We present a case of POH overlap syndrome (POH/PHP1a/1c) who showed a sporadic GNAS mutation, deep ectopic ossification, SGA, congenital tooth defect, and lack of AHO features. This patient met the diagnostic criteria of POH, and mild PTH and TSH resistance was detected.
PHP, the first known post-receptor hormone resistance, is caused by a partial deficiency of the α subunit of the stimulatory G protein (Gsα), which is a key component of the PTH/PTHrP signaling pathway. Since its first description, besides the molecular basis of PHP, various studies have revealed the existence of numerous subtypes and differential diagnoses associated with genetic alterations of the PTH/PTHrP pathway. The clinical and molecular overlap of PHP subtypes and other related disorders presents challenges for both differential diagnosis and genetic counseling [3].
In 2016, the EuroPHP network developed a new classification that encompasses all disorders involving impairments in PTH and/or PTHrP cAMP-mediated pathways [4]. Elli and Mantovani reviewed the major and minor features characterizing inactivating PHP or PTH/PTHrP signaling disorders (iPPSDs) as a group and the specificities and overlap associated with the most frequent subtypes [3]. Their descriptions on POH are in line with our findings
Because there are only a few detailed reports of POH overlap syndrome, there remain numerous unclear points regarding additional AHO or PHP features that are present alongside POH features. The diagnosis of POH overlap syndrome is made on the basis of only clinical symptoms [2]. There are further uncertainties about POH. For example, our patient was first diagnosed at age 13 years and 6 months despite POH usually being diagnosed within the first year of life [5]. Moreover, although Shore et al. demonstrated that most cases of POH are caused by paternally inherited inactivating mutations of GNAS [6], our patient showed both POH and PHP Ia, which are apparently due to a de novo mutations of GNAS.
Recently, Pereda et al. proposed new criteria and classifications of iPPSDs. Moreover, current work is focused on improving classifications of PHP and related disorders [7]. POH is diagnosed on the basis of three major criteria: superficial heterotopic ossification (HO) that progresses to deep connective tissue, no more than two AHO features, and no PTH resistance [8]. Progressive extension of HO into deep connective tissue, congenital tooth defects, and shortening of the left femoral neck are considered AHO symptoms. However, PTH tolerance is a characteristic symptom of PHP1A [1].
It has been recently reported that severe POH without PHP1A/1C features is caused by paternally inherited inactivating mutations of GNAS, whereas mild cases of POH with AHO/PHP1A features are caused by maternal inherited inactivating mutations of GNAS [9]. There have been three reports of a mild case of POH/PHP1A [10–12], which showed that hormone resistance was not observed at the time of initial POH identification, and hormone tolerance appeared months or years later (Table 1).
Table 1
Clinical and molecular characteristics of cases reported in the literature harboring mild POH
Authors
|
GNAS mutation
|
Familial transmission/mutated allele
|
Age of onset of Heterotopic ossification
|
Age of onset of PTH resistance
|
Age of onset of TSH resistance
|
Elli, F.M., et al.
|
c.565_568delGACT
|
denovo/maternal
|
6 months
|
3 years
|
3 years
|
Lebrun, M., et al.
|
c.565_568delGACT
|
denovo/maternal
|
6 months
|
1 year
|
1 year
|
Gelfand, L.M., et al.
|
c.546delC
|
de novo/unknown
|
1 month
|
16 months
|
4 months
|
The heterozygous mutation p.D189MfsTer14 of GNAS identified in our case is not only a POH hereditary mutation but also a mutation hotspot of AHO/PHP1A, so it may exhibit a wide range of phenotypes [8, 10]. Genetic background, modified genes, epigenetic modifications, and environmental factors are believed to be factors that contribute to POH overlap syndrome [9]. Further studies of the GNAS heterozygous mutation p.D189MfsTer14 may reveal the factors that are involved in POH overlap syndrome.
It remains unclear whether POH overlap syndrome is associated with progressive bone age, the appearance of intellectual impairment, or gonadal dysfunction [1]. In our case, there were no abnormalities in bone age progression, intelligence, or gonadal function. Given the rarity of POH/PHP1C/1C, further cases will need to be investigated to elucidate these uncertainties.
In summary, we present a rare case of POH overlap syndrome (POH/PHP1A/1C), which was diagnosed only by clinical symptoms. POH is usually diagnosed by the age of 1 year; however, our patient was first diagnosed at age 13 years and 6 months because the bone lesions were much milder than previously reported. Genetic background, modified genes, epigenetic modifications, and environmental factors are believed to be factors that contribute to POH overlap syndrome [9]. Further studies of POH cases will enable the identification of factors associated with POH overlap syndrome. Moreover, additional studies of the GNAS heterozygous mutation p.D189MfsTer14 will provide a better understanding of the factors involved in POH overlap syndrome.