Compound heterozygous variants in the ABCG8 gene in a Japanese girl with sitosterolemia.

Sitosterolemia is an autosomal recessive disorder that affects lipid metabolism and is characterized by elevated serum plant sterol levels, xanthomas, and accelerated atherosclerosis. In this study, we report a novel nonsense single-nucleotide variant, c.225G > A (p.Trp75*), and an East Asian population-specific missense multiple-nucleotide variant, c.1256_1257delTCinsAA (p.Ile419Lys), in the ABCG8 gene in a compound heterozygous state observed in a Japanese girl with sitosterolemia.

Pubertal Development and Pregnancy Outcomes in 46,XX Patients With Nonclassic Lipoid Congenital Adrenal Hyperplasia.

CONTEXT: Lipoid congenital adrenal hyperplasia (LCAH) is characterized by a disorder of steroidogenesis in both adrenal glands and gonads. 46,XX patients with classic LCAH usually have thelarche and menarche but show anovulatory menstruations and subsequent premature menopause. Only three patients with classic LCAH have been reported to successfully achieve delivery with the aid of assisted reproductive therapies for conception and progesterone replacement therapy during early pregnancy. In contrast, pubertal development and pregnancy outcomes in patients with nonclassic LCAH have not been fully elucidated. CASE DESCRIPTION: We report four Japanese women who had a diagnosis of primary adrenal insufficiency during infancy or childhood and carried compound heterozygous STAR mutations (p.Gln258* and p.Arg188His, p.Gln258* and p.Met225Thr, and p.Gln258* and p.Arg272Cys). In all four patients, thelarche and menarche spontaneously occurred from 10 to 11 years of age and from 12 to 14 years of age, respectively. Subsequently, their menstruation cycles were regular at almost 1-month intervals. Patient 1 conceived naturally twice, and patient 2 conceived with the use of clomiphene citrate for ovulation induction. These two patients maintained the pregnancies without progesterone replacement therapy and successfully delivered children. CONCLUSION: Patients with nonclassic LCAH maintain ovarian function, which enables normal pubertal development and a successful pregnancy outcome without progesterone replacement therapy.

A Familial Case of a Whole Germline CDC73 Deletion Discordant for Primary Hyperparathyroidism.

INTRODUCTION: Primary hyperparathyroidism (PHPT) occurs as part of familial syndromes, including CDC73-related disorders caused by germline pathogenic variants of the CDC73 gene, particularly in early adulthood. Herein, we report a familial case of a whole germline CDC73 deletion discordant for PHPT. CASE DESCRIPTION: A 15-year-old boy was admitted to our hospital because of persistent nausea and vomiting. Laboratory tests showed hypercalcemia (13.6 mg/dL), hypophosphatemia (2.4 mg/dL), and elevated intact PTH level (149 pg/mL). Imaging studies showed an enlarged single parathyroid gland. Thus, the diagnosis of PHPT was made. Microarray analysis of peripheral blood DNA showed a 3.4-Mb heterozygous deletion of 1q31 encompassing 11 genes, including CDC73. Total thyroidectomy/parathyroidectomy was performed; histology was compatible with parathyroid adenoma without any evidence of malignancy. DNA sequencing of the removed adenoma confirmed a hemizygous nonsense variant in the CDC73 gene in a mosaic manner, which was potentially involved in parathyroid tumorigenesis as the "second hit." Importantly, the same deletion was identified in his 52-year-old father who had an unremarkable medical history. CONCLUSIONS: These data clearly demonstrate the Knudson two-hit theory from a molecular viewpoint. Phenotypic variability and incomplete penetrance of CDC73-related disorders, even if caused by a gross deletion, should be noted in a clinical setting.