Dataset Information

Osteogenesis Imperfecta Due to Combined Heterozygous Mutations in Both COL1A1 and COL1A2, Coexisting With Pituitary Stalk Interruption Syndrome.

ABSTRACT: Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder, characterized by reduced bone content, fractures and skeletal malformation due to abnormal synthesis or dysfunction of type I collagen protein. Pituitary stalk interruption syndrome (PSIS) is usually associated with environmental and hereditary factors. Here, we report a rare case of OI and PSIS co-occurrence. A 19-year-old male patient sought treatment for growth delay and absent secondary sexual characteristics. Hormone measurements indicated the presence of hypopituitarism (secondary hypothyroidism, growth hormone deficiency, ACTH-cortisol hormone deficiency, hypogonadotropic hypogonadism). Pituitary magnetic resonance imaging indicated reduced morphology of the anterior lobe, absence of the pituitary stalk, and ectopic displacement of the posterior lobe to the infundibulum, supporting a diagnosis of PSIS. In addition, the patient, his monozygotic twin brother (no evidence of PSIS), and their mother all presented blue sclera and susceptibility to bone fractures before adulthood. Next-generation sequencing demonstrated that the family had compound heterozygous mutations in COL1A1 and COL1A2, with no known mutations related to PSIS, pituitary hormone deficiency (PHD), or holoprosencephaly (HPE). The mother experienced breech and natural delivery of the patient and his brother, respectively. Thus, we deduced that the patient's PSIS might have resulted from breech delivery. Although we cannot exclude the possibility that the proband might have an undetected genetic abnormality causing PSIS or increasing his susceptibility to damage to the hypothalamic-pituitary region due to the limitation of exome sequencing, this rare case suggests that breech delivery in the newborn with OI might be related to PSIS.

SUBMITTER: Wang D

PROVIDER: S-EPMC6447649 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Osteogenesis Imperfecta Due to Combined Heterozygous Mutations in Both <i>COL1A1</i> and <i>COL1A2</i>, Coexisting With Pituitary Stalk Interruption Syndrome.

Wang Dongdong D Zhang Mengmeng M Guan Haixia H Wang Xiaoli X

Frontiers in endocrinology 20190328

Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder, characterized by reduced bone content, fractures and skeletal malformation due to abnormal synthesis or dysfunction of type I collagen protein. Pituitary stalk interruption syndrome (PSIS) is usually associated with environmental and hereditary factors. Here, we report a rare case of OI and PSIS co-occurrence. A 19-year-old male patient sought treatment for growth delay and absent secondary sexual characteristics. Hormone m ...[more]

PMID: 30984112

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Project description:PurposeNearly 85%-90% of osteogenesis imperfecta (OI) cases are caused by autosome dominant mutations of COL1A1 and COL1A2 genes, of which de novo mutations cover a large proportion, whereas their characteristics remain to be elucidated. This study aims to compare the differences in clinical and genetic characteristics of de novo and inherited COL1A1/COL1A2 mutations of OI, assess the average paternal and maternal age at conception in de novo mutations, and research the rate of nonpenetrance in inherited mutations.Materials and methodsA retrospective comparison between de novo and inherited mutations was performed among 135 OI probands with COL1A1/COL1A2 mutations. Mutational analyses of all probands and their family members were completed by Sanger sequencing. A new clinical scoring system was developed to assess the clinical severity of OI quantitatively.ResultsA total of 51 probands (37.78%) with de novo mutations and 84 probands (62.22%) with inherited mutations were grouped by the results of the parental gene verification. The proportion of clinical type III (P<0.001) and clinical scores (P<0.001) were significantly higher in de novo mutations. Missense mutations covered a slightly higher proportion of de novo COL1A1 mutations (46.34%) compared with inherited COL1A1 mutations (33.33%), however, lacking a significant difference (P=0.1923). The mean BMD Z/T-score at the lumbar spine in de novo mutations was -2.3 ± 1.5, lower than inherited mutations (-1.7 ± 1.8), but lacking statistical significance (P=0.0742). There was no significant difference between the two groups in OI-related phenotypes (like fracture frequency, blue sclera, and hearing loss) and biochemical indexes. In de novo mutations, the average paternal and maternal age at conception was 29.2 (P<0.05) and 26.8 (P<0.0001), respectively, which were significantly younger than the average gestational age of the population. Additionally, 98.04% of pedigrees (50/51) with de novo mutations were spontaneous conception. The rate of nonpenetrance of parents with pathogenic variants in the inherited mutation group was 25.64% (20/78).ConclusionsOur data revealed that the proportion of clinical type III and clinical scores were significantly higher in de novo mutations than in inherited mutations, demonstrating that de novo mutations are more damaging because they have not undergone purifying selection.

Dataset Information

Osteogenesis Imperfecta Due to Combined Heterozygous Mutations in Both COL1A1 and COL1A2, Coexisting With Pituitary Stalk Interruption Syndrome.

Publications

Osteogenesis Imperfecta Due to Combined Heterozygous Mutations in Both <i>COL1A1</i> and <i>COL1A2</i>, Coexisting With Pituitary Stalk Interruption Syndrome.

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