David C. Kushner

Long-term treatment of central precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone. Effects on somatic growth and skeletal maturation

Abstract The gonadotropin-releasing hormone–like agonist d-Trp6-Pro9-NEt-LHRH (LHRHa) has been shown to induce a reversible short-term suppression of gonadotropins and gonadal steroids in patients with central precocious puberty. Since accelerated statural growth and bone maturation are clinical features of precocity not well controlled by conventional therapies, we examined the effects of prolonged LHRHa therapy for 18 consecutive months on growth and skeletal maturation in nine girls with neurogenic or idiopathic precocious puberty. Suppression of gonadotropin pulsations and gonadal steroids was maintained in all subjects. Growth velocity fell from a mean rate (±S.E.M.) of 9.35±0.64 cm per year during the 19 months before treatment to 4.58±0.60 cm per year during treatment (P<0.001). Bone age advanced a mean of 9.4 ±2.3 months during treatment. These changes resulted in a mean increase of 3.3 cm in predicted height (P<0.01). Complete suppression of the pituitary-gonadal axis can be maintained by LHRHa t...

Correlation of pulmonary signs and symptoms with chest radiographs in the pediatric age group

One hundred twenty-five pediatric emergency department patients were studied prospectively to determine whether any findings on the physical examination were predictive of abnormalities seen on chest radiograph. We attempted to find possible correlations between such clinical examination findings, recorded prior to radiographic examination, and three subgroups of radiographic findings: pneumonia, any major radiographic abnormality, and any radiographic abnormality whatsoever. The best screen for pneumonia was presence of fever (temperature greater than two standard deviations above age-related norms), with a sensitivity of 94% and a negative predictive value of 97%. The sign with highest positive and negative predictive value for the presence of any radiographic abnormalities was tachypnea. A subgroup with either normal breath sounds, or findings limited to wheezing, prolonged expiration, cough and/or rhonchi on chest examination proved to be at low risk for any major chest radiographic abnormality. Patients with other chest examination findings comprised a high-risk group with a 34% risk of a major radiographic abnormality, as compared to a 7% incidence in the low-risk group. Thus, absence of fever suggests absence of pneumonia, while chest examination findings other than wheezing, cough, prolonged expiration, or rhonchi significantly increase the likelihood of pneumonia in this population. Physical examination findings can help the clinician determine the need for chest radiography in the pediatric emergency patient.

Puberty without gonadotropins: a unique mechanism of sexual development

Recent evidence suggests that a group of children exists in whom premature sexual maturation occurs in the absence of pubertal levels of gonadotropins; that is, they have gonadotropin-independent precocious puberty. We compared six boys and one girl with this disorder with four boys and five girls with central precocious puberty, in which there is a pubertal pattern of gonadotropin release. The two groups were similar in age of onset, degree of sexual development, growth velocity, and rate of skeletal maturation. A family history of precocity was noted in four of the boys with gonadotropin-independent precocity, and the girl had McCune-Albright syndrome. Children with central precocious puberty demonstrated a pulsatile release of gonadotropins, pubertal responses to luteinizing hormone-releasing hormone, and complete suppression of gonadarche after exposure to an analogue of luteinizing hormone-releasing hormone (LHRHa). In contrast, children with gonadotropin-independent precocity demonstrated an absence of gonadotropin pulsations, variable responses to luteinizing hormone-releasing hormone, lack of suppression of puberty in response to LHRHa, and cyclic steroidogenesis. Tissue from testicular biopsies performed in five of six boys with gonadotropin-independent precocity showed a range from incipient pubertal development of the tubules with proliferation of Leydig cells to the appearance of normal adult testes. We conclude that gonadotropin-independent precocious puberty is a distinct syndrome, of unknown cause, that may be familial and may have been responsible for many previously reported cases of precocious puberty.

Adrenarche and skeletal maturation during luteinizing hormone releasing hormone analogue suppression of gonadarche.

During puberty the effects of adrenal androgens upon skeletal maturation are obscured by the influence of gonadal steroids. Suppression of gonadarche with an analogue of luteinizing hormone releasing hormone (LHRHa) affords an opportunity to examine the onset and progression of adrenarche in the absence of pubertal levels of gonadal steroids in a controlled fashion and to explore the relationship between adrenal androgens and the rate of epiphyseal maturation. In 29 children with central precocious puberty, gonadarche was suppressed with LHRHa administration for 1-4 yr. During LHRHa exposure, dehydroepiandrosterone sulfate (DHAS) levels, as an index of adrenal maturation, were constant or increased in an age-expected manner. The change in bone age for change in chronologic age decreased from 1.7 +/- 0.1 to 0.49 +/- 0.05 (P = 0.00005), indicating that the LHRHa-induced return to a prepubertal gonadal steroid environment was associated with a slowing of skeletal maturation. DHAS levels were correlated with the rate of skeletal advancement before (r = 0.57, P = 0.001) and during 12 to 48 mo of exposure to LHRHa (r = 0.52, P = 0.003). A negative correlation of DHAS values with subsequent increases in predicted mature height was observed (r = -0.49, P = 0.007). Thus, in children with central precocious puberty, adrenarche progressed normally during LHRHa suppression of gonadarche. In children with the onset of progression of adrenarche during maintenance of a prepubertal gonadal steroid milieu, there was less evidence than in preadrenarchal children of a restraint upon skeletal maturation. These data suggest that adrenal androgens contribute importantly to epiphyseal advancement during childhood.

The effect of the respiratory cycle on mediastinal and lung dimensions in Hodgkin's disease: implications for radiotherapy gated to respiration

Changes in mediastinal and lung dimensions during respiration were studied to assess the potential of radiotherapy gated to respiration to minimize normal tissue irradiation. Twelve patients with mediastinal Hodgkins disease were assessed using chest radiographs and thoracic computed tomography (CT) scans both during quiet breathing and at maximum inspiration in the standing, supine, and prone positions. A simple measure of the bulk of mediastinal disease, the ratio of the width of mediastinal mass to thoracic diameter, was determined from posteroanterior (PA) chest radiographs. The volumes of mediastinum, irradiated and protected lung if anteroposterior (AP) and PA mantle fields were used were determined from sequential thoracic CT scans and three‐dimensional treatment planning and compared at quiet breathing and deep inspiration. The mediastinal width to thoracic diameter ratio decreased from quiet breathing to deep inspiration an average of 3%, 9%, and 11% for the standing, supine, and prone positions, respectively. Lung volumes as measured from the thoracic CT scans showed that on average, 8% more lung was protected at deep inspiration than at quiet breathing, independent of treatment position. The maximum increase in the percentage of protected lung from quiet breathing to deep inspiration was seen in patients with extensive mediastinal adenopathy suggesting that radiotherapy gated to respiration may be most advantageous in the subset of patients.

Determination of leg length discrepancy. A comparison of weight-bearing and supine imaging.

Leg length discrepancy (LLD) may be determined by comparison of leg (lower extremity) lengths measured during physical examination or by radiographic means. Leg lengths may be measured with the patient in standing, weight-bearing position or in supine position. We used a low dose digital radiographic unit to test the hypothesis that there is a difference in LLD determined from radiographs obtained with the patient standing and those obtained with the patient supine. Conventional physical examination measurements also were compared with the radiographic measurements. The amount of LLD that is clinically meaningful has not been established, although 10 to 12 mm has been used as a threshold difference of clinical meaningfulness in the past. Analysis of our data, using 10 mm as the threshold of difference, reveals high level correlation by linear regression analysis and no significant difference by t-test between measurements obtained from standing and supine radiographs. A weak correlation and statistical difference existed between each set of radiographic measurements and physical examination measurements.

Esophageal stricture secondary to drug-induced toxic epidermal necrolysis

Toxic epidermal necrolysis is a cutaneous disorder with high morbidity and mortality. Esophageal stricture has rarely been reported following recovery from this abnormality. A case is presented demonstrating the occurrence of an esophageal stricture following successful therapy. New methods of treatment are changing the mortality and morbidity such that esophageal stricture will be observed more frequently.

Stage IA to IIB mediastinal Hodgkin's disease: three-dimensional volumetric assessment of response to treatment.

From 1979 to 1986, the response to treatment of 53 patients with stage IA to IIB mediastinal Hodgkins disease was evaluated by three-dimensional volumetric analysis using thoracic computed tomographic (CT) scans. The mean initial volume of mediastinal disease in 34 patients treated with mantle and para-aortic irradiation was 166 mL, whereas for 19 patients treated with two to six cycles of multiagent chemotherapy and mantle and para-aortic irradiation the mean initial volume was 446 mL. Preliminary data suggested that patients with mediastinal volumes of less than 200 mL had a lower mediastinal relapse rate (13%) than patients with volumes greater than 200 mL (32%). For 12 patients receiving six cycles of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP), those with a greater than 85% reduction in volume 1 to 2 months after chemotherapy had a lower incidence of mediastinal relapse (zero of six, 0%) compared with patients having 85% or less reduction in volume (four of six, 67%). The primary value of this technique is that it provides a sensitive assessment of response to treatment and may aid in monitoring the effectiveness of a given treatment.

Three-dimensional volumetric assessment of response to treatment: Stage I and II diffuse large cell lymphoma of the mediastinum

From 1981 to 1986, 12 patients with Stage I and II diffuse large cell lymphoma of the mediastinum were treated with 4 or more cycles of multiagent chemotherapy and for nine patients this was followed by mediastinal irradiation. The response to treatment was assessed by three-dimensional volumetric analysis utilizing thoracic CT scans. The initial mean tumor volume of the five patients relapsing was 540 ml in contrast to an initial mean tumor volume of 360 ml for the seven patients remaining in remission. Of the eight patients in whom mediastinal lymphoma volumes could be assessed 1-2 months after chemotherapy prior to mediastinal irradiation, the three patients who have relapsed had volumes of 292, 92, and 50 ml (mean volume 145 ml) in contrast to five patients who have remained in remission with residual volume abnormalities of 4-87 ml (mean volume 32 ml). Four patients in prolonged remission with CT scans taken one year after treatment have been noted to have mediastinal tumor volumes of 0-28 ml with a mean value of 10 ml. This volumetric technique to assess the extent of mediastinal large cell lymphoma from thoracic CT scans appears to be a useful method to quantitate the amount of disease at presentation as well as objectively monitor response to treatment.

Small carpal bone surface area, a characteristic of Turner's syndrome

An abnormality which has received little attention but may be easily recognized on radiographs of the hand of patients with Turners syndrome is described. Eleven of thirty-one patients (35.5%) with Turners syndrome were shown on radiographs of the hand to have a visually detectable smallness of the bone surface area of the carpus when compared to the area of the second through fifth metacarpals. Values for the “C/M” ratio (the area of the carpals divided by the area of the second through fifth metacarpals) were calculated for films of 31 individuals with gonadal dysgenesis and compared with those from bone age-matched films of seventy-six individuals with normal development of the hand and wrist. A consistent difference with minimal overlap was documented. For all of the films of patients with Turners syndrome the C/M ratio averaged 89% of the value in the films of the controls. In the 11 patients in whose films smallness was visually apparent, the C/M ratio averaged 82% of controls while in those where the diminution was detected only by planimetry the C/M ratio averaged 91% of controls. The incidence of a diminished C/M ratio was compared with the incidence of four other previously described signs of Turners syndrome; although not seen as often as the coarse reticular pattern or delayed bone age, the C/M sign was recognizable without planimetry at least as commonly as the “metacarpal sign,” and a decreased carpal angle and/or Madelungs deformity. Taken together, these several criteria suggest the radiographic diagnosis of Turners syndrome in more than 93% of cases.