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McCune–Albright Syndrome: An Overview of Clinical Features
PENS DEPARTMENT Editor: Jan M. Foote, DNP, ARNP, CPNP, FAANP
McCune–Albright Syndrome: An Overview of Clinical Features Beth Brillante BSN, RN, MBA a , Lori Guthrie BSN, RN-C, CCRC a , Carol Van Ryzin MS, RN, CPNP b, * a
National Institutes of Health, National Institute of Dental and Craniofacial Research, Skeletal Clinical Studies Unit, Bethesda, MD b National Institutes of Health, National Human Genome Research Institute, Bethesda, MD
A 20-month-old female presented with bloody discharge in her diaper. Significant findings on her physical examination included length greater than the 95th percentile, Tanner stage 2 breasts, and a large, light brown macule on her lower back near the crease of her buttocks with jagged edges that did not cross the midline. Pelvic ultrasound showed a large unilateral ovarian cyst. Skeletal maturity (bone age) was advanced. A 5-year-old male presented with leg pain and limp following a minor fall during a pillow fight with his brother. Radiographs showed a fracture at the site of a fibrous dysplastic lesion in the femoral neck with “ground glass” appearance. He had two light brown birthmarks with irregular borders on his posterior neck and chest. Neither crossed the midline of his body nor had changed much in size. These children had different clinical presentations, but they share the diagnosis of McCune–Albright syndrome. An overview of the clinical features of McCune–Albright syndrome follows.
Background McCune–Albright syndrome (MAS) is a rare and complex disease involving the skin, skeleton, and endocrine system that was described nearly 80 years ago. McCune described a 9-year-old female with precocious puberty, hyperpigmentation of the skin, and hyperthyroidism (McCune, 1936). Albright published a case series of five females with bone disease, areas of hyperpigmentation, and ⁎ Corresponding author: Carol Van Ryzin MS, RN, CPNP. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.pedn.2015.06.009 0882-5963/© 2015 Elsevier Inc. All rights reserved.
precocious puberty (Albright, Butler, Hampton, & Smith, 1937). MAS was initially defined as a triad of polyostotic fibrous dysplasia of bone, café au lait skin pigmentation, and precocious puberty (Dumitrescu & Collins, 2008). Diagnosis is most often established in early childhood, but may occur at birth due to the presence of café au lait macules. Symptoms of precocious puberty or fibrous dysplasia are the most common reasons that patients seek medical attention. MAS is caused by a mutation in the GNAS gene, located on the long arm (q) of chromosome 20 at position 13.3 (Genetics Home Reference, Staff and U.S. National Library of Medicine, 2009); Online Mendelian Inheritance in Man, OMIM®, 2011). This mutation is not inherited from either parent but occurs as a spontaneous mutation in early embryonic development. The estimated prevalence is one in 100,000 to 1,000,000, affecting both males and females across ethnic groups.
Clinical Features Over the years, the definition of MAS has been expanded and refined based on findings related to the manifestations and clinical course of the natural disease. The diagnosis is made when at least two of the following clinical features are present in an individual: café au lait macules, fibrous dysplasia, and autonomous endocrine hyperfunction (Boyce & Collins, 2015). Manifestations vary depending on the affected tissues. At least two of the primitive germ layers of the embryo
The Pediatric Endocrinology Nursing Society (PENS) is committed to the development and advancement of nurses in the art and science of pediatric endocrinology nursing and to improve the care of all children with endocrine disorders through the education of the pediatric healthcare community. To aid in achieving that goal, the purpose of the PENS department is to provide up-to-date reviews of topics relevant to the PENS membership and to the general readership of the Journal of Pediatric Nursing.
816 (the ectoderm, mesoderm, and endoderm) are affected. The timing of the mutation during early development defines and lays the foreground for the spectrum and severity of disease, which ranges from mild to severe.
Dermatologic Features Skin findings are the light brown café au lait macules (CALM), which arise from the ectoderm (Boyce & Collins, 2015). They are often the first noticeable feature of MAS appearing at or shortly after birth. Described as having irregular borders resembling the “coast of Maine,” they usually respect the midline of the body and follow the developmental lines of Blaschko–pattern of embryonic cell migration. Common locations are the posterior neck, base of the spine, trunk, and face. Size and location of CALM do not correlate with extent of disease or areas of bone disease. Neurofibromatosis (NF) is another disease with CALM as a diagnostic feature; however, in NF the borders are described as more smooth, resembling the “coast of California”. CALM may be found in 10% of the healthy population.
Skeletal Features The skeletal aspect of MAS is fibrous dysplasia (FD) and arises from the mesoderm (Boyce & Collins, 2015). FD by itself is not as rare as MAS. FD can be present in one bone, termed monostotic disease. Polyostotic FD, affecting more than one bone, involves any combination of bones of the craniofacial, axial and/or appendicular skeleton. The diagnosis of FD can be made by radiographs showing an expansile lesion(s) with a “ground glass” appearance; however, bone scans help define and monitor the extent of the disease (Dumitrescu & Collins, 2008). Two bone deformities that can occur are the “shepherd’s crook” deformity where the proximal femur has a curvature resembling a shepherd's crook, and the “wind-swept” deformity which is an abnormal valgus deformity of one knee in association with a varus deformity in the other knee (Dumitrescu & Collins, 2008; Riddle & Bui, 2013). Recurrent fractures and progressive deformity can lead to disability. Orthopedic surgery, physical therapy, and occupational therapy may improve mobility and function. Intravenous bisphosphonates have been demonstrated to reduce pain, but do not alter the course of the disease. Craniofacial lesions may present as a facial deformity or asymmetry caused by an expanding FD lesion. These lesions may be accompanied by vision changes, hearing impairment, nasal congestion and/or obstruction, pain, paresthesia, and/or dental malocclusion (Lee et al., 2012). Scoliosis is common and usually occurs at sites of vertebral FD. Significant deformity and even rarely death, may result, if untreated. Orthopedic surgery interventions may halt the progression of scoliosis (Stanton et al., 2012).
Endocrine Features Endocrinopathies may include precocious puberty, hyperthyroidism, growth hormone excess, phosphate wasting, and
PENS Department neonatal hypercortisolism. Children with MAS should be referred to pediatric endocrinology. Precocious puberty is present in about 85% of female cases and is often the presenting feature (Boyce & Collins, 2015). Ovarian cysts lead to estrogen production resulting in breast development, growth acceleration, and vaginal bleeding. Although less common in males, autonomous testosterone production can result in testicular enlargement, growth acceleration, pubic and axillary hair, and acne. Approximately one-third of individuals with MAS develop hyperthyroidism (Boyce & Collins, 2015). Production of excess thyroid hormone can lead to a hypermetabolic state, advanced skeletal maturity, increased bone turnover, and fractures. Other thyroid abnormalities include goiter, cysts, and nodules. Growth hormone excess occurs in 10–15% of individuals with MAS (Boyce & Collins, 2015). High levels of growth hormone may result in linear growth acceleration in children, worsening craniofacial FD, and features of acromegaly. Phosphate wasting with or without hypophosphatemia is an additional manifestation associated with FD (Boyce & Collins, 2015). This occurs when affected bones produce excess amounts of FGF23, a hormone that causes the kidneys to lose phosphorus in the urine. Neonatal Cushing syndrome is a rare complication of MAS resulting in excess cortisol production from the fetal adrenal gland (Boyce & Collins, 2015). Symptoms typically develop in the neonatal period leading to critical illness and can result in death.
Conclusion MAS is a complex disease with a phenotypic spectrum. A high index of suspicion is required in individuals with characteristic CALM and endocrine dysfunction or pathologic fractures. An interdisciplinary pediatric team, including endocrinology, orthopedic surgery, nursing, and therapists, can maximize functional outcomes in children with MAS. Pediatric nurses monitor growth, educate patients and families, and coordinate care for affected children. Children should receive personalized management targeting the specific clinical manifestations of their disease. Support groups such as the MAGIC Foundation and the Fibrous Dysplasia Foundation may be beneficial for the child and family.
Acknowledgments The authors would like to acknowledge the Intramural Research Program of the NIH, NIDCR.
References Albright, F., Butler, A. M., Hampton, A. O., & Smith, P. (1937). Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction with precocious puberty in females: Report of 5 cases. New England Journal of Medicine, 216, 727–746. Boyce, A. M., & Collins, M. T. (2015). Fibrous dysplasia/McCune-Albright syndrome. In R. A. Pagon, M. P. Adam, & H. H. Ardinger (Eds.), Gene Reviews®. Seattle, WA: University of Washington.
PENS Department Dumitrescu, C. E., & Collins, M. T. (2008). McCune-Albright syndrome. Orphanet Journal of Rare Diseases, 3, http://dx.doi.org/10.1186/17501172-3-12 (Retrieved from http://www.ojrd.com/content/3/1/12). Genetics Home Reference (Staff), & U.S. National Library of Medicine (2009). McCune-Albright Syndrome. Retrieved from http://ghr.nlm. nih.gov/condition/mccune-albright-syndrome Lee, J. S., FitzGibbon, E. J., Chen, Y. R., Kim, H. J., Lustig, L. R., & Akintoye, S. O. (2012). Clinical guidelines for the management of craniofacial fibrous dysplasia. Orphanet Journal of Rare Diseases, 7, S2, http://dx.doi.org/10.1186/1750-1172-7-S1-S2 (Retrieved from http://www.ojrd.com/content/7/S1/S2). McCune, D. J. (1936). Osteitis fibrousa cystica: The case of a nine-year-old girl who also exhibits precocious puberty, multiple pigmentation of the
817 skin and hyperthyroidism. American Journal of Diseases of Children, 52, 743–744. Online Mendelian Inheritance in Man, OMIM® (2011). #174800. Mc-Cune Albright syndrome; MAS. Retrieved from http://www.omim.org/entry/ 174800 Riddle, N. D., & Bui, M. M. (2013). Fibrous dysplasia. Archives of Pathology and Laboratory Medicine, 137, 134–138, http://dx.doi.org/ 10.5828.arpa/2012.0013-RS. Stanton, R. P., Ippolito, E., Springfield, D., Lindaman, L., Wientroub, S., & Leet, A. (2012). The surgical management of fibrous dysplasia of bone. Orphanet Journal of Rare Diseases, 7, S1, http://dx.doi.org/10.1186/ 1750-1172-7-S1-S1 (Retrieved from http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3359959/).
McCune–Albright Syndrome: An Overview of Clinical Features Beth Brillante BSN, RN, MBA a , Lori Guthrie BSN, RN-C, CCRC a , Carol Van Ryzin MS, RN, CPNP b, * a
National Institutes of Health, National Institute of Dental and Craniofacial Research, Skeletal Clinical Studies Unit, Bethesda, MD b National Institutes of Health, National Human Genome Research Institute, Bethesda, MD
A 20-month-old female presented with bloody discharge in her diaper. Significant findings on her physical examination included length greater than the 95th percentile, Tanner stage 2 breasts, and a large, light brown macule on her lower back near the crease of her buttocks with jagged edges that did not cross the midline. Pelvic ultrasound showed a large unilateral ovarian cyst. Skeletal maturity (bone age) was advanced. A 5-year-old male presented with leg pain and limp following a minor fall during a pillow fight with his brother. Radiographs showed a fracture at the site of a fibrous dysplastic lesion in the femoral neck with “ground glass” appearance. He had two light brown birthmarks with irregular borders on his posterior neck and chest. Neither crossed the midline of his body nor had changed much in size. These children had different clinical presentations, but they share the diagnosis of McCune–Albright syndrome. An overview of the clinical features of McCune–Albright syndrome follows.
Background McCune–Albright syndrome (MAS) is a rare and complex disease involving the skin, skeleton, and endocrine system that was described nearly 80 years ago. McCune described a 9-year-old female with precocious puberty, hyperpigmentation of the skin, and hyperthyroidism (McCune, 1936). Albright published a case series of five females with bone disease, areas of hyperpigmentation, and ⁎ Corresponding author: Carol Van Ryzin MS, RN, CPNP. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.pedn.2015.06.009 0882-5963/© 2015 Elsevier Inc. All rights reserved.
precocious puberty (Albright, Butler, Hampton, & Smith, 1937). MAS was initially defined as a triad of polyostotic fibrous dysplasia of bone, café au lait skin pigmentation, and precocious puberty (Dumitrescu & Collins, 2008). Diagnosis is most often established in early childhood, but may occur at birth due to the presence of café au lait macules. Symptoms of precocious puberty or fibrous dysplasia are the most common reasons that patients seek medical attention. MAS is caused by a mutation in the GNAS gene, located on the long arm (q) of chromosome 20 at position 13.3 (Genetics Home Reference, Staff and U.S. National Library of Medicine, 2009); Online Mendelian Inheritance in Man, OMIM®, 2011). This mutation is not inherited from either parent but occurs as a spontaneous mutation in early embryonic development. The estimated prevalence is one in 100,000 to 1,000,000, affecting both males and females across ethnic groups.
Clinical Features Over the years, the definition of MAS has been expanded and refined based on findings related to the manifestations and clinical course of the natural disease. The diagnosis is made when at least two of the following clinical features are present in an individual: café au lait macules, fibrous dysplasia, and autonomous endocrine hyperfunction (Boyce & Collins, 2015). Manifestations vary depending on the affected tissues. At least two of the primitive germ layers of the embryo
The Pediatric Endocrinology Nursing Society (PENS) is committed to the development and advancement of nurses in the art and science of pediatric endocrinology nursing and to improve the care of all children with endocrine disorders through the education of the pediatric healthcare community. To aid in achieving that goal, the purpose of the PENS department is to provide up-to-date reviews of topics relevant to the PENS membership and to the general readership of the Journal of Pediatric Nursing.
816 (the ectoderm, mesoderm, and endoderm) are affected. The timing of the mutation during early development defines and lays the foreground for the spectrum and severity of disease, which ranges from mild to severe.
Dermatologic Features Skin findings are the light brown café au lait macules (CALM), which arise from the ectoderm (Boyce & Collins, 2015). They are often the first noticeable feature of MAS appearing at or shortly after birth. Described as having irregular borders resembling the “coast of Maine,” they usually respect the midline of the body and follow the developmental lines of Blaschko–pattern of embryonic cell migration. Common locations are the posterior neck, base of the spine, trunk, and face. Size and location of CALM do not correlate with extent of disease or areas of bone disease. Neurofibromatosis (NF) is another disease with CALM as a diagnostic feature; however, in NF the borders are described as more smooth, resembling the “coast of California”. CALM may be found in 10% of the healthy population.
Skeletal Features The skeletal aspect of MAS is fibrous dysplasia (FD) and arises from the mesoderm (Boyce & Collins, 2015). FD by itself is not as rare as MAS. FD can be present in one bone, termed monostotic disease. Polyostotic FD, affecting more than one bone, involves any combination of bones of the craniofacial, axial and/or appendicular skeleton. The diagnosis of FD can be made by radiographs showing an expansile lesion(s) with a “ground glass” appearance; however, bone scans help define and monitor the extent of the disease (Dumitrescu & Collins, 2008). Two bone deformities that can occur are the “shepherd’s crook” deformity where the proximal femur has a curvature resembling a shepherd's crook, and the “wind-swept” deformity which is an abnormal valgus deformity of one knee in association with a varus deformity in the other knee (Dumitrescu & Collins, 2008; Riddle & Bui, 2013). Recurrent fractures and progressive deformity can lead to disability. Orthopedic surgery, physical therapy, and occupational therapy may improve mobility and function. Intravenous bisphosphonates have been demonstrated to reduce pain, but do not alter the course of the disease. Craniofacial lesions may present as a facial deformity or asymmetry caused by an expanding FD lesion. These lesions may be accompanied by vision changes, hearing impairment, nasal congestion and/or obstruction, pain, paresthesia, and/or dental malocclusion (Lee et al., 2012). Scoliosis is common and usually occurs at sites of vertebral FD. Significant deformity and even rarely death, may result, if untreated. Orthopedic surgery interventions may halt the progression of scoliosis (Stanton et al., 2012).
Endocrine Features Endocrinopathies may include precocious puberty, hyperthyroidism, growth hormone excess, phosphate wasting, and
PENS Department neonatal hypercortisolism. Children with MAS should be referred to pediatric endocrinology. Precocious puberty is present in about 85% of female cases and is often the presenting feature (Boyce & Collins, 2015). Ovarian cysts lead to estrogen production resulting in breast development, growth acceleration, and vaginal bleeding. Although less common in males, autonomous testosterone production can result in testicular enlargement, growth acceleration, pubic and axillary hair, and acne. Approximately one-third of individuals with MAS develop hyperthyroidism (Boyce & Collins, 2015). Production of excess thyroid hormone can lead to a hypermetabolic state, advanced skeletal maturity, increased bone turnover, and fractures. Other thyroid abnormalities include goiter, cysts, and nodules. Growth hormone excess occurs in 10–15% of individuals with MAS (Boyce & Collins, 2015). High levels of growth hormone may result in linear growth acceleration in children, worsening craniofacial FD, and features of acromegaly. Phosphate wasting with or without hypophosphatemia is an additional manifestation associated with FD (Boyce & Collins, 2015). This occurs when affected bones produce excess amounts of FGF23, a hormone that causes the kidneys to lose phosphorus in the urine. Neonatal Cushing syndrome is a rare complication of MAS resulting in excess cortisol production from the fetal adrenal gland (Boyce & Collins, 2015). Symptoms typically develop in the neonatal period leading to critical illness and can result in death.
Conclusion MAS is a complex disease with a phenotypic spectrum. A high index of suspicion is required in individuals with characteristic CALM and endocrine dysfunction or pathologic fractures. An interdisciplinary pediatric team, including endocrinology, orthopedic surgery, nursing, and therapists, can maximize functional outcomes in children with MAS. Pediatric nurses monitor growth, educate patients and families, and coordinate care for affected children. Children should receive personalized management targeting the specific clinical manifestations of their disease. Support groups such as the MAGIC Foundation and the Fibrous Dysplasia Foundation may be beneficial for the child and family.
Acknowledgments The authors would like to acknowledge the Intramural Research Program of the NIH, NIDCR.
References Albright, F., Butler, A. M., Hampton, A. O., & Smith, P. (1937). Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction with precocious puberty in females: Report of 5 cases. New England Journal of Medicine, 216, 727–746. Boyce, A. M., & Collins, M. T. (2015). Fibrous dysplasia/McCune-Albright syndrome. In R. A. Pagon, M. P. Adam, & H. H. Ardinger (Eds.), Gene Reviews®. Seattle, WA: University of Washington.
PENS Department Dumitrescu, C. E., & Collins, M. T. (2008). McCune-Albright syndrome. Orphanet Journal of Rare Diseases, 3, http://dx.doi.org/10.1186/17501172-3-12 (Retrieved from http://www.ojrd.com/content/3/1/12). Genetics Home Reference (Staff), & U.S. National Library of Medicine (2009). McCune-Albright Syndrome. Retrieved from http://ghr.nlm. nih.gov/condition/mccune-albright-syndrome Lee, J. S., FitzGibbon, E. J., Chen, Y. R., Kim, H. J., Lustig, L. R., & Akintoye, S. O. (2012). Clinical guidelines for the management of craniofacial fibrous dysplasia. Orphanet Journal of Rare Diseases, 7, S2, http://dx.doi.org/10.1186/1750-1172-7-S1-S2 (Retrieved from http://www.ojrd.com/content/7/S1/S2). McCune, D. J. (1936). Osteitis fibrousa cystica: The case of a nine-year-old girl who also exhibits precocious puberty, multiple pigmentation of the
817 skin and hyperthyroidism. American Journal of Diseases of Children, 52, 743–744. Online Mendelian Inheritance in Man, OMIM® (2011). #174800. Mc-Cune Albright syndrome; MAS. Retrieved from http://www.omim.org/entry/ 174800 Riddle, N. D., & Bui, M. M. (2013). Fibrous dysplasia. Archives of Pathology and Laboratory Medicine, 137, 134–138, http://dx.doi.org/ 10.5828.arpa/2012.0013-RS. Stanton, R. P., Ippolito, E., Springfield, D., Lindaman, L., Wientroub, S., & Leet, A. (2012). The surgical management of fibrous dysplasia of bone. Orphanet Journal of Rare Diseases, 7, S1, http://dx.doi.org/10.1186/ 1750-1172-7-S1-S1 (Retrieved from http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3359959/).