A 5-year-old girl presents to your office with a history of breast buds and vaginal bleeding. Laboratory studies done by her pediatrician show an elevated estradiol concentration with LH and FSH levels below the detection limit of the assays. Her medical history is notable for several long bone fractures associated with minimal trauma. Radiographs from her orthopedist reveal a progressive shepherd’s crook deformity of the left proximal femur with areas of “ground glass”–appearing bone. When you examine her head, you detect several areas of asymmetry in her skull. On skin examination, you observe the following (see photograph):
Pediatric ESAP is a great tool for board exam preparation and offers learners CME credits and MOC points upon completion. Test yourself with this case from Pediatric ESAP™, brought to you by The Endocrine Society’s Pediatric Self-Assessment Committee. For the answer to this case, go to page 30.
This patient is at increased risk for which one of the
C Malignant melanoma
D GH deficiency
E Optic glioma
Pediatric ESAP™ is a self-assessment tool that includes 100 clinical case-vignettes and extensive answer discussions in all areas of pediatric endocrinology. Pediatric ESAP is a great tool for board exam preparation and offers learners CME credits and MOC points upon completion. For more information, visit endoselfassessment.org.
The answer is:
This child has the classic triad of McCune-Albright syndrome (MAS): gonadotropin-independent precocious puberty, polyostotic fibrous dysplasia, and irregular café-au-lait spots with the typical “coast of Maine” border. This disorder is due to a sporadic postzygotic mutation in the GNAS gene, which leads to constitutive activation of Gsα. One of the more serious and disabling aspects of MAS is the polyostotic fibrous dysplasia; any bone can be aff ected, with the proximal femur and the craniofacial bones most commonly involved.
In addition to the bone fragility and deformity associated with fibrous dysplasia, the dysplastic bone lesions have the ability to overproduce fibroblast growth factor 23 (FGF23), a phosphaturic hormone normally produced by osteocytes. The development of hypophosphatemia in MAS is related to the skeletal disease burden. Periodic monitoring for hypophosphatemia is important in patients with MAS who have substantial fibrous dysplasia because untreated hypophosphatemia can result in rickets, muscle weakness, and further increased bone fragility. Patients with MAS who develop hypophosphatemia require treatment with phosphate and calcitriol, similar to other forms of FGF23-mediated hypophosphatemia, such as X-linked hypophosphatemic rickets.
MAS is associated with several other hyperfunctioning endocrinopathies, including Cushing syndrome, hyperthyroidism, and GH excess. GNAS mutations have not been identified in the parathyroids of patients with MAS; thus, hyperparathyroidism does not appear to be a component of this syndrome and would not be a cause of hypophosphatemia. Hormone deficiencies such as hypothyroidism (Answer B) and GH deficiency (Answer D) only occur, as expected, following surgical or ablative treatment for hormone excess conditions. Patients with fibrous dysplasia are at increased risk for sarcomatous transformation, but malignant endocrine tumors are rare.
MAS is often initially misdiagnosed as neurofibromatosis type 1, a disorder caused by inactivation of the tumor suppressor neurofibromin. Neurofibromatosis type 1 is characterized by café-au-lait spots with smooth borders (“coast of California”) and neurofibromas. Neurofibromatosis type 1 can be associated with mild skeletal abnormalities, fractures, scoliosis, and osteoporosis; however, aff ected patients do not develop the classic proximal femur deformities seen in MAS. Melanoma (Answer C) has not been reported in MAS, but can be seen in neurofibromatosis. Patients with neurofibromatosis type 1 may develop precocious puberty; however, unlike precocious puberty associated with MAS, it is gonadotropin dependent and is often associated with intracranial lesions, such as optic and hypothalamic gliomas (Answer E).