Homozygosity for a missense variant in COMP gene associated with severe pseudoachondroplasia.

The phenotypic spectrum associated with heterozygous mutations in cartilage oligomeric matrix protein gene (COMP) range from a mild form of multiple epiphyseal dysplasia (MED) to pseudoachondroplasia (PSACH). However, the phenotypic effect from biallelic COMP variants is unclear. We investigated a large consanguineous Pakistani family with a severe form of PSACH in 2 individuals. Another 14 family members presented with a mild PSACH phenotype similar to MED. Using exome sequencing and subsequent segregation analysis, we identified homozygosity for a COMP missense variant [c.1423G>A; p.(D475N)] in the 2 severely affected individuals, whereas family members with the mild PSACH phenotype were heterozygous. Our observations show for the first time that a biallelic COMP variant may be associated with pronounced and widespread skeletal malformations suggesting an additive effect of the 2 mutated alleles.

Can the TW3 bone age determination method provide additional criteria for growth hormone treatment in adopted girls with early puberty? A comparison of the Tanner-Whitehouse 3 method with the Greulich-Pyle and the Tanner-Whitehouse 2 methods.

BACKGROUND/AIMS: Gonadotropin-releasing hormone analogues (GnRHa) are the accepted treatment of idiopathic central precocious puberty. As it has been found that growth velocity may be decreased with GnRHa treatment, clinical trials with GnRHa combined with growth hormone (GH) have been carried out. In a recent study 46 adopted girls with early or precocious puberty were randomly assigned to treatment with either GnRHa or GnRHa combined with GH, and followed to final height (FH). It was found that FH was significantly higher in the combined treatment group, 158.9 compared with 155.8 cm in the GnRHa treated group. In order to select the patients who could benefit from added GH, predictions of FH at the start of treatment according to the methods of bone age determination of Greulich-Pyle (GP) and Tanner-Whitehouse 2 (TW2) were compared. It was found that the GP method was the most useful method for patient selection. Recently, a revision of the Tanner-Whitehouse method, named Tanner-Whitehouse 3 (TW3), has been developed. The present study examined the usefulness of the TW3 method in selecting suitable patients for combined treatment. METHOD: The TW3 method bone age determinations of the 46 girls were compared to the GP and TW2 method determinations, using the differences between actual FH and predicted adult height (PAH). Beside accuracy of prediction of FH, the criteria of efficiency of selection and replicability were applied in the comparison. RESULTS: We found that the GP method, also when compared to the TW3 method, gave the most accurate prediction of the FH on only GnRHa treatment. This gives the best ground for selection of patients who can benefit from combined treatment. The GP method was also the most efficient in selecting patients, i.e., it could select the least number of patients that needed the combined treatment. The only drawback of the GP method was that it requires an experienced pediatric radiologist. Automated methods are being developed and may soon facilitate the use of the GP method for those less experienced. The FH after combined treatment could be predicted with an equation including PAH GP as well as PAH TW3 as variables. CONCLUSION: The GP method remains the most useful method for selection of those patients who will benefit most from the addition of GH to GnRHa in the treatment of idiopathic central precocious or early puberty. FH prediction after combined treatment requires PAH GP as well as PAH TW3.

Can bone age determination provide criteria for growth hormone treatment in adopted girls with early puberty?

In treatment of idiopathic central precocious puberty, GnRH analogues (GnRHa) have been accepted as the treatment of choice. Since growth velocity may be impaired with GnRHa treatment growth hormone (GH) treatment has been added in clinical trials. Recently, a study followed adopted girls with early or precocious puberty on GnRHa or combined GnRHa and GH treatment to final height. It was found that final height was significantly higher in the combined treatment group, although the difference was small. It was seen that patients that were extremely short at arrival and short at start of treatment seemed to be candidates for combined treatment. We have now analysed the data in order to define criteria for the sub-group in need of combined GnRHa-GH treatment in order to achieve normal final height, i.e. above -2 SDS. Bone ages of 46 patients at start of treatment, randomized to either GnRHa treatment or GnRHa treatment combined with GH, were examined blindly by the same radiologist and the PAH calculated. The methods according to Greulich-Pyle / Bayley-Pinneau (GP/BP) and Tanner-Whitehouse (TW2) were used. Predictions versus final height data were analysed. The accuracy of FH prediction was greatest for GnRHa treated group using the GP/BP method. The GP/BP method gave useful cut off limits for when combined treatment was necessary to possibly achieve normal height. If pre-treatment GP/PAH was > 157cm, the patients attained normal height with GnRHa treatment only. Ten out of 13 (77%) such girls could be correctly identified. Using TW2 with a cut off of 164 cm, 9 out of 13 could be selected. Using a multi regression equation of best fit the number of correctly selected cases for GnRHa treatment only, could not be further increased in this group. We conclude that bone age determination and adult height prediction with the Greulich-Pyle/Bayley-Pinneau method, provides useful criteria for selecting the subgroup of adopted girls with early puberty where combined treatment with GnRHa and GH is not necessary to reach normal final height.

Chondrodysplasia punctata (CDP) with features of the tibia-metacarpal type and maternal phenytoin treatment during pregnancy.

We describe a 2-year-old boy with chondrodysplasia punctata (CDP). The boy was exposed to phenytoin, in combination with carbamazepine, during pregnancy. There has been previous evidence for a connection between phenytoin exposure during pregnancy and chondrodysplasia punctata. The boy had clinical and some radiological characteristic features of CDP, of the tibia-metacarpal type. We know of no other report on a child exposed to phenytoin during pregnancy who developed CDP of this type.

Prepubertal growth and growth hormone secretion in children after treatment for hematological malignancies, including autologous bone marrow transplantation.

Prepubertal growth standards were used to assess growth in 20 children who had undergone autologous bone marrow transplantation (ABMT) as part of their treatment for hematological malignancy. Most of the patients (16 of 20) were transplanted after a relapse of their disease. A negative change in height standard deviation score (H-SDS) was seen only in the group of patients (n = 7) who had received both cranial irradiation therapy (CRT) and 7.5-Gy single-fraction total body irradiation (TBI). Height changes in this group were observed from the time of diagnosis. In contrast, the groups of patients conditioned with chemotherapy only (n = 3) or both chemotherapy and TBI, without preceding CRT (n = 10), did not demonstrate a significant loss in H-SDS. Weight related to height demonstrated large individual differences over time. Spontaneous growth hormone (GH) secretion, as measured by a four-point sleep curve, was followed longitudinally and an increasing proportion of patients with low peak levels was seen in all patient groups. In summary, prepubertal growth was suppressed only in patients who received cranial irradiation before ABMT. Despite low GH peak levels, normal prepubertal growth was found in patients with no CRT before ABMT.

Growth hormone treatment in young children with Down's syndrome: effects on growth and psychomotor development.

BACKGROUND: Learning disability and short stature are cardinal signs of Down's syndrome. Insulin-like growth factor I (IGF-I), regulated by growth hormone (GH) from about 6 months of age, may be involved in brain development. AIMS: To study long term effects of GH on linear growth and psychomotor development in young children with Down's syndrome. Study design-Fifteen children with Down's syndrome were treated with GH for three years from the age of 6 to 9 months (mean, 7.4). Linear growth, psychomotor development, skeletal maturation, serum concentrations of IGF-I and its binding proteins (BPs), and cerebrospinal fluid (CSF) concentrations of IGF-II were studied. RESULTS: The mean height of the study group increased from -1.8 to -0.8 SDS (Swedish standard) during treatment, whereas that of a Down's syndrome control group fell from -1.7 to -2.2 SDS. Growth velocity declined after treatment stopped. Head growth did not accelerate during treatment. No significant difference in mental or gross motor development was found. The low concentrations of serum IGF-I and IGFBP-3 became normal during GH treatment. CONCLUSIONS: GH treatment results in normal growth velocity in Down's syndrome but does not affect head circumference or mental or gross motor development. Growth velocity declines after treatment stops.

Conventional radiography and bone scintigraphy in the prognostic evaluation of Legg-Calvé-Perthes disease.

PURPOSE: The role of conventional radiography and bone scintigraphy in predicting the outcome of Legg-Calvé-Perthes disease was investigated. MATERIAL AND METHODS: The 75 children reviewed (86 hips) were followed up to the primary healing of the disease. The findings at conventional radiography (obtained at presentation, at the time of maximum capital head involvement, and at the end of the healing process of the disease) were compared to early bone scintigraphy features. RESULTS AND CONCLUSIONS: Bone scintigraphy provided more accurate information concerning the extent of the necrotic process than initial radiographs. Moreover it could determine revascularization and consequently the stage of the disease. The methods was, however, unable to predict the outcome of the disease in some cases, particularly if it was performed late after the onset of symptoms. Conventional radiography provided important information about other parameters such as "head-at-risk" signs which facilitated treatment selection. Of these signs not only lateral subluxation but also metaphyseal changes strongly predispose to severe deformity of the hip joint.

Legg-Calvé-Perthes disease. Comparison of conventional radiography, MR imaging, bone scintigraphy and arthrography.

In a prospective study of 22 patients (24 hips) with Legg-Calvé-Perthes disease (LCPD) the findings at conventional radiography, arthrography, bone scintigraphy and MR imaging, obtained at the time of diagnosis, were compared. MR was superior to conventional radiography and bone scintigraphy in the detection of the extent of involvement in the femoral head. Arthrography was as good as or better than MR imaging in determining the shape of the articular surfaces and the occurrence of lateral subluxation. Conventional radiography was less sensitive in identifying the degree of lateral subluxation and the extent of the necrosis in the femoral head. MR imaging provided anatomical and pathophysiological information about the extent and location of head involvement as well as the degree of lateral subluxation. Revascularisation was more clearly demonstrated with MR than with bone scintigraphy, irrespective of symptom duration.

Multiple intestinal duplications in a child with thoracic myelomeningocele and hydrocephalus.

An infant with thoracic spina bifida, myelomeningocele and hydrocephalus was found to have intrathoracic gastric duplication and noncontiguous tubular duplication along two-thirds of the small bowel. The myelomeningocele was closed and the hydrocephalus relieved with a shunt. The intrathoracic duplication was excised in toto and the intra-abdominal malformation successfully treated by stripping the entire mucosal tube from within the duplication.

The Swedish experience with Salter's innominate osteotomy in the treatment of congenital subluxation and dislocation of the hip.

The results of 83 Salter's innominate osteotomies (i.o.) performed to correct congenital subluxation and dislocation of the hip joint in 76 patients were reviewed. The overall radiographic results were classified as excellent or good in 34 hips (41%) and as fair or failure in 49 hips (59%). The best results were obtained in subluxated hips, previously not treated or treated only with closed reduction, prior to i.o. in patients operated on before the age of 5 years. In that group of hips, excellent or good results were obtained in 18 of 20 hips (90%). The poorest results were obtained in hips with residual subluxation or dislocation after previous operation with a result of fair or failure obtained in 26 of 28 hips (93%).

Pelvic lipomatosis causing constriction of the lower urinary tract and the rectum. Case report.

Pelvic lipomatosis is a rare condition characterized by excessive accumulation of fat in the pelvis. The symptoms and the course of the disease are related to compression of the lower urinary tract and rectum. The clinical findings and radiological characteristics are described.

Radiologic assessment of resectability of carcinoma of the head of the pancreas.

Twenty-four patients with probably resectable carcinoma of the head of the pancreas were examined by means of CT, ERCP and US and supplemented with angiography to assess the resectability. Resection was possible in half of the patients. As the series consisted only of potentially resectable cases, those with obvious liver metastases at CT or US were not included. The 3 patients in whom CT or US revealed a tumour larger than 5 cm were inoperable. A distance less tan 5.5 cm between the hilum of the liver and the proximal margin of the tumour measured in the common bile duct at ERCP also meant inoperability. Invasion of the superior mesenteric or splenic vein at angiography as an indication of non-resectability was confirmed at laparotomy in 12 of 13 cases.

Arthrography of the hip in children. Technique, normal anatomy and findings in unstable hip joints.

A method by which bilateral hip arthrography was performed under general anaesthesia in 130 infants and children 1 month to 7 years of age is described. Significant contractures of the adductor muscles had been corrected before the examination. Most of the children were girls with unilateral congenital idiopathic hip instability detected before the age of one year. From films exposed in standardized projections valuable information was obtained about the configuration of the joint cavity and the size and shape of the femoral head. Criteria for normal appearance in infants of ages 2 to 12 months are presented. More reliable details on the relation between the articular surfaces, the radiographic anatomy of the acetabulum and the distribution of the contrast medium were yielded by stereoradiography. Closed reduction was usually accomplished successfully during the arthrography, which made beginning of definitive treatment under the same anaesthesia possible.

Neonatal hip instability. Reason for failure of early abduction treatment.

A series of nine children with hip joint instability in 17 hips, diagnosed neonatally, is presented. Seven had bilateral idiopathic instability and two instability secondary to arthrogryposis, one of them bilateral. After reduction seven of the children (14 hips) were treated with abduction devices, which in all cases did not lead to stability in one or both hips. In these cases arthrography revealed that closed reduction was impossible due to narrowing of the joint capsule (hour-glass shape) and the interposition of a capsular fold including the acetabular labrum. The same types of changes were seen within 1 or 2 months after birth in three hips which had had no abduction treatment before arthrography. At open reduction of 11 hips it was found that the narrowing of the capsule was caused by the tendons of the iliopsoas and rectus femoris muscles. Excision of the capsular fold (labrum) was not necessary. The femoral head was deformed and anteverted. Failure of conservative treatment can be due either to incomplete reduction or to inadequate immobilization. Our analysis has shown that the most probable reason is incomplete reduction due to interposition. An obstacle to reduction should be suspected if abduction is restricted at birth, if primary reduction is difficult and the position difficult to maintain or if instability persists after 8 weeks of treatment. On the basis of our material the incidence of such an impediment to reduction was 0.08 per thousand births in the region studied during a 5-year period.

Hip joint instability after the neonatal period. I. Value of measuring the acetabular angle.

The acetabular angle was measured by two independent observers in a consecutive series of 29 infants with idiopathic instability of the hip. The diagnosis was made at the age of 1 1/2 to 21 months, and was confirmed by arthrography. The average difference in the measurement values between the two observers was less than 2 degrees. In infants with unilateral instability the acetabular angle was always greater on the unstable side. This difference decreased after treatment. Criteria for pathologic angles are discussed. Measurement of the acetabular angle is of greatest value for assessing the effect of treatment, but is of limited usefulness in diagnosing instability, especially during the first 6 months of life, as the cartilaginous component of the joint is not included in the measurement. Arthrography is recommended in cases difficult to evaluate.

Hip joint instability after the neonatal period. II. The acetabular growth potential.

In 26 girls with idiopathic hip joint instability, diagnosed after the neonatal period, the acetabular angle is measured before and after treatment. A mathematical analysis of the acetabular growth potential in these hip joints and normal ones is presented. During treatment the monthly reduction of the acetabular angle is greater than in normal hip joints. The age limit for sole treatment in immobilisation without operative procedures is discussed.

Hip joint instability after the neonatal period. Diagnosis and treatment of 20 consecutive cases.

A consecutive series of 20 children (21 hips) with idiopathic hip joint instability, diagnosed after the neonatal period, is presented. The diagnosis was confirmed by hip joint arthrography. In all the children, 1.5-21 months old at the time of diagnosis, closed reduction could be achieved. They were treated in plaster directly or after treatment of contractures in the adductor muscles of the hip joint. Stability was rapidly attained during plaster treatment. The results of the treatment in plaster were checked by a second arthrography in two thirds of the cases, and all cases have been clinically and radiologically evaluated 1-4.5 years after diagnosis. All of the children developed clinically stable hips and they walk normally. In two hips signs of avascular necrosis of the femoral head were found and in three hips (two children) the skeletal development was markedly delayed. In 81 per cent (17/21 hips) the prognosis was considered good; it is uncertain in the remaining four hips. The appropriate period of fixation in plaster related to the age of the child is discussed.

Repair of renal pelvic defects with a capsular flap.

In a case of recurrent renal pelvic tumour a renal capsular flap was successfully used to repair the defect after excision of the tumour. This technique is recommended in difficult clinical situations when sacrifice of renal parenchyma is the only other alternative.