Usefulness of Ultrasonography in Diagnosing Congenital Adrenal Hyperplasia in Neonates

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1 Clin Pediatr Endocrinol 1993;2(2): Copyright (C)1993 by The Japanese Society for Pediatric Endocrinology Usefulness of Ultrasonography in Diagnosing Congenital Adrenal Hyperplasia in Neonates Kunio Wataki, Hisashi Ohnishi, Susumu Konda, Toshiyuki Yasuda, Shigeki Miyamoto, Kazunori Sanayama, Nozomu Sasaki and Hiroo Niimi Department of Pediatrics, School of Medicine, Chiba University (K.W., H.0., S.K., T.Y., H.N.), Department of Pediatrics, Narita Red Cross Hospital (K.S.), Division of Endocrinology, Chiba Children's Hospital (S.M., N.S.), Chiba, Japan. Abstract. The size of the right adrenal gland was ultrasonographically evaluated in nine neonates, who had elevated filter paper 17-hydroxyprogesterone concentrations in the neonatal screening and/or clinical presentation with genital hyperpigmentation. Ultrasonograms revealed that three of these neonates had an enlarged adrenal gland, and based on subsequent hormonal measurements and their clinical signs, all three were diagnosed as congenital adrenal hyperplasia due to a 21-hydroxylase deficiency. Sonography also revealed that the adrenal gland of the remaining six neonates was normal in size and they also were found to be hormonally normal. We conclude that sonographic measurement of the adrenal gland is a useful adjunct to achieving the diagnosis of congenital adrenal hyperplasia in the neonatal period. Key words: neonatal adrenal glands, neonatal screening, congenital adrenal hyperplasia, ultrasonography Introduction Congenital adrenal hyperplasia (CAH) results from an adrenal enzymatic deficiency in the pathways leading to synthesis of cortisol. The most frequent type is a 21- hydroxylase deficiency (21-OHD). A decrease in the production of cortisol leads to an increased ACTH secretion by the pituitary, resulting in hyperplasia of the adrenal glands. Received: April 28, 1993 Accepted: October Correspondence: Kunio Wataki, Department of Pediatrics, School of Medicine, Chiba University, Chiba-shi, Chiba 260 Japan Inohana, Chuo-ku, The molecular genetic basis of this disorder is now known to result from mutation in the CYP21 gene, which locates on the short arm of chromosome 6, encoding the adrenal cytochrome P-450 specific for steroid 21- hydroxylation. The mutations in the CYP21 gene are almost always either deletions or transfers of deleterious sequences from the adjacent pseudogene CYP21P to the active gene CYP21 [1]. In Japan, CAH due to 21-OHD was included in routine neonatal screening in 1989 by measuring filter paper 17-hydroxyprogesterone (17-OHP) concentrations. We have previously reported that during the neonatal period the normal right adrenal gland of term neonates 99

2 100 Vol.2/No.2 WATAKI et al. Fig. 1. Sonographic measurement-method and image of right adrenal gland. was visualized by ultrasonography (US) and gradually decreased in size up to one month, and the normal size of the right adrenal gland could be established [2]. Therefore, to determine whether US visualization of the adrenal gland during the neonatal period is an appropriate tool to assist in the diagnosis of CAH, we have measured the size of the right adrenal gland of neonates with an elevated 17-OHP concentration in the neonatal screening and/ or clinical presentation with genital hyperpigmentation. Materials and Methods The right adrenal glands of nine neonates suspected of having CAH were studied by US. Seven of the neonates had elevated 17-OHP concentrations in neonatal screening, and the remaining two sought medical advice because of hyperpigmentation and/or vomiting. Their gestational age ranged between 36 and 40 weeks and birth weight between 2440 and 3925g. US was performed by using a real-time linear scanner with a 5 MHz scanning trans-

3 December Ultrasonography in Diagnosing CAB ducer. The right adrenal gland of each neonate was identified in a sagittal projection from the upper abdomen in the anterior axillary line, according to the method of Oppenheimer et al. [3]. The adrenal gland length was defined as the maximum cephalocaudal diameter and the trace area was measured by tracing manually the outline of the adrenal ELISA), and has been expressed as the blood level (ng/ml). Screening procedure for elevated filter paper 17-OHP concentration is shown in Fig. 2. gland in the same cross-section of the length as indicated in Fig. 1. It must be noted that full measurement of the left adrenal was not always possible, due to the presence of stomach gas and the overlying bowel. The normal right adrenal length and trace area had been previously determined by the sonographic measurement of 111 neonates (46 neonates at 0 day: body weight 3,096 }333g (mean }SD), 34 neonates at 5 days, and 31 neonates at one month: body weight 4,454 }439g) [2]. As part of the neonatal screening, the 17-OHP concentration of each neonate was measured using a filter paper blood at the Chiba Health Service Association by ELISA (EIKEN 17-OHP D Fig. 2. Screening procedure for elevated filter paper 17-OHP concentration. Table 1: Clinical and Laboratory Characteristics and Results of Right Adrenal Sonographic Measurements of Nine Neonates

4 102 Vol.2/No.2 WATAKI et al. Results The results are summarized in Table 1. Three of the neonates (No.1-3) were diagnosed as having CAH due to 21-OHD, based on their extremely elevated 17-0HP concentrations and their clinical symptoms and signs, and the remaining six neonates (No. 4-9) were found to be normal. The length and trace area of the right adrenal gland of the three CAH neonates were all above +4SD, 27-30mm in length, and cmcm2 in trace area. However, the remaining six neonates with a normal adrenal gland size (below+2sd) were hormonally normal (Fig. 3). The adrenal gland shapes of the CAH neonates were typical adrenal shapes, resembling a "Y", but slightly distended. Follow-up examinations of the length and trace area of the right adrenal gland after initiation of adequate treatment in all three CAH patients are shown in Fig. 4. Fig. 4 indicates that initial enlarged adrenal glands of CAH patients decreased in size after adequate replacement therapy, and that it took a longer time for adrenal glands with severe CAH to become normal in size. Discussion The normal neonatal adrenal gland is sonographically visualized more easily than that of the adult, due to its proportionately larger size, a paucity of perirenal fat, and its closer location to the skin's surface [3]. Several reports have indicated the usefulness of US in detecting adrenal enlargement due to CAH. In this regard, Ghiacy et al. [4] and Sivit et al. [5] have measured the length and width of the adrenal gland of CAH neonates in accordance with the method described by Oppenheimer et al. and have compared the size of the adrenal gland of CAH neonates to the size of normal neonates ( cm in length and cm in width, established by Oppenheimer et al.). According to the report Fig. 3. Length and trace area of right adrenal gland of each patient measured by US. A: Length of right gland. B: Trace area of right gland. Closed circles in the brackets represent the mean }2SD and broken lines indicate the normal range which we previously reported. Open square= CAH patient (before treatment). Closed squares= CAH patients (after initiation of treatment). Open triangles= normal patients. Numbers= patient number (see Table 1). by Ghiacy, the right adrenal gland measured 3.9cm in length and 1cm in width in one CAH neonate. As for the report by Sivit, the

5 December Ultrasonography in Diagnosing CAH Fig. 4. Changes in length and trace area of right adrenal gland in 3 patients with CAH after initiation of treatment. adrenal gland size in six neonates with CAH ranged from 14.0mm to 29.0mm in length and from 4.0mm to 6.5mm in width. Sivit also reported that the sonographic finding of some neonatal CAH cases may appear to be normal and that the sonographic confirmation of a normal-sized adrenal gland does not exclude the possibility of CAH. Bryan et al. also have measured the width of the right adrenal gland in eight cases of neonatal CAH and have reported that their widths ranged from 3mm to 12mm [6]. Three patients clearly had an enlarged gland, three had borderline size, and two had a size within normal limits. As to the

6 104 WATAKI et al. Vol.2/No.2 variations in adrenal width, Bryan et al. suspected that increased adrenal thickness might be related to more marked degrees of virilization or to the presence of salt loss. Hauffa [7] and Menzel [8] used an ASI (adrenal size index) to evaluate adrenal size of normal neonates and CAH patients. According to their report, ASI was highly elevated in CAH neonates with severe salt loss, whereas it was at the upper limit of the normal range in CAH neonates without salt loss. Mizuseki reported that a CAH neonate with salt loss was found to have a remarkably enlarged adrenal gland, 50mm in length [9]. Based on these results and our findings, we suspect that adrenal enlargement is proportional to the severity of the enzyme deficiency. Very few reports have appeared with regard to measurements of the trace area of the adrenal gland by US in CAH patients, although ASI evaluation was close to the trace area. Hauffa noted that the simple measurement of the adrenal gland length would tend to underestimate or even miss early hyperplasia [7]. The external diameters of the adrenal gland, such as its length, might still be normal, whereas thickening of the central portion of the organ and loss of concavity already indicate an early stage of hyperplasia [8]. Thus, the sonographic measurement of the trace area can serve as a useful parameter to assess the presence of CAH. The complicated three-dimensional structure of the adrenal gland and its rapid postnatal decrease in size make it difficult to establish its normal size. In a preceding study we established the normal size of the adrenal gland's length and trace area in full term neonates at day 0, day 5, and at one month after birth [2], and observed in this study that sonographic assessment of hyperplastic adrenal glands was able to discriminate clearly CAH patients from normal neonates. US may be very useful in the evaluation of infants who have a positive neonatal CAH screening test but no clinical symptoms or signs and normal serum electrolytes, and especially who are boys. In conclusion, US measurement of the length and trace area of the adrenal gland is a useful adjunct to achieving a diagnosis of CAH. References 1. Strachan T. Molecular pathology of congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 1990; 32: Wataki K, Ohnishi H, Miyamoto H, Yasuda T, Niimi H. Ultrasonographic measurement of the normal neonatal adrenal glands. Acta Paediatr Jpn 1991; 95: (in Japanese). 3. Oppenheimer DA, Carroll BA, Yousem S. Sonography of the normal neonatal adrenal gland. Radiology 1983; 146: Ghiacy S, Dubbins PA, Baumer H. Ultrasound demonstration of congenital adrenal hyperplasia. J Clin Ultrasound 1985; 13: Sivit CJ, Hung W, Taylor GA, Catena LM, Brown-Jones C, Kushner DC. Sonography in neonatal congenital adrenal hyperplasia. AJR 1991; 156: Bryan PJ, Caldamone AA, Morrison SC, Yulish BS, Owens R. Ultrasound findings in the adreno-genital syndrome (congenital adrenal hyperplasia). J Ultrasound Med 1988; 7: Hauffa BP, Menzel D, Stolecke H. Agerelated changes in adrenal size during the first year of life in normal newborns, infants and patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: comparison of ultrasound and hormonal parameters. Eur J Pediatr 1988; 148: Menzel D, Hauffa BP. Changes in size and sonographic characteristics of the adrenal glands during the first year of life and the sonographic diagnosis of adrenal hyperplasia in infants with 21-hydroxylase deficiency. J Clin Ultrasound 1990; 18: Mizuseki K, Nakamura Y, Goto S, Kobayashi H, Mannami M, Kondo T, et al. Sonographic screening for congenital adrenal

7 December Ultrasonography in Diagnosing CAB hyperplasia. Jpn. J. Clin. Urol. 1992; 46: (in Japanese).