# 42 - SECTION 5 Disorders of Intermediary Metabolism

## SECTION 5 Disorders of Intermediary Metabolism

by short bulbous roots, pulp calcification, and radicular dentin depos­
ited in swirls. The disorder is caused by gene mutations in GALNT3, 
FGF23, or α-Klotho, leading to FGF23 deficiency or resistance. The 
reduced activity of FGF23 leads to increased renal tubular reabsorption 
of phosphate, elevated serum phosphate, and spontaneous soft tissue 
calcification from elevated calcium-phosphate concentration product.
The disease usually presents in childhood and continues throughout 
the patient’s life. The calcific masses are typically painless and grow at 
variable rates, sometimes becoming large and bulky. The masses are 
often located near major joints but remain extracapsular. Joint range of 
motion is not usually restricted unless the tumors are very large. Com­
plications include compression of neural structures and ulceration of 
the overlying skin with drainage of chalky fluid and risk of secondary 
infection. Small deposits not detected by standard radiographs may be 
detected by 99mTc bone scanning. The most common laboratory findings are 
hyperphosphatemia and elevated serum 1,25-dihydroxyvitamin D levels. 
Serum calcium, parathyroid hormone, and ALP levels are usually nor­
mal. Renal function is also usually normal. Urine calcium and phosphate 
excretions are low, and calcium and phosphate balances are positive.
An acquired form of the disease may occur with other causes of 
hyperphosphatemia, such as secondary hyperparathyroidism associ­
ated with hemodialysis, hypoparathyroidism, pseudohypoparathyroid­
ism, and massive cell lysis following chemotherapy for leukemia. Tissue 
trauma from joint movement may contribute to the periarticular cal­
cifications. Metastatic calcifications are also seen in conditions associ­
ated with hypercalcemia, such as in sarcoidosis, vitamin D intoxication, 
milk-alkali syndrome, and primary hyperparathyroidism. In these con­
ditions, however, mineral deposits are more likely to occur in protontransporting organs such as kidney, lungs, and gastric mucosa in which 
an alkaline milieu is generated by the proton pumps.
TREATMENT
Tumoral Calcinosis
Therapeutic successes have been achieved with surgical removal of 
subcutaneous calcified masses, which tend not to recur if all calci­
fication is removed from the site. Reduction of serum phosphate 
by chronic phosphorus restriction may be accomplished using low 
dietary phosphorus intake alone or in combination with oral phos­
phate binders. The addition of the phosphaturic agent acetazol­
amide may be useful. Limited experience using the phosphaturic 
action of calcitonin deserves further testing.
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■DYSTROPHIC CALCIFICATION
Posttraumatic calcification may occur with normal serum calcium 
and phosphate levels and normal ion-solubility product. The depos­
ited mineral is either in the form of amorphous calcium phosphate 
or hydroxyapatite crystals. Soft tissue calcification complicating con­
nective tissue disorders such as scleroderma, dermatomyositis, and 
systemic lupus erythematosus may involve localized areas of the skin 
or deeper subcutaneous tissue and is referred to as calcinosis circum­
scripta. Mineral deposition at sites of deeper tissue injury including 
periarticular sites is called calcinosis universalis.
■
■ECTOPIC OSSIFICATION
True extraskeletal bone formation that begins in areas of fasciitis 
following surgery, trauma, burns, or neurologic injury is referred to 
as myositis ossificans. The bone formed is organized as lamellar or 
trabecular, with normal osteoblasts and osteoclasts conducting active 
remodeling. Well-developed haversian systems and marrow elements 
may be present. A second cause of ectopic bone formation occurs in an 
inherited disorder, fibrodysplasia ossificans progressiva.
■
■FIBRODYSPLASIA OSSIFICANS PROGRESSIVA
This is also called myositis ossificans progressiva; it is a rare autosomal 
dominant disorder characterized by congenital deformities of the 
hands and feet and episodic soft tissue swellings that ossify. The disor­
der is caused by an activating mutation in activin receptor A type 1. Ectopic 
bone formation occurs in fascia, tendons, ligaments, and connective 

tissue within voluntary muscles. Tender, rubbery induration, some­
times precipitated by trauma, develops in the soft tissue and gradually 
calcifies. Eventually, heterotopic bone forms at these sites of soft tissue 
trauma. Morbidity results from heterotopic bone interfering with nor­
mal movement and function of muscle and other soft tissues. Mortality 
is usually related to restrictive lung disease caused by an inability of the 
chest to expand. Laboratory tests are unremarkable.

Until recently, there was no effective approved medical therapy. 
Bisphosphonates, glucocorticoids, and a low-calcium diet have largely 
been ineffective in halting progression of the ossification. Palovaro­
tene has been shown to reduce new heterotopic ossification by 60% 
versus historical controls but increased premature epiphyseal closure 
in children. In 2023, the therapy was approved in the United States for 
females over age 8 and males over age 10. Another potential therapeu­
tic option, REGN2477 (also known as garetosmab), an anti–activin A 
antibody, is in clinical trials. Surgical removal of ectopic bone is not 
recommended because the trauma of surgery may precipitate forma­
tion of new areas of heterotopic bone. Dental complications, including 
frozen jaw, may occur following injection of local anesthetics.
Heritable Disorders of Connective Tissue
CHAPTER 425
Acknowledgment
The authors acknowledge the contribution of Dr. Murray J. Favus to this 
chapter in previous editions of Harrison’s.
■
■FURTHER READING
Boyce AM, Collins MT: Fibrous dysplasia/McCune-Albright syn­
drome: A rare, mosaic disease of Gαs activation. Endocr Rev 41:345, 
2020.
De Castro LF et al: Safety and efficacy of denosumab for fibrous dys­
plasia of bone. N Eng J Med 388:8, 2023.
Pognolo RJ et al: Reduction of new heterotopic ossification (HO) in 
the open-label, phase 3 MOVE trial of palovarotene for fibrodysplasia 
ossificans progressive (FOP). J Bone Miner Res 38:3, 2022.
Ralston SH et al: Diagnosis and management of Paget’s disease of 
bone in adults: A clinical guideline. J Bone Miner Res 34:579, 2019.
Shapiro JR, Lewiecki EM: Hypophosphatasia in adults: Clinical 
assessment and treatment considerations. J Bone Miner Res 32:1977, 
2017.
Singer FR et al: Paget’s disease of bone: An endocrine society clinical 
practice guideline. J Clin Endocrinol Metab 99:4408, 2014.
Tan A et al: Long-term randomized trial of intensive versus symptom­
atic management in Paget’s disease of the bone: The PRISM-EZ Study. 
J Bone Miner Res 32:1165, 2017.
Wu CC et al: Diagnosis and management of osteopetrosis: Consensus 
guidelines from the osteopetrosis working group. J Clin Endocrinol 
Metab 102:3111, 2017.
Section 5	 Disorders of Intermediary 
Metabolism
Joan C. Marini, Fransiska Malfait

Heritable Disorders of 
Connective Tissue
CLASSIFICATION OF CONNECTIVE 

TISSUE DISORDERS
Some of the most common conditions that are transmitted genetically 
in families are disorders that produce clinically obvious changes in 
the bone, cartilage, skin, or relatively acellular tissues such as tendons