| Background and Objective: Inactivating Parathyroid hormone/Pathyroid hormone related protein signaling disorder(i PPSD)refers to all disorders caused by impaired signaling of parathyroid hormone and parathyroid hormone related protein action pathways.All disorders resulting from impaired conduction are newly named by the European PHP network in 2016,encompassing the previously familiar pseudohypoparathyroidism(PHP).According to the previous typing criteria of PHP,PHP were classified into PHP type I and PHP type II,and type I was further divided into five subtypes according to clinical manifestations and Gsα activity,etc.,namely PHP type I a,PHP type I b,PHP type I c,pseudo-pseudohypoparathyroidism(PPHP)and progressive osseous heteroplasia(POH).In recent years researchers have identified clinical and molecular overlap between PHP subtypes,thus in 2016 the European PHP network introduced the new concept of i PPSD,which is classified into i PPSD types 1 to 6depending on the genetic molecular defect.In this study,we analyzed the clinical and genetic characteristics of a patient with i PPSD and her family members,reviewed the relevant literature to summarize the clinical characteristics,diagnosis and treatment of patients with i PPSD,elaborated the correspondence between i PPSD and PHP,enhanced clinicians’ understanding of i PPSD and PHP,and reduced the misdiagnosis and underdiagnosis rate of i PPSD.Methods: We retrospectively analyzed the clinical manifestations and laboratory tests of one patient with i PPSD who attended the The First Affiliated Hospital of Dalian Medical University in March 2022,collected general informations,clinical manifestations,physical examination and related laboratory tests of the patient’s family members,performed GNAS gene testing and mutation analysis.Results:1.The proband has hypocalcemia-induced convulsions as the first manifestation,along with signs such as shortened fingers and toes,round face.The height growth curve suggests a slightly slow growth rate.Laboratory tests showed a low level of calcium and a high level of phosphate and PTH,normal 25 hydroxyvitamin D(25OHD),magnesium,and renal function,consistent with PTH resistance.thyroid stlmulating hormone(TSH)was elevated,free thyroxine and insulin-like growth factor-1(IGF-1)was decreased.thyroid autoantibodies,gonadal hormones,insulin(INS),growth hormone(GH)were normal.type Ⅰ amino-terminal peptide of collagen(PINP),β-C terminal telopeptide(β-CTX)were increased,N-terminal mid-fragment(N-MID),25 OHD were normal.Head computed tomography plain scan showed multiple foci of calcification in the frontal lobe and basal ganglia.X-ray of the left foot showed that the bone density of the distal part of the 4th metatarsal was reduced and slightly dilated,and irregular bone density shadow was seen laterally,which was considered as possible heterotopic ossification.c.568-571 del GACT,a nucleotide GACT deletion at sites of 568-571 th in the coding region of exon 7,was sequenced in the GNAS gene,resulting in a code-shifting mutation.Therefore,the diagnosis of the proband is i PPSD2.2.The proband’s mother has occasional weakness in both lower extremities,no signs of short stature,short fingers and toes.Laboratory tests showed normal calcium,phosphate and PTH,normal thyroid function and related antibodies,gonadal hormones,INS,GH and IGF-1,and normal bone metabolism(N-MID,PINP,β-CTX and 25OHD).Head computed tomography plain scan showed no abnormality.GNAS gene sequencing showed the same pathogenic mutation as in the proband,the diagnosis of the proband’s mother was i PPSD2.3.No manifestations of hypocalcemia in the father of the proband.There were no signs of short stature,short fingers and toes,no signs of round face and subcutaneous ossifications.Laboratory tests showed normal blood calcium,phosphate and PTH,thyroid function and related antibodies,gonadal hormones,INS,GH,IGF-1,and the four bone metabolism items.No abnormalities were seen on Head computed tomography plain scan.Genetic testing did not show mutations of i PPSD.The father of the proband is not an i PPSD patient.4.The proband’s grandfather has no manifestations of hypocalcemia.The physical examination revealed multiple bony protrusions on both metacarpophalangeal joints and interphalangeal joints with hard,non-smooth edges,no pressure pain,about 0.5～1.0 cm,some of the protrusions broke spontaneously,and the bony tissue was bare.The laboratory tests showed normal blood calcium,phosphate and PTH,normal thyroid function and related antibodies,gonadal hormones,INS,GH and IGF-1,and normal bone metabolism.Head computed tomography plain scan showed demyelination in the white matter.sequencing of the GNAS gene showed the same pathogenic mutation as in the preexisting patient.The diagnosis was i PPSD2.5.The proband’s grandmother has no manifestations of hypocalcemia.There were no signs of short stature,short fingers and toes,no signs of round face and subcutaneous ossifications.Laboratory tests showed normal blood calcium,phosphate and PTH,thyroid function and related antibodies,gonadal hormones,INS,GH,IGF-1,and the four bone metabolism items.No abnormalities were seen on Head computed tomography plain scan.Genetic testing did not show mutations of i PPSD.The father of the proband is not an i PPSD patient.Conclusions:1.According to the previous typing of PHP,the proband was diagnosed with PHP I a or PHP I c,and the proband ’s mother was diagnosed with POH or PPHP,the proband’s grandfather was diagnosed with PPHP,the typing is not very clear.But according to the new staging criteria of i PPSD,all three were diagnosed with i PPSD2,the new staging criteria allowed for a clearer and more accurate diagnosis of the patients.2.The same mutations in the GNAS gene occurred in the proband and her mother and her grandfather,but they have different clinical manifestations,verifying the existence of tissue specificity in Gsα and significant differences in phenotypes due to mutations in the paternal and maternal GNAS genes. |
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