Evaluating the variety of GNAS inactivation disorders and their clinical manifestations in 11 Chinese children.

BACKGROUND: The GNAS gene on chromosome 20q13.3, encodes the alpha-subunit of the stimulatory G protein, which is expressed in most tissues and regulated through reciprocal genomic imprinting. Disorders of GNAS inactivation produce several different clinical phenotypes including pseudohypoparathyroidism (PHP), pseudopseudohypoparathyroidism (PPHP), progressive osseous heteroplasia (POH), and osteoma cutis (OC). The clinical and biochemical characteristics overlap of PHP subtypes and other related disorders presents challenges for differential diagnosis. METHODS: We enrolled a total of 11 Chinese children with PHP in our study and analyzed their clinical characteristics, laboratory results, and genetic mutations. RESULTS: Among these 11 patients, nine of them (9/11) presented with resistance to parathyroid hormone (PTH); and nine (9/11) presented with an Albright's hereditary osteodystrophy (AHO) phenotype. GNAS abnormalities were detected in all 11 patients, including nine cases with GNAS gene variations and two cases with GNAS methylation defects. These GNAS variations included an intronic mutation (c.212 + 3_212 + 6delAAGT), three missense mutations (c.314C > T, c.308 T > C, c.1123G > T), two deletion mutations (c.565_568delGACT*2, c.74delA), and two splicing mutations (c.721 + 1G > A, c.432 + 1G > A). Three of these mutations, namely, c.314C > T, c.1123G > T, and c.721 + 1G > A, were found to be novel. This data was then used to assign a GNAS subtype to each of these patients with six cases diagnosed as PHP1a, two cases as PHP1b, one as PPHP, and two as POH. CONCLUSIONS: Evaluating patients with PTH resistance and AHO phenotype improved the genetic diagnosis of GNAS mutations significantly. In addition, our results suggest that when GNAS gene sequencing is negative, GNAS methylation study should be performed. Early genetic detection is required for the differential diagnosis of GNAS disorders and is critical to the clinician's ability to distinguish between heterotopic ossification in the POH and AHO phenotype.

Intracranial vascular calcification with extensive white matter changes in an autopsy case of pseudopseudohypoparathyroidism.

We herein report an autopsy case of a 69-year-old man with pseudopseudohypoparathyroidism. The patient suffered from mental retardation and spastic tetraparesis and had all the features of Albright's hereditary osteodystrophy with a normal response to parathyroid hormone in the Ellsworth-Howard test. Computed tomography demonstrated symmetrical massive brain calcification involving the bilateral basal ganglia, thalami, dentate nuclei and cerebral gray/white matter junctions, which was consistent with Fahr's syndrome. Magnetic resonance imaging revealed extensive white matter changes sparing the corpus callosum. Severe ossification of the posterior longitudinal ligament of the cervical spine was also demonstrated. A neuropathological examination revealed massive intracranial calcification within the walls of the blood vessels and capillaries with numerous calcium deposits. The calcium deposits aligned along the capillaries, and deposits in the vessel wall at the initial stage were confined to the border between the tunica media and adventitia. The vascular calcification in the basal ganglia continuously spread over the surrounding white matter into the cortex. The area of vascular calcification in the white matter was very well correlated with the area of the attenuated myelin staining. Axonal loss, myelin sheath loss and gliosis were observed in the white matter with severe vascular calcification. We should recognize the continuous area of vascular calcification and its correlation with extensive white matter changes as possible causes of neuropsychiatric symptoms in pseudopseudohypoparathyroidism with Fahr's syndrome.

Late-onset subcutaneous scalp calcifications in a patient with pseudo-pseudohypoparathyroidism.

Ectopic calcifications and even bone formation have been linked to GNAS gene mutations. A 51-year-old Caucasian female had been diagnosed of pseudo-pseudohypoparathyroidism (PPHP) in 1989. She has always had normal serum parathyroid hormone, calcium, and phosphorus levels. A non-contrast computed tomography of the head was done in 2013 and it showed finely speckled subcutaneous calcifications in the high convexity of the head. Cutaneous exploration did not show any abnormality. We herein report an unusual case of late-onset scalp calcifications in a patient with PPHP.

Total knee arthroplasty in a patient with pseudopseudohypoparathyroidism.

Pseudopseudohypoparathyroidism (PPH) is a rare genetic disorder characterized by multiple musculoskeletal anomalies and normal serum calcium, phosphate, and parathyroid hormone levels. Although the musculoskeletal manifestations of PPH are well known, little has been reported on the management of orthopedic problems. We report a case of total knee arthroplasty (TKA) performed in a patient with PPH. To our knowledge, this case is not only unique to the arthroplasty literature but is the first report of its kind. This report illustrates the unique pathoanatomy of PPH, the medical and surgical management required, and a previously unreported musculoskeletal abnormality associated with PPH: synovial osteochondromatosis of the knee. Common musculoskeletal anomalies associated with PPH include shortening/bowing of long bones; shortening of metacarpals, metatarsals, and/or phalanges; exostoses; calcification/ossification of subcutaneous and/or periarticular soft tissues; a thickened calvarium; microcephaly; bony coalitions of the hand; vertebral column abnormalities; cubitus valgus; radius/ulna curvus; coxa vara; coxa valga; and genu valgum. This case is the first to report an association of synovial osteochondromatosis with PPH. Because synovial osteochondromatosis and PPH share a common disorder of soft tissue calcification/ossification, as well as abnormal bone formation, this clinical finding does not seem merely coincidental.

Progressive osseous heteroplasia-like heterotopic ossification in a male infant with pseudohypoparathyroidism type Ia: a case report.

UNLABELLED: Pseudohypoparathyroidism (PHP) Ia is a rare condition associated with multiple hormone resistance and the Albright Hereditary Osteodystrophy (AHO) phenotype. Progressive osseous heteroplasia (POH) is characterized by progressive ossifications of dermal, skeletal muscle and deep connective tissue during childhood. Both PHP Ia and POH are caused by heterozygous inactivating mutations in the GNAS gene. Maternal inheritance of a GNAS mutation leads to an AHO phenotype with hormonal resistance (PHP Ia), whereas paternal inheritance leads to an AHO phenotype without the hormonal resistance (pseudopseudo-hypoparathyroidism). Pure POH (no other AHO features) is also caused by a paternal inheritance of GNAS mutations. Mutations that cause PHP Ia when maternally inherited can cause POH when paternally inherited. We present an unusual case of a boy with clinical features of both POH and PHP Ia, and a GNAS inactivating mutation. CASE PRESENTATION: The patient was referred at 1 month of age with a "knot on his leg". Plain radiographs revealed subcutaneous ossifications. PE at age 4 months included: length and weight >95%, a round face, short 4th metacarpals, and extensive subcutaneous ossifications of the lower limbs, buttocks, and back. Studies at age 4 months included an elevated TSH 12.4 mIU/l, free T4 0.86 ng/dl (0.8-2.3), PTH 61 pg/ml (10-65), calcium 9. 8 mg/dl (9.0-11.0), and phosphorus 6. 4 mg/dl (3.8-6.5). By age 16 months, the PTH was elevated at 126 pg/ml. Biopsies of the skin lesions demonstrated osteoma cutis consistent with POH. GNAS analysis revealed a heterozygous deletion in exon 7. The mutation was not detected in either parent. DISCUSSION: POH and PHP Ia are rare genetic disorders caused by loss of function mutations of the GNAS gene. POH and PHP Ia do not commonly occur in the same individual as they are associated with paternal versus maternal inheritance (imprinting) of an affected GNAS gene. Our patient has evidence of both severe POH and PHP Ia, apparently due to a de novo mutation in GNAS.