Tools
Albright Hereditary Osteodystrophy
Introduction
Albright hereditary osteodystrophy (AHO) phenotype was first described in 1942 by Fuller Albright.[1] AHO refers to a constellation of signs, including a round face, short stature with a stocky habitus, brachydactyly, subcutaneous ossification, and dental anomalies.[2] Developmental delay, obesity (early-onset), and relative macrocephaly may be the additional features of AHO.[3][4][5][6][7]
Etiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology
AHO phenotype is commonly observed in pseudohypoparathyroidism (PHP) type 1A, 1C, and pseudo-pseudohypoparathyroidism (PPHP), rarely observed in patients with PHP1B and not described in PHP2.[8][9] PHP occurs due to heterozygous inactivating mutation in the GNAS1 gene that codes for α-subunit of the stimulatory G protein. GNAS gene is located on the telomeric end of the long arm of chromosome 20 (20q13.2-20q13.3).[10] PHP1A and PHP1C result due to maternally inherited inactivating GNAS1 mutations, which manifest with AHO phenotype plus hormonal resistance. In contrast, those with paternally inherited GNAS1 mutations present with the AHO phenotype alone with no hormonal resistance (PPHP). PHP2B results due to methylation abnormalities of GNAS.[9]
Epidemiology
The data regarding the prevalence of Albright hereditary osteodystrophy is limited. The closely related disorder, PHP, has a prevalence of 0.34 to 1.1 per 100,000.[11][12] However, the prevalence of PHP is estimated to be approximately 1 per 20,000.[13]
Pathophysiology
In addition to PTH resistance, PHP1A and PHP1C are also associated with resistance to other hormones such as thyroid-stimulating hormone (TSH), growth hormone-releasing hormone (GHRH), gonadotropins, and calcitonin.[14] Skeletal abnormalities in Albright hereditary osteodystrophy include shortening of all long bones, but bones of hands and feet are the most affected. Short bones are not present at birth and manifest as the child grows due to premature closure of epiphyses, which reduces the period of growth.[15] Ectopic ossification, another characteristic feature of AHO, refers to extraskeletal bone formation (intramembranous ossification) and is not synonymous with ectopic calcification. Formation of ectopic ossification is not related to serum calcium and phosphorus levels but is the result of Gs-alpha deficiency in the mesenchymal stem cells, which leads to their differentiation into osteoblasts at extraskeletal sites such as subcutaneous tissue and dermis and the consequent new bone formation.[16] In PHP1A as well as PPHP, the extent of subcutaneous ossifications positively correlates with the severity of the mutations (more severe in patients with frames-shift and nonsense mutations).[17]
Short stature, a common feature of AHO, results due to various reasons. Few patients may have intrauterine growth retardation, but the growth deficit becomes more apparent over time due to reduced growth velocity after few years of birth, compromised pubertal growth spurt, and premature cessation of growth due to early fusion of epiphyses.[13] The latter probably results due to insufficient signaling at the PTH/PTHrP receptor, which results in accelerated differentiation of proliferating chondrocytes into hypertrophic cells. GHRH resistance and consequent growth hormone deficiency also partly contributes to growth failure.[13] Reduced energy expenditure, rather than excess energy consumption, has been demonstrated as the cause of early-onset obesity in a few recent studies.[18][19]
History and Physical
Adult short stature is a common finding and seen in 80% of PHP1A and 50% to 70% of PPHP patients.[15] Short stature is usually present during childhood, and a height percentile lower than that of an unaffected sibling or parent is usually observed. Small for gestational age (SGA) may be observed in few. Obesity is less commonly found, but most often has early-onset (before 2 years of age) with a round face.[20] Subcutaneous hard nodules representing ectopic ossification, often in the form of plaque shape, may be present. Heterotopic (subcutaneous) ossifications are equally common among PHP1A and PPHP.[17]
Short fourth and/or fifth metacarpals present as dimpling over the respective knuckles, which is also called ‘Archibald sign.’ When the fourth metacarpal is short, it forms the knuckle, knuckle, dimple, knuckle sign, whereas shortening of both fourth and fifth metacarpals leads to the knuckle, knuckle, dimple, dimple sign. The shortening of the distal phalanx of the thumb (murderer’s thumb or potter’s thumb) is the most common abnormality among AHO.[21] Brachydactyly may not be apparent at birth and may develop during childhood or adolescence.[15] Dental abnormalities are seen in a few patients and include failure of eruption of teeth, short blunted roots, altered dental pulps, hypodontia, and enamel hypoplasia.[22] Mild developmental delay and cognitive impairment may be present.
Clinical features of hypocalcemia may be present. Symptoms of hypocalcemia include jitteriness, seizures, and laryngeal stridor in infants and carpopedal spasm in children or adults. Symptoms of milder hypocalcemia include perioral numbness, paraesthesia, muscle cramps, carpopedal spasm (the sign of overt hypocalcemia), Chvostek and Trousseaus signsn.
Evaluation
Initial biochemical evaluation should include evaluation for PTH resistance (serum calcium, serum albumin, and serum phosphorus). Hypocalcemia, hyperphosphatemia, and elevated PTH in the absence of hypovitaminosis D, hypomagnesemia, and renal dysfunction are diagnostic of PTH resistance. In the setting of AHO, PTH resistance should be suspected even when serum calcium is normal if PTH is at high-normal to high with normal 25-hydroxy vitamin D.[15] If evidence of PTH resistance is present, evaluation for other hormonal resistance (serum thyroid-stimulating hormone and serum-free thyroxine) should be conducted. Usually, thyroid-stimulating hormone (TSH) is mildly elevated. All patients with PTH resistance, especially those with short stature, should be subjected to GH-IGF1 axis evaluation. Evaluation of gonadotropin resistance should be considered only in patients with pubertal delay.
Skeletal maturation should be monitored with roentgenography of the left hand at regular intervals. Roentgenography may also reveal short metacarpals, metatarsals, distal phalanges of thumbs, advanced bone age, and ectopic ossification.
Electrocardiogram may reveal prolonged QT in patients with hypocalcemia.
Computed tomography of the brain may reveal basal ganglia calcification and, in more severe cases, more diffuse calcification involving the subcortical white matter (Fahr syndrome).
Treatment / Management
Patients with pseudohypoparathyroidism are treated with oral calcium supplementation, calcitriol, and dietary phosphate restriction. Subclinical hypothyroidism may be treated with levothyroxine replacement. Growth hormone treatment is recommended for patients with a documented growth hormone deficiency, usually at doses used for SGA.[15] Sex steroid replacement should be offered in patients with delayed puberty due to gonadotropin resistance.(B3)
Differential Diagnosis
Individual features of Albright hereditary osteodystrophy are not unique to pseudohypoparathyroidism and are observed in other disorders as described below.[23] AHO should be distinguished from the below-described disorders, which closely mimic AHO.
Brachydactyly-mental retardation syndrome or AHO-like syndrome (HDAC4 loss of function mutation or 2q37 microdeletion): Brachydactyly, obesity, developmental delay, mental retardation, behavioral disorders are the common manifestations. Mild PTH resistance may be observed in AHO-like syndrome but not ectopic ossification.[24]
iPPSD4 or Acro-dysostosis type 1 (PRKRA1A mutation): Facial dysostosis and nasal hypoplasia, generalized, severe brachydactyly, and PTH resistance ± other hormonal resistance. A subset of patients with AHO with no abnormalities in the GNAS1 gene have mutations in the PRKRA1A gene.[25]
iPPSD5 or Acro-dysostosis type 2 (PDE4D mutation): Generalised and severe brachydactyly type E, facial dysostosis and nasal hypoplasia, mental retardation, decreased interpeduncular distance (PDE4D loss of function mutation). A subset of patients with AHO with no abnormalities in the GNAS1 gene have mutations in the PDE4D gene.[25]
iPPSD6 (PDE3A mutation): Short stature, brachydactyly E, hypertension, posterior inferior cerebellar artery loop.
Isolated brachydactyly E: HOXD13 mutation.
Brachydactyly E with short stature, PTHLH type (PTHLH mutation): Dental problems, learning difficulties, facial dysmorphism
Trichorhinophalangeal syndrome: Milder generalized brachydactyly E without carving of the phalangeal epiphyses, sparse hair, bulbous tip of the nose, thin upper lip, growth hormone deficiency, hip malformation.
Turner syndrome: Short stature, short IV metacarpal (no shortening of TP1), ovarian insufficiency, cubitus valgus, Madelung deformity
Prognosis
There is limited information regarding the prognosis of Albright hereditary osteodystrophy. Life expectancy is usually normal in patients with AHO. Severe-morbid obesity with associated complications such as obstructive sleep apnea, neuropsychiatric disorders, seizures, and cataracts are more common in AHO associated with PHP1A.[12]
Complications
Associated PTH resistance resulting in chronic hypocalcemia and hyperphosphatemia can lead to basal ganglia and subcortical white matter calcification and consequent neuropsychiatric disorders, movement disorders, and parkinsonism.[12][26][27]
The prevalence of carpal tunnel syndrome is higher in patients with AHO.[28]
Increased risk for sleep apnea has been reported in children with PHP1A.[29]
Insulin sensitivity is reduced in patients with PHP1A, which increases the risk of impaired glucose tolerance in them.[30]
Spinal stenosis is often described in patients with AHO, which can lead to lower extremity paraparesis.[31]
Heterotopic ossifications in or around the joints may rarely result in limited joint movements.[32]
Deterrence and Patient Education
Albright hereditary osteodystrophy is an inherited disorder. Once the disease is developed, there is no cure. However, regular screening for the associated manifestations, irrespective of the symptoms, helps to identify them early and helps in initiating timely treatment. In addition, testing for GNAS1 mutations and counseling are useful for patients planning to have children to know the risk of passing on their disease. Children born to affected males usually develop skeletal abnormalities only, whereas those born to affected females also develop hormonal abnormalities.
Enhancing Healthcare Team Outcomes
Albright hereditary osteodystrophy is a rare hereditary disorder. Patients with AHO may exhibit various signs and symptoms such as a round face, short stature, brachydactyly, subcutaneous ossification, seizures, carpopedal spasms, developmental delay, obesity, dental anomalies, neuropsychiatric disturbances, and parkinsonism.
Children and adolescents with AHO should schedule an evaluation and follow-up by a pediatric endocrinologist. Presentation with seizure or carpopedal spasm requires care in liaison with health care providers from emergency services. Management of intervening unrelated illnesses needs care from the general pediatrician. Clinical psychologist and/or developmental pediatrician may be involved in assessing the development and intelligence quotient and offering the essential treatment options for the identified abnormalities. A dentist may be consulted to detect and treat the associated dental anomalies. Consultation with a nutritionist is essential to prevent/treat obesity and also to guide a low phosphorus diet in patients with PHP1A and PHP1C. A pharmacist will ensure that the patient is on the right dose of medications prescribed and there are no inadvertent interactions between medications. Consultation with a neuropsychiatrist may be essential for the management of neuropsychiatric disorders, whereas consultation with a neurologist may be needed if movement disorders or parkinsonian features develop. Rarely, consultation with a surgeon and orthopedist may be required in patients with symptomatic heterotopic ossification. [Level 5]
References
MACGREGOR ME, WHITEHEAD TP. Pseudo-hypoparathyroidism; a description of three cases and a critical appraisal of earlier accounts of the disease. Archives of disease in childhood. 1954 Oct:29(147):398-418 [PubMed PMID: 13208312]
Level 3 (low-level) evidenceMantovani G, Elli FM. Inactivating PTH/PTHrP Signaling Disorders. Frontiers of hormone research. 2019:51():147-159. doi: 10.1159/000491045. Epub 2018 Nov 19 [PubMed PMID: 30641531]
Mouallem M, Shaharabany M, Weintrob N, Shalitin S, Nagelberg N, Shapira H, Zadik Z, Farfel Z. Cognitive impairment is prevalent in pseudohypoparathyroidism type Ia, but not in pseudopseudohypoparathyroidism: possible cerebral imprinting of Gsalpha. Clinical endocrinology. 2008 Feb:68(2):233-9 [PubMed PMID: 17803690]
Wilson LC, Trembath RC. Albright's hereditary osteodystrophy. Journal of medical genetics. 1994 Oct:31(10):779-84 [PubMed PMID: 7837255]
Wilson LC, Hall CM. Albright's hereditary osteodystrophy and pseudohypoparathyroidism. Seminars in musculoskeletal radiology. 2002 Dec:6(4):273-83 [PubMed PMID: 12541184]
Patten JL, Johns DR, Valle D, Eil C, Gruppuso PA, Steele G, Smallwood PM, Levine MA. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy. The New England journal of medicine. 1990 May 17:322(20):1412-9 [PubMed PMID: 2109828]
Level 3 (low-level) evidenceLong DN,McGuire S,Levine MA,Weinstein LS,Germain-Lee EL, Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity. The Journal of clinical endocrinology and metabolism. 2007 Mar; [PubMed PMID: 17164301]
Zeniya S, Yuno A, Watanabe T, Usui T, Moriki Y, Uno Y, Miake H. A 22-year-old woman with hypocalcemia and clinical features of albright hereditary osteodystrophy diagnosed with sporadic pseudohypoparathyroidism type Ib using a methylation-specific multiplex ligation-dependent probe amplification assay. Internal medicine (Tokyo, Japan). 2014:53(9):979-86 [PubMed PMID: 24785890]
Level 3 (low-level) evidenceThiele S, Mantovani G, Barlier A, Boldrin V, Bordogna P, De Sanctis L, Elli FM, Freson K, Garin I, Grybek V, Hanna P, Izzi B, Hiort O, Lecumberri B, Pereda A, Saraff V, Silve C, Turan S, Usardi A, Werner R, de Nanclares GP, Linglart A. From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network. European journal of endocrinology. 2016 Dec:175(6):P1-P17 [PubMed PMID: 27401862]
Gejman PV, Weinstein LS, Martinez M, Spiegel AM, Cao Q, Hsieh WT, Hoehe MR, Gershon ES. Genetic mapping of the Gs-alpha subunit gene (GNAS1) to the distal long arm of chromosome 20 using a polymorphism detected by denaturing gradient gel electrophoresis. Genomics. 1991 Apr:9(4):782-3 [PubMed PMID: 1674732]
Nakamura Y, Matsumoto T, Tamakoshi A, Kawamura T, Seino Y, Kasuga M, Yanagawa H, Ohno Y. Prevalence of idiopathic hypoparathyroidism and pseudohypoparathyroidism in Japan. Journal of epidemiology. 2000 Jan:10(1):29-33 [PubMed PMID: 10695258]
Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Pseudohypoparathyroidism - epidemiology, mortality and risk of complications. Clinical endocrinology. 2016 Jun:84(6):904-11. doi: 10.1111/cen.12948. Epub 2015 Oct 19 [PubMed PMID: 26387561]
Germain-Lee EL. Management of pseudohypoparathyroidism. Current opinion in pediatrics. 2019 Aug:31(4):537-549. doi: 10.1097/MOP.0000000000000783. Epub [PubMed PMID: 31145125]
Level 3 (low-level) evidenceLevine MA. An update on the clinical and molecular characteristics of pseudohypoparathyroidism. Current opinion in endocrinology, diabetes, and obesity. 2012 Dec:19(6):443-51. doi: 10.1097/MED.0b013e32835a255c. Epub [PubMed PMID: 23076042]
Level 3 (low-level) evidenceMantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A, Ahmed SF, Bufo R, Choplin T, De Filippo G, Devernois G, Eggermann T, Elli FM, Freson K, García Ramirez A, Germain-Lee EL, Groussin L, Hamdy N, Hanna P, Hiort O, Jüppner H, Kamenický P, Knight N, Kottler ML, Le Norcy E, Lecumberri B, Levine MA, Mäkitie O, Martin R, Martos-Moreno GÁ, Minagawa M, Murray P, Pereda A, Pignolo R, Rejnmark L, Rodado R, Rothenbuhler A, Saraff V, Shoemaker AH, Shore EM, Silve C, Turan S, Woods P, Zillikens MC, Perez de Nanclares G, Linglart A. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nature reviews. Endocrinology. 2018 Aug:14(8):476-500. doi: 10.1038/s41574-018-0042-0. Epub [PubMed PMID: 29959430]
Level 3 (low-level) evidencePignolo RJ, Xu M, Russell E, Richardson A, Kaplan J, Billings PC, Kaplan FS, Shore EM. Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2011 Nov:26(11):2647-55. doi: 10.1002/jbmr.481. Epub [PubMed PMID: 21812029]
Level 3 (low-level) evidenceSalemi P, Skalamera Olson JM, Dickson LE, Germain-Lee EL. Ossifications in Albright Hereditary Osteodystrophy: Role of Genotype, Inheritance, Sex, Age, Hormonal Status, and BMI. The Journal of clinical endocrinology and metabolism. 2018 Jan 1:103(1):158-168. doi: 10.1210/jc.2017-00860. Epub [PubMed PMID: 29059381]
Perez KM, Curley KL, Slaughter JC, Shoemaker AH. Glucose Homeostasis and Energy Balance in Children With Pseudohypoparathyroidism. The Journal of clinical endocrinology and metabolism. 2018 Nov 1:103(11):4265-4274. doi: 10.1210/jc.2018-01067. Epub [PubMed PMID: 30085125]
Shoemaker AH, Lomenick JP, Saville BR, Wang W, Buchowski MS, Cone RD. Energy expenditure in obese children with pseudohypoparathyroidism type 1a. International journal of obesity (2005). 2013 Aug:37(8):1147-53. doi: 10.1038/ijo.2012.200. Epub 2012 Dec 11 [PubMed PMID: 23229731]
Mantovani G, Spada A, Elli FM. Pseudohypoparathyroidism and Gsα-cAMP-linked disorders: current view and open issues. Nature reviews. Endocrinology. 2016 Jun:12(6):347-56. doi: 10.1038/nrendo.2016.52. Epub 2016 Apr 22 [PubMed PMID: 27109785]
Poznanski AK, Werder EA, Giedion A, Martin A, Shaw H. The pattern of shortening of the bones of the hand in PHP and PPHP--A comparison with brachydactyly E, Turner Syndrome, and acrodysostosis. Radiology. 1977 Jun:123(3):707-18 [PubMed PMID: 870942]
Hejlesen J,Underbjerg L,Gjørup H,Sikjaer T,Rejnmark L,Haubek D, Dental anomalies and orthodontic characteristics in patients with pseudohypoparathyroidism. BMC oral health. 2019 Dec 31; [PubMed PMID: 31892351]
Pereda A, Garin I, Garcia-Barcina M, Gener B, Beristain E, Ibañez AM, Perez de Nanclares G. Brachydactyly E: isolated or as a feature of a syndrome. Orphanet journal of rare diseases. 2013 Sep 12:8():141. doi: 10.1186/1750-1172-8-141. Epub 2013 Sep 12 [PubMed PMID: 24028571]
Elli FM, de Sanctis L, Madeo B, Maffini MA, Bordogna P, Pirelli A, Arosio M, Mantovani G. 2q37 Deletions in Patients With an Albright Hereditary Osteodystrophy Phenotype and PTH Resistance. Frontiers in endocrinology. 2019:10():604. doi: 10.3389/fendo.2019.00604. Epub 2019 Aug 29 [PubMed PMID: 31555217]
Elli FM, Bordogna P, de Sanctis L, Giachero F, Verrua E, Segni M, Mazzanti L, Boldrin V, Toromanovic A, Spada A, Mantovani G. Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed With Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2016 Jun:31(6):1215-24. doi: 10.1002/jbmr.2785. Epub 2016 Feb 9 [PubMed PMID: 26763073]
Hasani-Ranjbar S,Jouyandeh Z,Amoli MM,Soltani A,Arzaghi SM, A patient with features of albright hereditory osteodystrophy and unusual neuropsychiatric findings without coding Gsalpha mutations. Journal of diabetes and metabolic disorders. 2014; [PubMed PMID: 24959527]
Level 3 (low-level) evidenceSong CY, Zhao ZX, Li W, Sun CC, Liu YM. Pseudohypoparathyroidism with basal ganglia calcification: A case report of rare cause of reversible parkinsonism. Medicine. 2017 Mar:96(11):e6312. doi: 10.1097/MD.0000000000006312. Epub [PubMed PMID: 28296742]
Level 3 (low-level) evidenceJoseph AW, Shoemaker AH, Germain-Lee EL. Increased prevalence of carpal tunnel syndrome in albright hereditary osteodystrophy. The Journal of clinical endocrinology and metabolism. 2011 Jul:96(7):2065-73. doi: 10.1210/jc.2011-0013. Epub 2011 Apr 27 [PubMed PMID: 21525160]
Level 2 (mid-level) evidenceLandreth H, Malow BA, Shoemaker AH. Increased Prevalence of Sleep Apnea in Children with Pseudohypoparathyroidism Type 1a. Hormone research in paediatrics. 2015:84(1):1-5. doi: 10.1159/000381452. Epub 2015 Apr 23 [PubMed PMID: 25925491]
Muniyappa R,Warren MA,Zhao X,Aney SC,Courville AB,Chen KY,Brychta RJ,Germain-Lee EL,Weinstein LS,Skarulis MC, Reduced insulin sensitivity in adults with pseudohypoparathyroidism type 1a. The Journal of clinical endocrinology and metabolism. 2013 Nov; [PubMed PMID: 24030943]
Level 2 (mid-level) evidencevan Lindert EJ, Bartels RH, Noordam K. Spinal stenosis with paraparesis in albright hereditary osteodystrophy. Case report and review of the literature. Pediatric neurosurgery. 2008:44(4):337-40. doi: 10.1159/000138373. Epub 2008 Jun 13 [PubMed PMID: 18552518]
Level 3 (low-level) evidenceSarathi V, Patil A, Wade R, Bandgar TR, Shah NS. Intraarticular heterotopic ossification as the initial manifestation in a child with pseudohypoparathyroidism 1a. Indian journal of pediatrics. 2011 Jun:78(6):745-8. doi: 10.1007/s12098-010-0335-3. Epub 2011 Jan 13 [PubMed PMID: 21229336]
Level 3 (low-level) evidence