Optimal Pubertal Induction in Girls with Turner Syndrome Using Either Oral or Transdermal Estradiol: A Proposed Modern Strategy.

BACKGROUND: Most girls with Turner syndrome (TS) require pubertal induction with estrogen, followed by long term replacement. However, no adequately powered prospective studies comparing transdermal with oral 17ß-estradiol administration exist. This reflects the difficulty of securing funding to study a rare condition with relatively low morbidity/mortality when competing against conditions such as cancer and vascular disease. Protocol Consensus: The TS Working Group of the European Society for Paediatric Endocrinology (ESPE) has agreed to both a 3-year oral and a 3-year transdermal regimen for pubertal induction. Prerequisites include suitable 17ß-estradiol tablets and matrix patches to allow the delivery of incremental doses based on body weight. Study Proposal: An international prospective cohort study with single centre analysis is proposed in which clinicians and families are invited to choose either of the agreed regimens, usually starting at 11 years. We hypothesise that pubertal induction with transdermal estradiol will result in better outcomes for some key parameters. The primary outcome measure chosen is height gain during the induction period. ANALYSIS: Assessment of the demographics and drop-out rates of patients choosing either oral or transdermal preparations; and appropriate analysis of outcomes including pubertal height gain, final height, liver enzyme and lipid profile, adherence/acceptability, cardiovascular health, including systolic and diastolic blood pressure and aortic root diameter and bone health. CONCLUSION: The proposed model of prospective data collection according to internationally agreed protocols aims to break the current impasse in obtaining evidence-based management for TS and could be applied to other rare paediatric endocrine conditions.

Prevalence of growth hormone (GH) deficiency in previously GH-treated young adults with Prader-Willi syndrome.

OBJECTIVE: Some features of subjects with Prader-Willi syndrome (PWS) resemble those seen in growth hormone deficiency (GHD). Children with PWS are treated with growth hormone (GH), which has substantially changed their phenotype. Currently, young adults with PWS must discontinue GH after attainment of adult height when they do not fulfil the criteria of adult GHD. Limited information is available about the prevalence of GHD in adults with PWS. This study aimed to investigate the GH/insulin-like growth factor (IGF-I) axis and the prevalence of GHD in previously GH-treated young adults with PWS. DESIGN: Cross-sectional study in 60 young adults with PWS. MEASUREMENTS: Serum IGF-I and IGFBP-3 levels, GH peak during combined growth hormone-releasing hormone (GHRH)-arginine stimulation test. RESULTS: Serum IGF-I was <-2 standard deviation scores (SDS) in 2 (3%) patients, and IGFBP-3 was within the normal range in all but one patient. Median (IQR) GH peak was 17.8 µg/L (12.2; 29.7) [~53.4 mU/L] and below 9 µg/L in 9 (15%) patients. Not one patient fulfilled the criteria for adult GHD (GH peak < 9 µg/L and IGF-I < -2 SDS), also when BMI-dependent criteria were used. A higher BMI and a higher fat mass percentage were significantly associated with a lower GH peak. There was no significant difference in GH peak between patients with a deletion or a maternal uniparental disomy (mUPD). CONCLUSIONS: In a large group of previously GH-treated young adults with PWS, approximately 1 in 7 exhibited a GH peak <9 µg/L during a GHRH-arginine test. However, none of the patients fulfilled the consensus criteria for adult GHD.

Design and evaluation of a clinical competency committee.

INTRODUCTION: In postgraduate medical education, group decision-making has emerged as an essential tool to evaluate the clinical progress of residents. Clinical competency committees (CCCs) have been set up to ensure informed decision-making and provide feedback regarding performance of residents. Despite this important task, it remains unclear how CCCs actually function in practice and how their performance should be evaluated. METHODS: In the prototyping phase of a design-based approach, a CCC meeting was developed, using three theoretical design principles: (1) data from multiple assessment tools and multiple perspectives, (2) a shared mental model and (3) structured discussions. The meetings were held in a university children's hospital and evaluated using observations, interviews with CCC members and an open-ended questionnaire among residents. RESULTS: The structured discussions during the meetings provided a broad outline of resident performance, including identification of problematic and excellent residents. A shared mental model about the assessment criteria had developed over time. Residents were not always satisfied with the feedback they received after the meeting. Feedback that had been provided to a resident after the first CCC meeting was not addressed in the second meeting. DISCUSSION: The principles that were used to design the CCC meeting were feasible in practice. Structured discussions, based on data from multiple assessment tools and multiple perspectives, provided a broad outline of resident performance. Residency programs that wish to implement CCCs can build on our design principles and adjust the prototype to their particular context. When running a CCC, it is important to consider feedback that has been provided to a resident after the previous meeting and to evaluate whether it has improved the resident's performance.

Congenital diaphragmatic hernia is associated with nonscrotal testes.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a rare birth defect with a high mortality and morbidity. Nonscrotal testes (NST) are the most reported genital anomaly in boys. Both defects have known associated anomalies, but little is known about the association between CDH and NST. This study evaluates this association and the location of the NST in a large cohort of male CDH survivors. Moreover, we analyzed possible associative factors for NST in CDH patients. METHODS: A cohort of CDH patients, born between January 2000 and March 2014 and treated in a high volume expertise center, was evaluated retrospectively. Boys with a minimum follow-up of 18months were included. The patients were evaluated for testes location, performed orchidopexy, and possible associative factors such as birth weight, gestational age, other congenital anomalies and CDH characteristics (surgical treatment, approach and ECMO). RESULTS: Seventy-five CDH patients were included. Twenty-seven (36%) were diagnosed with NST, of which 22 (29%) received orchidopexy. In 54 patients (72%) there were reports on testes location at birth and location was known for all patients at the age of 18months, although side of NST was unknown in four. The location of the NST was mostly ipsilateral to the CDH (n=20, 87%), of which eight (35%) had a bilateral NST with a unilateral CDH. There were no significant differences in birth weight, gestational age, and CDH specific characteristics in patients with or without NST. CONCLUSION: This study shows a strong association between CDH and NST, with a prevalence of 36%. However, no specific characteristics of the CDH were related to the NST. The testes of all male CDH patients should be thoroughly evaluated in the first year of their life, to ensure a proper and timely treatment. LEVEL OF EVIDENCE: Level IV; case series.

Bone mineral density in young adults with Prader-Willi syndrome: A randomized, placebo-controlled, crossover GH trial.

CONTEXT: The prevalence of osteoporosis is increased in adults with Prader-Willi syndrome (PWS). In children with PWS, growth hormone (GH) treatment has beneficial effects on bone mineral density (BMD). BMD might deteriorate after cessation of GH at adult height (AH), while continuing GH might maintain BMD. OBJECTIVE: To investigate the effects of GH vs placebo, and furthermore the effects of sex steroid replacement therapy (SSRT), on BMD in GH-treated young adults with PWS who had attained AH. DESIGN: Two-year, randomized, double-blind, placebo-controlled, crossover GH study. PATIENTS: Twenty-seven young adults with PWS were stratified for gender and BMI and then randomly and blindly assigned to receive GH (0.67 mg/m2 /day) or placebo for 1 year, after which they crossed over to the alternative treatment for another year. MEASUREMENTS: Bone mineral density of the total body (BMDTB ) and lumbar spine (BMDLS ) SDS were measured by dual-energy x-ray absorptiometry. RESULTS: At AH, BMDTB SDS was significantly lower compared to healthy peers (P < .01), while BMADLS SDS was similar. Both BMDTB SDS and BMADLS SDS were similar during 1 year of GH vs 1 year of placebo. In hypogonadal young adults without SSRT, BMDTB SDS and BMADLS SDS decreased during the 2-year study (P = .11 and P = .01), regardless of GH or placebo, while BMDTB SDS increased in those with SSRT (P < .01). CONCLUSIONS: Compared to GH treatment, 1 year of placebo after attainment of AH does not deteriorate BMD SDS in young adults with PWS. In addition, our data suggest that GH is not able to prevent the decline in BMD SDS in hypogonadal young adults with PWS, unless it is combined with SSRT.

Phenotype in girls and women with Turner syndrome: Association between dysmorphic features, karyotype and cardio-aortic malformations.

INTRODUCTION: Turner syndrome (TS) is a genetic disorder characterized by the (partial) absence or a structural aberration of the second sex chromosome and is associated with a variety of phenotypes with specific physical features and cardio-aortic malformations. The objective of this study was to gain a better insight into the differences in dysmorphic features between girls and women with TS and to explore the association between these features, karyotype and cardio-aortic malformations. METHODS: This prospective study investigated 14 dysmorphic features of TS girls and women using a checklist. Three major phenotypic patterns were recognized (severe phenotype, lymphatic phenotype and skeletal phenotype). Patient data including karyotype and cardio-aortic malformations (bicuspid aortic valve (BAV) and aortic coarctation (COA)) were collected. Associations between the prevalence of dysmorphic features, karyotype and cardio-aortic malformations were analysed using chi2-test and odds ratios. RESULTS: A total of 202 patients (84 girls and 118 women) were analysed prospectively. Differences in prevalence of dysmorphic features were found between girls and women. A strong association was found between monosomy 45,X and the phenotypic patterns. Furthermore, an association was found between COA and lymphatic phenotype, but no association was found between karyotype and cardio-aortic malformations. CONCLUSION: This study uncovered a difference in dysmorphic features between girls and women. Monosomy 45,X is associated with a more severe phenotype, lymphatic phenotype and skeletal phenotype. All patients with TS should be screened for cardio-aortic malformations, because in contrast to previous reports, karyotype and cardio-aortic malformations showed no significant association.

Pancytopenia and Hypothyroidism in a Patient With Leukemic Infiltration of the Thyroid as the First Presentation of Acute Lymphoblastic Leukemia.

We report the case of a 16-year-old female patient with hypothyroidism, goiter, and pancytopenia. Biopsy of the thyroid showed leukemic infiltration. After confirmation of the diagnosis of B-lymphoblastic leukemia, treatment was started. Histologic follow-up at day 33 and 79 showed no residual signs of leukemic infiltration. Hypothyroidism persisted despite successful antileukemic treatment. Leukemic infiltration of the thyroid should be considered as a differential diagnosis in patients with hypothyroidism, goiter, and pancytopenia. We suggest that follow-up of thyroid function and histology should be incorporated in the follow-up of rare patients with acute lymphoblastic leukemia with thyroid infiltration.

Prenatal Treatment with Dexamethasone in Suspected Congenital Adrenal Hyperplasia and Orofacial Cleft: a Case Report and Review of the Literature.

Congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency is a genetic disorder that leads to hypocortisolism, hyperandrogenism and, in the most severe forms, also to hypoaldosteronism. Girls with classic CAH are born with virilized external genitalia. Prenatal dexamethasone (DXM) treatment can reduce virilization but may have side effects for mother and fetus. We present the first case of a girl who was born with CAH and an orofacial cleft. She was treated with prenatal DXM to prevent virilization. Oral clefts have to be considered as a potential side effect of prenatal DXM treatment.

Beneficial Effects of GH in Young Adults With Prader-Willi Syndrome: A 2-Year Crossover Trial.

CONTEXT: Patients with Prader-Willi syndrome (PWS) are severely at risk to develop morbid obesity, diabetes mellitus type 2, and cardiovascular disease, leading to high mortality. They have an increased fat mass (FM) and decreased lean body mass (LBM). During childhood, GH treatment counteracts the natural course of increasing obesity. Discontinuation of GH treatment at attainment of adult height (AH) might deteriorate their improved clinical condition, whereas continuation might benefit them. OBJECTIVE: To investigate the effects of GH versus placebo on body composition in young adults with PWS who were GH treated for many years during childhood and had attained AH. DESIGN: Two-year, randomized, double-blind, placebo-controlled crossover study with stratification for gender and body mass index in 27 young adults with PWS. SETTING: PWS Reference Center in The Netherlands. INTERVENTION: Crossover intervention with GH (0.67 mg/m2 · d) and placebo, both during 1 year. MAIN OUTCOME MEASURES: Body composition, measured by dual-energy x-ray absorptiometry. RESULTS: During placebo, FM increased (relative change +21.5%; P < .001). Compared with placebo, GH treatment resulted in lower FM (-2.9 kg; P = .004) and higher LBM (+1.5 kg; P = .005), representing relative changes of -17.3% FM and +3.5% LBM. Both limb and trunk FM percentage were lower during GH versus placebo (relative change +17.3% and +15.6%; P < .001 and P = .007, respectively). No GH-related adverse events occurred. CONCLUSIONS: GH-treated young adults with PWS who have attained AH benefit from continuation of GH treatment. FM increases during placebo, whereas GH versus placebo results in lower FM and higher LBM. Thus, GH treatment maintains the improved body composition without safety concerns.

Assessment of psychosocial problems in children with type 1 diabetes and their families: the added value of using standardised questionnaires in addition to clinical estimations of nurses and paediatricians.

AIMS AND OBJECTIVES: To investigate the assessment of psychosocial problems in children with type 1 diabetes by means of clinical estimations made by nurses and paediatricians and by using standardised questionnaires. BACKGROUND: Although children with type 1 diabetes and their parents show increased risk for psychosocial problems, standardised assessment of these problems lacks in diabetes care. DESIGN: By comparing these different modes of assessment, using a cross-sectional design, information about the additional value of using standardised questionnaires is provided. METHODS: Participants were 110 children with type 1 diabetes (aged 4-16), their parents, and healthcare professionals. Children filled out the Strengths and Difficulties Questionnaire and the Paediatric Quality of Life Inventory, Diabetes Module. Parents filled out the Strengths and Difficulties Questionnaire parent-report and the Parenting Stress Index. Independently, nurses and paediatricians filled out a short questionnaire, which assessed their clinical estimations of the children's psychosocial problems and quality of life, and parents' levels of parenting stress. Reports of children and parents were compared to clinical estimations. RESULTS: Children in our sample showed more psychosocial problems and lower health-related quality of life than their healthy peers. In approximately half of the children, dichotomous estimations by healthcare professionals and dichotomised reports by patients and parents were in agreement. In 10% of the children, no psychosocial problems were present according to professionals' estimations, although patients and parents-reported psychosocial problems. In 40%, psychosocial problems were present according to professionals' estimations, although parents and patients did not report psychosocial problems. CONCLUSION: Children with type 1 diabetes show more psychosocial problems than healthy children. Professionals seem to tend towards overestimating psychosocial problems. RELEVANCE TO CLINICAL PRACTICE: Extending the assessment of psychosocial problems with routine screening on patient-reported outcomes, using validated questionnaires, could be of additional value in tailoring care to the needs of the individual child and parents.

Growth hormone therapy, muscle thickness, and motor development in Prader-Willi syndrome: an RCT.

OBJECTIVE: To investigate the effect of physical training combined with growth hormone (GH) on muscle thickness and its relationship with muscle strength and motor development in infants with Prader-Willi syndrome (PWS). METHODS: In a randomized controlled trial, 22 infants with PWS (12.9 ± 7.1 months) were followed over 2 years to compare a treatment group (n = 10) with a waiting-list control group (n = 12). Muscle thickness of 4 muscle groups was measured by using ultrasound. Muscle strength was evaluated by using the Infant Muscle Strength meter. Motor performance was measured with the Gross Motor Function Measurement. Analyses of variance were used to evaluate between-group effects of GH on muscle thickness at 6 months and to compare pre- and posttreatment (after 12 months of GH) values. Multilevel analyses were used to evaluate effects of GH on muscle thickness over time, and multilevel bivariate analyses were used to test relationships between muscle thickness, muscle strength, and motor performance. RESULTS: A significant positive effect of GH on muscle thickness (P < .05) was found. Positive relationships were found between muscle thickness and muscle strength (r = 0.61, P < .001), muscle thickness and motor performance (r = 0.81, P < .001), and muscle strength and motor performance (r = 0.76, P < .001). CONCLUSIONS: GH increased muscle thickness, which was related to muscle strength and motor development in infants with PWS. Catch-up growth was faster in muscles that are most frequently used in early development. Because this effect was independent of GH, it suggests a training effect.

Karyotype-specific ear and hearing problems in young adults with Turner syndrome and the effect of oxandrolone treatment.

OBJECTIVE: To evaluate karyotype-specific ear and hearing problems in young-adult patients with Turner syndrome (TS) and assess the effects of previous treatment with oxandrolone (Ox). STUDY DESIGN: Double-blind follow-up study. SETTING: University hospital. PATIENTS: Sixty-five TS patients (mean age, 24.3 yr) previously treated with growth hormone combined with placebo, Ox 0.03 mg/kg per day, or Ox 0.06 mg/kg per day from the age of 8 years and estrogen from the age of 12 years. INTERVENTION: Ear examination was performed according to standard clinical practice. Air- and bone conduction thresholds were measured in decibel hearing level. MAIN OUTCOME MEASURES: We compared patients with total monosomy of the short arm of the X chromosome (Xp), monosomy 45,X and isochromosome 46,X,i(Xq), with patients with a partial monosomy Xp, mosaicism or other structural X chromosomal anomalies. We assessed the effect of previous Ox treatment. RESULTS: Sixty-six percent of the patients had a history of recurrent otitis media. We found hearing loss in 66% of the ears, including pure sensorineural hearing loss in 32%. Hearing thresholds in patients with a complete monosomy Xp were about 10 dB worse compared with those in patients with a partial monosomy Xp. Air- and bone conduction thresholds were not different between the placebo and Ox treatment groups. CONCLUSION: Young-adult TS individuals frequently have structural ear pathology, and many suffer from hearing loss. This indicates that careful follow-up to detect ear and hearing problems is necessary, especially for those with a monosomy 45,X or isochromosome 46,X,i(Xq). Ox does not seem to have an effect on hearing.

GATA4 mutations are a cause of neonatal and childhood-onset diabetes.

The GATA family zinc finger transcription factors GATA4 and GATA6 are known to play important roles in the development of the pancreas. In mice, both Gata4 and Gata6 are required for pancreatic development. In humans, GATA6 haploinsufficiency can cause pancreatic agenesis and heart defects. Congenital heart defects also are common in patients with GATA4 mutations and deletions, but the role of GATA4 in the developing human pancreas is unproven. We report five patients with deletions (n = 4) or mutations of the GATA4 gene who have diabetes and a variable exocrine phenotype. In four cases, diabetes presented in the neonatal period (age at diagnosis 1-7 days). A de novo GATA4 missense mutation (p.N273K) was identified in a patient with complete absence of the pancreas confirmed at postmortem. This mutation affects a highly conserved residue located in the second zinc finger domain of the GATA4 protein. In vitro studies showed reduced DNA binding and transactivational activity of the mutant protein. We show that GATA4 mutations/deletions are a cause of neonatal or childhood-onset diabetes with or without exocrine insufficiency. These results confirm a role for GATA4 in normal development of the human pancreas.

Buccal cell FISH and blood PCR-Y detect high rates of X chromosomal mosaicism and Y chromosomal derivatives in patients with Turner syndrome.

Turner syndrome (TS) is the result of (partial) X chromosome monosomy. In general, the diagnosis is based on karyotyping of 30 blood lymphocytes. This technique, however, does not rule out tissue mosaicism or low grade mosaicism in the blood. Because of the associated risk of gonadoblastoma, mosaicism is especially important in case this involves a Y chromosome. We investigated different approaches to improve the detection of mosaicisms in 162 adult women with TS (mean age 29.9 ± 10.3). Standard karyotyping identified 75 patients (46.3%) with a non-mosaic monosomy 45,X. Of these 75 patients, 63 underwent additional investigations including FISH on buccal cells with X- and Y-specific probes and PCR-Y on blood. FISH analysis of buccal cells revealed a mosaicism in 19 of the 63 patients (30.2%). In five patients the additional cell lines contained a (derivative) Y chromosome. With sensitive real-time PCR we confirmed the presence of this Y chromosome in blood in three of the five cases. Although Y chromosome material was established in ovarian tissue in two patients, no gonadoblastoma was found. Our results confirm the notion that TS patients with 45,X on conventional karyotyping often have tissue specific mosaicisms, some of which include a Y chromosome. Although further investigations are needed to estimate the risk of gonadoblastoma in patients with Y chromosome material in buccal cells, we conclude that FISH or real-time PCR on buccal cells should be considered in TS patients with 45,X on standard karyotyping.

Growth hormone combined with child-specific motor training improves motor development in infants with Prader-Willi syndrome: a randomized controlled trial.

Although severe motor problems in infants with Prader-Willi syndrome (PWS) are striking, motor development has never been studied longitudinally and the results of growth hormone (GH) treatment on motor development are contradictory. The authors studied whether GH treatment can enhance the effect of physical training on motor development in infants with PWS. Twenty-two infants were followed for two years during a randomized controlled trial. The treatment and control groups began GH after baseline or following a control period, respectively. Both groups followed a child-specific physical training program. Motor performance was measured every three months. Multi-level regression analysis revealed that motor development differed significantly between infants (p<.001), and this could be partially explained by baseline motor developmental level (p<.01). GH treatment enhanced the effects of child-specific physical training on both motor developmental rate and motor developmental potential. Moreover, this effect was more pronounced when GH treatment was initiated at a younger age.

Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome.

OBJECTIVE: Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment. DESIGN AND METHODS: During the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl, n=23; Ox 0.03, n=27; and Ox 0.06, n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition. RESULTS: Height gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2±4.9 cm, Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency. CONCLUSION: Ox 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe.

Cardiac evaluation in children with Prader-Willi syndrome.

AIM: To assess cardiac anatomy and myocardial systolic function in children with Prader-Willi syndrome (PWS). METHODS: Physical examination, electrocardiographic (ECG) recordings and transthoracic echocardiograms including two-dimensional speckle tracking echocardiography (2DSTE) were performed and evaluated in the Radboud University Hospital Nijmegen, the Netherlands. In total, 19 children diagnosed with PWS and 38 age-matched control subjects underwent cardiac evaluation. RESULTS: Abnormal ECG findings were detected in nine PWS patients. Echocardiography revealed mild structural cardiac abnormalities in two patients. Conventional echocardiographic findings did not indicate systolic left ventricular dysfunction, in contrast to 2DSTE examination. Global peak systolic strain (rate) measurements, in all three directions of contraction, were significantly lower in children with PWS (p < 0.001) compared with healthy age-matched children. In two-thirds of the patients, 2DSTE revealed abnormal systolic deformation (peak systolic strain as well as strain rate). T2P values in PWS patients were similar to control subject. Systolic myocardial function appears more affected in case of maternal uniparental disomy. CONCLUSION: Cardiac evaluation, including 2DSTE, detects frequent alterations in myocardial systolic function in children diagnosed with PWS, whose conventional echocardiographic findings did not indicate ventricular systolic dysfunction. Because cardiovascular morbidity and mortality is substantial in PWS, especially adults, we emphasize the need for cardiac assessment in PWS.

[Panhypopituitarism in one identical twin: the effect of hormone replacement]. / Panhypopituïtarisme bij helft van identieke tweeling. Het effect van hormonale substitutie.

BACKGROUND: Panhypopituitarism in childhood is rare. It is even rarer if the disorder appears in a boy with an identical but healthy twin brother. In such a patient it is useful to study the consequences of the hormone disorder and the effect of hormone replacement. CASE DESCRIPTION: A 6-year-old boy saw a paediatrician because of short stature. He was much shorter than his identical twin brother and he had more abdominal fat mass and a smaller penis. Laboratory tests identified hypothyroidism of central origin, in combination with hypocortisolism and growth hormone deficiency. Hormonal replacement resulted in an improvement in growth rate. At the age of 15 years, testosterone therapy was introduced because puberty had not occurred and his growth rate was low. Finally the patient grew a few centimetres taller than his twin brother. CONCLUSION: In the first year of life, panhypopituitarism has no negative consequences for growth. After this point, growth is clearly delayed. With sufficient replacement growth can completely catch up.