Table 2.
Clinical and biochemical features associated with the diagnosis of pseudohypoparathyroidism apart from PTH resistance, brachydactyly, and subcutaneous ossifications
| Specific Features | Description | Mechanism | References |
|---|---|---|---|
| Impaired fetal growth | Mild IUGR in mat GNAS mutations Significant IUGR in pat GNAS mutations Increased birth weight and or length in mat GNAS LOI Significant IUGR in PRKAR1A and PDE4D mutations | Gsα and XLas (and downstream signaling) contributes to fetal growth | 59,87,119 |
| Short stature | Short stature, z-score ≈ −2.5 in mat and pat GNAS mutations Lack of pubertal growth spurt in mat and pat GNAS mutations, and mat GNAS LOI | Gsα is crucial for the PTHrP signaling in the chondrocytes, especially during puberty | 59,78 |
| Obesity | Early-onset obesity in mat GNAS inactivation (mutations and LOI) Adult patients with a BMI >25 kg/m2 ≈ 70% of those with a mat GNAS mutation ≈ 55% of those with a mat GNAS LOI | Gsα is crucial for the melanocortin signaling in the periventricular nucleus of the hypothalamus that regulates satiety. In addition, Gsα deficiency contributes to a low energy expenditure, decreased lipolysis and GHRH resistance | 78,59,120,121 |
| Metabolic syndrome | Decreased insulin sensitivity in children and adults with mat GNAS mutations | Gsα deficiency and obesity | 122,123 |
| Sleep apnea | Increased frequency in ≈ 45% of those with a mat GNAS mutation Likely increased in patients with PRKAR1A and PDE4D mutations as well | Not related to obesity, maybe to the mid-face hypoplasia | 72 |
| Cognitive impairment | ≈ 70% of those with a mat GNAS mutation In small series: a subset of patients with PRKAR1A mutations and most patients with PDE4D mutations | cAMP is necessary for the neuronal development | 43,56,73,74 |
| Asthma | Increased prevalence in Patients with a mat or pat GNAS mutation Patients with a mat GNAS LOI Patients with acrodysostosis | 72,120,124 | |
| Dental symptoms | All descriptions in patients with mat GNAS mutations: enamel defects, blunted and shortened roots; hypodontia and oligodontia; failure of tooth eruption and tooth ankyloses | The defective signaling downstream of PTH1R in the tooth germ and cells may be involved | 125 |
| Cranial, skeletal, and neurologic anomalies | Craniosynostosis and Chiari 1 malformation may exist in patients with mat GNAS mutations and patients with acrodysostosis Carpal tunnel syndrome is as frequent as ≈ 70% of adults with a mat GNAS mutation Spinal stenosis has been described in case reports of patients with mat GNAS mutations and patients with acrodysostosis Sensorineural hearing loss in patients with mat GNAS mutations and patients with acrodysostosis | 43,56,76,126 | |
| TSH resistance | Is present since infancy in Patients with a mat GNAS mutation (average TSH is ≈ 14 ± 10 mUI/L); some patients may have overt hypothyroidism at birth ≈ 30–100 patients with a mat GNAS LOI (average TSH is ≈ 5 mUl/L) Patients with a mutation in PRKAR1A | Excessive TSH response to TRH Partial resistance to TSH in the thyroid gland | 48 |
| Calcitonin resistance | Is present in Patients with a mat GNAS mutation Patients with a mat GNAS LOI Patients with a mutation in PRKAR1A | 48 | |
| Gonadotropin resistance | Delayed puberty, oligo- and amenorrhea in girls; cryptorchidism in boys with mat GNAS mutations Variable reports on elevated levels of FSH/ LH. Prolactin deficiency in patients with a mat GNAS mutation | 22,79 | |
| GHRH resistance | GH deficiency: ≈ 50%−80% of children with a mat GNAS mutation | Defective Gsα signaling in the pituitary where Gsα is imprinted | 69,70,92,127 |
Abbreviations: BMI, body mass index; cAMP, cyclic AMP; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, GH releasing hormone; IUGR, intrauterine growth retardation; LH, luteinizing hormone; LOI, Loss of imprinting; mat, maternal; pat, paternal; PTH1R, PTH receptor type 1; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.