Debilitating hip degeneration in trichothiodystrophy: Association with ERCC2/XPD mutations, osteosclerosis, osteopenia, coxa valga, contractures, and osteonecrosis.

Trichothiodystrophy (TTD) is a rare, autosomal recessive, multisystem disorder of DNA repair and transcription with developmental delay and abnormalities in brain, eye, skin, nervous, and musculoskeletal systems. We followed a cohort of 37 patients with TTD at the National Institutes of Health (NIH) from 2001 to 2019 with a median age at last observation of 12 years (range 2-36). Some children with TTD developed rapidly debilitating hip degeneration (DHD): a distinctive pattern of hip pain, inability to walk, and avascular necrosis on imaging. Ten (27%) of the 37 patients had DHD at median age 8 years (range 5-12), followed by onset of imaging findings at median age 9 years (range 5-13). All 10 had mutations in the ERCC2/XPD gene. In 7 of the 10 affected patients, DHD rapidly became bilateral. DHD was associated with coxa valga, central osteosclerosis with peripheral osteopenia of the skeleton, and contractures/tightness of the lower limbs. Except for one patient, surgical interventions were generally not effective at preventing DHD. Four patients with DHD died at a median age of 11 years (range 9-15). TTD patients with ERCC2/XPD gene mutations have a high risk of musculoskeletal abnormalities and DHD leading to poor outcomes. Monitoring by history, physical examination, imaging, and by physical medicine and rehabilitation specialists may be warranted.

Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production.

Autosomal recessive mutations in proteasome subunit ß 8 (PSMB8), which encodes the inducible proteasome subunit ß5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes ß7), PSMB9 (encodes ß1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production.

Type V OI primary osteoblasts display increased mineralization despite decreased COL1A1 expression.

CONTEXT: Patients with type V osteogenesis imperfecta (OI) are heterozygous for a dominant IFITM5 c.-14C>T mutation, which adds five residues to the N terminus of bone-restricted interferon-induced transmembrane-like protein (BRIL), a transmembrane protein expressed in osteoblasts. Type V OI skeletal findings include hyperplastic callus formation, ossification of the forearm interosseous membrane, and dense metaphyseal bands. OBJECTIVE: The objective of this study was to examine the role of osteoblasts in the active mineralization traits of type V OI and the effect of the IFITM5 mutation on type I collagen. METHODS: We identified eight patients with the IFITM5 c.-14C>T mutation. Cultured osteoblasts from type V OI patients were used to study osteoblast differentiation and mineralization. RESULTS: We verified the expression and stability of mutant IFITM5 transcripts. In differentiated type V OI primary osteoblasts in culture, the IFITM5 expression and BRIL level is comparable with control. Both early and late markers of osteoblast differentiation are increased in type V OI osteoblasts. Mineralization, assayed by alizarin red staining, was increased in type V OI osteoblasts compared with control. However, type V OI osteoblasts have significantly decreased COL1A1 transcripts in mid- to late differentiation. Type I collagen protein is concomitantly decreased, with decreased cross-linked collagen in matrix and altered appearance of fibrils deposited in culture. CONCLUSIONS: This study demonstrates that type V OI mineralization has a gain-of-function mechanism at the osteoblast level, which likely underlies the overactive tissue mineralization seen in patients. Decreased type I collagen expression, secretion, and matrix incorporation establish type V OI as a collagen-related defect.

Skeletal maturation in children with Cushing syndrome is not consistently delayed: the role of corticotropin, obesity, and steroid hormones, and the effect of surgical cure.

OBJECTIVE: To assess skeletal maturity by measuring bone age (BA) in children with Cushing syndrome (CS) before and 1-year after transsphenoidal surgery or adrenalectomy, and to correlate BA with hormone levels and other measurements. STUDY DESIGN: This case series conducted at the National Institutes of Health Clinical Center included 93 children with Cushing disease (CD) (43 females; mean age, 12.3 ± 2.9 years) and 31 children with adrenocorticotropic hormone-independent CS (AICS) (22 females, mean age 10.3 ± 4.5 years). BA was obtained before surgery and at follow-up. Outcome measures were comparison of BA in CD vs AICS and analysis of the effects of hypercortisolism, insulin excess, body mass index, and androgen excess on BA. RESULTS: Twenty-six of the 124 children (21.0%) had advanced BA, compared with the expected general population prevalence of 2.5% (P < .0001). Only 4 of 124 (3.2%) had delayed BA. The majority of children (76%) had normal BA. The average BA z-score was similar in the children with CD and those with AICS (0.6 ± 1.4 vs 0.5 ± 1.8; P = .8865). Body mass index SDS and normalized values of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androsteonedione, estradiol, and testosterone were all significantly higher in the children with advanced BA vs those with normal or delayed BA. Fifty-nine children who remained in remission from CD had follow-up BA 1.2 ± 0.3 years after transsphenoidal surgery, demonstrating decreased BA z-score (1.0 ± 1.6 vs 0.3 ± 1.4; P < .0001). CONCLUSION: Contrary to common belief, endogenous CS in children appears to be associated with normal or even advanced skeletal maturation. When present, BA advancement in CS is related to obesity, insulin resistance, and elevated adrenal androgen levels and aromatization. This finding may have significant implications for treatment decisions and final height predictions in these children.

Systemic diagnostic testing in patients with apparently isolated uveal coloboma.

PURPOSE: To investigate the frequency and types of systemic findings in patients with apparently isolated uveal coloboma. DESIGN: Cross-sectional observational study. METHODS: setting: Single-center ophthalmic genetics clinic. study population: Ninety-nine patients with uveal coloboma seen at the National Eye Institute. observational procedure: Results of audiology testing, echocardiogram, brain magnetic resonance imaging, renal ultrasound, and total spine radiographs. main outcome measure: Prevalence of abnormal findings on systemic testing. RESULTS: Uveal coloboma affected only the anterior segment in 8 patients, only the posterior segment in 23 patients, and both anterior and posterior segments in 68 patients. Best-corrected visual acuity (BCVA) of eyes with coloboma was ≥20/40 in 45% of eyes; 23% of eyes had BCVA of ≤20/400. The majority of patients (74%) had good vision (>20/60) in at least 1 eye. Ten of the 19 patients (53%) who underwent echocardiography had abnormalities, with ventral septal defects being the most prevalent. Abnormal findings were observed in 5 of 72 patients (7%) who had a renal ultrasound and in 5 of 29 patients (17%) who underwent a brain MRI. Audiology testing revealed abnormalities in 13 of 75 patients (17%), and spine radiographs showed anomalies in 10 of 77 patients (13%). Most findings required no acute intervention. CONCLUSIONS: Although some patients with coloboma had evidence of extraocular abnormalities, the majority of findings on routine clinical examination did not require acute intervention, but some warranted follow-up. Results from the systemic evaluation of patients with coloboma should be interpreted with caution and in view of their clinical context.

Ultrasound is superior to computed tomography for assessment of medullary nephrocalcinosis in hypoparathyroidism.

CONTEXT: Nephrocalcinosis is a complication of hypoparathyroidism and other metabolic disorders. Imaging modalities include ultrasonography (US) and computed tomography (CT). Few studies have compared these modalities, and standard clinical practice is not defined. OBJECTIVE: The objective of the study was to determine the preferred method for assessing nephrocalcinosis. DESIGN: The design of the study was a retrospective, blinded analysis. SETTING: The study was conducted at a clinical research center. PATIENTS: Twenty-two hypoparathyroid subjects and 7 controls participated in the study. INTERVENTIONS: Contemporaneous renal US and CT images were reviewed in triplicate by 4 blinded radiologists. Nephrocalcinosis was classified using a 0-3 scale with 0 meaning no nephrocalcinosis and 3 meaning severe nephrocalcinosis. MAIN OUTCOME MEASURES: Intraobserver, interobserver, and interdevice agreements were measured. RESULTS: Intraobserver agreement was high, with an overall weighted kappa of 0.83 for CT and 0.89 for US. Interobserver agreement was similar between modalities, with kappas of 0.74 for US and 0.70 for CT. Only moderate agreement was found between US and CT scores, with an intermodality kappa of 0.47 and 60% concordance. Of discordant pairs, 81% had higher US scores and only 19% had higher CT scores. Of nephrocalcinosis seen on US and not CT, 45%, 46%, and 9% were grades 1, 2, and 3, respectively. Overall, US scores were higher than CT with a cumulative odds ratio (95% confidence interval) of 5.97 (2.60, 13.75) (P < .01). In controls, 100% of US ratings were 0, and 95% of CT ratings were 0. CONCLUSIONS: US is superior to CT for assessment of mild to moderate nephrocalcinosis in patients with hypoparathyroidism. This finding, in combination with its low cost, lack of radiation, and portability, defines US as the preferred modality for assessment of nephrocalcinosis.

Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia.

CONTEXT: Patients with congenital adrenal hyperplasia (CAH) often suffer from long-term complications secondary to chronic glucocorticoid therapy and suboptimal treatment regimens. OBJECTIVE: The aim of the study was to describe clinical characteristics of a large cohort of pediatric and adult CAH patients. DESIGN AND SETTING: We conducted a cross-sectional study of 244 CAH patients [183 classic, 61 nonclassic (NC)] included in a Natural History Study at the National Institutes of Health. MAIN OUTCOME MEASURE(S): Outcome variables of interest were height sd score, obesity, hypertensive blood pressure (BP), insulin resistance, metabolic syndrome, bone mineral density, hirsutism (females), and testicular adrenal rest (TART). RESULTS: The majority had elevated or suppressed androgens, with varied treatment regimens. Mean adult height SD score was -1.0 ± 1.1 for classic vs. -0.4 ± 0.9 for NC patients (P = 0.015). Obesity was present in approximately one third of patients, across phenotypes. Elevated BP was more common in classic than NC patients (P ≤ 0.01); pediatric hypertensive BP was associated with suppressed plasma renin activity (P = 0.001). Insulin resistance was common in classic children (27%) and adults (38% classic, 20% NC); 18% of adults had metabolic syndrome. The majority (61%) had low vitamin D; 37% of adults had low bone mineral density. Hirsutism was common (32% classic; 59% NC women). TART was found in classic males (33% boys; 44% men). CONCLUSIONS: Poor hormonal control and adverse outcomes are common in CAH, necessitating new treatments. Routine monitoring of classic children should include measuring BP and plasma renin activity. Osteoporosis prophylaxis and TART screening should begin during childhood. A longitudinal study is under way.

Cervical spine anomalies in Menkes disease: a radiologic finding potentially confused with child abuse.

BACKGROUND: Menkes disease is an X-linked recessive disorder of copper transport caused by mutations in ATP7A, a copper-transporting ATPase. Certain radiologic findings reported in this condition overlap with those caused by child abuse. However, cervical spine defects simulating cervical spine fracture, a known result of nonaccidental pediatric trauma, have not been reported previously in this illness. OBJECTIVE: To assess the frequency of cervical spine anomalies in Menkes disease after discovery of an apparent C2 posterior arch defect in a child participating in a clinical trial. MATERIALS AND METHODS: We examined cervical spine radiographs obtained in 35 children with Menkes disease enrolled in a clinical trial at the National Institutes of Health Clinical Center. RESULTS: Four of the 35 children with Menkes disease had apparent C2 posterior arch defects consistent with spondylolysis or incomplete/delayed ossification. CONCLUSION: Defects in C2 were found in 11% of infants and young children with Menkes disease. Discovery of cervical spine defects expands the spectrum of radiologic findings associated with this condition. As with other skeletal abnormalities, this feature simulates nonaccidental trauma. In the context of Menkes disease, suspicions of child abuse should be considered cautiously and tempered by these findings to avoid unwarranted accusations.

Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes.

OBJECTIVE: Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID) reduces systemic and organ-specific inflammation. However, the impact of long-term treatment has not been established. This study was undertaken to evaluate the long-term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID. METHODS: We conducted a cohort study of 26 NOMID patients ages 0.80-42.17 years who were followed up at the NIH and treated with anakinra 1-5 mg/kg/day for at least 36 months. Disease activity was assessed using daily diaries, questionnaires, and C-reactive protein level. Central nervous system (CNS) inflammation, hearing, vision, and safety were evaluated. RESULTS: Sustained improvements in diary scores, parent's/patient's and physician's global scores of disease activity, parent's/patient's pain scores, and inflammatory markers were observed (all P<0.001 at 36 and 60 months). At 36 and 60 months, CNS inflammation was suppressed, with decreased cerebrospinal fluid white blood cell counts (P=0.0026 and P=0.0076, respectively), albumin levels, and opening pressures (P=0.0012 and P<0.001, respectively). Most patients showed stable or improved hearing. Cochlear enhancement on magnetic resonance imaging correlated with continued hearing loss. Visual acuity and peripheral vision were stable. Low optic nerve size correlated with poor visual field. Bony lesions progressed. Adverse events other than viral infections were rare, and all patients continued to receive the medication. CONCLUSION: These findings indicate that anakinra provides sustained efficacy in the treatment of NOMID for up to 5 years, with the requirement of dose escalation. Damage progression in the CNS, ear, and eye, but not bone, is preventable. Anakinra is well tolerated overall.

Feasibility of simultaneous computed tomographic colonography and fully automated bone mineral densitometry in a single examination.

PURPOSE: To show the feasibility of calculating the bone mineral density (BMD) from computed tomographic colonography (CTC) scans using fully automated software. MATERIALS AND METHODS: Automated BMD measurement software was developed that measures the BMD of the first and second lumbar vertebrae on computed tomography and calculates the mean of the 2 values to provide a per patient BMD estimate. The software was validated in a reference population of 17 consecutive women who underwent quantitative computed tomography and in a population of 475 women from a consecutive series of asymptomatic patients enrolled in a CTC screening trial conducted at 3 medical centers. RESULTS: The mean (SD) BMD was 133.6 (34.6) mg/mL (95% confidence interval, 130.5-136.7; n = 475). In women aged 42 to 60 years (n = 316) and 61 to 79 years (n = 159), the mean (SD) BMDs were 143.1 (33.5) and 114.7 (28.3) mg/mL, respectively (P < 0.0001). Fully automated BMD measurements were reproducible for a given patient with 95% limits of agreement of -9.79 to 8.46 mg/mL for the mean difference between paired assessments on supine and prone CTC. CONCLUSIONS: Osteoporosis screening can be performed simultaneously with screening for colorectal polyps.

Familial clustering of pulmonary nontuberculous mycobacterial disease.

BACKGROUND: Nontuberculous mycobacteria (NTM) are environmental organisms associated with pulmonary disease without person-to-person transmission. Although genetic causes of disseminated NTM infection are well characterized, genetic causes for most human susceptibility to pulmonary NTM infection have not been determined. METHODS: Family histories for relevant disease characteristics were obtained as part of an ongoing natural history study. Six families were identified in which at least two blood relatives had pulmonary NTM. A systematic review of medical records extracted data relevant to pulmonary infection and baseline demographics. Data were reconfirmed by telephone interviews. RESULTS: Familial clustering of pulmonary NTM was proven in six families. Four of the families were white, and the majority of affected individuals were women. The average age at diagnosis was 56.4 +/- 10.7 years, the average height was 167.5 +/- 8.7 cm, and the mean BMI was 22.0 +/- 2.98 kg/m(2). Scoliosis was present in 31%. Five of 12 patients had cystic fibrosis transmembrane conductance regulator gene variations, but none had classic cystic fibrosis. Infections were caused by both slow and rapid growing mycobacteria, including Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium abscessus, and Mycobacterium massiliense. Family members were typically infected with different species of NTM. CONCLUSION: We identified six familial clusters of pulmonary NTM infection, suggesting that there are genetic factors contributing to host susceptibility to pulmonary infection with NTM among some individuals with nodular bronchiectatic disease.

An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.

BACKGROUND: Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS: We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS: We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS: We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)

Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome.

RATIONALE: Pulmonary nontuberculous mycobacterial (PNTM) disease is increasing, but predisposing features have been elusive. OBJECTIVES: To prospectively determine the morphotype, immunophenotype, and cystic fibrosis transmembrane conductance regulator genotype in a large cohort with PNTM. METHODS: We prospectively enrolled 63 patients with PNTM infection, each of whom had computerized tomography, echocardiogram, pulmonary function, and flow cytometry of peripheral blood. In vitro cytokine production in response to mitogen, LPS, and cytokines was performed. Anthropometric measurements were compared with National Health and Nutrition Examination Survey (NHANES) age- and ethnicity-matched female control subjects extracted from the NHANES 2001-2002 dataset. MEASUREMENTS AND MAIN RESULTS: Patients were 59.9 (+/-9.8 yr [SD]) old, and 5.4 (+/-7.9 yr) from diagnosis to enrollment. Patients were 95% female, 91% white, and 68% lifetime nonsmokers. A total of 46 were infected with Mycobacterium avium complex, M. xenopi, or M. kansasii; 17 were infected with rapidly growing mycobacteria. Female patients were significantly taller (164.7 vs. 161.0 cm; P < 0.001) and thinner (body mass index, 21.1 vs. 28.2; P < 0.001) than matched NHANES control subjects, and thinner (body mass index, 21.1 vs. 26.8; P = 0.002) than patients with disseminated nontuberculous mycobacterial infection. A total of 51% of patients had scoliosis, 11% pectus excavatum, and 9% mitral valve prolapse, all significantly more than reference populations. Stimulated cytokine production was similar to that of healthy control subjects, including the IFN-gamma/IL-12 pathway. CD4(+), CD8(+), B, and natural killer cell numbers were normal. A total of 36% of patients had mutations in the cystic fibrosis transmembrane conductance regulator gene. CONCLUSIONS: Patients with PNTM infection are taller and leaner than control subjects, with high rates of scoliosis, pectus excavatum, mitral valve prolapse, and cystic fibrosis transmembrane conductance regulator mutations, but without recognized immune defects.

Reduced abdominal adiposity and improved glucose tolerance in growth hormone-treated girls with Turner syndrome.

BACKGROUND: Individuals with Turner syndrome (TS) are at increased risk for impaired glucose tolerance and diabetes mellitus. It is unknown whether pharmacological GH treatment commonly used to treat short stature in TS alters this risk. OBJECTIVE: Our objective was to compare adiposity and glucose tolerance in GH-treated vs. untreated girls with TS. METHODS: In a cross sectional study, GH-treated girls with TS (n = 76; age 13.6 +/- 3.7 yr) were compared to girls with TS that never received GH (n = 26; age 13.8 +/- 3.5 yr). Protocol studies took place in the NIH Clinical Research Center from 2001-2006 and included oral glucose tolerance tests, body composition analysis by dual-energy x-ray absorptiometry, and abdominal fat quantification by magnetic resonance imaging. GH was not given during testing. RESULTS: Total body fat (35 +/- 8 vs. 28 +/- 8%, P < 0.0001), sc abdominal fat (183 vs. 100 ml, P = 0.001), and intraabdominal fat (50 vs. 33 ml, P < 0.0001) were significantly greater in untreated girls. Fasting glucose and insulin were similar, but the response to oral glucose was significantly impaired in the untreated group (28 vs. 7% with impaired glucose tolerance, P = 0.006). A specific excess of visceral fat and insulin resistance was apparent only in postpubertal girls that had never received GH. GH-treated girls demonstrated lower adiposity compared with untreated girls for an average of 2 yr after discontinuation of GH. CONCLUSIONS: Abdominal adiposity is significantly lower and glucose tolerance significantly better in GH-treated vs. untreated girls with TS, suggesting that beneficial effects upon body composition and regional fat deposition outweigh transient insulin antagonism associated with GH administration.

Letrozole treatment of precocious puberty in girls with the McCune-Albright syndrome: a pilot study.

CONTEXT: Girls with McCune-Albright syndrome (MAS) and related disorders have gonadotropin-independent precocious puberty due to estrogen secretion from ovarian cysts. Their puberty does not respond to GnRH agonist therapy, and short-acting aromatase inhibitors have had limited effectiveness. OBJECTIVE: Our objective was to assess the effectiveness of the potent, third-generation aromatase inhibitor letrozole in decreasing pubertal progression in girls with MAS and to assess the response of indices of bone turnover associated with the patients' polyostotic fibrous dysplasia. DESIGN: Subjects were evaluated at baseline and every 6 months for 12-36 months while on treatment with letrozole 1.5-2.0 mg/m(2).d. SETTING: This was an open-label therapeutic trial at a single clinical center. PATIENTS: Patients included nine girls aged 3-8 yr with MAS and/or gonadotropin-independent puberty. MAIN OUTCOME MEASURES: Measures included rates of linear growth, bone age advance, mean ovarian volume, estradiol, episodes of vaginal bleeding, and levels of the indices of bone metabolism: serum osteocalcin, alkaline phosphatase, urinary hydroxyproline, pyridinoline, deoxypyridinoline, and N-telopeptides. RESULTS: Girls had decreased rates of growth (P < or = 0.01) and bone age advance (P < or = 0.004) and cessation or slowing in their rates of bleeding over 12-36 months of therapy. Mean ovarian volume, estradiol, and indices of bone metabolism fell after 6 months (P < or = 0.05) but tended to rise by 24-36 months. Uterine volumes did not change. One girl had a ruptured ovarian cyst after 2 yr of treatment. CONCLUSIONS: This preliminary study suggests that letrozole may be effective therapy in some girls with MAS and/or gonadotropin-independent precocious puberty. Possible adverse effects include ovarian enlargement and cyst formation.

Arthropathy of neonatal onset multisystem inflammatory disease (NOMID/CINCA).

BACKGROUND: Neonatal onset multisystem inflammatory disease (NOMID), an autoinflammatory disease, is characterized by fever, chronic urticarial rash, CNS manifestations, and arthropathy. Approximately 50% of patients with NOMID have de novo missense mutations in CIAS1, which is associated with modulation of the IL-1b and apoptotic pathways. Approximately 60% of NOMID patients have prominent arthropathy, most commonly involving the knees, the cause of which remains poorly understood. OBJECTIVE: To more fully describe the findings of NOMID arthropathy on MRI and radiography and to provide a better understanding of the origin of the bony lesions. MATERIALS AND METHODS: We imaged 20 patients with NOMID to further investigate NOMID-associated bony lesions. RESULTS: Bony abnormalities were seen in the knees of 11/20 patients. The knee findings included enlarged, deformed femora and patellae in all and tibiae in the majority, without evidence of synovitis. Some patients had other joint involvement. Most had short stature and valgus or varus knee deformities. No association was noted between bony abnormalities and CIAS1 mutations. The abnormalities appeared to be the result of a mass-producing process. The resulting heterogeneously calcified masses appeared to originate in the physis and deformed the adjacent metaphysis and epiphysis. CONCLUSION: These findings suggest that the arthropathy of NOMID is the result of abnormal endochondral bone growth. Further investigation is needed to determine whether this deformity is triggered by inflammation early in development or by CIAS1 mutations causing abnormal chondrocyte apoptosis.

Effects of child- and adolescent-onset endogenous Cushing syndrome on bone mass, body composition, and growth: a 7-year prospective study into young adulthood.

UNLABELLED: The long-term effects on bone and fat mass in children with endogenous CS are unknown. In 14 children followed for 3-7 years into young adulthood after cure of CS, whereas bone mass largely recovered, persisting increases in total body and visceral fat suggests an increase risk of the metabolic syndrome. INTRODUCTION: Endogenous Cushing syndrome (CS) is associated with decreased bone mass and increased central fat mass. Whereas bone mass seems to improve after successful treatment, little is known about whether central fat persists. MATERIALS AND METHODS: This was a prospective study of 14 children (10 girls and 4 boys) and adolescents with CS who were successfully treated and remained eucortisolemic. Growth, puberty, bone mass, and body composition were evaluated at baseline and during regular follow-up for 3 years and in seven children for a further 4 years of remission to assess final adult height (FH), BMI, bone mass, and body composition. RESULTS: CS compromised growth, leading to about a -0.8 SD loss of FH and 0.9 SD increase in weight and BMI. BMD apparent density (BMAD) SD Score (SDS) at the lumbar spine (LS) at diagnosis were -1.8 and -1.25, respectively, and after 3 years of follow-up approached the mean with no further increase apparent up to 7 years of follow-up. Whereas hip BMD SDS increased from -1.3 at diagnosis to -0.40 at 3 years and 0 at 7 years of follow-up, femoral neck BMAD remained at or around 0 SDS at diagnosis and during follow-up. BMI was >25 kg/m(2) in five of seven adult subjects, most of whom were women. Total body fat and the ratio of visceral to subcutaneous was abnormally high in the majority of these subjects, whereas LS volumetric BMD was -0.7 SDS. CONCLUSIONS: Despite remission of CS, children and adolescents have significant alterations in body composition that result in a small but significant decrease in bone mass and increase in visceral adiposity. Although bone mass largely recovers after endogenous CS, changes in total and visceral fat suggest these subjects are at increased risk of the metabolic syndrome. Therefore, long-term monitoring of body fat and bone mass is mandatory after treatment of CS.

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition.

BACKGROUND: Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation. METHODS: We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare. RESULTS: All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events. CONCLUSIONS: Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. (ClinicalTrials.gov number, NCT00069329 [ClinicalTrials.gov].).