Albright hereditary osteodystrophy (AHO) phenotype was first described in 1942 by Fuller Albright. AHO refers to a constellation of signs including a round face, short stature with a stocky habitus, brachydactyly, subcutaneous ossification, and dental anomalies. Developmental delay, obesity (early-onset), and relative macrocephaly may be the additional features of AHO.
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. 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). PHP1A and PHP1C result due to maternally inherited inactivating GNAS1 mutations, which manifest with AHO phenotype plus hormonal resistance, whereas those with paternally inherited GNAS1 mutations present with AHO phenotype alone with no hormonal resistance (PPHP). PHP2B results due to methylation abnormalities of GNAS.
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. 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. 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. 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).
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. 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. Reduced energy expenditure, rather than excess energy consumption, has been demonstrated as the cause of early-onset obesity in a few recent studies.
Adult short stature is a common finding and seen in 80% of PHP1A and 50-70% of PPHP patients. 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, when present, most often has early-onset (before 2 years of age) with a round face. 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.
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 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. Brachydactyly may not be apparent at birth and may develop during childhood or adolescence. 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. 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’ sign and Trousseaus’ sign.
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 is 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. 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’s syndrome).
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. Sex steroid replacement should be offered in patients with delayed puberty due to gonadotropin resistance.
Individual features of Albright hereditary osteodystrophy are not unique to pseudohypoparathyroidism and are observed in other disorders as described below. 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.
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.
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.
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
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.
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.
The prevalence of carpal tunnel syndrome is higher in patients with AHO.
Increased risk for sleep apnea has been reported in children with PHP1A.
Insulin sensitivity is reduced in patients with PHP1A, which increases the risk of impaired glucose tolerance in them.
Spinal stenosis is often described in patients with AHO, which can lead to lower extremity paraparesis.
Heterotopic ossifications in or around the joints may rarely result in limited joint movements.
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. 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.
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 to assess development and intelligence quotient and to offer 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 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]
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