Radiological Features in Patients with Short Stature Homeobox-Containing (SHOX) Gene Deficiency and Turner Syndrome before and after 2 Years of GH Treatment.

BACKGROUND/AIMS: The short stature homeobox-containing (SHOX) gene is one of many genes that regulate longitudinal growth. The SHOX deficiency (SHOX-D) phenotype, caused by intragenic or regulatory region defects, ranges from normal stature to mesomelic skeletal dysplasia. We investigated differences in radiological anomalies between patients with SHOX-D and Turner syndrome (TS) and the effect of 2 years of growth hormone (GH) treatment on these anomalies. METHODS: Left hand/wrist, forearm and lower leg radiographs were assessed at baseline and after 2 years in children with genetically confirmed SHOX-D (GH-treated and untreated groups) and TS (GH-treated) in a randomised, controlled, multinational study. RESULTS: Radiological anomalies of hand, wrist and forearm were common in SHOX-D and TS. Radial bowing appeared more prevalent in SHOX-D, while lower leg anomalies were more common in TS. There were no significant differences in radiological findings between GH-treated and untreated patients with SHOX-D after 2 years. CONCLUSION: GH treatment had no systematic effect on skeletal findings in SHOX-D, based on limited radiological differences between the GH-treated and untreated groups at 2 years. Bone age radiographs allow assessment of radiological signs indicating a potential diagnosis of SHOX-D and may lead to earlier genetic confirmation and initiation of GH therapy.

A pilot study of growth hormone administration in boys with predicted adult short stature and near-ending growth.

CONTEXT: The growth-promoting effect of starting recombinant human growth hormone (rhGH) at the time of near-ending growth has not been studied in sexually mature boys who will have idiopathic short stature (ISS) as adults because it is believed that such an advanced stage of puberty would preclude favorable results. OBJECTIVES: 1) To explore the effects of starting rhGH administration at time of near-ending growth in boys with ISS. 2) To search for predictors of response to rhGH. SUBJECTS: Fifteen boys aged 15.5 ± 1 years terminating puberty were growing at a rate < 2 cm/6 months towards a predicted adult height (PAH) <-2.5 SDS. METHODS: Participants received 0.50 ± 0.06 mg/kg · wk of rhGH according to a target-to-treat protocol. When growth became less than 0.5 cm in 3 months or when height has reached 169 cm, rhGH was ceased. Testosterone, growth velocity (GV), height, serum IGF-1, bone age (BA) at hand-wrist and knee score were measured at onset; IGF-1 and height were monitored every 3 months. A formula for PAH was developed. Height increment (HI, adult height-starting height) and height gain (HG, adult height-PAH) were calculated. RESULTS: Following rhGH administration for 11.1 ± 4.8 months, GV-SDS increased from -2.5 ± 1.7 to 3.5 ± 4.3 (P = 2 × 10(-4)), HI = 8.5 ± 3.7 cm, HG = 6.8 ± 4.8 cm and adult height was -1.8 ± 0.9 SDS, compared to a PAH of -2.9 ± 0.6 SDS (P = 4 × 10(-4)). Knee score (P = 2 × 10(-3)), GV at rhGH onset (P = 8 × 10(-3)) and rhGH dose (P = 8 × 10(-3)) were identified as predictors of HI and HG, but BA was not. CONCLUSIONS: Our study suggests that 1) a short period of rhGH administration can increase true adult height significantly in boys with ISS at time of near-ending growth; and 2) knee score rather than BA should be used to identify rhGH responders. These preliminary observations await confirmation by larger randomized trials.

GH treatment to final height produces similar height gains in patients with SHOX deficiency and Turner syndrome: results of a multicenter trial.

CONTEXT: Growth impairment in short stature homeobox-containing gene (SHOX) deficiency and Turner syndrome share a similar etiology. Because of the established effect of GH treatment on height in patients with Turner syndrome, we hypothesized that GH therapy would also stimulate growth in patients with SHOX deficiency. OBJECTIVE: Our objectives were to evaluate long-term efficacy of GH treatment in short patients with SHOX deficiency and to compare the effect on final (adult) height (FH) in patients with SHOX deficiency and Turner syndrome. DESIGN AND SETTING: A prospective, multinational, open-label, randomized 3-arm study consisting of a 2-year control period and a subsequent extension period to FH. The treatment groups were 1) SHOX-D-C/GH (untreated during the control period, GH-treated during the extension), 2) SHOX-D-GH/GH, and 3) Turner-GH/GH (GH-treated during both study periods). PATIENTS: Short-statured prepubertal patients with genetically confirmed SHOX deficiency (n = 49) or Turner syndrome (n = 24) who participated in the extension. INTERVENTION: Depending on the study arm, patients received a daily sc injection of 0.05 mg/kg recombinant human GH from start of the study or start of the extension until attainment of FH or study closure. RESULTS: Height SD score gain from start of GH treatment to FH was similar between the combined SHOX-deficient groups (n = 28, 1.34 ± 0.18 [least-squares mean ± SE]) and the Turner group (n = 19, 1.32 ± 0.22). In this FH population, 57% of the patients with SHOX deficiency and 32% of the patients with Turner syndrome achieved a FH greater than -2 SD score. CONCLUSIONS: GH treatment in short children with SHOX deficiency showed similar long-term efficacy as seen in girls with Turner syndrome.

Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium.

AIM: To explore imatinib efficacy and pharmacokinetics in children and adolescents with refractory/relapsing solid tumours, expressing imatinib-sensitive receptor tyrosine kinases. METHODS: Exploratory study on imatinib in tumours expressing, at least, one of the receptors KIT or platelet-derived growth factor receptor (PDGFR). Standard radiological response evaluation, pharmacokinetics, gene mutations and positron emission tomography imaging were assessed. RESULTS: Thirty-six patients (median age: 13.7 years) with brain (12), mesenchymal/bone (14) or other solid tumours, received imatinib 340 mg/m(2)/d over a total of 255 months. Fifteen tumours expressed KIT in 30% cells, 19 expressed PDGFRA and 25 expressed PDGFRB. Twenty patients experienced grades 1-2 treatment-related toxicities. Ten patients achieved stable disease; one chordoma had metabolic response. Pharmacokinetic data showed high inter-patient variability (variation coefficient: 44% and 53% for plasma imatinib and CGP 74588 AUCs, respectively). CONCLUSIONS: Imatinib was tolerated well, but failed to show efficacy according to standard criteria in paediatric malignancies expressing KIT or PDGFR.

External and internal geometry of European adults.

The primary objective of the study was to bring a deeper knowledge of the human anthropometry, investigating the external and internal body geometry of small women, mid-sized men and tall men. Sixty-four healthy European adults were recruited. External measurements were performed using classical anthropometric instruments. Internal measurements of the trunk bones were performed using a stereo-radiographic 3D reconstruction technique. Besides the original procedure presented in this paper for performing in vivo geometrical data acquisition on numerous volunteers, this study provides an extensive description of both external and internal (trunk skeleton) human body geometry for three morphotypes. Moreover, this study proposes a global external and internal geometrical description of 5th female 50th male and 95th male percentile subjects. This study resulted in a unique geometrical database enabling improvement for numerical models of the human body for crash test simulation and offering numerous possibilities in the anthropometry field.

Cumulative effective doses delivered by radiographs to preterm infants in a neonatal intensive care unit.

OBJECTIVE: We sought to determine the number and distribution of radiographs and the cumulative effective radiograph doses (cED) received by a population of preterm infants (PIs) hospitalized in an NICU. STUDY DESIGN: We reviewed the files of all preterm infants (gestational age: <34 weeks) who were admitted to an NICU during an 18-month period and were discharged alive. A generalized additive model was used to study the relationship between cED and patient characteristics. RESULTS: Four hundred fifty files were analyzed. The median gestational age was 30.1 weeks (range: 24.1-33.9 weeks), and the median birth weight was 1250 g (range: 520-2760 g). The median number of radiographs per infant was 10.6 (range: 0-95), and the median cED was 138 microSv (range: 0-1450 microSv). The cumulative dose exceeded 500 microSv in 7.6% of the cases. Factors that influenced the cumulative effective dose were gestational age, birth weight, care procedures, and clinical adverse events. CONCLUSIONS: Given the potentially life-threatening complications of PIs, cumulative radiograph doses received in the ICU seem low with regard to environmental exposure and international recommendations. Additional studies are needed to evaluate the possible lifetime consequences of exposure to ionizing radiation at this age.

MRI of the olfactory bulbs and sulci in human fetuses.

BACKGROUND: There is limited knowledge of the MRI pattern of the development of fetal olfactory bulbs and sulci. OBJECTIVE: To describe the MRI appearance of olfactory bulbs and sulci in normal in vivo fetuses according to gestational age. MATERIALS AND METHODS: Olfactory bulbs and sulci were retrospectively assessed on brain MRI examinations of 88 normal fetuses between 24 and 39 weeks gestational age. Two reference centres were involved in the study and both used routine protocols that included axial and coronal T2- and T1-weighted sequences at 1.5 T. The results were compared both with the commonly used neuropathological data in the literature and with personal neuropathological data. Pearson's chi-squared test or Fisher's exact test were performed. One case of olfactory agenesis associated with CHARGE syndrome was identified. RESULTS: T2-weighted coronal sequences were the most sensitive for detecting olfactory bulbs and sulci. Olfactory sulci were significantly better detected from 30 weeks onwards (90.9-100%; P<0.001). MRI showed a posteroanterior development of these sulci. Olfactory bulbs were better detected from 30 to 34 weeks (80-90.9%; P<0.002). Comparison with neuropathological data confirmed the posteroanterior development of the sulci and showed an important delay in detection of the olfactory structures (bulbs and sulci). No difference was observed between the two centres involved. CONCLUSIONS: To date, fetal MRI can depict olfactory sulci from 30 weeks gestational age onwards and olfactory bulbs from 30 to 34 weeks gestational age. This preliminary reference standard is useful to assess the normality of the olfactory system and to diagnose olfactory agenesis.

[A new 2D and 3D imaging approach to musculoskeletal physiology and pathology with low-dose radiation and the standing position: the EOS system]. / Une nouvelle imagerie ostéo-articulaire basse dose en position debout: le systeme EOS.

Close collaboration between multidisciplinary specialists (physicists, biomecanical engineers, medical radiologists and pediatric orthopedic surgeons) has led to the development of a new low-dose radiation device named EOS. EOS has three main advantages: The use of a gaseous X-ray detector, invented by Georges Charpak (Nobel Prizewinner 1992), the dose necessary to obtain a 2D image of the skeletal system has been reduced by 8 to 10 times, while that required to obtain a 3D reconstruction from CT slices has fallen by a factor of 800 to 1000. The accuracy of the 3D reconstruction obtained with EOS is as good as that obtained with CT. The patient is examined in the standing (or seated) position, and is scanned simultaneously from head to feet, both frontally and laterally. This is a major advantage over conventional CT which requires the patient to be placed horizontally. -The 3D reconstructions of each element of the osteo-articular system are as precise as those obtained by conventional CT. EOS is also rapid, taking only 15 to 30 minutes to image the entire spine.

Unexplained mental retardation: is brain MRI useful?

BACKGROUND: Mental retardation (MR), defined as an IQ below 70, is a frequent cause of consultation in paediatrics. OBJECTIVE: To evaluate the yield of brain MRI in the diagnostic work-up of unexplained MR in children. PATIENTS AND METHODS: The MRI features and clinical data of 100 patients (age 1-18 years) affected with non-progressive MR of unknown origin were compared to an age-matched control group (n=100). Two radiologists conducted an independent review of the MRI scans. RESULTS: Univariate and multivariate analyses showed a higher incidence of brain anomalies in the MR group than in the control group (53 vs 17, OR=5.7 [2.9-11.1]), for signal abnormalities within the periventricular white matter (OR=20.3 [2.6-155.3]), lateral ventricular dilatation (OR=15.6 [2.0-124]), mild corpus callosum abnormalities (shortness, atrophy) (OR=6.8 [1.8-25.6]) and subtle cerebellar abnormalities, including fissure enlargement (OR=5.2 [1.1-26.2]). The diagnostic value of MRI abnormalities was considered good in 5% of patients (Alexander disease n=1, diffuse cortical malformation n=1, leukomalacia n=1, vermian agenesis n=1, commissural agenesis n=1), and weak in 48% of patients, in whom non-specific abnormalities did not lead to a diagnosis. Some clinical features resulted in a significantly higher percentage of abnormal MRI scans: abnormal neurological examination (82% vs 47%, P=0.008), abnormal skull circumference (66% vs 49%, P=0.04). Motor delay was associated with cerebellar abnormalities (P=0.01). CONCLUSIONS: This study confirms the weak diagnostic yield of MRI in mentally retarded children. The use of a control group has enabled us to identify the neuroimaging markers frequently associated with MR. Subgrouping patients according to neuroimaging markers and clinical signs should help identify those who would benefit from molecular studies.

Does asymptomatic septal agenesis exist? A review of 34 cases.

BACKGROUND: Primary septal agenesis (PSA) is a rare brain malformation that can be isolated or part of developmental brain abnormalities (holoprosencephaly, septo-optic dysplasia or cortical malformation). Such associated malformation can be subtle, leading to difficulties in the prenatal management of PSA. Moreover, the neurological prognosis of isolated PSA remains debatable. OBJECTIVE: The aims of the study were to specify the patterns and frequency of brain malformations associated with septal agenesis (SA), to identify the clinical prognosis, and to discuss the aetiology of PSA with the new insights provided by molecular genetics. MATERIALS AND METHODS: The study consisted of a 14-year retrospective review of brain MRI in 34 patients having PSA (mean age, 5 years). Chiasm and optic nerves were not evaluated. Post-hydrocephalus SA or incomplete data were excluded. The clinical data were correlated to the MRI patterns. RESULTS: The study disclosed 82.5% associated lesions with MRI (28/34): 11 neuronal migration disorders, 9 holoprosencephalies (HP), 7 pituitary stalk interruptions, 1 corpus callosum partial agenesis; 17.5% (6/34) of cases were apparently isolated PAS. Clinically, the patients had motor dysfunction in 68% (23/34), mental retardation in 65% (22/34), blindness in 24% (8/34), endocrinological defects in 21% (7/34) and epilepsy in 18% (6/34) of cases. Nine percent of patients (3/34) were neurologically normal (including one with scoliosis and two infants younger than 2 years at the last follow-up). Patients with bilateral cortical anomalies and HP (even if mild) had the worst neurological prognosis. A severe motor impairment was present without evidence of hemispheric anomaly in 12% of patients (4/34). Interestingly, the frontal lobes were involved in 90% of cortical anomalies and HP, supporting the malformative aetiology of PSA. CONCLUSIONS: PSA rarely appears isolated and severe psychomotor impairment may occur in apparently isolated forms. These unfavourable results should be highlighted and need to be confirmed by a prospective study.

Exclusion of the dymeclin and PAPSS2 genes in a novel form of spondyloepimetaphyseal dysplasia and mental retardation.

Spondyloepimetaphyseal dysplasias (SEMD) represent a heterogeneous group of conditions composed of at least 15 well-defined entities. The classification is based on clinical, radiological and molecular findings. Among them, several conditions also include a mental retardation (MR) syndrome, namely Wolcott-Rallison syndrome, Dyggve-Melchior-Clausen syndrome (DMC) and lysosomal storage disorders. Here, we report on a novel form of SEMD with MR in two Pakistani sisters born to first-cousin parents. SEMD, MR, microcephaly, ataxia, facial dysmorphism and hirsutism of back and legs were noted in the two children. Skeletal findings included flat vertebral bodies with irregular vertebral plates, irregular and flared metaphyses with vertical striations, small and irregular epiphyses, small carpal bones and narrow iliac wings without lacy pelvis iliac crest. Similarities with DMC prompted us to test and eventually exclude the DMC gene, dymeclin, by direct sequencing. Similarly, we excluded the PAPSS2 gene (3'-alpha phosphoadenosine 5'-phosphosulphate synthase 2) responsible for SEMD Pakistani type. The combination of features observed in the two sisters does not fit with any previously reported SEMD and represents therefore a novel form of autosomal recessive SEMD with MR.

Aortic dilatation in Turner syndrome: the role of MRI in early recognition.

BACKGROUND: Aortic dilatation and dissection are rare but important complications of Turner syndrome that increase the risk of sudden death in young patients. OBJECTIVE: To assess the value of aortic MRI in patients with Turner syndrome; in particular to demonstrate early aortic dilatation. MATERIALS AND METHODS: A total of 21 patients with Turner syndrome underwent MRI of the thoracic aorta with measurement of vessel diameter at four levels. RESULTS: Measurements were normal for age in 15 cases, two patients presented with values at the upper limit of normal and four had obvious dilatation of the ascending aorta. All were symptom free. CONCLUSIONS: MRI allows the non-invasive demonstration of early aortic dilatation, which may lead to earlier surgery in asymptomatic individuals.

Sedation in children undergoing CT scan or MRI: effect of time-course and tolerance of rectal chloral hydrate.

The aim of this paper was to describe the time-course of the sedative effect of rectal chloral hydrate (75 mg/kg) in children undergoing CT scan or MRI. Twenty children (2.13 +/- 1.43 years old) were administered 75 mg/kg chloral hydrate rectally (chloralhydrat-rectiole rectal formulation, Dr Mann-Pharma Lab, Berlin, Germany), before a CT scan or an NMR imaging. Sedation was measured at specific times using a sedation score of 1-6. Patients were continuously monitored for respiratory and heart rate, systolic and diastolic blood pressures, and oxygen saturation. About 82.35 and 94.11% of the patients had a score of sedation > or = 3 within 15 and 30 min, respectively. The mean time to effective sedation (score > or = 3) was of 0.30 +/- 0.14 h (median time, 0.25 h). The mean duration of effective sedation (score > or = 3) was 1.29 +/- 1.05 h (median duration, 0.75 h). A total of 93.1% of the X-ray sections were obtained without artifact and sedation was considered by radiologists to be efficient for 83.3% of the procedures. This sedation procedure appeared efficient and safe during ambulatory CT scan and NMR imaging. The long-term effect of chloral hydrate, however, remains to be evaluated.

Lacrimal location of sinus histiocytosis (Rosai-Dorfman-Destombes disease).

A 7-year-old West African male patient presented with recurrence of multiple cervical lymphadenopathy. Cervical node biopsy disclosed a sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman-Destombes disease). During follow-up, the patient developed a left orbital mass corresponding to an enlarged lacrimal gland shown by CT. The histologic features of the gland were consistent with the diagnosis, and with steroid treatment, the gland decreased in size. Although rare, the diagnosis of sinus histiocytosis with massive lymphadenopathy has to be considered in cases of lacrimal gland enlargement.

IMAGe association: additional clinical features and evidence for recessive autosomal inheritance.

Congenital adrenal hypoplasia (CAH) normally occurs in the neonatal period, with patients presenting with more or less severe salt-wasting syndrome. X-linked CAH has been associated with mutations in the DAX-1 gene, and boys have also been shown to have hypogonadotrophic hypogonadism. Recently, in three unrelated boys, CAH was associated with intrauterine growth retardation (IUGR), metaphyseal dysplasia and genital abnormalities, defining a new association called IMAGe. We now report four additional patients with this association, including the first living female. The four patients belong to two unrelated families (one brother and one sister from each family). These patients have the main clinical characteristics of IMAGe association: IUGR, facial dysmorphy (frontal bossing, broad nasal bridge, low-set ears), short limbs due to metaphyseal dysplasia, and adrenal insufficiency. As these patients are older than the initial three patients, we can also describe additional features: short adult height, normal puberty in boys as well as in the living girl. The boys have hypospadias associated with micropenis. The living girl came to clinical attention at the age of 5 years as a result of a familial survey, and careful questioning revealed that she had been suffering from mild adrenal insufficiency since early childhood. At least one boy has congenital hypotonia due to muscular dystrophy. In conclusion, these four new cases display familial transmission, strongly suggesting Mendelian autosomal recessive inheritance. Adrenal insufficiency may be mild. Hypotonia, described in all the patients, might be related to paucisymptomatic muscular dystrophy, as this condition is clearly heterogeneous varying with regard to severity, associated manifestations and outcome. If this symptom is part of the syndrome, which we cannot assume, it could help to localize the candidate gene.

Bilateral dysplasia epiphysealis hemimelica: report of two cases.

Dysplasia epiphysealis hemimelica is a rare congenital disorder characterised by unilateral bone overgrowth from large joints, mainly the ankle or knee. We present two cases with bilateral lesions; only two similar cases with bilateral involvement have been reported hitherto. The differential diagnosis is considered.

The intervertebral disk: a landmark for spinal diseases in children.

The aim of this paper is to describe the diagnostic value of the different radiological modifications of the intervertebral disk in children. Usual disk modifications include: disk-space narrowing; disk space enlargement; intervertebral disk calcifications; intervertebral disc prolapse; and signal modification in MRI. The gamuts (which are provided in the paper) of these different images must take into account the association with bone changes and the possibility of several disks' involvement. Calcifications are usually related to benign disorders.

Intralesional Ethibloc Injections in Bone Cysts.

Benign bone cysts (aneurysmal and unicameral) often require treatment to prevent pathological fractures. Percutaneous injections are less invasive than surgery. We describe the different percutaneous treatments available: local injection of steroids, calcitonin, or bone marrow in unicameral bone cysts, and Ethibloc(R)(Ethicon, Ethnor Laboratories, Nevilly Sur Seine, France) injection in both unicameral or aneurysmal bone cysts. Within the tumor, histologic modifications usually occur after these injections, due to the fibrogenic properties of the agent. Therefore, we emphasize the necessity of obtaining an histologic proof before any injection, especially in aneurysmal bone cysts.