroid hormone synthesis and secretion, as well as reduced renal calcium reabsorption [4]. ...
... This intermediate metabolite functions mainly as the storage form of vitamin D [11,12]. In the kidneys, calcidiol is further hydroxylated by the enzyme 1α-hydroxylase to form active calcitriol, resulting in increased absorption of intestinal calcium and phosphorus [4,9,[13][14][15][16]. 3 . The activity of 1α-hydroxylase and 24-hydroxylase is regulated mainly by PTH and FGF23. ...
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In this review, we describe genetic mutations affecting metabolic pathways of calcium and phosphorus homeostasis. Calcium and phosphorus homeostasis has tight hormonal regulation by three major hormones: vitamin D, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). We describe the physiology and pathophysiology of disorders, their biochemical profile, clinical characteristics, diagnostics, and treatments.
... In this case, since two suspicious lesions were encountered, FGF23 venous sampling could have been utilized, but the anatomical location and proximity of both lesions to each other Table 1 Genes tested on the Invitae hypophosphatemia next-generation sequencing panel (https://www.invitae.com/en/hypophosphatemia), with associated localization, diseases, and pathological mutations (Lloyd et al., 1996;Priante et al., 2017;Root, 2018). Panel is sensitive to deletions, insertions, duplications and copy number variants, and single-nucleotide polymorphisms (SNPs). ...
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Tumor-induced osteomalacia (TIO), caused by phosphaturic mesenchymal tumors (PMTs), is a rare paraneoplastic syndrome characterized by frequent bone fractures, bone pain, muscle weakness, and affected gait. These tumors typically secrete high levels of Fibroblastic Growth Factor 23 (FGF23), a hormone which acts on the kidney to cause hypophosphatemia, ultimately impairing bone mineralization. In this case report, we present a 41-year-old female with FGF23-mediated hypophosphatemia with a 26-year delay in TIO diagnosis and a concurrent misdiagnosis of X-linked hypophosphatemic rickets (XLH). Given an absence of family history of hypophosphatemia, a 13-gene hypophosphatemia panel including XLH (PHEX gene) was performed and came back negative prompting a diagnostic search for a PMT causing TIO. A 68Ga-DOTATATE PET/CT scan revealed the presence of a 9th right rib lesion, for which she underwent rib resection. The patient's laboratory values (notably serum phosphorus, calcium, and vitamin D) normalized, with FGF23 decreasing immediately after surgery, and symptoms resolving over the next three months. Chromogenic in situ hybridization (CISH) and RNA-sequencing of the tumor were positive for FGF23 (CISH) and the transcriptional marker FN1-FGFR1, a novel fusion gene between fibronectin (FN1) and Fibroblast Growth Factor Receptor 1 (FGFR1), previously determined to be present in the majority of TIO-associated tumors. This case demonstrates the notion that rare and diagnostically challenging disorders like TIO can be undiagnosed and/or misdiagnosed for many years, even by experienced clinicians and routine lab testing. It also underscores the power of novel tools available to clinicians such as gene panels, CISH, and RNA sequencing, and their ability to characterize TIO and its related tumors in the context of several phenotypically similar diseases.
... Sustained low (<0.81 mmol/L (<2.5 mg/dL for hypophosphatemia) and high (>1.46 mmol/L (generally 7-9 mg/dL for severe hyperphosphatemia)) serum Pi levels are known to result in significant health consequences and are generally the result of either hereditary or disease acquired syndromes [20,[30][31][32][33][34]. For healthy adults, dietary intake provides the primary source of serum Pi with the intestine being the main site of absorption, the kidney being the main site of excretion, and the skeleton being the main site of storage [35]. ...
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Extended conference paper, which summarizes an invited talk given by Dr. Shoji Ichikawa at the 37th International Sun Valley Workshop on Skeletal Tissue Biology. Dr. Ichikawa had received an ASBMR / Harold M. Frost Young Investigator Award for his research on the genetic basis of familial tumoral calcinosis. The paper describes the discovery of a missense mutation in the human Klotho gene and the functional analysis of this mutation (a full article on this work was published in The Journal of Clinical Investigation; Ichikawa S et al., J Clin Invest 2007; 117: 2684-2691).
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Mesenchymal stem cells (MSCs) are pluripotent cells located in bone marrow, muscles, and fat that can differentiate into a variety of tissues, including bone, cartilage, muscle and fat. Differentiation toward these lineages is controlled by a multitude of cytokines, which regulate the expression of cell-lineage specific sets of transcription factors. Among the cytokines involved in osteoblast differentiation are the Hedgehogs, BMPs, TGF-β, PTH, and WNTs. This chapter discusses signal transduction cascades initiated by these cytokines and their effect on osteoblast differentiation. The combined action of the signal transduction pathways induced by bone-promoting cytokines determines the commitment of MSCs toward the osteoblast lineage and the efficiency of bone formation. © 2013 American Society for Bone and Mineral Research. All rights reserved.
Chapter
Mesenchymal stem cells (MSCs) are pluripotent cells located in bone marrow, muscles, and fat that can differentiate into a variety of tissues, including bone, cartilage, muscle and fat. Differentiation toward these lineages is controlled by a multitude of cytokines, which regulate the expression of cell-lineage specific sets of transcription factors. Among the cytokines involved in osteoblast differentiation are the Hedgehogs, BMPs, TGF-ß, PTH, and WNTs. This chapter discusses signal transduction cascades initiated by these cytokines and their effect on osteoblast differentiation. The combined action of the signal transduction pathways induced by bone-promoting cytokines determines the commitment of MSCs toward the osteoblast lineage and the efficiency of bone formation.
Chapter
Pathological bone loss, regardless of etiology, invariably represents an increase in the rate at which the skeleton is degraded by osteoclasts relative to its formation by osteoblasts. Thus, the prevention of conditions such as osteoporosis requires an understanding of the molecular mechanisms of bone resorption. Macrophage-colony stimulating factor (M-CSF) contributes to the proliferation, survival, and differentiation of osteoclast precursors, as well as the survival and cytoskeletal rearrangement required for efficient bone resorption. This chapter discusses intracellular signaling pathways of osteoclasts. Three major protein classes are involved: adaptors, kinases, and transcription factors, with one significant exception, RANKL-induced release of Ca++, a pathway that activates the calmodulin-dependent phosphatase calcineurin. The chapter summarizes the modulatory effects of kinases and transcription factors, which together regulate receptor-driven proliferation and/or survival of precursors.