Clinical characteristics and genetic analysis of two cases of pseudohypoparathyroidism type Ⅰa with early-onset skin nodules as the diagnostic clue / 中华皮肤科杂志

Clinical features of and genetic mutations in two cases of pseudohypoparathyroidism type Ⅰ a(PHP Ⅰ a) with early-onset skin nodules were analyzed.Both of the two patients were males,and their ages at onset were 2 and 3 months respectively.They both presented with early-onset skin nodules as the main clinical manifestation,and were clinically characterized by a round face,short neck and early obesity.Histopathological examination of skin lesions showed subcutaneous ectopic osteogenesis in both patients.The first patient had low blood calcium,high blood phosphorus,high parathyroid hormone (PTH),and gene sequencing showed a heterozygous mutation c.399delT causing a T base deletion at position 399 in exon 5 of the GNAS gene.The second patient had normal blood calcium and phosphorus levels as well as normal PTH levels at early stage,and gene sequencing showed a heterozygous mutation c.939delT causing a T base deletion at position 939 in exon 9 of the GNAS gene.The blood PTH level was found to increase in the second patient after 1-year follow-up.Both the patients were confirmedly diagnosed with PHP Ⅰa.After treatment with vitamin D3,no new skin nodules occurred,and the blood calcium and phosphorus levels returned to normal.

A de novo mutation in GNAS cause severe pseudohypoparathyroidism typeⅠa / 临床儿科杂志

Objective To identify the GNAS gene mutation resulting in pseudohypoparathyroidism type Ⅰa (PHP-Ⅰa) in one patient. Methods The clinical data of a patient with pseudohypoparathyroidism type Ⅰa was retrospectively analyzed. All the 13 exons of GNAS were sequenced using Sanger method for the patient and the parents. The distribution of suspected causal mutation was screened in 478 healthy controls. To clarify the origin of the mutation, we performed targeted high-depth sequencing of GNAS exon harboring the mutation for the patient and the parents. Results The clinical data of the patient with the laboratory results of hypocalcaemia, hyperphosphataemia, elevated serum PTH, together with the features of AHO, conformed to the characterization of PHP-Ⅰa. The sequencing of GNAS exons identified a missense mutation (c.479G>C, p.R160P) located at exon 6 in the patient, which was absent in DNA of the parents. The mutation was not reported previously and was not found in the 478 healthy controls. We obtained about 8000-fold coverage from high-depth sequencing of DNA from peripheral blood of the patient and the parents. The disease-associated allele C identified in the patient was not observed in the parents. The number of reads with G allele (3984 reads) was roughly equal to that of C allele (4019 reads) from the targeted reanalysis of DNA of the patient. The results from high-depth sequencing indicated a de novo mutation in maternal germ cells. Conclusions We identified a new GNAS gene mutation (c.479G>C, p.R160P) caused PHP-Ia in a patient. Our results suggested the mutation was a maternal germline de novo mutation.

Identification of a novel mutation in a patient with pseudohypoparathyroidism type Ia / 소아과

Pseudohypoparathyroidism type Ia (PHP Ia) is a disorder characterized by multiform hormonal resistance including parathyroid hormone (PTH) resistance and Albright hereditary osteodystrophy (AHO). It is caused by heterozygous inactivating mutations within the Gs alpha-encoding GNAS exons. A 9-year-old boy presented with clinical and laboratory abnormalities including hypocalcemia, hyperphosphatemia, PTH resistance, multihormone resistance and AHO (round face, short stature, obesity, brachydactyly and osteoma cutis) which were typical of PHP Ia. He had a history of repeated convulsive episodes that started from the age of 2 months. A cranial computed tomography scan showed bilateral calcifications in the basal ganglia and his intelligence quotient testing indicated mild mental retardation. Family history revealed that the patient's maternal relatives, including his grandmother and 2 of his mother's siblings, had features suggestive of AHO. Sequencing of the GNAS gene of the patient identified a heterozygous nonsense mutation within exon 11 (c.637 C>T). The C>T transversion results in an amino acid substitution from Gln to stop codon at codon 213 (p.Gln213*). To our knowledge, this is a novel mutation in GNAS.