Eur J Pediatr (1992) 151 : 167-169

European Journal of

Pediatrics

9 Springer-Verlag 1992

Progressive high frequency hearing loss: an additional feature in the syndrome of congenital adrenal hypoplasia and gonadotrophin deficiency M. Zachmann, E. Fuchs, and A. Prader Department of Paediatrics, University of Zurich, Kinderspital, Steinwiesstrasse 75, 8032 Zfirich, Switzerland Received August 13, 1991 / Accepted after revision September 11, 1991

Abstract. In an earlier report, we f o u n d that X-linked congenital adrenal hypoplasia m a y be associated with g o n a d o t r o p h i n deficiency. This c o m b i n a t i o n has since b e e n confirmed by m a n y others. A t the last examination, our patients were 22.4, 19.9 and 17.5 years old. T h e y were doing well on replacement therapy with hydrocortisone, f l u o r o h y d r o c o r t i s o n e , and long-acting testosterone, but in all of t h e m , a progressive hearing loss had appeared, starting at high freqencies at a b o u t 14 years o f age. T h e loss progressed with age to lower frequencies, and the oldest patient had some remaining hearing capacity at 125-500 H z only with a perceptive hearing loss of - 9 5 dB at frequencies a b o v e 500 Hz. It is concluded that patients with this s y n d r o m e should be examined for hearing loss. X-linked adrenal hypoplasia m a y also be associated with glycerol kinase deficiency and m y o p a t h y . A molecular X P - d e l e t i o n has suggested a locus for hypog o n a d o t r o p h i c h y p o g o n a d i s m distal to the glycerol kinase and adrenal hypoplasia loci. T h e observations in our patients suggest that the locus for at least this type of Xlinked deafness m a y be in the same area.

Key words: Congenital adrenal hypoplasia - G o n a d o trophin deficiency - H e a r i n g loss - X-linked deafness

Introduction Studying patients with familial congenital adrenal hypoplasia [5], we f o u n d s o m e years ago that in the X-linked type g o n a d o t r o p h i n deficiency m a y be associated with the adrenocortical failure [19, 23]. This s y n d r o m e has since b e e n confirmed by m a n y others [3, 6, 7, 12, 14, 17]. T h e three brothers described earlier [23] developed well on r e p l a c e m e n t therapy, but we o b s e r v e d that in all of t h e m a progressive hearing loss a p p e a r e d , starting at about 14 years of age. Offprint requests to: M. Zachmann

Patients and results The following clinical observations were made in the three brothers since their data were published: they had considerably retarded bone maturation and transient short stature even before a pubertal bone age was reached. This was attributed to the lacking adrenarche and extremely low DHEA levels in addition to the gonadotrophin deficiency. The eldest brother (patient 1) was 22.4 years old at the last examination. His height was 170em (-1.1 SD, target height according to parental height 178.5 + 8.5 cm). His body proportions were normal (sitting height -1.1 SD, subischial leg height -0.8SD, head circumference +0.6 SD). His bone age had been adult 2 years earlier. He was doing well and fully working as a boat builder on replacement with hydrocortisone 25-30mg daily (corresponding to 13.7-16.4mg/m z per day), fluorohydrocortisone 0.ling daily, and long-acting testosterone 250rag/month intramuscularly. He has been wearing a hearing aid since the age of 20 years. The second brother (patient 2) was 19.9 years old. His height was 174.8 cm (-0.4 SD), weight 68.7 kg (+0.2 SD). His body proportions were normal (sitting height -0.1 SD), subischial leg height -0.5 SD, head circumference -1.1 SD). His bone age was retarded (14.75 years according to Greulich and Pyle [11], height prediction according to Bayley and Pinneau [2] 182.4 cm). He was doing well on replacement with hydrocortisone 30 mg daily (16.3 mg/m2 per day), fluorohydrocortisone 0.ling daily, and long-acting testosterone 100 mg/month. Unlike his older and younger brother, he had behavioural problems, was unable to follow normal school, and suffered from epilepsy, which required combined antiepileptic medicatf'on. This is thought to be due to severe hypoglycaemic episodes during infancy, and not to be related to the syndrome. The youngest brother (patient 3) was 17.5 years old. His height was 147.1cm (-4.4SD), weight 63 kg (-0.1SD). His body proportions were somewhat eunuchoid for chronological age (sitting height -4.8 SD, subischial leg height -2.9 SD, head circumference -1.4SD). His bone age was 13 years and his height prediction 167.2 cm. He was doing well on replacement with hydrocortisone 25 mg daily (16 mg/m2 per day), and fluorohydrocortisone 0.1 rag. Up to the last examination, he did not receive any testosterone, but treatment with long-acting testosterone 50 rag/month intramuscularly was then started. Glycerol kinase deficiency was excluded in all three patients by estimations of triglycerides, hydroxyphenyl hydracrylic acid and hippurie acid. High resolution chromosomal analysis in patients 1 and 2 revealed no structural anomalies. In patient 3, the analysis was not performed.

168 Patient

After the hearing loss had been noted in patient 1, ENT examinations and audiograms were also performed in the two brothers. The audiometric curves of the three patients are shown in Fig. 1. ENT examinations revealed no anatomical anomalies and no signs of inflammation or other middle ear disease. In all patients, the haering loss was considered to be of the perception type. From the curves, it can be seen, that it started at high frequencies, probably at the age of about 14 years, and progressed to reduced perception of the lower frequencies.

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X-linked congenital adrenal hypoplasia can occur alone [5, 18, 20], or it m a y be associated not only with gonadotrophin deficiency, but also with X-linked glycerol kinase deficiency [1, 5] and m y o p a t h y [8]. In recent work, there has been molecular genetic evidence for deletions [8]. In the patients with gonadotrophin deficiency, there has been some uncertainty as to whether pituitary gonadotrophins or hypothalamic gonadotrophin releasing horm o n e ( G n - R H ) were primarily lacking. In our original patients [23], there was no gonadotrophin response to short-term G n - R H stimulation, but long-term stimulation had not b e e n performed. Subsequently, evidence for a hypothalamic origin was presented [14], but nevertheless, long-term treatment with G n R H was reported not to be successful [4, 13], and the results differed from those obtained in other types of gonadotrophin deficiency such as Kallmann's syndrome [10]. The relationship between adrenal hypoplasia and gonadotrophin deficiency does not seem to be a hormonal or metabolic one, but recent work suggests a genetic relationship with vicinity of the loci for gonadotrophin deficiency, glycerol kinase, and adrenal hypoplasia [9, 22]. The occurrence of hearing loss in our patients, albeit in the absence of glycerol kinase deficiency, possibly could thus shed some light on the locus of X-linked deafness, which appears to be a heterogeneous disorder [21]. In conclusion, the observations in our patients demonstrate that a progressive perceptive hearing loss starting at about 14 years appears to be a c o m m o n or even obligate feature in males with X-linked congenital adrenal hypoplasia and gonadotrophin deficiency. Affected patients should be tested accordingly.

References

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Fig. 1. Audiograms of three brothers with congenital adrenal hypoplasia and gonadotrophin deficiency at different ages. Note the initial reduction at high frequencies in the youngest patient, and the progression towards lower frequencies with age

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