PEDIATRICS Vol. 120 No. 1 July 2007, pp. e102-e111 (doi:10.1542/peds.2006-2686)
ARTICLE |
Growth and Growth Hormone Therapy in Subjects With Mulibrey Nanism
a Department of Pediatric Endocrinology, Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
b Biomedicum Helsinki, Helsinki, Finland
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVES. Mulibrey nanism is a monogenic disorder with prenatal-onset growth restriction, mild dysmorphic features, and a strong tendency for insulin resistance but no major neurologic handicap. Growth hormone therapy has been shown to promote short-term growth in children born small for gestational age, but the experience with long-term therapy is insufficient. Growth in patients with mulibrey nanism has not been analyzed previously in detail.
METHODS. We evaluated the natural growth pattern and long-term impact of growth hormone treatment in the largest cohort of subjects with mulibrey nanism to date. The study included 72 living subjects followed up to 30 years. Thirty (18 female) were treated with recombinant human growth hormone for a median period of 5.7 years. Patients were reviewed at baseline and every 6 to 12 months during the therapy. Evaluation included assessment of height, weight, and pubertal status and laboratory analyses. Glucose metabolism was evaluated by oral glucose-tolerance test.
RESULTS. The patients were born small for gestational age with immature craniofacial features. They experienced a continuous deceleration in height (median decrement of 1.1 SDS) and weight for height (median reduction of 17%) in infancy followed by an incomplete catch-up growth lasting up to school age. The final adult height averaged 136 cm in girls and 150 cm in boys. Growth hormone treatment improved the prepubertal growth but had only little impact on adult height (+5 cm). The treated subjects showed earlier bone maturation and growth arrest but not a significant increase in insulin resistance. On the contrary, the subjects who were treated with growth hormone were slimmer and had less metabolic syndrome as young adults.
CONCLUSIONS. The patients with mulibrey nanism showed a distinct postnatal growth pattern. The growth hormone treatment was safe and induced a good short-term effect, but the impact on the adult height remained modest.
Key Words: genetic disease • fetal growth restriction • growth failure • growth hormone treatment • insulin resistance
Abbreviations: MUL—mulibrey nanism • TRIM—tripartite motif • SGA—small for gestational age • GH—growth hormone • BA—bone age • IGF—insulin-like growth factor • SDS—SD score • hSDS—height SD score • WFH—weight for height
Mulibrey (muscle-liver-brain-eye) nanism (MUL; Online Mendelian Inheritance in Man No. 253250) is a rare autosomal recessive disorder with growth restriction beginning in utero.1,2 Today some 130 patients are known worldwide, 88 of them from Finland. Sporadic cases have been reported from different ethnic groups all over the world.2 MUL is caused by mutations in the TRIM37 gene located on chromosome 17q22-q23.3 It encodes for TRIM37 protein, which is a member of the tripartite motif protein family (TRIM; composed of RING, B-box, and coiled-coil domains).4 TRIM37 is expressed in several tissues,5,6 has been localized to peroxisomes,4 and possesses E3 ubiquitin-ligase activity as several other RING proteins.7,8 Twelve different mutations have been reported in MUL patients, with 3 of them present in the Finnish patients with MUL: Fin-major (c.493-2A
G), Fin-minor (c.2212delG), and a new c.227T mutation.3,7,9
The dysmorphic features in MUL patients form a distinct entity with characteristic craniofacial features and constitutional gracility.2 Other typical findings are fibrous dysplasia of long bones, hepatomegaly, restrictive heart disease, cutaneous naevi flammae, yellowish dots in ocular fundi, and a J-shaped sella turcica.1,2 The patients are neurologically normal, but often mild muscular hypotonicity and slight delay in motor and speech development is evident.2 Feeding difficulties and respiratory tract infections, including severe pneumonias, are quite common in infancy. Congestive heart failure appears in 
10% of infants.2,10 An interesting recent finding is that patients with MUL show a dramatic change in glucose and lipid metabolism with age. Although the infants and children have a tendency for low glucose and insulin levels, a great majority developed severe insulin resistance and a full-blown metabolic syndrome between the ages of 11 and 20 years.11
Subjects with MUL form a homogenous group of small for gestational age (SGA) children. Growth hormone (GH) therapy has been shown to promote short-term growth both in SGA children and in children with a number of dysmorphic disorders, including Silver-Russell syndrome, but the experience with long-term therapy is still insufficient.12–15 Here we report the natural growth pattern of patients with MUL and their responsiveness to GH treatment. The results show a good short-term effect of GH in prepubertal children but only a modest impact on the adult height. Although subjects with MUL have a strong tendency for insulin resistance,11 GH seemed to have positive long-term effects on body weight and glucose metabolism.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients
Growth data on 72 patients (40 female) from 68 families were analyzed. All fulfilled the clinical diagnostic criteria of MUL.1,2 The diagnosis was also confirmed by genetic testing: 69 were homozygous for the Fin-major mutation, 2 were compound heterozygotes for the Fin-major and Fin-minor mutations, and 1 subject had the c.227T>C/Fin-major genotype. In infancy (0–24 months), upper respiratory tract infections and pneumonias were common problems, and half of the patients (38 of 72) exhibited some feeding difficulties, warranting nasogastric feeding or percutaneous gastrostomy (n = 6) in 21 of them. The feeding difficulty was classified as severe in 5 children because of prolonged and extremely poor and slow feeding, including fatigue and vomiting or total food neglect with no attempt for oral feeding. Congestive heart failure was diagnosed in 9 infants (13%) at a median age of 1.1 years.
Patient Follow-up
Since the early 1970s, clinical care of the Finnish patients with MUL has been centered in our institution. The patients have had physical examinations at 6- to 12-month intervals during childhood and puberty. Standing heights were measured with a stadiometer to the nearest millimeter, and the mean of 3 measurements was used. The weight was measured with an ordinary scale to the nearest 100 g. Height and weight measurements were made by the clinician or a trained nurse. When needed, growth data from birth records, child welfare centers, schools, and local hospitals were collected. Birth data were available from all 72 of the patients. A radiograph of the palm and wrist was obtained for evaluation of the bone age (BA). At baseline and annually thereafter BA was determined by a single observer (Dr Lipsanen-Nyman) according to the method described by Greulich and Pyle.16
GH Therapy
Thirty subjects (18 female) have been treated with recombinant human GH since the early 1990s. Fourteen of them are still on GH, and the duration of treatment ranges from 1.8 to 13.4 years (median: 5.7 years). The GH dose has been 0.035 mg/kg per day, and it has been adjusted to the patients' weight during the treatment. Decision on GH treatment was made on clinical grounds and was mainly based on auxological data. The patients were reviewed at baseline and at 3, 6, 9, and 12 months after initiation of the treatment and subsequently every 6 months.
Laboratory Examinations
Blood glucose, serum insulin, lipids, leptin, and insulin-like growth factor (IGF) 1 were measured annually since 1999 after an overnight fast. Serum IGF-1 levels were measured by radioimmunoassay (Incstar, Stillwater, MN), and serum leptin levels were assessed by specific radioimmunoassay (Linco Research Inc, St Louis, MO). A standard arginine or insulin-arginine tolerance test was used to evaluate the GH secretion. Serum GH concentrations were measured by monoclonal immunoradiometric assay (CIS Bio International, Gif-sur-Yvette, France) before the year 1995 and thereafter by AutoDelfia time-resolved immunofluorometric assay (PerkinElmer, Wallac, Turku, Finland). A peak serum GH response of >10 µg/L was considered normal, and a value 5 to 10 µg/L indicated partial GH deficiency. The patient was considered deficient in GH if the peak serum level was <5 µg/L in 2 separate tests. In patients receiving GH, blood counts and serum concentrations for liver, thyroid, and kidney function and glycohemoglobin A1C were followed as safety parameters. A 3-hour oral glucose-tolerance test (glucose load: 1.75 g/kg; maximum: 75 g) was performed on a subset of the patients, and glucose tolerance and insulin sensitivity were interpreted as described before.11
Data Analyses
Finnish growth standards were used for height and weight analysis.17 Height SD score (hSDS) was calculated for calendar age. Final hSDS was calculated from the standards of the Finns at the age of 18 years.
The weight of the patients was defined as the percentage of deviation from the age-specific median weight for height (WFH).18 Adult weights were also expressed as the BMI. Birth length, weight, and head circumference were expressed as SDSs according to the Finnish standards. The birth length and weight of patients born preterm (before 38 weeks of gestation) were extrapolated to term by using Finnish standards of prenatal growth.19 The onset of puberty was defined as stage P2G2 in boys and a stable breast stage of M2 in girls.20 Growth data were correlated to metabolic and endocrine parameters as described before.11
Wilcoxon test was performed for comparisons between the GH-treated and untreated patient groups. P values <.05 were defined as statistically significant. Metabolic and endocrine parameters were correlated with the hSDS increment during the preceding year, and the explanation rate was expressed as an R2 value.
The ethics committee of the Hospital for Children and Adolescents, University of Helsinki, approved the study. All of the patients or their guardians gave informed consent.
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Size at Birth
At birth, the infants with MUL were both short and light. The median birth length and weight adjusted to 40 weeks of gestation were 44.8 cm (median hSDS: –3.0) and 2300 g (median SDS: –3.0) for the girls and 45.0 cm (median hSDS: –2.8) and 2350 g (median SDS: –2.9) for the boys, respectively. The median occipitofrontal head circumference SDS was –0.5 (range: –0.9 to 0.8), indicating spared cranial growth with macrocephaly relative to birth length.
Height in Untreated Patients With MUL
The growth failure progressed in infancy with a median hSDS decrement of 1.1 from birth to 2.0 years of age (Fig 1). In 9 children with congestive heart failure and 5 with severe prolonged feeding difficulties, the linear growth decelerated even further. Their median hSDS at 2.0 years of age was –5.1 (range: –5.9 to –3.8) and –5.4 (range: –4.3 to –7.4), respectively, as compared with hSDS of –4.4 in children only mildly affected with these problems. Two children were born severely premature at gestation week 32, with a birth length SDS of –6.4 and –4.0, respectively. Their postnatal growth was most severely affected so that their hSDS at 2.0 years of age was –7.8 and –7.3.
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Infant growth deceleration was followed by a sustained period of spontaneous incomplete catch-up growth, which lasted up to school age (Fig 1). From 7 to 8 years onward, the median hSDS remained fairly stable in most patients. At the onset of puberty, the median hSDS was –3.6 (range: –6.3 to –1.0; Table 1 and Fig 1). The pubertal growth spurt was weak or absent (Fig 1). Twenty-five of the patients (13 female) have reached their adult height. The final adult height was, on average, 136 cm (range: 130–155 cm; median hSDS: –5.1) in female subjects and 150 cm (range: 147–162 cm; median hSDS: –4.1) in male subjects.
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Height in Patients With MUL Receiving GH Therapy
Thirty patients (18 female) have received GH therapy on average for 5.7 years (range: 1.8–13.4 years). At commencement of GH therapy, the median age was 4.4 years (range: 1.6–8.9 years), and the median hSDS was –4.7 (range: –7.8 to –2.0). The GH treatment improved growth temporarily so that the growth velocity reached its peak 12 to 18 months after the start (Figs 1 and 2 and Table 2). During the first year, the increment was 1.0 SDS on average, and by the onset of puberty, it was 1.8 SDS (range: 0.2–2.7 SDS). The hSDS was at pubertal onset 0.7 greater in the GH-treated compared with the untreated children (P < .02). During puberty, the median hSDS remained stable at –2.9 (Table 1). Two children with prolonged severe feeding difficulties and 3 with congestive heart failure were treated with GH. Three of them responded very poorly to the therapy, and the treatment was discontinued after 1.8, 2.0, and 2.4 years. The GH treatment still continues in 2 subjects, but the response has been modest. Both of the 2 children born severely premature received GH, but their responses have so far been poor.
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By now, 16 patients (8 female) receiving GH have reached their adult height with a median of 142 cm (range: 137–154 cm) and 155 cm (range: 150–163 cm) in female and male subjects, respectively (Fig 2). The corresponding median adult hSDS according to the Finnish standards was –4.2 in the female subjects and –3.6 in the male subjects (Fig 1 and Table 1). Thus, the difference in the final hSDS between the treated and untreated patients was 0.6 (
5 cm; P < .03; Fig 1). The female subjects seemed to benefit slightly more (by 0.4 hSDS) than the male subjects (P < .05). The pubertal growth was poor (Fig 1). The GH-treated female and male subjects reached their final height 1.1 and 0.6 years earlier than their untreated counterparts (P < .005 and P < .03, respectively). No correlation was found between the adult height and the age at start of the GH treatment, duration of the treatment, height at onset of puberty, GH peak during provocation, or the serum IGF-1 levels before commencement of the GH treatment.
WFH in GH-Treated and Untreated Subjects
Weight gain during infancy was very poor in all of the children, and during the 2 first years there was a continuous deceleration of the WFH (Fig 1). Children remained thin until puberty when WFH started to increase, more rapidly in the girls (Fig 1).
After commencement of GH therapy the median WFH increased. At onset of puberty, no difference in WFH was observed between the GH-treated and untreated subjects (Table 1). However, when reaching the adult height, the subjects treated with GH had remained slimmer than the untreated patients. Their median WFH was 0% (–20% to 24%) in the male subjects and 16% (–3% to 34%) in the female subjects, whereas the corresponding values in the untreated patients were 15% (–2% to 25%) and 25% (3% to 75%), respectively (P < .005; Table 1 and Fig 1).
BA and Puberty in GH-Treated and Untreated Subjects
The BA in young children was clearly delayed relative to chronologic age with a BA/chronologic age of 0.85 at 2 years. No significant difference in BA was found between the GH-treated and untreated subjects up to the age of 8 years (Fig 1). Thereafter, the bone maturation accelerated, particularly in the GH-treated patients, so that a significant difference (1.09 vs 0.92) in BA was evident at the age of 10 years (P < .01). At the onset of puberty, the ratio of BA and chronological age was 1.06 and 0.92 in the GH-treated and untreated patients, respectively (P < .03). The difference remained significant throughout puberty so that this ratio at the age of 14 years was 1.05 and 0.95 in the treated and untreated patients, respectively (P < .03; Figs 1 and 3).
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There was a wide individual variation in the onset of puberty with a median age of 12.5 and 13.0 years for boys and girls, respectively (Table 1). No significant difference was noted between the GH-treated and untreated patients. However, the duration from stage 2 breast development to menarche was shorter, and menarche occurred
3.0 years earlier in the GH-treated compared with untreated girls (Table 1).
GH Production in Children With MUL
The GH production was assessed by the arginine or arginine-insulin stimulation tests in 38 children with MUL at a median age of 5.1 years (range: 2.0–15 years). The response was normal (>10 µg/L) in 26% (10 of 38), subnormal (range: 5–10 µg/L) in 58% (22 of 38), and low (<5 µg/L) in 16% (6 of 38). The distribution was similar in those 26 individuals who were treated with GH after the tests (27% normal, 62% subnormal, and 11% low). Serum IGF-1 levels were evaluated in 26 prepubertal children who had not received GH treatment. All had normal serum concentrations of IGF-1, but half of them had an IGF-1 value in the lowest quartile of the reference range.
Growth and Glucose Metabolism in Children With MUL
Data on glucose metabolism, including an oral glucose-tolerance test, were available from 13 children (median age: 6.4 years; range: 3.4–9.7 years) who had received GH during the preceding year (6 currently on GH) and 17 without any growth promoting therapy (median age: 7.1 years; range: 3.2–10.6 years). In both groups, the patients with the greatest hSDS increment during the preceding year presented the highest levels of fasting serum insulin (R2 = 0.69 and 0.62), postload peak insulin (R2 = 0.72 and 0.72), serum IGF-1 (R2 = 0.54 and 0.58), and serum leptin (R2 = 0.57 and 0.58; Fig 4). In all 30 of the children, serum fasting insulin and postload peak insulin levels correlated well with the serum IGF-1 concentration with explanation rates (R2 value) of 0.66 and 0.71, respectively (Fig 4). Overall, the GH-treated children had slightly higher serum fasting insulin (median: 9 vs 5 mU/L; P = .05) and postload peak insulin (median: 152 vs 89 mU/L; P = .08, not significant) concentrations compared with the untreated children. The same was noted in pubertal female subjects. The difference in fasting (15 vs 11 mU/L) or postload peak insulin concentrations (200 vs 173 mU/L), however, did not reach statistical significance.
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Glucose Metabolism in GH-Treated and Untreated Young Adults With MUL
Glucose metabolism was analyzed in 12 adults (median age: 24.2 years) who had been treated with GH in childhood and in 11 untreated subjects (median age: 23.9 years). Patients in the treatment group were lighter (WFH 0% vs 15%; P < .04), had a lower BMI (17 vs 21 kg/m2; P < .04), and showed lower fasting blood glucose (4.4 vs 5.0 mmol/L; P < .05) than the untreated subjects. Moreover, their blood pressure (median: 120/76 vs 133/83 mmHg), total serum cholesterol (median: 4.0 vs 5.2 mmol/L), and postload peak serum insulin (192 vs 250 mU/L) were lower than in untreated subjects, although the comparison did not reach statistical significance (Table 3). Also, the frequency of metabolic syndrome was twice as high (64% vs 33%) in the GH-treated compared with the untreated subjects.
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Of all newborns, 2.5% are born SGA, and 10% to 15% of them lack postnatal catch-up growth and remain persistently short.21 Many of them have chromosome abnormalities, monogenic disorders, or familial or sporadic syndromes.22 We report here the natural growth pattern and impact of long-term GH treatment in a monogenic disorder, MUL. To our knowledge, this study provides the longest follow-up time of the GH therapy in subjects who represent a homogenous subgroup of children with prenatal growth restriction.
Our results clearly show that patients with MUL are born SGA and not only fail in early postnatal catch-up growth but also experience a continuous deceleration both in height and weight development through infancy (
24 months). This wasting is followed by a subsequent spontaneous but incomplete catch-up growth until the age of 7 to 8 years. This growth pattern and the early catch-down in height and weight resembles those of infants born very preterm (at weeks 23–25 of gestation) experiencing postnatal extrauterine growth restriction.23–25 Growth in preterm infants decelerates as they become exposed to extrauterine life, and their energy expenditure shifts to promote survival rather than growth.23 Infants with MUL born at term not only grow as premature infants, they also present many premature features, such as relative macrocephaly, wide skull sutures and prominent forehead (Fig 3), and an immature craniofacial skeleton: the peculiar shape of sella turcica in MUL resembles the shape of the bony sphenoid before the cartilaginous dorsum sellae has ossified.26 Also, the shape of the skull and the size relationship between the skull and the face are in line with an idea of delayed prenatal and postnatal maturation in MUL.2,26 The fact that half of the infants with MUL have serious feeding difficulties and are prone to severe pneumonias proposes immaturity as well, because similar problems are common among preterm infants with immature lungs and bowel function.25,27 Although the frequency of feeding difficulties in patients with MUL is strikingly high, it seems that only severe and prolonged feeding difficulties had a negative impact on the linear growth.
Most patients with MUL had at least partial GH deficiency and showed subnormal or low-normal levels of serum IGF-1. Evidence of disturbances in the GH-IGF axis, such as GH deficiency and resistance, has been reported previously in short children born SGA.28,29 IGF-1 and IGF-2 are major regulators of prenatal and postnatal growth, and reduced IGF-1 levels have been observed in children who are born SGA.29,30 Also, gene-knockout studies have shown a major impact of IGF-1 on prenatal and postnatal growth.30 Recent observations of variation in methylation patterns regulating imprinting and expression of IGF-2 in Silver-Russell syndrome further highlight the role of growth factors in IUGR.31 The precise role of the GH-IGF axis in the poor growth of subjects with MUL remains to be elucidated.
The long-term GH treatment had little impact on the adult height of subjects with MUL (hSDS increment of 0.6 = 5 cm), which is in line with results reported previously in patients with Silver-Russell syndrome and skeletal dysplasias.13,32 The gain in height was mainly achieved before the onset of puberty, as has been seen in previous studies on SGA.33 A substantial catch-up growth was observed, especially in the first 2 years, and, at the time of discontinuation of the GH therapy, there was a median hSDS increment of 1.9 compared with baseline data. Bone maturation and growth arrest, however, occurred early in patients receiving GH, which explains why the adult height in the treated patients still remained very poor as compared with the general population. The subjects treated with GH were slightly smaller at 2 years of age (median hSDS: –4.4 vs –4.7), which may cause a small bias. The adult height correlated poorly with the parental target height, and no predictive factor for the growth response was found. Five patients (3 on GH) with only minor heart and neonatal problems reached closest to their target height, suggesting that the overall severity of the disease influences the linear growth. However, even these subjects remained between –1.5 and –3.2 hSDS below their target height.
It is interesting to note that most MUL patients develop insulin resistance in childhood and metabolic syndrome with severe insulin resistance after puberty.11 Because GH is an insulin antagonist and may induce hyperinsulinemia, we were especially concerned about the glucose metabolism in the GH-treated patients with MUL. Importantly, the preexisting insulin responsiveness was not significantly increased by the GH therapy in prepubertal or pubertal children. Moreover, the adult patients who had received GH had lowered WFH and BMI, and their deterioration of the glucose metabolism seemed less severe as compared with untreated subjects with MUL. Whether this holds when a larger number of patients with MUL has reached the adulthood remains to be seen. However, favorable changes in body composition, BMI, and the lipid atherogenic index have been presented in large cohorts of SGA children on GH therapy.34
It is also interesting to note that the greatest increment in height was observed in those children with the highest fasting and postload peak serum insulin concentrations, suggesting that insulin might improve the spontaneous childhood growth and accelerate the short-term catch-up growth after commencement of GH therapy. Indeed, insulin is a well-known growth-promoting factor both prenatally and postnatally. It regulates the IGF-1 concentration by facilitating the binding of GH to its receptor, stimulates the production of IGF-1, and increases bioavailability of IGF-1 by suppressing the hepatic synthesis of IGF binding protein.35,36 Moreover, in a recent study involving non-GH-treated SGA girls, a rapid progression in pubertal growth tempo and progression to menarche driven by insulin was observed.37,38 Our results are in line with this, suggesting that the aggravated levels of insulin might underlie the faster pubertal tempo to menarche seen in female subjects with MUL on GH treatment. However, although female subjects with MUL have spontaneous puberty with menarche, they present early irregularity of menstrual periods with subsequent ovarian failure.39 Because pubertal growth is driven primarily by estrogen,40 it is possible that sex steroids have an impact on the poor pubertal growth in patients with MUL.
The TRIM37 mutations in the Finnish patients with MUL result in a nonfunctional TRIM37 protein. TRIM37 has been localized to peroxisomes in cell cultures and found to act as an E3 ubiquitin ligase.4,7 The ubiqutin-proteosome pathway has been implicated in the pathogenesis of type 2 diabetes and growth failure.11,41 GH receptor is a key regulator of cellular metabolism and requires an active ubiquitination system for both endocytosis and degradation of GH receptor.42 Recently discovered mutations in the gene cullin 7 (CUL7) on human chromosome 6p21 have been identified to result in the autosomal recessive 3-M syndrome, with features resembling those of MUL, including severe prenatal and postnatal growth retardation, facial dysmorphism, large head circumference, and normal intelligence. It is interesting to note that the CUL7 is crucial in assembling an E3 ubiquitin-ligase complex and thereby promotes ubiquitination.43 Mutations in the CUL7 gene result in defective ubiquitination linking impaired ubiquitination to the pathogenesis of prenatal-onset growth failure in humans. MUL seems to be a novel example of such conditions.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our study provides results on the GH treatment in a homogenous subgroup of SGA children failing to catch up. The children with MUL share several features with the very preterm infants, and the data may bring information to the debate on the GH treatment in very preterm children experiencing extrauterine growth restriction.23,25 The GH therapy in the subjects with MUL was safe and improved the growth in the short-term. However, the impact of GH therapy on the adult height was modest compared with the short-term response, which should be kept in mind when this mode of therapy is planned. Whether the same situation is noted in other growth-deficiency syndromes or in very preterm children remains to be seen.
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ACKNOWLEDGMENTS |
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This study was supported by the Finnish Foundation for Pediatric Research, Finska Läkaresällskapet, Finnish State Grant TYH 3304, the Finnish Academy, the Sigrid Juselius Foundation, the Wilhelm and Else Stockmann Foundation, and the K. Albin Johansson Foundation.
We thank the families of our patients and express our gratitude to the patients' local pediatricians for excellent cowork. We express special gratitude to Prof Jaakko Perheentupa for his pivotal early role in the diagnosis and treatment of patients with Mulibrey nanism.
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FOOTNOTES |
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Accepted Dec 12, 2006.
Address correspondence to Marita Lipsanen-Nyman, MD, PhD, Hospital for Children and Adolescents, Department of Pediatric Endocrinology, University of Helsinki, 00290 Helsinki, Finland. E-mail: marita.lipsanen{at}hus.fi
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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