Skeletal Disproportion Research Articles

FETAL ULTRASOUND ANATOMY AND MORPHOMETRIC PARAMETERS OF THE ULNA AND RADIUS IN FETUSES OF 19-22 WEEKS OF GESTATION

Assessment of the length of the long tubular bones of the fetus, including the ulna and radius, is used in modern fetal anatomy and to estimate the gestational age of the fetus. In addition, assessment of the length of the long tubular bones of the skeleton is important for the detection of skeletal disproportion, namely achondroplasia and hypochondroplasia. Congenital defects can also be diagnosed prenatally by ultrasound.Objective of the research. To determine the morphometric parameters of ulna and radius length at 19-22 weeks of gestation.Materials and methods. To determine the fetal anatomy of the structures of the ulna and radius, we used an imaging method such as ultrasound scanning. Fetometric measurements of the length of the fetal ulna and radius were performed using intravital ultrasound (IVUS) at 19-22 weeks of gestation. We analyzed 44 fetal ultrasounds in women with normal pregnancies.Results. From the 19th to the 22nd week of intrauterine development, the length of the right ulna increases from 2.77±0.17 mm to 3.22±0.12 mm, while the length of the left ulna increases from 2.73±0.16 mm to 3.26±0.15 mm. From the 19th to the 22nd week of intrauterine development, the length of the right radius increases from 2.50±0.12 mm to 2.92±0.22 mm, while the length of the left radius increases from 2.46±0.12 mm to 2.88±0.20 mm.Conclusions. Fetometry of the ulna and radius bones by ultrasound is one of the basic studies of fetal development. The bones of the forearm grow almost equally during the study period and no signifi cant diff erences in their growth are observed. We found that the period of intensive growth of forearm bones in the second trimester is 20-21 weeks of gestation, and the period of slow growth is 19-20 weeks of gestation.

Final height in a boy with achondroplasia treated with growth hormone- case report

Achondroplasia is the most common genetic form of skeletal dysplasia in humans. It is characterized by short stature and skeletal disproportion. Patients with this condition have comorbidities, such as cardiovascular problems, spinal cord problems, hearing and dental problems as well as psychological issues. We report final height of 147 cm in a 17-year-old boy treated with growth hormone, however without improvement in body proportions. Surgical therapy for limb lengthening had been proposed, which the patient refused. At this age he developed hypertension and was referred to a cardiologist, nephrologist, as well as to an orthopedic surgeon and psychologist. Recently, a new treatment with vosoritide has been introduced, promising better height outcome, but uncertain phenotype improvement. Multidisciplinary approach is recommended for these patients and close monitoring during childhood, adolescence and adulthood. Genetic counseling is also advised.
 

THU164 Design Of The New InsiGHTS Trial: A Multicenter, Phase 2, Randomized, Open-label, Active Controlled Study To Investigate The Safety, Tolerability, And Efficacy Of Lonapegsomatropin In Prepubertal Individuals With Turner Syndrome

Abstract Disclosure: K.O. Klein: Advisory Board Member; Self; Abbvie, Tolmar. Consulting Fee; Self; Abbvie, Tolmar. Grant Recipient; Self; Arbor. Research Investigator; Self; Abbvie, Arbor. Speaker; Self; Abbvie. P. Backeljauw: Advisory Board Member; Self; Ascendis Pharma. Consulting Fee; Self; Novo Nordisk, Novartis Pharmaceuticals, Ascendis Pharma, BioMarin Pharmaceutical, Tolmar, Cavalry Biosciences, Ipsen. Research Investigator; Self; Novo Nordisk, Novartis Pharmaceuticals, Ipsen. Speaker; Self; Ascendis Pharma. S. Abdelrahman: Employee; Self; Ascendis Pharma. P. Lai: Employee; Self; Ascendis Pharma. M. Mao: Employee; Self; Ascendis Pharma. A. Shu: Employee; Self; Ascendis Pharma. Background: Turner syndrome (TS) is characterized by the complete or partial absence of one X chromosome. Common clinical features include skeletal disproportion (growth failure, skeletal dysplasia, and low bone mass) and premature ovarian insufficiency in addition to a range of comorbidities including increased risk of thyroid disease, heart abnormalities, and diabetes mellitus. At this time, individuals with TS are treated with daily somatropin (human growth hormone [hGH]) which is effective at promoting height gain and may improve body composition. However, daily somatropin therapy has been associated with poor adherence which may result in reduced therapeutic efficacy. Lonapegsomatropin, a once-weekly prodrug of somatropin, is currently FDA- and EMA-approved for the treatment of pediatric GHD, and safety and efficacy have been established in 3 phase 3 trials. Lonapegsomatropin uses TransCon® technology, which combines a parent drug transiently linked to an inert carrier to achieve sustained release of somatropin. The phase 2 New InsiGHTS trial investigates the safety, tolerability, and efficacy of once-weekly lonapegsomatropin in individuals with TS. Methods: In this phase 2, parallel arm, dose-finding study, eligible prepubertal individuals with TS (aged 1 to 10 years) from the US are planned for inclusion with the aim of randomizing 48 individuals, 1:1:1:1, to lonapegsomatropin (0.24, 0.30, 0.36 mg/kg/week) or daily somatropin (0.05 mg/kg/day [0.35 mg/kg/week], a dose consistent with treatment guidelines) and stratifying them by chronological age (<4 and ≥4 years). The primary objective is to compare once-weekly lonapegsomatropin to daily somatropin in promoting linear growth at 26 weeks. Secondary objectives include additional growth parameters, safety, adherence, and pharmacokinetic/ pharmacodynamic measures that will be assessed at specified timepoints over the 104 week treatment period. Enrolled individuals must be diagnosed with TS (confirmed by genetic testing), GH-treatment naïve, exhibit impaired growth, have bone age ≤ chronological age, and be biochemically euthyroid. Exclusion criteria include diagnosis of diabetes mellitus, history of celiac disease or known clinically significant congenital or acquired cardiac dysfunction that might interfere with growth, and treatment with growth-influencing medication, among others. Dose reductions will be allowed at any time if average insulin-like growth factor-1 standard deviation score > +2.5; and/or in case of adverse events. Conclusions: The phase 2 New InsiGHTS trial is the first time that once-weekly lonapegsomatropin will be studied in individuals with TS. New InsiGHTS will provide an opportunity to examine the impact of lonapegsomatropin in a population whose short stature is not due to GH deficiency. Presentation: Thursday, June 15, 2023

Genetic diagnosis of skeletal dysplasias causing short stature in children

Short stature may often be due to skeletal dysplasias affecting the limbs, spine, or both. A careful clinical evaluation will help in identifying the rhizomelic and mesomelic shortening of the limbs and scoliosis. The mutations in different genes involved in various pathways in skeletal development lead to phenotypes that present from infancy to childhood or adulthood. A systematic clinical evaluation with identification of the limb bowing or deformity, dysmorphic features, radiological findings from skull to toes, and a single gene or multi-gene panel testing will help in making an appropriate diagnosis. The clinical clues to skeletal dysplasia include skeletal disproportion, unexplained limb bowing, recurrent fractures, facial dysmorphism including flat facies and blue sclera in severe cases, and sometimes typical digital or cardiac abnormalities. The following review focuses on the postnatal presentation of skeletal dysplasias mostly referred for evaluation of short stature.

Facial Esthetic Analysis of Nepalese Subjects

Background: Facial beauty is a prime concern in facial esthetic treatments and facial plastic surgery. The cephalometric can be used in the diagnosis, treatment planning, assessing the growth pattern in the craniofacial complex and skeletal disproportion with the relationships of the teeth to their supporting bone. Objective: The objective of this research was to analyze the face, evaluate the variability between males and females, and determine the cephalometric norms of Nepalese subjects based on Ricketts analysis. Materials and Methods: Craniofacial analysis of 106 Nepalese Brahmins subjects (60 females and 46 males) was done using the lateral cephalogram. The samples were criteria selected who met the criteria; well-balanced face, class I canine relation, and class I molar relation with normal occlusion. Ten parameters of Ricketts analysis were measured and analyzed using SPSS 20. The results were compared among males and females using Independent T-test with P value = 0.05. Results: The mean values of the facial axis, mandibular plane angle, mandibular arc, convexity at A were higher among the Brahmin females compared to Brahmin males. While the mean values of lower facial height, lower incisor to A Pog distance, lower incisor to A Pog angle, upper molar to PTV, and distance from lower lip to E plane were higher among the Brahmin males compared to Brahmin females. Female had smaller craniofacial variables compared to males. The mean values of upper molar position are higher for both males and females compared to the standard value of 12 ±3 mm; however, the mean values are significantly higher among males compared to females (P = 0.001). It showed that the facial axis, chin position, lower facial height, and facial depth were no significant differences between Nepalese males and females. Conclusion: There was sexual dimorphism in craniofacial features in Nepalese Brahmins. Female had smaller craniofacial variables compared to males. This research provided an overview of craniofacial features and they can be a norm for Nepalese Brahmins in orthodontic diagnosis and treatment planning.

Skeletal disproportion in girls with Turner syndrome and longitudinal change with growth‐promoting therapy

Short stature in Turner syndrome (TS) may be accompanied by skeletal disproportion. This retrospective study investigates growth and disproportion from early childhood to adult height. Data were collected from 59 girls prior to growth hormone (rhGH) treatment and in 30 girls followed up longitudinally. Standard deviation scores (SDS) for height (Ht), sitting height (SH) and sub-ischial leg length (LL) were compared and a disproportion score (SH SDS - LL SDS) calculated. In 59 girls, mean (SD) age 6.6 (2.1) years prior to rhGH treatment, LL SDS of -3.4 (1.1) was significantly lower than SH SDS of -1.2 (0.8) [p<.001]. In girls with Ht SDS < -2.0, disproportion score was > +2.0 in 27 (63%), cf eight (50%) with Ht SDS ≥ -2.0. For the longitudinal analysis, skeletal disproportion prior to rhGH was+2.4 (1.1) and+1.7 (1.0) on rhGH but prior to introduction of oestrogen [p<.001]. Disproportion at adult height was+1.1 (0.8), which was less marked than at the earlier time points [p<.001 for both comparisons]. Change in disproportion SDS over the first two years of rhGH predicted overall change in disproportion from baseline to adult height [R2 51.7%, p<.001]. TS is associated with skeletal disproportion, which is more severe in the shortest girls and present in only half of those with milder degrees of short stature. Growth-promoting therapy may improve disproportion during both the childhood and pubertal phases of growth. Change in disproportion status two years after starting rhGH helps predict disproportion at adult height.

Chondrodysplasia and growth failure in children after early hematopoietic stem cell transplantation for non-oncologic disorders.

Bone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non-oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH-associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants). All children had normal growth and no sign of chondrodysplasia at birth and prior to their primary disease. After HSCT, all children developed growth failure, with standard deviation scores for height at or below -3. Radiographically, all children had changes in the spine, metaphyses and epiphyses, compatible with a spondyloepimetaphyseal dysplasia. Genomic sequencing failed to detect pathogenic variants in genes associated with osteochondrodysplasias. We propose that such chondrodysplasia with growth failure is a novel, rare, but clinically important complication following early HSCT for non-oncologic pediatric diseases. The pathogenesis is unknown but could possibly involve loss or perturbation of the cartilage-bone stem cell population.

SHOX deficiency in children with growth impairment: evaluation of known and new auxological and radiological indicators

BackgroundThe phenotypic features of SHOX deficiency (SHOX-D) are highly variable and can be very mild, especially in young children. The aim of this retrospective study was to evaluate auxological and radiological indicators that could be predictive of SHOX-D in children.MethodsMolecular analysis of the SHOX gene was performed in 296 subjects with growth impairment or skeletal disproportion, without alternative diagnosis. Auxological variables and radiographs of the hand, wrist and forearm were evaluated.ResultsSHOX mutations (88% inherited, 12% de novo) were identified in 52 subjects. The most predictive auxological indicators of SHOX-D were an increased sitting height/height ratio and a decreased arm span/height ratio. The convexity of distal radial metaphysis at X-ray, not yet reported in literature, was also found to be predictive of SHOX-D. In young children, stratification of data by bone age also highlighted ulnar tilt, lucency of the ulnar border of the distal radius and enlarged radius as the radiological signs most related to SHOX-D .ConclusionsIn this study, the analysis of auxological and radiological indicators in SHOX-D children allowed to identify an additional early radiological sign and underlines the importance of family auxological evaluation.

Disproportion and dysmorphism in an adult Belgian population with Turner syndrome: risk factors for chronic diseases?

ABSTRACT Background Turner syndrome (TS) is characterized by dysmorphism and body disproportion. TS women are also susceptible to a range of chronic disorders including arterial hypertension (AHT), osteoporosis, sensorineural hearing loss (SNHL), type 2 diabetes mellitus (DM2) and thyroid disease. The association between dysmorphism/body disproportion and chronic disease has never been studied in TS women. The effect of growth hormone treatment on body disproportion is also unclear. Objectives: to analyze dysmorphic features and body disproportion in TS women in relation to the presence of chronic disease and to document the effect of growth hormone therapy on body disproportion. Method 76 adult TS women with a regular follow up at the TS clinic UZ Ghent were invited to participate. Detailed body measurements were performed in 44 volunteering TS women. Scoring systems for overall dysmorphism, craniofacial dysmorphism, thoracic and limb abnormalities and skeletal disproportion were developed. Results TS women with a higher dysmorphism score were more at risk for AHT (p = 0.04) as well as those with a higher sitting height/standing height ratio (p < 0.05). Prevalence of AHT, osteoporosis and DM 2 was lower in TS women treated with GH during childhood (p < 0.05). Conclusions Adult TS women with relatively short legs or with more physical dysmorphic stigmata were more at risk for AHT. GH therapy does not seem to increase the risk of chronic disease on the long term.

Skeletal disproportion in glucocorticoid-treated boys with Duchenne muscular dystrophy

We aimed to compare body segment and bone lengths in glucocorticoid-treated boys with Duchenne muscular dystrophy (DMD) with healthy controls using dual-energy absorptiometry (DXA) images. Total height (Ht), sitting height (SH), leg length (LL) and bone lengths (femur, tibia) in boys with DMD and age-matched control boys were measured using DXA. Thirty boys with DMD (median age 10.0 years (6.1, 16.8)) were compared with 30 controls. SH in DMD was 3.3 cm lower (95% CI − 6.1, − 0.66; p = 0.016). LL in DMD was 7.3 cm lower (95% CI − 11.2, − 3.4; p < 0.0001). SH:LL of boys with DMD was higher by 0.08 (95% CI 0.04, 0.12; p < 0.0001). Femur length in DMD was 2.4 cm lower (95% CI − 4.6, − 0.12; p = 0.04), whereas tibial length in DMD was 4.8 cm lower (95% CI − 6.7, − 2.9; p < 0.0001). SH:LL was not associated with duration of glucocorticoid use (SH:LL β = 0.003, 95% CI − 0.01 to 0.002, p = 0.72).Conclusion: Glucocorticoid-treated boys with DMD exhibit skeletal disproportion with relatively shorter leg length and more marked reduction of distal long bones. As glucocorticoid excess is not associated with such disproportion, our findings raise the possibility of an intrinsic disorder of growth in DMD.What is Known• Severe growth impairment and short stature are commonly observed in boys with Duchenne muscular dystrophy (DMD), especially those treated with long-term glucocorticoids (GC).• In other groups of children with chronic conditions and/or disorders of puberty, skeletal disproportion with lower spinal length has been reported.What is New• Growth impairment in GC-treated boys with DMD was associated with skeletal disproportion in relation to age, with lower limbs and distal long bones affected to a greater degree.

Long-Term Skeletal Disproportion in Childhood-Onset Crohn’s Disease

Background: It is unclear whether Crohn’s disease (CD) is associated with skeletal disproportion in adulthood. Methods: Height (Ht), sitting height (SHt) and leg length were studied in 44 children (male: 22), 23 adults (male: 10) with childhood-onset (CO) CD and 26 adults (male: 9) with adult-onset (AO) CD with a median (range) age of 13.7 (10, 17.3), 21.5 (18, 32) and 31.0 (22, 40) years, respectively. Results: Adults with CO-CD had a median Ht standard deviation score (SDS) of –0.9 (–2.3, 0.0) compared to 0.6 (–0.8, 1.0) in those with AO-CD (p < 0.05). Compared to a normal population, men, but not women, with CO-CD also had lower median SHt SDS at –1.1 (2.5, –0.5) (p < 0.05). The expected positive association that is normally found between leg length and SHt SDS was not evident in the adults with CO-CD. Conclusion: Short stature in adults with CO-CD is more pronounced in men and may be associated with poor spinal growth.

Acanthosis nigricans in a Japanese boy with hypochondroplasia due to a K650T mutation in FGFR3.

.Acanthosis nigricans (AN) is observed in some cases of skeletal dysplasia. However, AN has occasionally been reported in patients with hypochondroplasia (HCH), and a clinical diagnosis is sometimes difficult when its physical and radiological features are mild. Mutations in the gene encoding the fibroblast growth factor receptor 3 (FGFR3) have been identified as the cause of some types of skeletal dysplasia, which is diagnostically useful. Here, we report the case of a 3-yr-old Japanese boy who presented with AN. His height, weight, head circumference, and arm span were 91.7 cm (–1.95 SD), 16.3 kg, 54.0 cm (+2.6 SD), and 88.0 cm, respectively. In addition to the AN, he also exhibited a mild height deficit and macrocephaly, which prompted a search for FGFR3 mutations, although no skeletal disproportion, exaggerated lumbar lordosis, or facial dysmorphism was observed, and only slight radiological abnormalities were noted. A definitive diagnosis of HCH was made based on FGFR3 gene analysis, which detected a heterozygous K650T mutation. Insulin insensitivity was not found to have contributed to the development of AN. In individuals with AN, careful assessments for symptoms of HCH are important, regardless of the presence or absence of a short stature, and FGFR3 gene analysis is recommended in such cases.

Radiographic evaluation of stillbirth: what does it contribute?

Despite advances in perinatal care, stillbirth is relatively common (1/160 births) and frequently remains unexplained. Most recent protocols for etiologic evaluation of stillbirth either omit radiography or reserve it for infants with obvious skeletal disproportion. Over the past 30 years, the Wisconsin Stillbirth Service Program has collected radiographic images from 2,032 stillbirths and second trimester losses, of which about 25% (517) showed abnormalities. Review of these images by a medical geneticist showed that radiographs yielded a diagnosis in 45% of the infants with abnormalities (11.5% of all radiographs obtained) and were critical, yielding a diagnosis that would otherwise have been missed or incomplete in 1.5% of the total infants. The probability of a diagnosis was not significantly different between miscarriages <20 weeks and stillbirths. Diagnoses were mainly fetal, most commonly sporadic birth defects, idiopathic hydrops, chromosome abnormalities, and skeletal dysplasias, but chorioamnionitis with fetal sepsis, complications of twinning, and cord accidents were also diagnosed radiographically. Radiographs may help direct the use of newer technologies such as chromosomal microarray or gene sequencing. Limiting radiographs to infants with obvious skeletal disproportion would have resulted in many of these diagnoses, including 4/24 skeletal dysplasias, being overlooked. We recommend at least an anterior/posterior babygram film as part of the permanent record of all second trimester losses and stillbirths.

A 3-Dimensional Anthropometric Evaluation of Facial Morphology Among Chinese and Greek Population

The use of 3-dimensional (3D) facial imaging has taken greater importance as orthodontists use the soft tissue paradigm in the evaluation of skeletal disproportion. Studies have shown that faces defer in populations. To date, no anthropometric evaluations have been made of Chinese and Greek faces. The aim of this study was to compare facial morphologies of Greeks and Chinese using 3D facial anthropometric landmarks. Three-dimensional facial images were acquired via a commercially available stereophotogrammetric camera capture system. The 3dMD face system captured 245 subjects from 2 population groups (Chinese [n = 72] and Greek [n = 173]), and each population was categorized into male and female groups for evaluation. All subjects in the group were between 18 and 30 years old and had no apparent facial anomalies. Twenty-five anthropometric landmarks were identified on the 3D faces of each subject. Soft tissue nasion was set as the "zeroed" reference landmark. Twenty landmark distances were constructed and evaluated within 3 dimensions of space. Six angles, 4 proportions, and 1 construct were also calculated. Student t test was used to analyze each data set obtained within each subgroup. Distinct facial differences were noted between the subgroups evaluated. When comparing differences of sexes in 2 populations (eg, male Greeks and male Chinese), significant differences were noted in more than 80% of the landmark distances calculated. One hundred percent of the angular were significant, and the Chinese were broader in width to height facial proportions. In evaluating the lips to the esthetic line, the Chinese population had more protrusive lips. There are differences in the facial morphologies of subjects obtained from a Chinese population versus that of a Greek population.

A novel 110-bp insertion in a patient with homocysteinuria.

Homocysteinuria is an inherited recessive disorder caused by cystathionine beta-synthase (CBS) deficiency that has a wide spectrum of clinical manifestations, including ocular lens dislocation, skeletal disproportion, osteoporosis, vascular thrombosis, and central nervous system dysfunction [1]. The CBS enzyme catalyzes the synthesis of cystathionine from homocysteine and serine in the methionine pathway. This results in accumulation of homocysteine and methionine in plasma, leading to excretion of excessive urinary homocysteine. CBS deficiency has a worldwide incidence of 1/344,000 live births (range: 1/58,000-1/1000 live births) [2]. Human CBS is located in the cytoplasm of cells and is composed of 4 identical 63-kDa subunits. The CBS gene is located on the long (q) arm of chromosome 21 at position 22.3, encodes a protein consisting of 551 amino acids, and has 16 exons [3]. Herein we report a patient with homocysteinuria that was a carrier of compound heterozygote mutations in the CBS gene, 1 of which is novel, and a discussion of the clinical and molecular findings. A 14-year-old boy was referred to our hospital for evaluation of ocular symptoms that began approximately 1 year earlier. He was the first born of non-consanguineous parents that had lost 1 fetus. Family history of neurologic and thromboembolic disease was negative. Pregnancy and delivery were uneventful. The proband had neuromotor developmental delay. At the age of 10 years he had a clonic seizure of the left side. He had a marfanoid face and neurological examination showed left-sided central facial palsy, and mild left hemiparesis. Complete blood count results were normal. Cranial CT showed an area of low attenuation in the left frontoparietal region consistent with infarction. Prothrombotic work-up results were as follows: serum methionine level: 4.7 mg / dL (normal: 0.09-0.6 mg/dL); free homocysteine concentration: 50 mmol/L (normal: <12.5 mmol/L); urine homocysteine concentration: 360 mmol/L (normal: 5-15 mmol/L). The patient was diagnosed as homocysteinuria, and hydroxy cobalamin injections, vitamin B6, acetyl-salicylic acid, and a low-methionine diet were started and maintained.

Facial templates: a new perspective in three dimensions

This paper describes the use of adult facial template in gender-specific facial analysis. Eighty adults, mean age 24.5, were selected for the study. Laser-scanned images of the subjects were obtained under a reproducible and controlled environment with two Minolta Vivid 900 (Osaka, Japan) optical laser-scanning devices assembled as a stereo-pair. A set of left and right scanned images was taken for each subject and each scan took an average of 2.5 s. These scanned images were processed and merged to form a composite three-dimensional soft tissue reproduction of the subjects using commercially available reverse modelling software. The differences in facial morphology were measured using shell deviation colour maps. The facial template was used to compare differences between males vs. females groups and two subjects with facial disproportions. The difference between the male and female facial templates was 1.28 +/- 1.02 mm. The areas of greatest deviation were at the nasal, zygomatic area and lower jaw line. The results of the surface deviation maps between the templates and subjects with facial disproportion showed that the results could be applied for orthodontic diagnosis. The construction of the adult facial templates provides an interesting perspective into measuring changes in groups of patients and also acts as a useful template for the comparison of skeletal disproportion.

SHOX intragenic microsatellite analysis in patients with short stature.

SHOX haplo-insufficiency is considered the molecular basis of short stature in patients with Turner's syndrome, and gives rise to the short stature with mesomelic dysplasia and Madelung deformity of patients with Leri-Weill syndrome. Analysis of the intragenic SHOX microsatellite to define its utility in detecting SHOX haplo-insufficiency in patients with short stature. 207 patients with short stature (57 girls with Turner's syndrome [TS] [24 mosaicisms]; 73 children with isolated short stature [ISS]; 77 patients with short stature and skeletal disproportion) and 30 control subjects. DNA extraction and PCR amplification of the intragenic SHOX microsatellite, at the 5'-untranslated region. SSCP and partial sequencing of the SHOX gene in one patient with Madelung deformity and two SHOX alleles. DXS1055 (Xp) and DXS1192 (Xq) microsatellites were also analyzed, together with DXS233 and DXS234 at 0 and 2 cM of the pseudoautosomal region (PAR), in patients with one SHOX allele. 1. 93% of patients with TS had a single SHOX allele, and allele unbalance was detected in the remainder. 2. Patients with ISS were not different from the normal population with respect to SHOX heterozygosity (0.92 and 0.93, respectively; p = 0.997). 3. Patients with short stature and skeletal disproportion showed a higher frequency of SHOX homo/hemizygosity (0.27 vs 0.08; p = 0.027). 4. Five patients with short stature with SHOX haplo-insufficiency were detected: three had Madelung deformity (inherited Yq;Xp translocation, de novo PAR deletion, and SHOX microdeletion), and two had de novo/inherited Xp partial monosomy. The SHOX intragenic microsatellite might be a useful molecular marker to detect TS (including Xp distal deletions). SHOX haplo-insufficiency seems not to be an important contributor to ISS, but when skeletal disproportion is associated with short stature, a significant proportion of patients is found to have a single SHOX allele. Some of these patients were found to be SHOX haplo-insufficient upon molecular, cytogenetic and radiological examination.

Are random controlled trials appropriate for orthodontics?

In orthodontics, cost effectiveness is especially difficult to assess because of the wide range of problems and cures and a lack of precise scientific information about their success rates. While many would accept that the basic problem is skeletal disproportion, there are diverse views about the underlying cause. Over the last hundred years treatment has ranged from extracting teeth in every patient to never extracting teeth, each view being held with fierce conviction. You would think that a bit of clear-minded research would have settled the debate. But no, there is still wide disagreement.

Phenotypic recognition of maternal (mosaic) and paternal (segmental) isodisomy for chromosome 14 without a Robertsonian translocation

We report 2 cases of UPD-14 initially suspected on the basis of clinical rather than cytogenetic clues. The girl with maternal isodisomy presented prenatally with a positive triple marker screen for Down syndrome but a 46, XX karyotype on amniocentesis. Growth retardation, borderline microcephaly, hypotonia and multiple minor anomalies prompted a placental chromosome study that showed non-mosaic trisomy 14. Blood karyotype was normal and UPD-14 was confirmed at 6 weeks. She continues to have hypotonia and delayed motor but normal cognitive skills at 2-1/2 years despite the appearance of streaky hyperpigmentation on all four limbs suggesting low-grade mosaicism for a trisomic cell line.The boy with paternal isodisomy was found by prenatal ultrasound to have an omphalocele, polyhydramnios and mild skeletal disproportion but chromosomes were 46, XY in amniocytes, lymphocytes and fibroblasts. Major anomalies involving the CNS and cardiovascular system were noted postnatally. The unusual radiographic appearance of his ribs resembled that described in other reports of paternal UPD-14 (Walter, 1996; Cotter, 1997). Molecular confirmation was obtained at 7 months but a plugged tracheostomy tube caused severe anoxic brain injury and he remains hospitalized at 10 months Markers from 14pter through 14q11.2 (D14S740 and D14S1422) are biparental while those from 14q12 (D14S599 and D14S306) through 14qter are uniparental. This implies that paternally imprinted genes on chromosome 14 are located at least 20 cM from the terminal short arm

Skeletal proportions and metabolic disorders in adults.

The present study investigated the associations of stature, lower leg length (LLL) and demi-arm span (demi-AS) with major predisposing cardiovascular risk factors and coronary heart disease. Cross-sectional study set at Glasgow Royal Infirmary of a subsample of 543 men and 646 women aged 25-66 y from the random MONICA sample. ASSOCIATED MEASURES: LLL, demi-AS, blood pressure, plasma total cholesterol, diabetes mellitus and coronary heart disease (angina, angioplasty, heart attack, and coronary artery bypass graft). The numbers (and proportions) of men and women, respectively, with hypertension were 126 (23.6%) and 80 (14.0%), hypercholesterolaemia 155 (29.0%) and 171 (30.1%), coronary heart disease 53 (10.1%) and 47 (8.4%), and diabetes 15 (2.9%) and 9 (1.6%). Results were adjusted for age, social class and smoking. Analysis of variance showed that in men, shortness of height, LLL or demi-AS were all associated significantly (P < 0.05) with hypercholesterolaemia. Long LLL, high ratios of LLL:height or LLL:demi-As were associated significantly (P < 0.05) with diabetes mellitus. In women, shortness of height or LLL were associated with significantly (P < 0.05) with coronary heart disease. High ratio of demi-AS:height or low ratio of LLL:demi-AS was associated significantly (P < 0.05) with coronary heart disease. Short stature and limb lengths, and also altered skeletal proportions, which may reflect interrupted early growth, are associated with several metabolic disorders. Skeletal disproportion associates with diabetes in men and coronary heart disease in women.