Differences in dental and bone maturation in regions with or without hemihypertrophy in two patients with Russell-Silver syndrome

Hemihypertrophy (hemihyperplasia) is defined as asymmetric body overgrowth of one or more body parts. Hemihypertrophy can be isolated or be part of well-defined syndromes, such as Russell-Silver syndrome (RSS). RSS is characterized by severe intrauterine growth retardation, postnatal short stature, asymmetry of the face, body, and limbs, short and incurved fifth fingers, broad forehead, pointed small triangular shaped face, girdle nose, normal psychomotor development, variations in the pattern of sexual development, and dental and oral abnormalities. The aim of this study was to determine whether or not there was any difference in the maturity of bone in left and right hand-wrist radiographs and dental development in the right and left jaws of two patients with RSS. In addition, the clinical features of the syndrome are discussed.     

Russell-Silver syndrome and hypopituitarism. Patient report and literature review

Russell-Silver syndrome (RSS) is a sporadic form of prenatal onset dwarfism with typical facial features, variable asymmetry, and linear growth 3 to 4 SDs below the mean. Endocrinologic studies are usually normal; however, six cases of RSS with growth hormone deficiency have been reported, three of which had additional pituitary abnormalities. We describe another case, a 7-year-old girl with RSS and deficiencies of growth hormone, corticotropin, and thyroid-stimulating hormone. Replacement therapy including growth hormone resulted in an improved growth velocity, though twice the usual dose of growth hormone was required and short stature persisted. Since growth hormone secretion is usually normal in RSS, the existence of individuals with RSS phenotype and hypopituitarism including growth hormone deficiency suggests etiologic heterogeneity. We recommend that those individuals with RSS phenotype and a continuous significant decline in height velocity be investigated for pituitary abnormalities. Unusually high replacement doses of growth hormone may be required to overcome deficiency.     

A rare type of low birthweight dwarfism: The Dubowitz syndrome

Two patients with the Dubowitz syndrome are presented. This presumably recessive inherited syndrome was first defined by Grosse et al. (1971). So far 11 patients with this syndrome have been described. Major clinical findings are intrauterine and postnatal growth retardation, considerable microcephaly, mild mental retardation, hyperactivity, hyperextensibility of joints, eczema and a characteristic appearance of the face due to marked epicanthic folds, blepharophimosis, broadening of the bridge and tip of the nose and retrognathia. Minor anomalies as clinodactyly of the fifth digits, cutaneous syndactyly of toes, foot deformity, sacral dimple and cryptorchidism may be seen. The exclusion of the non genetic fetal alcohol syndrome presents serious diagnostic problems.     

First Genetic Screening for Maternal Uniparental Disomy of Chromosome 7 in Turkish Silver-Russell Syndrome Patients

Objective

Silver–Russell syndrome (SRS) is a clinically and genetically heterogeneous syndrome which is characterized by severe intrauterine and postnatal growth retardation, and typical characteristic facial dysmorphisms. It has been associated with maternal uniparental disomy (UPD) for chromosome 7 and hypomethylation of imprinting control region 1 (IGF2/H19) in 11p15. UPD refers to the situation in which both copies of a chromosome pair have originated from one parent. UPD can be presented both as partial heterodisomy and isodisomy. The aim of this study was to determine the maternal UPD7 (matUPD7) in 13 Turkish SRS patients.

Methods

Genotyping for matUPD7 was performed with microsatellite markers by polymerase chain reaction.

Findings

The maternal UPD7 including the entire chromosome was identified in 1/13 (7.6%) of individuals within SRS patients. There were no significant differences between clinical features of matUPD7 case and other SRS cases except congenital heart defects.

Conclusion

It is often difficult to establish diagnosis of a child with intrauterine growth retardation (IUGR), growth failure and dysmorphic features. Thus, screening for matUPD7 in IUGR children with growth failure and mild SRS features might be a valuable diagnostic tool.     

The Dubowitz syndrome--one more case

A boy with the Dubowitz syndrome is presented. This autosomal recessive disorder is characterized by variable degrees of intrauterine and postnatal growth retardation, microcephaly, mild mental retardation, hyperactivity, "eczema", characteristic facial appearance and combination of minor abnormalities. Thirty-eight cases of this syndrome have been reported in the literature. Symptoms and difficulties in differential diagnosis are discussed.     

Serum insulin-like growth factor 1 and serum growth-promoting activity during the first postnatal year in infants with intrauterine growth retardation

Follow-up from birth to age 12 months was obtained in 21 infants born with intrauterine growth retardation. Serum insulin-like growth factor 1 was measured by radioimmunoassay. The bioassayable growth-promoting activity of the serum was measured as the "thymidine activity" on lectin-activated lymphocytes at 5 days and 1, 3, 6, 9, and 12 months, and was compared with control values. Depending on their length at age 12 months, the intrauterine growth retardation infants were divided into three groups: at or above the average (n = 8, group A), between the mean and -2 SD (n = 7, group B), or less than -2 SD (n = 6, group C). No differences in nutritional indexes or in head circumference were found between the three groups. Insulin-like growth factor 1 was significantly lower at age 5 days in intrauterine growth retardation than in control infants. It increased slowly in groups A and B to reach the control values at age 9 and 12 months. In group C it remained significantly subnormal at 1 yr of age. Thymidine activity was also significantly lower at age 5 days in intrauterine growth retardation compared with control infants. It increased sharply at age 1-3 months in groups A and B but remained significantly lower in group C up to 1 yr of age. Although individual values of insulin-like growth factor 1 and thymidine activity were closely correlated, the increase of length during the first postnatal year correlated significantly with the thymidine activity levels at 1 and 3 months but not with the insulin-like growth factor 1 levels at 1, 3, and 6 months.(ABSTRACT TRUNCATED AT 250 WORDS)     

Growth in a case of Russell-Silver syndrome treated for hypopituitarism

The growth characteristics of Russell-Silver syndrome (RSS) include dwarfism of prenatal onset, moderate retardation of bone age and normal postnatal height velocity. We describe a case of hypopituitarism in a girl with typical RSS who suffered from a severe trauma at birth. Signs of hypopituitarism appeared during childhood. Before substitutive treatment, a short course of human growth hormone (hGH) induced a moderate rise in plasma IGF-I levels which was within the range observed in other pituitary dwarfs. Under replacement therapy, catch-up growth was similar to what is observed in other growth hormone deficient children. However, bone age matured much faster than chronological age. This observation appears to be a particular feature of RSS, possibly enhanced by hGH therapy. An improvement of adult height beyond the final height usually observed in RSS children without endocrine disturbances should therefore not be expected from hGH therapy. Growth hormone deficiency and RSS do not appear to be causally related. However, in each child with RSS, a particular attention should be given to a decreased height velocity, a severely delayed bone age as well as a history of major perinatal problems. Should one of these factors be found, a careful evaluation of the hypothalamo-pituitary axis ought to be performed with, accordingly, an appropriate substitutive therapy.     

Hypotonia at six years in prematurely-born or small-for-gestational-age children

A neurological follow up study was done of 143 full-term infants who were small for gestational age based on intrauterine growth retardation and of 49 preterm appropriate-for-gestational-age (PTAGA) infants at the age of 6 years. Findings were compared with those of a reference group of 192 full-term appropriate-for-gestational-age (FTAGA) children. In 11% of the children of both study groups, hypotonia was found without any other neurological deviancy. This type of hypotonia was absent in the reference group, whereas minor neurological dysfunction consisting of hypotonia with other neurological signs was found in all the three groups of children. No relation was found with obstetrical or neonatal variables, including severity of growth retardation and gestational age, or with weight, body height or head circumference at 6 years. The possible interference of preterm birth or intrauterine growth retardation with, and the role of placental mechanisms in, fetal and early postnatal muscle development is discussed.     

Long-term hormone replacement therapy in two patients with Kabuki syndrome and growth hormone deficiency

The Kabuki syndrome is characterized by mental retardation (mild-to-moderate), skeletal anomalies, typical facial appearance and post-natal growth deficiency. The authors describe two patients with Kabuki syndrome and proven growth hormone deficiency. The first patient has been on GH replacement therapy for 4 years; the second for 11 years. On the basis of a sufficiently long follow-up period the Authors discuss the advisability of replacement therapy with growth hormone in patients with Kabuki syndrome.     

Clinical study of dentocraniofacial characteristics in patients with Williams syndrome

Williams syndrome (WS) is a rare congenital anomaly that is characterized by distinctive facial features, congenital heart disease, and behavioral characteristics that include mental retardation. However, only a few reports have documented the dentocraniofacial morphological characteristics of WS in Japanese individuals. The aim of this study was to analyze the dentocraniofacial morphology and growth patterns in a group of nine Japanese subjects (two males and seven females; mean age at admission, 10.1 years) with WS. The analytical methods included an initial medical questionnaire, lateral cephalography, panoramic radiography, dental casts, and oral examinations. The dental findings showed congenitally missing teeth, microdontia, and peg‐shaped teeth. Regarding cranial morphology, microcephaly occurred at high frequencies, and a short posterior cranial base and thick calvarial bones, including frontal, parietal, and occipital bones, were seen in patients with WS. An analysis of maxillofacial morphology showed the large gonial angles and lingual inclination of the lower incisors in patients with WS. In addition, the chin button was deficient and in three of four growing subjects the maxillofacial growth pattern demonstrated a downward and backward tendency. The results of this study provide important information that will improve our understanding of the characteristics of patients with WS.     

The Dubowitz syndrome

The Dubowitz syndrome is a rare, autosomal, recessively inherited disorder of intrauterine and postnatal growth retardation leading to microcephaly, moderate mental retardation and such characteristic facial anomalies as telecanthus, epicanthic folds, blepharophimosis, ptosis, broadening of the bridge and tip of the nose, abnormal ears and retrogenia. Further findings include hyperactivity, eczema, cryptorchidism in the affected males, and brachy-clinodactyly of the fifth fingers. Thirty-three cases with this syndrome have been reported in the literature. Five additional patients are presented. All five are sporadic cases. The diagnostic symptoms and the differential diagnosis are discussed.     

Altered growth, hypoglycemia, hypoalaninemia, and ketonemia in the young rat: postnatal consequences of intrauterine growth retardation

We characterized some of the consequences of intrauterine growth retardation in rat pups growth retarded [small for gestational age (SGA)] due to bilateral maternal uterine artery ligation. Pups of sham and nonoperated (normal) mothers served as controls. SGA pups had significantly reduced body and carcass mass throughout the study while body mass did not differ between sham and normal pups after 4 days. Brain mass was similar in the three groups at any age, while at 21 days and later, SGA liver weight as % body mass exceeded that of sham or normals. At 21 days, a 48-h fast reduced plasma glucose significantly in SGA compared to sham and normal pups; SGA plasma insulin was decreased and glucagon increased. Hepatic phosphoenolpyruvate carboxykinase activity and glycogen content were similar among groups. SGA pups did have significantly reduced plasma alanine and elevated betahydroxybutyrate levels. No differences in the responses to fasting occurred at 28 or 35 days. These data indicate that intrauterine growth retardation has profound effects on postnatal growth and metabolism.     

Dentomaxillofacial characteristics of ectodermal dysplasia

The aim of this retrospective hospital‐based study was to elucidate the dentomaxillofacial characteristics of ectodermal dysplasia. Six Japanese individuals (one male and five female; age range, 12.7–27.2 years) underwent comprehensive examinations, including history recording, cephalometric analysis, panoramic radiography, and analysis of dental models. All the subjects had two or more major manifestations for clinical diagnosis of ectodermal dysplasia (e.g., defects of hair, teeth, nails, and sweat glands). They presented hypodontia (mean number of missing teeth, 9.5; range, 5–14), especially in the premolar region, and enamel dysplasia. Five subjects had bilateral molar occlusion, whereas one subject had unilateral molar occlusion. The common skeletal features were small facial height, maxillary hypoplasia, counterclockwise rotation of the mandible, and mandibular protrusion. Interestingly, the maxillary first molars were located in higher positions and the upper anterior facial height was smaller than the Japanese norm. The results suggest that vertical and anteroposterior maxillary growth retardation, rather than lack of occlusal support due to hypodontia, leads to reduced anterior facial height in individuals with ectodermal dysplasia.     

ICR1 epimutations in llp15 are restricted to patients with Silver-Russell syndrome features

(Epi)mutations affecting chromosome llp15 are well known to be associated with growth disturbances. The finding of llp15 mutations in the overgrowth disease Beckwith-Wiedemann syndrome led to the identification of imprinted growth-promoting genes which are expressed paternally and of imprinted growth-suppressing genes in the same region that are expressed maternally. An opposite epimutation in the same region is associated with Silver-Russell syndrome (SRS), a growth retardation disorder characterised by a typical facial gestalt, clinodactyly V and asymmetry. In more than 30% of patients with SRS, hypomethylation of the telomeric llp15 imprinting domain (ICR1) can be detected. However, the general significance of this epimutation for human growth retardation was unclear. In a previous study' we showed that the ICR1 epimutation is not present in growth retarded patients with dysmorphisms not typical for SRS, but its role in the development of isolated growth restriction needed to be further elucidated. We therefore screened 30 patients with isolated pre- and postnatal growth retardation (IUGR/PNGR) and 65 patients diagnosed with SRS by external clinicians for ICR1I epimutations. In the latter group clinical data were rarely provided. These 65 'SRS' patients were additionally analysed for maternal uniparental disomy 7 (matUPD7). We excluded ICR1 hypomethylation in all 30 patients with isolated growth retardation. In the SRS group, we detected four cases with ICR1 epimutation and three with matUPD7. By combining our data with those from our previous study we could show that the hypomethylation of ICR1 in llp15 is indeed restricted to patients with SRS features and can be disregarded in isolated IUGR/PNGR. Thus, testing for the epimutation is indicated only in case of growth restriction in association with clinical signs reminiscent of SRS. The low detection rate of the ICR1 epimutation in our 'SRS' group can be explained by the clinical heterogeneity of cases referred by external institutions.     

The effect of perinatal risk factors on growth in very preterm infants at 2 years of age: the Leiden Follow-Up Project on Prematurity

OBJECTIVE: To describe growth in infants <32 weeks GA. To assess the relationship between growth and perinatal factors (like intrauterine growth retardation and the postnatal use of dexamethasone) and neurodevelopmental outcome. DESIGN: Regional, prospective study in two health regions in the Netherlands. Part of the Leiden Follow-Up Project on Prematurity (LFUPP). PATIENTS: 196 live born infants with GA <32 weeks. METHODS: At two years corrected age length, weight and head circumference of 160 of 196 surviving infants (82%) were evaluated. Standard Deviation Scores were calculated and means were compared to Dutch growth references. Mean SDS for length was corrected for the mean SDS for target height. Birth weight (BW)-SDS for gestational age (GA) was calculated according to Swedish references. RESULTS: Length, weight and weight-for-length were equally impaired in both sexes at two years in premature infants compared to Dutch growth charts. Catch-up in length and weight occurred mostly in the first year of life. Intrauterine growth retardation was associated with impairment of all growth parameters. The use of postnatal dexamethasone was associated with shorter length, lower weight, lower weight for length and smaller head circumference; this effect remained after correction for GA, BW and BW-SDS. Growth retardation (length and weight) was associated with an abnormal neurologic examination; smaller head circumference also with mental and psychomotor delay. CONCLUSION: Growth at two years corrected age in children born <32 weeks is impaired. Postnatal dexamethasone is associated with impairment of all growth parameters including head circumference, which may be a significant contributing factor for abnormal neurodevelopmental outcome.     

Autistic regression in a child with Silver-Russell Syndrome and maternal UPD 7

Silver-Russell syndrome (SRS) is a heterogeneous syndrome which is characterized by severe intrauterine and postnatal growth retardation and typical dysmorphic features. In 5-10% of SRS patients, a maternal uniparental disomy of chromosome 7 (UPD7) can be detected.We describe a 4.5-y old boy. Physical examination at the age of 4.5 y was remarkable for small stature, relatively big head, triangular face, broad forehead, pointed chin and clinodactyly. He had hypopigmented macules on his back with no evidence of asymmetry/hemihypertrophy. Clinical diagnosis of Silver-Russell syndrome was made. Maternal UPD of chromosome 7 was found, confirming the diagnosis. Along with the clinical findings that are described in this syndrome he had moderate developmental delay which is not commonly found in these patients and underwent an autistic regression around the age of 2 years. This association has only once been described before in this syndrome. A possible explanation is that the autism is not a part of SRS but is due to the UPD. Our case suggests an association of autistic regression with a locus on chromosome 7.     

IUGR大鼠胰岛素样生长因子与小肠及体格发育关系的研究

目的：生后早期的生长主要受营养的调控,营养物质-胰岛素-胰岛素样生长因子(IGF)轴在胎儿宫内发育迟缓(IUGR)生长追赶及胃肠发育中起着重要的作用,而胃肠发育又与营养物质的吸收、生长追赶关系密切。目前国内有关IUGR出生时小肠发育状况报道甚少,且仅限于IUGR出生时胃肠形态结构的观察。该研究探讨生后早期不同蛋白质和热卡水平的营养干预如何调控IGF系统及影响IUGR大鼠的小肠发育和体格生长追赶,并追踪至成年期。方法：采用孕母饥饿法建立IUGR模型。64只IUGR新生鼠随机分为4组：IUGR正常饮食组(SC组),饮食中蛋白含量20%;IUGR高蛋白组(SH组),饮食中蛋白含量占30%;IUGR低蛋白组(SL组),饮食中蛋白含量为10%;IUGR高热卡组(SA组),饮食中热卡较其它组高20%。16只正常新生鼠为正常对照组(C组)予以正常饮食。幼鼠3周断乳后继续予原饮食模式1周,第4周起各组均予正常饮食喂养。分别于出生时及生后第4周、12周测定各组大鼠的血清IGF-1、胰岛素生长因子结合蛋白-3(IGFBP-3)浓度及体重、身长和小肠重量、长度。结果：IUGR大鼠虽然宫内营养不良,但SH组及SA组呈快速小肠发育和体格生长追赶伴IGFs水平明显升高,其中4周时SH组IGFs水平显著高于其余各组(P0.05)。SL组4周和8周的体重、身长、小肠长度和重量均低于其它4组(P0.05)。结论：4周时血清IGF-1是反映生长追赶的灵敏指标,与小肠和体格的生长追赶呈正相关,至成年期这种相关性消失。     

Severe upper airway stenosis in a boy with partial monosomy 16p13.3pter and partial trisomy 16q22qter

We report the case of a boy with a de novo partial monosomy 16p13-pter and partial trisomy 16q22-qter detected by fluorescence in situ hybridization using subtelomeric probes for 16p and 16q. The boy had facial characteristics, skeletal features, congenital heart defects, an imperforate anus, urogenital malformations, pre/postnatal growth retardation, and psychomotor retardation, most of which have been reported both in partial monosomy 16p and partial trisomy 16q. In addition, he suffered from upper airway stenosis due to possible laryngeal stenosis with subglottic webs. The upper airway stenosis could be a rare complication of partial monosomy 16p or partial trisomy 16q, or a nonspecific malformation resulting from chromosomal abnormalities.     

Intrauterine growth correlation to postnatal growth — influence of risk factors and complications in pregnancy

In a population of 616 pregnant women with increased risk of intrauterine growth retardation, we examined the relationship of third trimester fetal growth to maternal and pregnancy risk factors, the infants condition at birth, and postnatal growth. Intrauterine growth velocity was calculated from repeated estimations of fetal weight using ultrasound. Postnatal growth up to 3 months was measured in 313 of the infants. Intrauterine growth velocity was directly correlated to birth weight deviation (R = 0.35, P < 0.0001) and inversely correlated to postnatal growth (R = 0.21, P = 0.0001). Heavy smoking throughout pregnancy was the most pronounced factor associated with loss of fetal growth percentiles (P = 0.006), and it was also associated with postnatal catchup (P = 0.01). Infants who needed neonatal care had significantly lower intrauterine growth velocities compared to the rest of the study group; no correlation was found between intrauterine growth velocity and Apgar scores or umbilical pH. It is concluded that growth retardation in the third trimester can be identified by ultrasound fetometry, and is associated with maladaptation at birth and postnatal catchup. However, the correlations were weak suggesting that deviation at birth reflects, only to a limited degree, acceleration or deceleration of growth in the third trimester.