In Japan, anabolic steroid hormone (ASH) treatment for Turner syndrome (TS) to promote growth had been provided before GH therapy for TS was approved. ASH effectively improved the adult height (AH) of TS patients without spontaneous puberty but decreased the AH of TS patients with spontaneous puberty. Although GH therapy for TS was approved in 1991, the approved dosage remained 0.5 IU/kg/wk for GH-deficient TS patients and improved AH by approximately 7 cm. However, AH did not reach –2 standard deviations in healthy girls. In 1999, the requirement of GH deficiency was removed and a dose of 1.0 IU/kg/wk was approved. Although an increase in AH was expected, no reports showed significant improvements in AH at a high dose of GH. GH + ASH combination therapy was reevaluated and recommended for TS patients with gonadal failure and an extremely short stature or those who respond poorly to GH therapy. Although early estrogen replacement therapy is recommended to improve psychological quality of life and prevent osteoporosis, it lowered AH even at a low dose of ethinyl estradiol (25 ng/kg/d). The initiation of ethynyl estradiol at an extremely low dose (1–5 ng/kg/d) at a relatively young age successfully improved AH.
Acromesomelic dysplasia, type Maroteaux (AMDM) is a congenital bone dysplasia characterized by disproportionate, acromesomelic shortening of the limbs and mild spondylar dysplasia. AMDM is caused by biallelic loss-of-function mutations in NPR2 encoding natriuretic peptide receptor-B. We report on a 25-yr-old Japanese woman with AMDM. Her height was 119.0 cm (–7.4 SD) and weight 35 kg (–2.3 SD). She had acromesomelic shortening of limbs and severe brachydactyly. Radiological examination showed that her metacarpals and phalanges were short and wide, and her vertebral bodies were mildly flattened. Molecular analysis revealed a novel homozygous NPR2 mutation (c.1163G>A, p.Arg388Gln). We performed in vitro functional studies using HA-tagged wild-type (WT) and Arg388Gln vectors (HA-WT-NPRB and HA-R388Q-NPRB). Cells expressing HA-R388Q-NPRB showed negligible cGMP responses to C-type natriuretic peptide (CNP) stimulation, indicating that the mutation led to severe loss-of-function. By immunofluorescence experiments under permeabilized conditions, HA-WT-NPRB was expressed on plasma membrane, while HA-R388Q-NPRB co-localized with an Endoplasmic Reticulum marker. Cells co-expressing R388Q and the WT exhibited lower responses under CNP treatment than cells co-expressing the WT and empty vectors. Thus, it was thought that R388Q caused a dominant-negative effect with a defect in cellular trafficking to the plasma membrane.
Newborn screening (NBS) can detect 21-hydroxylase deficiency (21-OHD), allowing for early treatment initiation. However, many patients present with adrenal crises or hyponatremia at their first visit. Age (in days) of hyponatremia development in infants with salt-wasting (SW)-type 21-OHD remains unclear. Therefore, we determined the earliest age of hyponatremia diagnosis in this retrospective observational study using medical records of 40 patients with classic 21-OHD in Niigata Prefecture, Japan, from April 1989 to March 2019. We determined the earliest diagnosis of hyponatremia (serum sodium levels < 130 mEq/L) and created a sodium decrease rate model to estimate hyponatremia development age. Of 23 patients with SW-type 21-OHD, 10 (43.5%) were identified during NBS; the earliest case to present with hyponatremia was at day 7. Serum sodium levels were significantly and negatively correlated with age in days, and hyponatremia was estimated to develop at 6.6 d after birth. Genotype or serum 17-hydroxyprogesterone levels were not associated with sodium decrease rate. Thus, hyponatremia development age is earlier (within 7 d) than the previously described time-point (10–14 d) in infants with SW-type 21-OHD. Efforts to reduce the time lag from obtaining results to consultation may be required in patients with high 17-hydroxyprogesterone levels on NBS.
Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome is a rare condition characterized by symptomatic ACTH deficiency and primary hypogammaglobulinemia, caused by pathogenic variants of the nuclear factor kappa-B subunit 2 (NF-κB2) gene. We report the case of a 9-yr-old boy diagnosed with common variable immunodeficiency at the age of 3, who is under monthly intravenous immunoglobulin. The patient was admitted twice to the pediatric emergency service at the age of 9 due to symptomatic hypoglycemic events. During the hypoglycemic crisis, serum cortisol was low (< 0.1 μg/dL), ACTH level was inappropriately low (4.4 ng/L) and the ACTH stimulation test failed to raise the blood cortisol level. Pituitary magnetic resonance imaging showed a hypoplastic pituitary. Other pituitary deficiencies, primary hyperinsulinism and other metabolic diseases were excluded. He started hydrocortisone replacement treatment while maintaining immunoglobulin substitution and he remains asymptomatic. Molecular analysis revealed the heterozygous nonsense pathogenic variant, c.2557C>T (Arg853Ter) in the NF-κB2 gene. Thus, symptomatic hypoglycemia in a child with primary immunodeficiency should raise the suspicion of DAVID syndrome, prompting NF-κB2 molecular analysis, to allow timely and appropriated therapy and genetic counseling.
Hypophosphatasia (HPP) is a rare skeletal disorder caused by loss-of-function mutations in Alkaline Phosphatase, Biomineralization associated (ALPL) gene that encodes tissue-nonspecific alkaline phosphatase. Odontohypophosphatasia (odonto-HPP), a mild form of HPP, is characterized only by oral manifestations including premature exfoliation of deciduous teeth. Enzyme replacement therapy (ERT) is effective in severe HPP cases; however, information about its efficacy for odonto-HPP is limited. A 2-yr-old girl was referred to our hospital for mobility of her deciduous teeth with low serum alkaline phosphatase (ALP) level of 253 U/L (reference range: 410–1,150 U/L) and high urine phosphoethanolamine level of 1,419.9 µmol/g·Cre (7–70 µmol/g·Cre). She had no history of bone fractures; however, several members of her family had low serum ALP levels with a history of pathological fractures. She had a novel heterozygous missense mutation (c.1183A>T, p.Ile395Phe) in ALPL, and therefore, was diagnosed with odonto-HPP. After she was provided ERT to prevent premature exfoliation, no tooth mobility was observed. However, two deciduous teeth exfoliated two months after starting ERT, which was possibly triggered by a bout of common cold. Starting ERT following tooth mobility might be relatively late. Previous studies on experimental mice showed that starting ERT at birth may be effective in preventing premature exfoliation of deciduous teeth.