Start small, think big: Growth monitoring, genetic analysis, treatment and quality of life in children with growth disorders Stalman, S.E.

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1 UvA-DARE (Digital Academic Repository) Start small, think big: Growth monitoring, genetic analysis, treatment and quality of life in children with growth disorders Stalman, S.E. Link to publication Citation for published version (APA): Stalman, S. E. (201). Start small, think big: Growth monitoring, genetic analysis, treatment and quality of life in children with growth disorders General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 20 Nov 2018

2 chapter Positive Effect of Growth Hormone Treatment in Maternal Uniparental Disomy Chromosome 14 Susanne E. Stalman, Gerdine A. Kamp, Yvonne M. Hendriks, Raoul C.M. Hennekam, Joost Rotteveel Clinical Endocrinology (Oxf ) 2015;83(5):71-

3 Abstract Objective Maternal uniparental disomy of chromosome 14 (matupd(14)) resembles Prader Willi syndrome (PWS). As positive effects of growth hormone (GH) are observed in individuals with PWS, treatment with GH may be useful in individuals with matupd(14) as well. The aim of this study was to investigate the effect of GH treatment on growth and body composition in children with matupd(14). Design This is a prospective observational study of GH treatment in two girls with matupd(14) during 2 years, and spontaneous growth in another matupd(14) girl of similar age. Patients Three girls (patient A, B and C, aged 8 9, 11 4 and 12 7 years, respectively) with matupd(14) were included in this study. Measurements Patients A and B were treated with GH during 2 years. Patient C was not treated with GH, as she was diagnosed at an age at which she attained near-final height. Main outcome measures included height, weight, body proportions, IGF-1, bone age, and DXA scan for body composition. Results In both treated girls, a considerable increase in height (from 2 3SD and 1 2SD to 1 2SD and 0 SD, respectively) and IGF-1 levels (from +0 1SD and 1 4SD to +1 3SD and +0 9SD, respectively) and, in patient A, a decrease in weight (+1 2 SD to 0 7SD), and improved body composition (fat percentage from 51 5% to 45 4%) were found. Both experienced improved muscle strength. Conclusions GH treatment in matupd(14) cases can show beneficial effects on growth and body composition if started in time. Larger, international studies to determine detailed effectivity and side effects are suggested. 10 Part III

4 Introduction Uniparental disomy (UPD) is the inheritance of both homologues of a chromosome pair from the same parent. The phenotype of patients with UPD depends on the chromosome or chromosome segment involved, the parent of origin and whether abnormal variants are located on the chromosome (segment). Maternal uniparental disomy 14 (matupd(14); Temple syndrome) is an infrequently described entity, first reported in 1991 [1],characterized by prenatal and postnatal growth retardation, hypotonia, feeding difficulties, small hands and feet, unusual face, truncal obesity, advanced bone age, early puberty and, in some, mild-to-moderate intellectual disability [2, 3]. The majority (70 80%) of individuals with matupd(14) inherit two maternal chromosomes 14. In the remaining individuals, the phenotype is caused by a normal (biparental) disomy but loss of function of the paternal allel due to a methylation disturbance [2]. The phenotype of matupd(14) and, especially, the short stature and truncal obesity are similar to the phenotype in Prader Willi syndrome (PWS) (Table 1) [4]. Growth Table 1. Clinical features of matupd(14) [2, 4, 10, 11, 13, 25] compared to those in Prader Willi syndrome [2-29] Clinical feature matupd(14) Prader Willi syndrome Neonatal features Prematurity + Low birth weight + Feeding difficulties + + Hypotonia + + Growth Short stature + + Truncal obesity + + Face Supra-orbital fullness + Unusual forehead + (prominent) + (narrow) Almond-shaped eyes + + Low-set ears + Up-turned nose + Thin upper vermillion + Short philtrum + High-arched palate + + Growth Hormone Treatment in matupd(14) 107

5 Table 1. Clinical features of matupd(14) [2, 4, 10, 11, 13, 25] compared to those in Prader Willi syndrome [2-29] (continued) Clinical feature matupd(14) Prader Willi syndrome Downturned corners of the mouth + + Micrognathia + + Muscoskeletal features Small hands and feet + + Clinodactyly + Hypotonia + + Hypermobile joints + + Kyphosis or scoliosis + + Advanced bone age + Endocrine features Precocious puberty + Cryptorchidism + + Cognition/Behaviour Motor developmental delay + + Speech developmental delay + + Intellectual disability ± + Behavioural problems + Other Recurrent otitis media + hormone (GH) treatment in children with PWS has been shown to improve growth, body composition and muscle strength [2, 5], and possibly has a positive effect on cognition []. Consensus guidelines for GH therapy in PWS have been proposed [7]. The comparable combination of short stature and early puberty in individuals with matupd(14) suggested treatment with GH can be useful in this entity as well. If early puberty is present, gonadotropin-releasing hormone analogue (GnRHa) could be given in addition to the GH treatment [2, 8]. We hypothesized that GH can have a beneficial effect on height and body composition in individuals with matupd(14). This treatment has not been reported in detail in matupd(14) before. We describe the effect of GH treatment during a 2-year follow-up period in two girls with matupd(14) on growth and body composition, and compare these to a third matupd(14) girl who could not be treated anymore. 108 Part III

6 Materials and Methods Patients Patient A is an 8 9-year-old Dutch girl, born at 38 weeks of gestation to nonconsanguineous parents, with a birth weight of 2340 g ( 2 1 SD); length at birth is unknown. Father s height is 188 cm and mother s height 174 cm, resulting in a target height (TH) of 173 cm (+0 5 SD). At 1 year of age, she was evidently hypotonic. Motor development was delayed, and she was able to walk at 23 months. Speech development was delayed as well, possibly related to recurrent ear infections. At 7 0 years, her physical appearance was characterized by short stature (113 9 cm; 2 1 SD), truncal obesity, supraorbital fullness, square and low-set ears, a small up-turned nose, open-mouth appearance and loose hand joints. She was prepubertal. Her social behaviour is normal. Genetic evaluations at 2 8 years of age showed a maternal uniparental disomy of chromosome 14. In some cells, a paternal chromosome 14 was also present (trisomy 14 mosaicism). The clinical features were characteristic for matupd(14) and did not match those of a trisomy 14 mosaicism [9]. Patient B is an 11 4-year-old Dutch girl, born to nonconsanguineous parents at 40 weeks of gestation, with a birth weight of 2300 g ( 2 9 SD); length at birth is unknown. TH is cm ( 0 1 SD), father s height is 185 cm, and mother s height is 18 cm. During pregnancy, oligohydramnios and intra-uterine growth retardation (IUGR) had been observed. In the neonatal period, hypotonia and feeding difficulties were present. Motor development and speech were delayed. She had recurrent ear infections. At 9 3 years, physical examination showed height within the normal range (131 8 cm; 1 2 SD), truncal obesity, a high forehead, supraorbital fullness, low-set ears, a small up-turned nose, mandibular prognathism, hypermobile joints and bilateral simian flexion creases. She is diagnosed with an autism spectrum disorder. She has followed an early pubertal development, with Tanner breast stage B2 present at the age of 8 5 years, after which GnRHa treatment (triptoreline 3 75 mg/4 weeks) had been started. Genetic evaluation at the age of 5 showed maternal uniparental disomy of chromosome 14 (matupd(14)). Patient C is a 12 7-year-old girl, born at 41 weeks of gestation to nonconsanguineous parents, with a birth weight of 2880 g ( 1 8 SD) and birth length of 48 cm ( 1 SD). Father s height is 1 cm and mother s height 19 cm, and TH is 14 1 cm ( 1 1 SD). During infancy, no feeding difficulties or hypotonia were seen. She was able to walk at age 1 5, and speech development was delayed. She was seen by a paediatrician Growth Hormone Treatment in matupd(14) 109

7 elsewhere from birth until the age of four. In that period, a specific diagnosis was not revealed. At the age of 11 5, she presented at our clinic with short stature (135 cm, 2 8 SD), generalized obesity, an up-turned nose, a narrow palate, crowding of the tooth, downturned corners of the mouth, small hand and feet and short metacarpals four and five. At the age of 11 5, she had her menarche and showed an advanced bone age (13 75 years). Clinical genetic analyses allowed the diagnosis of matupd(14). GH treatment was considered to be of little use for height gain due to her age and early maturation. Predicted adult height was cm ( 5 1 SD). Treatment Treatment with GH was started at the age of 9 (patient A) and 9 3 (patient B), respectively. Before treatment anthropometrics, endocrine status and body composition by dual-energy X-ray absorptiometry (DXA) scan (Table 2) were determined. Both patients had decreased IGF-1 levels and increased fat mass before GH treatment. In all patients, anthropometrics were recorded as well as laboratory findings at baseline. In patients A and B, endocrine status and body composition were determined after respectively one and 2 years of treatment, and additionally, muscle strength was evaluated anamnestically. Both patients were treated with somatropin (recombinant human growth hormone), initially with 0 48 mg/m2 per day in patient A and 0 34 mg/m2 per day in patient B. In patient A, the dosage was increased to 0 53 mg/m2 per day after 1 year. 110 Part III

8 Table 2. Patient characteristics: baseline and at follow-up Baseline 1-year follow-up 2-year follow-up Patient A Patient B Patient C Patient A Patient B Patient C Patient A Patient B Growth and puberty Height, cm (SDS) ( 2 3) ( 1 2) ( 3 1) ( 1 ) ( 0 4) ( 3 0) ( 1 2) ( 0 ) Target height, cm (SDS) 173 (+0 5) ( 0 1) 13 7 ( 1 1) 20 (+1 2) 3 2 (+2 4) 34 0 (+2 3) 24 1 (+0 5) 51 8 (+2 5) 49 5 (+3 0) 27 1 ( 0 7) 55 8 (+2 3) Weight, kg (weight for height SDS) BMI, kg/m2 (SDS) 17 4 (+1 4) 21 8 (+2 4) 21 1 (+1 7) 1 3 (+0 5) 25 7 (+2 8) 2 8 (+2 ) 1 3 (+0 3) 25 (+2 ) Tanner B, stage Laboratory and radiographic investigations IGF-1, nmol/l (SDS) 20 (+0 1) 1 0 ( 1 4) 44 5 (+0 8) 30 (+0 7) 38 (+0 7) 43 (+1 3) 47 (+0 9) TSH, mu/l ft4, pmol/l Bone age advancement, years Body composition Total mass, kg Lean mass, kg Fat mass, kg Fat percentage, %, (SDS) 51 5* 49 5 (+2 1) 45 4 (+1 7) 51 2 (+2 3) 0 59* 0 82 (+0 5) 0 5 ( 2 0) 0 84 ( 0 7) Mean BMD, g/cm2 (z-score) BMD, bone mineral density; BMI, body mass index; ft4, free thyroxine; IGF-1, insulin-like growth factor 1; SDS, standard deviation score; TSH, thyroidstimulating hormone. * Too young for calculating SDS or z-score [30]. Growth Hormone Treatment in matupd(14) 111

9 Ethical approval This observational study did not fall under the Medical Research Involving Human Subjects Act, and therefore, informed consent was not required. In both patients, treatment with GH was approved by the forum of the National Registration GH treatment in the Netherlands. Written approval was given by the parents for the use of the anonymized medical records and the anonymized test results of their child for teaching, research and/or publication in a medical journal by the participating departments of VU University Medical Center, Amsterdam and Tergooi Hospitals, Blaricum. Results The results in both patients during the follow-up during 2 years are summarized in Table 2 and Fig. 1 (Patient A: a-c, Patient B: d-f ), showing a considerable increased growth and IGF-1 levels in both patients since GH treatment was initiated and a decrease in weight and improvement of body composition in patient A. In patient B, weight and body composition remained stable. In Fig. 1 (g i), patient C is demonstrated, in which height SDS (HSDS) further decreased below 3 0 SD and weight for height and BMI increased above +3 0 and +2 5 SD, respectively. Anamnestically, muscle strength in patients A and B improved after the initiation of GH treatment, both experienced increased muscle strength during exercise. 112 Part III

10 a b c Obesity Overweight Normal weight Underweight Extreme underweight Height (cm) Weight (kg) BMI (kg/m²) Mean Start GH Start GH Target height Mean Start GH Age (years) Age (years) Height (cm) Height (cm) Age (years) Age (years) d e f Obesity Overweight Normal weight Underweight Extreme underweight Height (cm) Weight (kg) BMI (kg/m²) Start GH Mean Start GH Start GH Mean Target height Age (years) Age (years) Height (cm) Height (cm) Age (years) Age (years) g h i Obesity Overweight Normal weight Underweight Extreme underweight Height (cm) Weight (kg) BMI (kg/m²) Mean Mean Target height Age (years) Height (cm) Age (years) Figure 1. An overview of height for age, weight for height and BMI for age in patient A (figure a, b and c), patient B (figure d, e and f ) and patient C (figure g, h and i). The start of GH treatment is indicated with the arrows. Abbreviations: BMI=body mass index; GH=growth hormone. Growth Hormone Treatment in matupd(14) 113

11 Discussion We provide here the first detailed report including a 2-year follow-up of GH treatment in matupd(14). The literature data on the spontaneous course of growth and body composition in matupd(14) have been analysed using 51 published cases[10]. The majority of patients had a HSDS below 1 0 (mean height at 0 7 year 2 0SD and at 7 1 year 1 SD), and the median adult height was 2 04 SDS (range 2 0 to 4 0 SDS). After the initial failure to thrive, obesity was present in 49 of the matupd(14) patients[10]. Others [2] reported obesity in 0% of cases, without the compulsory eating habits as seen in PWS. Two reports [11, 12] have mentioned the effect of GH treatment on height gain in matupd(14), and in both patients, this was reported as effective : in one, no further information was provided [12]; in the other, HSDS increased from 2 5 at the age of to HSDS 1 5 SD at the age of 12 [11]. No data on GH and IGF-1 levels, body composition or side effects were provided. In the present patients treated with GH, HSDS changed from 2 3 and 1 2 to 1 2 and 0 in 2 years time, respectively. The IGF-1 levels increased from +0 1 and 1 4 to +1 3 and +0 9 in that same period. Regarding body composition, the results were less consistent among the two patients. In patient A, a decrease in weight for height SDS was seen, from +1 2 to 0 7, and the fat percentage decreased from 51 5% to 45 4%. In patient B, weight for height SDS remained stable (+2 4 to +2 3) as well as her fat percentage (49 5% to 51 2%). In patient C, who did not receive treatment, HSDS further decreased and weight increased. The resemblance in phenotypes of matupd(14) and PWS has been evaluated in a series of four patients with matupd(14), referred because of a suspicion for the presence of Prader Willi syndrome [13]. All had been referred in infancy, suggesting that matupd(14) and PWS resemble each other significantly at least during this period. Features that in general were present in matupd(14) and not in PWS, included lessspecific facial characteristics (frontal bossing, highly arched palate and micrognathia), prenatal growth failure, on average a higher level of cognitive development and precocious puberty (Table 1). The combination of age-dependent failure to thrive, short stature and precocious puberty was considered to be the best clinical diagnostic handle for matupd(14). As these become more evident with age, distinction from PWS will become more easy with increasing age. Other reports also describe this variable, agedependent phenotype of matupd(14) [2, 11]. There are several other disorders sharing major manifestation with matupd(14) such as congenital hypothyroidism [14], the 114 Part III

12 PWS-like phenotype in fragile X syndrome [15], 2qter subtelomeric microdeletion [1], Bardet Biedl syndrome, Cohen syndrome and Alström syndrome [17], but in each, other major manifestations allow relatively easy differentiation. Short stature, obesity and reduced muscle strength are typically present in children with severe congenital (isolated) GH deficiency (GHD). It is uncertain whether these features in PWS can be explained by the impaired GH secretion in PWS [18-22]. The plasma levels of IGF-I are reduced in most children with PWS [19-21]. In matupd(14), children deficient GH secretion has been described in matupd(14) [11], but data on IGF-I levels are lacking. In our patients, IGF-1 levels at baseline were within the normal range. Following PWS guidelines, growth hormone stimulation tests were not performed. In both presently treated patients, GH treatment was started at a low dosage ( mg/m2) to evaluate the effect and, after a year, slightly increased to 0 53 mg/m2 in patient A. The guidelines for GH treatment in PWS advice infants and children with PWS to start with 0 5 mg/m2 per day, with adjustments towards 1 0 mg/m2 per day [7]. In the presently described matupd(14) patients, growth and IGF-1 levels rapidly increased after the start of GH treatment, and also a decrease in weight occurred in one patient (Fig. 1b and c). IGF-1 levels were kept below 2 0 SD because IGF-1 levels above 2 0 SD are associated with a slightly increased risk for developing malignancies [23].Using the present schedule, both treated patients remained euthyroid during treatment and no side effects were evident. Based on this (limited) experience, we recommend to initially start with a low dosage and determine adjustment of the dosage guided by IGF-1 levels, whilst monitoring effect parameters height, weight and DXA results. The average age of diagnosing matupd(14) reported in literature is late, at 9 years, mainly explained by the age-dependent manifestations of the entity [11]. For optimal clinical management of matupd(14), it would be advantageous to diagnosis the entity at an earlier age. Precocious puberty can best be treated in an early phase, and mean menarche in matupd(14) is at 10 years [2, 10]. The same may hold for the treatment of obesity: in PWS, GH treatment is advised to start before the onset of obesity, which is typically at 2 years [7]. Following this reasoning, GH treatment in matupd(14) should start before 3 years as obesity typically arises at that time [2]. This is supported by the fact that that body composition of patient B, in which treatment was started at age 9 3, did not improve. In addition, in patient B, a decrease in bone mineral density (BMD) was seen (+0 5 to 0 7 SD). Although conflicting results have been reported, the combination of decreasing BMD and a negative effect on body composition could pos- Growth Hormone Treatment in matupd(14) 115

13 sibly also be caused by GnRHa treatment in this patient [24]. Still, body composition remained stable in this patient in contrast to the untreated patient in which increasing obesity is seen. Lastly, early diagnosis of matupd(14) allows timely genetic counselling of the family. Therefore, we suggest to perform diagnostic studies for matupd(14) in patients suspected to have PWS in whom methylation testing for PWS is found negative. If precocious puberty is present in someone who is suspected to have PWS, we suggest testing for matupd(14) even before testing for PWS. We realize we describe GH treatment in only two matupd(14) patients, and have data on follow-up of 2 years only. Long-term follow-up in a larger cohort will be needed to allow for more firm conclusions with respect to optimal GH dosage schemes, determination of any side effects, objective measurements of muscle strength and assessment of cognitive functioning. As matupd(14) is an orphan disorder, this likely will need an international collaborative study. We conclude that this report of GH treatment in two matupd(14) cases provides a good indication that GH treatment shows beneficial effects particularly if started at an early age, and suggest a larger, international study to determine effects and side effects in detail. Acknowledgements We are very grateful to the patients and their parents, for their generous collaboration. This work was funded by the Department of Pediatrics, Tergooi Hospitals, Blaricum, The Netherlands. Disclosure Statement The authors have nothing to declare. 11 Part III

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