Jaffé-lichtenstein-uehlinger syndrome Q78.1

Jaffé-Lichtenstein-Uehlinger syndrome is a historical term for a form of fibrous bone dysplasia that typically presents as polyostotic. In this condition, normal bone marrow is replaced by immature, mechanically inferior fibro-osseous tissue. Clinical consequences include bone pain, swelling, and deformities, as well as an increased risk of fractures.

Dermatologically, the condition may be associated with segmental café-au-lait spots. If autonomic endocrine dysfunction also occurs—particularly precocious puberty, hyperthyroidism, or growth hormone excess, the condition is now classified as McCune-Albright syndrome or as part of the spectrum of fibrous dysplasia/McCune-Albright disease (FD/MAS).The suffix “Uehlinger” is now used almost exclusively in older German-language literature and does not denote a molecularly distinct disease.

The cause is postzygotic somatic activating variants of the GNAS gene on chromosome 20q13.32. Among other things, GNAS encodes the α-subunit of the stimulatory heterotrimeric G protein, Gαs. These variants reduce the intrinsic GTPase activity of Gαs. As a result, the protein remains constitutively activated, leading to sustained stimulation of adenylate cyclase and increased intracellular cAMP signaling. In osteogenic progenitor cells, this leads to:

• impaired differentiation of mature osteoblasts,
• formation of immature reticular bone beams,
• proliferation of fibrous stroma,
• increased bone resorption,
• partially increased FGF23 production with renal phosphate loss.

Since the mutation arises only after fertilization, a somatic mosaic is present. The timing and distribution of the mutated cell clones account for the wide range of phenotypes—from a single bone lesion to the multisystemic McCune-Albright syndrome. Vertical inheritance is not known; the disease is therefore genetically determined but generally not hereditary.

A clinically prominent skeletal malformation that begins between the ages of 5 and 15 and progresses in episodes. 

The condition usually manifests during childhood or adolescence. The clinical spectrum depends on the number, location, and extent of the affected bones. Skeletal manifestations:

• mono- or polyostotic bone lesions,
• bone pain and load-dependent symptoms,
• pathological fractures,
• axial deviations and limb deformities,
• coxa vara, or “shepherd’s crook deformity,” of the proximal femur,
• leg length discrepancies,
• scoliosis,
• craniofacial asymmetry, proptosis, or impairment of vision and hearing due to skull involvement.

Skeletal lesions develop primarily during the growth period. Their formation decreases significantly after skeletal maturation is complete; however, existing lesions may persist and continue to cause symptoms or deformities.

Skin manifestations:

• Café-au-lait macules, often unilateral or segmental with irregular, fringed borders, may be present at birth or in early childhood. They frequently respect the midline and are figuratively described as the “Coast of Maine.”

Associated Endocrine Manifestations (Endocrine dysfunction supports classification within the FD/MAS spectrum):

• Gonadotropin-independent precocious puberty,
• autonomic hyperthyroidism,
• excess growth hormone,
• infantile hypercortisolism,
• phosphate loss syndrome due to FGF23 overproduction.

The diagnosis is based on clinical findings and imaging. Typical features include:

• intramedullary, expansive fibro-ossous lesions,
• a ground-glass-like matrix,
• thinning and distension of the cortical bone,
• usually sharp margins without an aggressive periosteal reaction.

To assess the extent of skeletal involvement, X-rays, CT scans—particularly of the craniofacial skeleton—MRI in selected situations, and, if necessary, bone scintigraphy are used.

Molecular genetic testing for an activating GNAS variant can confirm the diagnosis. Due to mosaicism, testing the affected tissue is more sensitive than analyzing blood. A negative result does not rule out the disease; decalcified bone material can also lead to false-negative results.

There is no causal treatment available to correct the GNAS mosaic mutation. The approach depends on symptoms, fracture risk, deformity, and organ involvement.

The course of the disease is highly variable. Monostotic forms often remain asymptomatic, while severe polyostotic disease can lead to recurrent fractures, deformities, chronic pain, and functional limitations. Malignant transformation, usually to osteosarcoma, is rare and affects significantly fewer than 1% of patients; the risk increases following prior radiation therapy. Radiation therapy to affected bones should therefore be avoided.

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2. Boyce AM et al. (2024) Fibrous dysplasia/McCune-Albright syndrome. In: GeneReviews^®. University of Washington, Seattle; updated 2024.
3. Chapurlat RD et al. (2008) Fibrous dysplasia of bone and McCune-Albright syndrome. Best Pract Res Clin Rheumatol 22:55–69.
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