[Influence of Parental Body Measurements on Birth Weight of Eutrophic Term Newborns with Special Consideration of Paternal Body Measurements]. / Zum Einfluss von Körpermaßen der Eltern auf das Geburtsgewicht von eutrophen Termingeborenen (TG) unter besonderer Berücksichtigung der Körperhöhe und des Körpergewichts des Vaters.

A significant influence of maternal body height and weight on neonatal birth outcome has been confirmed before, whereas the influence of paternal traits is rather unknown. In order to analyze the correlation between parental body measurements and the birth weight of newborns, data of 1312 eutrophic term newborns and their parents were collected based on a multicenter study in 10 participating German maternity clinics. The collected data included the birth weight of the infants and the body height and weight of their parents. The results show a significant correlation between infant birth weight and maternal body height. Even with a constant body height and body weight of fathers in a range between 176-184 cm and 76-84 kg, taller mothers gave birth to children with a higher birth weight than shorter mothers. Furthermore, higher maternal body weight is also correlated with increased birth weights, although this correlation is attenuated in higher maternal weight groups. Data regarding body weight and body height of fathers showed similar results with regard to birth weight of the newborns. At a constant maternal body height (164-172 cm) and weight (56-64 kg), the body weight of newborns significantly correlates with the body height of fathers but not with their body weight. The multivariable regression analysis resulted in the following ranking of influence factors on the birth weight of newborns: 1) body height of mother, 2) body weight of mother, 3) body height of father. The results gave support to the assumption of a certain genetic influence of parental body stature on their neonates but argue for an even stronger impact of maternal environmental conditions on the developmental status of neonates.

From melody to words: The role of sex hormones in early language development.

Contribution to Special Issue on Fast effects of steroids. Human infants are the most proficient of the few vocal learner species. Sharing similar principles in terms of the generation and modification of complex sounds, cross-vocal learner comparisons are a suitable strategy when it comes to better understanding the evolution and mechanisms of auditory-vocal learning in human infants. This approach will also help us to understand sex differences in relation to vocal development towards language, the underlying brain mechanisms thereof and sex-specific hormonal effects. Although we are still far from being capable of discovering the "fast effects of steroids" in human infants, we have identified that peripheral hormones (blood serum) are important regulators of vocal behaviour towards language during a transitory hormone surge ("mini-puberty") that is comparable in its extent to puberty. This new area of research in human infants provides a promising opportunity to not only better understand early language acquisition from an ontogenetic and phylogenetic perspective, but to also identify reliable clinical risk-markers in infants for the development of later language disorders.

Dyslexia risk variant rs600753 is linked with dyslexia-specific differential allelic expression of DYX1C1.

An increasing number of genetic variants involved in dyslexia development were discovered during the last years, yet little is known about the molecular functional mechanisms of these SNPs. In this study we investigated whether dyslexia candidate SNPs have a direct, disease-specific effect on local expression levels of the assumed target gene by using a differential allelic expression assay. In total, 12 SNPs previously associated with dyslexia and related phenotypes were suitable for analysis. Transcripts corresponding to four SNPs were sufficiently expressed in 28 cell lines originating from controls and a family affected by dyslexia. We observed a significant effect of rs600753 on expression levels of DYX1C1 in forward and reverse sequencing approaches. The expression level of the rs600753 risk allele was increased in the respective seven cell lines from members of the dyslexia family which might be due to a disturbed transcription factor binding sites. When considering our results in the context of neuroanatomical dyslexia-specific findings, we speculate that this mechanism may be part of the pathomechanisms underlying the dyslexia-specific brain phenotype. Our results suggest that allele-specific DYX1C1 expression levels depend on genetic variants of rs600753 and contribute to dyslexia. However, these results are preliminary and need replication.

Hormonal 'minipuberty' influences the somatic development of boys but not of girls up to the age of 6 years.

OBJECTIVE: Hormonal 'minipuberty' refers to a transient sex-specific surge of LH, FSH, testosterone (T) and estradiol (E2) in the first few months of life. We hypothesized a potential long-term effect of this hormonal surge on somatic parameters in the following years and therefore designed this longitudinal study. DESIGN: A hierarchical multiple regression analysis was used to analyse the potential influence of hormone concentrations during minipuberty on anthropometric measurements conducted in the first 6 years of life. PATIENTS: Thirty-five healthy babies (17 male, 18 female) were the participants. MEASUREMENTS: Testosterone, E2, SHBG, LH and FSH were measured at the ages of four, eight and 20 weeks. Anthropometric measurements were taken eight times in the first 12 months, then every 6 months up to the age of 6 years. RESULTS: A significant negative effect was found in boys between testosterone and LH levels at 8 weeks and body weight up to the age of 6 years and BMI up to 6 years (LH) and 3 years (T), respectively. A further negative effect was found between E2 levels at the age of 20 weeks and body weight as well as body length in the years that followed. A positive effect was observed between E2 at the age of 4 weeks and skinfold thickness up to the age of 6 years in boys. No significant effects were found in girls. CONCLUSIONS: The findings seem to reflect an up to now unknown long-term influence of the physiological early hormonal surge on the subsequent male but not female somatic development.

Sex hormone influence on human infants' sound characteristics: melody in spontaneous crying.

The specific impact of sex hormones on brain development and acoustic communication is known from animal models. Sex steroid hormones secreted during early development play an essential role in hemispheric organization and the functional lateralization of the brain, e.g. language. In animals, these hormones are well-known regulators of vocal motor behaviour. Here, the association between melody properties of infants' sounds and serum concentrations of sex steroids was investigated. Spontaneous crying was sampled in 18 healthy infants, averaging two samples taken at four and eight weeks, respectively. Blood samples were taken within a day of the crying samples. The fundamental frequency contour (melody) was analysed quantitatively and the infants' frequency modulation skills expressed by a melody complexity index (MCI). These skills provide prosodic primitives for later language. A hierarchical, multiple regression approach revealed a significant, robust relationship between the individual MCIs and the unbound, bioactive fraction of oestradiol at four weeks as well as with the four-to-eight-week difference in androstenedione. No robust relationship was found between the MCI and testosterone. Our findings suggest that oestradiol may have effects on the development and function of the auditory-vocal system in human infants that are as powerful as those in vocal-learning animals.

Somatic classification of neonates based on birth weight, length, and head circumference: quantification of the effects of maternal BMI and smoking.

We defined neonates as small, appropriate, or large for gestational age (SGA, AGA, LGA) based on birth weight, length, and head circumference. We analyzed the effects on the somatic classification of maternal body mass index (BMI) (<18.5, 18.5-24.99, 25.0-29.99, ≥ 30) and smoking during pregnancy (0, 1-7, 8-14, ≥ 15 cigarettes daily). Data were from the German Perinatal Survey (1998-2000; 433,669 cases). The following refers to the classification by birth weight. In the normal maternal weight population SGA rates increased with cigarette consumption: 9.8%, 17.8%, 21.6%, and 25.4% for non-smokers, and smokers of 1-7, 8-14, and ≥ 15 cigarettes daily, respectively. In non-smoking underweight women the SGA rate was 17.4%. In underweight smokers of ≥ 15 cigarettes daily the SGA rate was 38.5% [odds ratio 5.77, 95% confidence interval 5.10-6.53, compared with normal weight non-smokers]. In the normal maternal weight population, LGA rates were 9.9%, 5.3%, 4.6%, and 3.5% for non-smokers, and smokers of 1-7, 8-14, and ≥ 15 cigarettes daily, respectively. In the obese, LGA rates were 20.9% (non-smokers) and 11.4% (≥ 15 cigarettes). Similar findings were obtained for the somatic classifications based on birth length and head circumference. Results for the various combinations of maternal BMI and smoking status in the three classification systems are described. Our findings may assist in individualized risk assessment for SGA and LGA births.

Obesity in pregnant women: a 20-year analysis of the German experience.

BACKGROUND/OBJECTIVE: To investigate the longitudinal development of maternal body weight and analyze the influence of obesity on obstetrics during more than two decades in Germany. SUBJECTS/METHODS: Data collected from the Federal state of Schleswig-Holstein (German Perinatal Survey) were analyzed with regard to the dynamics of maternal anthropometric variables (body weight, BMI) between 1995-7 and 2004-17. In total 335,511 mothers substantiated the presented study-collective. The statistical analysis was performed using IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY. RESULTS: Maternal BMI advanced significantly over the study period. Among a rise in mean periconceptional body weight (67.6-72.0 kg), the segment of obese women increased disproportionately (in average 9.4-19.2%). Despite the observed trend to late giving birth (mean maternal age 1995: 29.3 vs. 30.7 years in 2017), it was not advanced maternal age but parity that influenced the continuous increase in maternal weight (mean maternal body weight 1995-7: primi- bi-, multiparae 67.4, 68.3 and 69.0 kg vs. 2004-17: primi- bi-, multiparae 70.0, 71.5 and 73.2 kg respectively). CONCLUSION: Obesity is a major problem on health issues in obstetrics. Advancing maternal BMI, increasing mother's age and derived prenatal risks considerably complicate pregnancy and delivery. It has to be emphasized that its consequences do not end with delivery or childbed, but represent a livelong burden to the mother and their offspring. Hence, multimodal strategies to reduce/control periconceptional body weight are mandatory.

Minipuberty: Why Does it Happen?

Minipuberty describes the transient sex-specific activation of the hypothalamic-pituitary-gonadal (HPG) axis during the first 6 months of life in boys and during the first 2 years in girls. It leads to a rise of luteinizing hormone, follicle-stimulating hormone, estradiol, and testosterone. The existence of minipuberty has been known for >40 years, but we still do not fully understand why it takes place. Current thinking suggests that it is an essential imprinting period for different body functions. Firstly, minipuberty plays an important role in genital organ development; testosterone influences penile growth, the number of Sertoli cells, and spermatogenesis. Secondly, it seems to influence the infant's body composition; testosterone likely has an imprinting effect on BMI and body weight of boys and growth velocity in the first 6 months of life. Thirdly, it affects cognitive functions; testosterone has an impact on language organization in the infant brain and estradiol affects laryngeal sound production and baby babbling. There are inconsistent findings concerning the impact of minipuberty on sex-specific playing behavior. Minipuberty is an interesting field of research, and further studies in this area will teach us more about this exciting period of human development.

Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome.

BACKGROUND: Patients with mutations or deletions of the Short Stature Homeobox-containing(SHOX) gene have variable degrees of growth impairment, with or without mesomelic skeletal dysplasia. If untreated, short patients with SHOX deficiency remain short in adulthood. Growth hormone (GH) treatment improves short-term linear growth; however, there are no data on GH treatment effects on final height. PATIENTS: In a retrospective study, we assessed the relative effects of GH on final height gain in patients with SHOX deficiency (n = 14; 12 females) and Turner syndrome (TS) (n = 158). Patients were included if they fulfilled the following criteria: genetically-confirmed SHOX deficiency or TS, baseline height SDS <1.5, GH treatment started at Tanner stage < or =2, duration of GH treatment >2 years, and final height attained. RESULTS: Both groups of patients were short at baseline (height SDS [mean +/- SD]: SHOX deficiency, -3.3 +/- 0.9; TS, -2.9 +/- 0.8). Height SDS gain from baseline to final height was significant for each patient group (SHOX deficiency, 1.1 +/- 0.7; TS, 1.2 +/- 0.8; p < 0.001); however, it was not significantly different between groups (p = 0.708). CONCLUSIONS: Patients with SHOX deficiency receive similar final height benefit from GH treatment to those with TS.

Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies.

CONTEXT: The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency. OBJECTIVES: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations. DESIGN: The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments. PATIENTS: A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study. RESULTS: In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive. CONCLUSIONS: LHX4 mutations are a relatively rare cause of combined pituitary hormone deficiency. This report extends the range of phenotypes associated with LHX4 gene mutations and describes three novel exonic mutations in the gene.

Sex hormone testosterone affects language organization in the infant brain.

Using a phonological discrimination paradigm, we show that the brain responses of 4-week-old infants systematically vary as a function of biological sex and testosterone level. Females who are generally low on testosterone demonstrated a clear phonological discrimination effect with a bilateral distribution. In male infants this effect systematically varied as a function of testosterone level. Males with high testosterone showed no discrimination effect, whereas males with low testosterone displayed a discrimination effect, which was clearly left-lateralized. The present data provide evidence for a strong influence of testosterone on language function and lateralization already present during the first weeks of life.

Inspiratory Phonation in Baby Voice.

OBJECTIVE: This study aimed to evaluate the developmental occurrence of inspiratory phonations (IPs) in the spontaneous cries of healthy infants across the first 10 weeks of life. STUDY DESIGN: This is a populational retrospective study. PARTICIPANTS: The spontaneous crying of 17 healthy infants (10 were male) was retrospectively investigated. MATERIALS AND METHODS: Sound files of spontaneously uttered cries that were repeatedly recorded once per week for across the first 10 weeks of life were retrospectively analyzed. Frequency spectra and waveforms were used to identify the occurrence of IPs and to measure the duration and fundamental frequency (fo) of each instance of IP. RESULTS: A consistent number of IPs were identified across the 10-week period. All infants were observed to produce IPs in their spontaneous cries, although the frequency of occurrence was not consistent across infants. A marked sex difference was observed with female infants producing a higher number of IPs compared to males. The duration and fo of IPs did not differ significantly across the 10 weeks or between sexes. CONCLUSIONS: The production of IPs is a regularly occurring phenomenon in healthy, normally developing infants' spontaneous crying. The proportional difference in the production of IPs between female and male infants, observed for the first time here, is postulated to be linked to sex-based differences (including steroidal hormones) in respiratory anatomy and physiology.

External skeletal robusticity of children and adolescents - European references from birth to adulthood and international comparisons.

ABSTRACT: Background: In our modern world, the way of life in nutritional and activity behaviour has changed. As a consequence, parallel trends of an epidemic of overweight and a decline in external skeletal robusticity are observed in children and adolescents. Aim: We aim to develop reference centiles for external skeletal robusticity of European girls and boys aged 0 to 18 years using the Frame Index as an indicator and identify population specific age-related patterns. Methods: We analysed cross-sectional & longitudinal data on body height and elbow breadth of boys and girls from Europe (0-18 years, n = 41.679), India (7-18 years, n = 3.297) and South Africa (3-18 years, n = 4.346). As an indicator of external skeletal robusticity Frame Index after Frisancho (1990) was used. We developed centiles for boys and girls using the LMS-method and its extension. Results: Boys have greater external skeletal robusticity than girls. Whereas in girls Frame Index decreases continuously during growth, an increase of Frame Index from 12 to 16 years in European boys can be observed. Indian and South African boys are almost similar in Frame Index to European boys. In girls, the pattern is slightly different. Whereas South African girls are similar to European girls, Indian girls show a lesser external skeletal robusticity. Conclusion: Accurate references for external skeletal robusticity are needed to evaluate if skeletal development is adequate per age. They should be used to monitor effects of changes in way of life and physical activity levels in children and adolescents to avoid negative health outcomes like osteoporosis and arthrosis.

Fundamental Frequency of Crying in Two-month-old Boys and Girls: Do Sex Hormones During Mini-puberty Mediate Differences?

OBJECTIVE: To evaluate whether the puberty-like sex hormone surge during the first months of life (mini-puberty) affects fundamental frequency (fo) in infant crying as one would derive from hormone influences on voice in adults. STUDY DESIGN: Populational prospective study. PARTICIPANTS: Twenty healthy normal-hearing infants (nine boys) were recruited for participation. METHODS: Spontaneously uttered cries were collected from each infant at 8 weeks of age. The cries were acoustically analyzed for mean fo and fo range. The fo properties were correlated to the average serum levels of bioavailable estradiol (E2) (mean E2/sex hormone-binding globulin [SHBG]) and testosterone (T) (mean T/SHBG) across the second month of life. RESULTS: Whereas no significant hormone effect was found for mean fo, a significant negative correlation (r = -0.55) was found between fo range and mean E2/SHBG. No indication for a T influence on fo features was found at this age. Although girls showed a slightly higher mean E2 concentration than boys did, the observed differences in cry fo range were judged to be reflective of an infant's serum concentration of E2 rather than a sex-based difference. CONCLUSION: In the absence of laryngeal size differences between female and male infants, the result was interpreted as indicative of an E2 influence on viscoelastic properties of the vocal folds. In our opinion, the investigation of young infants' vocalizations during the early postnatal surge of sex steroids (mini-puberty) may advance our understanding of the mechanisms mediating average sex differences in vocal development and early communication.

Cross-sectional analysis of universal vitamin D supplementation in former East Germany during the first year of life.

BACKGROUND: Universal vitamin D supplementation is controversial. Preventative examinations and public health initiatives in former East Germany that included vitamin D prophylaxis for children were regulated by official recommendations and guidelines. The aim of this study is to analyse the impact of a standardised nationwide guideline for universal supplementation with 400 International Units (IU) vitamin D3/day during the first year of life on clinical and biochemical parameters and the influence of surrounding factors. METHODS: This is a cross-sectional analysis looking at data from a field study of 3481 term-born children during their first year of life that was conducted in 1989. RESULTS: There were no significant clinical signs of rickets. 25 hydroxyvitamin D (25(OH)D) (mean and SEM, total analyses n=572) after birth (n=28) was 36(7) nmol/L, at 1 month 64(4) nmol/L (n=70, p<0.0001), 91(5) nmol/L at 3 months (n=95, p<0.0001), 65(8) nmol/L at 8 months (n=21, p=0.005) and ranged between 33 and 109 nmol/L until 12 months. Less than 0.2% of analyses revealed pathological levels for calcium or phosphate. Alkaline phosphatase (ALP) levels (n=690) were >1500 U/L (95th percentile) in 3.6%. Participants were on breastmilk or vitamin D-free formula, with solids added from 6 months of age. There were seasonal variations in 25(OH)D levels with a rise during spring and autumn. Thus this analysis is unique as sun exposure and supplementation can be considered as the only vitamin D sources. CONCLUSIONS: We conclude that universal supplementation with 400 IU of vitamin D3 during the first year of life is safe and provides sufficient 25(OH)D levels in Germany.

Fundamental Frequency Variation in Crying of Mandarin and German Neonates.

OBJECTIVES: This study examined whether prenatal exposure to either a tonal or a nontonal maternal language affects fundamental frequency (fo) properties in neonatal crying. STUDY DESIGN: This is a population prospective study. PARTICIPANTS: A total of 102 neonates within the first week of life served as the participants. METHODS: Spontaneously uttered cries (N = 6480) by Chinese (tonal language group) and German neonates (nontonal group) were quantitatively analyzed. For each cry utterance, mean fo and four characteristic variation measures (fo range, fo fluctuation, pitch sigma, and pitch sigma fluctuation) were calculated, averaged for individual neonates, and compared between groups. RESULTS: A multiple analysis of variance highlighted a significant multivariate effect for language group: Wilks λ = .76, F(6, 95) = 4.96, P < .0001, ηp2 = .24. Subsequent univariate analyses revealed significant group differences for fo variation measures, with values higher in the tonal language group. The mean fo did not differ between groups. CONCLUSIONS: Data regarding fo variation in infant cries have been suggested as providing critical insight into the maturity of neurophysiological vocal control. Our findings, alongside with auditive perception studies, further underscore the assumption of an early shaping effect of maternal speech, particularly fo-based features, on cry features of newborns. Further studies are needed to reexamine this observation and to assess its potential diagnostic relevance.

Baby babbling at five months linked to sex hormone levels in early infancy.

Gender-dependent differentiation of the brain at morphological, neurochemical and functional levels of organization have been shown to be primarily controlled by sex differences in gonadal hormone concentrations during pre- and early postnatal development. Indeed, previous studies have reported that pre- and perinatal hormonal environments influence brain development and, consequently, affect sex specific long-term language outcomes. Herein, we investigated whether postnatal surges of estrogen (estradiol) and androgen (testosterone) may predict properties of pre-speech babbling at five months. This study is the first attempt to investigate a possible correlation between sex hormones and infants' articulatory skills during the typical postnatal period of extended hormonal activity known as 'mini-puberty.' A hierarchical, multiple regression approach revealed a significant, robust positive relationship between 4-week concentrations of estradiol and individual articulatory skills. In contrast, testosterone concentrations at five months negatively correlated with articulatory skills at the same age in both boys and girls. Our findings reinforce the assumption of the importance of sex hormones for auditory-vocal development towards language in human infants.

Sex hormones in early infancy seem to predict aspects of later language development.

Sex differences in the development of cognitive behavior such as language have long been of great research interest. Lately, researchers have started to associate language function and brain differences with diverse sex hormones (e.g., testosterone/estradiol). However, results concerning the impact of early postnatal sex hormone concentration on the child's later language development are rare. Here, we analyze the impact of testosterone and estradiol in girls and boys as well as their neurophysiological phonemic discrimination at age 5months on language development at age 4years. Interestingly, we found strong positive estradiol and negative testosterone impact on later language performance at age 4years, which was true for both girls and boys. These results demonstrate that postnatal sex hormone surge might be viewed as one factor determining later language development, independent of gender.

SHOX haploinsufficiency and Leri-Weill dyschondrosteosis: prevalence and growth failure in relation to mutation, sex, and degree of wrist deformity.

SHOX mutations causing haploinsufficiency were reported in Leri-Weill dyschondrosteosis (LWD), which is characterized by mesomelic short stature and Madelung deformity of the wrists. The aim of this study was to determine the prevalence of SHOX mutations in LWD and to investigate the degree of growth failure in relation to mutation, sex, age of menarche, and wrist deformity. We studied 20 families with 24 affected children (18 females) and nine affected parents (seven females). All patients presented with bilateral Madelung deformity and shortening of the limbs. Height, sitting height, parental height, birth length, age of menarche, and presence of minor abnormalities were recorded. The degree of Madelung deformity was estimated by analysis of left hand radiographs. Microsatellite typing of the SHOX locus was used for detection of SHOX deletions and PCR direct sequencing for the detection of SHOX point mutations. In 14 of 20 families (70%), SHOX mutations were detected, with seven deletions (four de novo) and seven point mutations (one de novo). The latter included five missense mutations of the SHOX homeodomain, one nonsense mutation (E102X) truncating the whole homeodomain, and one point mutation (X293R) causing a C-terminal elongation of SHOX. Median age of the affected children was 13.4 yr (range, 6.1-18.3), mean height sd score (SDS) (sd in parentheses) was -2.85 (1.04), and mean sitting height/height ratio SDS was +3.06 (1.09). Mean birth length SDS was -0.59 (1.26). Growth failure occurred before school age. Height change during a median follow-up of 7.4 yr (range, 2.3-11.3) was insignificant with a mean change in height SDS of -0.10 (0.52). Mean height SDS of affected parents was -2.70 (0.85) vs. -0.91 (1.10) in unaffected parents. Height loss due to LWD was estimated calculating delta height defined by actual height SDS minus target height SDS of the unaffected parent(s). In the children, mean delta height SDS was -2.16 (1.06), the loss being greater in girls at -2.30 (1.02) than in boys at -1.72 (1.09) (P = 0.32). In patients with SHOX deletions, it was -2.14 (1.15) vs. -1.67 (0.73) for the SHOX point mutation group (P = 0.38). Mean delta height SDS was -2.26 (0.68) for the girls with early menarche (<12 yr) vs. -2.08 (0.91) for the other postmenarcheal girls (P = 0.72). Height loss in patients with radiologically severe wrist deformities in comparison with those having milder radiological signs was -2.81 (1.01) vs. -1.70 (1.04) (P = 0.03). GH treatment in five children during a median duration of 3.4 yr (range, 1.5-9.8 yr) with a median dosage of 0.23 mg/kg.wk (range, 0.14-0.25) resulted in a mean height SDS gain of +0.82 (0.34). In conclusion, SHOX defects were the main cause of LWD. Growth failure occurred during the first years of life with a mean height loss of 2.16 SDS whereas pubertal growth may only be mildly or not affected. Children with a severe degree of wrist deformity were significantly shorter than those with mild deformities. No statistically significant effects of type of mutation, age of menarche, or sex on height were observed. The effect of GH therapy varied between individuals and needs to be examined in controlled studies.