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Linear Growth Characteristics of Congenitally GH-Deficient Infants from Birth to One Year of Age

Division of Endocrinology and Diabetes, Children’s Hospital of Buffalo, State University of New York at Buffalo School of Medicine and Biomedical Science, Buffalo, New York 14222

Abstract

Birth length has been reported to be either normal or reduced in infants with congenital GH deficiency (CGHD). We evaluated 46 infants with CGHD followed in a single regional medical center. All were born full term and had peak GH of less than 10 µg/liter after provocative stimulation. Length SD score at birth was normal but subsequently showed deceleration, at 6 months and 12 months of age, before GH treatment. The majority were delivered vaginally (83%), and delivery was uncomplicated in 61%. Four patients (9%) had breech vaginal delivery. Perinatal morbidities were found in 72% of infants and included jaundice (n = 17), hypoglycemia with or without seizure (n = 14), and hypoxemia (n = 5). Multiple pituitary hormone deficiencies were found in 85% of the subjects. Organic lesions were documented in all 22 subjects who had magnetic resonance imaging and in 4 of 11 subjects who had computed tomography scan. Only the hypoglycemic infants received early GH treatment. Growth data in hypoglycemic and normoglycemic CGHD infants were not significantly different. In our population, CGHD did not adversely affect fetal growth but is essential for normal linear growth during early infancy. Congenital developmental abnormalities in the hypothalamic-pituitary region are the most common cause of CGHD and are best diagnosed by an magnetic resonance imaging study.

OPINIONS DIFFER as to the impact of GH deficiency on fetal growth. Reports of normal birth length and normal early linear growth in infants with congenital hypopituitarism have implied that fetal growth is GH-independent (1, 2, 3, 4). Recent studies have presented data showing reduced birth lengths in this infant population. The authors concluded that GH is necessary for normal growth of the fetus and young infant (5, 6, 7, 8, 9). This hypothesis is also supported by the findings of reduced birth length in infants with GH resistance caused by mutations in the GH receptor gene (10).

Infants with congenital hypopituitarism comprise a heterogeneous population, because the deficiency of GH is either isolated or combined with other pituitary hormone deficits. Etiology is also variable. Before the availability of magnetic resonance imaging (MRI), it was assumed that perinatal injury from complicated deliveries was a frequent cause of hypopituitarism (5, 11, 12, 13). However, it was not always possible to distinguish whether the birth trauma was the cause of or the consequence of hypopituitarism. Recent studies of patients with either isolated GH deficiency or multiple pituitary hormone deficiencies suggest that infants with developmental abnormalities in the stalk or pituitary gland are at increased risk for perinatal complications (14).

We undertook this study to obtain additional information about birth lengths and linear growth of infants diagnosed with congenital GH deficiency (CGHD) who were followed in our institution. Another aim of the study was to improve our understanding about the causes for congenital hypopituitarism, focusing on perinatal complications and their relationship to the presence of defects in the hypothalamic-pituitary region.

Materials and Methods

The clinic records of 46 patients (28 males and 18 females), diagnosed with CGHD and followed at Children’s Hospital of Buffalo between 1962 to 1997, were reviewed. In instances where required information was not available in the record, parents were contacted by phone and interviewed by one of the investigators. Patients with prematurity, chromosomal abnormality, dysmorphic syndromes, prenatal infections, and intrauterine growth retardation were excluded.

The diagnosis of CGHD, with or without other pituitary hormone deficiencies, was based on the following criteria: 1) abnormal age-adjusted growth velocity and height (linear growth less than 7 cm/yr in the first 2 yr of life and height less than the 3rd percentile, respectively), with normal body proportions; 2) peak GH response less than 10 µg/liter, by RIA, during two of the following provocative tests: spontaneous hypoglycemia, arginine, L-dopa, or insulin hypoglycemia; 3) low serum cortisol (less than 220 nM) during hypoglycemia; 4) low serum T₄, with low or normal TSH levels; 5) low gonadotropin production, presenting as micropenis and/or hypoplastic testes in infancy or low gonadotropin responses to LHRH documented at a pubertal age; 6) decreased renal concentrating ability, which was corrected by antidiuretic hormone; and 7) anatomic abnormalities in the hypothalamic-pituitary region, documented by MRI or computed tomography (CT) scan.

Birth length, birth weight, and subsequent measurements of length and weight at 6 months and at 12 months old were obtained from the clinic records. Birth lengths were obtained using either a measuring board or tape measure. Subsequent lengths were done using the measuring board. Lengths were standardized using data provided by the National Center for Health Statistics. Information about maternal health during pregnancy, type of delivery, perinatal complications, and postnatal morbidities were derived from the medical records or an interview with the parent. The results of hormonal studies to document pituitary hormone deficiencies, imaging studies of the brain, and data related to age of diagnosis and initiation of GH therapy were also determined from the clinic charts. The dose of GH was standardized for body weight, i.e. 0.043 mg/kg·d, sc. The mean length and weight at birth, at 6 months old, and at 1 yr of age were expressed in SD score (SDS). Statistical analysis was performed using ANOVA and Pearson correlation.

Results

Growth data

Length SDS and weight SDS (mean ± SD) were normal in the 46 patients at birth; and subsequently, both parameters decelerated within the first year of life (Table 1). Length SDS was 0.4 above the mean at birth, -1.25 SDS at 6 months, and -1.8 SDS at 1 yr (Fig. 1). Birth length SDS was not different in infants with isolated GH deficiency vs. those with multiple pituitary hormone deficiencies. At 6 months old, both groups had length SDS below the mean, with more severe deceleration in the infants with multiple pituitary hormone deficiencies, although this was not statistically significant. At 12 months of age, both groups of infants showed equally severe linear growth deceleration. There was no correlation between birth length and length at 6 and 12 months, with hypoglycemia. Growth deceleration in the hypoglycemic and nonhypoglycemic groups was of similar severity. Weight SDS was normal at birth and decelerated at 6 months and 12 months (Table 1). Weight deceleration was less severe than the length deceleration.

View larger version (7K): [in this window] [in a new window]   Figure 1. Length SDS was 0.4 above the mean at birth, -1.25 SDS at 6 months, and -1.8 SDS at 1 yr of age.

Most of the infants were delivered vaginally (83%), and the majority of the vaginal deliveries were uncomplicated (61%). Seven infants (15%) were delivered by cesarean section because of repeat cesarean section (2 of 7), failure of induction (2 of 7), breech presentation (1 of 7), fetal distress (1 of 7), and dystocia (1 of 7). Four patients (9%) were born by breech vaginal delivery. Among the infants with multiple pituitary hormone deficiencies (n = 39), the number of babies born via uncomplicated delivery was not significantly different from the number of babies born by complicated delivery. In addition, developmental abnormalities of the hypothalamus and pituitary gland were not related to the type of delivery, i.e. they occurred in 11 infants born by uncomplicated delivery and in 13 infants born via complicated delivery.

Various perinatal morbidities were found in 72% of the infants in the study and were usually transient. The most common problems were jaundice (n = 17) and hypoglycemia (n = 14). Five infants had asphyxia at birth and, among these babies, four had complicated vaginal or cesarean deliveries. Other perinatal problems included transient seizures from hypoglycemia (n = 5), feeding problems (n = 1), and poor weight gain (n = 1). One infant developed sepsis and fever immediately after birth and was found to have duodenal atresia.

Complexity of hypopituitarism

Fifteen percent of the subjects had isolated GHD, and 85% had multiple pituitary hormone deficiencies. Among the 46 subjects, 100% had GH deficiency, 57% had TSH deficiency, 52% had gonadotropin deficiency, 46% had ACTH deficiency, and 6% had ADH deficiency.

All of the 22 subjects evaluated by MRI had documented organic lesions in the hypothalamic and pituitary regions. Four of the 11 patients who had CT scan of the brain also showed abnormal findings, whereas none of the sella x-rays in 7 patients showed any abnormality. The abnormalities found were pituitary gland hypoplasia or aplasia, ectopic pituitary gland, septooptic dysplasia, isolated absence of septum pellucidum, stalk abnormalities, empty sella, and holoprosencephaly. Multiple abnormalities were observed in some patients. All of the 20 patients who were evaluated before the availability of MRI technology had been categorized as having idiopathic hypopituitarism based on negative sella x-rays and CT examination studies.

Age at diagnosis of CGHD and age at initiation of GH therapy

The age at diagnosis of CGHD (mean ± SD) was 5.3 ± 3.8 yr, and the mean age at initiation of GH therapy was 5.8 ± 4.0 yr. The 20 patients who had early onset of hypoglycemia were diagnosed and treated at an earlier age, compared with the 26 patients who had no hypoglycemia. Eight patients with severe hypoglycemia, as evidenced by seizures, were diagnosed at 1.6 ± 1.6 yr and were started on GH treatment at 1.9 ± 1.5 yr. Twelve patients with transient neonatal hypoglycemia were diagnosed at 3.7 ± 0.5 yr and were treated at a mean age of 3.9 ± 2.4 yr. Those without hypoglycemia were diagnosed at 7.3 ± 3.6 yr, and GH therapy started at 8.1 ± 3.9 yr.

The peak stimulated GH concentration (mean ± SD) for all 46 patients was 2.9 ± 2.5 µg/liter. Patients with severe hypoglycemia had a peak of 4.0 ± 4.9 µg/liter, and those with transient hypoglycemia had a peak of 2.8 ± 1.7 µg/liter. Those without hypoglycemia had a peak of 2.7 ± 2.5 µg/liter. The peak GH levels among these groups were not statistically significant.

Discussion

Our population of full-term infants born with either isolated CGHD or multiple pituitary hormone deficiencies had normal lengths and weights at birth. By 6 and 12 months of age, all manifested growth deceleration. Weight deceleration is also present but to a lesser degree. Our observations do not concur with recent reports of reduced birth lengths in infants with CGHD (5, 6, 7, 8, 9). However, there is general agreement that early onset of progressive growth deceleration is a major characteristic in these children, even though disagreement exists about the birth length findings. The clinical data confirms that GH plays an essential role in early linear growth during infancy (1, 2, 3, 4, 5, 6, 7, 8, 9). The most compelling evidence for a pivotal role of GH during fetal life is the finding of abnormal birth length in infants with total absence of GH attributable to either a deletion or null mutation in the pituitary GH gene (15). In addition, GH resistance (Laron dwarfism) caused by mutations in the GH receptor is associated with poor linear fetal growth (10). It is possible that infants with total absence or resistance to GH are undergrown, whereas other infants with structural lesions in the hypothalamic-pituitary area have less severe forms of fetal GH deficiency that do not prevent attainment of normal birth length.

Hypoglycemia at birth or in the first months of life is the main complaint that leads to early diagnosis of CGHD (4, 16). In our study, 12 infants with early transient hypoglycemia failed to be diagnosed as GH-deficient because their hypoglycemia resolved and their birth lengths were normal. Recurrence of fasting hypoglycemia, at a later age, coupled with poor linear growth, were the main reasons for their subsequent diagnosis of CGHD. Our data show that birth lengths in infants with hypoglycemia were not significantly different from those of infants with no documented hypoglycemia. Also, growth deceleration in the children with hypoglycemia was not more severe than in the normoglycemic group. Therefore, early linear growth failure was the major characteristic of CGHD and was not influenced by the presence or absence of hypoglycemia. Hypoglycemia was caused by GH deficiency with or without cortisol deficiency; the latter is known to impair gluconeogenesis (16). In our study, 14 of the 20 children with hypoglycemia were ACTH/cortisol-deficient.

Some studies have suggested that perinatal injury leads to CGHD (11, 12, 13). Although a majority of our patients had perinatal morbidities, the prevalence of breech presentation and the severity of the perinatal complications were less than reported by these authors. In contrast, other investigators propose that a congenital developmental anomaly in the hypothalamic-pituitary or midbrain region is the main etiology for CGHD (17, 18, 19, 20, 21, 22, 23, 24, 25). In our study, all of the 22 infants who had an MRI of the brain manifested congenital malformations in the pituitary and/or hypothalamus. In contrast, only 4 of 11, and none of the 7 babies who had CT or plain sella x-rays, respectively, were found to have an abnormality in the pituitary-hypothalamic region. We propose that developmental abnormalities in the hypothalamic-pituitary region are the main cause of CGHD in our patients and that these defects place the infant at risk for morbidity. Current advances in molecular endocrinology has revealed that GHD may also result from mutations in genes controlling the ontogeny of cells within the pituitary gland, such as somatotrophs, thyrotrophs, lactotrophs, and gonadotrophs (15).

We conclude that CGHD results from congenital developmental abnormalities in the hypothalamic-pituitary region that cause an increased risk for perinatal morbidity. The most definitive method for detection of developmental anomalies in the pituitary-hypothalamic region is the MRI. CGHD does not seem to impact adversely on fetal growth. However, it is possible that the infants in our study population had a lesser degree of GH deficiency, compared with children with GH resistance or GH gene deletion.

Acknowledgments

Footnotes

Address all correspondence and requests for reprints to: Margaret H. MacGillivray, M.D., Children’s Hospital of Buffalo, 219 Bryant Street, Buffalo, New York 14222.

Abbreviations: CGHD, Congenital GH deficiency; MRI, magnetic resonance imaging; CT, computed tomography; SDS, SD score.

Received April 23, 2001.

Accepted July 23, 2001.

References

1. Gluckman PD, Liggins GC 1984 Regulation of fetal growth. In: Beard RW, Nathanielsz PW, eds. Fetal physiology and medicine. 2nd ed. New York: Marcel Dekker; 511–558
2. MacGillivray MH 1990 Disorders of growth and development. In: Felig P, Baxter JD, Frohman LA, eds. Endocrinology and metabolism. 3rd ed. New York: MacGraw Hill Inc; 1645–1646
3. Karlberg J, Albertsson-Wikland K 1988 Infancy growth pattern related to growth hormone deficiency. Acta Paediatr 77:385–391
4. Lovinger RD, Kaplan SL, Grumbach MM 1975 Congenital hypopituitarism associated with neonatal hypoglycemia and microphallus: four cases secondary to hypothalamic hormone deficiencies. J Pediatr 87:1171–81[CrossRef][Medline]
5. Albertsson-Wikland K, Niklasson A, Karlberg P 1990 Birth data for patients who later develop growth hormone deficiency: preliminary analysis of a national register. Acta Paediatr Suppl 370:115–120
6. Gluckman PD, Gunn AJ, Wray A, Cutfield WS, Chatelain PG, Guilbaud O, Ambler GR, Wilton P, Albertsson-Wikland K1992 Congenital idiopathic growth hormone deficiency associated with prenatal and early postnatal growth failure. J Pediatr 121:920–923
7. Wit JM, Van Unen H 1992 Growth of infants with neonatal growth hormone deficiency. Arch Dis Child 67:920–924[Abstract]
8. Niklasson A, Karlberg P, Albertsson-Wikland K, and the Swedish Pediatric Study Group for GH Treatment 1994 Normal weight for length in newborn infants in whom growth hormone deficiency was later diagnosed. Acta Paediatr 83:192–195[Medline]
9. De Luca F, Bernasconi S, Blandino A, Cavallo L, Cisternino M 1995 Auxological, clinical and neuroradiological findings in infants with early onset growth hormone deficiency. Acta Paediatr 84:561–565[Medline]
10. Laron Z, Pilos P, Klinger B 1993 Growth curves for Laron syndrome. Arch Dis Child 68:768–770[Abstract]
11. Craft WH, Underwood LE, Van Wyk JJ 1980 High incidence of perinatal insult in children with idiopathic hypopituitarism. J Pediatr 96:397–402[CrossRef][Medline]
12. Gacs G 1984 Perinatal factors in the etiology of hypopituitarism. Helv Paediatr Acta 42:137–144
13. Surtees R, Adams J, Price D, Clayton P, Shalet S 1987 Association of adverse perinatal events with an empty sella turcica in children with growth hormone deficiency. Horm Res 28:5–12[Medline]
14. Maghnie M, Larizza D, Triulzi F, Sampaolo P, Guiseppe S, Severi F 1991 Hypopituitarism and stalk agenesis: a congenital syndrome worsened by breech delivery? Horm Res 35:104–108[Medline]
15. Mullis P, Fluck C 1999 Molecular genetics of growth hormone deficiency. In: Ranke M, Wilton P, eds. Growth hormone therapy in KIGS—10 years’ experience. Leipzig: Johann Ambrosius Barth Verlag; 31–42
16. Blethen SL 1996 Hypopituitarism. In: Lifshitz F, ed. Pediatric endocrinology. New York: Marcel Dekker, Inc; 19–23
17. Pocecco M, De Campo C, Marinoni S, Tomurasini G, Basso T, Muzzolini C, Sacher B 1988 High frequency of empty sella syndrome in children with growth hormone deficiency. Helv Paediatr Acta 43:295–301
18. Yukizane S, Kimura Y, Yamashita Y, Matsuishi T, Horikawa H, Ando H, Yamashita F 1990 Growth hormone deficiency of hypothalamic origin in septo-optic dysplasia. Eur J Pediatr 150:30–33
19. Argyropoulou M, Perignon F, Brauner R, Brunelle F 1992 Magnetic resonance imaging in the diagnosis of growth hormone deficiency. J Pediat 120:886–891[CrossRef][Medline]
20. Rappaport R 1995 Magnetic resonance imaging in pituitary disease. Growth Genet Horm 11:1–5
21. Bozzola M, Adamsbaum C, Biscaldi I, Zecca M, Cisternino M, Genovese E, Richard I, Kalifa G, Chaussain JL 1996 Role of magnetic resonance imaging in the diagnosis and prognosis of growth hormone deficiency. Clin Endocrinol (Oxf) 45:21–26
22. Kornreich L, Horev G, Lazar L, Schwarz M, Sulkes J, Pertzelan A 1998 MR findings in growth hormone deficiency: correlation with severity of hypopituitarism. Am J Neuroradiol 19:1495–1499[Abstract]
23. Nagel BHP, Palmbach M, Ranke M 1999 Magnetic resonance imaging in growth hormone deficiency. In: Ranke M, Wilton P, eds. Growth hormone therapy in KIGS—10 years’ experience. Leipzig: Johann Ambrosius Barth Verlag; 65–71
24. Longas A, Mayayo E, Labarta J 1999 Congenital growth hormone deficiency arising from central cranial malformations: experience in KIGS. In: Ranke M, Wilton P, eds. Growth hormone therapy in KIGS—10 years’ experience. Leipzig: Johann Ambrosius Barth Verlag; 135–146
25. Arrigo T, De Luca F, Maghnie M, Blandino A, Lombardo F, Messina MF, Wasniewska M 1998 Relationships between neuroradiological and clinical features in apparently idiopathic hypopituitarism. Eur J Endocrinol 139:84–88

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