å¡ CASE REPORT D Noonan Syndrome Presenting Growth Hormone Neurosecretory Dysfunction Katsuya Tanaka, Akira Sato, Takeshi Naito, Kimihiro Kuramochi, Hideo Itabashi and Yoshihiro Takemura Noonan syndrome has been diagnosed by the characteristic physical stigmata for more than two decades. Recent studies of growth hormone secretory pattern provide a new category of growth hormone neurosecretory dysfunction to characterize short stature. We describe herein a case of growth hormone neurosecretory dysfunction in a 16-year-old boy with Noonan syndrome. Growth hormone neurosecretory dysfunction was diagnosed primarily based on the low amplitude and small numbers of the spontaneous bursts of growth hormone secretion during 12-hour nocturnal growth hormone sampling. Treatment with synthetic human growth hormone has markedly accelerated the growth velocity for one year and a half. This case notes the wide spectrum of short stature in Noonan syndrome and the effectiveness of treatment with human growth31: hormone. (Internal Medicine 908-911, 1992) Key words: dwarfism, mental retardation, IGF-I, recombinant human growth hormone
Intr oducti on
except for the short stature and mental retardation. At the age of nine, he was noted at another facility that Noonan syndrome was first recognized as a clinical growth hormone (GH) release by provocative testings entity by Noonan and Ehmke in 1963 (1). The principal was normal. His parents and a brother were physically clinical features of Noonan syndrome include character and mentally normal. Physical examination on admission istic facial appearance, short stature, mental retardation, was remarkable for short stature (136cm) well below neck signs, congenital heart lesions, somatic anomalies, 2 SD (Fig. 1), the characteristic appearances of face, and the lack a significant chromosomal head and neck such as ocular hypertelorism, downward However, theof cause of short stature found inanomaly. the majority slanting palpebral fissures, low-set ears, webbed neck, of the patients with this syndrome has not been elucidated low posterior hairline, and cubitus valgus, but did not yet (2-4). Herein, we describe a patient of Noonan show congenital heart lesions, thoracic cage deformities, syndrome in whom growth hormone neurosecretory nor cryptorchism (Fig. 2). His body proportions were dysfunction is responsible for the short stature and appropriate for his height. Axillar and pubic hair did the growth velocity after replacement therapy with not develop and the genitalia showed a small penis exogenous synthetic human growth hormone (hGH) has-been markedly accelerated for a period of one year and testes (Tanner stage I). The results of neurological and a half. examination were negative. Bone age determined from hands and wrists roentgenograms was four years behind Case Report the chronological age. Admission laboratory examination was normal except for elevated alkaline-phosphatase The patient, a 16-year-old male, was admitted to this activity (93 IU/1). High-resolution computed tomography hospital in October 1988 for the endocrinological evalu scanning of the sella turcica and hypothalamus showed ation of short stature. He was born of a full-term preg no abnormalities. Chromosomal analysis showed 46 XY nancy and thereafter had been in a good state of health karyotype with normal banding. The patient's intelli From the Department of Internal Medicine, Koshigaya Hospital, gence Dokkyo University of Medicine, Koshigaya quotient (IQ) School by Wechsler Adult Intelligence Received for publication August 16, 1991; Accepted for publication March 16, 1992 Scale (WAIS) estimated to beKoshigaya verbal IQ 61, per- Dokkyo Universi Reprint requests should be addressed to Dr. Katsuya Tanaka, the Department of was Internal Medicine, Hospital, School of Medicine, 2-1-50 Minami Koshigaya, Koshigaya, Saitama 343, Japan 908
Internal
Medicine
Vol. 31, No. 7 (July
1992)
Growth Hormonein Noonan Syndrome
Fig. 1. Cumulative growth curve and height velocity for the patient and for Japanese boys (mean±SD). -o- represents the growth curve for the patient and -à"- represents the height velocity for the patient. The arrow indicates the commencement of hGH administration. The inset shows the height attained per month after hGH treatment. formance IQ 79 and the Full Scale IQ 67. The results of endocrinological examinations showed thyroxine 95.5 nmol/1, triiodothyronine 2.02 nmol/1, normal diurnal rhythm of plasma cortisol (8:00 AM; 190.4 nM, 4:00 PM; 146.3nM, and ll:00 PM; 35.9nM), testosterone 0.12 nmol/1, urinary 17-hydroxycorticosteroid 7.45 /imol/day and 17-ketosteroid 17.7/^mol/day. Basal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations were 14U/l and 13 U/l and increased 30 minutes after intravenous administration of luteinizing hormone-releasing hormone (LHRH) (100 /ig) to 66 U/l and 26U/l, respectively. Basal thyrotropin (TSH) and prolactin (PRL) concentrations were 1.6mU/l and 25 /ig/l, and increased 30 minutes after intravenous administration of thyrotropin-releasing hormone (TRH) (500fig) to 6.2mU/l and 75 ^g/l, respectively. GH after intravenous administration of arginine (0.5 g/kg) and growth hormone-releasing hormone (1 /ig/kg) increased from the basal values of 2.1 and 3.1pig/l to the peak values of 16.0 and 15.2jug/1, respectively (Fig. 3). The endogenous nocturnal pulsatile secretion of GH of which samples were obtained every 20 minutes for 12 hours from 9:00 PM to 9:00 AM disclosed that there were only 4 GH peaks greater than 3 /ig/1 and the mean GH concen tration for over the Internal Medicine Vol. 12 31, hours No. 7 was (July 2.31 1992) ± 2.26 (SD) pigll (Fig. 4). The low baseline level of insulin-like growth
Fig. 2. The patient at 16 years old with clinical features of ocular hyper telorism (covered), downward slanting palpebral fissures (covered), low-set ears, low posterior hairline, webbed neck, cubitus valgus, short stature and sexual infantilism.
120
Fig. 3. Growth hormone responses after intravenous ad ministration of growth hormone-releasing hormone (GRH) (o) (1 /jg/kg) or arginine (à") (0.5g/kg). factor I (IGF-I) of 0.37U/l responded to the acute administration of hGH intramuscularly for three days with an increase in IGF-I level of 0.85U/l. After the tests, the patient was treated with hGH 4U (0.125 U/kg) 909
Tanaka et al somatomedin-C (IGF-I) for age. Rather than a 24-hour GH secretion study, in this patient we examined the 12-hour nocturnal GH secretory pattern which was suggested most useful to identify GHND (6). Magnitude and numbers of the spontaneous bursts of GH secretion are age-related and transition from early puberty to adolescence is associated with increased numbers of GH surges (7, 8). The result of 12-hour nocturnal GH secretion showed a conspicuously low amplitude and 21222324 1 2 3 4 5 6 7 8 9 small numbers of bursts of spontaneous GH secretion, The period of sleeping clock time compatible with GHND. This case fulfilled the criteria Fig. 4. The twelve-hour growth hormone secretory profile. Sam for GHND. The marked slowing of growth velocity noted before the age of ten is thought to be the result of ples were obtained every 20 minutes from 21:00 to 9:00. The patient's GHND that probably had been in his childhood. Bercu sleeping period was from 23:00 to 7:00. Growth hormone secretory peaks over 3/ig/l were four and the mean (±SD) growth hormoneKitajima and Diamond mentioned the association of Noonan et al reported a 14-year-old girl with Noonan concentration was 2.31 ± 2.26jUg/1. syndrome and GHND though data were not shown presenting GHND who responded to the (6). three times a week for a period of one year and a half. administration of propranolol (20mg a day); she grew The growth velocity accelerated more than three fold 1.9 cm over a three-month period but did not present any compared to the mean growth velocity of the previous effect of hGH administration (9). In the present case the five years [1.9± 0.2 (SD) cm per year] (Fig. 1). marked acceleration of growth velocity after hGH treat ment indicates the effectiveness of hGH treatment in Discussion short stature. Although GHND is most responsible for short stature in this case, it is difficult to identify the Noonan syndrome has been diagnosed for more than primary abnormality in complex neural pathways of GH two decades by the characteristic stigmata consisting of facial appearances, short stature, undescended testes, secretion growth hormone-releasing hormone , In childrenincluding of GHND, a disruption at any level in the heart lesions, cubitus valgus and mental retardation, somatostatin, and neurotransmitters at manycould levelsmodify (10). neurotransmitter-neurohormonal pathways since the exact etiologic factors and possible mode of GH secretion ultimately expressed as poor growth inheritance of the syndrome have not been determined velocity and short stature. Therefore, the pathways yet (2-4). This case represented most of the diagnostic and levels impaired in GHND seem to differ among stigmata of Noonan syndrome and occurred sporadically individual cases.is that the appearance of the sexual Another concern since his parents and a brother were normal. We were characteristics of puberty was delayed in the present interested in the cause of the short stature in this case case. It has been reported that puberty is delayed in since short stature in Noonan syndrome is a common but GH-deficient children (ll, 12). The precise signal that not invariable feature. There is no definite agreement initiates and maintains puberty is not known although to date on the cause of short stature, that is, genetic, a critical level of body fat has been hypothesized to be prenatal, perinatal or postnatal. Collins and Turner (3) a signal (13). The significant increases in LH and FSH suggested that it might be, at least in part, postnatal after intravenous administration of LHRH in this case in origin, although there was no constant relationship indicate that the pituitary-gonadal axis was normal and between a reflection of the difficulties in the early years Since was reported thatthat GHpuberty administration in GH these itresponses suggest is imminent (14). of life such as feeding problems, failure to thrive and deficient children initiates puberty (ll), we expect the recurrent infection and the shortness of stature. In appearance of sexual characteristics of puberty under Since this they patient had normal reserve confirmed addition, suggested that GH the shortness of stature hGH treatment in this patient. by the conventional provocative testings, non-GH The present observations of a patient of Noonan was best growth considered as a component the syndrome deficient retardation was mostoflikely. GH neuro(3). syndrome presenting GHND resulting in short stature, secretory dysfunction (GHND) was reported by Spiliotis who was treated effectively with hGH suggest that et al in 1984 and criteria for the diagnosis of GHND was short stature in Noonan syndrome has a wide spectrum proposed (5); 1) height 10/ig/l), 6) low 910
Internal
Medicine
Vol. 31, No. 7 (July
1992)
Growth Hormonein Noonan Syndrome 8) Finkelstein JW, Roffwarg HP, Boyar RM, et al. Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. J Clin Endocrinol Metab 35: 665, 1972. Noonan JA, Ehmke DA. Associated noncardiac malformations 9) Kitajima N, Chihara K, Kishimoto M, et al. A case of Noonan in children with congenital heart disease. J Pediatr 63: 468, 1963. syndrome accompanying by growth hormone-neurosecretory Noonan JA. Hypertelorism with Turner phenotype: A new dysfunction. Folia Endocrinol Jpn 64: abstract No 27, 1988 syndrome with associated congenital heart disease. Am J Dis(in Japanese). 10) Martin JB, Reichlin S. Regulation of growth hormone secretion Child 116: 373, 1968. Collins E, Turner G. The Noonan syndrome - A review of theand its disorders, in: Clinical Endocrinology, F.A. Davis Company, clinical and genetic features of 27 cases. J Pediatr 83: 941, 1973. Philadelphia, 1987, p. 223. Nora JJ, Nora AH, Sinha AK, et al. The Ullrich-Noonan synll) Tanner JM, Whitehouse RH. A note on the bone age at which drome (Turner phenotype). Am J Dis Child 127: 48, 1974. patients with true isolated growth deficiency enter puberty. J Spiliotis BE, August GP, Hung W, et al. Growth hormone Clin Endocrinol Metab 41: 788, 1975. 12) Goodman HG, Grumbach MM, Kaplan SL. Growth and growth neurosecretory dysfunction: A treatable cause of short stature. JAMA 251: 2223, 1984. hormone. N Engl J Med 278: 57, 1968. Bercu BB, Diamond FB Jr. A determination of stature: Regu13) Frisch RE. Body fat, puberty and fertility. Biol Rev 59: 161, lation of growth hormone secretion. Adv Pediatr 33: 331, 1986. 1989. Miller JD, Tannenbaum GS, Colle E, et al. Daytime pulsatile14) Griffin JE, Wilson JD. Disorders of the testes and male repro ductive tract, in: Textbook of Endocrinology. Wilson JD, Foster growth hormone secretion during childhood and adolescence. J DW, Eds. W.B. Saunders Company, Philadelphia, 1985, p. 283 Clin Endocrinol Metab 55: 989, 1982. References
Internal
Medicine
Vol. 31, No. 7 (July
1992)
911
Intr oducti on
except for the short stature and mental retardation. At the age of nine, he was noted at another facility that Noonan syndrome was first recognized as a clinical growth hormone (GH) release by provocative testings entity by Noonan and Ehmke in 1963 (1). The principal was normal. His parents and a brother were physically clinical features of Noonan syndrome include character and mentally normal. Physical examination on admission istic facial appearance, short stature, mental retardation, was remarkable for short stature (136cm) well below neck signs, congenital heart lesions, somatic anomalies, 2 SD (Fig. 1), the characteristic appearances of face, and the lack a significant chromosomal head and neck such as ocular hypertelorism, downward However, theof cause of short stature found inanomaly. the majority slanting palpebral fissures, low-set ears, webbed neck, of the patients with this syndrome has not been elucidated low posterior hairline, and cubitus valgus, but did not yet (2-4). Herein, we describe a patient of Noonan show congenital heart lesions, thoracic cage deformities, syndrome in whom growth hormone neurosecretory nor cryptorchism (Fig. 2). His body proportions were dysfunction is responsible for the short stature and appropriate for his height. Axillar and pubic hair did the growth velocity after replacement therapy with not develop and the genitalia showed a small penis exogenous synthetic human growth hormone (hGH) has-been markedly accelerated for a period of one year and testes (Tanner stage I). The results of neurological and a half. examination were negative. Bone age determined from hands and wrists roentgenograms was four years behind Case Report the chronological age. Admission laboratory examination was normal except for elevated alkaline-phosphatase The patient, a 16-year-old male, was admitted to this activity (93 IU/1). High-resolution computed tomography hospital in October 1988 for the endocrinological evalu scanning of the sella turcica and hypothalamus showed ation of short stature. He was born of a full-term preg no abnormalities. Chromosomal analysis showed 46 XY nancy and thereafter had been in a good state of health karyotype with normal banding. The patient's intelli From the Department of Internal Medicine, Koshigaya Hospital, gence Dokkyo University of Medicine, Koshigaya quotient (IQ) School by Wechsler Adult Intelligence Received for publication August 16, 1991; Accepted for publication March 16, 1992 Scale (WAIS) estimated to beKoshigaya verbal IQ 61, per- Dokkyo Universi Reprint requests should be addressed to Dr. Katsuya Tanaka, the Department of was Internal Medicine, Hospital, School of Medicine, 2-1-50 Minami Koshigaya, Koshigaya, Saitama 343, Japan 908
Internal
Medicine
Vol. 31, No. 7 (July
1992)
Growth Hormonein Noonan Syndrome
Fig. 1. Cumulative growth curve and height velocity for the patient and for Japanese boys (mean±SD). -o- represents the growth curve for the patient and -à"- represents the height velocity for the patient. The arrow indicates the commencement of hGH administration. The inset shows the height attained per month after hGH treatment. formance IQ 79 and the Full Scale IQ 67. The results of endocrinological examinations showed thyroxine 95.5 nmol/1, triiodothyronine 2.02 nmol/1, normal diurnal rhythm of plasma cortisol (8:00 AM; 190.4 nM, 4:00 PM; 146.3nM, and ll:00 PM; 35.9nM), testosterone 0.12 nmol/1, urinary 17-hydroxycorticosteroid 7.45 /imol/day and 17-ketosteroid 17.7/^mol/day. Basal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations were 14U/l and 13 U/l and increased 30 minutes after intravenous administration of luteinizing hormone-releasing hormone (LHRH) (100 /ig) to 66 U/l and 26U/l, respectively. Basal thyrotropin (TSH) and prolactin (PRL) concentrations were 1.6mU/l and 25 /ig/l, and increased 30 minutes after intravenous administration of thyrotropin-releasing hormone (TRH) (500fig) to 6.2mU/l and 75 ^g/l, respectively. GH after intravenous administration of arginine (0.5 g/kg) and growth hormone-releasing hormone (1 /ig/kg) increased from the basal values of 2.1 and 3.1pig/l to the peak values of 16.0 and 15.2jug/1, respectively (Fig. 3). The endogenous nocturnal pulsatile secretion of GH of which samples were obtained every 20 minutes for 12 hours from 9:00 PM to 9:00 AM disclosed that there were only 4 GH peaks greater than 3 /ig/1 and the mean GH concen tration for over the Internal Medicine Vol. 12 31, hours No. 7 was (July 2.31 1992) ± 2.26 (SD) pigll (Fig. 4). The low baseline level of insulin-like growth
Fig. 2. The patient at 16 years old with clinical features of ocular hyper telorism (covered), downward slanting palpebral fissures (covered), low-set ears, low posterior hairline, webbed neck, cubitus valgus, short stature and sexual infantilism.
120
Fig. 3. Growth hormone responses after intravenous ad ministration of growth hormone-releasing hormone (GRH) (o) (1 /jg/kg) or arginine (à") (0.5g/kg). factor I (IGF-I) of 0.37U/l responded to the acute administration of hGH intramuscularly for three days with an increase in IGF-I level of 0.85U/l. After the tests, the patient was treated with hGH 4U (0.125 U/kg) 909
Tanaka et al somatomedin-C (IGF-I) for age. Rather than a 24-hour GH secretion study, in this patient we examined the 12-hour nocturnal GH secretory pattern which was suggested most useful to identify GHND (6). Magnitude and numbers of the spontaneous bursts of GH secretion are age-related and transition from early puberty to adolescence is associated with increased numbers of GH surges (7, 8). The result of 12-hour nocturnal GH secretion showed a conspicuously low amplitude and 21222324 1 2 3 4 5 6 7 8 9 small numbers of bursts of spontaneous GH secretion, The period of sleeping clock time compatible with GHND. This case fulfilled the criteria Fig. 4. The twelve-hour growth hormone secretory profile. Sam for GHND. The marked slowing of growth velocity noted before the age of ten is thought to be the result of ples were obtained every 20 minutes from 21:00 to 9:00. The patient's GHND that probably had been in his childhood. Bercu sleeping period was from 23:00 to 7:00. Growth hormone secretory peaks over 3/ig/l were four and the mean (±SD) growth hormoneKitajima and Diamond mentioned the association of Noonan et al reported a 14-year-old girl with Noonan concentration was 2.31 ± 2.26jUg/1. syndrome and GHND though data were not shown presenting GHND who responded to the (6). three times a week for a period of one year and a half. administration of propranolol (20mg a day); she grew The growth velocity accelerated more than three fold 1.9 cm over a three-month period but did not present any compared to the mean growth velocity of the previous effect of hGH administration (9). In the present case the five years [1.9± 0.2 (SD) cm per year] (Fig. 1). marked acceleration of growth velocity after hGH treat ment indicates the effectiveness of hGH treatment in Discussion short stature. Although GHND is most responsible for short stature in this case, it is difficult to identify the Noonan syndrome has been diagnosed for more than primary abnormality in complex neural pathways of GH two decades by the characteristic stigmata consisting of facial appearances, short stature, undescended testes, secretion growth hormone-releasing hormone , In childrenincluding of GHND, a disruption at any level in the heart lesions, cubitus valgus and mental retardation, somatostatin, and neurotransmitters at manycould levelsmodify (10). neurotransmitter-neurohormonal pathways since the exact etiologic factors and possible mode of GH secretion ultimately expressed as poor growth inheritance of the syndrome have not been determined velocity and short stature. Therefore, the pathways yet (2-4). This case represented most of the diagnostic and levels impaired in GHND seem to differ among stigmata of Noonan syndrome and occurred sporadically individual cases.is that the appearance of the sexual Another concern since his parents and a brother were normal. We were characteristics of puberty was delayed in the present interested in the cause of the short stature in this case case. It has been reported that puberty is delayed in since short stature in Noonan syndrome is a common but GH-deficient children (ll, 12). The precise signal that not invariable feature. There is no definite agreement initiates and maintains puberty is not known although to date on the cause of short stature, that is, genetic, a critical level of body fat has been hypothesized to be prenatal, perinatal or postnatal. Collins and Turner (3) a signal (13). The significant increases in LH and FSH suggested that it might be, at least in part, postnatal after intravenous administration of LHRH in this case in origin, although there was no constant relationship indicate that the pituitary-gonadal axis was normal and between a reflection of the difficulties in the early years Since was reported thatthat GHpuberty administration in GH these itresponses suggest is imminent (14). of life such as feeding problems, failure to thrive and deficient children initiates puberty (ll), we expect the recurrent infection and the shortness of stature. In appearance of sexual characteristics of puberty under Since this they patient had normal reserve confirmed addition, suggested that GH the shortness of stature hGH treatment in this patient. by the conventional provocative testings, non-GH The present observations of a patient of Noonan was best growth considered as a component the syndrome deficient retardation was mostoflikely. GH neuro(3). syndrome presenting GHND resulting in short stature, secretory dysfunction (GHND) was reported by Spiliotis who was treated effectively with hGH suggest that et al in 1984 and criteria for the diagnosis of GHND was short stature in Noonan syndrome has a wide spectrum proposed (5); 1) height 10/ig/l), 6) low 910
Internal
Medicine
Vol. 31, No. 7 (July
1992)
Growth Hormonein Noonan Syndrome 8) Finkelstein JW, Roffwarg HP, Boyar RM, et al. Age-related change in the twenty-four-hour spontaneous secretion of growth hormone. J Clin Endocrinol Metab 35: 665, 1972. Noonan JA, Ehmke DA. Associated noncardiac malformations 9) Kitajima N, Chihara K, Kishimoto M, et al. A case of Noonan in children with congenital heart disease. J Pediatr 63: 468, 1963. syndrome accompanying by growth hormone-neurosecretory Noonan JA. Hypertelorism with Turner phenotype: A new dysfunction. Folia Endocrinol Jpn 64: abstract No 27, 1988 syndrome with associated congenital heart disease. Am J Dis(in Japanese). 10) Martin JB, Reichlin S. Regulation of growth hormone secretion Child 116: 373, 1968. Collins E, Turner G. The Noonan syndrome - A review of theand its disorders, in: Clinical Endocrinology, F.A. Davis Company, clinical and genetic features of 27 cases. J Pediatr 83: 941, 1973. Philadelphia, 1987, p. 223. Nora JJ, Nora AH, Sinha AK, et al. The Ullrich-Noonan synll) Tanner JM, Whitehouse RH. A note on the bone age at which drome (Turner phenotype). Am J Dis Child 127: 48, 1974. patients with true isolated growth deficiency enter puberty. J Spiliotis BE, August GP, Hung W, et al. Growth hormone Clin Endocrinol Metab 41: 788, 1975. 12) Goodman HG, Grumbach MM, Kaplan SL. Growth and growth neurosecretory dysfunction: A treatable cause of short stature. JAMA 251: 2223, 1984. hormone. N Engl J Med 278: 57, 1968. Bercu BB, Diamond FB Jr. A determination of stature: Regu13) Frisch RE. Body fat, puberty and fertility. Biol Rev 59: 161, lation of growth hormone secretion. Adv Pediatr 33: 331, 1986. 1989. Miller JD, Tannenbaum GS, Colle E, et al. Daytime pulsatile14) Griffin JE, Wilson JD. Disorders of the testes and male repro ductive tract, in: Textbook of Endocrinology. Wilson JD, Foster growth hormone secretion during childhood and adolescence. J DW, Eds. W.B. Saunders Company, Philadelphia, 1985, p. 283 Clin Endocrinol Metab 55: 989, 1982. References
Internal
Medicine
Vol. 31, No. 7 (July
1992)
911
