DLG2 variants in patients with pubertal disorders.

PURPOSE: Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions. METHODS: Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH. RESULTS: We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH. CONCLUSION: The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.

Plasma midkine concentrations in healthy children, children with increased and decreased adiposity, and children with short stature.

BACKGROUND: Midkine (MDK), one of the heparin-binding growth factors, is highly expressed in multiple organs during embryogenesis. Plasma concentrations have been reported to be elevated in patients with a variety of malignancies, in adults with obesity, and in children with short stature, diabetes, and obesity. However, the concentrations in healthy children and their relationships to age, nutrition, and linear growth have not been well studied. SUBJECTS AND METHODS: Plasma MDK was measured by immunoassay in 222 healthy, normal-weight children (age 0-18 yrs, 101 boys), 206 healthy adults (age 18-91 yrs, 60 males), 61 children with BMI ≥ 95th percentile (age 4-18 yrs, 20 boys), 20 girls and young women with anorexia nervosa (age 14-23 yrs), and 75 children with idiopathic short stature (age 3-18 yrs, 42 boys). Body fat was evaluated by dual-energy X-ray absorptiometry (DXA) in a subset of subjects. The associations of MDK with age, sex, adiposity, race/ethnicity and stature were evaluated. RESULTS: In healthy children, plasma MDK concentrations declined with age (r = -0.54, P < 0.001) with values highest in infants. The decline occurred primarily during the first year of life. Plasma MDK did not significantly differ between males and females or between race/ethnic groups. MDK concentrations were not correlated with BMI SDS, fat mass (kg) or percent total body fat, and no difference in MDK was found between children with anorexia nervosa, healthy weight and obesity. For children with idiopathic short stature, MDK concentrations did not differ significantly from normal height subjects, or according to height SDS or IGF-1 SDS. CONCLUSIONS: In healthy children, plasma MDK concentrations declined with age and were not significantly associated with sex, adiposity, or stature-for-age. These findings provide useful reference data for studies of plasma MDK in children with malignancies and other pathological conditions.

Unique Variant of NOD2 Pediatric Granulomatous Arthritis With Severe 1,25-Dihydroxyvitamin D-Mediated Hypercalcemia and Generalized Osteosclerosis.

Pediatric granulomatous arthritis (PGA) refers to two formerly separate entities: autosomal dominant Blau syndrome (BS) and its sporadic phenocopy early-onset sarcoidosis (EOS). In 2001 BS and in 2005 EOS became explained by heterozygous mutations within the gene that encodes nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also called caspase recruitment domain-containing protein 15 (CARD15). NOD2 is a microbe sensor in leukocyte cytosol that activates and regulates inflammation. PGA is characterized by a triad of autoinflammatory problems (dermatitis, uveitis, and arthritis) in early childhood, which suggests the causal NOD2/CARD15 mutations are activating defects. Additional complications of PGA were recognized especially when NOD2 mutation analysis became generally available. However, in PGA, hypercalcemia is only briefly mentioned, and generalized osteosclerosis is not reported, although NOD2 regulates NF-κB signaling essential for osteoclastogenesis and osteoclast function. Herein, we report a 4-year-old girl with PGA uniquely complicated by severe 1,25(OH)2 D-mediated hypercalcemia, nephrocalcinosis, and compromised renal function together with radiological and histopathological features of osteopetrosis (OPT). The classic triad of PGA complications was absent, although joint pain and an antalgic gait accompanied wrist, knee, and ankle swelling and soft non-tender masses over her hands, knees, and feet. MRI revealed tenosynovitis in her hands and suprapatellar effusions. Synovial biopsy demonstrated reactive synovitis without granulomas. Spontaneous resolution of metaphyseal osteosclerosis occurred while biochemical markers indicated active bone turnover. Anti-inflammatory medications suppressed circulating 1,25(OH)2 D, corrected the hypercalcemia, and improved her renal function, joint pain and swelling, and gait. Mutation analysis excluded idiopathic infantile hypercalcemia, type 1, and known forms of OPT, and identified a heterozygous germline missense mutation in NOD2 common in PGA (c.1001G>A, p.Arg334Gln). Thus, radiological and histological findings of OPT and severe hypercalcemia from apparent extrarenal production of 1,25(OH)2 D can complicate NOD2-associated PGA. Although the skeletal findings seem inconsequential, treatment of the hypercalcemia is crucial to protect the kidneys. © 2018 American Society for Bone and Mineral Research.

Catastrophic injuries in pole vaulters: a prospective 9-year follow-up study.

BACKGROUND: A prior review of catastrophic pole vaulting injuries from 1982 through 1998 revealed an average of 2.0 injuries per year, with 69% (1.38 per year) of the injuries secondary to athletes landing off the sides or back of the landing pad and 25% (0.5 per year) from athletes landing in the vault box. In 2003, several rule changes for the sport of pole vaulting were mandated, including enlarging the minimum dimensions of the landing pad. HYPOTHESIS/PURPOSE: Our goals were to (1) identify the post-2003 rule change incidence and profile of catastrophic pole vaulting injuries through 2011 and compare them, where possible, with the prior incidence and profile and (2) determine, via a questionnaire, the frequency with which pole vaulters land in the vault box. We hypothesized that the new, larger landing pads would reduce the number of catastrophic injuries. STUDY DESIGN: Descriptive epidemiology study. METHODS: We prospectively reviewed all catastrophic pole vaulting injuries (ie, brain hemorrhage; skull, spine, or pelvic fracture; substantial pulmonary or intra-abdominal injury) in the United States from 2003 through 2011, surveyed 3335 pole vaulters to determine the frequency of landing in the vault box, and compared results with those in the literature. RESULTS: From 2003 to 2011, 19 catastrophic injuries occurred (average of 2.1 per year), with the majority (n = 14, 74%, 1.55 per year) landing in or around the vault box. Four (21%, 0.44 per year) injuries occurred when an athlete landed off the sides or back of the landing pad and 1 (5%) when the pole broke. There were 11 (58%) major head injuries (1 fatality), 4 (21%) spine fractures (1 with paraplegia), 2 (11%) pelvic fractures (both with intra-abdominal injuries), 1 (5%) brain stem injury (fatal), and 1 (5%) thoracic injury (rib fractures and pneumothorax). The annual fatality rate fell from 1.0 in the prior study to 0.22 in the current study. According to the pole vaulters survey, during their careers, 77.12% (n = 2572) landed in the vault box 1 to 3 times, 15.92% (n = 531) never landed in the vault box, 6.12% (n = 204) landed in the vault box 4 to 6 times, and 0.84% (n = 28) landed in the vault box 7 or more times. CONCLUSION: The 2003 rule changes have markedly reduced the number of catastrophic injuries, especially fatalities, from pole vaulters missing the back or sides of the landing pads; however, the average annual rate of catastrophic injuries from pole vaulters landing in the vault box has more than tripled over the past decade and remains a major problem.