As denoted by its name, AHO is an osteodystrophy. Classically, there is brachydactyly due to shortening of the metacarpals and metatarsals most often involving metacarpals/metatarsals III, IV and V, although any can be involved, as well as the distal phalanx of the thumb, which is often broad and short (Fig. 1a–d). These features are often a key to diagnosis, particularly for patients with PPHP who may have no other signs. The most frequent presentation for PPHP occurs when a mother brings her child with PHP1A to clinic and is then noticed to have physical features of AHO that were not previously considered medically significant. The proposed mechanism of the brachydactyly is ineffective PTHrP receptor signal transduction resulting in accelerated differentiation of chondrocytes [18–20]. The brachydactyly is usually not apparent in infancy but evolves over time and is variable even among family members. Another important manifestation of AHO is Archibald's sign: when making a fist, there is absence of one or more knuckles (Fig. 1e). All of these hand/foot abnormalities can lead to problems with fine and gross motor activities  as well as carpal tunnel syndrome  and other orthopaedic issues [2,22].
Adult short stature occurs in both PHP1A and PPHP and is partly due to early closure of the epiphyses of the long bones secondary to premature chondrocyte differentiation. This typically begins near the start of adolescence (ages 9–13 years), at which time there is rapid advancement in the bone age and lack of a pubertal growth spurt [2,6,23–25]. However, during most of childhood, children are often NOT short. Therefore, short stature in childhood should not be used as one of the diagnostic criteria. Unfortunately, many children are diagnosed late due to this misconception (personal observation). All adults have shortened final heights if no interventions are taken. On occasion, the advanced bone age in children is misconstrued as early-onset puberty, and patients are inadvertently started on GnRH agonists (personal observation). Because of the shortened hand bones, the hand/wrist bone age is often advanced [26,27] (even as early as 2 years of age, personal observation) and is ahead of the knee bone age, which is usually more accurate, although adult height cannot be predicted [2,23,25]. The biallelic expression of GNAS in bone and chondrocytes likely explains the similar phenotype of short stature and brachydactyly in both PHP1A and PPHP [18,19,28]. Growth hormone (GH) deficiency due to GHRH resistance is frequent [23,24] in PHP1A (next section) and also compromises height.
Another striking feature of PHP1A and PPHP is the development of SCOs that can be painful and impair activities of daily living (Fig. 2) [2,29]. These ossifications are unique to disorders involving mutations in GNAS and are often a key to diagnosis. SCO can range greatly in size and number and can occur spontaneously as early as birth; they frequently occur in areas of trauma/pressure, such as the heel, belt area or bridge of the nose from glasses. When in isolation, the condition is termed osteoma cutis, but this can also be the first sign of a more severe PHP disorder (Table 1). In a recent investigation of 67 AHO patients monitored for development of these SCO over a 16-year time span [30▪], about 70% of AHO patients were found to have SCO, with the same frequency seen in PHP1A and PPHP. Males are more affected than females, and a greater severity of SCO is found in patients with frameshift and nonsense mutations. Severity within families is similar, and SCO tend to worsen with age. There is no definitive treatment, and removal can cause regrowth that is worse [30▪].
The differences in phenotype between PHP1A and PPHP reflect differences in the expression of the maternal versus paternal alleles in different tissues. This was shown through extensive investigation of murine models with heterozygous disruption of Gnas exon 1 or exon 2 (homozygous is lethal) as well as human studies showing evidence of tissue-specific silencing of Gαs expression from the paternal allele. The imprinting is partial in most tissues, with preferential expression of the maternal allele in the renal cortex, thyroid, gonad and pituitary, thereby causing the hormonal resistances to PTH, TSH, LH, FSH, and GHRH, respectively; there is biallelic expression in other tissues such as skin, renal medulla, heart, adipocytes, chondrocytes and bone [18,23,24,28,31–39]. As previously mentioned, dorsomedial hypothalamic imprinting has recently been shown to be the basis of the severe obesity that is present in PHP1A but not in PPHP [9,10▪▪,40].
PTH resistance is the hallmark of PHP1A. It is typically not present at birth and develops later in childhood with an elevation in PTH usually followed by hyperphosphatemia and then hypocalcaemia, although some patients do not develop hypocalcaemia until later (for review, ). This emphasizes the need to screen for maternal GNAS mutations in the presence of SCOs alone, even in the absence of PTH resistance [41▪]. Occasionally, patients present with seizures, especially those previously undiagnosed. For diagnostic purposes, it is important to document that 25-hydroxyvitamin D levels are normal at the time of the PTH measurement, as secondary hyperparathyroidism can contribute to PTH elevations; magnesium levels also need to be verified as normal. Hypercalciuria is rarely observed in PHP1A because imprinting occurs only in proximal renal tubules and not in the ascending limb or the collecting ducts [2,34,42]. There is reduced excretion of phosphate and reduced 1,25-dihydroxyvitamin D mediated uptake of calcium, whereas calcium reabsorption in the distal parts of the kidney remains unaffected. The risk of nephrocalcinosis is low, although it can rarely occur; renal ultrasounds are indicated only if there is hypercalciuria (personal observation, [43▪]). In addition, dual-energy x-ray absorptiometry (DXA) should only be performed for a clinical indication, as PHP1A patients typically have normal to increased bone mineral density .
TSH resistance is very commonly associated with PTH resistance with resulting normal or low thyroxine levels. The TSH resistance is mild due to partial imprinting in the thyroid [35–37] and presents without a goitre. It is often detected in infants during the newborn screen, being mistaken for congenital hypothyroidism. An infant with a ‘positive’ congenital hypothyroidism screen and ossifications should immediately trigger screening for PHP1A. In general, if an infant or child with hypothyroidism is being successfully treated with levothyroxine but continues to have an excessive increase in weight, the possible diagnosis of PHP1A should be entertained.
Patients with PHP1A have evidence of hypogonadism and incomplete sexual maturation , most likely due to partial imprinting in gonadal tissue , but pubertal onset occurs at the usual time. Amenorrhea or oligomenorrhea is common in women [45,46], and oestrogen therapy is often needed, being aware of the potential risk of DVT formation (personal observation). Elevated LH/FSH levels would be expected in the face of gonadotropin resistance, but this is not consistently observed . Although it is difficult to assess the true reproductive fitness of PHP1A patients due to their cognitive and social issues (see below), studies in Gnas exon 1 knockout mice have revealed significantly reduced fertility in females with maternally derived disrupted alleles (and minimally in those with paternally derived disrupted alleles) .
A markedly increased prevalence of GH deficiency occurs in PHP1A (about two-thirds of patients) due to resistance to GHRH secondary to partial imprinting in the pituitary [2,23,24,38]. Treatment with recombinant GH results in an increased growth velocity [23,25,47,48] in PHP1A. A long-standing clinical trial of GH treatment in GH-deficient children with PHP1A through final height  is showing promising preliminary results with a significant increase in final adult height compared with untreated GH-deficient PHP1A adults [48,unpublished observation]. Testing for GH status, as well as recombinant GH treatment for GH-deficient PHP1A patients, is part of the 2018 Consensus guidelines [17▪▪]. All PHP1A patients with moderate to severe obesity and/or snoring were screened with ENT examinations and sleep studies prior to treatment in the aforementioned GH trial, as GH treatment carries the potential risk of worsening obstructive sleep apnoea (OSA), such as from tonsillar/adenoidal hypertrophy [48,49]. This is important to include in standard of care treatment of GH-deficient PHP1A patients with recombinant GH (personal experience).
Although GH deficiency contributes to short stature in about two-thirds of patients with PHP1A, the premature fusion of the epiphyses has a large impact on the final adult height, as previously discussed. A study of GH-sufficient PHP1A children treated with GH is still underway in order to determine the effect on final adult height of increasing growth velocity maximally prior to the premature epiphyseal fusion . Overall, it has been noticed that GH treatment does not increase ossification growth [30▪] or have atypical side effects [48,49].
Classically, the obesity in AHO had been described as occurring similarly in both PHP1A and PPHP. However, approximately a decade ago, severe obesity was found to be a feature of PHP1A only and not PPHP . This was the first indication that hypothalamic imprinting may be involved. Early-onset obesity was also significant. Morbid obesity without evidence of hyperphagia was identified [2,50], and it was discovered that the cause of rapid weight gain in childhood was not hyperphagia but rather a decrease in resting energy expenditure (REE) [51,52,53▪]. In adults with PHP1A, there are higher rates of type 2 diabetes and reduced insulin sensitivity compared with obese controls . However, it was recently reported that children with PHP1A are at a high risk for dysglycaemia without reduced insulin sensitivity and have lower HgbA1c levels than controls. Interestingly, these children seem to have an increased sucrose preference as well [53▪].
The prevalence of sleep apnoea in PHP1A (including both OSA and central apnoea) was found to occur at a 4.4-fold greater relative risk than similarly obese children in a retrospective study, which was out of proportion to the obesity alone . A recent prospective study revealed that significant OSA occurred in 60% of children with PHP1A and seemed amplified possibly due to their craniofacial issues, along with an increased prevalence of hypotonia and asthma [22,56▪].
Patients with PPHP have overall higher social functioning as adults than those with PHP1A (unpublished). Interestingly, studies in mice demonstrated that females with a maternally inherited mutation neglected their young, resulting in nearly 80% mortality among pups before weaning, in contrast with those with a paternally inherited mutation, which showed normal mothering behaviour. This suggests the possibility of abnormal behaviour due to paternal imprinting in the CNS . Cognitive testing in a single kindred with AHO implicated imprinting, with PHP1A family members being more affected than those with PPHP , although this study was limited by the small number of patients and by the use of a single measure for cognitive function. Abnormalities in olfaction and hearing have also been reported in PHP1A and are not present in PPHP [63–66], suggesting the involvement of GNAS imprinting in other parts of the CNS.
Overall, the cognitive and behavioural issues can lead to difficulties with independent living in adulthood, and a tremendous amount of support and advocacy from the medical team is needed for the patients and their families long-term (personal experience and [67▪]).
PHP1B is characterized by PTH resistance without clear AHO signs or other hormonal resistances, although these patients have occasional mild brachydactyly and mild TSH resistance . Recently, early-onset obesity was defined as an important feature of PHP1B by Grüters-Kieslich et al.[68▪], and in a small kindred of three PHP1B children, decreased REE and dysglycaemia were recently reported, similar to PHP1A [53▪]. These findings further emphasize the overlap in the PHP disorders. Ossifications are very rare in PHP1B (none seen by author), and cognitive issues are not typically observed. Recently, bone mineral density studies of 48 patients with PHP1B stressed that PTH needs to be maintained at appropriate levels when treating to avoid adverse effects on bone [69▪].
This review provides the background necessary to understand PHP1A, PPHP and PHP1B within the framework of recent advances and management of the conditions. A summary table is provided as a practical management tool for use in clinic. In addition, the spectrum of other PHP disorders is introduced. As we learn more about PHP, it is clear that there is an overlap between the various types. These disorders are complex and require comprehensive management. Being an advocate for these patients is vital to improving their quality of life. The 2018 international Consensus Statement is a major stride in improving patient care.
Papers of particular interest, published within the annual period of review, have been highlighted as:
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The impressive work from this investigation in Gαs knockout mice demonstrated that Gαs imprinting in the melanocortin 4 receptor-expressing cells in the dorsomedial hypothalamus provides an explanation for the obesity in PHP1A; this represents the culmination of years of critical work by several of these investigators.
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This study examined a large group of patients with Albright hereditary osteodystrophy over a span of 16 years and found that about 70% of both PHP1A and PPHP patients had SCOs, which were more extensive in those with frameshift and nonsense mutations and which were more pronounced in males than in females.
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40. Chen M, Wang J, Dickerson KE, et al. Central nervous system imprinting of the G protein G(s)alpha and its role in metabolic regulation. Cell Metab 2009; 9:548–555.
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This study emphasizes the need to screen for maternal GNAS mutations in the presence of SCOs or positive family history even in the absence of PTH resistance, as the PTH elevations can develop late.
42. Haldeman-Englert CR, Hurst AC, Levine MA. Disorders of GNAS
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Hypercalciuria is not typical in PHP1A, and this study further emphasizes that renal ultrasounds are indicated only when hypercalciuria is present.
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These results support the investigators’ prior studies showing that decreased REE, not severe hyperphagia, is one of the main causes of abnormal weight gain in PHP and is the first study to show that children with PHP are at an increased risk for dysglycaemia without having reduced insulin sensitivity.
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This study emphasizes the tremendous importance of advocacy and support for PHP patients and their families.
68▪. Grüters-Kieslich A, Reyes M, Sharma A, et al. Early-onset obesity: unrecognized first evidence for GNAS
mutations and methylation changes. J Clin Endocrinol Metab 2017; 102:2670–2677.
This study demonstrated that obesity can be the first clinical evidence for PHP1B in an infant or young child and highlights the need to consider testing for methylation defects of GNAS in the setting of early-onset obesity.
69▪. Chu X, Zhu Y, Wang O, et al. Bone mineral density and its serial changes are associated with PTH levels in pseudohypoparathyroidism
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The importance of maintaining PTH levels within the normal range to maintain bone health is demonstrated in this largest study of bone mineral density in PHP1B.
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This study investigated the largest cohort of patients with PHP1A, PPHP and PHP1B for growth parameters and emphasizes that childhood height does not predict adult stature and that maternal mutations or methylation defects of GNAS (i.e. PHP1A and PHP1B) can lead to significant early-onset obesity that can persist throughout adulthood.
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