Hyperammonemia in a girl who inherited a likely pathogenic variant of the ornithine transcarbamylase gene from her asymptomatic father-A peculiar pattern of X-linked recessive inheritance.

A three-year-old Chinese girl presented with hyperammonemia was diagnosed biochemically and genetically (heterozygous for a novel likely pathogenic missense variant c.476T>A) as having ornithine transcarbamylase (OTC) deficiency, a rare X-linked recessive urea cycle disorders. Extensive family genetic screening eventually revealed paternal gonadosomatic mosaicism.

Denosumab versus alendronate in long-term glucocorticoid users: A 12-month randomized controlled trial.

OBJECTIVES: To compare the efficacy of denosumab and alendronate on raising spine bone mineral density (BMD) in long-term glucocorticoid (GC) users. METHODS: Adult patients receiving long-term prednisolone (≥2.5 mg/day for ≥1 year) were recruited and randomized to either subcutaneous denosumab (60 mg/6 months) or oral alendronate (70 mg/week). BMD (lumbar spine, femoral neck, hip) and bone markers (serum P1NP and CTX) were measured at month 0, 6 and 12. The difference in spine BMD (primary outcome) at month 12 was compared between the two groups. RESULTS: 139 subjects were recruited (age 50.0 ± 12.7 years; 96% women): 69 assigned denosumab and 70 assigned alendronate. At entry, 73(53%) patients were osteoporotic and 82(59%) patients were naive to the bisphosphonates. Baseline clinical characteristics and BMD values were similar in the two groups. At month 12, a significant gain in mean BMD at the lumbar spine (+3.5 ± 2.5%; p<0.001), hip (+0.9 ± 2.8%; p=0.01) and femoral neck (+1.04 ± 4.1%; p=0.047); was observed in denosumab-treated patients, whereas the corresponding change was +2.5 ± 2.9% (p<0.001), +1.6 ± 2.7% (p<0.001) and + 1.5 ± 3.9% (p=0.002) in the alendronate group. The spine, but not the hip or femoral neck, BMD at month 12 was significantly higher in the denosumab than alendronate group after adjustment for baseline BMD values, age, sex, osteoporosis risk factors and the cumulative prednisolone doses received in one year. The drop in P1NP and CTX was significantly higher in the denosumab than alendronate group. Frequency of adverse events (AEs), including infections, was similar in the two treatment arms. Seven patients withdrew from the study but not related to AEs. CONCLUSIONS: In patients receiving long-term GCs, denosumab is superior to alendronate in raising the spine BMD after 12 months. Both drugs are well-tolerated.

Nephrogenic syndrome of inappropriate antidiuresis - An ethnically, genetically and phenotypically diverse disorder: First report in a Chinese adult and review of published cases.

BACKGROUND: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare inherited disorder characterised by hyponatraemia. To date, most reported cases are Caucasians with gain-of-function variants in AVPR2, an X-linked gene which encodes the vasopressin V2 receptor (V2R). Recently, germline gain-of-function variants in the stimulatory G protein α-subunit (Gsα) were reported to cause dominantly inherited NSIAD. CASE REPORT: We report the first Chinese adult diagnosed with NSIAD. He was found to be hemizygous for R137C-V2R, the most prevalent pathogenic variant among Caucasians. After the genetic diagnosis and counselling on the importance of fluid restriction, he had no recurrence of hyponatraemia to date. LITERATURE REVIEW: Case reports of NSIAD published in the English literature in PubMed were reviewed to summarise the genetic and phenotypic heterogeneity of this disorder. CONCLUSION: NSIAD is ethnically, genetically and phenotypically diverse. The diagnosis should especially be considered in young patients with otherwise unexplained hyponatraemia. Target analysis of R137C-V2R should make the diagnosis in most cases. Genetic testing could confirm the diagnosis, motivate adherence to treatment, offer the possibility of genotype-guided therapy, and allow cascade screening to prevent hyponatraemia.

Case Report: The first familial hCG syndrome in a Chinese family.

Familial hCG syndrome is a rare and benign cause of elevated serum beta human chorionic gonadotropin (hCG). We present here a case of familial hCG syndrome diagnosed in a Hong Kong Chinese family, which we believe to be the first reported in Chinese. A 38-year-old woman presented with incidental finding of persistently elevated hCG, analytically confirmed both in urine and blood. Extensive radiological and biochemical work-up were performed but were negative for pregnancy and malignancy. Testing of another asymptomatic family member revealed unexplained elevation of serum hCG, confirming the diagnosis of familial hCG syndrome. Knowledge and awareness of this entity among clinicians are important to avoid unnecessary investigations and treatment in affected families.

Isolated 17,20-Lyase Deficiency in a CYB5A Mutated Female With Normal Sexual Development and Fertility.

Isolated 17,20-lyase deficiency may be caused by mutations in the CYP17A1 (coding for cytochrome P450c17), POR (coding for cytochrome P450 oxidoreductase) and CYB5A (coding for microsomal cytochrome b5) genes. Of these, mutations in the CYB5A gene have thus far only been described in genetic males who presented with methemoglobinemia and 46,XY disorders of sex development (DSD) due to 17,20-lyase deficiency. A 24-year-old Chinese woman presented to the hematology outpatient clinic with purplish discoloration of fingers, toes, and lips since childhood. Investigations confirmed methemoglobinemia. A homozygous c.105C>G (p.Tyr35Ter) nonsense mutation was detected in the CYB5A gene. Hormonal studies showed isolated 17,20-lyase deficiency. Interestingly, she had a completely normal female phenotype with no DSD, normal pubertal development, and spontaneous pregnancy giving birth uneventfully to a healthy female infant. The sex hormone-related features of genetic females with 17,20-lyase deficiency due to cytochrome b5 gene mutation appear to differ from that of females with 17,20-lyase deficiency caused by other genetic defects who presented with hypergonadotropic hypogonadism and infertility and differ from genetic males with the same mutation.

Contiguous gene deletion in a Chinese family with X-linked nephrogenic diabetes insipidus: challenges in early diagnosis and implications for affected families.

Nephrogenic diabetes insipidus (NDI) is a rare disorder of the renal collecting tubules, characterized by an inability to concentrate urine due to an impaired response to arginine vasopressin (AVP), resulting in dilute urine and polyuria. Causes of NDI are heterogeneous and diagnosing congenital NDI (cNDI) in young infants is clinically challenging, as typical symptoms are often unappreciated or inconspicuous. Instead, young infants may present with non-specific signs such as vomiting, poor feeding, failure to thrive, unexplained fevers, irritability, constipation or diarrhea. We report a 37-day-old infant who presented with polyuria and severe hypernatremic dehydration that was unresponsive to vasopressin. The patient was treated with amiloride, indomethacin and hydrochlorothiazide. Genetic analysis revealed a novel contiguous deletion involving the entire AVPR2 gene and the last exon of the adjacent ARHGAP4 gene. A study of the family confirmed the carrier status in the mother. This case illustrates the importance of molecular testing in confirming the diagnosis in the index patient, as well as in identifying asymptomatic at-risk female carriers so that appropriate genetic counselling can be given for reproductive planning. All pediatric patients with suspected cNDI should undergo genetic analysis for a definitive diagnosis.