Genetic IGF1R defects: new cases expand the spectrum of clinical features.

PURPOSE: We aimed to identify the phenotypic variability of IGF1R defects in a cohort of short children with normal GH secretion gathered through the last decade. PATIENTS AND METHODS: Fifty children (25 girls) with short stature and a basal/stimulated growth hormone (GH) over 10 ng/ml having either a low birth weight or microcephaly were enrolled. MLPA and then Sanger sequence analysis were performed to detect IGF1R defects. The auxological and metabolic evaluation were carried out in index cases and their first degree family members whenever available. RESULTS: A total of seven (14%) IGF1R defects were detected. Two IGF1R deletions and five heterozygous variants (one frameshift, four missense) were identified. Three (likely) pathogenic, one VUS and one likely benign were classified by using ACMG. All children with IGF1R defects had a height < - 2.5SDS, birth weight < - 1.4SDS, and head circumference < - 1.36SDS. IGF-1 ranged from - 2.44 to 2.13 SDS. One child with a 15q terminal deletion had a normal phenotype and intelligence, whereas low IQ is a finding in a case with missense variant. Two parents who carried IGF1R mutations had diabetes mellitus, hypertension and hyperlipidemia, one of whom also had hypergonadotropic hypogonadism. CONCLUSION: We found a deletion or variant in IGF1R in 14% of short children. Birth weight, head circumference, intelligence, dysmorphic features, IGF-1 levels and even height are not consistent among patients. Additionally, metabolic and gonadal complications may appear during adulthood, suggesting that patients should be followed into adulthood to monitor for these late complications.

Identification of point mutations and large rearrangements in the BRCA1 gene in 667 Turkish unselected ovarian cancer patients.

OBJECTIVE: The aim of this study was to evaluate the prevalence and spectrum of a known founder mutation, 5382insC and large genomic rearrangements (LGRs) in BRCA1 in ovarian cancer patients in Turkey. The additional aim was to determine the genetic testing strategy in Turkish breast/ovarian cancer family. METHODS: Six hundred and sixty-seven ovarian cancer patients from five large geographical regions in Turkey, 61 of which had family history of breast/ovarian cancer, were tested for the mutation 5382insC by mutagenically separated polymerase chain reaction and direct sequencing of the entire coding sequence and the splicing sites. Additionally, multiplex ligation-dependent probe amplification (MLPA) was performed for large mutational scanning of BRCA1 gene in unselected ovarian cancer. RESULTS: In this study, BRCA1 point mutations were observed in 1% of all patients and 9.8% of familial cases: 5382insC, unique novel missense variant-G1748S and unclassified splice site variant IVS20+5A>T. 5382insC was observed in two patients. However, G1748S, previously unreported, was found in four patients and thus led to the conclusion that this mutation may be unique to Turkey. A splice site variant, IVS20+5A>T, was detected in three patients, with two of them including G1748S and IVS20+5A>T, together. Using MLPA, six different distinct LGRs in BRCA1 were observed: the deletion of E1A-1B-2, E11, E17-19, E18 and E18-19 and duplication of E5-9. The prevalence of LGRs in this study was 40.9% among patients with family history. The deletion of E1A-1B-2 was the common mutation, and patients with this deletion were referred to us from four different geographical regions in Turkey. Therefore, it was hypothesized that this deletion covering E1-2 is common in Turkey. CONCLUSION: LGRs in BRCA1 were strongly associated with positive family history among the Turkish population. On the basis of these findings, it can be recommended that a low-cost screening for LGRs in BRCA1 may be the first-line mutation detection method in families with strong breast/ovarian cancer history in Turkey.