Short Stature and Turner Skeletal Features in an 11-Year-Old Boy with a Ring Y Chromosome Missing the Short Stature Homeobox Containing Gene

We report on an 11-yr-old boy with short stature and Turner skeletal features. Chromosome analysis revealed a 46,X,r(Y)(p11.3q11.2) karyotype, and FISH analysis showed loss of the Short stature homeobox containing gene (SHOX) from the ring Y chromosome. The results are consistent with the association of SHOX haploinsufficiency with short stature and Turner skeletal features, and suggest the importance of SHOX analysis in boys with Turner-like skeletal phenotype.     

Longitudinal Observation of a Patient with Leri-Weill Dyschondrosteosis and SHOX Haploinsufficiency

Haploinsufficiency of the short stature homeobox-containing (SHOX) gene causes Turner skeletal features, a certain proportion of idiopathic short stature and Leri-Weill dyschondrosteosis (LWD). Here we report a Japanese female with LWD. Her physical growth, skeletal deformity, and endocrine status were recorded longitudinally. She exhibited a constant growth rate (average + 6.2 cm/yr) from 6 to 9 yr old, followed by a downward shift at 10 yr old. Her final height was 135 cm (–4.4 SD for an adult female) and weight was 50.5 kg (–0.3 SD) at 12 yr and 10 mo old. Mesomelia and cubitus valgus were noticed from 2 yr old, and metaphyseal lucency and epiphyseal hypoplasia of the medial side of the distal radius were detected at 6 yr old. Madelung deformity was obvious at 10 yr old, when menarche occurred. Fluorescence in situ hybridization (FISH) analysis demonstrated a single copy of the SHOX gene. The short stature of the patient was thought to be exaggerated by the combination of SHOX haploinsufficiency and relatively early puberty.     

Het syndroom van Turner klinische – symptomatologie en genetische aspecten

Turner syndrome is characterised by growth retardation, ovarian dysgenesis, typical bodily features and organ malformations. The distribution and severity of its typical features (webbed neck, shield chest, retrognatia, ptosis, and cubitus valgus) vary between individuals. Associated organ malformations are mainly of the heart and kidneys. Turner syndrome is caused by totally or partly absent second X chromosome. The resulting haploinsufficiency of certain pseudoautosomal genes may be an explanation for its phenotype. One of the genes responsible for the short stature of these patients has been identified and is called the shox gene.     

Effect of 24 months of recombinant growth hormone on height and body proportions in SHOX haploinsufficiency

Leri-Weill syndrome (LWS) is a skeletal dysplasia with mesomelic short stature, bilateral Madelung deformity (BMD) and SHOX (short stature homeobox-containing gene) haploinsufficiency. The effect of 24 months of recombinant human growth hormone (rhGH) therapy on the stature and BMD of two females with SHOX haploinsufficiency (demonstrated by fluorescence in situ hybridisation) and LWS was evaluated. Both patients demonstrated an increase in height standard deviation score (SDS) and height velocity SDS over the 24 months of therapy. Patient 1 demonstrated a relative increase in arm-span and upper segment measurements with rhGH while patient 2 demonstrated a relative increase in lower limb length. There was appropriate advancement of bone age, no adverse events and no significant deterioration in BMD. In this study, 24 months of rhGH was a safe and effective therapy for the disproportionate short stature of SHOX haploinsufficiency, with no clinical deterioration of BMD.     

Short stature caused by isolated SHOX gene haploinsufficiency: update on the diagnosis and treatment

Heterozygous SHOX defects are observed in about 50 to 90% of patients with Leri-Weill dyschondrosteosis (LWD), a common dominant inherited skeletal dysplasia; and in 2 to 15% of children with idiopathic short stature (ISS), indicating that SHOX defects are the most important monogenetic cause of short stature. In addition, children selected by disproportionate idiopathic short stature had a higher frequency of SHOX mutations (22%). A careful clinical evaluation of family members with short stature is recommended since it usually revealed LWD patients in families first classified as having ISS or familial short stature. SHOX-molecular analysis is indicated in families with LWD and ISS children with disproportionate short stature. Treatment with recombinant human growth hormone is considered an accepted approach to treat short stature associated with isolated SHOX defect. Here we review clinical, molecular and therapeutic aspects of SHOX haploinsufficiency.     

Short stature homeobox-containing gene deletion screening by fluorescence in situ hybridisation in patients with short stature

The short stature homeobox-containing gene (SHOX) on the short arm of the X and Y chromosomes is an important determining factor of stature phenotype. Absence of the SHOX gene is a main cause for short stature in patients with Turner syndrome. Mutations of the SHOX gene can also be responsible for Léri-Weill syndrome (dyschondrosteosis). The aim of this study was to determine the frequency of SHOX deletions in short stature children and to delineate indications for SHOX deletion screening. Out of 50 probands, 35 had idiopathic short stature, 12 cases showed additional anomalies of the forearms (in particular Madelung deformity) and three patients were affected by a congenital heart defect. Chromosomal investigations with fluoresence in situ hybridisation did not reveal a SHOX deletion in any patient with idiopathic short stature. In five of the 12 patients (41.7%) with anomalies of the forearms, a SHOX deletion on one sex chromosome could be detected. No deletion was observed in the three cases with additional heart defects. CONCLUSION: The frequency of short stature homeobox-containing gene deletions in patients with idiopathic short stature appears to be very low and does not require a fluorescence in situ hybridisation analysis. Short stature in association with anomalies of the forearms such as Madelung deformity makes a deletion more probable and therefore screening for such deletions is recommended in these cases.     

Familial growth and skeletal features associated with SHOX haploinsufficiency

This study was designed to determine the intrafamilial effect of SHOX haploinsufficiency on stature, by comparing the growth and phenotype of 26 SHOX haploinsufficient individuals with 45 relatives and population standards. It confirmed that SHOX haploinsufficiency leads to growth restriction from birth to final height. Compared to unaffected siblings, the SHOX haploinsufficient cohort was 2.14 SDS (3.8 cm) shorter at birth and 2.1 SDS shorter through childhood. At final height females were 2.4 SDS (14.4 cm) shorter and males 0.8 SDS (5.3 cm) shorter than normal siblings. The family height analysis suggests that the effect of SHOX haploinsufficiency on growth may have been previously underestimated at birth and overestimated in males at final height. SHOX haploinsufficiency leads to short arms in 92%, bilateral Madelung deformity in 73% and short stature in 54%. Females were more severely affected than males. We conclude that SHOX is a major growth gene and that mutations are associated with a broad range of phenotype.     

Prepubertal gonadoblastoma in a 46,XY female patient with features of Turner syndrome

46,XY gonadal dysgenesis was diagnosed in a 5.5-year-old phenotypically female patient who had physical and somatic stigmata of Turner syndrome such as webbed neck, low hairline, widely spaced nipples, cubitus valgus and coarctation of the aorta. Bilateral streak gonads were removed and an unsuspected gonadoblastoma was found in right gonad.     

Deletion of the short arm of the X chromosome: A hereditary form of Turner syndrome

In the mothers of two girls with Turner syndrome due to a deletion of the short arm of an X chromosome, the same chromosomal anomaly was detected. Both mothers and daughters had short stature but normal pubertal development. Short parents and normal pubertal development do not exclude Turner syndrome in a girl with small stature.     

The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: contrasting children with Leri-Weill dyschondrosteosis and Turner syndrome

OBJECTIVE: To evaluate the growth disorder and phenotype in prepubertal children with Leri-Weill dyschondrosteosis (LWD), a dominantly inherited skeletal dysplasia, and to compare the findings from girls with Turner syndrome (TS). STUDY DESIGN: We studied the auxologic and phenotypic characteristics in 34 prepubertal LWD subjects (ages 1 to 10 years; 20 girls, 14 boys) with confirmed short stature homeobox-containing gene (SHOX) abnormalities. For comparative purposes, we evaluated similar physical and growth parameters in 76 girls with TS (ages 1 to 19 years) and 24 girls with LWD (ages 1 to 15 years) by using data collected from the postmarketing observational study, GeNeSIS. RESULTS: In the clinic sample LWD subjects, height standard deviation score ranged from -5.5 to +0.1 (-2.3 +/- 1.3, girls and -1.8 +/- 0.6, boys). Wrist changes related to Madelung deformity were present in 18 of 34 (53%) LWD subjects. In comparing the LWD and TS populations in the GeNeSIS sample, Madelung deformity, increased carrying angle, and scoliosis were more prevalent in the LWD population, whereas high arched palate was similarly prevalent in the two populations. CONCLUSIONS: Short stature is common in both LWD (girls and boys) and TS (girls). Clinical clues to the diagnosis of SHOX haploinsufficiency in childhood include short stature, short limbs, wrist changes, and tibial bowing.     

SHOX intragenic microsatellite analysis in patients with short stature

BACKGROUND: 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. OBJECTIVE: Analysis of the intragenic SHOX microsatellite to define its utility in detecting SHOX haplo-insufficiency in patients with short stature. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Severe,atypical form of dyschondrosteosis (report of two cases)

We report a mother and her son with unique mesomelic dysplasia. The mesomelic shortening in the upper extremities presents features of Leri-Weill syndrome (dyschondrosteosis) (OMIM 127300), that of the lower extremities is consistent with Langer mesomelic dysplasia (OMIM 249700). Molecular studies showed a heterozygous short stature homeobox gene ( SHOX)deletion in both patients. A second genetic defect in the other SHOX allele was not found. Conclusion:Our study broadens the phenotypic spectrum associated with short stature homeobox gene functional haploinsufficiency.     

Mosaic pentasomy X/tetrasomy X syndrome and premature ovarian failure

A 16 year-old girl with pentasomy X mosaicism (47,XXX(1) 48,XXXX(12)/49,XXXXX) presented with primary amenorrhea. She had epicanthal folds, long philtrum, high-arched palate, facial asymmetry, short webbed neck, low posterior hairline, mild scoliosis, cubitus valgus, mental retardation and clinodactily. She was diagnosed with osteoporosis and premature ovarian failure.     

Gonadal dysgenesis (Turner’s syndrome)

Summary A case of clinical gonadal dysgenesis is reported. The main features in this case were short stature, sexual infantilism, webbed neck, cubitus valgus, increased arm span, short phalanges of toes. hypoplastic rib, spina bifida, fused cervical vertebrae and mental retardation. The literature on the subject is briefly reviewed. From the Department of Pediatrics, Medical College, Udaipur.     

A girl with an end-to-end fusion of two X's

An abnormal large chromosome was seen in the karyotype of a 3-year-old girl with features of Turner's syndrome: i.e., short stature, cubitus valgus, coarctation of aorta. With the banding technics this abnormal chromosome appears to be the result of a fusion of two X chromosomes, short arm-to-short arm. This chromosome has two regions with C-heterochromatin and is late replicating.     

45,X Turner综合征合并中枢性性早熟1例报告并文献复习

目的总结Turner综合征(TS)合并中枢性性早熟的诊断和治疗经验,提高对该病的认识。方法报道1例45,X TS合并中枢性性早熟诊断、治疗和随访病例,对相关文献进行复习。结果患儿,女,7.5岁,因"乳房增大半年"就诊。身高117.9 cm(P_(7.2)),体重32.5 kg,肥胖外观,无高腭弓、颈蹼、盾形胸和肘外翻,乳房Tanner分期Ⅱ期,心肺查体未见异常,外阴阴毛Tanner分期Ⅰ期。辅助检查:促性腺激素释放激素(LHRH)激发试验峰值:黄体生成素(LH)11.9 U·L~(-1),卵泡刺激素(FSH)34.2 U·L~(-1),雌二醇(E2)39.3 ng·L~(-1)。盆腔超声示卵巢增大。骨龄9.7岁。应用促性腺激素释放激素类似物(GnRHa)治疗2.7年后,身高131.4 cm,骨龄12岁,联合重组人生长激素(rh GH)继续治疗2.3年,身高148.4 cm,骨龄13岁。停药1年半后身高154.2 cm,接近遗传靶身高,检测LH 11.9 U·L~(-1),FSH 50.5 U·L~(-1),E2 38.9ng·L~(-1),染色体:45,X。系统文献检索国外仅有6例TS合并中枢性性早熟的病例报告,其中5例染色体为嵌合体,1例为1条X染色体的片段缺失。结论单体型TS可出现中枢性性早熟,GnRHa联合rh GH治疗能够改善患儿成年终身高。     

Genetische Formen des Kleinwuchses und neue Behandlungskonzepte

Short stature is a multidisciplinary pediatric topic. This article focuses on genetic chondro-osseous short stature conditions. Exemplary cases from various categories are presented. Examples of skeletal dysplasia discussed are hypophosphatasia, a primary disorder of bone metabolism and mucopolysaccharidosis type IVA (Morquio syndrome) a lysosomal storage disorder causing bone dysplasia. For both conditions enzyme replacement therapy (ERT) has recently become available. The Silver-Russell syndrome and 3M syndrome both particularly involve the skeleton. Special consideration is given to the disease entities belonging to the short stature homeobox gene (SHOX) and the fibroblast growth factor receptor-3 (FGFR3) skeletal dysplasia groups which may present as very mild and relatively unspecific short stature conditions. A characteristic member of the latter group is achondroplasia for which novel therapeutic options are currently being developed.     

Kleinwuchs und Therapie

Short stature is a diagnostic challenge because of the enormous spectrum of physiological maturation and growth patterns in childhood. A carefully drawn growth chart and calculation of the familial target height are required for a correct analysis. A low growth velocity, a height below the familial target, severe short stature and disproportionate or syndromic short stature are rational reasons for referral to a growth specialist. For clinical assessment a small for gestational age (SGA) patient history, presence of minor or major anomalies and skeletal disproportions should guide the diagnostic approach. Bone age estimation may enable the differentiation between inborn (primary) and acquired (secondary) growth failure. Growth hormone (GH) stimulation tests should only be performed if GH deficiency is very likely based on the foregone diagnostics. Constitutional delay of growth and puberty should not be confused with GH deficiency. A GH therapy is effective in GH deficiency and allows a normal growth within the familial target range in the majority of treated children. In addition, the diagnosis and therapy of Turner syndrome, SGA short stature and short stature homeobox-containing gene (SHOX) deficiency are discussed.     

Low stature in males with normal phenotype and 45,X/46,XY mosaicism

There is wide variation in the clinical expression of 45,X/46,XY mosaicism. Ninety percent of prenatally diagnosed boys have normal male phenotype at birth, while those diagnosed postnatally show a wide spectrum of phenotypes, ranging from Turner syndrome, mixed gonadal dysgenesis, and male pseudohermaphroditism to apparent normality. We report the clinical, cytogenetic, endocrinologic and histologic findings in three boys with an apparently normal male phenotype and 45,X/46,XY mosaicism who were diagnosed postnatally because of their short stature. With the exception of one patient with Turner stigmata, no other abnormal features were found. No correlation between the proportion of 45,X/46,XY cell lines in blood, gonads and phenotype was found. Both prenatally and postnatally diagnosed boys with normal male phenotype must be followed-up because they can develop late-onset abnormalities, such as dysgenetic testes leading to infertility or neoplastic transformation, and short stature, which could be improved with growth hormone therapy.